Background: Coronavirus disease 2019 (COVID-19) pandemic are causing significant damages to many nations. For mitigating its risk, Japan’s Prime Minister called on all elementary, junior high and high schools nationwide to close beginning March 1, 2020. However, its effectiveness in decreasing disease burden has not been investigated. Methods: We used daily data on the report of COVID-19 and coronavirus infection incidence in Japan until March 31, 2020. Time series analysis were conducted using Bayesian method. Local linear trend models with interventional effect were constructed for number of newly reported cases of COVID-19, including asymptomatic infections. We considered that the effects of intervention start to appear 9 days after the school closure; i.e., on March 9. Results: The intervention of school closure did not appear to decrease the incidence of coronavirus infection. If the effectiveness of school closure began on March 9, mean coefficient α for effectiveness of the measure was calculated to be 0.08 (95% credible interval -0.36 to 0.65), and the actual reported cases were more than predicted, yet with rather wide credible interval. Sensitivity analyses using different dates also showed similar results. Conclusions: School closure carried out in Japan did not show the effectiveness to mitigate the transmission of novel coronavirus infection.

Introduction: An epidemic of Coronavirus Disease 2019 (COVID-19) begun in December 2019 in China, causing a Public Health Emergency of International Concern. Among raised questions, clinical, laboratory, and imaging features have been partially characterized in some observational studies. No systematic reviews have been published on this matter. Methods: We performed a systematic literature review with meta-analysis, using three databases to assess clinical, laboratory, imaging features, and outcomes of COVID-19 confirmed cases. Observational studies, and also case reports, were included and analyzed separately. We performed a random-effects model meta-analysis to calculate the pooled prevalence and 95% confidence interval (95%CI). Results: 660 articles were retrieved (1/1/2020-2/23/2020). After screening by abstract/title, 27 articles were selected for full-text assessment. Of them, 19 were finally included for qualitative and quantitative analyses. Additionally, 39 case report articles were included and analyzed separately. For 656 patients, fever (88.7%, 95%CI 84.5-92.9%), cough (57.6%, 40.8-74.4%) and dyspnea (45.6%, 10.9-80.4%) were the most prevalent manifestations. Among the patients, 20.3% (95%CI 10.0-30.6%) required intensive care unit (ICU), with 32.8% presenting acute respiratory distress syndrome (ARDS) (95%CI 13.7-51.8), 6.2% (95%CI 3.1-9.3) with shock and 13.9% (95%CI 6.2-21.5%) of hospitalized patients with fatal outcomes (case fatality rate, CFR).Conclusion: COVID-19 brings a huge burden to healthcare facilities, especially in patients with comorbidities. ICU was required for approximately 20% of polymorbid, COVID-19 infected patients and this group was associated with a CFR of over 13%. As this virus spreads globally, countries need to urgently prepare human resources, infrastructure, and facilities to treat severe COVID-19.

3M syndrome is a rare disorder that involves the gene CUL7. CUL7 modulates odour detection, conditions the olfactory response (OR) and plays a role in olfactory system development. Despite this involvement, there are no direct studies on olfactory functional effects in 3M syndrome. The purpose of the present work was to analyse the cortical OR, through chemosensory event-related potentials (CSERP) and power spectra calculated by electroencephalogram (EEG) signals recorded in 3M infants: two twins (3M-N) and an additional subject (3M-O). The results suggest that olfactory processing is diversified. Comparison of N1 and LPC components indicated substantial differences in 3M syndrome that may be a consequence of a modified olfactory processing pattern. Moreover, the presence of delta rhythms in 3M-O and 3M-N clearly indicates their involvement with OR, since the delta rhythm is closely connected to chemosensory perception, in particular to olfactory perception.

Rodents are known to be reservoir hosts for at least 60 zoonotic diseases and are known to play an important role in their transmission and spreading in different ways. We sampled different rodent communities within and around human settlements in Northern Senegal, an area subjected to major environmental transformations associated with global changes. Herein, we conducted an epidemiological study on their bacterial communities.One hundred and seventy-one (171) invasive and native rodents were captured, 50 from outdoors trapping sites and 121 rodents from indoors habitats, consisting on 5 species. DNA of thirteen pathogens have been successfully screened on the rodent’s spleens. We found: 2.3% of positive spleens to Piroplasmida and amplified one which gives a potentially new species Candidatus “Theileria senegalensis”; 9.35% of Bartonella spp. and amplified 10, giving three genotypes. 3.5% of filariasis species; 18.12% of Anaplasmataceae species and amplified only 5, giving a new potential species Candidatus “Ehrlichia senegalensis”; 2.33 % of Hepatozoon spp.; 3.5% of Kinetoplastidae spp; and 15.2% of Borrelia spp. and amplified 8 belonging all to Borrelia crocidurae.Some of the species of pathogens carried by the rodents of our studied area may be unknown because most of those we have identified are new species. In one bacterial taxon, Anaplasma, a positive correlation between host body mass and infection was found. Overall, male and invasive rodents appeared less infected than female and native ones, respectively.

In this review, we discuss the insulin resistance (IR) and its development in the insulin target tissues that leads to diabetes. Also, we highlight the use of induced pluripotent stem cells (iPSCs) to understand the mechanisms underlying the development of IR. IR is associated with several metabolic disorders, including type 2 diabetes (T2D). The development of IR in insulin target tissues involves genetic and acquired factors. Persons at genetic risk for T2D tend to develop IR several years before glucose intolerance. Although there are currently several mouse models for both IR and T2D that had provided a lot of information about the disease, these models cannot recapitulate all the aspects of this complex disease as seen in each individual. Patient-specific iPSCs can overcome the hurdles faced with the classical mouse models for studying IR. iPSC technology can generate cells genetically identical to IR individuals, which can help in distinguishing between genetic and acquired defects in insulin sensitivity. Combining the technologies of the genome editing and iPSCs may provide important information about the inherited factors underlying the development of different forms of IR. Further studies are required to fill the gaps in understanding the pathogenesis of IR and diabetes.

Regular exercise can reduce depression. However, the uptake of exercise is limited in patients with end-stage renal disease undergoing hemodialysis. To address the gap, we designed a gamified non-weight-bearing exercise program (Exergame), which can be executed during hemodialysis treatment. The Exergame is virtually supervised based on its interactive feedback via wearable sensors attached on lower extremities. We examined the effectiveness of this program to reduce depression symptom compared to supervised exercise in 73 hemodialysis patients (age=64.5±8.7years, BMI=31.6±7.6kg/m2). Participants were randomized into an Exergame group (EG) or a Supervised-exercise group (SG). Both groups received similar exercise tasks for 4-week, 3-session per week, 30-min per session, during hemodialysis treatment. Depression symptom was assessed at baseline and 4-week using Center for Epidemiologic Studies Depression (CES-D). Both groups showed significant reduction in depression score (37%, p<0.001, Cohen’s effect size d=0.69 in EG vs. 41%, p<0.001, d=0.65 in SG) with no between-group difference for the observed effect (p>0.050). The EG expressed a positive exercise experience including fun, safety, and helpfulness of sensor-feedback. Together, results suggested that the virtually-supervised low-intensity Exergame is feasible during routine hemodialysis treatment. It is as effective as supervised-exercise to reduce depression symptom, while reducing burden of administrating exercise in dialysis clinics.

Background: The pathogenesis of duodenal ulcer has never been explained although the first description of this disease in medical literature appeared in 1817. Marshall et al. concluded that Helicobacter pylori was the most important etiological factor for duodenal ulcer in 1988, but the etiology based on this bacterium is controversial and how the bacterial infection leads to ulceration is presently unknown. Objectives: This study aims to identify the cause of duodenal ulcer, address the controversial issues surrounding Helicobacter pylori, elucidate the roles of gastric acid, and describe the pathological process of duodenal ulceration. Methods: First, a comprehensive systematic review on peptic ulcers (including gastric ulcer and duodenal ulcer) was conducted and the results were summarized. Second, a recently published causal relationship was employed to identify the etiology of peptic ulcers. Third, novel concepts and methods were applied to analyze the existing data on duodenal ulcer. Results: The etiology of duodenal ulcer and the roles of Helicobacter pylori and gastric acid in this disease were identified. The controversies surrounding Helicobacter pylori were addressed, and many characteristics and phenomena/observations of duodenal ulcer were elucidated. The pathological process of duodenal ulceration was described. Conclusion: Existing data accumulated over the past 300 years was sufficient, when analyzed using novel concepts, to understand the pathogenesis of duodenal ulcer. Duodenal ulcer is not an infectious disease caused by the infection of Helicobacter pylori, but a psychosomatic disease triggered by psychological stress. Helicobacter pylori plays a secondary role in only the late phase of duodenal ulceration.

In healthy adult brain, glial cell line-derived neurotrophic factor (GDNF) is exclusively expressed by neurons and in some instances, it has furthermore been shown to derive from a single neuronal subpopulation. Secreted GDNF acts in a paracrine fashion by forming a complex with GDNF family receptor α1 (GFRα1) which is mainly expressed by neurons and can act in cis as a membrane-bound or in trans as a soluble factor. The GDNF/GFRα1 complex signals through interaction with RET (“rearranged during transfection”) or with a lower affinity with neural cell adhesion molecule (NCAM). GDNF can also signal independently from GFRα1 via interaction with syndecan-3. RET being expressed by neurons involved in several pathways: nigro-striatal dopaminergic neurons, motor neurons, enteric neurons, sensory neurons, etc. could be the main determinant of the specificity of GDNF pro-survival effect. In injured brain, de novo expression of GDNF occurs in glial cells. Neuroinflammation has been reported to induce GDNF expression in activated astrocytes and microglia, infiltrating macrophages, nestin-positive neural stem cells and neuron/glia (NG2) progenitors. This disease-related GDNF overexpression can be either beneficial or detrimental depending on the localization in the brain and the level and duration of glial cells activation. Some reports also describe upregulation of RET and GFRα1 in glial cells, suggesting that GDNF could modulate neuroinflammation.

Inflammatory bowel disease (IBD) is a chronic disease mediated by the immune system and characterized by the inflammation of the gastrointestinal tract. This study is to understand how the use of parenteral nutrition (PN) can affect the adult population diagnosed with IBD. We conducted a systematic review, meta-analysis and a meta-regression. On the different databases, (MEDLINE, Scopus, Cochrane, LILACS, CINAHL, WOS) we found 119 registers, the accuracy was 16% (19 registers); After a Full-text review, only 15 research studies were selected for qualitative synthesis and 10 for Meta-analysis and Meta-regression. The variables used were Crohn’s Disease Activity Index (CDAI), albumin, body weight (BW) and post-operative complications (COM). PN has shown to have efficacy for the treatment of IBD and is compatible with other medicines. The CDAI and albumin improve although the effect of PN are greater after a while. However, the effect on the albumin could be less than the observed value in the meta-analysis, due to a possible publication bias. The BW does not change after intervention. COM utilizing PN has been observed, although the proportion is low.

In this study, we evaluated the potential of fungal endophytes to control yellow rust in wheat (Triticum aestivum L.) as endophytes are beneficial microbes and alternate to pesticides for confronting pathogens. The in-vitro efficacy of the fungal endophytes isolated from different desert plants was evaluated and the best four namely Colletotrichum lindemuthianum, Piriformospora indica, Acremonium lolii and Trichoderma viride were selected. Seeds of two susceptible wheat genotypes namely Fareed-06 and Shafaq-06 obtained from screening experiment were inoculated by dipping in four endophytic spore suspensions and were sown using randomized complete block design under factorial arrangement. Data concerning about area under disease progress curve, final disease severity percentage, coefficient of infection,1000- grains weight and grain yield were recorded. Results showed that endophyte P. indica showed significant decrease in final disease severity (FDS) and area under disease progress curve (AUDPC), resultantly 12.2% grain yield gain in rust susceptible wheat genotypes of Fareed-06 and Shafaq-06 followed by the endophytes T. viride, C. lindemuthianum and A. lolii with the grain yield gain of 10.6%, 06.2% and 04.2% respectively. In crux, fungal endophytes are valuable microbes which can be employed to induce tolerance against P. striiformis in yellow rust vulnerable areas for better and sustainable wheat production.

COPD is currently the fourth leading cause of death in the world. Globally, due to continued exposure to COPD risk factors and an aging population, the burden of COPD is expected to increase in the coming decades. The BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index is a practical and multidimensional predictor for prognosis of COPD, and better than FEV1.We used the database of Kaohsiung Chang Gung Memorial Hospital medical center, Taiwan to analyze the correlation between BODE index, healthcare resource utilization, and Charlson comorbidity index (CCI). This retrospective study to collect COPD patients with complete BODE index data who had undergone a 6-minute walk examination in our hospital from January 2015 to December 2016. The medical cost and comorbidities database were analyzed from January 1, 2015, to August 31, 2017. Of 396 patients, 382 (96.5%) were male, with an average age of 71.3 ± 8.4 years. There was a significant association between the BODE index and the CCI of COPD patients (p < 0.001). Healthcare resource utilization was positively correlated with the BODE index during the 32 months of retrospective clinical outcomes: positively correlated with the number of hospitalizations (p<0.001), hospitalization days (p<0.001), hospitalization expenses (p=0.005), and total medical expenses (p=0.024), respectively. Our findings provide the crucial information for clinician to predict medical burden and comorbidities in patients with COPD by using BODE index.

Inflammatory bowel disease (IBD) is a chronic disease mediated by the immune system and characterized by the inflammation of the gastrointestinal tract. One of the possible treatments for this pathology is a change in the type of diet, the enteral nutrition (EN) is one of them. This study is to understand how the use of EN can affect the adult population diagnosed with IBD. We conducted a systematic review, meta-analysis and a meta-regression. On the different databases, (MEDLINE, Scopus, Cochrane, LILACS, Cinhal, WOS) we found 363 registers, the accuracy was 12% (44 registers); After a Full-text review, only 30 research studies were selected for qualitative synthesis and 11 for Meta-analysis and Meta-regression. The variables used were Crohn’s Disease Activity Index (CDAI), C-Reactive Protein (CRP) and Erythrocyte Sedimentation Rate (ESR). EN has shown to have efficacy for the treatment of Crohn’s Disease and is compatible with other medicines. As for the CDAI or the rates of remission, there were no differences between enteral and parenteral nutrition. Polymeric formulas, have shown better results with respect to the CRP. The long-term treatment could dilute the good CDAI results that are obtained at the start of the EN treatment.

Fatty acids and glucose are the main bioenergetic substrates in mammals that are alternatively used during the transition between fasting and feeding. Impairment of mitochondrial fatty acid oxidation causes mitochondrial myopathy leading to decreased physical performance. Here, we report that haploinsufficiency of ADCK2, a member of the aarF domain-containing mitochondrial protein kinase family, in human is associated with liver dysfunction and severe mitochondrial myopathy with lipid droplets in skeletal muscle. In order to better understand the etiology of this rare disorder, we generated a heterozygous Adck2 knockout mouse model to perform in vivo and cellular studies using integrated analysis of physiological and omics data (transcriptomics-metabolomics). The data show that Aldh2+/- mice exhibits impaired fatty acid oxidation, liver dysfunction, and mitochondrial myopathy in skeletal muscle resulting in lower physical performance. Significant decrease in CoQ biosynthesis was observed and supplementation with CoQ partially rescued the phenotype both in the human subject and mouse model. These results indicate that ADCK2 is involved in organismal fatty acid metabolism and in CoQ biosynthesis in skeletal muscle. We propose that patients with isolated myopathies and myopathies involving lipid accumulation be tested for possible ADCK2 defect as they are likely to be responsive to CoQ supplementation.

Fish currently provide 6.7% of all protein consumed by humans globally, nevertheless, aquaculture system has been linked to fish and environmental contamination and disease outbreak. This study aims to isolate, identify, and characterise, bacteria in fish and pond water as well as the antibiotic profile of detected Coliforms. The susceptibility of the isolates was tested using the Kirby-Bauer disc diffusion method on Mueller Hinton agar. A total of forty (40) isolates were isolated from the water samples of which (5) species were Gram Positive bacteria and 35 species of Gram Negative bacteria. The temperature for all ponds ranged from 25°C to 28°C. The mean bacteria count for pond C1 to T2 were 4.9 × 102, 4.9 × 102, 5.4 × 102, 2.5 × 102, 2.2 × 102, and 1.9 × 102 CFU/ml respectively. All isolates were 100% resistant to ceftazidime, cefuroxime and augmentin. More resistance to cefixime (80%) and gentamicin (73.3%) and nitrofurantoin (66.7%) was recorded. However, only 16.6% and 8.3% of the isolates were resistant to ciprofloxacin and ofloxacin respectively. The multiple antimicrobial resistance index (MARI) ranged from 0.5 to 0.9. The water quality parameters (temperature and pH) and the type of bacteria detected in all pond type did not differ significantly. The Multi-drug resistance bacteria detected could be pathogenic to fish and consumers.

The standard of care measures for kidney function, proteinuria, and serum creatinine (SCr) are poor predictors of early stage kidney disease. Measures that can detect chronic kidney disease in its earlier stages are needed to enable therapeutic intervention and reduce adverse outcomes of chronic kidney disease. We have developed the Kidney Injury Test (KIT) and a novel KIT Score based on the composite measurement and validation of multiple biomarkers across a unique set of 397 urine samples. The test is performed on urine samples that require no processing at the site of collection and without target sequencing or amplification. We sought to verify that the pre-defined KIT test, KIT Score, and clinical thresholds correlate with established chronic kidney disease (CKD) and may provide predictive information of early kidney injury status above and beyond proteinuria and renal function measurements alone. Statistical analyses across six DNA, protein, and metabolite markers were performed on a subset of residual spot urine samples with CKD that met assay performance quality controls from patients attending the clinical labs at the University of California, San Francisco (UCSF) as part of an ongoing IRB approved prospective study. Inclusion criteria included selection of patients with confirmed CKD and normal healthy controls; exclusion criteria included incomplete or missing information for sample classification, logistical delays in transport/processing of urine samples or low sample volume, and acute kidney injury. Multivariate logistic regression of kidney injury status and likelihood ratio statistics were used to assess the contribution of the KIT Score for prediction of kidney injury status and stage of CKD as well as assess the potential contribution of the KIT Score for detection of early stage CKD above and beyond traditional measures of renal function. Urine samples were processed by a proprietary immunoprobe for measuring cfDNA, methylated cfDNA, clusterin, CXCL10, total protein, and creatinine. The KIT Score and stratified KIT Score Risk Group (High versus Low) had a sensitivity and specificity for detection of kidney injury status (healthy or CKD) of 97.3% (95% CI: 94.6%–99.3%) and 94.1% (95% CI: 82.3%–100%). In addition, in patients with normal renal function [eGFR ≥ 90], the KIT Score clearly identifies those with predisposing risk factors for CKD, which could not be picked up by eGFR or proteinuria (p < 0.001). The KIT Score uncovers a burden of kidney injury that may yet be incompletely recognized, opening the door for earlier detection, intervention and preservation of renal function.

Oats represents a promising alternative to small-grain cereals from Triticeae group (wheat, barley, rye) for persons suffering from any form of gluten intolerance, especially celiac disease (CD), since oat-specific prolamins avenins reveal generally lower gluten content and immunoreactivity. Recent studies on avenin molecular structure revealed large genetic variability in avenin sequences affecting the spectrum of gluten peptides produced by hydrolases in human digestive tract. The aim of the present review is to summarise recent knowledge obtained in laboratory in vitro studies focused on the effect of avenin-derived peptides on reactivity of crucial components of human immune system such as dendritic cells (DC) and T-cells. The other part of the review summarises the results of clinical studies with CD patients including oat products in their diet. Since different clinical studies revealed contradictory results regarding potential safety of oats for CD patients, the focus has to be directed at genetic variability in oat avenins. Identification of avenin isoforms with minimum CD immunoreactivity will open up ways leading to designing novel oat cultivars suitable for CD patients. Knowledge on immunoreactivity of gluten peptides together with breeding new oat cultivars revealing minimum avenin immunoreactivity with respect to CD as well as application of food processing technologies leading to gluten content reduction should result in development of gluten-free oats safe for celiacs.

Purpose: This paper extends previous works to include the role of therapeutic gardens in the healing environment as an intervention for bettering the clinical outcomes of Alzheimer’s and dementia patients, the positive impact of healing gardens and the innovative application of technologies with nature, for promoting cognitive rehabilitation in this particular patient population.Methods: Using ISI Web of Science, PubMed, ProQuest Central, MEDLIN, Scopus and Google Scholar, a relevant literature search on the positive health implications of therapeutic gardens on Alzheimer’s and dementia patients’ in the healthcare milieu was conducted.Results: Health implication of therapeutic gardens on Alzheimer’s and dementia patients’ spans across physical, social, psychological and cognitive effects. Virtual reality (VR) technologies offer positive cognitive outcomes to Alzheimer's disease (AD) and dementia patients.Conclusion: Therapeutic gardens should be extended for speedier recovery of other patient populations. Future directions in the design of healthcare gardens with a focus on patient experience are inferred.

Perfect cardiovascular health (CVH) has been defined by the American Heart Association as the lack of cardiovascular disease and the presence of seven key factors and health behaviors. In this study, we aimed to estimate the prevalence of ideal and poor CVH among the Polish adult population, taking the chosen socio-demographic factors into consideration. This is a cross-sectional study conducted among 3,901 adults without cardiovascular diseases, aged between 35 and 64 years. Participants completed a questionnaire, and they had anthropometric and physiological measurements taken. Blood samples were analyzed for fasting glucose and cholesterol levels. Ideal CVH was found in 5.4% of the participants, with the advantage of being toward city dwellers over those living in the rural areas (6.3% vs. 5.0%) p = 0.02. In case of the residents of rural areas, their likelihood of having an ideal body mass index (BMI) was found to be 22% lower (odds ratio (OR) = 0.78; 95% CI: 0.66–0.92), their likelihood of having an ideal diet was found to be 27% lower (OR = 0.71; 95% CI: 0.54–0.94), their likelihood of having perfect blood pressure was found to be 29% lower (OR = 0.71; 95% CI: 0.56–0.89), and their likelihood of having the perfect glucose levels were found to be 28% lower (OR = 0.72; 95% CI: 0.63–0.84), than the residents of urban areas. The prevalence of ideal cardiovascular behaviors and factors is lower in the rural community compared with people living in the city. Results indicate that more effort should be dedicated toward the country’s health policy, specifically concerning primary prevention. Preventive actions in the field of cardiovascular disease should be addressed to the residents of rural areas to a larger extent.

El Niño Southern Oscillation (ENSO) is an important of mode of climatic variability that through altering climate patterns exerts a discernible impact on ecosystems and society. For this reason, ENSO has attracted much interest in the climate and health science community with many analysts investigating ENSO health links through considering the degree of dependency of the incidence of a range of climate diseases on the occurrence of El Niño events. Because of the mounting interest in the relationship between ENSO as a major mode of climatic variability and health this paper presents an overview of the basic characteristics of the ENSO phenomenon and its climate impacts, discusses the use of ENSO indices in climate and health research and outlines the present understanding of ENSO health associations. Also touched upon are ENSO-based seasonal health forecasting and the possible impacts of climate change on ENSO and the implications this holds for future assessments of ENSO health associations. The review concludes that there is still some way to go before a thorough understanding of the association between ENSO and health is achieved with a need to move beyond analyses undertaken through a purely statistical lens with due acknowledgement that ENSO as a complex non-canonical phenomenon and that simple ENSO health associations should not be expected.

Inflammatory Bowel Disease (IBD) is characterized by chronic remitting and relapsing inflammation of the lower gastrointestinal tract. The etiology underlying IBD remains unknown but is thought to involve a hypersensitive immune response to environmental antigen, including the microbiota. Diagnosis and monitoring of disease is heavily reliant on endoscopy, which is invasive and does not provide information regarding specific mediators. This review describes recent developments in imaging of IBD with a focus on PET and SPECT imaging of inflammatory mediators, and how this may be applied to the microbiota.

Biomarkers have the potential to aid in the study of Alzheimer’s disease (AD); unfortunately, AD biomarker values often have a high degree of overlap between healthy and AD individuals. This study investigates the potential utility of a series of novel AD biomarkers, the sixty second ¹²⁹Xe retention time, and the xenon washout parameter, based on the washout of hyperpolarized ¹²⁹Xe from the brain of AD participants following inhalation. The xenon washout parameter is influenced by cerebral perfusion, T1 relaxation of xenon, and the xenon partition coefficient, all factors influenced by AD. Participants with Alzheimer’s disease (n=4) and healthy volunteers (n=4) were imaged using hyperpolarized ¹²⁹Xe magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) to determine the amount of retain xenon in the brain. At 60 sec post breath hold, AD patients retained significantly higher amounts of ¹²⁹Xe compared to healthy controls. Data was fit to a pharmacokinetic model and the xenon washout parameter was extracted. Xenon washout in white and grey matter occurs at a slower rate in Alzheimer’s participants (¹²⁹Xe half-life time of 42s and 43s, respectively) relative to controls (20s and 16s, respectively). Following larger scale clinical trials for validation, the xenon washout parameter has the potential to become a useful biomarker for the support of an AD diagnosis.

Age-related diseases (ARDs) are the leading cause of death worldwide, and contribute to 90% of mortality in developed countries. Interestingly, the mortality rates of individual ARDs increase exponentially with age. Processes described by the exponential growth function typically involve a branching chain reaction or, more generally, a positive feedback loop. Here I propose that each ARD is mediated by one or several positive feedback loops (vicious cycles). I then identify critical vicious cycles in five major ARDs: atherosclerosis, hypertension, diabetes, Alzheimer’s and Parkinson’s. I also propose that the progression of ARDs can be halted by selectively interrupting the vicious cycles and suggest the most promising targets. An evolutionary perspective is also offered.

Dystrophin-deficient cardiomyopathy (DDC) is currently the leading cause of death in patients with dystrophinopathies. Targeting myocardial fibrosis (MF) has become a major therapeutic goal in order to prevent the occurrence of DDC. We aimed to review and summarize the current evidence about the role of the renin-angiotensin-aldosterone system (RAAS) in the development and perpetuation of MF in DCC. We conducted a comprehensive search of peer-reviewed English literature on PubMed about this subject. We found increasing preclinical evidence from studies in animal models during the last 20 years pointing out a central role of RAAS in the development of MF in DDC. Local tissue RAAS acts directly mainly through its main fibrotic component angiotensin II (ANG2) and its transducer receptor (AT1R) and downstream TGF-b pathway. Also, it modulates the actions of most of the remaining pro-fibrotic factors involved in DDC. Despite limited clinical evidence, RAAS blockade constitutes the most studied, available and promising therapeutic strategy against MF and DDC. Conclusion: Based on the evidence reviewed, it would be recommendable to start RAAS blockade therapy through angiotensin converter enzyme inhibitors (ACEI) or AT1R blockers (ARBs) alone or in combination with mineralocorticoid receptor antagonists (MRa) at the youngest age after the diagnosis of dystrophinopathies, in order to delay the occurrence or slow the progression of MF, even before the detection of any cardiovascular alteration.

The central promise of personalized medicine is individualized treatments that target molecular mechanisms underlying the physiological changes and symptoms arising from disease. We demonstrate a bioinformatics analysis pipeline as a proof-of-principle to test the feasibility and practicality of comparative transcriptomics to classify two of the most popular in vivo diet-induced models of coronary atherosclerosis, apolipoprotein E null mice and New Zealand White rabbits. Transcriptomics analyses indicate the two models extensively share dysregulated genes albeit with some unique pathways. For instance, while both models have alterations in the mitochondrion, the biochemical pathway analysis revealed, Complex IV in the electron transfer chain is higher in mice, whereas the rest of the electron transfer chain components are higher in the rabbits. Several fatty acids anabolic pathways are expressed higher in mice, whereas fatty acids and lipids degradation pathways are higher in rabbits. This reflects the differences between two translational models of atherosclerosis. This study validates transcriptome analysis as a potential method to precisely identify altered cellular and molecular pathways in atherosclerotic disease, which can be used to individualize treatment even in the absence of genetic data.

An HFMD outbreak spread over the city of Hải Phòng from Summer 2011 to Autumn 2012. This epidemic was chosen because it was the very first HFMD epidemic in North Vietnam, eliminating thus interferences with previous outbreaks. This epidemic displayed 3 separate waves. A complete dataset was collected for more than 9500 patients during this period, which enabled us to analyze this epidemic at different scales. Access to the healthcare system was crucial during this period, with a reorganization of the system in February-March 2012. An analysis at commune level enables us to track the epidemic along certain communication routes. The three-waves structure reveals a wide disparity at district level. We develop a mathematical model showing high accuracy at the adjustment of data for both the total number of cases and for the number of cases per week. As a consequence, the model was able to accurately determine the dates of beginning and end of each wave and to show that they overlapped. Using mathematical functions associated with this model, it was possible to calculate the probability for a patient to belong to a specific wave.

The inclusion of various chemical substances in personal care products (PCPs) and cosmetic formulations can be associated with disruption and damage to the nervous system. Microplastics, benzophenones, parabens, phthalates and metals are among the most common chemical substances found in cosmetics that have been shown to induce neurotoxic mechanisms. Although cosmetic neurotoxin exposure is believed to be minimal, different exposure scenarios of cosmetics suggest that these neurotoxins remain a threat. Special attention should be paid to early exposure in the first gestation weeks, when critical processes, like the migration and proliferation of the neural crest derived cells start to form the ENS. Importantly, cosmetic’s neurotoxins can cross the placenta barrier and so affect the future embryo, but are also secreted in the breast milk, so that babies remain exposed for longer periods, even after birth. In this review we explore how neurotoxins contained in cosmetic and PCPs may have a role in the pathogenesis of various neurodevelopment disorders and neurodegenerative diseases, and therefore also in congenital enteric aganglionosis as well as in postnatal motility disorders. Understanding the mechanisms of these chemicals used in cosmetic formulations and their role in neurotoxicity is crucial to determining the safety of use for cosmetic products during pregnancy.

Introduction: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, predominantly affecting older adults. Understanding the multifaceted factors contributing to AD is crucial for developing effective prevention and intervention strategies. This narrative review synthesizes current literature on the various factors influencing the development and progression of AD in older adult populations.Methods: A comprehensive search was conducted across electronic databases including PubMed, Web of Science, and PsycINFO using relevant keywords such as "Alzheimer's disease," "risk factors," "genetics," "environmental factors," and "lifestyle." Studies published between 2000 and 2023 were included, focusing on factors associated with AD in individuals aged 65 years and older.Results: The review identified several key factors contributing to AD in older adults. Genetic predisposition, particularly the presence of apolipoprotein E (APOE) ε4 allele, emerged as a significant risk factor. Environmental factors such as air pollution, pesticides, and heavy metals were also implicated. Furthermore, lifestyle factors including physical inactivity, poor diet, and smoking were associated with increased AD risk. Chronic conditions such as diabetes and cardiovascular diseases were found to exacerbate cognitive decline in older adults.Conclusion: This narrative review highlights the complex interplay of genetic, environmental, and lifestyle factors in the development and progression of Alzheimer's disease among older adults. Understanding these factors is crucial for targeted interventions aimed at reducing AD risk and improving cognitive health outcomes in aging populations. Future research should focus on longitudinal studies and personalized medicine approaches to elucidate specific mechanisms underlying AD pathogenesis and to develop effective preventive strategies.

Hyperuricemia (HU), characterized by elevated uric acid (UA) levels in the blood, represents a global health concern associated with various conditions, including cardiovascular diseases, gout, hypertension, metabolic syndrome, renal dysfunction, and neurodegenerative diseases. This review offers a contemporary analysis of HU, encompassing its causes, associated health risks, diagnosis, treatment, and future outlook. Recent studies have underscored the multifaceted origin of HU, implicating genetic predisposition, dietary patterns, lifestyle choices, and environmental influences. Genetic variations affecting enzymes and transporters involved in purine metabolism and UA excretion have been identified, laying the groundwork for personalized treatment strategies. Advances in diagnostic imaging and omics technologies provide enhanced precision in the detection and evaluation of risks. While pharmacological interventions remain central to managing HU, persistent challenges such as treatment resistance prompt exploration of novel drug targets and lifestyle modifications. Chinese herbal medicines offer a potentially alternative approach with fewer side effects. Emerging research on the impact of gut microbiota on UA metabolism opens new therapeutic avenues. Despite progress, challenges such as optimizing treatment duration and understanding long-term effects persist. Collaborative efforts are crucial to address these challenges and advance our comprehension of HU. The integration of precision medicine and holistic patient care approaches holds promise for improving outcomes and enhancing quality of life for individuals with HU.

Background: Parkinson's disease (PD) is a neurodegenerative disorder that affects both patients and their caregivers, particularly parents who often become informal caregivers. Caring for someone with PD is linked to increased psychiatric morbidity and persistent anxiety-depressive distress. Methods: This study investigates the burden on caregivers of PD patients using multi-dimensional scales and identifies the personological and environmental factors contributing to this burden. Results: 20.6% of participants reported a severe burden according to the Caregiver Burden Inventory (CBI), while 13.8% had a moderate to severe burden according to the Zarit Caregiver Burden Inventory (ZBI). The Family Strain Questionnaire Short Form (FSQ-SF) high-lighted a minority of caregivers needing psychological support, with some cases requiring ur-gent attention, particularly in stress-related symptoms (SR) and urgent support (U). The Depres-sion Anxiety Stress Scales Short Version (DASS-21) results showed a higher prevalence of stress-related symptoms compared to anxiety and depression. Retired caregivers reported higher ZBI scores and lower life satisfaction levels compared to working caregivers. Additionally, years of schooling negatively correlated with the ZBI score. T-test analysis indicated that caregivers of patients with cognitive impairment were at greater risk compared to caregivers of patients with-out cognitive impairment. Conclusions: The results underscore the need for early recognition of risky situations and adequate support for caregivers.

The Ro60 autoantigen is an RNA-binding protein, and a core component of nucleocytoplasmic ribonucleoprotein (RNP) complexes. Ro60 is essential in RNA metabolism, cell stress response pathways, and cellular homeostasis. It stabilises and mediates quality control and cellular dis-tribution of YRNAs, retroelement transcripts, and misfolded RNAs. Ro60 transcriptional dysregulation or loss of function can result in the generation and release of RNA fragments from YRNAs and other small RNAs. Small RNA fragments can instigate an inflammatory cascade through endosomal TLRs and cytoplasmic RNA sensors, which typically sense patho-gen-associated molecular patterns (PAMPs) and mount the first line of defence against invading pathogens. However, recognition of host-originating RNA moieties from Ro60 RNP complexes can activate inflammatory response pathways and compromise self-tolerance. Autoreactive B cells may produce antibodies targeting extracellular Ro60 RNP complexes. Ro60 autoantibodies serve as diagnostic markers for various autoimmune diseases including Sjögren's disease (SjD) and systemic lupus erythematosus (SLE), and they may also act as predictive markers for an-ti-drug antibody response among rheumatic patients. Understanding Ro60’s structure, function, and role in self-tolerance can enhance our understanding of the underlying molecular mecha-nisms of autoimmune conditions.

Despite chronic fibrosis and associated excess extracellular matrix (ECM) deposition and crosslinking occurring in many pathological conditions, few in vitro studies examine how fibrosis-induced ECM stiffening impacts lymphatic endothelial cells (LEC) behavior and subsequent new lymphatic vessel growth and function. This study examined the stiffening profile of PhotoCol®—commercially available methacrylated type I collagen—photo-crosslinked with photoinitiators Lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), Irgacure 2959 (IRG), and Ruthenium/Sodium Persulfate (Ru/SPS) prior to evaluating PhotoCol® permeability and LEC response to PhotoCol® at low and high stiffness levels representing normal and fibrotic ECM stiffness. Ru/SPS produced the highest maximum stiffness for photo-crosslinked PhotoCol® hydrogels. While Ru/SPS stiffness values did not differ significantly with increased light exposure, permeability decreased significantly with increasing light exposure for 40 kDa dextran. Finally, LECs on softer PhotoCol® appeared smaller with less prominent VE-Cadherin (cell-cell junction) and F-actin expression compared to cells on stiffer PhotoCol®. Overall, PhotoCol® with Ru/SPS photoinitiator provides the fibrillar microstructure and dynamic stiffness range that enables systematic study of LEC stiffness responses relevant to the stiffened ECM observed in pathologies with significant fibrotic activity. Therefore, this study demonstrates the utility of PhotoCol® with Ru/SPS for disease modeling applications, particularly modeling lymphatic vascular growth and function during fibrosis.

An analysis of 1300+ existing ACE mutations revealed that 400+ are damaging and led us to hy-pothesize that carriers of heterozygous loss-of-function (LoF) ACE mutations (which result in low ACE levels) could be at risk for the development of late-onset Alzheimer’s disease (AD) [Danilov, 2024]. Here we quantified blood ACE levels in EDTA-plasma from 41patients with 10 different heterozygous ACE mutations, as well as 33 controls, and estimated the effect of these mutations on ACE phenotype using a set of mAbs to ACE and two ACE substrates. We found that relatively frequent (~1%) AD-associated ACE mutations in the N domain of ACE, Y215C and G325R are truly damaging and, likely, transport-deficient, with ACE levels in plasma only ~50% of controls. Another AD-associated ACE mutation, R1250Q, in the cytoplasmic tail, did not cause a decrease in ACE and, likely, did not affect surface ACE expression. We have also developed a method to identify patients with anti-catalytic mutations in the N domain. These mutations may result in reduced degradation of amyloid beta peptide Aβ42, an important component for amyloid deposition. Consequently, these could pose a risk factor for the development of AD. Therefore, a systematic analysis of blood ACE levels in patients with all ACE mutations has potential to identify individuals at an increased risk of late-onset AD. These individuals may benefit from future preventive or therapeutic interventions involving a combination of chemical and pharmacological chaperones, as well as proteasome inhibitors, aiming to enhance ACE protein traffic. This approach has been previously demonstrated in a cell model of the transport-deficient ACE mutation, Q1069R [Danilov, 2010].

Background: Alzheimer's Disease (AD) is a progressive and incurable condition that prompts the exploration of interventions to slow its advancement and enhance the quality of life. The cortical brain waves could have a role in the process of executive function deterioration, increasing dementia symptoms. Objective: To interrogate the effects of physical exercise, and non-invasive brain stimulation, both in electrophysiological behavior of the brain, the executive functions, and dementia symptoms in older adults with AD. Methods: One hundred and sixteen older adults were grouped (n=22 each): GAE (AD, PMED+NIBS), GCP (AD, PMED), GCN (AD, NIBS), GCS (control, no intervention). Binaural beats were used as a non-invasive brain stimulation, physical exercise, or both, were applied during 16 weeks. Pre/post measurements included Alpha Band, and SMR Rhythms, executive functions, and dementia symptoms. Results: GCS showed no significant changes (p>0.05). GCN and GCS slightly enhanced inhibitory control (p>0.05) and working memory (p>0.05). In contrast, GCP and GAE improved executive function (p

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease that predominantly affects women in the childbearing age. Pregnancy in SLE patients poses unique challenges due to the po-tential impact on maternal and fetal outcomes. We provide an overview of the management of SLE during pregnancy, including pre-conception risk stratification and counselling, treatment, and disease activity monitoring. These assessments are critical to minimize maternal and fetal adverse events in SLE pregnant patients. Disease flares, preeclampsia, antiphospholipid syn-drome complications, and maternal mortality are the major risks for a woman with SLE during gestation. Timely treatment of SLE relapse, differentiation of preeclampsia from lupus nephritis, and tailored management for antiphospholipid syndrome are essential for a successful pregnan-cy. Fetal outcomes include neonatal lupus (NL), preterm birth, cesarean delivery, fetal growth re-striction (FGR), and small for gestational age (SGA) infants. We focused on NL, linked to mater-nal anti-Ro/SS-A and anti-La/SS-B antibodies, which can lead to various manifestations, partic-ularly cardiac abnormalities in newborns. While there is a common consensus regarding the pre-ventive effect of hydroxychloroquine, the role of echocardiographic monitoring and fluorinated steroid treatment is still debated. Finally, close postpartum monitoring and counseling for sub-sequent pregnancies are crucial aspects of care.

This report elucidates the first surgical correction of an infundibular muscular ventricular septal defect (VSD) in a one-year-old Ragdoll cat via cardiac arrest using cardiopulmonary bypass, a method that is rarely used in feline cardiac surgery. VSDs can lead to congestive heart failure and pulmonary hypertension, particularly in patients with large shunts. This case involved a VSD that was atypically located and classified under the Soto classification instead of the standard Kirklin classification. Detailed echocardiography revealed that the defect required intervention owing to left heart and main pulmonary artery enlargement. Despite the VSD being located on the contralateral side, as anticipated in the preoperative examinations, the choice of median sternotomy allowed for successful closure of the defect. Conversely, the insertion of two cannulas into the ascending aorta resulted in damage to the adjacent thoracic duct, causing transient chylothorax, which resolved with conservative treatment. Cardiac arrest induced by a cardioplegic solution facilitated the surgical procedure, although it has led to anemia in cats. However, on postoperative day 490, the patient exhibited only minor residual shunting with normalized heart size, and remained healthy. This technique appears to be a viable treatment option for congenital heart disease in cats.

The gut microbiota (GM) communicates with the brain via biochemical signaling constituting the gut-brain axis, which significantly regulates the body's physiological processes. The GM dysbiosis can impact the digestive system and the functioning of the central nervous system (CNS) linked to the onset of neurodegenerative diseases. In this review, the scientific data compiled from diverse sources primarily emphasizes the neuropathological characteristics linked to the accumulation of modified insoluble proteins (such as β-Amyloid peptides and hyperphosphorylated tau proteins) in Alzheimer’s Disease (AD) and the potential impact of gut microbiota (GM) on AD susceptibility or resilience. The specific GM profile of human beings may serve as an essential tool for preventing or progressing neurodegenerative diseases like AD. This review focuses mainly on the effect of gut microfauna on the gut-brain axis in the onset and progression of AD. The GM produces various bioactive molecules that may serve as proinflammatory or anti-inflammatory signaling, contributing directly or indirectly to the repression or progression of neurodegenerative disorders by modulating the response of the brain axis. Human studies must focus on further understanding the gut-brain axis and venture to clarify microbiota-based therapeutic strategies for AD.

Panax notoginseng (Burk.) F. H. Chen, a valuable Chinese herb in Yunnan Province, is susceptible to leaf spot caused by Boeremia linicola. Nonetheless, effective control methods against leaf spot in P. notoginseng are lacking. We surveyed understorey P. notoginseng bases in Lincang, Lancang, and Xundian, with incidence rate reaching 80% and an average disease index of 25 in severe cases. We found that pathogenic bacteria overwinter in infected leaves and soil, with conidia and conidiophores serving as the primary infection source. The strain B. linicola LYB-2 showed the best growth at 20°C and pH 5.0. We also screened control agents using the plate and face-off culture methods. Tetramycin exhibited 38.56–74.67% inhibition with an EC50 of 0.60 mg/L. Copper abietate showed 3.10–34.76% inhibition with an EC50 of 3,120.05 mg/L. Trichoderma atroviride and T. harzianum exhibited inhibition rates of 52.48% and 44.19%, respectively, while Bacillus subtilis reached 78.45%. Field tests demonstrated significant control effects with 20% copper abresinate, B. subtilis, T. virenceae BH-10 preparation, and 0.3% tetramycin, achieving 82.57%, 72.56%, 71.3%, and 70.2% inhibition, respectively. These findings support their eco-friendly use for preventing and controlling leaf spot disease in P. notoginseng forests; we provide vital scientific evidence for disease prediction and green control strategies.

Background Sarcopenia is a state with progressive and generalized loss of skeletal muscle mass and strength. It is a serious complication occurring in chronic kidney disease (CKD) patients which increases morbidity and mortality rate. Sarcopenia is diagnosed when loss of both compartments - muscle strength and skeletal muscle quality or quantity are present. However, there are still numerous patients, also with CKD, diagnosed as pre-sarcopenic individuals with low muscle strength and normal skeletal muscle quality or quantity and conversely, with correct muscle strength and decreased skeletal muscle mass, who are prone to develop sarcopenia in future life. It is crucial to examine numerous variables possibly associated with changes of skeletal muscle mass and muscle strength in terms of preventing the development of sarcopenia. The aim of the study was to investigate anthropometric and clinical correlates and sources of variation in both skeletal muscle mass and muscle strength in advanced stages of CKD. Methods The study sample consisted of 84 non-dialysis dependent patients of both sexes (including 45.2% of women) with eGFR < 45 ml/min/1.73m²: 26.2% with eGFR 30-44 mL/min/1.73 m², 65.5% with eGFR 15-29 mL/min/1.73 m² and 8.3% with eGFR < 15 mL/min/1.73 m². Muscle strength was estimated by measuring hand grip strength (HGS) with the use of handheld hydraulic dynamometer. Muscle quantity was measured by bioimpedance spectroscopy using Body Composition Monitor. Appendicular skeletal muscle mass (ASM) was calculated according to Lin’s formula. Serum creatinine, urea, uric acid and albumin were measured. Results In bivariate analysis we found that ASM significantly and positively correlated with anthropometric variables such as body mass (r=0.903, p<0.001), NH weight (r=0.882, p<0.001), height (r=0.694, p<0.001), body mass index (BMI) (r=0.701, p<0.001), lean tissue mass (LTM) (r=0.664, p<0.001), lean tissue index (LTI) (r=0.433, p<0.001), fat mass (r=0.614, p<0.001) and fat tissue index (FTI) (r=0.449, p<0.001), and was negatively associated with clinical variable such as hydration status (p<0.001). HGS significantly and positively correlated with anthropometric parameters such as body mass (r=0.319, p=0.003), NH weight (r=0.315, p=0.004), height (r=0.666, p<0.001), LTM (r=0.490, p<0.001), LTI (r=0.238, p=0.029), and ASM (r=0.501, p<0.001), and was negatively associated with clinical variables like uric acid (p=0.039) and urea (p<0.001). After adjustment for age, sex and height, HGS remained significantly and negatively related with uric acid (β=-1.078, p=0.041) and hydration status (β=-0.805, p=0.042). Conclusions In CKD patients, ASM is determined mainly by anthropometric parameters but HGS - both by anthropometric and clinical variables specific for CKD.

Apple replant disease (ARD) is a complex issue caused by various fungal, oomycetes pathogens and parasites which can differ in their abundance between sites within a geographic region. Knowledge of the specific etiology of ARD at a particular site is required in order to develop commercially viable soil management strategies to combat specific/individual components of the disease. In this study we analyzed the soil from six ARD sites for the presence of fungal, bacterial and oomycetes communities and plant parasitic nematodes. Five fungal, and 17 bacterial classes were differentially represented in the microbiomes from different locations. Mortierellomycetes was the most abundant fungal taxa represented followed by Sordariomycetes. Mortierella exigua a fungal endophyte was the most abundant fungal amplicon sequence variant (ASV) in the core microbiome. Proteobacteria was the most prevalent phylum identified in orchard soils. Several potential phytopathogenic fungi involved in ARD and endophytes including Fusarium oxysporum, F. solani, Nectria ramulariae, Ilyonectria robusta and Nectriaceae were identfied in the orchard soil. Pythium attrantheridium (Globisporangium attrantheridium), P. monospermum and P. ultimum (Globisporangium ultimum) were the most abundant oomycete taxa identified in these soil samples. Six different groups of plant-parasitic nematodes were found across the six orchards soil. Root-lesion nematodes, Pratylenchus spp., which are commonly associated with ARD, were identified in all orchards soil at population densities ranging from 12 to 33/100 cm3 soil. This research contributes valuable understanding of the ARD complex as the apple industry needs alternative approaches to combat the disease.

Background Homologous recombination deficiency (HRD) evolved into a major diagnostic marker in high grade ovarian cancer (HGOC) predicting the response to poly (Adenosine diphosphate-ribose) polymerase inhibitors (PARPi) and also platinum-based therapy. In addition to HRD, the type of peritoneal tumor spread influences treatment response and patient survival; miliary type tumor spread has poorer predicted outcome than non-miliary type tumor spread. Methods Known methods for HRD assessment were adapted for our technical requirements and the Predictive-value Integrated Genomic Instability Score (PIGIS) for HRD assessment evolved as an outcome. PIGIS was validated in HGOC samples from 122 patients. We used PIGIS to analyze whether the type of tumor spread correlated with HRD status and whether this had an impact on survival. Results We demonstrated that PIGIS can discriminate HRD positive from HRD negative samples. Tumors with miliary tumor spread are HRD negative and have a very bad prognosis with a progression free survival (PFS) of 15.6 months and an overall survival (OS) of 3.9 years. However, HRD negative non-miliary spreading tumors in our cohort had a much better prognosis (PFS 35.4 months, OS 8.9 years), similar to HRD positive tumors (PFS 34.7 months, OS 8.9 years). Conclusions Our results indicate that in a predominantly PARPi naïve cohort the type of tumor spread might be a better predictor of response to platinum sensitivity than HRD. It remains to be determined, whether this also applies for sensitivity to PARPi.

Patients with predominantly antibody deficiencies (PAD) display hypogammaglobulinemia with a high prevalence of infections, along with autoimmune manifestations, benign and malignant lymphoproliferation and granulomatous disease. It is noteworthy that PAD patients, even those with defects in the same causative genes display a variable clinical phenotype, suggesting that additional genetic polymorphisms, located in either immune-related or non-immune-related genes, may affect their clinical and laboratory phenotype. In this context, we analyzed 80 PAD patients, including 70 with common variable immunodeficiency (CVID) for SERPINA1 defects, in order to investigate their possible contribution to PAD clinical phenotype. Eight CVID patients carried heterozygous pathogenic SERPINA1 defects with normal alpha-1 antitrypsin levels. Interestingly, the presence of the Z allele (rs28929474) which was found in three patients, was significantly associated with liver disease; hepatic complications were also observed in patients carrying the p.Leu23Gln (rs1379209512) and the p.Phe76del (rs775982338) alleles. Conversely, no correlation of SERPINA1 defective variants with respiratory complications was observed, although patients with pathogenic variants exhibit a reduced probability of developing autoimmune diseases. Therefore, we recommend SERPINA1 genetic analysis in PAD, in order to identify patients with a higher risk for liver disease.

This review article focuses on the role of Artificial Intelligence (AI) in transforming healthcare in Africa, specifically in combatting infectious diseases, neglected tropical diseases (NTDs), and antimicrobial resistance. We provide a comprehensive overview of the significance of AI in the healthcare industry, highlighting its urgency and importance in addressing these specific health challenges in Africa. We begin by discussing the role of AI in infectious disease surveillance and outbreak detection. We explore how AI technology can be employed for real-time tracking and prediction of outbreaks, providing examples of successful AI applications in infectious disease surveillance within the African context.Next, we examine the potential of AI-enabled diagnosis and treatment for faster and more accurate diagnoses of infectious diseases and NTDs. We highlight specific examples of AI applications in diagnosing and treating these diseases in Africa, showcasing the potential of AI to improve clinical outcomes and save lives.Furthermore, we focus on how AI-driven drug discovery and development can expedite the search for new treatments for infectious diseases and combat antimicrobial resistance. We present examples of AI applications in drug discovery within the African context, illustrating the potential for AI to revolutionize the development of effective therapeutics.In addition, we delve into how AI-powered public health interventions can enhance the design and implementation of targeted interventions. We explore how AI can optimize resource allocation and facilitate data-driven decision-making processes, providing examples of AI applications in public health in Africa.Finally, we address the challenges and limitations of implementing AI in combatting infectious diseases, NTDs, and antimicrobial resistance in Africa. We discuss potential barriers and ethical concerns surrounding AI applications in healthcare, aiming to encourage informed and responsible utilization of AI technologies.Overall, this review emphasizes the importance and potential of AI in combatting infectious diseases, NTDs, and antimicrobial resistance in Africa. It positions AI as a catalyst for revolutionizing healthcare in the region, leading to more effective disease surveillance, diagnosis, treatment, drug discovery, and public health interventions.

This retrospective study examines 248 test-bolus examinations preceding contrast-enhanced magnetic resonance angiography (CE-MRA) to extract clinically relevant data for critical limb ischemia (CLI) management. Methods involved a retrospective review of test-bolus exams, analysing 60 graphs for time-to-peak (TTP), full-width half-maximum (FWHM) time, and time to continual rise in signal intensity. These values were correlated with heart function parameters (ejection fraction, ASA-Classification, Lee-Index, and MET-Score). Results indicate a mean TTP of 31.2 ± 7.3s, showing a correlation between ejection fraction and ASA classification. Patients with atrial fibrillation exhibited prolonged TTP compared to those without. Despite population heterogeneity, findings facilitate risk stratification for limb-saving interventions in CLI. TTP emerges as a potential clinical cardiovascular parameter and a risk factor for vascular interventions. Given the variation in injection protocols across centres, this study underscores the importance of precise bolus arrival time documentation for future multicentre studies.

We propose that a dietary reduction of Lipopolysaccharide (LPS) could reduce risk and slow the progression of cognitive decline and Alzheimer’s disease. LPS is a component of the highly inflammatory cell membrane of Gram-negative bacteria. The highest dietary sources of LPS are processed meat and dairy products, which can sharply raise plasma LPS within one to two hours. The LPS in these foods is packaged into chylomicrons, which enter the bloodstream. Smaller amounts of LPS from colonic microbiota do not account for the sharp postprandial increase of plasma LPS. Once in the bloodstream, LPS can trigger the release of inflammatory cytokines within three hours. LPS can increase cytokines via LPS binding protein and cluster of differentiation-14, triggering toll-like receptor-4, and activating nuclear factor kappa-B. Nuclear factor kappa-B can increase cytokine levels, including interleukin-1-beta, interleukin-6, and tumor necrosis factor-alpha. LPS and inflammatory cytokines are higher in Alzheimer’s disease, both in plasma and in the central nervous system. These cytokines can enter the brain via active transport and induce microglial activation and inflammatory damage in the brain, including loss of synapses and neurons. Elevated brain inflammation from dietary LPS can contribute to cognitive impairment and increased risk of dementia.

Background: Amyloid beta peptides (Aβ) have been identified as the main pathogenic agents in Alzheimer’s disease (AD). Soluble Aβ oligomers, rather than monomer or insoluble amyloid fibrils, show membrane-binding capacity to red blood cells (RBCs) and trigger several morphological and functional alterations in RBCs that can result in impaired oxygen transport and delivery. Since bioactive lipids have been recently proposed as potent protective agents against Aβ toxicity, we investigated the role of sphingosine-1-phosphate (S1P) in signaling pathways involved in the mechanism underlying ATP release in Aβ-treated RBCs. Methods: In RBCs following different treatments, ATP, 2,3 DPG, cAMP levels, and caspase 3 activity were determined by spectrophotometric and immunoassay. Results: S1P rescued the inhibition of ATP release from RBCs triggered by Aβ through a mechanism involving caspase-3 and restoring 2,3 DPG and cAMP levels within the cell. Conclusions: These findings reveal the molecular basis of S1P protection against Aβ in RBCs and suggest new therapeutic avenues in AD.

Background: Penile squamous cell carcinoma (PSCC) is classified into two prognostically distinct types: human papillomavirus (HPV)-associated and HPV-independent. Conversely, the impact of p53 status on prognosis remains controversial. We correlated HPV and p53 status with prognosis in a large series of PSCC patients. p53 was analysed according to a recently described immunohistochemical (IHC) pattern-based framework that includes two normal (scattered, mid-epithelial) and four abnormal patterns (diffuse, basal overexpression, cytoplasmic and null) and closely correlates with TP53 mutational status. Methods: A total of 122 patients with surgically treated PSCC in three hospitals in Barcelona, Spain, were included. Based on HPV in situ hybridization and p16 and p53 IHC expression, the tumors were classified into three molecular types: HPV-associated, HPV-independent/p53 normal, and HPV-independent/p53 abnormal. All patients were followed for at least 22 months (median 56.9 months), and disease-specific survival (DSS) was analysed. Results: Thirty-six tumors (29%) were HPV-associated, 35 (29%) were HPV-independent/p53 normal, and 51 (42%) were HPV-independent/p53 abnormal. Disease-related deaths were observed in 3/36 (8%), 0/35 (0%) and 14/51 (27%) of the patients, respectively (p&lt;0.001). A total of 7/14 deaths in the latter group were patients with tumors showing p53 patterns not recognized in the classical p53 IHC interpretation (basal, null, cytoplasmic). According to our multivariate analysis, HPV-independent/p53 abnormal tumors and advanced stage were associated with impaired DSS (hazard ratio=23.4, 95% confidence interval [CI]= 2.7-3095.3; p=0.001 and 16.3, 95% CI=1.8-2151.5; p=0.008, respectively). CONCLUSION: Compared with patients with HPV-associated and HPV-independent/p53-normal PSCC, patients with HPV-independent/p53 abnormal PSCC have worse clinical outcomes. p53 IHC results define two prognostic categories in HPV-independent PSCC: HPV-independent/p53-normal tumors as low-risk tumors, whereas HPV-independent/p53-abnormal tumors as aggressive neoplasms.

Neutrophil elastase (NE) is taken up by macrophages, retains intracellular protease activity and induces a pro-inflammatory phenotype. However, the mechanism of NE-induced pro-inflammatory polarization of macrophages is not well understood. We hypothesized that intracellular NE degrades histone deacetylases (HDAC) and Sirtuins, disrupting the balance of lysine acetylation and deacetylation, and resulting in nuclear to cytoplasmic translocation of a major alarmin, High Mobility Group Box 1 (HMGB1), a pro-inflammatory response in macrophages. Human blood monocytes were obtained from healthy donors, or from subjects with cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD). Monocytes were differentiated into blood monocyte derived macrophages (BMDM) in vitro. Human BMDM were exposed to NE or control vehicle and the abundance of HDACs and Sirtuins was determined by western blotting of total cell lysates or nuclear extracts, or determined by ELISA. HDAC, Sirtuin, and Histone acetyltransferase (HAT) activities were measured. NE degraded most HDACs and Sirtuin (Sirt)1, resulting in decreased HDAC and sirtuin activities, with minimal change in HAT activity. We then evaluated whether the NE-induced loss of Sirt activity or loss of HDAC activities would alter the cellular localization of HMGB1. NE-treatment or treatment with Trichostatin A (TSA), a global HDAC inhibitor, both increased HMGB1 translocation from the nucleus to the cytoplasm, consistent with HMGB1 activation. NE significantly degraded Class I and II HDAC family members and Sirt 1 which shifted BMDM to a pro-inflammatory phenotype.

Artificial intelligence (AI) has emerged as a powerful tool for addressing the challenges posed by climate change and their impact on public health. By leveraging its capacity to analyze and predict climatic patterns, AI offers opportunities to enhance resource management and develop effective strategies for climate change mitigation. Moreover, AI can contribute to generating sustainable solutions that address the complex and interconnected nature of climate change. For example, AI can enable the optimization of energy consumption and facilitate the integration of renewable energy sources into existing systems. It can also support the development of climate models that provide timely and accurate predictions, enabling policymakers to implement proactive measures for disaster preparedness and response. Furthermore, AI-powered disease surveillance and mitigation techniques can improve public health outcomes by identifying patterns and trends in the spread of diseases in relation to climatic factors.However, the widespread adoption of AI-based solutions is not without challenges. Ethical concerns surrounding privacy and data ownership must be addressed, as the use of AI requires access to large datasets, raising potential privacy risks. Technical constraints, such as limited computational power and the need for sophisticated algorithms, also pose obstacles to the implementation of AI in climate change mitigation strategies. Furthermore, issues related to the accessibility and affordability of AI technologies must be resolved to ensure equitable distribution and maximize its potential impact on public health.To fully harness the power of AI in addressing climate change and improving public health outcomes, it is crucial to promote innovation, multidisciplinary collaboration, and open data science. Innovation can drive the development of new AI algorithms and technologies specifically tailored to address climate change challenges. Multidisciplinary approaches that bring together experts from diverse fields, including climate science, public health, and computer science, can foster a holistic understanding of complex systems and enable the design of comprehensive solutions. Finally, open data science practices, such as sharing data and algorithms, can facilitate collaboration and accelerate progress in mitigating climate change and its public health impacts.In conclusion, AI offers promising opportunities for effectively addressing climate change and its impact on public health. However, to fully realize its potential, it is essential to tackle ethical and privacy concerns, overcome technical constraints, and ensure accessibility and affordability. By promoting innovation, multidisciplinary collaboration, and open data science, we can unlock the transformative power of AI in mitigating climate change and improving public health outcomes.

Acute and chronic graft versus host disease (a/cGVHD) are major complications of allogeneic stem cell transplantation and a frequent cause of non relapse-mortality. The treatment of a/cGVHD consists of steroid administration at full dose. In the case of aGVHD, around 60 % of patients with grade III/IV fails to respond (steroid-resistant, SR), requiring a second line therapy. Extracorporeal photopheresis (ECP) represents a good option for second line treatment, leading to multiorgan response in several patients. Here, we have evaluated the performances of a cytofluorimetric quality control of the first ECP procedure in 29 patients with severe SR aGVHD who underwent ECP. The quality control represents a check control of in vitro cell apoptosis/death induction in collected and irradiated CD3+ cells by ECP. Our analysis shows that in more than 70 % quality controls a relevant apoptotosis/death of CD3+ cells was observed after cell irradiation, as compared to non-irradiated controls. Albeit observed in a small patients’ series, the occurrence of relevant in vitro effect after ECP relates to less procedures and/or to a better survival on ECP. Age, disease, gender, aGVHD grade and time from transplant to the first ECP had not impact on ECP efficacy in this patients’ series.

This analytical cross-sectional study was designed to evaluate the association between glycemic control and peripheral arterial disease in patients with diabetic foot with more than ten years of evolution of diabetes mellitus who attended the diabetic foot outpatient clinic of the Guillermo Almenara National Hospital between June 2015 and February 2017. Glycosylated hemoglobin (HbA1C) and ankle-brachial index (ABI) were used to diagnose glycemic control and peripheral arterial disease, respectively. A generalized Poisson log-linear regression model was used to calculate the crude (cPR) and adjusted (aPR) prevalence ratios, with 95% confidence intervals, and a significance level of p < 0.05. 226 patients were included in the study, finding 23% (n=52) with good glycemic control, and 44.7% (n=101) with peripheral arterial disease. The adjusted model found statistically significant associations for glycemic control, age, and sedentary lifestyle with peripheral arterial disease. Compared with patients with good glycemic control, those with poor glycemic control had a 34% higher probability of presenting peripheral arterial disease (aPR: 1.34, 95%CI: 1.01-1.79, p=0.045). The prevalence of good glycemic control in the population with diabetic foot is low. Poor glycemic control was found to be independently associated with the presence of peripheral arterial disease.

Cadmium (Cd) is a metal with no nutritional or physiological value, but is found in most people because it is a contaminant in nearly all food types. The intestinal absorption rate determines the body burden of Cd because humans lack a physiologic mechanism for excretion of the metal. Most acquired Cd accumulates in the kidneys, in which the Cd content increases through age 50 but falls thereafter. The decline from maximal kidney content is probably due to release of Cd from injured tubular cells into urine and replacement of destroyed nephrons by scar tissue. Chronic kidney disease is diagnosed when the estimated glomerular filtration rate (eGFR) falls below 60 mL/min/1.73 m2, or when albuminuria is present. Albuminuria is defined as an albumin-to-creatinine ratio ≥ 30 mg/g creatinine in women or ≥ 20 mg/g creatinine in men that persists for at least 3 months. Generally, Cd-induced reductions in eGFR are not reversible, and Cd nephropathy may progress to end-stage kidney disease. There is no evidence that elimination of current environmental exposure can reverse Cd nephropathy, and no theoretical reason to believe that such a reversal is possible. This review provides an update of knowledge concerning CKD in population environmentally exposed to Cd. Special attention is devoted to mechanisms of Cd-induced albuminuria concurrently with eGFR reductions, and the difficult challenge of exposure guidelines sufficient to eliminate the risk of Cd-induced CKD is addressed.

We conducted this systematic review with the objective to understand the efficacy and safety of proton pump inhibitors [PPIs] in the pediatric population. We have used PubMed to identify randomized controlled trials [RCTs] published between 1st June 2010 and 30th June 2023, in patients from birth to 18 years old, with gastroesophageal reflux disease [GERD], who received treatment with any PPI. The literature yielded 76 articles and 13 met inclusion criteria. For infants, PPIs were equal to placebo in reducing GERD symptoms in 4 articles. In 1, the number of GER episodes and esophageal acid exposure were lower in infants who received PPIs and left lateral position, but there was no significant improvement in symptoms. In another publication, the combination of PPIs and feeding modifications [FM] was not more effective than PPIs alone. For children and adolescents, PPIs were effective in improving symptoms and achieving mucosal and histological healing, which was subsequently maintained. To conclude, PPIs are not effective to reduce symptoms related to GERD in infants, but are effective in older children, along with histological remission. Generally, PPIs are well tolerated, but it is important to not forget the possible adverse events [AE], especially if they are used for a long time.

Verticillium wilt (VW) is an important and widespread disease of cotton and once established is long lived and difficult to manage. In Australia, the non-defoliating pathotype of Verticillium dahliae is the most common, and extremely virulent. Breeding cotton varieties with increased VW resistance is the most economical and effective method of controlling this disease and is greatly aided by understanding the genetics of resistance. In this study, VW resistance was investigated in 240 F7 recombinant inbred lines (RIL) derived from a cross between MCU-5 that has good resistance and Siokra 1-4 which is susceptible. Using a controlled environment bioassay, we found that resistance based on plant survival or shoot biomass was complex but with major contributions from chromosomes D03 and D09, with genomic prediction analysis estimating a prediction accuracy of 0.73 based on survival scores compared to 0.36 for shoot biomass. Transcriptome analysis of MCU-5 and Siokra 1-4 roots uninfected or infected with V. dahliae revealed that the two cultivars displayed very different root transcriptomes and responded differently to V. dahliae infection. Ninety-nine differentially expressed genes were located in the two mapped resistance regions and so are potential candidates for further identifying the genes responsible for VW resistance.

Healthcare visits were reduced during COVID-19 pandemic causing the disturbance of the sustainability in NAFLD monitoring. Telemedicine acts to maintain connectivity between patients and healthcare professionals. This review aimed to assess telemedicine helps to monitoring in NAFLD. The database was searched from The PubMedCentral and ScienceDirect from 2020 to 2023. We assessed the Cochrane Risk of Bias (RoB) for randomized controlled trial (RCT) and the Newcastle-Ottawa scale for non-RCTs systematic reviews. Meta-analyses with random-effects model to determine the pooled mean difference (MD) and p-value. There were three RCT and two non-RCT were included (n=239) with 56.9% males and the mean age was 51.3 years. Median intervention lasted 5.5 months. The parameter were body weight (BW), body mass index (BMI), waist circumference, liver function (AST/ALT), lipid profile and HbA1c. Metaanalysis showed telemedicine had a significant effect on improving outcomes for BW (MD -2.81: 95% CI, -4.11, -1.51, P 0.0001) and BMI (MD -1.01: 95% CI, -1.47, -0.55, P 0.0001) compared to standard care, while the AST/ALT were not significantly reduced. Other laboratory parameter were decreased from systematic reviews. Telemedicine through mobile-based applications could be an option for monitoring body weight and BMI in NAFLD patients facing the pandemic.

Background: Parkinson's disease (PD) is a global disease. However, there is a lack of research specifically focused on the AfrAbia population. Climate change, driven mainly by global warming, is linked to detrimental health impacts, including an increased frequency and intensity of heat waves. Neurological diseases, including neurodegenerative syndromes like Alzheimer's disease, Parkinson's disease, and motor neuron illnesses, have been increasingly seen and recorded in scientific literature. Although there is much literature demonstrating the growth in neurodegenerative disorders, the relationship between environmental variables such as global warming, air pollution, heavy metals, and pesticides and the higher occurrence of these illnesses is still unknown. Objective: The current article primarily aims to examine the relationship between climatic changes, air pollution, pesticides, heavy metals, and the occurrence of PD. Initially, we evaluate the influence of exposure to these variables on the cause or origin of Parkinson's disease. In addition, we will investigate how these variables disrupt processes such as excitotoxicity, oxidative stress, and neuroinflammation, all of which are strongly linked to Parkinson's disease (PD). Conclusions: This research presents a plausible rationale for the adverse effects of environmental influences on the brain, which are pivotal in the progression or onset of Parkinson's disease from an AfrAbian standpoint.

Emotional intelligence can contribute to quality of life and as a health predictor. The aim of this study is to analyze emotional intelligence, quality of life and the correlation factors associated in patients undergoing chronic hemodialysis. A quantitative, observational, cross-sectional design was performed, and one hundred and thirty-eight multi-centers hemodialysis patients were recruited. A battery of questionnaires, including Trait Meta-Mood Scale (TMMS-24), Kidney Disease Quality of Life-Short Form (KDQOL-SF), and an ad-hoc sociodemographic questionnaire, were answered. Sex differences existed when assessing the three dimensions of emotional intelligence: ranked by order, the highest scores in males were in clarity, repair, and attention. However, in females were in repair, clarity, and attention. Males had higher scores than females in emotional role (p=0.045). Younger participants had better scores in all physical functions (p=0.001) and vitality (p=0.038) than older. Moreover, those who had a higher level of education presented better physical function (p=0.027) and higher scores in emotional wellbeing (p=0.036). Finally, in females, emotional attention (p=0.046) and repair (p<0.001) were strongly associated with general health perception. The assessment of emotional intelligence considering sex differences in patients undergoing chronic hemodialysis can be an indicator of quality of life including the use in health interventions.

Eggplant or brinjal is one of the most consumed and important nutrient-dense tropical solanaceous vegetable crops grown worldwide. Little leaf is a disease especially widespread in brinjal in India where it is associated with the presence of phytoplasmas. To clarify the epidemiology of this disease and verify its seed transmission potential, seedlings and their progeny derived from symptomatic mother plants field-collected in Dharwad district of Karnataka State, India, were sowed under insect proof conditions in greenhouse. The resulting first- and second-generation seedlings obtained were tested at different times after germination by DNA extraction and amplification of 16S rRNA gene of phytoplasmas. Tissues from field collected symptomatic brinjal plants were also tested following the same procedure. The amplicons obtained were subjected to restriction fragment length polymorphism (RFLP) analysis and sequencing for phytoplasma identification. The detected phytoplasmas belonged to 16SrI, 16SrII, 16SrIII, 16SrV, 16SrVI, and 16SrXII groups. Several fruits produced from the first-generation seedlings showed germination of the seeds inside the fruit and resulted to be phytoplasma positive. This demonstrates the seed transmission of phytoplasmas in eggplants for two subsequent generations. This finding highlights the risk of additional source of infection represented by asymptomatic and infected seedlings under field conditions and contribute to explain the epidemic spread of phytoplasmas in brinjal cultivations in India and in the other eggplant growing areas of the world.

: Crohn’s disease (CD) is a multifactorial chronic disorder that involves a combination of factors as genetic, immune response and gut microbiota. Actually, the therapy comprises salicylates, immunosuppressive agents, corticosteroids, biologic drugs. International guidelines don’t recommend the use of antibiotics except for septic complications of CD patients. The increased evidence of the implication of gut bacteria in this chronic disease support the rationale for using antibiotics as primary treatment of active CD. In the last decades several pathogens have been reported to be involved in the development of CD, but only Escherichia coli (E.coli) species and Mycobacterium avium paratubercolosis (MAP), aroused the interest due to their strong association with CD pathogenesis. Several meta-analyses have been published concerning antibiotic treatment in CD patients but randomized trials of antibiotic treatments against E.coli and MAP did not show prolonged benefits, and only generated conflicting results so much so that several questions are still unresolved regarding trial design, antibiotic dosing, the formulation used, the treatment course and the outcome measures. In this article we attempted to provide an overview and update of the trials on antibiotic treatment in active CD patients taking into account the role of pathogens, the mechanism by which the different antibiotics act on harmful pathogens, and antibiotic resistance. Finally, we also tried to draw new lines for future studies to use antibiotics to treat active CD patients

The vertebrate basal ganglia are thought to play an important role in action selection—the resolution of conflicts between alternative motor programs. The effective operation of basal ganglia circuitry is also known to rely on appropriate levels of tonic dopamine transmission. We show that when the tonic level of simulated dopamine in a robotic model of the basal ganglia is significantly reduced or increased, relative to an effective operating baseline, a variety of behavioral outcomes are observed that provide interesting comparisons with the results of human and animal studies. The main findings were that progressive reductions in the levels of simulated dopamine caused a slowing of the robot’s movements and eventually an inability to initiate movement. These states were partially relieved at increased salience levels (stronger sensory/motivational input). Conversely, increased levels of simulated dopamine could cause distortion of the robot’s motor acts through partially-expressed motor activity relating to losing actions; this could also lead to increased frequency of switching between behaviors. Levels of simulated dopamine that were either significantly lower or higher than baseline could cause changes to the timing of behavior switching that could cause a loss of behavioral integration, sometimes leaving the robot in a ‘behavioral trap’. That some analogous traits are observed in animals and humans affected by dopamine dysregulation suggests that embodied (robotic) models could prove useful in understanding the role of dopamine neurotransmission in basal ganglia function and dysfunction. That the effects of simulated dopamine on robot action selection were partially, but not fully, predictable from the selection properties of the non-embodied basal ganglia model, also points to the added value of using robotic models to explore the relationship between brain activity and behavior.

While typically exhibiting characteristic features, fungal infections can sometimes present in an unusual context, having improbable localization (eyelid, face, joint), mimicking other skin diseases such as eczema, psoriasis, or mycosis fungoides, and appearing with unexpected color, shape, or distribution. The emergence of such a challenging clinical pictures is attributed to complex interplay of host characteristics (hygiene, aging population), environment (climate change), advances in medical procedures, and agent factors (fungal resistance, species emergence). We aim to provide a better understanding of unusual epidemiological contexts and atypical manifestations of fungal superficial diseases, knowing that there is no pre-established clinical guide for these conditions.

Cellular therapies have started an important new therapeutic direction for Autistic Spectrum Disease (ASD), and the ample diversity of ASD pathophysiology and the different types of cell therapies need an equally ample effort for studying the applicable ASD causes and the specific benefits of cell therapies via clinical studies.CORDUS Clinical Study is a crossover study in which autologous cord blood was administered intravenously to 56 patients between January 2019 and July 2023, and has compared its efficacy versus an individualized combination of supplements; both treatments were administered in a different sequence to all participants. Treatment efficacy was evaluated pre- and post- treatments by an independent psychotherapist with ATEC, Q-CHAT and a 16-item comparative table score, after interviews with the children’s parents and therapists.Cord blood was beneficial in the group of 3–7-year-old children (n=28; 3 out of 4 children – 78.57% - improved scores), but was much less effective in kids older than 8 years or with body weight of more than 35 kg (n=28; 1 out of 10 children improved scores). Individualized supplements were more efficacious than cord blood in 5 cases out of 28, while in 23 kids cord blood brought more improvement than supplements; 6 kids registered minor or no improvement. Statistically significant improvements were seen after cord blood infusion on areas such as verbalization and social interaction, but not on irritability or aggressive behavior; also ample individual differences were noted. No serious adverse reactions were noted during and after cord blood or supplement administration.

The main characteristic of polycystic kidney disease is the development of multiple fluid filled renal cysts. The discovery of mislocated Na,K-ATPase in the apical membrane of cyst lining epithelia alluded to a reversal of polarity as a possible explanation to the fluid secretion. The topic of apical Na,K-ATPase in cysts remains controversial. We investigated the localization of the Na,K-ATPase and assessed the apical-basolateral polarization of cyst lining epithelia by means of immunohistochemistry in kidney tissue from six polycystic kidney disease patients undergoing nephrectomy. The Na,K-ATPase α1 subunit was conventionally situated in the basolateral membrane of all immunoreactive cysts. Proteins of the Crumbs and partitioning defective (Par) complexes were localized to the apical membrane domain in cyst epithelial cells. The apical t-SNARE protein Syntaxin-3 also immunolocalized to the apical domain of cyst lining epithelial cells. Proteins of the basolateral Scribble complex immunolocalized to the basolateral domain of cysts. Furthermore, we confirmed that cysts can originate from virtually any tubular segment with preserved polarity. In conclusion, we find no evidence of a reversal in apical-basolateral polarity in cyst lining epithelia in polycystic kidney disease.

Both scleroderma and immunoglobulin G4-related disease (IgG4-RD) are systemic fibro-inflammatory diseases characterised by lymphoplasmacytic infiltrates. IgG4-RD and systemic Sclerosis (SSc) may share common pathophysiological mechanisms, but no examples of co-occurrence of the diseases have been found. Autologous haematopoietic stem cell transplantation (AHSCT) is implemented in selected rapidly progressive SSc with high risk of organ failure. However, existing guidelines are based on clinical trials that do not represent the entire patient population and exclude critically ill patients with no therapeutic alternatives. Examples of AHSCT in IgG4-RD are absent. We report the case of AHSCT in a female patient with overlapping progressive diffuse SSc and sinonasal IgG4-RD. Despite immunosuppressive therapy, IgG4-RD developed and clinically manifested shortly before AHSCT. Lacking therapeutic alternatives, after 11 years of SSc therapy, the 44-year-old successfully underwent AHSCT. The 63-month follow-up showed regression of symptoms. Only after surgical treatment (bilateral ethmoidectomy, sphenoidotomy, intranasal buccal antrostomy) the initially progressive clinical course of IgG4-RD remained indolent.

Approximately 6% of adults worldwide suffer from peripheral artery disease (PAD) primarily caused by atherosclerosis of lower limb arteries. Despite optimal medicine and revascularization, many PAD patients remain symptomatic and progress to critical limb ischemia (CLI) and risk major amputation. Delivery of pro-angiogenic factors as proteins or DNA, stem or progenitor cells confers vascular regeneration and functional recovery in animal models of CLI, but the effects are not well replicated in patients and no pro-angiogenic biopharmacological procedures are approved in the US. The reasons are unclear, but animal models that do not represent clinical PAD/CLI are implicated. Consequently, it is unclear whether the obstacles to clinical success lie in the toxic biochemical milieu of human CLI, or in procedures that were optimized by inappropriate models. The question is significant because the former case requires abandonment of current strategies, while the latter encourages continued optimization. These issues are discussed in the context of relevant preclinical and clinical data, and it is concluded that preclinical mouse models that include age and atherosclerosis as the only comorbidities that are consistently present and active in clinical trial patients are essential to predict clinical success. Of the reviewed materials, no biopharmacological procedure that failed in clinical trials had been tested in animal models that included advanced age and atherosclerosis relevant to PAD/CLI.

BACE1 is involved in the production of beta-amyloid peptides, and inhibiting its activity is a potential therapeutic strategy for managing Alzheimer's disease, as excessive beta-amyloid accumulation is a characteristic feature of the disease.Computational results suggest that hypericin has the potential to act as an inhibitor of BACE1. The Molecular Docking results indicate a high binding affinity between hypericin and BACE1, with a notable binding energy score of -10.3 kcal/mol. Additionally, the formation of various chemical bonds, including hydrogen bonds and hydrophobic bonds, further supports the idea that hypericin may effectively interact with the active site of BACE1. It's important to note that while the in silico Molecular Docking results are promising, further in vitro and in vivo studies would be necessary to validate and better understand the inhibitory potential of hypericin against BACE1. Additionally, the practical application of hypericin as a BACE1 inhibitor in a therapeutic context would require careful consideration of factors such as bioavailability, safety, and efficacy.

Milroy's disease (MD), also known as hereditary lymphedema type I, is a rare autosomal dominantly inherited primary lymphedema. It accounts for approximately twenty percent of all primary lymphedemas. MD typically presents clinically with bilateral lower extremity lymphedema. Our case report is about a rare case of MD presenting with unilateral lymphedema in both upper and lower extremities in a patient admitted to our clinic. A 24-year-old woman who had been under observation for lymphedema since she was 8 years old was diagnosed with MD by physical examination, venous Doppler ultrasound, whole body lymphoscintigraphy, and molecular genetic testing in our clinic, and partial improvement was achieved with Complete Decongestive Therapy, the gold standard treatment for lymphedema. Genetic counseling services may be especially useful for the patient and family. Although MD is rarely seen in the literature, many more studies are needed to identify carrier variants in the community.

The phenomenon of decreased serum uric acid (UA) levels in patients with Parkinson’s disease (PD) and its relationship with purine metabolic pathways remain unclear. We compared inosine, hy-poxanthine, xanthine, and UA levels in serum and cerebrospinal fluid (CSF) of PD patients with those of controls, and investigated the effect of changes in the purine metabolic system on UA levels in PD. Overall, 134 samples (serum, 45 PD patients and 30 controls; CSF, 39 PD patients and 20 controls), were analyzed using liquid chromatography-tandem mass spectrometry. A general linear model (GLM) was used to investigate relationships among purine metabolites. Compared to controls, PD patients had significantly lower UA levels in the serum and CSF, and serum and CSF UA levels were significantly correlated. Additionally, in PD, decreased serum hypoxanthine levels were observed with decreased CSF inosine and hypoxanthine levels, suggesting the involvement of the purine recycling system. GLM analysis indicated that the reduced UA levels in PD were mainly due to sources other than the purine metabolic system, such as exercise, nutritional indices, muscle volume, or adipose tissue. Our results highlight the impairment of purine recycling pathways in PD, as evidenced by the decreased serum hypoxanthine and CSF inosine.

.Celiac disease (CeD) is a chronic, autoimmune disorder triggered by the ingestion of gluten, affecting around 1% of the global population. It is a multifactorial disease involving both genetics and environ-mental factors. Nowadays, the only available treatment for CeD is a life-long gluten-free diet (GFD), which can cause a significant burden for patients, since symptoms and mucosal injury can persist de-spite apparent compliance with a GFD. That could also lead to psychological consequences and affect the quality of life of these patients. Thankfully, recent advances in understanding the pathogenesis of CeD and the availability of various targets have made it feasible to explore pharmaceutical treatments specific to CeD. Recently, the FDA has highlighted the unmet needs of adult patients on GFD who expe-rience ongoing symptoms attributed to CeD and also show persistent duodenal villous atrophy. This re-view will outline the limitations of a GFD, describe the targets of potential novel treatment of CeD and provide an overview of the primary clinical trials involving oral and injectable agents for a non-dietary treatment of CeD.

Sporadic Alzheimer’s disease (AD) derives from an interplay among environmental factors and genetic variants, while epigenetic modifications have been expected to affect the onset and progression of its complex etiopathology. Heterozygous carriers of the apolipoprotein E gene (APOE)4 allele have a 4-fold increased risk of developing AD, while APOE 4/4-carriers have a 12-fold increased risk in comparison with the APOE 3-carriers. The main longevity factor is the homozygous APOE ε3/ε3 genotype. In the present narrative review article, we summarized and described the role of APOE epigenetics in aging and AD pathophysiology. It is not fully understood how APOE variants may increase or decrease AD risk, but this gene is known to affect amyloid- and tau-mediated neurodegeneration directly or indirectly, also by affecting lipid metabolism and inflammation. For sporadic AD, epigenetic regulatory mechanisms may control and influence APOE expression in response to external insults. Diet, a major environmental factor, has been significant associated with physical exercise, cognitive function, and the methylation level of several cytosine-phosphate-guanine (CpG) dinucleotides sites of APOE.

Rheumatoid arthritis (RA) is an autoimmune disease mainly characterized by joint inflammation. It presents extra-articular manifestations, with the lungs one of the affected areas. Among these, damage to the pulmonary interstitium (Interstitial Lung Disease -ILD) has been linked to proteins involved in the inflammatory process and related to extracellular matrix deposition and lung fibrosis establishment. Peptidyl arginine deiminase enzymes (PAD), which carry out protein citrullination, play a role in this context. A genetic association analysis was conducted on genes encoding two PAD isoforms, PAD2 and PAD4. This analysis also included ancestry informative markers and protein level determination in samples from patients with rheumatoid arthritis, RA-associated ILD, and clinically healthy controls. Significant single nucleotide variations (SNV) and a haplotype were identified as susceptibility factors for ILD-RA development. Elevated levels of PAD4 were found in ILD-RA cases, while PADI2 showed an association with RA susceptibility. This document presents the data obtained from the conducted research, which has been published.

Rationale: Chronic Granulomatous Disease (CGD) is a rare primary immunodeficiency. Although most mutations are linked to the X chromosome, therefore affecting males, there are autosomal recessive forms that therefore affect both sexes. Clinically it is characterized by recurrent and severe bacterial and fungal infections, with formation of granulomas, due to the inability of phagocytes to generate reactive oxygen compounds, necessary for the intracellular death of phagocytosed microorganisms. Patient concerns: We reported a 12-year-old boy with pneumonia with pneumatocele of possible staphylococcal etiology at one year of age, bilateral orchitis secondary to Salmonella with hematogenous spread, osteomyelitis due to Salmonella, gastroenteritis due to Salmonella enteritidis, liver abscesses due to Staphycococcus aureus and lymphomatoid papulosis and pyodermititis. Diagnoses: In the biochemical diagnosis, the presence of yellow dye (NBT) and absence of dark bluish black dye (formazan) was evidenced. Regarding the genetic diagnosis, the presence of the mutation in exon 10 of CYBB (OMIM 306400) (Xp21.1) that encodes the gp91phox protein was demonstrated. Interventions and outcomes: Treatment was started with trimethoprim/sulfamethoxazole 400/80 mg every 24 hours via oral, and antifungal prophylaxis with itraconazole 200 mg every 24 hours orally is added, after which he does not present serious bacterial or fungal infections, not being able to administer immunomodulatory treatment with recombinant human Interferon gamma-1b. Lessons: The clinical finding of frequent severe infections associated with granulomas, CGD should be suspected. Treatment of this primary immunodeficiency is trimethoprim/sulfamethoxazole and itraconazole. Importantly, it indicated that the mutation in exon 10 of CYBB (Xp21.1) that encodes the gp91phox might influence the pathogenesis of CGD.

Background: Galectin-3 (Gal-3) overexpression is associated with fibroblastic proliferation and the production of collagen, resulting in increased cardiac fibrosis and remodelling. Aim of the study was to investigate on the expression of Gal-3 in hypertrophic hearts. We examined 19 surgical specimens taken from interventricular septum of 8 patients with Tetralogy of Fallot, 4 patients with aortic valve stenosis, 1 cardiac explant affected from dilated cardiomyopathy, and 6 myocardial biopsies of patients submitted to heart transplantation. Methods: All the samples were routinely processed, stained with Hematoxylin-Eosin, Trichromic stain and elastic fiber stain and selected by having the morphological features of myocardial hy-pertrophy: myocytolysis, nuclear pleomorphism, interstitial fibrosis. Results: At immunohistochemistry, myocardial fibers showed cytoplasmic expression of Gal-3 in the 4 patients with aortic valve stenosis (diffuse in 3 and mild in 1), in the 1 patient with cardiac explant (mild) and in the 4/6 transplanted hearts (mild and focal in 3 and diffuse in 1). The 8 patients affected from Tetralogy of Fallot and 2 patients with transplanted hearts resulted negative. Conclusions: The results agreed with the hypothesis that Gal-3 may play a role in cardiac hyper-trophy; its expression in myocardial fibers is not related with the morphological aspects as suggested by the absence in pediatric cases. The presence in myocardial biopsies taken from transplanted hearts would suggest a possible role in predicting clinical outcome of such patients.

The enteric nervous system (ENS) is principally derived from vagal neural crest cells that migrate caudally along the entire length of the gastrointestinal tract, giving rise to neurons and glial cells in two ganglionated plexuses. Incomplete migration of enteric neural crest-derived cells (ENCDC) leads to Hirschsprung disease, a congenital disorder characterized by the absence of enteric ganglia along variable lengths of the colorectum. Our recent data [1] support an essential role for the avian ceca, present at the junction of midgut and hindgut, in hindgut ENS development, since ablation of the cecal buds leads to incomplete ENCDC colonization of the hindgut. In situ hybridization shows bone morphogenetic protein-4 (BMP4) highly expressed in the cecal mesenchyme, leading us to hypothesize that cecal BMP4 is required for hindgut ENS development. To test this, we modulated BMP4 activity using embryonic intestinal organ culture techniques and retroviral infection in ovo. We show that overexpression or inhibition of BMP4 in the ceca disrupts hindgut ENS development, with GDNF playing an important regulatory role. Our results suggest that these two important signaling pathways are required for normal ENCDC migration and enteric ganglion formation in the developing hindgut ENS.

We investigated whether cigarette smoking and dietary acid load (DAL) are associated with the risk of chronic obstructive pulmonary disease (COPD) in middle-aged healthy Korean men. Healthy men without diagnosed chronic disease (40-64 yrs) from the KNHANES-VI (2013–2015) included in the analysis (n=774) were subdivided by smoking status and DAL levels as estimated by the net endogenous acid production (NEAP) quartile. Current smokers tended to have a higher risk of COPD than non-smokers before and after the adjustment. When divided by the DAL quartile, the Q4 tended to have a higher risk of COPD than the Q1. Additionally, current smokers with lower (Q2), modest (Q3), and highest NEAP scores (Q4) showed more than 4-fold higher risks of COPD than the non-smokers with the lowest NEAP scores (Q1). Ex–smokers with higher NEAP scores (Q3 and Q4) showed more than 4-fold higher risks of COPD than the Q1. Interestingly, the risk of COPD was also more than 6-fold higher in non-smokers with the highest NEAP scores compared to the Q1. NEAP scores and smoking status synergistically increased the risk of COPD in middle-aged healthy Korean men. It suggests that DAL levels are an important factor for the prevention and management of COPD.

Human prion diseases (HPDs) are fatal neurodegenerative disorders characterized by abnormal prion proteins (PrPSc). Numerous techniques have been devised to detect prion seeding activity, each with limitations. Here, we developed a technology for in vitro amplification of abnormal prion proteins (PrPSc), thereby enabling their sensitive detection. Using the real-time quaking-induced conversion (RT-QuIC) PrPSc amplification assay, we could detect ≥1 fg of PrPSc in diluted human prion disease brain homogenate. Although RT-QuIC assay is suitable for detecting prion seeding activity in a variety of specimens, its accuracy in whole blood, blood plasma, or blood-contaminated tissues is reduced. To circumvent this issue and move toward developing a blood test for prions, we introduced an immunoprecipitation step at the beginning of the RT-QuIC reaction. We refer to this enhanced method as “eQuIC”. eQuIC utilizes three types of human monoclonal antibodies, which significantly increased its sensitivity—making it approximately 1000 times more sensitive than the original RT-QuIC assay. Nevertheless, when we tested the blood (serum, plasma, and whole blood) of six patients with sporadic human prion disease using eQuIC, we were unable to detect prion activity. Therefore, we concluded that the detection of prion seeding activities in blood samples from patients with sporadic prion disease remains challenging; thus, alternative methods beyond RT-QuIC and eQuIC will be necessary for future research.

Introduction: Chronic Obstructive Pulmonary Disease (COPD) is a common, preventable and treatable disease. The first PREM (Patient Reported Outcome Measure) type questionnaire that has been dedicated to asses experience of care in COPD is the PREM-C9. Aim: To create a Polish version of the PREM-C9 and determine its the psychometric characteristics. Methods: The validation procedure involved forward and back translation and included 42 COPD patients. The psychometric properties were assessed using Cronbach's alpha, Bartlett's test, Kaiser-Meyer-Olkin and Spearman correlation coefficient. The validity of the questionnaire was assessed using Principal Component Analysis for the extracted principal components. The validity of the factor analysis was demonstrated by the Bartlett's sphericity test and the Kaiser-Meyer-Olkin (KMO). Factor analysis was performed using the Oblimin and Varimax rotation. The reliability of the questionnaire was assessed using the Cronbach's alpha. Results: The Polish version of the PREM-C9 questionnaire met all validation criteria: face, translation, psychometric, functional and reconstruction equivalence. The Spearman correlation results between Polish PREM-C9&amp;CAT: rho= 0,44, p=0,003539; HADS-Anxiety: rho= 0.370864, p=0,015612, HADS-Depression: rho= 0,387405, p=0,011253. Conclusion: The developed Polish PREM-C9 questionnaire is a reliable and valid tool that assesses Polish COPD patients' experiences of their disease and the care they receive.

The epidemiological and clinical pathological aspects of polioencephalomalacia (PEM) in five buffaloes (buffaloes 01 to 05) in the amazon biome are described. Epidemiological data were obtained during the clinical visit in which the animals with clinical signs compatible with polioencephalomalacia were submitted to a general and specific clinical examination of the nervous system. During the necropsy of the five animals, the intensity and location of the lesions were evaluated and fragments from different organs were collected and fixed in 10% buffered formalin and sent to the Pathological Anatomy Sector of the Federal Rural University of Rio de Janeiro for histopathological examination. Of the five studied animals, all were of the Murrah breed, four male and one female, with ages ranging from two months to one year. Two buffaloes (buffalo 01 and 02) were from the municipality of Castanhal, Pará, kept in an extensive breeding system on Urochloa brizantha pasture. Buffaloes 03 and 04 belonged to a property located in the municipality of Cachoeira do Arari, Marajó Island, Pará, and buffalo 05 was from a property located in the municipality of Itaubal, state of Amapá, all of them were raised in an extensive system in flooded of native pasture. At the clinical examination, all buffaloes had a body score between 2.5 and 3 (scale from 1 to 5), and there was noted decreased alertness, postural changes, marked hypermetria when stimulated to move, total or partial blindness demonstrated by colliding to the corral structures, head pressing and circumduction of the hindquarters when supported on the forelimbs, opisthotonos, muscle tremors, convulsions, paddling movements, sialorrhea, decrease in palpebral and pupillary reflexes and eyeball rotation placing the pupillary slit in a vertical position. At necropsy, mild lesions characterized by edema and flattening of the cerebral convolutions were observed. Histopathological examination showed laminar necrosis of the cerebral cortex. The diagnosis of polioencephalomalacia was based on epidemiological, clinical-pathological, and histopathological findings, similar to findings in other ruminants. The cause of polioencephalomalacia in the studied buffaloes was not established, which indicates the need for further studies to elucidate this disease in the species, mainly in the Amazon region.

Background: Alzheimer's disease causes great changes, with the prefrontal cortex be-ing frequently damaged zones, affecting physical and cognitive behavioural and compromising autonomy and quality of life. Objective: To evaluate the effectiveness of feedback-based tech-nology on the improvement of physical-cognitive capacities in Alzheimer. Methods: Forty pa-tients with Alzheimer were recruited from the Santa Elena Alzheimer's Association, Seville, of which 15 ended up being pilot participants, divided randomly into controls (8) and experi-mental (7). They were evaluated with: Cognitive Mini-Examination Scale, Oddball Test and At-tention Network, Berg Scale, Tinetti, Timed up and Go and Geriatric Deterioration Scale. The experimental group was treated with feedback-based technology under the supervision of physiotherapists, during 16 thirty-minute sessions, twice a week. The control group performed their usual care. Result: A significant improvement was observed in the experimental group (Cognitive Mini-Examination and Tinetti). In the group of control, a worsening of physical and motor skills was evidenced because of the degenerative disease. Discussion/Conclusion: This treatment could be a strategy to keep the patient in early stages for longer, and improve quali-ty of life delaying dependency. It creates intergenerational bonds and use at home to promote treatment adherence.

Mild cognitive impairment (MCI) is when brain function declines. It is a transition stage between normal aging and Alzheimer's disease (AD) and may be an underlying symptom of AD. Improper use of test instruments or imperfect test methods in clinical practice often leads to variations in test results. In addition, there may be resistance from the subject if he/she has to undergo multiple screening tests simultaneously. Therefore, the objective of this study was to use virtual reality to create an image testing scenario that integrates Mini-Cog, Short Portable Mental Status Questionnaire (SPMSQ), Mini-mental Status Examination (MMSE), Saint Louis University Mental Status Examination (SLUMS), Clinical Dementia Rating (CDR), and Cognitive Abilities Screening Instrument (CASI), and combine fuzzy logic control (FLC) technology to develop an MCI forecasting system. There were 24 middle-aged to older adults aged 50 to 65 years who participated in the evaluation experiment. The results showed that the MCI forecasting system developed in this study is highly correlated with the traditional screening tests, including Mini-Cog, SPMSQ, MMSE, SLUMS, and CASI. The forecasting system can provide an integrated reference score for testers in making judgments. In addition, the distribution of the System Usability Scale (SUS) evaluation scores for the MCI forecasting system revealed that 87.5% were grade C (good to use) or above, and 29.2% were grade B (extremely good to use) or above. The forecasting system receives positive feedback from the subjects.

Some studies show that patients with mutations in the SNCA gene, which codifies for the alpha-synuclein protein, show a particular phenotype. The effects of SNCA Single Nucleotide Polymorphism (SNPs) in recently diagnosed, drug-naïve patients with PD have been less explored. Therefore, we set out to explore the differences in the clinical characteristics of recently diagnosed drug-naïve sporadic PD patients with or without SNCA rs3910105 or rs356181 SNPs. Patients with a clinical diagnosis of PD in the Parkinson’s Progression Markers Initiative (PPMI) database entered the study. We excluded those with missing data, dementia, psychiatric conditions, a diagnosis change over the first five years from the initial PD diagnosis, or with a familial history of PD. Subjects were evaluated with the MDS-Unified PD Rating Scale (MDS-UPDRS), DAT imaging, the Geriatric Depression Scale (GDS), the State-Trait Anxiety Inventory (STAI), the Montreal Cognitive Assessment (MoCA), the SCOPA-AUT for autonomic function, the Epworth Sleepiness Scale (ESS), the RBD Questionnaire, and the University of Pennsylvania Smell Identification Test (UPSIT). We included 308 PD patients fulfilling all inclusion and exclusion criteria. A logistic regression analysis and Machine-Learning models did not disclose any difference between patients either with or without the SNCA rs3910105 SNP or with or without the SNCA rs3910105 polymorphism. Our results suggest that the SNCA polymorphisms rs3910105 and rs356181 have no impact on the phenotype of idiopathic, sporadic, recently diagnosed, drug naïve PD patients.

Alzheimer’s disease (AD) is an age-related neuropsychiatric disorder and a common cause of progressive dementia. Diltiazem (DTZ), the non-dihydropyridine benzothiazepine class of calcium channel blocker (CCB), used clinically in angina and other cardiovascular disorders have proven neurological benefits. In the present study, the neuroprotective anti-dementia effects of DTZ against intra-cerebroventricular-streptozotocin (ICV-STZ)-induced sporadic AD (SAD)-type rat model was investigated. ICV-STZ-induced cognitive impairments were measured by passive avoidance and Morris water maze tasks. Anti-oxidative enzyme status, pro-inflammatory markers, and amyloid-beta (Aβ) protein expression in rat brain tissues were measured by ELISA kits, Western blotting, and immunostaining techniques. Data revealed that ICV-STZ injection in rats significantly induced cognitive deficits and altered the levels of oxidative and pro-inflammatory markers (p &lt; 0.05 ~ p &lt; 0.001). Treatment with DTZ (10 mg/kg, 20 mg/kg, and 40 mg/kg. p.o.) daily for twenty-one days, 1 h before a single ICV-STZ (3 mg/kg) injection, significantly improved cognitive impairments, ameliorated the ICV-STZ-induced altered nitrite, pro-inflammatory cytokines (TNF-α, and IL-1β) and anti-oxidative enzyme levels (superoxide dismutase, lipid peroxidation, and glutathione). Further, DTZ restored the increased Aβ protein expression in ICV-STZ-induced brain tissue Considering the data obtained, DTZ exhibited a potential neuroprotective anti-dementia role in ICV-STZ-induced SAD-type conditions in rats and might be repurposed as a potential therapeutic agent in the treatment and management of AD and related dementia pathologies.

Wheat has a large and diverse repertoire of NLRs involved in disease resistance, with over 1,500 NLRs detected in some studies. These NLR genes occur as singletons or clusters containing copies of NLRs from different phylogenetic clades. The number of NLRs and cluster size can differ drastically among ecotypes and cultivars. Primarily, duplication has led to the evolution and diversification of NLR genes. Among the various mechanisms, whole genome duplication (WGD) is the most intense and leading cause, contributing to the complex evolutionary history and abundant gene set of hexaploid wheat. Tandem duplication or recombination is another major mechanism of NLR gene expansion in wheat. The diversity and divergence of duplicate NLR genes are responsible for the broad-spectrum resistance of most plant species with limited R genes. Understanding the mechanisms underlying the rapid evolution and diversification of wheat NLR genes will help improve disease resistance in crops. The present review focuses on the diversity and divergence of duplicate NLR genes and their contribution to wheat disease resistance. Moreover, we provide an overview of disease resistance-associated gene duplication and the underlying strategies in wheat.

Aging is a major risk factor for Alzheimer's disease (AD). AD mouse models are frequently used to assess pathology, behavior, and memory in AD research. While the pathological characteristics of AD are well established, our understanding of the changes in the metabolic phenotypes with age and pathology is limited. In this work, we used the Promethion cage systems® to monitor changes in physiological metabolic and behavioral parameters with age and pathology in wild-type and 5xFAD mouse models. Then, we assessed whether these parameters could be altered by treatment with oleocanthal, a phenolic compound with neuroprotective properties. Findings demonstrated metabolic parameters such as body weight, food and water intake, energy expenditure, dehydration, and respiratory exchange rate, and the behavioral parameters of sleep patterns and anxiety-like behavior are altered by age and pathology. However, the effect of pathology on these parameters was significantly greater than normal aging, which could be linked to amyloid-β deposition and blood-brain barrier (BBB) disruption. In addition, and for the first time, our findings suggest an inverse correlation between sleep hours and BBB breakdown. Treatment with oleocanthal improved the assessed parameters and reduced anxiety-like behavior symptoms and sleep disturbances. In conclusion, aging and AD are associated with metabolism and behavior changes, with the changes being greater with the latter, which were rectified by oleocanthal. In addition, our findings suggest that monitoring changes in metabolic and behavioral phenotypes could provide a valuable tool to assess disease severity and treatment efficacy in AD mouse models.

Papillary thyroid cancer (PTC) is commonly characterized by multifocality, which is associated with aggressive features and a less favorable prognosis. The current study aimed to compare the clinicopathologic characteristics and long-term oncological outcomes of bilateral and unilateral multifocal PTC. The medical records of 1745 patients with multifocal PTC who underwent thyroid surgery at Seoul St. Mary’s Hospital were retrospectively reviewed. The clinicopathological characteristics and recurrence rates were compared based on cancer laterality. Further, 357 patients who underwent total thyroidectomy were matched to investigate the recurrence risk and disease-free survival (DFS). Before propensity score matching (PSM), there was no significant difference in the recurrence rate between the bilateral and unilateral multifocal PTC groups. Cancer laterality was not a predictor of DFS based on the Cox regression analyses. However, after PSM, unilateral multifocality was associated with a significantly high risk of recurrence. Similarly, unilateral multifocality was associated with a significantly poor DFS based on the Kaplan–Meier analysis. Compared with bilateral PTC, unilateral multifocal PTC was associated with a poor DFS. A comprehensive preoperative examination should be performed to detect multifocality before the initial surgical intervention for optimal treatment. Postoperative short-term follow-up is recommended for unilateral multifocal PTC for recurrence surveillance.

Chronic pulmonary diseases such as asthma, COPD, and Idiopathic pulmonary fibrosis are significant causes of mortality and morbidity worldwide. Currently, there is no radical treatment for many chronic pulmonary diseases, and the treatment options focus on relieving the symptoms and improving lung function. Therefore, efficient therapeutic agents are highly needed. Bronchial epithelial cells and airway smooth muscle cells and their crosstalk play a significant role in the pathogenesis of these diseases. Thus, targeting the interactions of these two cell types could open the door to a new generation of effective therapeutic options. However, the studies on how these two cell types interact and how their crosstalk adds up to respiratory diseases are not well established. With the rise of modern research tools and technology, such as lab-on-chip, organoids, co-culture techniques, and advanced immunofluorescence imaging, a substantial degree of evidence about these cell interactions emerged. Hence, this contribution aims to summarize the growing evidence of bronchial epithelial cells and airway smooth muscle cells crosstalk under normal and pathophysiological conditions. The review first deliberates the effects of both healthy and stressed epithelial cells on airway smooth muscle cells, taking into account three themes; contraction, migration, and proliferation. Then, it discusses the impact of airway smooth muscle cells on the epithelium in inflammatory settings. Later, it examines the role of airway smooth muscle cells in the early development of bronchial epithelial cells and their recovery after injury.

Alzheimer’s disease (AD) is characterized by the formation of senile plaques consisting fibrillated amyloid-β (Aβ), dystrophic neurites, and the neurofibrillary tangles of tau. The oligomers/fibrillar Aβ damages the neurons or initiate an intracellular signaling cascade for neuronal cell death leading to Aβ toxicity. The Aβ is a 4 kDa molecular weight peptide originating from the C-terminal region of the amyloid precursor protein via proteolytic cleavage. Apart from the typical AD hallmarks, certain deficits in metabolic alterations have been identified. This study describes the emerging features of AD from the aspect of alternation in the main pathway of carbohydrate metabolism in the human brain. Particularly, the neurons in patients with AD favor glycolysis despite a normal mitochondrial function indicating a Warburg-like effect. In addition, certain dietary patterns are well known for their properties in preventing AD. Among those, a ketogenic diet may substantially improve the symptoms of AD. An effective therapeutic method in the treatment, mitigation, and prevention of AD has not yet been established. Therefore, the researchers pursue the development and establishment of novel therapies effective in suppressing AD symptoms and the elucidation of their underlying protective mechanisms against neurodegeneration aiming for AD therapy in near future.

Amyloids were conventionally referred to as extracellular and intracellular accumulation of Aβ42 peptide which causes the formation of plaques and neurofibrillary tangles inside the brain leading to the pathogenesis in Alzheimer’s disease. Subsequently, amyloid-like deposition was found in the etiology of Prion diseases, Parkinson disease, Type II Diabetes and Cancer which was attributed to the aggregation of Prion protein, α-Synuclein, Islet Amyloid Polypeptide Protein and p53 protein respectively. Hence, traditionally amyloids were considered as aggregates formed by the proteins or peptides exclusively. However, since the last decade it has been discovered that other metabolites like single amino acids, nucleobases, lipids, glucose derivatives etc. have propensity to form amyloid-like toxic assemblies. Several studies suggest direct implications of these metabolite assemblies in the patho-physiology of various Inborn errors of metabolisms like Phenylketonuria, Tyrosinemia, Cystinuria and Gaucher’s disease to name a few. In this review, we present a comprehensive literature overview which suggests amyloid-like structure formation as a common phenomenon for the disease progression and pathogenesis in multiple syndromes. The review on this topic is urgently required to create awareness about the understanding of fundamental molecular mechanism behind the origin of diseases from an amyloid perspective and possibly look for a common therapeutic strategy for the treatment of these maladies by designing generic amyloid inhibitors.

Demyelinating diseases alter myelin or the coating surrounding most nerve fibers in the central and peripheral nervous systems. The grouping of human central nervous system demyelinating disorders today includes Multiple Sclerosis (MS) and Neuromyelitis Optica Spectrum Disorders (NMOSD) as distinct disease categories. Each disease is caused by a complex combination of genetic and environmental variables, many involving an autoimmune response. Even though these conditions are fundamentally similar, research into genetic factors, their unique clinical manifestations, and lesion pathology has helped with differential diagnosis and disease pathogenesis knowledge. This review aims to synthesize the genetic approaches that explain the differential susceptibility between these diseases, explore the overlapping clinical features, and pathological findings, discuss existing and emerging hypotheses on the etiology of demyelination, and assess recent pathogenicity studies and their implications for human demyelination. This review presents critical information from previous studies on the disease, which asks several questions to understand the gaps in research in this field.

Alzheimer's disease (AD) is an incurable neurodegenerative disorder. Early screening, particularly in blood has been regarded as an effective approach for AD diagnosis and prevention. In addition, metabolic dysfunction has been demonstrated to be closely related to AD, which might be reflected in whole blood transcriptome. Hence, we hypothesized that establishment of diagnostic model based on metabolic signatures of blood is a workable strategy. To the end, we initially constructed metabolic pathway pairwise (MPP) signatures to characterize the interplay among metabolic pathways. Then, a series of bioinformatic methodologies, e.g., differential expression analysis, functional enrichment analysis, and network analysis, etc. were used to investigate the molecular mechanism behind AD. Moreover, an unsupervised clustering analysis based on the MPP signature profile via Non-Negative Matrix Factorization (NMF) algorithm was utilized to stratify AD patients. Finally, aimed at distinguishing AD patients from non-AD group, a metabolic pathway-pairwise scoring system (MPPSS) was established using multi-machine learning methods. As a result, many metabolic pathways correlated to AD were disclosed, including oxidative phosphorylation and fatty acid biosynthesis, etc. NMF clustering analysis divided AD patients into two subgroups (S1 and S2), which exhibit distinct activities of metabolism and immunity. Typically, oxidative phosphorylation in S2 exhibits a lower activity than that in S1 and non-AD group, suggesting the patients in S2 might possess a more compromised brain metabolism. Additionally, Immune infiltration analysis showed that the patients in S2 might have phenomena of immune suppression, compared with S1 and non-AD group. These findings indicated that S2 probably have a more severe progression of AD. Finally, MPPSS could achieve an AUC of 0.73 in training dataset, 0.71 in testing dataset and an AUC of 0.82 on weighted average in five external validation datasets. Overall, our study successfully established a novel metabolism-based scoring system for AD diagnosis using blood transcriptome, and provided new insight into the molecular mechanism of metabolic dysfunction implicated in AD.

Beyond plasma glucose-lowering in patients with type 2 diabetes, sodium- glucose cotransporter 2 inhibitors (SGLT2i) significantly reduced the hospitalization for heart failure (HF) and retarded the progression of chronic kidney disease (CKD). Endothelial dysfunction is not only involved in the development and progression of cardiovascular disease (CVD), and is also associated with the progression of CKD. In patients with type 2 diabetes, hyperglycemia, insulin resistance, hyperinsulinemia and dyslipidemia induce the development of endothelial dysfunction. SGLT2i have shown an improvement in endothelial dysfunction, as assessed by flow-mediated vasodila-tion, in individuals at high risk for CVD. Along with an improvement of endothelial dysfunction, SGLT2i showed improvements in oxidative stress, inflammation, mitochondrial dysfunction, glucotoxicity such as advanced glycation end products signaling and nitric oxide bioavailability. The improvements in endothelial dysfunc-tion and such endothelium-derived factors may play an important role in preventing the development of coronary artery disease, coronary microvascular dysfunction and diabetic cardiomyopathy which cause HF and in retarding CKD. The suppression of the development of HF and the progression of CKD achieved by SGLT2i might have been largely induced by the improvement of vascular endothelial function by SGLT2i.

Newcastle disease (ND) is a highly contagious and usually causes severe illness that affects Aves all over the world, including domestic poultry. Depending on the virus's virulence, it can impact the nervous, respiratory, and digestive systems and causes up to 100% mortality. The chIFITM genes are activated in response to viral infection. The current study was conducted to quantify the mRNA of chIFITM genes in vitro in response to ND viral infection. It also examined its ability to inhibit ND virus replication in Chicken Embryo Fibroblast (CEF) cells of Aseel and Kadaknath breeds. Results from the study showed that the expression of all chIFITM genes was significantly upregulated throughout the period in the infected CEF cells of both breeds compared to uninfected CEF cells. In CEF cells of the Kadaknath breed, elevated levels of expression of the chIFITM3 gene dramatically reduced the ND viral growth and the viral load was 60% lower than in CEF cells of the Aseel breed. The expression level of the chIFITMs in Kadaknath ranged from 2.39 to 11.68 log2 folds higher than that of control CEFs, and was consistently (p<0.01) higher than Aseel CEFs. Similar to this, IFN-γ gene expresses strongly quickly and peaks at 13.9 log2 fold at 48 hpi. The result suggests that the Kadaknath chicken breed may have a higher level of disease tolerance compared to the Aseel chicken.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) have been linked to changes in amino acid (ΑΑ) levels. The current observational study sought to investigate the relationship between plasma AA concentrations in a NAFLD population and MRI parameters reflecting inflammation and fibrosis, inflammatory and oxidative stress markers, and disease-related anthropometric and biochemical indicators. Approach & Results: Plasma AA levels were quantified with liquid chromatography in 97 NAFLD patients from the MAST4HEALTH study. Medical, anthropometric and lifestyle characteristics were collected and biochemical parameters, as well as inflammatory and oxidative stress biomarkers were measured. In total, males and subjects with higher MRI-proton density fat fraction (MRI-PDFF) exhibited higher plasma AA levels compared to females and subjects with lower PDFF respectively. Several associations of AAs with disease related markers were revealed, with the more prominent ones being those of aromatic amino acids with log-PDFF (beta: 1.190E-02, p-Value: 0.001) and log-ALT (beta: 7.55E-03, p-Value: 0.001), of branched amino acids with log-insulin (beta: 1.97E-03, p-Value: 1.16E-04) and of ethanolamine (beta: 0.036, p-Value: 3.65E-04) and L-ornithine (beta: 5.4E-04, p-Value: 0.021) with log-total antioxidant status (TAS). Conclusions: Plasma AA levels varied according to sex, BMI, and several MRI clinical factors. Furthermore, significant relationships were demonstrated between AA and several disease indicators, such as MRI parameters, biochemical and oxidative stress indices, showing the potential utility of AAs as diagnostic dis-ease-related indicators activity.

Dietary iron assimilation is critical for health and essential to prevent iron deficient states and related comorbidities, such as anemia. The bioavailability of iron is limited, while its absorption and metabolism are tightly controlled to keep body iron stores within a relatively narrow range. Genetic inactivation of the iron hormone hepcidin causes hereditary hemochromatosis, an endocrine disorder of iron overload characterized by chronic hyperabsorption of dietary iron, with deleterious clinical complications if untreated. The impact of high dietary iron intake and elevated body iron stores in the general population is not well understood. Herein, we summarize epidemiological data suggesting that high intake of heme iron, which is abundant in meat products, poses a risk factor for metabolic syndrome pathologies, cardiovascular diseases, and some cancers. We discuss clinical relevance and potential limitations of data from cohort studies, as well as the need to establish causality and elucidate molecular mechanisms.

The present study examined mechanisms underlying memory deficits in patients with Parkinson disease (PD)and their associations with structural metrics. Nineteen PD and 22 matched controls underwent two memory experiments. In experiment 1 (delayed memory task), subjects were asked to remember an array of colored rectangles with varying memory set sizes [Low-Load (2 items), Low-Load with Distractor, &amp; High-Load (5 items)]. After a 7s delay period, they reported whether the orientation of any relevant figures had changed (test period). In experiment 2 (working memory task), memory arrays were presented in varying set sizes (2 to 6 items) with no distractors that were followed by a 2s delay period and subsequent test period. Brain MRI data were acquired to assess structural differences (volumes and cortical thickness) in brain areas related to attention, working memory storage, and episodic memory. Compared to controls, PD patients had lower memory capacity scores in all memory load conditions for experiment 1 (p &lt;0.021) whereas there were no group differences in any memory load conditions for experiment 2 (p&gt;0.06). In addition, PD patients had lower thickness in the left superior temporal gyrus (p=0.02). Lower thickness values in the left superior temporal gyrus were significant predictors of lower delayed memory performance in Low-Load and Low-Load with Distractor conditions (ps’&lt;0.044) and working memory performance of memory load conditions of 4 and 5 items (p’s&lt;0.012). The present findings suggest that PD patients may have intact working memory storage capacity but impaired attentional filtering and memory consolidation that may lead to lower delayed memory scores. Lower delayed memory in PD may partly be associated with lower cortical thickness in the left superior temporal gyrus.

In recent years, new therapies have been developed based on molecules that target mo-lecular mechanisms involved in both the initiation and maintenance of the oncogenic process. Among these molecules are the poly (ADP-ribose) polymerase 1 (PARP1) inhibitors. PARP1 has emerged as a target with great therapeutic potential for some tumor types, drawing attention to this enzyme and resulting in many small molecule inhibitors of its enzymatic activity. Thus, many PARP inhibitors are currently in clinical trials for the treatment of homologous recombina-tion (HR)-deficient tumors, BRCA-related cancers, taking advantage of synthetic lethality. In ad-dition, several novel cellular functions unrelated to its role in DNA repair have been described, including post-translational modification of transcription factors, or acting through pro-tein-protein interactions as a co-activator or co-repressor of transcription. Previously, we report-ed that this enzyme may play a key role as a transcriptional co-activator of an important compo-nent of cell cycle regulation, the transcription factor E2F1. Here, we show that PARP inhibitors, which interfere with its activity in cell cycle regulation, do so without affecting its enzymatic function.

The emergence of pathogenic fungi is a major and rapidly growing problem (7% increase) that affects human and animal health, ecosystems, food security and the economy worldwide. The Dermocystida group in particular has emerged relatively recently and includes species that affect both humans and animals. Within this group, one species in particular, Sphareothecum destruens, also known as the Rosette agent, represents a major risk to global aquatic biodiversity and aquaculture and has caused severe declines in wild fish populations in Europe and large losses in salmon farms in the USA. It is a species that has been associated with a healthy carrier for millions of years but the host has managed in recent decades to invade parts of Southeast Asia, Central Asia, Europe and North Africa. In order to better understand the emergence of this new disease, we have for the first time synthesised current knowledge on the distribution, detection, prevalence of S. destruens as well as the associated mortality curves, and the potential economic impact in countries where the healthy carrier has been introduced. Finally, we propose solutions and perspectives to manage and mitigate the emergence of this fungus in countries where it has been introduced.

Abstract. Marek's disease virus is an oncogenic avian herpesvirus and the problem of oncogenicity of this virus for humans remains unexplored. This pathology appeared in broiler chickens of 30 days and older, that is from now on the contact with poultry meat carries the risk of infecting people. This article analyzes the risks of the emergence of the epidemic potential of the Marek's disease virus in the Russian Federation taking into account the characteristics of modern pig and poultry farming. It was found that COVID 19 can serve as an additional factor in reducing the resistance of the population to herpesvirus infections. The COVID 19 epidemic is accompanied by folic acid deficiency which also increases the risk of contamination of diseases associated with DNA viruses, including an extended risk of animal viruse infection. Since, according to our estimates, Marek's disease occurred in at least 25% of broiler poultry farms in the Russian Federation, a possible expand in mortality from neoplasms of the reproductive system for the Russian Federation as a whole can contribute to the dynamics of oncological diseases of reproductive organs and breast cancer. Since 2011 a contagious form of intestinal pathology, vesicular enteritis, has widely spread at poultry farms in the Russian Federation. During periods of extending incidence of vesicular enteritis, we recorded cases of inflammation of the facial nerves and subfebrile temperature in contact persons, bursts of oncological diseases in veterinary personnel (ovarian cancer, breast cancer), abnormal and synchronous increases in the incidence of infectious larengotracheitis and Marek's disease in chickens under the age of 40 days which requires additional monitoring studies.

Chagas disease (CD) is one of the most devasting parasitic diseases in the Americas affecting 7 to 8 million people worldwide. In vitro and in vivo experiments have demonstrated that decreased growth hormone (GH) serum levels occur as CD progresses. Interestingly, inactivating mutations in the GH receptor in humans induce Laron syndrome (LS), a clinical entity characterized by increased GH and decreased insulin growth factor-1 (IGF-1) serum levels. The largest cohort of LS subjects lives in the southern provinces of Ecuador. Remarkably, CD prevalence in these individuals is diminished despite living in highly endemic areas. In the current ex vivo study, we employed serum from GHR -/- mice, also known as LS mice (a model of GH resistance with high GH and low IGF-1 levels), and serum from bovine GH (bGH) transgenic mice (high GH and IGF-1), to test the effect on T. cruzi infection. We infected mouse fibroblast L-cells treated with serum from each type of mouse with metacyclic trypomastigotes from Trypanosoma cruzi (etiological CD infectious agent). Treatment with GHR-/- serum (LS mice) significantly decreased infection by 28% compared to 48% seen in control wild-type mouse serum (WT). Treatment with bGH mouse serum significantly decreased infection by only 41% compared to 54% from WT controls. Our results suggest that high GH and low IGF-1 in blood circulation, as typically seen in LS individuals, confers partial protection against T. cruzi infection.

Marek’s Disease (MD) has a significant impact on both the global poultry economy and animal welfare. The disease pathology can include neurological damage and tumour formation. Sexual dimorphism in immunity and known higher susceptibility of females to MD makes the chicken Z chromosome (GGZ) a particularly attractive target to study the chicken MD response. Previously, we used a Hy-Line F6 population from a full-sib advanced intercross line to map MD QTL regions (QTLRs) on all chicken autosomes. Here we mapped MD QTLRs on GGZ in the previously utilized F6 population with individual genotypes and phenotypes, and in eight elite commercial egg production lines with daughter-tested sires and selective DNA pooling (SDP). Four MD QTLRs were found from each analysis. Some of these QTLRs overlap regions from previous reports. All QTLRs were tested by indiviuals from the same eight lines used in the SDP and genotyped with markers located within and around the QTLRs. All QTLRs were confirmed. The results exemplify the complexity of MD resistance in chickens and the complex distribution of P-values and LD pattern and their effect on localization of the causative elements. Considering the fragments and interdigitated LD blocks while using LD to aid localization of causative elements, one must look beyond the insignificant markers, for possible distant markers and blocks in high LD with the significant block. The QTLRs found here may explain at least part of the gender differences in MD tolerance, and provide targets for mitigating the effects of MD.

Fabry disease is a lysosomal storage disorder caused by the deficiency of the α-galactosidase-A enzyme. Cardiac, renal, and neurological involvement significantly reduces life expectancy. Until a few years ago, treatment options for Fabry disease were limited to enzyme replacement therapy with agalsidase alfa or beta administered by intravenous infusion every 2 weeks. Migalastat (Galafold®) is an oral pharmacological chaperone that increases enzyme activity of “amenable” mutations. The safety and efficacy of migalastat were supported in the phase III FACETS and ATTRACT studies, compared to available enzyme replacement therapies; showing a reduction in left ventricular mass, and stabilization of kidney function and plasma Lyso-Gb3. Similar results were confirmed in subsequent extension publications, both in patients who started migalastat as their first treatment and in patients who were previously on enzyme replacement therapy and switched to migalastat. In this review we describe the safety and efficacy of switching from enzyme replacement therapy to migalastat in patients with Fabry disease and “amenable” mutations, referring to publications available to date.