Diseases, Volume 8, Issue 2 (June 2020) – 17 articles

Proper folding to attain a defined three-dimensional structure is a prerequisite for the functionality of a protein. Improper folding that eventually leads to formation of protein aggregates is a hallmark of several neurodegenerative disorders. Loss of protein homeostasis triggered by cellular stress conditions is a major contributing factor for the formation of these toxic aggregates. A conserved class of proteins called chaperones and co-chaperones is implicated in maintaining the cellular protein homeostasis. Expanding the body of evidence highlights the role of chaperones as central mediators in the formation, de-aggregation and degradation of the aggregates. Altered expression and function of chaperones is associated with many neurodegenerative diseases including Parkinson’s disease. Several studies indicate that chaperones are at the center of the cause and effect cycle of this disease. An overview of the various chaperones that are associated with homeostasis of Parkinson’s disease-related proteins and their role in pathogenicity will be discussed in this review. Full article

Depression and obesity are very common pathologies. Both cause significant problems of both morbidity and mortality and have decisive impacts not only on the health and well-being of patients, but also on socioeconomic and health expenditure aspects. Many epidemiological studies, clinical studies and meta-analyses support the association between mood disorders and obesity in relationships to different conditions such as the severity of depression, the severity of obesity, gender, socioeconomic status, genetic susceptibility, environmental influences and adverse experiences of childhood. Currently, both depression and obesity are considered pathologies with a high-inflammatory impact; it is believed that several overlapping factors, such as the activation of the cortico-adrenal axis, the exaggerated and prolonged response of the innate immune system and proinflammatory cytokines to stress factors and pathogens—as well as alterations of the intestinal microbiota which promote intestinal permeability—can favor the expression of an increasingly proinflammatory phenotype that can be considered a key and common phenomenon between these two widespread pathologies. The purpose of this literature review is to evaluate the common and interacting mechanisms between depression and obesity. Full article

Pulmonary arterial hypertension (PAH) is a devastating disease with significant morbidity and mortality. There are many psychosocial and financial implications of this disease; however, little is known how this affects the treatment of PAH patients. A questionnaire-based prospective cohort study was performed on 106 PAH patients from a Pulmonary Hypertension Center and the Pulmonary Hypertension Association national conference in 2018. The demographic, treatment, psychosocial, employment, financial impact on treatment data was obtained. The majority of patients had cardiopulmonary symptoms despite treatment. The symptoms affected their social and work lives, with about one in three applying for disability because of their PAH. The majority of PAH patients had insurance coverage, but still noted a significant financial burden of the disease, with nearly a half who needed financial assistance to pay for their PAH medications. Thirty (28.3%; 95% CI, 20.6–37.5%) patients mentioned they changed their medication regimen, with some skipping doses outright (28 [26.4%; 95% CI, 19–35.6%]) in order to save money. PAH continues to cause significant psychosocial and financial burden on patients despite advances in medications. This impact ranged from dissatisfaction with quality of life, to unemployment, to altering their medication regimen to save money. Full article

Background & Aims: The pathogenesis of primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) remains unclear. The aim of this study was to reveal certain single nucleotide polymorphisms (SNP) in genes for regulatory proteins in the immunologic pathway possibly going along with susceptibility of attaining PBC or PSC. Methods: 126 patients with either PBC or PSC with clinical and laboratory data were enrolled in the study. SNPs in three genes (CTLA-4, ICOS, and FOX-P3) which are suspected to play a key role in the autoimmune pathway were analyzed to determine allele variants. Gene expression was measured by RealTime PCR using mRNA. Results: Patients with cirrhosis had a lower number of CTLA-4 copies than patients without cirrhosis (p = 0.04). Accordingly, patients with lower CTLA-4 copies had a poorer recovery of gamma-glutamyltransferase (GGT) in course of their disease (−69.8 U/l vs. −176.1 U/l p = 0.04). Two SNP allele variants (CTLA4 rs733618 and FOXP3 rs2280883) associated with low CTLA-4 expression could be determined. Patients having both variants showed worsening of GGT (−61.7 U/l vs. −132.6 U/l, p = 0.04) and a trend towards a more progressive disease in terms of cirrhosis. (24% vs. 13% p = ns). Conclusions: Low expression of CTLA-4 is associated with a more advanced disease in patients with PBC and PSC. Furthermore, we identified two SNP allele variants (CTLA4-SNP rs733618 and FOXP3-SNP rs2280883) associated with a lower CTLA-4 expression and possibly a more severe course of the diseases. Taken together, these results provide further evidence for the involvement of the immune system in the pathogenesis of these two cholestatic liver diseases. Lay summary: Primary biliary cholangitis and primary sclerosing cholangitis are chronic diseases of the bile ducts. Their cause remains widely unclear, but evidence suggests the immune system plays a central role. This study shows that gene alterations connected to the immune system might play a role in the course of the disease. Full article

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by the progressive destruction of the intrahepatic bile ducts. Currently, the first line drug for PBC is ursodeoxycholic acid (UDCA) characterized by anti-apoptotic, anti-inflammatory and protective actions on cholangiocytes. Despite its recognized therapeutic action, 30–40% of PBC patients only partially benefit from UDCA therapy. This has led to the identification of the role of the farnesoid x receptor (FXR) in cholestatic liver diseases and, consequently, to the development of obeticholic acid (OCA), a steroid FXR agonist that has been recently approved for the treatment of PBC. OCA though is not effective in all patients and can cause itch, which eventually induces treatment drop out. Therefore, the search for new therapeutic strategies for PBC has begun. This review, in addition to summarizing the current treatments for PBC, provides overview of the chemical characteristics of new steroid FXR agonist candidates that could represent a future perspective for the treatment of PBC. Full article

Pathogenic variants in the MT-ATP6 are a well-known cause for maternally inherited mitochondrial disorders associated with a wide range of clinical phenotypes. Here, we present a 31- year old female with insulin-dependent diabetes mellitus, recurrent lactic acidosis and ketoacidosis recurrent infections with suspected immunodeficiency with T cell lymphopenia and hypogammaglobulinemia as well as proximal tetraparesis with severe muscle and limb pain and rapid physical exhaustion. Muscle biopsy and respiratory chain activities were normal. Single-exome sequencing revealed a variant in the MT-ATP6 gene: m.9143T>C. Analysis of further specimen of the index and mother (segregation studies) revealed the highest mutation load in muscle (99% level of mtDNA heteroplasmy) of the index patient. Interestingly, acute metabolic and physical decompensation during recurrent illness was documented to be a common clinical feature in patients with MT-ATP6 variants. However, it was not mentioned as a key symptom. Thus, we suggest that the clinical spectrum might be expanded in ATP6-associated diseases. Full article

The prevalence of dementia has substantially increased worldwide. Currently, there is no cure for dementia or Alzheimer’s disease (AD), and care for affected patients is financially and psychologically costly. Of late, more attention has been given to preventive interventions—in particular, physical activity/exercise. In this review, examine the risk factors associated with AD and the effects physical activity may play in the prevention of the degenerative process of this disease, loss of memory and cognitive performance in the elderly. To date, research has shown that physical activity, especially aerobic exercise, has a protective effect on cognitive function and memory in the elderly and Alzheimer’s patients. In comparison with aerobic exercise, several strength training studies have also shown positive effects, and the rare studies that compare the two different modalities show no difference. Full article

Urinary tract infections (UTIs) are among the most common infections requiring medical attention worldwide. The production of biofilms is an important step in UTIs, not only from a mechanistic point of view, but this may also confer additional resistance, distinct from other aspects of multidrug resistance (MDR). A total of two hundred and fifty (n = 250) Escherichia coli isolates, originating from clean-catch urine samples, were included in this study. The isolates were classified into five groups: wild-type, ciprofloxacin-resistant, fosfomycin-resistant, trimethoprim-sulfamethoxazole-resistant and extended spectrum β-lactamase (ESBL)-producing strains. The bacterial specimens were cultured using eosine methylene blue agar and the colony morphology of isolates were recorded. Antimicrobial susceptibility testing was performed using the Kirby–Bauer disk diffusion method and E-tests. Biofilm-formation of the isolates was carried out with the crystal violet tube-adherence method. n = 76 isolates (30.4%) produced large colonies (>3 mm), mucoid variant colonies were produced in n = 135 cases (54.0%), and n = 119 (47.6%) were positive for biofilm formation. The agreement (i.e., predictive value) of mucoid variant colonies in regard to biofilm production in the tube-adherence assay was 0.881 overall. Significant variation was seen in the case of the group of ESBL-producers in the ratio of biofilm-producing isolates. The relationship between biofilm-production and other resistance determinants has been extensively studied. However, no definite conclusion can be reached from the currently available data. Full article

Growth Differentiation Factor-15 (GDF-15) is a strong predictor of decreased myocardial salvage and subsequent higher risk of death in patients with STEMI, but no information has been published regarding the association of GDF-15 levels with coronary blood flow in STEMI. We hypothesized that elevated GDF-15 levels would be associated with impaired flow and perfusion in the setting of STEMI treated with primary PCI. Eighty consecutive patients who were admitted with STEMI within 6 h from symptom onset were enrolled in the study. Patients were divided into two groups based upon the Thrombolysis in Myocardial Infarction (TIMI) flow grade. Group 1 was defined as TIMI Grade 0, 1 and 2 flows. Angiographic success was defined as TIMI 3 flow (group 2). GDF-15 and high sensitive CRP were measured. Major adverse cardiac events (MACE) were defined as stent thrombosis, nonfatal myocardial infarction and in-hospital mortality. There were 35 patients (mean age 64 ± 11.8 and 20% female) in group 1 and 45 patients (mean age 66.8 ± 11.5 and 29% female) in group 2. GDF-15 and hs-CRP levels were significantly higher in group 1 than in group 2 (1670 ± 831pg/mL vs. 733 ± 124 pg/mL, p < 0.001; and 19.8 ± 10.6 vs. 11.3 ± 4.9, p < 0.001). GDF-15 level ≥920 pg/mL measured on admission had a 94% sensitivity and 91% specificity in predicting no-reflow at ROC curve analysis. In-hospital MACE was also significantly higher in group 1 (28.6% vs. 2.2%, p: 0.001). Additionally, there was a significant correlation between hs-CRP and GDF-15 (r: 0.6030.56; p < 0.001). The GDF-15 level on admission is a strong and independent predictor of poor coronary blood flow following primary PCI and in hospital MACE among patients with STEMI. Except for predictive value, GDF-15 levels may be a useful biomarker for the stratification of risk in patients with STEMI, and may carry further therapeutic implications. Full article

Malaria remains the biggest threat to public health, especially among pregnant women and young children in sub-Saharan Africa. Prompt and accurate diagnosis is critical for effective case management and detection of drug resistance. Conventionally, microscopy and rapid diagnostic tests (RDTs) are the tools of choice for malaria diagnosis. RDTs are simple to use and have been extensively used in the diagnosis of malaria among travelers to malaria-endemic regions, routine case management, and surveillance studies. Most RDTs target the histidine-rich protein (PfHRP) which is exclusively found in Plasmodium falciparum and a metabolic enzyme Plasmodium lactate dehydrogenase (pLDH) which is common among all Plasmodium species. Other RDTs incorporate the enzyme aldolase that is produced by all Plasmodium species. Recently, studies have reported false-negative RDTs primarily due to the deletion of the histidine-rich protein (pfhrp2 and pfhrp3) genes in field isolates of P. falciparum. Herein, we review published literature to establish pfhrp2/pfhrp3 deletions, the extent of these deletions in different geographical regions, and the implication in malaria control. We searched for publications on pfhrp2/pfhrp3 deletions and retrieved all publications that reported on this subject. Overall, 20 publications reported on pfhrp2/pfhrp3 deletions, and most of these studies were done in Central and South America, with very few in Asia and Africa. The few studies in Africa that reported on the occurrence of pfhrp2/pfhrp3 deletions rarely evaluated deletions on the flanking genes. More studies are required to evaluate the existence and extent of these gene deletions, whose presence may lead to delayed or missed treatment. This information will guide appropriate diagnostic approaches in the respective areas. Full article

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of oral hypoglycemic agents which increase urinary glucose excretion by suppressing glucose reabsorption at the proximal tubule in the kidney. SGLT2 inhibitors lower glycated hemoglobin (HbA1c) by 0.6–0.8% (6–8 mmol/mol) without increasing the risk of hypoglycemia and induce weight loss and improve various metabolic parameters including blood pressure, lipid profile and hyperuricemia. Recent cardiovascular (CV) outcome trials have shown the improvement of CV and renal outcomes by treatment with the SGLT2 inhibitors, empagliflozin, canagliflozin, and dapagliflozin. The mechanisms by which SGLT2 inhibitors improve CV outcome appear not to be glucose-lowering or anti-atherosclerotic effects, but rather hemodynamic effects through osmotic diuresis and natriuresis. Generally, SGLT2 inhibitors are well-tolerated, but their adverse effects include genitourinary tract infection and dehydration. Euglycemic diabetic ketoacidosis is a rare but severe adverse event for which patients under SGLT2 inhibitor treatment should be carefully monitored. The possibility of an increase in risk of lower-extremity amputation and bone fracture has also been reported with canagliflozin. Clinical trials and real-world data have suggested that SGLT2 inhibitors improve CV and renal outcomes and mortality in patients with type 2 diabetes (T2DM), especially in those with prior CV events, heart failure, or chronic kidney disease. Results of recent trials including individuals without diabetes may change the positioning of this drug as ″a drug for cardiorenal protection″. This review summarizes the potential of SGLT2 inhibitors and discusses their role in the treatment of T2DM. Full article

Crohn’s Disease (CD) and Ulcerative Colitis (UC) are world-wide health problems in which intestinal dysbiosis or adverse functional changes in the microbiome are causative or exacerbating factors. The reduced abundance and diversity of the microbiome may be a result of a lack of exposure to vital commensal microbes or overexposure to competitive pathobionts during early life. Alternatively, many commensal bacteria may not find a suitable intestinal niche or fail to proliferate or function in a protective/competitive manner if they do colonize. Bacteria express a range of factors, such as fimbriae, flagella, and secretory compounds that enable them to attach to the gut, modulate metabolism, and outcompete other species. However, the host also releases factors, such as secretory IgA, antimicrobial factors, hormones, and mucins, which can prevent or regulate bacterial interactions with the gut or disable the bacterium. The delicate balance between these competing host and bacteria factors dictates whether a bacterium can colonize, proliferate or function in the intestine. Impaired functioning of NOD2 in Paneth cells and disrupted colonic mucus production are exacerbating features of CD and UC, respectively, that contribute to dysbiosis. This review evaluates the roles of these and other the host, bacterial and environmental factors in inflammatory bowel diseases. Full article

Background: Parkinson′s disease (PD) is the second most prevalent neurodegenerative disease in older individuals. Neurorehabilitation-based interventions such as those improving gait are crucial for a holistic approach and to limit falls. Several studies have recently shown that mechanical plantar foot stimulation is a beneficial intervention for improving gait impairment in PD patients. The objective of this scoping review is to evaluate the beneficial effects of this stimulation on gait parameters, and to analyse protocols of foot stimulation and other effects in non-motor symptoms. Relevant articles were searched in the Medline database using Pubmed and Scopus, using the primary search terms ‘foot stimulation’ OR ‘plantar stimulation’ AND ‘Parkinson’s disease*’. Several protocols have been used for mechanical plantar foot stimulation (ranging from medical devices to textured insoles). The gait parameters that have been shown to be improved are stride length and walking speed. The beneficial effects are achieved after both acute and repeated plantar foot stimulation. Beneficial effects are observed in other organs and systems, such as muscle activation, brain connectivity, cardiovascular control in the central nervous system, and the release of brain-derived neurotrophic factor and cortisol in blood added evidence about this intervention’s impact on brain function. Mechanical plantar foot stimulation is a safe and effective add-on treatment able for improving gait impairments in PD patients during the L-dopa off state. Randomized and controlled clinical trials to study its eventual potentiating effect with different pharmacotherapy regimens are warranted. Full article

Antibiotic resistance is increasing to an extent where efficacy is not guaranteed when treating infection. Biofilm formation has been shown to complicate treatment, whereby the formation of biofilm is associated with higher minimum inhibitory concentration values of antibiotic. The objective of the current paper was to determine whether biofilm formation is variable among uropathogenic Escherichia coli isolates and whether formation is associated with recurrent urinary tract infection (UTI), and whether it can be predicted by phenotypic appearance on culture medium A total of 62 E. coli isolates that were reported as the causative agent of UTI were studied (33 from patients denoted as having recurrent UTI and 29 from patients not specified as having recurrent UTI). The biofilm forming capability was determined using a standard microtitre plate method, using E. coli ATCC 25922 as the positive control. The majority of isolates (93.6%) were found to be biofilm formers, whereby 81% were denoted as strong or very strong producers of biofilm when compared to the positive control. Through the use of a Wilcox test, the difference in biofilm forming propensity between the two patient populations was found to not be statistically significant (p = 0.5). Furthermore, it was noted that colony morphology was not a reliable predictor of biofilm-forming propensity. The findings of this study indicate that biofilm formation is very common among uropathogens, and they suggest that the biofilm-forming capability might be considered when treating UTI. Clinical details indicating a recurrent infection were not predictors of biofilm formation. Full article

Hepatitis B virus (HBV) infection is the most common form of viral hepatitis and remains a global public health problem, even though the HBV vaccine is available. HBV leads to chronic liver disease, including cirrhosis, liver cancer, and death. This study aimed to identify disparities in HBV vaccine coverage with the serological test by race/ethnicity, adjusting for gender and age. In this study, 5735 adult participants were included, obtaining data from the National Health and Nutrition Examination Survey (NHANES), 2015–2016. Proc survey frequency, bivariate- and multivariate logistic regression in the weighted sample were performed due to the complex survey design of NHANES. Data were analyzed using SAS, version 9.2.4. The overall prevalence of HBV vaccine coverage was only 23.3% (95% CI: 20.7%, 25.9%). In a multivariate logistic regression model, data showed that Mexican Americans (OR 0.57, 95% CI: 0.38, 0.86) and African Americans (OR 0.70, 95% CI 0.56, 0.84) had lower vaccine coverage compared to Whites. Females had (OR 1.55, 95% CI: 1.30, 1.85) higher vaccine coverage compared to men. Older age groups (30–49 years) (OR 0.41, 95% CI: 0.32, 0.52) and age group ≥ 50 years (OR 0.18, 95% CI 0.14, 0.23) had lower vaccine coverage compared to younger adults aged 18–29 years. Full article

Fecal Microbiota Transplantation (FMT) is suggested as an efficacious therapeutic strategy for restoring intestinal microbial balance, and thus for treating disease associated with alteration of gut microbiota. FMT consists of the administration of fresh or frozen fecal microorganisms from a healthy donor into the intestinal tract of diseased patients. At this time, in according to healthcare authorities, FMT is mainly used to treat recurrent Clostridium difficile. Despite the existence of a few existing stool banks worldwide and many studies of the FMT, there is no standard method for producing material for FMT, and there are a multitude of factors that can vary between the institutions. The main constraints for the therapeutic uses of FMT are safety concerns and acceptability. Technical and logistical issues arise when establishing such a non-standardized treatment into clinical practice with safety and proper governance. In this context, our manuscript describes a process of donor safety screening for FMT compiling clinical and biological examinations, questionnaires and interviews of donors. The potential risk of transmission of SARS-CoV-2 virus by the use of fecal microbiota for transplantation must be taken urgently into consideration. We discuss a standardized procedure of collection, preparation and cryopreservation of fecal samples through to the administration of material to patients, and explore the risks and limits of this method of FMT. The future success of medicine employing microbiota transplantation will be tightly related to its modulation and manipulation to combat dysbiosis. To achieve this goal, standard and strict methods need to be established before performing any type of FMT. Full article

Weight cycling (WC) is a common phenomenon in patients with obesity, however, its consequence on body composition has not yet been fully understood. Therefore, we aimed to determine whether multiple WC can negatively affect the latter, especially in terms of body fat distribution in female adults seeking treatment that are overweight or obese. Body composition was obtained using a segmental body composition analyser (MC-780MA, Tanita Corp., Tokyo, Japan) in 125 adult females who had been referred to the Department of Nutrition and Dietetics at the Beirut Arab University (Lebanon). WC was defined as intentional weight loss of ≥3 kg followed by involuntary weight regain of ≥3 kg, and participants were categorized as WC if they had experienced ≥2 cycles. Ninety of the 125 participants met the criteria for WC and displayed a higher total and trunk fat mass than those without WC. This was confirmed through linear regression analysis, showing that multiple WC were associated with increased fat mass (FM) by nearly 4.2 kg (β = 4.23, 95%CI: 0.81–7.65, p = 0.016)–2.4 kg in the trunk region (β = 2.35, 95%CI: 0.786–3.917, p = 0.004) when compared to the non-WC group, after adjusting for age and fat-free mass. In conclusion, multiple WC is associated with increased body fat, especially in the central region. Future studies are needed to examine the impact of this fat distribution on health outcomes in this phenotype of patients. Full article