The Role of GLP1-RAs in Direct Modulation of Lipid Metabolism in Hepatic Tissue as Determined Using In Vitro Models of NAFLD.

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have been shown to improve glucose and lipid homeostasis, promote weight loss, and reduce cardiovascular risk factors. They are a promising therapeutic option for non-alcoholic fatty liver disease (NAFLD), the most common liver disease, associated with T2DM, obesity, and metabolic syndrome. GLP-1RAs have been approved for the treatment of T2DM and obesity, but not for NAFLD. Most recent clinical trials have suggested the importance of early pharmacologic intervention with GLP-1RAs in alleviating and limiting NAFLD, as well as highlighting the relative scarcity of in vitro studies on semaglutide, indicating the need for further research. However, extra-hepatic factors contribute to the GLP-1RA results of in vivo studies. Cell culture models of NAFLD can be helpful in eliminating extrahepatic effects on the alleviation of hepatic steatosis, modulation of lipid metabolism pathways, reduction of inflammation, and prevention of the progression of NAFLD to severe hepatic conditions. In this review article, we discuss the role of GLP-1 and GLP-1RA in the treatment of NAFLD using human hepatocyte models.

Mechanistic-Based Classification of Endocytosis-Related Inhibitors: Does It Aid in Assigning Drugs against SARS-CoV-2?

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) canonically utilizes clathrin-mediated endocytosis (CME) and several other endocytic mechanisms to invade airway epithelial cells. Endocytic inhibitors, particularly those targeting CME-related proteins, have been identified as promising antiviral drugs. Currently, these inhibitors are ambiguously classified as chemical, pharmaceutical, or natural inhibitors. However, their varying mechanisms may suggest a more realistic classification system. Herein, we present a new mechanistic-based classification of endocytosis inhibitors, in which they are segregated among four distinct classes including: (i) inhibitors that disrupt endocytosis-related protein-protein interactions, and assembly or dissociation of complexes; (ii) inhibitors of large dynamin GTPase and/or kinase/phosphatase activities associated with endocytosis; (iii) inhibitors that modulate the structure of subcellular components, especially the plasma membrane, and actin; and (iv) inhibitors that cause physiological or metabolic alterations in the endocytosis niche. Excluding antiviral drugs designed to halt SARS-CoV-2 replication, other drugs, either FDA-approved or suggested through basic research, could be systematically assigned to one of these classes. We observed that many anti-SARS-CoV-2 drugs could be included either in class III or IV as they interfere with the structural or physiological integrity of subcellular components, respectively. This perspective may contribute to our understanding of the relative efficacy of endocytosis-related inhibitors and support the optimization of their individual or combined antiviral potential against SARS-CoV-2. However, their selectivity, combined effects, and possible interactions with non-endocytic cellular targets need more clarification.

Future Prospects, Approaches, and the Government's Role in the Development of a Hepatitis C Virus Vaccine.

Developing a safe and effective vaccine against the hepatitis C virus (HCV) remains a top priority for global health. Despite recent advances in antiviral therapies, the high cost and limited accessibility of these treatments impede their widespread application, particularly in resource-limited settings. Therefore, the development of the HCV vaccine remains a necessity. This review article analyzes the current technologies, future prospects, strategies, HCV genomic targets, and the governmental role in HCV vaccine development. We discuss the current epidemiological landscape of HCV infection and the potential of HCV structural and non-structural protein antigens as vaccine targets. In addition, the involvement of government agencies and policymakers in supporting and facilitating the development of HCV vaccines is emphasized. We explore how vaccine development regulatory channels and frameworks affect research goals, funding, and public health policy. The significance of international and public-private partnerships in accelerating the development of an HCV vaccine is examined. Finally, the future directions for developing an HCV vaccine are discussed. In conclusion, the review highlights the urgent need for a preventive vaccine to fight the global HCV disease and the significance of collaborative efforts between scientists, politicians, and public health organizations to reach this important public health goal.

Targeting the Wnt Signaling Pathway in Liver Fibrosis for Drug Options: An Update.

Liver fibrosis is a life-threatening disease, with challenging morbidity and mortality for healthcare systems worldwide. It imparts an enormous economic burden to societies, making continuous research and informational updates about its pathogenesis and treatment crucial. This review's focus is on the current knowledge about the Wnt signaling pathway, serving as an important pathway in liver fibrosis development and activation of hepatic stellate cells (HSCs). Two types of Wnt pathways are distinguished, namely the ß-catenin-dependent canonical and non-canonical Ca2+ or planar cell polarity (PCP)-dependent pathway. The dynamic balance of physiologically healthy liver and hepatocytes is disturbed by repeated liver injuries. Activation of the ß-catenin Wnt pathway prevents the regeneration of hepatocytes by the replacement of extracellular matrix (ECM), leading to the appearance of scar tissue and the formation of regenerated nodular hepatocytes, lacking the original function of healthy hepatocytes. Therefore, liver function is reduced due to the severely advanced disease. Selective inhibition of ß-catenin inhibits inflammatory processes (since chemokines and pro-inflammatory cytokines are produced during Wnt activation), reduces growth of activated HSCs and reduces collagen synthesis and angiogenesis, thereby reducing the progression of liver fibrosis in vivo. While the canonical Wnt pathway is usually inactive in a physiologically healthy liver, it shows activity during cell regeneration or renewal and in certain pathophysiological conditions, such as liver diseases and cancer. Targeted blocking of some of the basic components of the Wnt pathway is a therapeutic approach. These include the frizzled transmembrane receptor (Fz) receptors using the secreted frizzled-related protein family (sFRP), Fz-coreceptors low-density LRP 5/6 through dickkopf-related protein 1 (DKK1) or niclosamide, glycogen kinase-3 beta (GSK-3ß) using SB-216763, cyclic-AMP response element-binding protein (CBP) using PRI-724 and ICG-001, the lymphoid enhancer binding factor (LEF)/T cell-specific transcription factor (TCF) system as well as Wnt inhibitory factor 1 (WIF1) and miR-17-5p using pinostilbene hydrate (PSH). Significant progress has been made in inhibiting Wnt and thus stopping the progression of liver fibrosis by diminishing key components for its action. Comprehending the role of the Wnt signaling pathway in liver fibrosis may lead to discovery of novel targets in liver fibrosis therapeutic strategies' development.

A coincidence of HLA-B27 negative spondyloarthritis and paravertebral non-Hodgkin's lymphoma--a lesson to be learnt from the past experience.

We reported a case of a 71-year-old woman with progressive low back pain and neurologic symptoms of lower extremities, who in the background had the coexistence of spondyloarthritis (SpA) and non Hodgkin's lymphoma of the paravertebral location. This example describes a situation where SpA with minimal sacroiliac joints affection has nevertheless led to the overt axial SpA. This situation included undifferentiated or reactive SpA, as well as unusual disease context, presented with late-life disease onset, older age, female gender and no obvious hereditary predisposition. This combination of comorbid factors could allow environmental and disease-specific factors to accumulate over time and to, by modifying the primary, low-penetrant genetic background, lead to the development of lymphoma. By achieving better understanding of disease pathophysiology dynamic, we will be able to improve our capabilities to navigate biologic therapy in the future, in order to prevent the development of both, overt SpA and lymphoproliferative disease.

Influence of age on the survival and mortality rate in acute caustic poisonings.

OBJECTIVE: Acute poisonings with caustic substances can cause severe chemical injuries to the upper gastrointestinal tract, which can be localized from the mouth to the small intestines. They are seen very often among young people in their most productive years. The aim of this study is to examine the influence of patient's age on the mortality rate and survival of patients with acute caustic poisonings, and also to analyze their correlation. MATERIAL AND METHODS: We studied medical records from 415 patients, aged between 14 and 90 years, who were hospitalized and treated at the University Clinic for toxicology and urgent internal medicine, Skopje, Republic of Macedonia, in the period between 2007 and 2011. RESULTS: In the survey we included 415 patients with acute corrosive poisonings, from which 295 (71.08%) were females and 120 (28. 92%) were males. 388 (93.49%) from the total number of patients ingested the corrosive agent with suicidal attempt and 27 (6.5%) ingested it accidentally. CONCLUSION: Unregulated production, import, packing and labeling of various caustic agents, due to inappropriate legislative, made them one of the most often abused substances in everyday life, especially in developing countries where the number of caustic poisonings rises.

Respiratory complications from acute corrosive poisonings in adults.

INTRODUCTION: Acute corrosive poisonings are caused by ingestion of corrosive chemicals which are most commonly used as household agents. Intoxications with these kind of agents produce numerous and severe post-corrosive complications of the upper gastrointestinal tract. On the other hand, our experience showed that corrosive agents may also cause injuries of the respiratory system, which makes the treatment very hard and additionally complicates the severe clinical condition of the patient. OBJECTIVE: The aim of the study is to show the incidence of respiratory complications in acute corrosive poisonings, the need of various clinical investigations and also the treatment and final outcome of these kind of poisoning. METHODS: We retrospectively analyzed clinical records of 415 patients hospitalized and treated at the University clinic for toxicology and urgent internal medicine, in Skopje, Republic of Macedonia, in the period between 2007 and 2011. The protocol consisted of methods for analyzing the systemic complications, with an accent on the post-corrosive respiratory complications. RESULTS: From the total number of patients even 98 (23.61%) exhibited systemic complications, from which 51 (52.04%) are respiratory complications. The majority of patients are female (n=40, 78.43%) and the most common complication is pneumonia (n=47). The youngest patient in this study was 14 and the oldest was 87 years old. CONCLUSION: Besides the gastrointestinal complications in the acute corrosive poisonings respiratory complications are also very often. They complicate the clinical state of patient and very often lead to fatal endings.

[Gout as a systemic disease: systemic manifestations and comorbidities of hyperuricaemia]. / Giht kao sustavna bolest: sistemske manifestacije i komorbiditeti u hiperuricemiji.

Gout is a recurrent inflammation of one or more joints that occurs because of disposal monosodium urate crystals in joints and other structures in soft tissues. Gout is a common metabolic disorder characterized by chronic hyperuricemia, serum urate levels > or = 360 mmol/1 (> 6.8 mg/ dl), which exceeds the physiological threshold of saturation. Well known complications of gout are tophi, deforming arthropathy, urolithiasis, chronic urate nephropathy, acute uric nephropathy (usually secondary due to chemotherapy), avascular necrosis of the femoral head. The risk of developing gout is directly linked to the development of hyperuricemia. Numerous evidence-based clinical and epidemiological study of urinary acid as an independent risk factor for developing hypertension, cardiovascular disease, chronic kidney disease, stroke and metabolic syndrome revalued the role of uric acid in human health and disease. In gout, as in other rheumatic disease, extraarticular manifestations are of utmost importance for morbidity and mortality.

Clinical characteristics of patients with spondyloarthritides and HLA-B27 positive antigen.

The aim of this study was to present our experiences in diagnosing spondyloarthritides (SpA), and to list the most common clinical features of HLA-B27 positive patients. The study included 65 HLA-B27 positive patients with confirmed diagnosis of ankylosing spondylitis (AS) and psoriatic arthritis (PsA) who were analyzed between 2009 and 2010 in Clinic of Internal Medicine in Osijek. The diagnosis of seronegative spondyloarthritides was based on the ASAS (Assessment in AS Working Group) classification criteria for axial and then supplemented with ASAS criteria for peripheral SpA and was confirmed by radiological techniques. For diagnosing the ankylosing spondylitis (AS), there have been applied the modified New York criteria. Radiological criteria for definite sacroiliitis according to the modified New York criteria is bilateral sacroiliitis, grade 2-4 (> or = 2) or unilateral sacroiliitis, grade 3-4. For diagnosing the psoriatic arthritis (PsA), there were used CASPAR diagnostic criteria. Other features of SpA are defined within the existing classification criteria. HLA-B27 antigen was determined by direct immune-fluorescence technique using flow cytometer. The average age of patients was 50.34 years, of whom 27 female (41.53%), 38 male (58.46%). Duration of illness was 15.79 years on average. With 75.38% of patients, there had been determined the diagnosis of AS; 24.62% of patients had the diagnosis of PsA. The most common clinical characteristics that patients had were: inflammatory back pain (pain Inflammation along the lumbosacral spine), peripheral arthritis, intermittent pain in the gluteus, sacroiliitis, enthesitis, uveitis, dactilitis.

[Epidemiology of spondylarthritides]. / Epidemiologija spondiloartritisa.

Epidemiologic studies on spondyloarttritides (SpA) encompass mode descriptions on disease appearance within the population, levels of disease frequency: incidence and prevalence, comorbidity, mortality, geographical distribution and clinical features, as well as risk factors for disease appearance. Ethnical, genetic, environmental performers are linked with appearance and expression of the disease. Clear distinction among SpA subgroups, especially in their early phases might not always be possible due to clinical picture overlapping, thus within the initial phase of the disease, the diagnosis of certain SpA diseases might be underestimated. SpA prevalence with various different populations varies between 0.21% up to 1.9% worldwide, and it varies between 1% up to 2% within Europe. With Eskimo population on Alaska and population of Siberia, prevalence rates appear to be from 2% up to 3.4%. SpA are rare with African and Japanese populations. Differences between ethnical groups might be explained by different criteria for selection of a target population, but with differences in HLA-B27 frequency as well. HLA-B27 subtypes distribution plays significant impact on AS prevalence with different race/ethnical groups. Challenges that aggravate the exact evaluation of the SpA diseases with the population, include comprise heterogeneity of population, lack of application feasibility of valid criteria (like testing on HLA-B27 antigen, pelvis radiography and MR), but also transition issue of certain SpA symptoms (eg. peripheral arthritis, enthesitis). Spondyloarthtritis (SpA) present a serious health, social and economical problem everywhere in the world. Uniform data for all populations are significant for making a proper picture on this disease group arduousness, and for epidemiological studies such data, because of their mutual overlapping, should be united within one single group.

Program of the university clinic of toxicology, skopje, republic of macedonia in treatment of drug addiction (buprenorfin treatment protocol).

The program of our Clinic includes, not only treatment of acute intoxication with opioids and other drugs, but also comprehends clinical investigations and treatment of the somatic complications of this population. For the first time in our country our Clinic offers to this population the alternative way of treatment with Buprenorfin. The Clinic started with this protocol on August 1, 2009. During a period of two years, the treatment with Buprenorfine has been initiated in 353 patients, of which 211 regularly attend the medical check ups. This model is used according to the national clinical guidelines and procedures for the use of buprenorfine in the treatment of opioid dependence The dose of this medicament depends on the evolution of the withdrawal symptoms. We have used the objective and subjective opioid withdrawal scale for the observation of these symptoms (OOWS ; SOWS - Handelsman et al 1987). This protocol starts with a complete clinical investigations, (i.e. where all patients undergo the inclusion and exclusion criteria with a written consent). Afterwards, the patients are hospitalized and start with a Buprenorfin teratment. After period of 7-10 days hospitalization they come to our Clinic, like outpatients for a regular controls. We have precise evidence for every patient who comes for control (e.g. medical record with all biochemical and toxicological screenings). All patients are recommended a tight cooperation with psychiatrists who are specialized to treat the problematic drug addictions.

Fulminant meningococcal sepsis in a young child--a case report.

We are presenting a case of isolated fulminant meningococcal sepsis with two and a half year old child. Initial symptoms were obscure and common to many medical conditions, but also previously described as symptoms of meningococcal sepsis. Unrecognizing the seriousness of the condition child died at home, within few hours after examination and discharge from the hospital. Autopsy and microbiological findings unquestionably proved that the child died from septic shock caused by fulminant meningococcal sepsis.

[Arthritis in paraneoplastic syndrome--a way to early cancer diagnosis? A case report]. / Artritis u sklopu paraneoplasticnog sindroma- -put do rane dijagnoze neoplazme? Prikaz bolesnika.

Paraneoplastic syndrome is defined by clinical, radiological, and biological features associated with malignant disease without direct tumor invasion. The aim of our study was to present clinical and laboratory features of six cases ofparaneoplastic arthritis, witch can help to establish early cancer diagnosis, and help to distinguish paraneoplastic arthritis from other rheumatic diseases. According to our case analysis, pareneoplastic arthritis has occurred in both sex equally, all patients were older than 45 years, in most of cases it occurred within 14 months before cancer diagnosis, usually in early stage of cancer. Clinical features of paraneoplastic arthritis were: symmetric poliarthritis, usually were affected small hand joints and knees, predominant acute onset, and rheumatic nodes weren't present. Laboratory tests showed: high inflammatory markers (C-reactive protein, and erythrocyte sedimentation level), negative rheumatoid factor, and negative anti-citrullinated protein antibody. X-ray scan did not show signs of joint destruction. Long term remission ofparaneoplastic arthritis was achieved by treatment of cancer.

[Diagnostic and therapeutic approach to pregnant women suspect on antiphospholipid syndrome]. / Dijagnosticko-terapijski pristup trudnicama suspektnim na antifosfolipidni sindrom.

Antiphospholipid syndrome includes the presence of antiphospholipid antibodies, vascular thrombosis and reproductive function disturbances. The aim was to show our diagnostic and therapeutic experiences. 62 women were included in study, 32 with primary antiphospholipd syndrome (PAPS), and 30 with secondary antiphospholipid syndrome (SAPS). 36 were pregnant and studied prospectively throughout pregnancy and six weeks after the delivery. Lupus-anticoagulant (LA) was positive in 23 patients with PAPS (71.9%), and in 10 patients with SAPS (33.3%). In SAPS group anticardiolipin antibodies (aCL) was positive in 8 patients (26.6%) compared to PAPS group with 3 aCL positive patients (9.4%). Antibeta2glycoprotein1 (antibeta2GP1) was positive in 3 patients with PAPS. Complications in previous pregnancies were in 25 cases (69.4%) spontaneous abortion, in 7 cases (19.4%) preeclampsia with intrauterine growth restriction (IUGR) in 3 patients. In 4 cases the complication was fetal death in utero. Average pregnancy lasted 37.06+/-0.707 weeks. Therapy with low dose aspirin and low-molecular-weight heparin was successful in 97.2%.

Vascular thrombosis associated with antiphospholipide syndrome.

The aim of this study was to present our diagnostic and therapeutic experience with antiphospholipide syndrome (APS) and vascular thrombosis. Ninety-nine patients with positive antiphospholipide antibodies (aPL) and vascular thrombosis were included in the study: forty patients, according to clinical classification criteria, had primary antiphospholipide syndrome (PAPS), and fifty-nine patients had secondary antiphospholipide syndrome (SAPS). In PAPS group, 82.5% of the patients were LA-positive, 37.5% of the patients were IgG aCL-positive, 27.5% of the patients were IgM aCL-positive, and 15% of the patients were IgG antibeta2GPI-positive. In SAPS group, 61% of the patients were LA-positive, 50.8% of the patients were IgG aCL-positive, and 47.5% of the patients were IgM aCL-positive. Administered therapy was low molecular weight heparin (LMWH) throughout 7 days, followed by warfarin with prothrombin time maintained between 2.0 and 3.0 INR.

Giant cell arteritis: how to diagnose?--a case report.

We present a case of 77 years old male with suspected giant cell arteritis. With anamnesis, physical examination, immunological tests, Colour Doppler ultrasonography of superficial temporal artery and finally with patohistological analysis of temporal artery biopsy, we came to right diagnosis.

Antibody profile of pregnant women with antiphospholipid syndrome and pregnancy outcome after treatment with low dose aspirin and low-weight-molecular heparin.

The aim of the research was to show our diagnostic and therapeutic experience with antiphospholipid syndrome (APS) in pregnant women. 36 pregnant women suspect on APS were included in the study: 32 with primary antiphospholipd syndrome (PAPS) and 4 with secondary antiphospholipid syndrome (SAPS). All pregnant women received low-molecular-weight-heparin (LMWH) and low dose aspirin (LDA) therapy. Control group represented 26 women with SAPS and previous bad reproductive anamnesis. Average pregnancy lasted 37.06 +/- 0.707 weeks. LMWH and LDA therapy was successful in 97.22%. Lupus anticoagulant (LA) was found to be more frequent in PAPS group (71.87%). Anticardiolipin antibodies (aCL) were found to be more frequent in SAPS (26.66%). For three patients (3.37%), PAPS was diagnosed due to a fact that they had positive antibeta2-glycoproteinl (antibeta-GP1). To make APS diagnosis, it is of great importance to search for all antiphospholipid antibodies. LMWH and low dose of acetylsalicylic acid should be the first choice therapy.

Anti-citrullinated antibodies, radiological joint damages and their correlations with disease activity score (DAS28).

Determination of anti-citrullinated peptides (anti-CCP) specificity as a predictor of joint erosive changes, correlation between their serum level and radiological damages as well as disease activity score (DAS28). A trial has been conducted on a 211 patient sample fulfilling ACR criteria for rheumatoid arthritis (RA). There was assigned anti-CCP serum level, disease activity score by the formula for DAS28(3)-CRP and assessed radiological changes degree after Steinbrocker score. In 132 patient (62.559%) the serum anti-CCP concentration was positive for RA. Specificity of the test was 100% and sensitivity 65% (Z = 0.731, p = 0.465). There is a medium intensity correlation between variables representing anti-CCP and Steinbrocker score. Pearson's coefficient was 0.479 and Spearman's rank correlation coefficient was 0.614, i.e. statistically significant (p = 0.000). There is no statistically significant correlation between variables representing anti-CCP and DAS28(3)-CRP Anti-CCP are good RA predictor and their concentration correlate with radiological damages degree.

The incidence of stroke in Baranya county (east Croatia).

The aim of this retrospective study was to provide a survey of the incidence of stroke in Baranya, Croatia, on patients examined at Beli Manastir Health Center Department of Emergency from November 1, 1997 (the time of Baranya reintegration into the legal system of the Republic of Croatia after the war) till December 31, 2001. A total of 513 patients with symptoms of cerebrovascular diseases, or one patient every third day on an average, were examined. Total incidence of stroke was 16.09 per 10,000 population. The majority of patients were in the 61-80 age group with an incidence of 46.94/10,000 after the age of 60, 15-fold that was recorded in younger age groups. The most common risk factors recorded in examined group included hypertension, heart diseases, hyperlipidemia and diabetes mellitus. Total stroke mortality was 38.38%, whereas mortality in patients with hemorrhagic and ischemic stroke was 62.85% and 33.52%, respectively. The ratio of ischemic and hemorrhagic stroke in study subjects was 5:1, and in the causes of death 2.5:1. Out of 81 deceased stroke patients, 96.3% died within first 28 of admission. All of the patients with hemorrhagic stroke died within first 28 days, most within first 7 days (81.8%), whereas 94.9% of patients with ischemic stroke died within first 28 days.

Insulin resistance and androgens in healthy women with different body fat distributions.

OBJECTIVE: To compare androgens and sex hormone-binding globulin (SHBG) levels, and indices of insulin sensitivity (the response of plasma insulin and C-peptide in OGTT, insulin resistance and beta-cell activity estimated with the homeostasis assessment model (HOMA model) in healthy obese premenopausal women with different body fat distributions. PATIENTS AND METHODS: Free testosterone, androstenedione, SHBG levels and responses of plasma glucose, insulin and C-peptide in OGTT were examined in 74 healthy premenopausal women (19 with lower-body obesity (WHR < 0.80), 20 with pure abdominal obesity (WHR > 0.85), 19 with predominant abdominal obesity (WHR 0.81-0.85) and 18 normal-weight women). Insulin resistance and beta-cell function were estimated with the HOMA model. RESULTS: Both fasting and glucose-induced insulin levels were higher in women with pure abdominal obesity than in the controls (p < 0.001) and in those with lower-body obesity (P < 0.01). Insulin resistance was also higher in women with pure abdominal obesity than in the controls (p < 0.01) and those with lower-body obesity (p < 0.05). Free testosterone (p < 0.01) was higher and SHBG (p < 0.001) was lower in women with abdominal obesity than in the control group and those with lower-body obesity. Insulin significantly correlated with SHBG, and this correlation was independent of androgens, obesity and obesity type. Beta-cell function positively correlated with free testosterone, whereas insulin resistance negatively correlated with SHBG, and was independent of obesity and obesity type. CONCLUSIONS: In healthy premenopausal women, increased BMI and more pronounced abdominal fat accumulation was associated with increased androgenic activity (higher free testosterone and lower SHBG levels) and with insulin resistance estimated using the HOMA model, as well as with increasing basal and glucose-induced insulin levels. SHBG levels correlated with insulin and insulin resistance independently of the degree of obesity, obesity type and androgens, whereas beta-cell function correlated only with free testosterone.