Diseases Of Different Etiologies Research Articles

Insulin Resistance/Hyperinsulinemia, Neglected Risk Factor for the Development and Worsening of Heart Failure with Preserved Ejection Fraction.

Heart failure (HF) has become a subject of continuous interest since it was declared a new pandemic in 1997 because of the exponential increase in hospitalizations for HF in the latest years. HF is the final state to which all heart diseases of different etiologies lead if not adequately treated. It is highly prevalent worldwide, with a progressive increase with age, reaching a prevalence of 10% in subjects over the age of 65 years. During the last two decades, it was possible to see that the prevalence of heart failure with preserved ejection fraction (HFpEF) was increasing while that of heart failure with reduced ejection fraction (HFrEF) was decreasing. HFpEF is typically characterized by concentric remodeling of the left ventricle (LV) with impaired diastolic function and increased filling pressures. Over the years, also the prevalence of insulin resistance (IR)/hyperinsulinemia (Hyperins) in the general adult population has progressively increased, primarily due to lifestyle changes, particularly in developed and developing countries, with a range that globally ranges between 15.5% and 46.5%. Notably, over 50% of patients with HF also have IR/Hyperins, and the percentage is even higher in those with HFpEF. In the scientific literature, it has been well highlighted that the increased circulating levels of insulin, associated with conditions of insulin resistance, are responsible for progressive cardiovascular alterations over the years that could stimulate the development and/or the worsening of HFpEF. The aim of this manuscript was to review the scientific literature that supports a pathophysiologic connection between IR/Hyperins and HFpEF to stimulate the scientific community toward the identification of hyperinsulinemia associated with insulin resistance as an independent cardiovascular risk factor in the development and worsening of HF, believing that its adequate screening in the general population and an appropriate treatment could reduce the prevalence of HFpEF and improve its progression.

Native and engineered extracellular vesicles: novel tools for treating liver disease.

Liver diseases are classified as acute liver damage and chronic liver disease, with recurring liver damage causing liver fibrosis and progression to cirrhosis and hepatoma. Liver transplantation is the only effective treatment for end-stage liver diseases; therefore, novel therapies are required. Extracellular vesicles (EVs) are endogenous nanocarriers involved in cell-to-cell communication that play important roles in immune regulation, tissue repair and regeneration. Native EVs can potentially be used for various liver diseases owing to their high biocompatibility, low immunogenicity and tissue permeability and engineered EVs with surface modification or cargo loading could further optimize therapeutic effects. In this review, we firstly introduced the mechanisms and effects of native EVs derived from different cells and tissues to treat liver diseases of different etiologies. Additionally, we summarized the possible methods to facilitate liver targeting and improve cargo-loading efficiency. In the treatment of liver disease, the detailed engineered methods and the latest delivery strategies were also discussed. Finally, we pointed out the limitations and challenges of EVs for future development and applications. We hope that this review could provide a useful reference for the development of EVs and promote the clinical translation.

Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis

Progressive hepatic damage and fibrosis are major features of chronic liver diseases of different etiology, yet the underlying molecular mechanisms remain to be fully defined. N-RAS, a member of the RAS family of small guanine nucleotide-binding proteins also encompassing the highly homologous H-RAS and K-RAS isoforms, was previously reported to modulate cell death and renal fibrosis; however, its role in liver damage and fibrogenesis remains unknown. Here, we approached this question by using N-RAS deficient (N-RAS−/−) mice and two experimental models of liver injury and fibrosis, namely carbon tetrachloride (CCl4) intoxication and bile duct ligation (BDL). In wild-type (N-RAS+/+) mice both hepatotoxic procedures augmented N-RAS expression in the liver. Compared to N-RAS+/+ counterparts, N-RAS−/− mice subjected to either CCl4 or BDL showed exacerbated liver injury and fibrosis, which was associated with enhanced hepatic stellate cell (HSC) activation and leukocyte infiltration in the damaged liver. At the molecular level, after CCl4 or BDL, N-RAS−/− livers exhibited augmented expression of necroptotic death markers along with JNK1/2 hyperactivation. In line with this, N-RAS ablation in a human hepatocytic cell line resulted in enhanced activation of JNK and necroptosis mediators in response to cell death stimuli. Of note, loss of hepatic N-RAS expression was characteristic of chronic liver disease patients with fibrosis. Collectively, our study unveils a novel role for N-RAS as a negative controller of the progression of liver injury and fibrogenesis, by critically downregulating signaling pathways leading to hepatocyte necroptosis. Furthermore, it suggests that N-RAS may be of potential clinical value as prognostic biomarker of progressive fibrotic liver damage, or as a novel therapeutic target for the treatment of chronic liver disease.

#6741 TRANSCRIPTION FACTOR ATF3 EXACERBATES RENAL FIBROSIS THROUGH RECRUITING HISTONE ACETYLASES

Abstract Background and Aims Chronic kidney disease (CKD) threatens public health around the world. Renal fibrosis is a final common pathology in renal diseases of different etiologies. However, no efficient, broadly applicable anti-fibrotic therapies exist. Histone acetylation is an epigenetic modification involved in the regulation of multiple disease-specific gene expressions, balanced by histone acetyltransferases and histone deacetylase (HDAC) enzymes. Transcription factors (TF) could recruit histone-modifying enzymes and alter gene expression. But now, much remains unknown about the role of histone acetylation and whether there exits the regulator of it in fibrosis of CKD. Here, we for the first time explored a novel aspect of ATF3 promoting kidney fibrosis via recruiting the histone acetylases to fibrosis-related genes in CKD. Method We constructed a CKD mouse model by using adenine and oxonate. Serum were taken for the measurement of BUN and creatinine. Kidneys were harvested and processed for histological, sequencing, qRT-PCR, and western blotting analysis. RNA-seq and ChIP-seq (antibody: H3K27ac) of mouse kidneys were conducted for profiling the differential gene expression and H3K27ac. GO and KEGG analysis was performed for annotation of the function. Motif analysis was applied for searching the regulator of H3K27ac. Biopsy samples of patients with common CKD were used for immunohistochemical analysis. ATF3-KO mice were also conducted for defining the function of ATF3 in CKD. To profile the ATF3 binding site on chromatin, ChIP-seq of ATF3 in mice kidneys of normal control and CKD were also performed. Besides, the data contained ATF3 interact protein in databases (ChIP-atlas and BioGrid) and the results of protein interaction prediction were integrated for finding the protein-protein interaction of ATF3. TGF-β- stimulated TCMK-1 cell served as the cell model for further mechanism validation. CO-IP in cells clarifies that ATF3 could recruit the histone acetyltransferases. ChIP-qPCR of the fibrosis gene was performed to further verify the mechanism of ATF3-regulated gene expression. Results Firstly, compared with the normal control, histone modification H3K27ac repertoire was changed in chronic kidney disease. 11859 H3K27ac peaks specific to CKD, and 14996 H3K27ac peaks specific to healthy mice kidneys were found. The binding intensity of these regions has altered dramatically in the kidney of CKD. Pearson correlation analysis and function annotation showed that CKD-specific changes of H3K27ac were associated with fibrosis gene expression. Motif analysis showed that ATF3 in the top 10 TFs that may interact with H3K27ac. Among those TFs, ATF3 elicited the highest expression. Besides, ATF3 could co-localize with H3K27ac along the mice genome globally. By immunohistochemical staining analysis, we observed the upregulation of ATF3 in the kidneys of patients with biopsy-proven CKD. We found that knocking out the ATF3 could significantly reduce kidney damage in CKD mice. In parallel with improved morphological injuries, the level of kidney fibrosis gene expression was also significantly reduced in ATF3–/– mice. Furthermore, the H3K27ac on the mice chromatin altered along with the knockout of ATF3, and several fibrosis-related gene expressions which elevated in CKD were decreased by deficiency of ATF3. On the region of gene cd2, H3K27ac disappeared with the knockout of ATF3 in CKD. We found that ATF3 could interact with histone acetyltransferases (CBP, KAT7, P300) to promote the H3K27ac. Further evidenced by ChIP-qPCR of fibrosis gene cd2, we found that ATF3 could recruit the histone acetyltransferases on the fibrosis gene to promote the H3K27ac to provoke the gene expression in the cell model. Conclusion We profiled the landscape of H3K27ac in CKD, explored the epigenetic regulator of H3K27ac, and revealed that ATF3 promotes renal fibrosis in CKD. Notably, we for the first time explored a novel mechanism of ATF3 about recruiting histone acetyltransferases to regulate the H3K27ac on fibrosis gene. Our data highlighted that ATF3 might represent a potential therapeutic target against fibrotic kidney diseases.

A meta-analysis of the clinical significance of neutrophil-to-lymphocyte ratios in interstitial lung disease.

Interstitial lung disease (ILD) is a group of diffuse parenchymal infiltrating diseases of different etiologies. The neutrophil-to-lymphocyte ratio (NLR) can reflect ILD's existence, progression, and prognosis and is currently regarded as a promising biological marker. This meta-analysis assessed elevated NLR levels in ILD for their predictive value. From inception to July 27, 2022, the Scopus, Cochrane Library, Web of Science, Embase, and PubMed databases were checked thoroughly. We used the weighted mean difference (WMD) and 95% confidence interval (CI) to compare blood NLR values between groups. We examined the relationship between poor prognoses and elevated NLR concentrations in ILD patients using odds ratios (ORs) and 95% CI. After initially including 443 studies, 24 were ultimately analyzed. Fifteen studies(ILD:n = 2,912, Non-ILD: n = 2,868) revealed that the NLR values in the ILD group were relatively high (WMD = 0.61, 95% CI 0.43-0.79, p = 0.001). Eight articles (with poor prognoses: n = 407, without poor prognoses: n = 340) indicated that ILD patients with poor prognoses had higher NLR values (WMD = 1.33, 95% CI 0.32-2.33, p = 0.01). This distinction was especially noticeable in patients with the connective tissue disease (CTD)associated with ILD subgroup (WMD = 3.53, 95% CI 1.54-5.51, p = 0.0005). The pooled OR for increased NLR levels forecasting poor prognoses of ILD was 1.09 (95% CI 1.03-1.15, p = 0.0008). Increasing blood NLR values have clinical significance and application value for detecting ILD and predicting its poor prognosis, especially in CTD patients.

Synergistic Effects of Caffeine in Combination with Conventional Drugs: Perspectives of a Drug That Never Ages.

Plants have been known since ancient times for their healing properties, being used as preparations against human diseases of different etiologies. More recently, natural products have been studied and characterized, isolating the phytochemicals responsible for their bioactivity. Most certainly, there are currently numerous active compounds extracted from plants and used as drugs, dietary supplements, or sources of bioactive molecules that are useful in modern drug discovery. Furthermore, phytotherapeutics can modulate the clinical effects of co-administered conventional drugs. In the last few decades, the interest has increased even more in studying the positive synergistic effects between plant-derived bioactives and conventional drugs. Indeed, synergism is a process where multiple compounds act together to exert a merged effect that is greater than that of each of them summed together. The synergistic effects between phytotherapeutics and conventional drugs have been described in different therapeutic areas, and many drugs are based on synergistic interactions with plant derivatives. Among them, caffeine has shown positive synergistic effects with different conventional drugs. Indeed, in addition to their multiple pharmacological activities, a growing body of evidence highlights the synergistic effects of caffeine with different conventional drugs in various therapeutic fields. This review aims to provide an overview of the synergistic therapeutic effects of caffeine and conventional drugs, summarizing the progress reported to date.

The shaping of gut immunity in cirrhosis.

Cirrhosis is the common end-stage of chronic liver diseases of different etiology. The altered bile acids metabolism in the cirrhotic liver and the increase in the blood-brain barrier permeability, along with the progressive dysbiosis of intestinal microbiota, contribute to gut immunity changes, from compromised antimicrobial host defense to pro-inflammatory adaptive responses. In turn, these changes elicit a disruption in the epithelial and gut vascular barriers, promoting the increased access of potential pathogenic microbial antigens to portal circulation, further aggravating liver disease. After summarizing the key aspects of gut immunity during homeostasis, this review is intended to update the contribution of liver and brain metabolites in shaping the intestinal immune status and, in turn, to understand how the loss of homeostasis in the gut-associated lymphoid tissue, as present in cirrhosis, cooperates in the advanced chronic liver disease progression. Finally, several therapeutic approaches targeting the intestinal homeostasis in cirrhosis are discussed.

Relationships between the Content of Micro- and Macroelements in Animal Samples and Diseases of Different Etiologies

Many of the micro- and macro-elements (MMEs) required by the body are found in environmental objects in concentrations different from their original concentration that can lead to dangerous animal diseases ("microelementoses"). The aim was to study the features of MME (accumulating in wild and exotic animals) in connection with particular diseases. The work using 67 mammal species from four Russian zoological institutions was completed in 2022. Studies of 820 cleaned and defatted samples (hair, fur, etc.) after "wet-acid-ashing" on an electric stove and in a muffle furnace were performed using a Kvant-2A atomic absorption spectrometer. The content of zinc, copper, iron, cadmium, lead, and arsenic was assessed. The level of MME accumulation in the animal body contributes not only to the MME status and the development of various concomitant diseases, but the condition itself can occur by intake of a number of micronutrients and/or drugs. Particular correlations between the accumulation of Zn and skin, oncological diseases, Cu-musculoskeletal, cardiovascular diseases, Fe-oncological diseases, Pb-metabolic, nervous, oncological diseases, and Cd-cardiovascular diseases were established. Therefore, monitoring of the MME status of the organism must be carried out regularly (optimally once every 6 months).

Fli1 and Tissue Fibrosis in Various Diseases.

Being initially described as a factor of virally-induced leukemias, Fli1 (Friend leukemia integration 1) has attracted considerable interest lately due to its role in both healthy physiology and a variety of pathological conditions. Over the past few years, Fli1 has been found to be one of the crucial regulators of normal hematopoiesis, vasculogenesis, and immune response. However, abnormal expression of Fli1 due to genetic predisposition, epigenetic reprogramming (modifications), or environmental factors is associated with a few diseases of different etiology. Fli1 hyperexpression leads to malignant transformation of cells and progression of cancers such as Ewing's sarcoma. Deficiency in Fli1 is implicated in the development of systemic sclerosis and hypertensive disorders, which are often accompanied by pronounced fibrosis in different organs. This review summarizes the initial findings and the most recent advances in defining the role of Fli1 in diseases of different origin with emphasis on its pro-fibrotic potential.

Occult hepatitis B virus infection in patients with chronic liver disease of different etiology in a Brazilian referral center: comparison of two different hepatitis B virus deoxyribonucleic acid amplification protocols: a cross-sectional study.

Occult hepatitis B virus infection (OBI) is defined as the presence of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) in the liver of individuals with undetectable hepatitis B virus surface antigen (HBsAg) in the serum. The actual prevalence of OBI and its clinical relevance are not yet fully understood. To evaluate the prevalence of HBV DNA in liver biopsies of HBsAg-negative patients with chronic liver disease of different etiologies in a referral center in Brazil and compare two different HBV DNA amplification protocols to detect HBV. This cross-sectional observational study was conducted at the Liver Outpatient Clinic, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, between January 2016 and December 2019. HBV DNA was investigated in 104 liver biopsy samples from individuals with chronic liver disease of different etiologies, in whom HBsAg was undetectable in serum by nested-polymerase chain reaction (nested-PCR), using two different protocols. OBI, diagnosed by detecting HBV DNA using both protocols, was detected in 6.7% of the 104 individuals investigated. Both protocols showed a good reliability. In addition to the differences in the prevalence of HBV infection in different regions, variations in the polymerase chain reaction technique used for HBV DNA amplification may be responsible for the large variations in the prevalence of OBI identified in different studies. There is a need for better standardization of the diagnostic methods used to diagnose this entity.

A study on the diagnostic value of GP73 in liver fibrosis among patients with chronic liver disease

Objective: This study aimed to evaluate the diagnostic value of serum Golgi protein 73(GP73) alone and GP73 combined with liver stiffness measurement (LSM), aspartate aminotransferase/platelet ratio index (APRI), and 4-factor-based fibrosis index (FIB4) in diagnosing liver fibrosis in patients with chronic liver disease of different etiologies. Methods: A diagnostic test. A total of 68 patients who underwent liver biopsy in the Department of Traditional and Western Medical Hepatology of the Third Hospital of Hebei Medical University from October 2019 to December 2020 were selected to detect serum GP73 levels. iLivTouch was used to assess liver stiffness measurement (LSM). In addition, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), total bilirubin (TBil), direct bilirubin (DBil), triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL) levels, and peripheral platelet (PLT) counts were assayed. The correlation between GP73 and the above indexes was assessed, and APRI and FIB-4 were calculated. SPSS 21.0 statistical software was used for statistical analysis. The area under the receiver operating characteristic curve was calculated to evaluate diagnostic efficacy of GP73 in identifying hepatic fibrosis stages. Furthermore, the difference between GP73 and liver stiffness, as well as APRI and FIB4 in diagnosing significant fibrosis was assessed. Results: Based on liver biopsy, 13, 18, 17, and 20 cases were diagnosed as stages S0-1, S2, S3, and S4, respectively. The AUC of GP73 diagnosing hepatic fibrosis stage S≥3 and S=4 were 0.806 and 0.844 at cut-off points of 2.06 and 3.27 μg/L, and the sensitivity and specificity were 93.5%, 61.5%, 90.0%, 70.3%, respectively. In addition, GP73 levels were positively correlated with the degree of liver fibrosis (r=0.547, P<0.001). Conclusions: The efficacy of serum GP73 level in diagnosing the degree of liver fibrosis in patients with chronic liver disease from different causes was significantly higher than that of APRI, FIB4, and LSM. The combination of GP73 and FIB4 can further improve the accuracy of diagnosis of liver fibrosis staging S≥3 and S=4, which is a reliable serological marker for the diagnosis of fibrosis in patients with chronic liver disease.

Oxygen saturation determination by photoplethysmographic and electrochemical methods: comparison of results in adult patients with pulmonary diseases

Pulse oximetry is widely introduced to determine ox-ygen saturation of the blood. For patients with pulmonary diseases oxygen saturation is a major parameter used for the assessment of pulmonary gas exchange. The objec-tive of our study was to compare the results of oxy gen saturation measured by photoplethysmographic and elec-trochemical methods in patients with pulmonary disea-ses. Materials and methods. The authors studied 252 pa-tients with pulmonary diseases of different etiology. All the patients underwent pulse oximetry (SpO2) and blood gas analysis (SaO2) for oxygen saturation measurement, as well as spirometry. Results. We have established high direct correlations (R=0.869) between oxygen saturation levels determined by different methods. The mean abso-lute value of the difference between SpO2 and SaO2 was 0.74±2.35 pp. The value of the difference was influenced by the value of partial pressure of oxygen in the blood: if РаО2 was higher than 80 mm Hg, the mean va lue of the dif-ference (Md) was 0.1 pp (percentage points), and the con-sistency limit ranged from –2.6 to 2.8 pp; as РаО2 lo wered, the results increased to the maximum at РаО2 ofless than 60 mm Hg (Md=0.8 pp; the consistency limit could reach±±8.0 pp). The saturation value measured by pulse oxime-try with supposed hypoxemia of less than 60 mm Hg was possible at SpO2 of less than 93%. The difference between SpO2 and SaO2 beyond 3.0 pp was detec ted in 47 (18.7%) patients with pulmonary diseases. It was more frequent-ly determined in patients with interstitial lung diseases (34.0%) than patients with other pulmonary diseases (12.5–16.6%). Conclusion. Oxygen saturation determina-tion by pulse oximetry adequately shows pulmonary gas exchange in patients with pulmonary diseases and can be used in practical pulmonology. Though, blood gas analysis results should be specified if SpO2 is 93% or lower.

Prevalence of Hepatitis E Virus in Patients with Chronic Hepatopathy in a Reference Center of Bahia State, Brazil

Introduction: Hepatitis E virus infection can lead to severe liver disease and unregulated hepatitis in patients with a history of previous chronic liver disease of different etiologies. Objective: To determine the seroprevalence of hepatitis E in untreated carriers of hepatitis C virus, hepatitis B virus, autoimmune hepatitis and in patients with drug-induced liver disease. Materials and Methods: This is a cross-sectional study with a total sample of 301 outpatient hepatology volunteers. The detection of anti-HEV IgM and IgG antibodies was determined using the ELISA (RecomWell anti-HEV IgG and IgM, Mikrogen®, Germany), One-step real-time PCR was used for the detection of HEV-RNA (Taqman, Life Technologies TM, Foster City, CA, USA). Results: The overall prevalence of anti-HEV IgG and IgM in the population studied was 12.95% and 2.3%, respectively. The prevalence by group were: anti-HEV IgG: hepatitis C virus with 13.2%, hepatitis B virus with 13%, autoimmune hepatitis with 8.1 and drug-induced liver disease with 21.1. Patients with HCV chronic hepatitis and positive HCV IgG serology showed an increase in transaminase levels in 66.7% (10/15) of the cases, while in the seronegative patients this increase was present in 42.4% (42/99) of the cases (p&lt;0.05). Conclusions: A high seroprevalence of HEV was observed. Among the patients with serology concomitantly positive for anti HEV IgG and IgM, 57.1% (4/7) had higher levels of TGO and TGP, suggesting acute HEV infection. A relationship between hepatitis C and E virus co-infection and elevated transaminase levels has been demonstrated. Future studies with evaluation of several clinical parameters are necessary.

Do Patients With Arterial Occlusive Disease of Different Etiologies Benefit Equally From Cilostazol?

Cilostazol is a guideline-recommended drug that improves intermittent claudication and quality of life in patients with chronic atherosclerotic peripheral arterial disease. The drug is used for most etiologies of arterial occlusive diseases in clinical practice. This study aimed to evaluate whether patients benefit equally from cilostazol regardless of etiology. Patients on cilostazol were divided into 4 groups according to arterial occlusive disease etiology: (1) atherosclerosis, (2) diabetic angiopathy, (3) embolism/thrombosis, and (4) Buerger disease. Patients' maximum walking distance, ankle-brachial index score and distal tissue oxygen saturation (Sto2), clinical improvement onset time, ability to reach maximum benefit time, vascular surgeries, and wounds were compared before they started cilostazol and after 12 months. Results were evaluated at a statistical significance of P < .05. In 194 patients, 307 target extremities were evaluated in the 4 disease groups. After cilostazol use, maximum walking distance, ankle-brachial index score, and distal Sto2 increased significantly in all groups (P < .001), but distal Sto2 in the diabetic angiopathy and Buerger disease groups was significantly lower than in the atherosclerosis group (P < .001). Ankle-brachial index and distal Sto2 differences in the Buerger disease group were significantly lower (both P < .001). The vascular surgery counts decreased significantly in the atherosclerosis and embolism/thrombosis groups (P = .019 and P = .004, respectively). Patients with nonatherosclerotic arterial occlusive disease also benefit from cilostazol, but patients with Buerger disease or diabetic angiopathy seem to benefit less. Combining cilostazol with anticoagulant or antiaggregant agents and closer monitoring of these patients may produce better results.

Improvement of liver fibrosis verification using new minimally invasive markers in patients with chronic diffuse liver diseases

The aim of our research was to obtain new minimally invasive serum markers of fibrotic changes of liver in patients with chronic diffuse liver diseases of different etiology and compare them with traditional markers. 364 patients aged 30 to 66 years were examined: 221 women (60.7%) and 143 men (39.3%). Depending on the etiological factors, all patients were divided into 4 groups: group I consisted of 108 patients with non-alcoholic fatty liver disease (NAFLD), group II – 143 patients with chronic hepatitis associated with virus C (CHC), group III – 56 patients with alcoholic liver disease (ALD), group IV – 57 patients with toxic drug-induced hepatitis (TH). The control group consisted of 30 practically healthy people. Using correlation and ROC-analyzes, we obtained minimally invasive diagnostics markers that show the risk of developing liver fibrosis. For patients with NAFLD these were the levels of HOMA-IR, TNFα/IL-10 and α1-acid glycopeptide content, which are better in quality of the diagnostic model than the traditional Forns index, APRI, FIB-4, AAR. For patients with CHC, these were the protein-bound hydroxyproline (HPp/b) /HPf ratio, phospholipids content, and IL-6, CD4+ levels, which are better diagnostic models than the traditional Forns index, APRI, FIB-4, AAR. The following markers were obtained for patients with ALD – TNFα levels, HPp/b and glycosaminoglycans content, which are better diagnostic models than the traditional Forns index, APRI, FIB-4, AAR. For patients with TH, these were medium molecular weight peptides content, IL-6/IL-10 ratio and CD4+/CD8+, which are better diagnostic models than the traditional Forns index, APRI, FIB-4, AAR. Thus, new minimally invasive markers of fibrosis in patients with chronic diffuse liver diseases have been obtained.

Therapeutic Effect of a Latent Form of Cortistatin in Experimental Inflammatory and Fibrotic Disorders.

Cortistatin is a cyclic neuropeptide that recently emerged as an attractive therapeutic factor for treating inflammatory, autoimmune, fibrotic, and pain disorders. Despite of its efficiency and apparent safety in experimental preclinical models, its short half-life in body fluids and its potential pleiotropic effects, due to its promiscuity for several receptors expressed in various cells and tissues, represent two major drawbacks for the clinical translation of cortistatin-based therapies. Therefore, the design of new strategies focused on increasing the stability, bioavailability, and target specificity of cortistatin are lately demanded by the industry. Here, we generated by molecular engineering a new cortistatin-based prodrug formulation that includes, beside the bioactive cortistatin, a molecular-shield provided by the latency-associated protein of the transforming growth factor-β1 and a cleavage site specifically recognized by metalloproteinases, which are abundant in inflammatory/fibrotic foci. Using different models of sepsis, inflammatory bowel disease, scleroderma, and pulmonary fibrosis, we demonstrated that this latent form of cortistatin was a highly effective protection against these severe disorders. Noteworthy, from a therapeutic point of view, is that latent cortistatin seems to require significantly lower doses and fewer administrations than naive cortistatin to reach the same efficacy. Finally, the metalloproteinase-cleavage site was essential for the latent molecule to exert its therapeutic action. In summary, latent cortistatin emerges as a promising innovative therapeutic tool for treating chronic diseases of different etiologies with difficult clinical solutions and as a starting point for a rational development of prodrugs based on the use of bioactive peptides.

New Biomarkers and Their Potential Role in Heart Failure Treatment Optimisation-An African Perspective.

Heart failure is a clinical syndrome resulting from various cardiovascular diseases of different aetiologies and pathophysiology. These varying pathologies involve several complex mechanisms that lead to the activation of the neurohumoral system, inflammation, angiogenesis, apoptosis, fibrosis, and eventually adverse cardiac remodelling associated with a progressive decline in cardiac function. Once a diagnosis is made, the cardiac function has a gradual decline characterised by multiple hospital admissions. It is therefore imperative to identify patients at different stages of the heart failure continuum to better risk stratify and initiate optimal management strategies. Biomarkers may play a role in the diagnosis, prognostication, and monitoring response to treatment. This review discusses the epidemiology of heart failure and biomarkers commonly used in clinical practice such as natriuretic peptides and cardiac troponins. In addition, we provide a brief overview of novel biomarkers and genetic coding and non-coding biomarkers used in the management of patients with heart failure. We also discuss barriers that hinder the clinical application of novel biomarkers. Finally, we appraise the value of polygenic risk scoring, focusing on sub-Saharan Africa.

Afectación respiratoria en las enfermedades inmunomediadas sistémicas. Enfermedad pulmonar intersticial difusa y enfermedades autoinmunes sistémicas

Diffuse interstitial lung diseases (DILD) comprise a heterogeneous set of diseases of different etiologies. Among them, one of the most important groups for their severity and frequency are DILD secondary to systemic autoimmune diseases. Connective tissue diseases (CTD), or connectopathies, are a group of diseases with an autoimmune basis with systemic repercussions. DILD appears with a varying frequency in each of them, although when it does, it tends to have important implications on the severity of the symptoms and prognosis. In this update, we will attempt to explain the different types of DILD, in its inflammatory and predominantly fibrotic forms, that emerge secondarily to the main types of known CTD as well as their diagnostic and therapeutic approach.

A CLINICAL STUDY OF NON-TRAUMATIC PARAPLEGIA IN PATIENTS ADMITTED IN ASSAM MEDICAL COLLEGE AND HOSPITAL.

Background: Paraplegia is a common and an important cause of disablement in all age group and in both sexes. In the days of ancient medicine it was most problematic for the physicians and surgeons to treat the cases and they considered it as “Hopeless”( Edwin Smith Papyrus, Breasted, 1930) written 4000 years ago. Paraplegia is caused by variety of diseases of different etiology from cerebral cortex to muscles. But measures should be taken to diagnose every possible cause and to offer best modality of treatment to eliminate the sufferings of patients. Materials And Methods: 50 patients of non-traumatic paraplegia were studied at Assam Medical College and Hospital from July 2005 to June 2006. Patients underwent a detailed clinical evaluation followed by laboratory investigations and neuroimaging studies. In our study the maximum incidence was in Results: the 4th decade (32%), the next being in the third decade (26%). Out of 50 cases there were 38 males (76%) and 12 females (24%). The occupation of the patients were cultivators (24%), housewife (24%), laborer (18%), student (10%), clerk (8%), teacher (4%), driver (4%), businessman ( 2%), engineer (2%), peon ( 2%). Acute onset was observed in 18 cases (36%), subacute onset in 4 cases (8%) and insidious in 28 cases (56%). The etiologies were found to be Transverse myelitis (20%), L.G.B.S (20%), Pott's paraplegia (16%), Lumbar disc prolapse (16%), Spinal tumor ( 8%), dorsal disc prolapse (4%), spinal arachnoiditis (4%), radiation myelitis (4%). We thus Conclusion: conclude that the present study shows acute transverse myelitis to be the commonest cause and spinal tuberculosis the second most common etiology of non-traumatic paraplegia. The patterns of clinical presentation and incidences of paraplegia due to various etiologies in this study bear close resemblance to the ones described by other workers.

Clinical Characteristics and Potential Mechanisms in Patients with Abnormal Liver Function Indices and Elevated Serum IgG4.

We analyzed the etiological classification and clinical characteristics of patients with abnormal liver function indices and elevated serum IgG4 levels and investigated the effects of intrahepatic follicular helper T cell (Tfh) infiltration and serum IL-21. Clinical data (age, sex, past history, clinical manifestations, laboratory tests, imaging, diagnosis, and treatment) and etiology of liver injury from 136 patients were analyzed. We compared the general condition, clinical characteristics, and laboratory tests of 19 AIH (autoimmune hepatitis) patients with elevated serum IgG4 levels with those of 20 AIH patients with normal serum IgG4 levels admitted at the same time. Five patients with AIH and elevated serum IgG4 levels and five AIH patients with normal IgG4 levels were matched by sex, age, and liver function, and Tfh infiltration in liver biopsy tissues of patients in both groups was determined by immunofluorescence staining. Five AIH patients with elevated serum IgG4 levels were selected for measurement of serum interleukin-21 (IL-21) levels by enzyme-linked immunosorbent assay (ELISA), seventeen AIH patients with normal serum IgG4 were matched by sex, age, and liver function indices, and 29 physically healthy individuals matched by sex and age were selected as the control group. The changes in patients with IgG4-RD and abnormal liver function before and after glucocorticoid treatment were measured. Patients (136) with abnormal liver function indices and elevated serum IgG4 levels were diagnosed with liver disease of different etiologies. IgG4-related disease was the most frequent, followed by AIH and malignancy. Abnormal liver function indices with high serum IgG4 were most commonly seen as elevated gamma glutamyl transferase (GGT). The AIH group with elevated serum IgG4 had increased intrahepatic levels of Tfh. IL-21 in AIH patients with elevated IgG4 was higher than in patients with normal IgG4 and healthy controls. Patients (n = 28) with abnormal liver function indices and IgG4-related disease received glucocorticoid therapy for six months, and ALT, AST, ALKP, GGT, TBil, DBil, IgG, IgG4, and IgE were significantly lower after treatment. Elevated serum IgG4 was seen in patients with abnormal liver function indices with diverse causes. Tfh infiltration and increased IL-21 production may be related to the pathogenesis of AIH with elevated serum IgG4. Glucocorticoid therapy is effective in patients with abnormal liver function indices and IgG4-related disease. Assessing immune function in patients with abnormal liver function indices and elevated serum IgG4 levels should facilitate diagnosis and treatment of the disease.