Contributing role of metabolic genes APOE, FTO, and LPL in the development of atrial fibrillation: insights from a case-control study.

OBJECTIVE: The aim of the study was to examine the expression profile of genes (APOE, FTO, and LPL) associated with metabolic syndrome (MetS) in subjects with concomitant atrial fibrillation (AF). METHODS: A total of 690 subjects were categorized into control, AF without MetS, and AF with MetS. RESULTS: The expression profiles of the APOE, FTO, and LPL genes were decreased in AF subjects and AF subjects with MetS as compared to the controls. In AF without the MetS group, an inverse relationship was found between the expression of the LPL gene with body mass index (BMI) and a positive relationship with creatine kinase-MB, whereas expression of the FTO gene was inversely associated with fasting blood glucose and positively with cardiac troponin I in AF suffering from MetS. Expression of the LPL gene was directly linked with systolic blood pressure (SBP) and high-density lipoprotein-cholesterol (HDL-C), whereas an inverse correlation with heart rate and expression of the FTO gene in AF with MetS were shown. The expression of the LPL gene was inversely related to BMI in subjects with AF. The expression of the LPL gene was positively correlated with SBP and HDL-C and negatively correlated with heart rate, while the expression of the FTO gene was an important predictor of AF with MetS. CONCLUSION: The decreased expression of APOE, FTO, and LPL genes in AF with and without MetS indicates their potential contributing role in the pathogenesis of AF.

Comprehensive Multidisciplinary Management of Hyper-IgE Syndrome in an 11-Year-Old Female: A Pediatric Case Report.

Hyper-IgE syndrome (HIES) or Job syndrome is a rare immunodeficiency characterized by elevated levels of IgE and recurrent infections, eczema, and connective tissue abnormalities. Patients with HIES are prone to recurrent pyogenic and opportunistic infections due to impaired immune responses. Here, we present the case of an 11-year-old female diagnosed with HIES, who was admitted to the hospital with bacterial pneumonia and leg pain associated with a history of osteopenia. The patient's clinical course included fever, cough, throat pain, and leg pain. Management involved a rigorous course of antibiotics, antifungals, and cultures of pertinent pathogens, along with imaging of the lower extremity. This case underscores the importance of appropriate management strategies for patients with HIES and their comorbidities to mitigate the risk of infections and improve patient outcomes.

Cardiometabolic Risk Factors Related to Atrial Fibrillation and Metabolic Syndrome in the Pakistani Population.

Background and Objectives: This study aimed to examine the relationship between cardiometabolic risk factors and atrial fibrillation (AF) and the simultaneous presence of AF and metabolic syndrome (MetS) in the Pakistani population. Materials and Methods: A total of 690 subjects were enrolled (n = 230 patients with AF, n = 230 patients with AF and MetS, and n = 230 controls). The associations between cardiometabolic parameters and AF with and without MetS were analyzed by univariable and multivariable binary regression analyses. Results: Body mass index (BMI), fasting blood glucose (FBG), and triglycerides (TG) were independently positively correlated, but the glomerular filtration rate (GFR) and sodium were independently negatively correlated with AF. An increase in BMI, FBG, and TG levels by one unit measure increased the probability by 55.1%, 20.6%, and 1.3%, respectively, for the AF occurrence. A decrease in GFR and sodium levels increased the probability by 4.3% and 33.6%, respectively, for the AF occurrence. On the other hand, uric acid was independently negatively correlated, whereas sodium was independently positively correlated, with MetS and AF. A decrease in uric acid levels and an increase in sodium levels by 1 unit measure increased the probability for MetS and AF by 23.2% and 7.5%, respectively. Conclusions: Cost-effective and routinely measured parameters, i.e., BMI, FBG TG, GFR, and sodium levels, can be reliable indicators of AF, whereas serum uric acid and sodium levels are independently associated with AF and MetS in the Pakistani population. Timely recognition and the control of modifiable cardiometabolic risk factors are of great significance in the prevention of AF development.

Interleukins: pathophysiological role in acute pancreatitis.

Acute pancreatitis (AP) is a common inflammatory state characterized by a clinical course that can lead to serious local and extrapancreatic organ malfunction and failure. Interleukins (ILs) are biologically active glycoproteins primarily produced by macrophages and lymphocytes. According to the literature, there are many ILs. However, this article represents a summary of the role of ILs in AP, such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, and IL-20. The ways to modulate IL activity to reduce inflammation and improve outcomes in individuals with this condition are under investigation. Drugs that target specific ILs might be developed to mitigate the effects of AP.

The Association between Coagulation and Atrial Fibrillation.

The existing literature highlights the presence of numerous coagulation factors and markers. Elevated levels of coagulation factors are associated with both existing and newly diagnosed cases of atrial fibrillation (AF). However, this article summarizes the role of coagulation in the pathogenesis of AF, which includes fibrinogen and fibrin, prothrombin, thrombomodulin, soluble urokinase plasminogen activator receptor, von Willebrand factor, P-selectin, D-dimer, plasminogen activator inhibitor-1, and platelet activation. Coagulation irregularities play a significant role in the pathogenesis of AF.

Role of Cardiac Biomarkers in Hepatic Disorders: A Literature Review.

Various studies have reported the association between cardiac markers and hepatic disorders. The main objective of this review article was to elucidate the significance of important cardiac indicators such as ischemia-modified albumin, cardiac troponin, cardiac natriuretic peptides, creatine kinase, creatine kinase-MB, lactate dehydrogenase, heart-type fatty acid-binding protein, osteopontin, soluble suppression of tumorigenicity 2, C-reactive protein, and lipoprotein(a) in the development of hepatic disorders. In addition, it highlighted recent notable discoveries and accomplishments in this field and identified areas requiring further investigation, ongoing discussions, and potential avenues for future research. Early identification and control of these cardiac markers might be helpful to control the prevalence of hepatic disorders associated with cardiovascular diseases.

Contributing role of metabolic genes APOE, FTO, and LPL in the development of atrial fibrillation: insights from a case-control study

SUMMARY OBJECTIVE: The aim of the study was to examine the expression profile of genes (APOE, FTO, and LPL) associated with metabolic syndrome (MetS) in subjects with concomitant atrial fibrillation (AF). METHODS: A total of 690 subjects were categorized into control, AF without MetS, and AF with MetS. RESULTS: The expression profiles of the APOE, FTO, and LPL genes were decreased in AF subjects and AF subjects with MetS as compared to the controls. In AF without the MetS group, an inverse relationship was found between the expression of the LPL gene with body mass index (BMI) and a positive relationship with creatine kinase-MB, whereas expression of the FTO gene was inversely associated with fasting blood glucose and positively with cardiac troponin I in AF suffering from MetS. Expression of the LPL gene was directly linked with systolic blood pressure (SBP) and high-density lipoprotein-cholesterol (HDL-C), whereas an inverse correlation with heart rate and expression of the FTO gene in AF with MetS were shown. The expression of the LPL gene was inversely related to BMI in subjects with AF. The expression of the LPL gene was positively correlated with SBP and HDL-C and negatively correlated with heart rate, while the expression of the FTO gene was an important predictor of AF with MetS. CONCLUSION: The decreased expression of APOE, FTO, and LPL genes in AF with and without MetS indicates their potential contributing role in the pathogenesis of AF.

Fractionation of Xanthium strumarium L. foliage phenolics, in-vitro antioxidant activities, and in-vivo anti-diabetic potential.

Introduction: The present research aimed to fractionate Xanthium strumarium L. (XSL) foliage phenolics into a set of solvents and evaluate their antioxidant potential and in-vivo anti-diabetic activity against Alloxan monohydrate-induced diabetic mice. Methodology: For this purpose, XSL foliage was fractionated into petroleum ether, ethyl acetate, ethanol, and water via orbital type shaking and tested for the presence of phenolics, and their antioxidant and antidiabetic potential. Results and discussion: The results revealed that the ethyl acetate fraction of XSL foliage contained the highest amount of total phenolics 95.25 mg GAE/g of extract, followed by ethanol (65.14 mg GAE/g), petroleum ether (25.12 mg GAE/g), water (12.20 mg GAE/g), and XSL powder (69.13 mg GAE/g). At the end of treatment time (day 18 of oral administration of 400 mg/kg body weight of mice), the ethyl acetate fraction significantly (p ≤ 0.05) lowered blood glucose level (353 ± 10.6 to 220 ± 25.5 mg/dL) which might due to the elevated level of phenolic compounds in this fraction. Conclusion: Overall, it can be speculated that ethyl acetate and ethanol may work efficiently for the enrichment of XSL phenolic without compromising their antidiabetic potential.

Association of adiponectin gene expression with atrial fibrillation in a Pakistani populace.

Adiponectin, an adipocytokine produced and secreted by adipose tissue, has anti-diabetic, anti-atherogenic, and anti-inflammatory properties. This case-control study was aimed to assess the expression and serum levels of adiponectin in subject suffereing from atrial fibrillation (AF). The study's subjects (n = 690) were enrolled from the Punjab Institute of Cardiology, Lahore and were grouped into control, AF without Metabolic syndrome (MetS), and AF with MetS groups. Along with the collection of demographic data, an analysis of adiponectin and biochemical parameters were performed. A highly significant difference in serum levels of adiponectin was observed among the control, AF without MetS, and AF with MetS groups (61.61 ± 45.30 ng/ml, 37.20 ± 19.46 ng/ml, 63.78 ± 61.69 ng/ml). The expression analysis of adiponectin was decreased (n-fold = Ì´ 0.30) in AF without MetS group as compared to control group (n-fold = ~ 1.16) but increased in AF with MetS group (n-fold = Ì´ 6.26). The correlation analysis revealed a highly significant positive relationship between the expression of the adiponectin gene with waist-to-hip ratio (WHR) in AF without MetS group. Whereas, serum adiponectin was negatively related to serum triglycerides (TG) in AF with MetS group. In multiple regression analysis using adiponectin expression as the dependent variable, WHR was a determinant in AF without MetS. Whereas, when serum adiponectin was used as the dependent variable, serum TG was the determinant in group AF with MetS. The present study implicates that decreased expression and serum levels of adiponectin were associated with the development of AF in which WHR and serum TG also contributed towards the onset of atrial fibrillation.

Correction: Mutational analysis in sodium-borate cotransporter SLC4A11 in consanguineous families from Punjab, Pakistan.

[This corrects the article DOI: 10.1371/journal.pone.0273685.].

Biallelic variants in NSUN6 cause an autosomal recessive neurodevelopmental disorder.

PURPOSE: 5-methylcytosine RNA modifications are driven by NSUN methyltransferases. Although variants in NSUN2 and NSUN3 were associated with neurodevelopmental diseases, the physiological role of NSUN6 modifications on transfer RNAs and messenger RNAs remained elusive. METHODS: We combined exome sequencing of consanguineous families with functional characterization to identify a new neurodevelopmental disorder gene. RESULTS: We identified 3 unrelated consanguineous families with deleterious homozygous variants in NSUN6. Two of these variants are predicted to be loss-of-function. One maps to the first exon and is predicted to lead to the absence of NSUN6 via nonsense-mediated decay, whereas we showed that the other maps to the last exon and encodes a protein that does not fold correctly. Likewise, we demonstrated that the missense variant identified in the third family has lost its enzymatic activity and is unable to bind the methyl donor S-adenosyl-L-methionine. The affected individuals present with developmental delay, intellectual disability, motor delay, and behavioral anomalies. Homozygous ablation of the NSUN6 ortholog in Drosophila led to locomotion and learning impairment. CONCLUSION: Our data provide evidence that biallelic pathogenic variants in NSUN6 cause one form of autosomal recessive intellectual disability, establishing another link between RNA modification and cognition.

A Biallelic Truncating Variant in the TPR Domain of GEMIN5 Associated with Intellectual Disability and Cerebral Atrophy.

GEMIN5 is a multifunctional RNA-binding protein required for the assembly of survival motor neurons. Several bi-allelic truncating and missense variants in this gene are reported to cause a neurodevelopmental disorder characterized by cerebellar atrophy, intellectual disability (ID), and motor dysfunction. Whole exome sequencing of a Pakistani consanguineous family with three brothers affected by ID, cerebral atrophy, mobility, and speech impairment revealed a novel homozygous 3bp-deletion NM_015465.5:c.3162_3164del that leads to the loss of NM_015465.5 (NP_056280.2):p. (Asp1054_Ala1055delinsGlu) amino acid in one of the α-helixes of the tetratricopeptide repeats of GEMIN5. In silico 3D representations of the GEMIN5 dimerization domain show that this variant likely affects the orientation of the downstream sidechains out of the helix axis, which would affect the packing with neighboring helices. The phenotype of all affected siblings overlaps well with previously reported patients, suggesting that NM_015465.5: c.3162_3164del (NP_056280.2):p. (Asp1054_Ala1055delinsGlu) is a novel GEMIN5 pathogenic variant. Overall, our data expands the molecular and clinical phenotype of the recently described neurodevelopmental disorder with cerebellar atrophy and motor dysfunction (NEDCAM) syndrome.

Expression of pro-inflammatory cytokines (IL-6 & IL-18) exacerbate the risk of diabetic nephropathy in the Pakistani population.

BACKGROUND: Diabetic nephropathy (DN) is a micro-chronic diabetic consequence induced by metabolic and hemodynamic abnormalities. Free radicals react with other critical cellular components, causing progression of aberrant renal function. OBJECTIVE: This case control study was aimed to determine the role of IL-6 and IL-18 in diabetic nephropathy in Pakistani population. METHODS AND MATERIALS: The study's subjects (n = 180 from Lahore, Gujranwala, and Karachi) were divided into control, diabetes mellitus (DM) and diabetic nephropathy (DN) groups. The serum concentration of IL-6 & IL-18 were determined by enzyme-linked immunosorbent assay (ELISA). The expression analysis of IL-6 & IL-18 were performed by Real Time PCR. RESULTS: The significant increase in serum levels of IL-6 were observed among the control, DM and DN groups (15.3 ± 24.1 pg/ml, 34.7 ± 24.0 pg/ml, 52.6 ± 33.2 pg/ml) whereas no significant difference was observed in serum levels of IL-18. The expression analysis of IL-6 was increased by more than forty three fold in DN group (n-fold = ~43.6) as compared to DM & control whereas the expression profile of IL-18 decreased in DN group (n-fold = ~0.89). In DN group the correlation analysis revealed direct association of GFR with serum IL-6 (r = 0.1114) & inverse relationship with serum IL-18 (r = - 0.097). In multiple regression analysis using GFR as the dependent variable, BMI and expression of IL-18 were determinants in DM subjects, but only uric acid in DN subjects. CONCLUSION: The present study implicates that increased expression of IL-6 and decreased of IL-18 was associated with development of DN in Pakistani population.

A Rare Case of Type B Neonatal Pyruvate Carboxylase Enzyme Deficiency Presenting With Refractory Lactic Acidosis in the Early Neonatal Period.

Pyruvate carboxylase (PC) enzyme deficiency is a rare genetic disorder inherited in an autosomal recessive (AR) manner. PC, a mitochondrial enzyme, converts pyruvate to oxaloacetate (OAA), which enters the tricarboxylic acid (TCA) cycle. Based on the tissue type, intermediate metabolites of the TCA cycle play a vital role in gluconeogenesis, lipogenesis, synthesis of nicotinamide adenine dinucleotide phosphate (NADPH), and neurotransmitter glutamate in the astrocytes. The severity of clinical presentation depends on the type of PC deficiency and on the residual enzyme activity. We present a term female infant admitted with refractory lactic acidosis that developed soon after birth. On biochemical evaluation, serum ammonia was 125 µmol/L; plasma amino acid analysis showed elevated citrulline, lysine, proline, decreased glutamine, and aspartic acid; urine organic acid analysis showed markedly increased lactic acid, and moderately elevated 3-hydroxy-butyric and acetoacetic acid. MRI brain demonstrated abnormal diffuse white matter edema, loculated and septate large cysts along the caudothalamic notch as well as lateral aspect of the frontal horn bilaterally. Magnetic resonance (MR) spectroscopy showed large amounts of lactate peak. Molecular genetic analysis showed two pathogenic variants in the PC gene confirming the diagnosis of PC enzyme deficiency. The infant was discharged home on palliative and hospice care, and she died on the 22nd day after birth.

A Neonate With Diabetes Mellitus, Congenital Hypothyroidism, and Congenital Glaucoma.

Neonatal diabetes mellitus (NDM) is a rare condition with more than 20 monogenic genes associated with it. GLIS3 gene-encoded GLI similar protein 3, as a transcription factor, is involved in the development of the pancreas, liver, kidneys, eye, and thyroid. We report a preterm female neonate with coarse facial features and hyperglycemia, later diagnosed with neonatal diabetes mellitus, congenital hypothyroidism (CH), congenital glaucoma (CG), and renal cysts, secondary to GLIS3 gene mutation. It is a rare genetic disorder involving multiple organ systems with progressive development of symptoms requiring long-term surveillance and management.

Mutational analysis in sodium-borate cotransporter SLC4A11 in consanguineous families from Punjab, Pakistan.

AIM: To identify the molecular basis of Congenital Hereditary Endothelial Dystrophy CHED caused by mutations in SLC4A11, in the consanguineous Pakistani families. METHODS: A total of 7 consanguineous families affected with Congenital Hereditary Endothelial Dystrophy were diagnosed and registered with the help of ophthalmologists. Blood samples were collected from affected and unaffected members of the enrolled families. Mutational analysis was carried out by DNA sequencing using both Sanger and Whole Exome Sequencing (WES). Probands of each pedigree from the 7 families were used for WES. Results were analyzed with the help of different bioinformatics tools. RESULTS: The sequencing results demonstrated three known homozygous mutations in gene SLC4A11 in probands of 7 families. These mutations p.Glu675Ala, p.Val824Met, and p.Arg158fs include 2 missense and 1 frameshift mutation. The mutations result in amino acids that were highly conserved in SLC4A11 across different species. The mutations were segregated with the disease phenotype in the families. CONCLUSION: This study reports 3 mutations in 7 families. One of the pathogenic mutations (p.R158fs) was identified for the first time in the Pakistani population. However, two mutations (p.Glu675Ala, p.Val824Met) were previously reported in two and one Pakistani family respectively. As these mutations segregate with the disease phenotype and bioinformatics tool also liable them as pathogenic, they are deemed as probable cause of underlying disease.

Biomarkers of Metabolic Syndrome: Role in Pathogenesis and Pathophysiology Of Atrial Fibrillation.

The relationship between Metabolic syndrome and Atrial Fibrillation is confirmed by many studies. The components of Metabolic syndrome cause remodeling of the atrial. Metabolic syndrome and metabolic derangements of the syndrome could be the cause of the pathogenesis of AF. This review article discusses the major biomarkers of Metabolic syndrome and their role in the pathogenesis of AF. The biomarkers are adiponectin, leptin, Leptin/ Adiponectin ratio, TNF-α, Interleukin-6, Interleukin-10, PTX3, ghrelin, uric acid, and OxLDL.The elevated plasma levels of adiponectin were linked to the presence of persistent AF. Leptin signaling contributes to angiotensin-II evoked AF and atrial fibrosis. Tumor necrosis factor-alpha involvement has been shown in the pathogenesis of chronic AF. Similarly, Valvular AF patients showed high levels of TNF-α. Increased left atrial size was associated with the interleukin-6 because it is a well-known risk factor for AF. Interleukin-10 as well as TNF-α were linked to AF recurrence after catheter ablation. PTX3 could be superior to other inflammatory markers that were reported to be elevated in AF. The serum ghrelin concentration in AF patients was reduced and significantly increased after treatment. Elevated levels of uric acid could be related to the burden of AF. Increased OxLDL was found in AF as compared to sinus rhythm control.

Association of Interleukin 10 (IL-10) Gene with Type 2 Diabetes Mellitus by Single Nucleotide Polymorphism of Its Promotor Region G/A 1082.

Interleukin 10 (IL-10) is an anti-inflammatory cytokine with lower circulating levels in patients with type 2 diabetes mellitus (T2DM). Cytokines such as IL-10 downregulate the production of pro-inflammatory cytokines, which impair proper function of insulin. So any mutation in the IL-10 gene results in increased production of proinflammatory cytokines, which in turn affect insulin action and cause T2DM. In this study, a polymorphism (rs1800896) in the gene (IL-10) and its association with T2DM was determined with the amplification-refractory mutation system with PCR (ARMS-PCR). Study subjects were divided in two groups, control and T2DM. DNA was extracted from blood, and ARMS-PCR was performed by using specific primers for the promoter region. An amplified product was obtained at 258 base pairs (bp). In the control group, heterozygous bands with both alleles (A/G) were present, whereas AA and GG homozygosity was observed in the T2DM group. This polymorphism (rs1800896) in the IL-10 gene is associated with T2DM. Physical measurements were also obtained, and significant differences between the groups were determined with an independent t-test. Significance was based on a p-value level of 0.05 or less, and highly significant was based on a p-value of 0.01 or less at 95% confidence interval.

Cardiac toxicity of heavy metals (cadmium and mercury) and pharmacological intervention by vitamin C in rabbits.

Mercury and cadmium are highly dangerous metals that can lead to disastrous effects in animals and humans. The aim of the current research was to elucidate the poisonous effects of mercuric chloride and cadmium chloride individually and in combination on biochemical profiles of plasma and their accumulation in heart. The therapeutic effect of vitamin C against these metals in rabbits was also studied. Mercuric chloride (1.2 µg/g), cadmium chloride (1.5 µg/g), and vitamin C (150 µg/g of body weight) were orally given to treatment groups of the rabbits (1-control; 2-vitamin; 3-CdCl2; 4-HgCl2; 5-vitamin + CdCl2; 6-vitamin + HgCl2; 7-CdCl2 + HgCl2, and 8-vitamin + CdCl2 + HgCl2. After the biometric determination of all intoxicated rabbits, biochemical parameters, viz low-density lipoproteins (LDL), high-density lipoproteins (HDL), cholesterol, creatine kinase, and troponin T (TnT) were analyzed using available kits. Levels of cholesterol (0.7 ± 0.1 mmol/l), creatine kinase (2985.2 ± 11 IU/L), LDL (20.35 ± 1.31 mg/dl), and troponin T (1.22 ± 0.03 µg/l) were significantly (P < 0.05) increased. HDL (84.78 ± 4.30 mg/dl) was significantly (P < 0.05) decreased, while supplementation of vitamin C decreased the adverse effects of CdCl2 and HgCl2 on biochemical parameters in all metal-exposed groups. A similar trend was also seen in rabbits treated with CdCl2 + vitamin and vitamin + CdCl2 + HgCl2. Accumulation of Cd and Hg was higher in heart tissues. This study, therefore, provides awareness on the cardiac toxicity of mercury and cadmium chlorides in the rabbits and the possible protective role of vitamin C against the perturbations induced by metals.