Prevalence, Clinical Characteristics, and Clinical Outcomes of New-onset Diabetes Mellitus among COVID-19 Patients in Developing and Developed Countries: A Systematic Review.

Diabetes mellitus (DM) is linked to poor clinical outcomes and high mortality in Coronavirus patients. The primary objective of this systematic review was to determine the prevalence, clinical features, glycemic parameters, and outcomes of newly diagnosed diabetes in individuals with COVID-19 in developing and developed countries. By searching PubMed, Medline, Scopus, Embase, Google Scholar, and PakMediNet databases, an online literature search was conducted from March 2020 to November 2021.

Substance Abuse and Mental Health Issues Among HIV/AIDS Patients.

Psychiatric morbidity commonly coexists with substance abuse and HIV/AIDS around the globe. This review study aimed to determine the available literature on the prevalence of common substance abuse/use and common mental health illnesses among HIV/AIDS patients worldwide to help policymakers design appropriate strategies to limit extensive substance use and prevent common mental and health illnesses. For the comprehensive literature review, Google Scholar, PubMed Central, Medline, and PakMediNet biomedical databases were searched for original and reviewed studies published in English, from January 2000 to September 2021.

Validity of the patient health questionnaires (phq-2 and phq-9) for screening depression among human immunodeficiency virus patients in Lahore, Pakistan.

Background: Many human immunodeficiency virus (HIV) infected patients suffer from depr-ession, but a little focus is given to detecting and treating depression in primary health care. Detection of depression can be improved by introducing short, reliable, and valid screening instruments.

Aim: To determine the psychometric properties of the patient health questionnaire-2 (PHQ-2) and patient health questionnaire-9 (PHQ-9) for depression screening and diagnosis, and the sensitivity and specificity of the PHQ-2 in HIV infected patients.

Fronto-striatal connectivity patterns account for the impact of methylphenidate on choice impulsivity among healthy adults.

Choice impulsivity depicts a preference towards smaller-sooner rewards over larger-delayed rewards, and is often assessed using a delay discounting (DD) task. Previous research uncovered the prominent role of dopaminergic signaling within fronto-striatal circuits in mediating choice impulsivity. Administration of methylphenidate (MPH), an indirect dopaminergic agonist, was shown to reduce choice impulsivity in animals and pathological populations, although significant inter-individual variability in these effects was reported.

Probenecid, an organic anion transporter 1 and 3 inhibitor, increases plasma and brain exposure of N-acetylcysteine.

1. N-acetylcysteine (NAC) is being investigated as an antioxidant for several conditions including traumatic brain injury, but the mechanism by which it crosses membrane barriers is unknown. We have attempted to understand how the transporter inhibitor, probenecid, affects NAC pharmacokinetics and to evaluate the interaction of NAC with transporters.

Lipid peroxidation is not the primary mechanism of bilirubin-induced neurologic dysfunction in jaundiced Gunn rat pups.

Background: Hazardous levels of bilirubin produce oxidative stress in vitro and may play a role in the genesis of bilirubin-induced neurologic dysfunction (BIND). We hypothesized that the antioxidants taurourosdeoxycholic acid (TUDCA), 12S-hydroxy-1,12-pyrazolinominocycline (PMIN), and minocycline (MNC) inhibit oxidative stress and block BIND in hyperbilirubinemic j/j Gunn rat pups that were given sulfadimethoxine to induce bilirubin encephalopathy.

Methods: At peak postnatal hyperbilirubinemia, j/j Gunn rat pups were dosed with sulfadimethoxine to induce bilirubin encephalopathy.

Effect of nuclear factor κB inhibition on serotype 9 adeno-associated viral (AAV9) minidystrophin gene transfer to the mdx mouse.

Gene therapy studies for Duchenne muscular dystrophy (DMD) have focused on viral vector-mediated gene transfer to provide therapeutic protein expression or treatment with drugs to limit dystrophic changes in muscle. The pathological activation of the nuclear factor (NF)-κB signaling pathway has emerged as an important cause of dystrophic muscle changes in muscular dystrophy. Furthermore, activation of NF-κB may inhibit gene transfer by promoting inflammation in response to the transgene or vector.

Systemic delivery of NEMO binding domain/IKKγ inhibitory peptide to young mdx mice improves dystrophic skeletal muscle histopathology.

The activation of nuclear factor κB (NF-κB) contributes to muscle degeneration that results from dystrophin deficiency in human Duchenne muscular dystrophy (DMD) and in the mdx mouse. In dystrophic muscle, NF-κB participates in inflammation and failure of muscle regeneration. Peptides containing the NF-κB Essential Modulator (NEMO) binding domain (NBD) disrupt the IκB kinase complex, thus blocking NF-κB activation.

Frequency of anaemia and renal insufficiency in patients with heart failure.

Background: Heart Failure (HF) is a common disease with a high mortality rate. Anaemia and renal failure (RF) are often present in patients with HF and associated with worse prognosis. Objective of study was to evaluate the prevalence of anaemia and RF in patients with HF.

Genetic determinants of major blood lipids in Pakistanis compared with Europeans.

Background: Evidence is sparse about the genetic determinants of major lipids in Pakistanis.

Methods And Results: Variants (n=45 000) across 2000 genes were assessed in 3200 Pakistanis and compared with 2450 Germans using the same gene array and similar lipid assays. We also did a meta-analysis of selected lipid-related variants in Europeans.

Improvement of the mdx mouse dystrophic phenotype by systemic in utero AAV8 delivery of a minidystrophin gene.

Duchenne muscular dystrophy (DMD) is a devastating primary muscle disease with pathological changes in skeletal muscle that are ongoing at the time of birth. Progressive deterioration in striated muscle function in affected individuals ultimately results in early death due to cardio-pulmonary failure. As affected individuals can be identified before birth by prenatal genetic testing for DMD, gene replacement treatment can be started in utero.

Association of the 9p21.3 locus with risk of first-ever myocardial infarction in Pakistanis: case-control study in South Asia and updated meta-analysis of Europeans.

Objective: To examine variants at the 9p21 locus in a case-control study of acute myocardial infarction (MI) in Pakistanis and to perform an updated meta-analysis of published studies in people of European ancestry.

Methods And Results: A total of 1851 patients with first-ever confirmed MI and 1903 controls were genotyped for 89 tagging single-nucleotide polymorphisms at locus 9p21, including the lead variant (rs1333049) identified by the Wellcome Trust Case Control Consortium. Minor allele frequencies and extent of linkage disequilibrium observed in Pakistanis were broadly similar to those seen in Europeans.

The Pakistan Risk of Myocardial Infarction Study: a resource for the study of genetic, lifestyle and other determinants of myocardial infarction in South Asia.

The burden of coronary heart disease (CHD) is increasing at a greater rate in South Asia than in any other region globally, but there is little direct evidence about its determinants. The Pakistan Risk of Myocardial Infarction Study (PROMIS) is an epidemiological resource to enable reliable study of genetic, lifestyle and other determinants of CHD in South Asia. By March 2009, PROMIS had recruited over 5,000 cases of first-ever confirmed acute myocardial infarction (MI) and over 5,000 matched controls aged 30-80 years.

Calculated free bilirubin levels and neurotoxicity.

Although most bilirubin in the circulation is bound to albumin, a relatively small fraction remains unbound. The concentration of this 'free' bilirubin (B(F)) is believed to dictate the biologic effects of bilirubin in jaundiced newborns, including its neurotoxicity. The threshold at which B(F) produces changes in cellular function culminating in permanent cell injury and cell death has been the subject of considerable debate.

ABC transporter (P-gp/ABCB1, MRP1/ABCC1, BCRP/ABCG2) expression in the developing human CNS.

P-glycoprotein (P-gp/ABCB1), multidrug resistance associated protein 1 (MRP1/ABCC1), and breast cancer resistance protein (BCRP/ABCG2) are plasma membrane efflux pumps that limit the intracellular uptake and retention of numerous lipophilic, amphipathic xeno- and endobiotics. Little is known about the neonatal and developmental expression of P-gp/ABCB1, MRP1/ABCC1, and BCRP/ABCG2 in the human central nervous system (CNS), therefore post-mortem CNS tissue from infants born at 22 (0/7)-42 (0/7) weeks of gestation and adults was immunostained to determine their ontogeny and cellular localization. P-gp/ABCB1 immunostaining was observed in microvessel endothelial cells as early as 22 (0/7) weeks, increasing in prevalence and intensity with maturation, and later in gestation in large pyramidal neurons.

Unconjugated bilirubin efflux by bovine brain microvascular endothelial cells in vitro.

Objectives: The passage of unconjugated bilirubin (UCB) across the blood-brain barrier into the central nervous system is a crucial first step in the development of kernicterus. The objective of the current study was to characterize the passage of UCB across primary bovine brain microvascular endothelial cell (BBMVEC) monolayers in vitro.

Design: Experimental study.

Calculated in vivo free bilirubin levels in the central nervous system of Gunn rat pups.

In vitro studies suggest a free bilirubin (B(F)) concentration in the range of 71-770 nmol/L can induce neurotoxicity. In vivo data regarding central nervous system (CNS) B(F) levels have not been determined. We calculated in vivo CNS B(F) levels in Gunn rat pups (15-19 d old; heterozygous nonjaundiced Gunn rats (J/j) and homozygous jaundiced Gunn rats (j/j); saline or sulfadimethoxine treated) based on 1) total brain bilirubin (TBB) content, 2) brain albumin level, 3) CNS bilirubin binding capacity attributable to brain albumin determined using an ultrafiltration technique, and 4) published Gunn rat albumin-bilirubin binding constants (k).

Skeletal muscle glucose transporter protein responses to antenatal glucocorticoids in the ovine fetus.

We investigated the effects of maternal antenatal dexamethasone (Dex) treatment given as a single course (4 doses) or multiple courses (20 doses) on fetal skeletal muscle glucose transporter (GLUT) protein concentrations at 70% of gestation (106 to 107 days with term being 145 to 150 days) in the ovine fetus. Antenatal corticosteroid administration was associated with a decrease in endogenous fetal plasma cortisol concentrations (P < 0.05), fetal hyperglycemia (P < 0.

Sex-specific regional brain bilirubin content in hyperbilirubinemic Gunn rat pups.

Background: The hyperbilirubinemic j/j Gunn rat is frequently used to study the effects of neonatal hyperbilirubinemia on the developing central nervous system (CNS). Despite evidence that the cerebellar region and males are predisposed to bilirubin-induced brain injury in this animal model, there are limited regional and no sex-specific brain bilirubin content data.

Objective/methods: To characterize and contrast the regional (cortex, brainstem, cerebellum) and sex-specific CNS bilirubin contents of hyperbilirubinemic j/j Gunn rat pups and their age-matched (15-19 days) nonjaundiced J/j counterparts.

IUGR alters postnatal rat skeletal muscle peroxisome proliferator-activated receptor-gamma coactivator-1 gene expression in a fiber specific manner.

Uteroplacental insufficiency and subsequent intrauterine growth retardation (IUGR) increase the risk of insulin resistance in humans and rats. Aberrant skeletal muscle lipid metabolism contributes to the pathogenesis of insulin resistance. Peroxisome proliferator-activated receptor-gamma co-activator-1 (PGC-1) is a transcriptional co-activator that affects gene expression of key lipid metabolizing enzymes such as carnitine palmitoyl-transferase I (mCPTI).

Understanding neonatal hyperbilirubinaemia in the era of genomics.

The genomics revolution offers novel approaches to scientific investigation. Application of genomics technologies including microarray gene chips will provide a more complete picture of biological phenomena and help define the genetic contribution to disease by monitoring changes in expression across thousands of genes in physiological and clinical contexts. We briefly summarize identified genetic components that contribute to the genesis of neonatal hyperbilirubinaemia with a focus on inborn errors of hepatic bilirubin conjugation and discuss the potential use of microarray gene expression profiling technology to enhance our understanding of the pathogenesis of hyperbilirubinaemic neuronal cell injury.

P-glycoprotein and bilirubin disposition.

P-glycoprotein (Pgp), an ATP-dependent plasma membrane efflux pump, is expressed in abundance on the luminal aspect of brain capillary endothelial cells and astrocytes of the blood-brain barrier where it limits the passage of a variety of lipophilic substrates into the central nervous system. This review summarizes current evidence characterizing (1) unconjugated bilirubin as a potential substrate for Pgp and (2) the ontogeny of Pgp expression at the blood-brain barrier and apical brush border epithelium of the gastrointestinal tract, findings that may provide insights regarding the disposition of bilirubin in immature subjects.

P-glycoprotein expression in mouse brain increases with maturation.

The mdr1a isoform of P-glycoprotein (Pgp) is an integral plasma membrane efflux pump expressed in adult brain capillary endothelial cells and astrocytes of the blood-brain barrier. We determined the developmental pattern of Pgp expression in brain tissue at embryonic day 16 (E16), day of life 0 (D0), day of life 7 (D7), day of life 21 (D21), and adults (Ad). The relative expression of Pgp mRNA and protein was indexed as a percent (mean +/- SEM) of D0 levels.