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In the current study, the possible outcome of gender difference and genotypic polymorphism of the ABCB1 gene encoding P-glycoprotein on the pharmacokinetics of azithromycin has been evaluated. An open-label, comparative pharmacokinetic study was done in healthy Pakistani volunteers (females (n = 8) and males (n = 8)). They were administered a single 500 mg oral dose of azithromycin. Blood samples ([approximately equal to] 5 mL) were collected in heparinized tubes and the HPLC/MS/MS method was used to determine azithromycin plasma levels. ABCB1 polymorphism (single nucleotide polymorphisms) at C3435T, G26SST was performed using the RFLP-PCR method. The Student t test was applied to compare pharmacokinetic parameters of azithromycin between male and female human subjects (at 95% CI) using GraphPad Prism-8. A significant difference was observed in pharmacokinetic parameters between males and females, as [C.sub.max] in males (230 [+ or -] 80.2 ng/mL) was significantly higher than in females (224.9 [+ or -] 75.5 ng/mL), while [(AUC).sup.t.sub.0] was also significantly higher (p < 0.05) in males (2102 [+ or -] 200.3 ng * [h.sup.-1] * [mL.sup.-1]) compared to females (1825.7 [+ or -] 225.4 ng x [h.sup.-1] * [mL.sup.-1]). There was a significant variation in [C.sub.max] and AUC in three ABCB1 genotyping groups as well. Gender difference and ABCB1 gene polymorphisms have a significant impact on the pharmacokinetics of azithromycin, as they contribute to interindividual variability in therapeutic response. Key words: gene polymorphism, pharmacokinetics, gender differences, ABCB1. Dans la presente etude, nous avons evalue les resultats eventuels de la pharmacocinetique de l'azithromycine quant a la difference entre les sexes et entre les polymorphismes genotypiques du gene ABCB1 codant la P-glycoproteine. Nous avons mene une etude pharmacocinetique comparative ouverte chez des volontaires pakistanais sains (femmes (n = 8) et hommes (n = 8)). Nous leur avons administre une dose unique d'azithromycine a 500 mg par voie orale. Nous avons preleve des echantillons de sang ([approximately equal to] 5 mL) dans des tubes heparines, et etabli les taux plasmatiques d'azithromycine a l'aide de la chromatographie liquide a haute performance avec spectrometrie de masse et de la spectrometrie de masse. Le polymorphisme du gene ABCB1 (polymorphismes mononucleotidiques) etait etabli a C3435T et a G26SST a l'aide de la methode de RFLP-PCR. Nous avons applique un test t de Student en vue de comparer les parametres pharmacocinetiques de l'azithromycine entre les sujets masculins et feminins (IC a 95 %) a l'aide de la trousse GraphPad Prism-8. Nous avons observe une difference marquee entre les hommes et les femmes quant aux parametres pharmacocinetiques, avec une Cmax nettement plus elevee chez les hommes (230 [+ or -] 80,2 ng/mL) que chez les femmes (224,9 [+ or -] 75,5 ng/ml), tandis que l'[(ASC).sup.t.sub.0] etait aussi nettement plus elevee (p < 0,05) chez les hommes (2102 [+ or -] 200,3 ng * [h.sup.-1] * [mL.sup.-1]) que chez les femmes (1825,7 [+ or -] 225,4 ng x [h.sup.-1] * [mL.sup.-1).] Nous avons aussi observe une variation marquee du Cmax et de l'ASC dans trois groupes de genotypes de ABCB1. Les differences entre les sexes et entre les polymorphismes du gene ABCB1 avaient une incidence marquee sur les proprietes pharmacocinetiques de l'azithromycine avec une participation a la variabilite de la reponse therapeutique entre les sujets. [Traduit par la Redaction] Mots-cles: polymorphisme genique, pharmacocinetique, differences entre les sexes, ABCB1., Introduction The concept of personalized medicine emphasizes the identification of variables that affect the disease course and therapy (Holdcroft 2007; Walden 2007). Among various factors influencing the drug concentrations in [...]

Background: Intellectual disability (ID) can be associated with different syndromes such as Rubinstein‐Taybi syndrome (RSTS) and can also be related to conditions such as metabolic encephalomyopathic crises, recurrent,with rhabdomyolysis, cardiac arrhythmias and neurodegeneration. Rare congenital RSTS1 (OMIM 180849) is characterized by mental and growth retardation, significant and duplicated distal phalanges of thumbs and halluces, facial dysmorphisms, and an elevated risk of malignancies. Microdeletions and point mutations in the CREB‐binding protein (CREBBP) gene, located at 16p13.3, have been reported to cause RSTS. By contrast, TANGO2‐related metabolic encephalopathy and arrhythmia (TRMEA) is a rare metabolic condition that causes repeated metabolic crises, hypoglycemia, lactic acidosis, rhabdomyolysis, arrhythmias and encephalopathy with cognitive decline. Clinicians need more clinical and genetic evidence to detect and comprehend the phenotypic spectrum of this disorder. Methods: Exome sequencing was used to identify the disease‐causing variants in two affected families A and B from District Kohat and District Karak, Khyber Pakhtunkhwa. Affected individuals from both families presented symptoms of ID, developmental delay and behavioral abnormalities. The validation and co‐segregation analysis of the filtered variant was carried out using Sanger sequencing. Results: In the present study, two families (A and B) exhibiting various forms of IDs were enrolled. In Family A, exome sequencing revealed a novel missense variant (NM 004380.3: c.4571A>G; NP_004371.2: p.Lys1524Arg) in the CREBBP gene, whereas, in Family B, a splice site variant (NM 152906.7: c.605 + 1G>A) in the TANGO2 gene was identified. Sanger sequencing of both variants confirmed their segregation with ID in both families. The in silico tools verified the aberrant changes in the CREBBP protein structure. Wild‐type and mutant CREBBP protein structures were superimposed and conformational changes were observed likely altering the protein function. Conclusions: RSTS and TRMEA are exceedingly rare disorders for which specific clinical characteristics have been clearly established, but more investigations are underway and required. Multicenter studies are needed to increase our understanding of the clinical phenotypes, mainly showing the genotype–phenotype associations. [ABSTRACT FROM AUTHOR]

Intellectual disability (ID) is a neurodevelopmental disorder which appears frequently as the result of genetic mutations and may be syndromic (S-ID) or non-syndromic (NS-ID). ID causes an important economic burden, for patient's family, health systems, and society. Identifying genes that cause S-ID can easily be evaluated due to the clinical symptoms or physical anomalies. However, in the case of NS-ID due to the absence of co-morbid features, the latest molecular genetic techniques can be used to understand the genetic defects that underlie it. Recent studies have shown that non-syndromic autosomal recessive (NS-ARID) is extremely heterogeneous and contributes much more than X-linked ID. However, very little is known about the genes and loci involved in NS-ARID relative to X-linked ID, and whose complete genetic etiology remains obscure. In this review article, the known genetic etiology of NS-ARID and possible relationships between genes and the associated molecular pathways of their encoded proteins has been reviewed which will enhance our understanding about the underlying genes and mechanisms in NS-ARID.

Oculocutaneous albinism (OCA) is a genetic disorder of melanin synthesis that results in hypopigmentation in hair, skin and eyes. OCA has been reported in individuals from all ethnic backgrounds but it is more common among those with Europeans ancestry. OCA is heterogeneous group of disorders and seven types of OCA are caused by mutations in TYR (OCA1), OCA2 (OCA2), TYRP1 (OCA3), SLC45A2 (OCA4), SLC24A5 (OCA6) and C10oRF11 (OCA7) genes. However, MC1R gene variants have been reported that modify OCA2 phenotype but the knowledge about the function ofMC1R gene in melanogenesis, and genotype-phenotype association, in case of OCA, is limited. In this review article we present a comprehensive description of classification of OCA, role of MSH-R in melanin synthesis, the sequence variations in MC1R and their association with OCA. This review will enhance our understanding of MC1R gene variants involved in human OCA2 phenotype.

Abstract Background The epidemiological significance of Hepatitis B virus genotypes has been well established and becoming an essential concern day by day however, much little is known about the mixed infection with more than one Hepatitis B virus genotypes and their clinical relevance. Methods Intravenous drug abusers are considered as a major risk group for the acquisition and transmission of blood borne infections like hepatitis B, however, in Pakistan, no such data has ever been reported about the epidemiology of HBV and its genotypes in Injecting Drug Users. 250 individuals were analyzed for hepatitis B virus genotypes after prior screening with serological assay for the detection of HBsAg. Results 56 (22.4%) individuals were found positive on ELSIA for HBsAg. The genotype distribution was found to be as: genotype D, 62.5%; genotype A, 8.92% while 28.57% individuals were found to be infected with a mixture of genotype A and D. Conclusion There is an urgent need of the time to develop public health care policies with special emphasis towards the control of HBV transmission through high risk groups especially Injecting Drug Users.

Respiratory tract infections (RTIs) are the most common infectious diseases in humans and are the major cause of mortality and morbidity in Pakistan. These infections are the leading causes of consultations in primary care in Pakistan. Therefore, this study was aimed at determining bacterial pathogens of respiratory tract infections and the susceptibility patterns of bacterial isolates to antibiotics. The study was conducted between February, 2013 and March, 2014 in North Waziristan region of Pakistan. Sputum specimens were collected aseptically from 227 patients and cultured on the appropriate bacteriological media. Bacterial isolates were identified by biochemical tests and their antibiotics susceptibility patterns were determined by standard methods. Out of 227, various species of bacteria were isolated from 152 (75%) specimens. The prevalence of bacteria species isolated were as follows Pseudomonas aeruginosa (42.8%), Streptococcus pneumoniae, (26.7%), Corynebacterium diphtheria (10.6%), Staphylococcus aureus (5.9%), Proteus vulgaris (4.6%), Micrococcus species (3.3%), Klebsiella pneumoniae (2.6%) and Bacillus species (2.6%). The susceptibility patterns varied among bacterial species depending on the antibiotics. For the susceptibility test 11 commercially available antibiotics against bacterial isolates were used. The results revealed that generally the bacterial isolates were susceptible to gentamicin (80.9%), meropenem (75 %), ceftazidime (62.5%), cefotaxime (57.9%) and ceftriazone (57.9%) and resistant to penicillin (84.9%) and doxycycline (78.9%). The antibiotics gentamicin (100%) meropenem (100%), ceftriaxone (58.5%), ciprofloxacin (60%) trimethoprim (60%), ceftazidime (66.2%) and cefotaxime (64.6%) were observed effective against the P. aeruginosa isolates. The findings of our study provide significant information for empiric therapy of patients with RTIs in North Waziristan region of Pakistan. [ABSTRACT FROM AUTHOR]

Aim: To investigate the genetic basis of autosomal recessive retinitis pigmentosa (arRP) in two consanguineous/ endogamous Pakistani families., Methods: Whole exome sequencing (WES) was performed on genomic DNA samples of patients with arRP to identify disease causing mutations. Sanger sequencing was performed to confirm familial segregation of identified mutations, and potential pathogenicity was determined by predictions of the mutations' functions., Results: A novel homozygous frameshift mutation [NM&#95;000440.2:c.1054delG, p. (Gln352Argfs*4); Chr5:g.149286886del (GRCh37)] in the PDE6A gene in an endogamous family and a novel homozygous splice site mutation [NM&#95;033100.3:c.1168-1G>A, Chr10:g.85968484G>A (GRCh37)] in the CDHR1 gene in a consanguineous family were identified. The PDE6A variant p. (Gln352Argfs*4) was predicted to be deleterious or pathogenic, whilst the CDHR1 variant c.1168-1G>A was predicted to result in potential alteration of splicing., Conclusion: This study expands the spectrum of genetic variants for arRP in Pakistani families., (International Journal of Ophthalmology Press.)

Aim: To map Usher phenotype in a consanguineous Pakistani family and identify disease-associated mutation in a causative gene to establish phenotype-genotype correlation., Methods: A consanguineous Pakistani family in which Usher phenotype was segregating as an autosomal recessive trait was ascertained. On the basis of results of clinical investigations of affected members of this family disease was diagnosed as Usher syndrome (USH). To identify the locus responsible for the Usher phenotype in this family, genomic DNA from blood sample of each individual was genotyped using microsatellite Short Tandem Repeat (STR) markers for the known Usher syndrome loci. Then direct sequencing was performed to find out disease associated mutations in the candidate gene., Results: By genetic linkage analysis, the USH phenotype of this family was mapped to PCDH15 locus on chromosome 10q21.1. Three different point mutations in exon 11 of PCDH15 were identified and one of them, c.1304A>C was found to be segregating with the disease phenotype in Pakistani family with Usher phenotype. This, c.1304A>C transversion mutation predicts an amino-acid substitution of aspartic acid with an alanine at residue number 435 (p.D435A) of its protein product. Moreover, in silico analysis revealed conservation of aspartic acid at position 435 and predicated this change as pathogenic., Conclusion: The identification of c.1304A>C pathogenic mutation in PCDH15 gene and its association with Usher syndrome in a consanguineous Pakistani family is the first example of a missense mutation of PCDH15 causing USH1 phenotype. In previous reports, it was hypothesized that severe mutations such as truncated protein of PCDH15 led to the Usher I phenotype and that missense variants are mainly responsible for non-syndromic hearing impairment.