CYP2C19*17 association with higher plasma 4-hydroxy tamoxifen in Pakistani (estrogen-positive) breast cancer patients.

Breast cancer (BC) continues to be the most common cancer in the women worldwide. Since estrogen receptor (ER)-positive BC accounts for the majority of newly diagnosed cases, endocrine therapy is advised to utilize either tamoxifen (Tam) or aromatase inhibitors. The use of Tam as a monotherapy or in conjunction with an aromatase inhibitor following two or three years of endocrine therapy has long been recommended. When used adjuvantly, Tam medication reduces BC mortality and relapses, while it extends survival times in metastatic BC when used in conjunction with other treatments. Unfortunately, the efficiency of Tam varies considerably. This study was conducted to explore the influence of genetic polymorphisms in CYP2C19 gene on Tam's pharmacogenetics and pharmacokinetics in estrogen-positive BC patients. Data from healthy, unrelated individuals (n = 410; control group) and ER-positive BC patients (n = 430) receiving 20 mg of Tam per day were recruited. Steady-state plasma concentrations of Tam and its three metabolites were quantified using the high-performance liquid chromatography in the patients. The CYP2C19 polymorphisms were genotyped using an Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR) approach. More than 65% of healthy individuals were extensive metabolizers (*1/*1) for CYP2C19, whereas more than 70% of ER-positive BC patients were rapid and ultrarapid metabolizers (*1/17*, *17/17*). The polymorphism CYP2C19*17 is significantly associated with higher 4-hydroxytamoxifen (4-OH-Tam). Patients with the *17/*17 genotype exhibited 1- to 1.5-fold higher 4-OH-Tam, which was also high in patients with the *1/*2 and *2/*2 genotypes.

Systemic lupus erythematosus with secondary thrombotic thrombocytopenic purpura and acute parkinsonism: A case report.

Systemic lupus erythematosus (SLE) is an autoimmune disease that has certain characteristic features but can also present with misleading signs and symptoms especially when it is of late-onset. Various case reports address its association with thrombotic thrombocytopenic purpura (TTP), however, its association with parkinsonism remains unclear. We present the case of a 58-year-old male who reported with acute-onset parkinsonism along with some gastrointestinal symptoms. Detailed laboratory investigations unmasked the underlying SLE with an overlapping picture of TTP. This unusual presentation in a resource-constrained setting created challenges and subsequent delays in the diagnosis and management of the patient. Despite urgent care, the patient's age, presence of overlapping conditions, and multi-organ involvement were some of the factors due to which the treatment failed and he could not survive. We report the association of SLE with secondary TTP and parkinsonism. More studies are needed to provide a greater understanding of these associations and various risk factors that drive them.

SIRTI and cortisol in unexplained infertile females; a cross sectional study, in Karachi Pakistan.

OBJECTIVE: To explore a disparity in anti-oxidants (SIRT1) and pro-oxidants (cortisol) levels as a plausible cause of unexplained infertility in females. METHODOLOGY: It was a cross sectional study in which 342 females with unexplained infertility were recruited from ACIMC outpatient clinic: 135 infertile cases and 207 fertile controls. Biochemical estimation of serum cortisol and SIRT1 was performed using Enzyme Linked Immuno Sorbent Assay. Statistical comparisons were performed using Student-t test and Mann-Whitney U test. Associations between circulating hormone levels and infertility were determined using Spearman's rank correlation. Associations were considered significant where value of p was less than 0.05. RESULTS: The stress hormones profile of case and control demonstrated that the antioxidant SIRT1 was significantly lower in infertile females when compared with the fertile (p =< 0.001) while (the oxidant) Cortisol showed a contrast of results with higher values of in infertile females when compared with fertile counterparts (p =< 0.01). There was a strong negative association observed between SIRT1 and cortisol serum level (r = 0.244, p < 0.001). CONCLUSION: Chronic stress causes oxidative stress that is depicted by a decrease in antioxidant levels in infertile females.

Rhesus Isoimmunization: Late-onset Hemolytic Disease of the Newborn Without Jaundice.

Rhesus (Rh) isoimmunization commonly presents with anemia and jaundice of varying intensity in the early postnatal period and is usually treated with phototherapy and exchange transfusion. Rarely, babies with mild or no symptoms at birth may present later with severe hemolytic anemia. This report describes a newborn infant with no postnatal jaundice who presented during the second week of life with severe anemia. These findings indicate the importance of regular follow-up and close monitoring of Rh-isoimmunized infants during the first two months of life for delayed onset anemia.

Genetic Polymorphism of CYP2C19 in Pakistani Population.

CYP2C19 polymorphism is associated with pretreatment drug response prediction, metabolism, and disposition. Pakistan consists of a population comprising of various ethnic groups residing in different regions of the country each claiming diverse ethnic origins. The identification of CYP450 genotypic composition of these populations is therefore necessary to avoid adverse drug reactions in these individuals. The main objective of the study was to investigate the prevalence of CYP2C19*2 and CYP2C19*17 alleles in these ethnic groups. The study was conducted on one thousand and twenty-eight (n = 1028) healthy volunteers from nine ethnic groups of Pakistan namely Brusho (n = 28), Hazara (n = 102), Kalash (n = 64), Pathan (n = 170), Punjabi (n = 218), Saraiki (n = 59), Brahui (n = 118), Parsi (n = 90), and Sindhi (n = 179). DNA was extracted from leukocytes and analyzed by allele specific amplification polymerase chain reaction (ASA-PCR). Multi allelic polymorphism of CYP2C19 led to four distinct phenotypes identified as extensive metabolizer (EM), poor metabolizer (PM), intermediate metabolizer (IM), and ultra-rapid metabolizer (UM). Over all, the percentage of predicted poor metabolizer allele was 29.0% compared to UM allele (23.70%). Among the studied groups, Saraiki and Brahui showed highest percentage of PM allele (40%, 36%) whereas Parsi and Hazara had highest percentage of UM allele (37% and 30% respectively). In conclusion, the high allele frequency of PM (CYP2C19*2 and *17) in Pakistani population led to the recommendation of a pre-treatment test to monitor drug response and dosage (personalized medicine) to avoid post-treatment adverse drug reactions.

Factor XIII deficiency with intracranial haemorrhage.

A 5-year-old girl presented to paediatric emergency with fever and seizures for a short duration. At first, meningitis was suspected and management was started empirically. There was no improvement in the clinical condition of the patient and investigations revealed spontaneous intracranial haemorrhage (ICH) secondary to factor XIII deficiency. The child was transfused cryoprecipitate and managed conservatively for ICH. She became asymptomatic and was kept on monthly cryoprecipitate transfusions. This case report summarises factor XIII deficiency in ICH which was not suspected initially, but diagnosed later on after CT scan head and factor XIII assay. This report also highlights events occurring during its management.