Association of Mitochondrial HVS-I Region Variants with Type 2 Diabetes in Pakistani Diabetic Subjects.

OBJECTIVE: To analyse mitochondrial hypervariable segment I (HVS-I) variations in Pakistani type 2 diabetic subjects. STUDY DESIGN: Case-control study. Place and Duration of the Study: National Institute of Diabetes and Endocrinology, Dow University of Health Sciences, Karachi, Pakistan, between January 2019 to January 2021. METHODOLOGY: DNA from whole blood was isolated, and mitochondrial HVS-I region (16024-16370) of 92 individuals, including 47 controls and 45 diabetics, was amplified, sequenced, and analysed. RESULTS: Ninety-two variable sites in the sequenced region were identified and individuals were classified into 56 different haplotypes according to phylotree 17.0 classifications, where major haplotype M5 was nearly 2-fold higher in diabetes. Fischer's exact test revealed variant 16189T>C significantly associated with diabetes (Odds ratio = 12.9, 95% CI = 0.6917 - 2400248) as compared to controls. The authors further analysed 1000 Genomes Project data of Pakistani Control subjects (i.e. PJL, n=96) and found that besides 16189T>C (Odds ratio = 5.875, 95% CI = 1.093 - 31.57, p <0.0339), 16264C>T (Odds ratio = 16, 95% CI = 0.8026 - 314.7, p <0.0310) also showed significant association with diabetic subjects. Comparing diabetic subject data with global control population data of the 1000 Genomes Project, significant associations of eight variants in the studied region were found. CONCLUSION: Based on the results of this case-control study, it can be concluded that specific variations in the mitochondrial hypervariable segment I (HVS-I) region are significantly associated with type 2 diabetes in the Pakistani population. The major haplotype M5 was found to be higher in diabetic subjects and variants 16189T>C and 16264C>T were significantly associated with diabetes. These findings suggest that mitochondrial DNA variations may play a role in the development of type 2 diabetes in the Pakistani population. KEY WORDS: Diabetes Mellitus, HVS-1 region, Diabetic subjects, Mitochondrial genomics, Pakistani population.

A Novel Predictive Model for Hospital Survival in Patients who are Critically Ill with Dialysis-Dependent AKI: A Retrospective Single-Center Exploratory Study.

Background: Mortality of patients who are critically ill with AKI initiated on RRT is very high. Identifying modifiable and unmodifiable clinical variables at dialysis start that are associated with hospital survival can help, not only in prognostication, but also in clinical triaging. Methods: A retrospective observational study was conducted on patients with AKI-D who were initiated on RRT in the medical and surgical intensive care units (ICUs) of a high-acuity academic medical center from January 2010 through December 2015. We excluded patients with suspected poisoning, ESKD, stage 5 CKD not on dialysis, or patients with AKI-D initiated on RRT outside of the ICU setting. The primary outcome was in-hospital mortality. Results: Of the 416 patients who were critically ill with AKI-D admitted to the medical (38%), surgical (41%), and cardiac (21%) ICUs, with nearly 75% on artificial organ support, the mean age 62.1±14.8 years, mean SOFA score was 11.8±4.3, dialysis was initiated using continuous RRT in 261 (63%) and intermittent hemodialysis in 155 (37%) patients. Incidence of survival to hospital discharge was 48%. Using multivariable logistic regression with stepwise backward elimination, a prognostic model was created that included the variables age, CKD, COPD, admission, and within 24 hours of the start SOFA score, refractory hyperkalemia and uremic encephalopathy as dialysis indications, BUN >100 mg/dl, serum creatinine, serum lactate, serum albumin, CRRT as initial modality, severe volume overload, and abdominal surgery. The model exhibited good calibration (goodness of fit test, P=0.83) and excellent discrimination (optimism-corrected C statistic 0.93). Conclusions: In this single-center, diverse, critically ill AKI-D population, a novel prognostic model that combined widely used ICU scores, clinical and biochemical data at dialysis start, and dialysis indication and modality, robustly predicted short-term survival. External validation is needed to prove the generalizability of the study findings.

Adhesion molecule L1 inhibition increases infarct size in cerebral ischemia-reperfusion without change in blood-brain barrier disruption.

OBJECTIVE: Neural cell adhesion molecule L1CAM (L1) is involved in neuroprotection. To investigate a possible neuroprotective effect of L1 during ischemia, we determined whether blocking L1 with an antagonistic antibody would worsen the outcome of focal cerebral ischemia-reperfusion and increase blood-brain barrier (BBB) disruption. METHODS: Transient middle cerebral artery occlusion (MCAO) was performed in anesthetized rats. Five µg of antagonistic mouse IgG monoclonal L1 antibody 324 or non-immune control mouse IgG was applied on the ischemic-reperfused cortex during one hour of MCAO and two hours of reperfusion. At two hours of reperfusion, BBB permeability, size of infarct using tetrazolium staining, number of TUNEL-labeled apoptotic cells, and immunohistochemistry for expression of PTEN and p53 were studied. RESULTS: The antagonistic L1 antibody 324 increased the percentage of cortical infarct area (+36%), but did not affect BBB permeability in the ischemic-reperfused cortex. The antagonistic L1 antibody increased number of apoptotic neurons and p53 expression, but decreased PTEN expression. CONCLUSION: Functional antagonism of L1 increases infarct size by increasing numbers of apoptotic neurons without affecting BBB permeability during the early stage of cerebral ischemia-reperfusion. Our data suggest that L1 affects primarily the brain parenchyma rather than BBB during early stages of cerebral ischemia-reperfusion and that endogenous brain L1 may be neuroprotective.

Improvement of the Patient Safety Culture in the Primary Health Care Corporation - Qatar.

OBJECTIVES: Primary Health Care Corporation (PHCC) is the public primary health care provider in Qatar. Having a patient safety culture (PSC) is the keystone to enabling a continuous process to improve the quality of services and to reduce errors. The objective of this study was to assess the impact of accreditation, quality improvement trainings, and patient safety (PS) trainings on the improvement of the PSC at the PHCC in Qatar. METHODS: The Medical Office Survey on Patient Safety Culture from the Agency for Healthcare Research and Quality was used in 2012 and 2015 to assess the culture of PS and health care quality in the 21 health centers. The results of the two surveys were compared using the χ2 test. A P value of less than 0.05 was considered significant. RESULTS: Out of 2689 staff working in the 21 health centers, 1810 (67.3%) completed the survey in 2012, and 2616 (70.0%) of 3735 completed the survey in 2015. The comparison between 2012 and 2015 survey's results showed a statistically significant improvement for all the 10 dimensions (P < 0.05). Although a statistically significant difference was observed between 2012 and 2015 results for work pressure and pace, three of the four questions of the work pressure and pace dimension presented nonsignificant differences. CONCLUSIONS: The survey was a good tool to raise awareness on PS and quality issues at PHCC. There is evidence that the implementation of accreditation program, the quality improvement trainings, and PS trainings helped the organization improve its PS culture.

Awareness, use and perceptions about E-cigarettes among adult smokers in Karachi, Pakistan.

OBJECTIVE: To estimate the prevalence of awareness, current use and intention to use of e-cigarettes among adult smokers. METHODS: This cross-sectional survey was carried out at the Aga Khan University Hospital, Karachi, from July to August 2016, and comprised people aged above 18 years who had smoked more than 100 cigarettes in their lifetime. Convenience sampling method was used. A self-administered questionnaire was used to collect data. SPSS 22 was used for data analysis.. RESULTS: Of the 387 participants, 359(92.8%) were male. The overall mean age was 32.4±12.6 years. Moreover, 215(55.5%) respondents belonged to the middle socio-economic class. Besides, 249(64.3%) respondents were aware of e-cigarettes while 39(10.1%) used them, and 81(20.9%) wanted to use them. Socio-economic status was the best predictor for awareness about e-cigarettes (p<0.001), while gender (p=0.001), occupation

Diabetic ketoacidosis characteristics and differences In type 1 versus type 2 diabetes patients.

BACKGROUND: Diabetes is undoubtedly one of the most challenging health problems of the 21st century. It is well known that diabetes once develop can lead to several complications. Diabetic ketoacidosis (DKA) is one of the life-threatening complications of diabetes. This study was designed to determine the frequency of DKA in diabetes patients and find out the clinical and biochemical determinants of DKA. METHODS: This descriptive study was conducted at Aga Khan University Hospital (AKUH) Karachi, Pakistan from January 2010 to February 2016. All known or newly diagnosed diabetic patients of >16 years of age irrespective of gender and type of diabetes were included. Information regarding patient's demographics, presenting symptoms, precipitating causes of DKA, biochemical profiles and outcome at the time of discharge was collected. RESULTS: Majority (54.7%) had moderate and 12.4% had severe DKA at presentation. Previous history of DKA was found higher in type 1 diabetes patients (T1DM) (14%) as compare to (4%) type 2 diabetes patients (T2DM) (p<0.05). DKA severity was observed more (12%) in newly diagnosed (T1DM) (p<0.05). Comorbidities were found more (81%) in (T2DM) (p<0.05) Mortality was also observed higher in Type 2 diabetes patients (p<0.05). CONCLUSIONS: Majority of the diabetics had moderate to severe DKA at presentation. Mortality and morbidity related with DKA was found considerably higher among patients with T2DM while infection, myocardial infarction and stroke found as triggering factors in these patients.

Idiopathic hypogonadotropic hypogonadism reversal after testosterone replacement in a 34-year-old male.

A 34-year-old male presented to the endocrinology clinic with the complaint of the absence of facial, axillary and pubic hairs. Further history revealed absent ejaculations and decreased early morning erections. The patient had no history of headaches, visual problems or anosmia. On physical examination, there were sparse facial, axillary and pubic hairs, bilateral gynaecomastia, stretch penile length of 5 cm and bilateral testicular volume of 10 mL. Laboratory investigations showed low luteinising hormone, follicular stimulating hormone and testosterone with normal prolactin and thyroid profile. MRI of the pituitary gland showed no evidence of pituitary microadenoma or macroadenoma. The patient was started on testosterone injections. After 9 months of testosterone replacement, the patient's testicular size increased to 20 mL bilaterally and his penile length increased to the mean adult size for his age with normal testosterone and luteinising hormone. He was, thus, advised to discontinue testosterone therapy.

Primary adrenal non-Hodgkin lymphoma: a case report and review of the literature.

BACKGROUND: Lymphomas are cancers that arise from the white blood cells and have been traditionally divided into two large subtypes: Hodgkin and non-Hodgkin lymphoma. B-cell lymphoma is the most common subtype of non-Hodgkin lymphoma; almost 85% of patients with lymphoma have this variant. Lymphomas can potentially arise from any lymphoid tissue located in the body; however, primary adrenal non-Hodgkin lymphoma is extremely rare. We report the history, examination findings, and laboratory results of a 50-year-old man diagnosed with a primary left adrenal diffuse large B-cell lymphoma. CASE PRESENTATION: A 50-year-old Pakistani man presented to our hospital with progressively increasing pain and fullness in the left upper quadrant of his abdomen, generalized weakness, easy fatigability, and decreased appetite of 1.5 months' duration. On examination, he had a blood pressure of 140/80 mmHg with no postural drop, a pulse rate of 106 beats/minute, and no fever. His past medical history was significant for pulmonary tuberculosis 2 years earlier, for which he received antituberculous therapy. Computed tomography revealed a heterogeneous enhancing soft tissue density mass in the left adrenal gland. It measured 7.1 × 5.6 × 9.5 cm. Further laboratory workup revealed the following levels: sodium 135 mEq/L, potassium 4.5 mEq/L, lactate dehydrogenase 905 IU/L, renin 364 IU/ml, aldosterone 5.79 ng/dl, dehydroepiandrosterone sulfate 79.20 µg/dl, urinary vanillylmandelic acid 6.4 mg/24 hours, and a low-dose overnight dexamethasone suppression test result of 3.20 µg/dl. The patient underwent left adrenalectomy. Histopathological test results showed a diffuse large B-cell lymphoma. Immunohistochemical stains were strongly positive for CD20 and negative for CD3, CD5, CD10, and cyclin D1. The patient's Ki-67 (Mib-1) index was approximately 80%. He received a total of six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (rituximab was not given, owing to financial constraints) and was routinely followed pre- and postchemotherapy at our hematology clinic with complete blood count and serum lactate dehydrogenase evaluations. The patient responded to chemotherapy and is currently doing well. CONCLUSIONS: Primary adrenal lymphoma is an extremely rare but rapidly progressive disease. It generally carries a poor prognosis, partly because an optimal treatment protocol has not yet been established. Further studies with larger sample sizes are needed to establish the best treatment option and increase overall survival.

Rasburicase-Induced Methemoglobinemia in a Patient with Glucose-6- Phosphate Dehydrogenase Deficiency.

BACKGROUND: Rasburicase is commonly used in patients with hematologic malignancies for tumor lysis syndrome prophylaxis and management. Methemoglobinemia is a serious rare adverse effect of rasburicase, more common in patients with G6PD deficiency. Prompt diagnosis and appropriate management of this condition can make the difference between successful recovery and significant morbidity. Here we discuss the link of rasburicase with methemoglobinemia and the pathophysiology behind increased incidence of this side effect in G6PD deficient patients. METHODS: We report the case of a 73-year-old African American man who developed methemoglobinemia on rasburicase treatment, who was later confirmed to be G6PD deficient. We reviewed the literature using Pubmed and Google Scholar using the following key words: "methemoglobinemia", "rasburicase", "urate oxidase", tumor lysis syndrome", G6PD deficiency", "hemolytic anemia" and "hyperuricemia". RESULTS: Rasburicase-induced methemoglobinemia is more common in patients with G6PD deficiency, and rasburicase is therefore contraindicated in these patients. Clinical presentation includes cyanosis, pallor, methemoglobin levels of 8-12%, and oxygen saturation gap which is evident from ABG analysis, though pulse oximetry is normal. Treatment consists of oxygen supplementation, ascorbic acid and blood transfusion. Importantly, methylene blue is avoided as therapy in G6PD deficiency as it can worsen the methemoglobinemia. CONCLUSION: Rasburicase-induced methemoglobinemia is a serious concern, especially in African- American patients. It should be considered when clinical signs and symptoms are present. Knowledge of this side effect is important in early diagnosis and successful management of the condition.

Three siblings with familial non-medullary thyroid carcinoma: a case series.

BACKGROUND: In 2015, thyroid carcinoma affected approximately 63,000 people in the USA, yet it remains one of the most treatable cancers. It is mainly classified into medullary and non-medullary types. Conventionally, medullary carcinoma was associated with heritability but increasing reports have now begun to associate non-medullary thyroid carcinoma with a genetic predisposition as well. It is important to identify a possible familial association in patients diagnosed with non-medullary thyroid carcinoma because these cancers behave more destructively than would otherwise be expected. Therefore, it is important to aggressively manage such patients and screening of close relatives might be justified. Our case series presents a diagnosis of familial, non-syndromic, non-medullary carcinoma of the thyroid gland in three brothers diagnosed over a span of 6 years. CASE PRESENTATIONS: We report the history, signs and symptoms, laboratory results, imaging, and histopathology of the thyroid gland of three Pakistani brothers of 58 years, 55 years, and 52 years from Sindh with non-medullary thyroid carcinoma. Only Patients 1 and 3 had active complaints of swelling and pruritus, respectively, whereas Patient 2 was asymptomatic. Patients 2 and 3 had advanced disease at presentation with lymph node metastasis. All patients underwent a total thyroidectomy with Patients 2 and 3 requiring a neck dissection as well. No previous exposure to radiation was present in any of the patients. Their mother had died from adrenal carcinoma but also had a swelling in the front of her neck which was never investigated. All patients remained stable at follow-up. CONCLUSIONS: Non-medullary thyroid carcinoma is classically considered a sporadic condition. Our case report emphasizes a high index of suspicion, a detailed family history, and screening of first degree relatives when evaluating patients with non-medullary thyroid carcinoma to rule out familial cases which might behave more aggressively.

Euglycaemic diabetic ketoacidosis in a patient with type 2 diabetes started on empagliflozin.

Diabetes ketoacidosis (DKA) is largely associated with type 1 diabetes and has hyperglycaemia as a cardinal feature. We discuss the case of a 42-year-old man, a patient with type 2 diabetes, who presented to the emergency room, with nausea, vomiting and abdominal pain. He had recently changed his diabetes medications and started on an SGLT2 inhibitor (empagliflozin) along with metformin, pioglitazone, liraglutide and self-adjusted exogenous insulin. DKA was suspected in the wake of clinical examination and lab findings but glucose levels were below the cut-off for DKA; therefore, he was diagnosed with euglycaemic DKA. He was successfully managed with intravenous hydration and insulin infusion. We discuss the link of SGLT2 inhibitors with DKA and the pathophysiology behind euglycaemic DKA.

KCNQ1 rs2237895 polymorphism is associated with Gestational Diabetes in Pakistani Women.

BACKGROUND AND OBJECTIVE: Genetic studies on gestational diabetes (GDM) are relatively scarce; moreover, limited data is available for KCNQ1 polymorphism in Pakistani pregnant women. We aimed to determine the frequency of KCNQ1 rs2237895 in GDM and normal pregnant controls and its association with GDM-related phenotypes. METHODS: A total of 637 pregnant females (429 controls and 208 cases) in their second trimester were classified according to the International Association of the Diabetes and Pregnancy Study criteria in this study. Their blood samples were genotyped for KCNQ1 SNP rs2237895 using PCR-RFLP method and sequencing. Fasting and two hour-post glucose load blood levels, serum HbA1c, insulin, and anthropometric assessment was performed.: Pearson's Chi Square test, Mann- Whitney U test, and regression analyses were performed. A p-value of <0.05 was considered significant. RESULTS: The variant genotyped was in Hardy-Weinberg equilibrium (p>0.05). The rs2237895 showed an association with GDM (OR 2.281; 1.388-3.746: p <0.001) and remained significant after multiple adjustments for age and body mass index (OR 2.068; 1.430-2.997: p=0.005). The C allele showed positive association with insulin level, and HOMA-IR in study subjects. CONCLUSIONS: This study identifies that KCNQ1 rs2237895 polymorphisms might be associated with risk of GDM in Pakistani population and that it is related to higher glucose levels and insulin resistance. Further large scale studies are required to consolidate on the functional aspect of this polymorphism.

Effect of raised body fat on vitamin D, leptin and bone mass.

OBJECTIVE: To estimate leptin, vitamin D and bone mineral density levels in individuals with high fat mass, and to assess any correlation. METHODS: The cross-sectional study was conducted at the Basic Medical Sciences Institute, Jinnah Post Graduate Medical Centre, Karachi, and Aga Khan University, Karachi, from August 2012 to July 2014, and comprised healthy male volunteers between the ages of 18-60 years. Body fat percentage was determined using bioelectrical impedance analysis and the participants were classified as: Group A (15-21.9); Group B (22-27.9); and Group C (>28). Bone mineral density was calculated by ultrasound bone densitometer (T-score between +1 and ?1 considered normal). Enzyme-linked immunosorbent assay kits were used to determine the levels of vitamin D and leptin. SPSS 19 was used for statistical analysis. RESULTS: A total of 132 male subjects participated in this study, with each of the 3 groups having 44(33.3%). Despite all groups having low Vitamin D, a marked decrease was observed in group C compared to groups A and B (p <0.018). Bone mineral density T-score was <-1; total calcium was within normal range in all three groups. Serum leptin was raised in Group C compared to group A and B (p=0.03). Body fat percentage was negatively associated with vitamin D (p=0.004; r = -0.351), while it was positively correlated with leptin (p =0.038; r = 0.256). CONCLUSIONS: Excess of body fat percentage led to decreased vitamin D and raised leptin. However, bone mineral density and calcium levels were within normal range, suggesting that other factors might have played a role in maintaining bone mass in obese individuals, such as leptin.