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Objectives: To evaluate and compare the pharmacokinetic parameters, especially bioavailability, of annatto-based tocotrienol with palm tocotrienol-rich fraction in healthy human volunteers for better therapeutic outcome. Method: The systematic review was conducted between April and August 2021 in accordance with the Preferred Reporting Items for Systematic Review and Meta Analysis guidelines, and comprised search on PubMed, Google Scholar, Pakmedinet and Google search engines for open-label or double-blind randomised controlled trials involving healthy human volunteers published till January 2021. Key words used included annatto-based tocotrienol, palm tocotrienol-rich fraction, absorption and bioavailability. Boolean operators were also used, like tocotrienol AND bioavailability, annatto tocotrienol AND pharmacokinetics. Results: Of the 230 articles identified, 50(21.7%) articles met the eligibility criteria. Of them, 7(14%) were selected for data extraction and detailed analysis. Pharmacokinetic parameters of annatto-based tocotrienol were better than palm-derived tocotrienol. Oral administration of all the isomers of annatto-based tocotrienols resulted in dose-dependent increase in area under curve and plasma levels. Amongst all the isomers of annatto-based and palm-derived tocotrienol, delta isomer of annatto-based tocotrienol had the highest bioavailability with area under curve 7450±89 ng/ml, time to reach peak plasma levels 4 hours, maximum plasma concentration 1591±43 ng/nl and elimination half-life 2. 68 ±0.29 hrs. Pharmacokinetic parameters of delta isomer of annatto-based tocotrienol was greater than palm tocotrienol-rich fraction. Conclusion: Bioavailability of annatto-based tocotrienol was better than that of palm-derived tocotrienol-rich fraction. Delta isomer of annatto-based tocotrienol had the highest bioavailability amongst all isomers of tocotrienol.

Early diagnosis of coronary artery disease (CAD) in patients with chest pain is a challenge. Currently diagnosis of CAD is confirmed by coronary angiography, which is invasive and not easily available in developing countries. Therefore, it is imperative to establish noninvasive biomarker for early diagnosis of CAD in patients with angina and determine the diagnostic accuracy of inflammatory biomarkers of atherosclerosis in comparison to angiography and correlate with severity of CAD in patients with angina. Diagnostic accuracy study was carried out in tertiary care hospitals, Rawalpindi, Pakistan. Total of 58 patients aged 55.24 ± 11.61 years, with chest pain and troponin-I -ve, having coronary artery stenosis ≥50% were included as cases of CAD and 55 subjects having stenosis50% were included as controls. Nuclear factor kappa-B (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hs-CRP) were analyzed on immunoassay analyzers. The receiver operating characteristic curve analysis revealed significant (

Objective: To determine the frequency of disorders leading to sudden cardiac death (SCD). Study Design: Cross-sectional study. Place and duration of study: Pathology Lab in collaboration with the Cardiology Department, AFIC & NIHD, Rawalpindi Pakistan, from Jan 2017 to Dec 2018. Methodology: A total of 305 cases of sudden cardiac death reported within the last 24 hours of a death to AFIC Rawalpindi were included consecutively. Cases with a history of extracardiac diseases leading to sudden death were excluded. Most of the included cases were diagnosed phenotypically based on clinical examination, biochemistry, ECG, echocardiography, angiography, thallium scan, electro-physiological studies, cardiac CT scan, MRI and routine autopsy whenever recommended. Results: Out of 305 cases, 197 (65%) were males and 108 (35%) females. Disorders leading to SCD were found in 178 (58.3%) cases due to ischemic heart disease (IHD), aortic dissection (0.7%), hypertrophic cardiomyopathy (HCM) (0.3%), dilated cardiomyopathy (DCM) (10.5%), congenital heart disease (12.1%) and valvular heart disease (7.9%). While in cardiac channelopathies, catecholaminergic polymorphic ventricular tachycardia (CPVT) in 5 (1.6%) and congenital long QT syndrome (LQTS) in 2 (0.7%) cases. However, 24 (7.9%) cases remained as sudden unexplained deaths (SUD). Conclusion: In our setup, ischemic heart disease and dilated cardiomyopathy were the commonest causes of sudden cardiac death, followed by congenital heart disease and valvular heart diseases.

MicroRNAs (miRNAs) play a key role in the regulation of genes for normal metabolism in the liver. Dysregulation of miRNAs is involved in the development and progression of non-alcoholic fatty liver disease (NAFLD). We aimed to explore changes in circulating miRNA expression in response to delta-tocotrienol (δT3) and alpha-tocopherol (αTF) supplementation and correlate them with relevant biochemical markers in patients with NAFLD. In total, 100 patients with NAFLD were randomized to either receive δT3 (n = 50) 300 mg or αTF (n = 50) 268 mg twice/day for 48 weeks. Plasma expression of miRNA-122, -21, -103a-2, -421, -375 and -34a were determined at baseline, 24 and 48 weeks of intervention using RT-qPCR. Both δT3 and αTF significantly downregulated expression of miRNA-122, -21, -103a-2, -421, -375 and -34a. Moreover, δT3 was more effective than αTF in reducing expression of miRNA-375 and -34a. A significant correlation was observed between miRNA expression and biochemical markers of hepatic steatosis, insulin resistance (IR), oxidative stress (OS), inflammation and apoptosis. δT3 and αTF exert hepato-protective effects by downregulating miRNAs involved in hepatic steatosis, IR, OS, inflammation and apoptosis in patients with NAFLD. Furthermore, δT3 has more pronounced effects than αTF in reducing miR-375 and miR-34a, which are linked to regulation of inflammation and apoptosis.

An interlaboratory study was conducted through the Vitamin D Standardization Program (VDSP) to assess commutability of Standard Reference Materials(®) (SRMs) and proficiency testing/external quality assessment (PT/EQA) samples for determination of serum total 25-hydroxyvitamin D [25(OH)D] using ligand binding assays and liquid chromatography – tandem mass spectrometry (LC-MS/MS). A set of 50 single-donor serum samples were assigned target values for 25-hydroxyvitamin D(2) [25(OH)D(2)] and 25-hydroxyvitamin D(3) [25(OH)D(3)] using Reference Measurement Procedures (RMPs). SRM and PT/EQA samples evaluated included SRM 972a (four levels), SRM 2973, six College of American Pathologists (CAP) Accuracy-Based Vitamin D (ABVD) samples, and nine Vitamin D External Quality Assessment Scheme (DEQAS) samples. Results were received from 28 different laboratories using 20 ligand binding assays and 14 LC-MS/MS methods. Using the test assay results for total serum 25(OH)D [i.e., the sum of 25(OH)D(2) and 25(OH)D(3)] determined for the single-donor samples and the RMP target values, the linear regression and 95% prediction intervals (PIs) were calculated. Using a subset of 42 samples that had concentrations of 25(OH)D(2) below 30 nmol/L, one or more of the SRM and PT/EQA samples with high concentrations of 25(OH)D(2) were deemed non-commutable using 5 of 11 unique ligand binding assays. SRM 972a (Level 4), which has high exogenous concentration of 3-epi-25(OH)D(3) was deemed non-commutable for 50% of the LC-MS/MS assays.

The study aimed to ascertain the effects of delta-tocotrienol (δT3) supplementation on glycemic control, oxidative stress, inflammation and related micro-ribonucleic acid (miRNA) expression in patients with type 2 diabetes mellitus (T2DM). Total 110 patients of T2DM on oral hypoglycemic agents, were randomly divided into tocotrienol and placebo groups and given 250 mg δT3 or cellulose soft gel capsule once daily respectively for 24 weeks. Glycemic control, oxidative stress, inflammatory biomarkers, and miRNAs expression were measured in serum at baseline and end of the intervention by using standard laboratory methods. Compared to the placebo, δT3 supplementation resulted in a significant (p ≤ .05) reduction [mean difference (95% confidence interval)] in plasma glucose [-0.48 (-0.65, -0.30)], insulin [-1.19 (-1.51, -0.87)], homeostatic model assessment of insulin resistance [-0.67 (-0.86, -0.49)], glycosylated hemoglobin [-0.53 (-0.79, -0.28)], malondialdehyde [-0.34 (-0.45, -0.22)], high sensitive-C-reactive protein[-0.35 (-0.54, -0.16)], tumor necrosis factor-alpha [-1.22 (-1.62, -0.83)], and interleukin-6[-2.30 (-2.91, -1.68)]. More than twofold downregulation in miRNA-375, miRNA-34a, miRNA-21, and upregulation in miRNA-126, miRNA-132 expression was observed in the δT3 group compared to the placebo. The study demonstrated that δT3 supplementation in addition to oral hypoglycemic agents, improved glycemic control, inflammation, oxidative stress, and miRNA expression in T2DM without any adverse effect. Thus, δT3 might be considered as an effective dietary supplement to prevent long-term diabetic complications.

OBJECTIVE To find out the use of screening and confirmatory tests for diagnosis of multiple myeloma as ordered by clinicians. STUDY DESIGN An Audit. PLACE AND DURATION OF STUDY Department of Chemical Pathology and Endocrinology, Armed Forces Institute of Pathology, Rawalpindi, from January 2012 to January 2017. METHODOLOGY Data retrieved from Laboratory Information Management system (LIMs) by selecting serum protein electrophoresis (SPE) as screening test and immunoelectophoresis (IE) and immunofixation (IF) as confirmatory tests. RESULTS There were 3,108 tests of serum protein electrophoesis and 1,329 tests of immunoelectophoresis had been performed in last five year. Cost-effective clinical audit of SPE tests showed that only 17.1% tests of SPE were either used for proper diagnosis of multiple myeloma (totally justified tests 13%) or useful for diagnosis of other important diseases whose early diagnosis were helpful for patients management (partially justified tests 4.1%). The cost related to these tests were justified while 82.8% tests of SPE were either normal (total unjustified tests 24.4%), or diagnosed irrevalent and nonspecific diseases (partially unjustified 58.4%). IE and IF audit revealed that only 26.6% tests were properly utilised for diagnosis and differentiation of multiple myeloma and its subtypes and cost attributable to these tests were justified while 73.4% of these confirmatory tests were normal and cost related to them was not justified. CONCLUSION Overutilisation of laboratory tests for diagnosis of multiple myeloma can be minimised by proper clinical scrutiny of request forms.

Objectives: Interleukin-6 receptor (IL-6R) gene (A>C, rs8192284) polymorphismhas been associated with inflammatory biomarkers. We sought to investigate the association ofIL-6R gene (A>C, rs8192284) polymorphism with IL-6, IL-18 and hS-CRP levels in PCAD. StudyDesign: Case control study. Setting: Army Medical College, National University of Sciencesand Technology, Islamabad, Pakistan Methods: Total 520 subjects were recruited. 281 PCADpatients aged ≤45 years with >70% stenosis in at least one major coronary vessel along with239 age and sex matched controls were recruited. IL-6R polymorphism was determined byTaqMan genotyping while IL-6 and IL-18 levels were measured using ELISA technique and hSCRPon Immulite 2000. Results: The genotype distribution of IL-6R(rs8192284) in the cases andcontrols was: AA-56%(n=143);AC-36% (n=102); and CC-13% (n=36) and AA-59%(n=139);AC-33% (n=80); CC-8% (n=20) respectively. The risk allele frequency was significantly differentbetween the cases and controls (p=0.038) .IL-6 levels were significantly high (p

Introduction: Genetic information which is specific to an individual has thepotential to improve Coronary Artery Disease (CAD) risk prediction. 13 CAD risk SNPs wereselected by removing SNPs in loci which had not been identified in CARDIoGRAMplusC4DGWAS. Linkage disequilibrium patterns differ between ethnic groups pointing towards theneed to investigate how the gene score would perform in different populations which is stilllargely unknown. Objective of the study was to investigate whether the 13 SNP CAD risk genescore has a role in the risk prediction of Pakistani Premature Coronary Artery Disease (CAD)cases and controls and to compare the CAD risk allele frequency between Pakistanis andCaucasians (samples obtained from the Northwick Park Heart Study II). Study Design: Casecontrolstudy. Setting: Army Medical College, National University of Sciences and Technology(NUST) in collaboration with the Cardiovascular Genetics Institute, University College London,UK. Materials and Methods: Total of 650 subjects with a history of chest pain were selected bynon-probability convenience sampling. Out of these subjects with > 70% stenosis in at least 1coronary vessel on angiography were labelled as Premature coronary Artery disease (PCAD)cases (n=340). The 13 SNPs were genotyped in a Pakistani case-control study (n=340 CADcases, 310 controls) using KASPar and Taqman assays. The use of 13 SNP gene score wastested in the prospective Northwick Park Heart Study (NPHSII) of 2775 healthy UK men (284cases) and the Pakistani case-control study subjects (n=650). Results: Mean ± SD age ofCAD patients was 42.7±3.80yrs while in controls it was 39.0±7.8yrs. Complete genotypingwas obtained for 635 samples (333 cases, 302 controls). The mean 13 SNP gene score wassignificantly higher in cases compared to controls (p=0.044). Odds ratio for CAD for eachquintile of 13 SNPs gene score showed a trend for higher quintiles of gene score to haveincreased odds ratio for CAD (p-value for trend=0.01) especially after adjusting for age, sexand ethnicity. There was a significant difference in risk allele frequency between Pakistanis andCaucasians (NPHSII) for all CAD risk SNPs except rs599839 (SORT1) (p=0.08). Conclusion:A 13 SNP gene score has significant potential role at differentiating between Pakistani PCADcases and controls. Risk allele frequencies for CAD differ significantly between Pakistanis andCaucasians stressing the need to develop population specific gene score keeping in view theethnic stratification.

Background Premature Coronary Artery Disease (PCAD) occurs almost a decade earlier in the South Asian population as compared to the West. Inclusion of genetic information can prove to be a robust measure to improve early risk prediction of PCAD. Aim was to estimate the genotypic distribution and risk allele frequencies of 13 Coronary Artery Disease (CAD) risk Single Nucleotide Polymorphisms in loci identified by the CARDIoGRAMplusC4D consortium namely MIA3 rs17465637 ; 9p21 rs10757274 ; CXCL12 rs1746048 ; APOA5 rs662799 ; APOB rs1042031 ; LPA rs3798220 ; LPA 10455872 ; MRAS rs9818870 ; LPL rs328 ; SORT1 rs646776 ; PCSK9 rs11591147 ; APOE rs429358 ; APOE rs7412 in Pakistani PCAD patients and controls. Moreover, the differential serum cytokine levels (IL-18 , IL-10 , IL-6 , TNF-alpha , IL-18:IL-10 & TNF-alpha:IL-10 ratios) with respect to the genotypic distribution of these selected SNPs were determined. Material and methods The case-control study was carried out in National University of Sciences and Technology, Islamabad in collaboration with the Cardiovascular Genetics Institute, University College London, UK. Subjects (n = 340) with >70% stenosis in at least a single major coronary artery on angiography were taken as PCAD cases along with 310 angiographically verified controls. ELISA was performed for measuring the concentrations of serum IL18, TNFA, IL6 and IL10. Genotyping was done using TAQMAN and KASPar assays. Results The risk allele frequencies (RAF) of APOE rs7412, CXCL12 rs1746048, 9p21 rs10757274, MIA3 rs17465637 and SORT1 rs646776 were significantly higher in the PCAD cases as compared to the controls. APOE rs429358 had the greatest influence among the selected GWAS/CARDIoGRAMplusC4D consortium CAD risk SNPs by significantly altering the serum levels of TNF-alpha, IL-10 and TNF-alpha:IL-10 ratio. It was followed by APOE rs7412 and CXCL12 rs1746048 which significantly altered the serum levels of IL-18; TNF-alpha and IL-18; IL-18:IL-10 ratio respectively. The cytokine imbalance denoted by IL-18:IL-10 was significantly higher in the risk allele carriers MIA3 rs17465637 and CXCL12 rs1746048 while TNF-alpha:IL-10 ratio was significantly raised in the risk allele carriers of APOE rs429358 ; MRAS rs9818870 and LPL rs328 . Conclusion The association of the selected SNPs with differential serum cytokine levels especially the cytokine imbalance points towards their potential causal role in the immune inflammatory pathogenic pathway of PCAD.

Cardiomyopathy is the leading cause of mortality in beta-thalassaemia major (BTM) patients. Brain natriuretic peptide (BNP) has been used for latent cardiac dysfunction in heart patients other than thalassaemic patients. The objective was to determine its role in subclinical detection of iron-induced cardiotoxicity in BTM patients.EDTA plasma was taken from 33 thalassaemic patients and 29 healthy controls, stored at -20 degrees C until analysis. The median (range) age of thalassaemic major children was 10 (6-21) years and mean serum ferritin levels were 3956 (1929-6979) microg/L. The BTM children had significantly (P0.01) higher BNP median (range) 83.94 (45.93-196.80) pg/mL as compared to controls 55.62 (32.58-99.84) pg/mL. Mitral E-wave velocities were found higher in patients rather than controls (132.12 +/- 29.40 vs. 117.70 +/- 24.81; P0.05). The E/Ea ratio was significantly higher in BTM patients than in the control group (16.35 +/- 6.01 vs. 19.26 +/- 4.67; P = 0.001). We found a significant positive correlation between BNP and E/Ea ratio (r = 0.53; P0.01). BNP at a cut-off value of 84.39 pg/mL was highly accurate in ruling out diastolic dysfunction (E/Ea8) with a sensitivity of 80% and a specificity of 88%.BNP has a good predictive value in detecting latent LV dysfunction in BTM patients.

Background We aimed to elucidate the association between gamma glutamyl transferase (GGT) activity with prevalence of premature coronary artery disease (CAD) in young Pakistani patients undergoing diagnostic coronary angiography. Methods A total of 218 young adults (age≤45 years) underwent diagnostic angiography. Serum samples were taken from all the patients and analyzed for serum GGT activity, cholesterol and triglycerides. Results Coronary artery disease patients had significantly increased GGT activity ( P =.001) and exhibited a significant positive correlation with blood pressure, cholesterol, blood glucose, and smoking and negative correlation with total antioxidant status ( P Conclusion The study revealed good diagnostic accuracy at cutoff of 35 U/L with a sensitivity of 92%, specificity of 81%, and diagnostic odds ratio of 48 in estimation of premature CAD in young Pakistanis.

Lead poisoning is a well recognized environmental health problem in children. Independent association of iron deficiency and lead exposure with elevated blood lead level (BLL) has been reported. Whether iron deficiency in combination with chronic lead exposure increases BLL and susceptibility to its harmful effects in children needs to be elucidated.In this case-control study, 246 children were randomly recruited. They comprised 123 children of lead smelters/battery recycle plant workers living close to the industries at Wah/Gujranwala, Pakistan (lead exposed group) and 123 children living 30 km away from the industrial area (controls). Blood lead analysis was carried out on the anodic stripping voltammeter lead analyzer 3010B. Blood counting was done on a Sysmex hematological analyzer and serum ferritin was determined by kit method on Immulite-1000.Of the 123 children in each group, 42 (34%) were iron deficient in the exposed group while 35 (28%) in the controls. The children's median age was 4 years (69 males and 54 females in each group). Lead exposed iron deficient children had significantly higher BLL median (quartile) 13.1 μg/dL (10.1-16.8) as compared with 9.6 μg/dL (7.6-10.3) in the iron deficient controls (P0.05). Elevated BLL level was found in 31% of the lead exposed children and in 11% of the controls. Lead exposed children revealed a stronger negative correlation (r= -0.54; P=0.001) between BLL and serum ferritin than the controls (r=-0.36; P=0.01).Iron deficiency in combination with lead exposure synergistically elevates blood lead levels and susceptibility to its harmful effects in children.

Lead is a persistent toxic metal and associated with impairment of various body functions in occupational workers. The main objective was to determine the lead-induced oxidative stress and adverse health effects by biochemical markers in industrial workers. One hundred and forty-eight males consisting of 87 lead-exposed industrial workers and 61 controls were included. Blood lead level (BLL) was determined on a 3010B ESA lead analyzer. Blood complete counts were done on a hematology analyzer. Biochemical markers including serum uric acid, urea, creatinine, phosphate, alanine aminotransferase (ALT), and gamma glutamyltransferase (GGT) were measured on a Selectra E auto analyzer. Serum malondialdehyde (MDA) was measured spectrophotometrically and C-reactive protein (CRP) on Immulite-1000. Results revealed that lead-exposed workers had significantly high BLLs, median (range), 29.1 (9.0-61.1) microg/dL compared with controls, 8.3 (1.0-21.7) microg/dL. Oxidative stress (MDA, GGT) and inflammatory markers (high-sensitivity CRP) were significantly increased (P < or = 0.05). Blood pressure was raised, whereas hemoglobin was decreased in exposed group (P < or = 0.002). Serum urea, uric acid, phosphate, and ALT were significantly raised in lead-exposed workers (P < or = 0.001). Serum albumin, total proteins, and glomerular filtration rate (GFR) were decreased. Blood lead showed a significant positive correlation with serum GGT (r = 0.63), MDA (r = 0.71), CRP (r = 0.75), urea (r = 0.34), creatinine (r = 0.51), and uric acid (r = 0.29) (P < or = 0.01). It is concluded that lead exposure increases oxidative stress that correlates with adverse changes in hematological, renal, and hepatic function in the occupational workers. Elevated blood lead has positive correlation with oxidative stress, inflammatory and biochemical markers that might be used to detect impairment in the body function in lead exposed workers.

Background In recent years inappropriate and excessive use of clinical laboratory facilities has become a cause of concern and has led to concurrent rise in the laboratory errors and the health care costs. The aim of the study was to find out the frequency of incomplete laboratory request forms, inappropriate test requests at various professional levels and the financial impact of uncollected reports at Armed Forces Institute of Pathology (AFIP) and Combined Military Hospital (CMH) Laboratory Rawalpindi. Methods The cross-sectional descriptive study was conducted during a three month period from April to June 2012 at AFIP and CMH Laboratory Rawalpindi. A total of 1000 laboratory request forms were collected and scrutinized for completion from AFIP (n=500) and CMH Rawalpindi laboratory (n=500). 536 request forms of costly/specialized tests from different departments of AFIP were studied to find out the professional level of test request. The total number of tests performed at AFIP during the study period and number of uncollected reports were noted. The financial impact of these uncollected reports was also calculated. Collection of data and sorting were done manually. Patient confidentiality was maintained. Microsoft excel software and SPSS-17 were used for analysis. The study was approved by the Institutional Ethical Review Committee. Results Out of a total of 1000 forms studied none was completely filled with clinical notes being present in only 2.4% and 13% of forms sent to CMH and AFIP respectively. 62% of the expensive investigations were requested by specialists while 38% were ordered by residents and general practitioners but the percentage of avoidable expensive tests ordered by the general practitioners and residents was significantly higher than the specialists(p Conclusion Processing incomplete laboratory request forms and injudicious use of laboratory facilities leads to incorrect interpretation of laboratory test results affecting outcome of the overall treatment.