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Bibi Kulsoom,1,2 Tahir Sultan Shamsi,1 Nasir Ali Afsar3 1Center of Excellence in Molecular Medicine, National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi, Pakistan; 2Department of Biochemistry, Jinnah Medical and Dental College, Karachi, Pakistan; 3Department of Pharmacology, Jinnah Medical and Dental College, Karachi, Pakistan Purpose: Acute myeloid leukemia patients are commonly treated with cytarabine (Ara-C) and anthracyclines but the sustained remission rate is not very promising. We explored the role of drug-metabolizing enzymes and transporters in the therapeutic response.Patients and methods: Bone marrow and peripheral blood samples of 90 newly diagnosed acute myeloid leukemia patients treated with standard 3+7 regimen were analyzed through real-time PCR for expression of human equilibrative nucleoside transporter 1, deoxycytidine kinase, cytidine deaminase (CDA), deoxycytidine monophosphate deaminase (dCMPD) and topoisomerase IIα (Topo-IIa). The expression of these markers was studied in relationship with good (persistent remission) and poor therapeutic response (relapse/resistance).Results: High Topo-IIa expression in peripheral blood was associated with good response (P=0.006). Relapse was higher among low expressors of Topo-IIa in peripheral blood (OR: 26.25). Bone marrow Topo-IIa expression followed a similar trend but did not reach statistical significance. In contrast, patients with high bone marrow dCMPD expression had poor response (OR: 3; P=0.043). One-year disease-free survival (DFS) was better among those with high bone marrow Topo-IIa (P=0.04) or CDA (P=0.03) expression. High bone marrow Topo-IIa expression also had better DFS at 6 months (P=0.04) and at 12 months (P=0.04).Conclusion: High expression of Topo-IIa in peripheral blood is a favorable indicator of persistent remission, good therapeutic response and DFS. High dCMPD and low CDA expression in bone marrow is associated with poor therapeutic outcome. Keywords: topoisomerase IIα, hENT1, dCMPD, CDA, dCK, survival, AML, antimetabolites, anthracyclines

Bibi Kulsoom,1 Tahir Sultan Shamsi,1 Nasir Ali Afsar,2,3 Zahida Memon,4 Nikhat Ahmed,4 Syed Nazrul Hasnain5 1National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi, Pakistan; 2Jinnah Medical and Dental College, Karachi, Pakistan; 3College of Medicine, Alfaisal University, Riyadh, Saudi Arabia; 4Ziauddin University, Karachi, Pakistan; 5Dow International Medical College, Karachi, Pakistan Purpose: Many anticancer drugs induce apoptosis in malignant cells, and resistance to apoptosis could lead to suboptimal or no therapeutic benefit. Two cytoplasmic proteins, B-cell lymphoma protein 2 (Bcl-2)-associated X (Bax) and Bcl-2, act as a promoter and an inhibitor of apoptosis, respectively. Both Bax and Bcl-2 as well as their ratio have been regarded as prognostic markers in various cancers. However, conflicting results have been reported. A clear understanding of apoptosis has also become crucial due to reports about anti-Bcl-2 chemotherapy. We explored the relationship of Bax and Bcl-2 gene expression and their ratio with the therapeutic response in acute myeloid leukemia (AML) patients.Patients and methods: Bone marrow and/or blood samples from 90 AML patients treated with cytarabine and daunorubicin were included. Expression of Bax and Bcl-2 was determined through real-time polymerase chain reaction by using ΔΔCt method of relative expression.Results: Bax and Bcl-2 expression among marrow and blood samples correlated with each other (rs=0.5, p

Bibi Kulsoom,1 Nasir Ali Afsar2 1Department of Biochemistry, 2Department of Pharmacology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia Background: Contemporary literature suggests that medical education might adversely affect students’ mental health. Alfaisal University in Riyadh, Saudi Arabia is a developing institution; hence, there has been a concern regarding the mental well-being of the students.Objectives: This study was designed to assess the traits of depression, anxiety, and stress among students in relation to potential underlying reasons.Methods: All 575 medical students across the 5 years of study participated by filling out the Depression, Anxiety, and Stress Scale-21 (DASS-21) questionnaire anonymously twice. Firstly, 2–3 weeks before a major examination (pre-examination), and secondly, during regular classes (post-examination). Correlation was sought regarding sex, year of scholarship, attendance of a premedical university preparatory program (UPP), housing, and smoking. Subjective comments from students were also obtained.Results: A total of 76.8% and 74.9% of students participated in pre- and post-examination groups, respectively. The majority were the children of expatriate workers in Saudi Arabia, and included Arabs, South Asians, and North Americans. Prevalence of depression, anxiety, and stress was high (43%, 63%, and 41%, respectively) which reduced (to 30%, 47%, and 30%, respectively) to some extent after examinations. Saudis and those who had attended UPP had higher DASS-21 scores. Smoking and female sex predicted higher levels of “baseline” depression, anxiety, or stress. The students perceived the curriculum and schedule to be the primary causes of their high DASS-21 scores.Conclusion: The students had high “baseline” traits of depression, anxiety, and stress, and these were higher if an examination was near, especially among Saudis and those who had attended UPP. Smoking and female sex predicted higher levels of “baseline” depression, anxiety, or stress. Students suggested that study burden and a busy schedule were the major reasons for their high DASS-21 scores. Keywords: DASS, examination, medical education, smoking, depression, anxiety, stress

Abstract Photoreceptor cell death and immune cell infiltration are two major events that contribute to retinal degeneration. However, the relationship between these two events has not been well delineated, primarily because of an inadequate understanding of the immunological processes involved in photoreceptor degeneration, especially that of peripheral leukocytes that infiltrate the subretinal space and retinal tissues. In this work, we characterized the role of leukocyte infiltration within the detached retina. We observed that CD45+ CD11b+ Ly6G+ neutrophils and CD45+ CD11b+ Ly6G− Ly6C+ monocytes are the predominant peripheral immune cell populations that infiltrate the retinal and subretinal space after detachment. Selective depletion of monocytes or neutrophils using cell-specific targeting is neuroprotective for photoreceptors. These results indicate that peripheral innate immune cells contribute to photoreceptor degeneration, and targeting these immune cell populations could be therapeutic during retinal detachment.

Objective: Vitamin D deficiency in Chronic Kidney Disease is a known fact, but the data regarding the prevalence and extent of vitamin D deficiency in different stages of Chronic Kidney Disease is scarce. This leads to a delay in addressing this issue. We conducted this study to assess vitamin-D deficiency in different stages of Chronic Kidney Disease to improve the evidence available to Physicians and Nephrologists which can help them better address this common finding in Chronic Kidney Disease., Methods: This retrospective study from a tertiary care hospital in Karachi, Pakistan, included adult Chronic Kidney Disease patients who had their serum 25 Hydroxy vitamin D levels done. The patients were classified according to stages of Chronic Kidney Disease using Estimated Glomerular Filtration Rate values. Appropriate statistical tests were performed to find a correlation between the severity of vitamin D deficiency in different stages of Chronic Kidney Disease with a statistically significant p value of <0.05 and a 95% confidence interval., Results: In total, 148 patients were included in the study. All patients had serum 25 Hydroxy vitamin D levels less than 30 ng/ml. The severity of vitamin D deficiency was observed to increase progressively from stage 3A Chronic Kidney Disease through stage 5. Vitamin D levels in Chronic Kidney Disease stage 3 were significantly greater than in Chronic Kidney Disease stages 4 and 5 ( p value < 0.001), and stage 5 patients had the lowest vitamin D levels in our study. Similar, statistically significant findings were observed for serum phosphate levels, too, with stage 5 Chronic Kidney Disease patients having a greater serum phosphate concentration than stages 3A and 3B ( p value = 0.002, 0.006)., Conclusion: All Chronic Kidney Disease patients in our study either had vitamin D insufficiency or deficiency. In addition, we observed a significant decrease in vitamin D levels from Chronic Kidney Disease stage 3 to stage 5. Greater serum phosphate levels were detected in stage 5 compared to stages 3A and 3B., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Shape memory polymers (SMPs), although offer a suite of advantages such as ease of processability and lower density, lag behind their shape memory alloy counterparts, in terms of mechanical properties such as recovery stress and cyclability. Reinforcing SMPs with inorganic nanowires and carbon nanotubes (CNTs) is a sought-after pathway for tailoring their mechanical properties. Here, inorganic nanowires also offer the added advantage of covalently binding the fillers to the surrounding polymer matrices via organic molecules. The SMP composites (SMPCs) thus obtained have well-engineered nanowire-polymer interfaces, which could be used to tune their mechanical properties. A well-known method of fabricating SMPCs involving casting dispersions of nanowires (or CNTs) in mixtures of monomers and crosslinkers typically results in marginal improvements in the mechanical properties of the fabricated SMPCs. This is owed to the constraints imposed by the rule-of-mixture principles. To circumvent this limitation, a new method for SMPC fabrication is designed and presented. This involves infiltrating polymers into pre-fabricated nanowire foams. The pre-fabricated foams were fabricated by consolidating measured quantities of nanowires and a sacrificial material, such as (NH 4 ) 2 CO 3 , followed by heating the consolidated mixtures for subliming the sacrificial material. Similar to the case of traditional composites, use of silanes to functionalize the nanowire surfaces allowed for the formation of bonds between both the nanowire-nanowire and the nanowire-polymer interfaces. SMPCs fabricated using TiO 2 nanowires and SMP composed of neopentyl glycol diglycidyl ether and poly(propylene glycol) bis(2-aminopropyl ether) (Jeffamine D230) in a 2:1 molar ratio exhibited a 300% improvement in the elastic modulus relative to that of the SMP. This increase was significantly higher than SMPC made using the traditional fabrication route. Well-known powder metallurgy techniques employed for the fabrication of these SMPCs make this strategy applicable for obtaining other SMPCs of any desired shape and chemical composition., (© 2022 IOP Publishing Ltd.)

Objective:  To determine and compare the distribution of oestrogen and progesterone receptors (ER and PR) expression between normal kidneys and chronic pyelonephritis., Study Design: Comparative-descriptive study., Place and Duration of Study: King Faisal Specialist Hospital and Research Centre, and Alfaisal University, Riyadh, Saudi Arabia, between January 2017 and December 2018.  Methodology: Renal specimens, including 41 chronic pyelonephritis, and 21 healthy specimens were examined. ER/PR expression was determined immunohistochemically, termed focal if <50% of nuclei stained positively, and diffuse when >50%. The intensity of staining was labelled weak (pale), moderate or strong., Results: Majority of samples showed presence of diffuse ER (82.9% diseased; 71.4% healthy) and focal PR (53.7% diseased; 76.2% healthy), mostly with strong intensity. ER and PR distribution whether focal or diffuse, correlated with each other in 41.9%. All proportions comparisons showed p values greater than 0.05., Conclusion: There was a trend of diffuse renal stromal expression of ER and PR in chronic pyelonephritis as compared to healthy specimens. However, the difference did not reach statistical significance. Key Words: Oestrogen receptor, Progesterone receptor, Chronic pyelonephritis, Renal cancer, Renal stroma.

Learning clinical skills in a large group of undergraduate medical students is challenging. Innovative technology-based modalities are being evaluated to complement limited hospital rotations. We determined the effectiveness of clinical skills-related audiovisual (AV) aids embedded in electronic-problem-based learning (PBL) sessions, in terms of students' feedback and formative Objective Structured Clinical Examinations (OSCE) grades. This mixed-method study was conducted during the Cardiovascular System module in year 3 of the Bachelor of Medicine, Bachelor of Surgery program. The AV aids, mainly consisting of abnormal chest auscultation sounds, were linked to the cases for the intervention group. The control group received only a description of clinical signs. Sessions were conducted using an intranet platform. At the end of the module, feedback was obtained from intervention group students and faculty using a self-administered questionnaire. The learning was compared between intervention and control groups through an OSCE. Finally, focus group interviews were conducted to explore factors underlying deviation from the expected results. Out of 110 intervention group students, 86 (78%) responded. The students appreciated the inclusion of AV aids, as suggested by a high average satisfaction score of 4.2 (SD 0.8). They agreed that, apart from being appropriate and relevant, the aids improved the learning environment and engagement in the process. The tutors also gave a similar feedback. However, no difference in the OSCE scores was found between control and intervention groups. The study indicates that inclusion of AV aids improved students' engagement and classroom environment in electronic-PBL sessions, but did not improve diagnostic abilities based on the learned clinical skills.

This study investigated the effect of different nitrogen sources, namely, ammonium chloride and glutamate, on photoheterotrophic metabolism of Rhodobacter capsulatus grown on acetate as the carbon source. Genes that were significantly differentially expressed according to Affymetrix microarray data were categorized into Clusters of Orthologous Groups functional categories and those in acetate assimilation, hydrogen production, and photosynthetic electron transport pathways were analyzed in detail. Genes related to hydrogen production metabolism were significantly downregulated in cultures grown on ammonium chloride when compared to those grown on glutamate. In contrast, photosynthetic electron transport and acetate assimilation pathway genes were upregulated. In detail, aceA encoding isocitrate lyase, a unique enzyme of the glyoxylate cycle and ccrA encoding the rate limiting crotonyl-CoA carboxylase/reductase enzyme of ethylmalonyl-coA pathway were significantly upregulated. Our findings indicate for the first time that R. capsulatus can operate both glyoxylate and ethylmalonyl-coA cycles for acetate assimilation.

Genetic polymorphism of drug metabolizing enzymes and transporters may influence drug response. The frequency varies substantially between ethnicities thus having implications on appropriate selection and dosage of various drugs in different populations. The distribution of genetic polymorphisms in healthy Pakistanis has so far not been described. In this study, 155 healthy adults (98 females) were included from all districts of Karachi. DNA was extracted from saliva and genotyped for relevant SNVs in CYP1A1, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5 as well as ALDH3A1, GSTA1, ABCB1 and ABCC2. About 64% of the participants were born to parents who were unrelated to each other. There was generally a higher prevalence (p < 0.05) of variant alleles of CYP450 1A2, 2B6, 2C19, 3A5, ALDH3A1, GSTM1 as well as ABCB1 and ABCC2 in this study cohort than in other ethnicities reported in the HapMap database. In contrast, the prevalence of variant alleles was lower in GSTA1. Therefore, in the Pakistani population sample from Karachi a significantly different prevalence of variant drug metabolizing enzymes and ABC transporters was observed as compared to other ethnicities, which could have putative clinical consequences on drug efficacy and safety.

There is conflicting evidence that MDR1, MRP2 and LRP expression is responsible for chemotherapy resistance. We conducted this study to explore their role in AML therapy outcomes. Bone marrow and peripheral blood samples of 90 AML patients, receiving chemotherapy, were analyzed by real time PCR. Gene expression was calculated by the 2 -ΔΔCt method. The patients who had a persistent remission were labelled 'Good Responder' (GRes) whereas, those with relapse or drug resistance were labelled 'Poor Responders' (PRes). Higher LRP expression in bone marrow, but not in peripheral blood, was positively associated with persistent remission (p = 0.001), GRes (p = 0.002), 1-year overall as well as disease-free survival (p = 0.02 and p = 0.007, respectively). Marrow and blood MDR1 and MRP2 expression did not differ significantly between the above groups. Logistic regression analysis showed that only a diagnosis of acute promyelocytic leukemia (APL; M3) or high marrow LRP expression significantly predicted a favorable therapeutic outcome. This is the first report showing that high bone marrow LRP expression predicts significant favorable therapeutic outcome. Peripheral blood LRP expression as well as marrow and blood MDR1 and MRP2 expression have no predictive value in AML patients treated with standard dose cytarabine and daunorubicin 3+7 regimen.

Objective: To explore the effects of simulation training on paediatric residents' confidence and skills in managing advanced skills in critical care., Methods: The study was conducted at Alfaisal University, Riyadh, Saudi Arabia, from March to June 2016, and comprised junior residents in paediatrics. All paediatric residents (years 1 and 2) were recruited into two workshops, held one week apart. The first workshop covered lumbar puncture/ cerebrospinal fluid interpretation, oral intubation, bone marrow aspiration, and critical airway management. The second workshop covered chest tube insertion, pleural tap, insertion of central line, and arthrocentesis. The participants were surveyed using a 5-point Likert scale survey pre- and post-course, assessing their confidence. Their practical skills were assessed using a pre-objective structured clinical examination on the same day and post-course objective structured clinical examination a week later on selected skills. The outcome measures were: (1) pre-/post-course confidence rating, and (2) pre-/post-course objective structured clinical examination results. Data was analysed using SPSS 20., Results: Of the 16 participants, 8(50%) were boys and 8(50%) girls. Besides, 13(81%) residents were in year-1 and 3(19%) in year-2. Median post-course confidence level ranks for all the skills were higher (p<0.05). There was no improvement in mean pre-objective structured clinical examination scores (2.31±2.66/ 7.46±3.02) and post- objective structured clinical examination scores (22.54±4.39/ 31.85±6.90) in Year 1 residents (p<0.001)., Conclusions: Simulation course was significantly successful in improving residents' clinical skills and confidence in performing critical tasks.

Objectives: The qualitative subjective assessment has been exercised either by self-reflection (self-assessment (SA)) or by an observer (peer assessment (PA)) and is considered to play an important role in students' development. The objectivity of PA and SA by students as well as those by faculty examiners has remained debated. This matters most when it comes to a high-stakes examination. We explored the degree of objectivity in PA, SA, as well as the global rating by examiners being Examiners' Subjective Assessment (ESA) compared with Objective Structured Clinical Examinations (OSCE)., Design: Prospective cohort study., Setting: Undergraduate medical students at Alfaisal University, Riyadh., Participants: All second-year medical students (n=164) of genders, taking a course to learn clinical history taking and general physical examination., Main Outcome Measures: A Likert scale questionnaire was distributed among the participants during selected clinical skills sessions. Each student was evaluated randomly by peers (PA) as well as by himself/herself (SA). Two OSCEs were conducted where students were assessed by an examiner objectively as well as subjectively (ESA) for a global rating of confidence and well-preparedness. OSCE-1 had fewer topics and stations, whereas OSCE-2 was terminal and full scale., Results: OSCE-1 (B=0.10) and ESA (B=8.16) predicted OSCE-2 scores. 'No nervousness' in PA (r=0.185, p=0.018) and 'confidence' in SA (r=0.207, p=0.008) correlated with 'confidence' in ESA. In 'well-preparedness', SA correlated with ESA (r=0.234, p=0.003)., Conclusions: OSCE-1 and ESA predicted students' performance in the OSCE-2, a high-stakes evaluation, indicating practical 'objectivity' in ESA, whereas SA and PA had minimal predictive role. Certain components of SA and PA correlated with ESA, suggesting partial objectivity given the limited objectiveness of ESA. Such difference in 'qualitative' objectivity probably reflects experience. Thus, subjective assessment can be used with some degree of objectivity for continuous assessment., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The goal of this study was to explore the effects of trans-placental tetanus toxoid (TT) and pertussis (PT) antibodies on an infant's response to vaccination in the context of antenatal immunization with tetanus but not with pertussis. 38 mothers received a single dose of TT vaccine during pregnancy. Infants received tetanus and pertussis vaccines at 6, 10 and 14 wk of age. TT and PT anti-IgG secretion by infant lymphocytes was measured at 15 wk. Plasma antibodies were measured at 6 wk (pre-vaccination), 15 wk and 1 y of age. Prior to vaccination, TT and PT antibody were detected in 94.6% and 15.2% of infants. At 15 wk anti-TT-IgG and anti-PT-IgG in plasma was increased by 7-9 fold over pre-vaccination levels, while at 1 y plasma anti-TT-IgG was decreased by approximately 5-fold from the peak and had returned to near the pre-vaccination level. At 1 y plasma anti-PT-IgG was decreased by 2-fold 1 yfrom the 15 wk level. However, 89.5% and 82.3% of infants at 1 y had protective levels of anti-TT and anti-PT IgG, respectively. Pre-vaccination plasma IgG levels were associated with lower vaccine-specific IgG secretion by infant lymphocytes at 15 wk (p < 0.10). This apparent inhibition was seen for anti-TT-IgG at both 15 wk (p < 0.05) and t 1 y (p < 0.10) of age. In summary, we report an apparent inhibitory effect of passively derived maternal antibody on an infants' own antibody response to the same vaccine. However, since the cut-off values for protective titers are low, infants had protective antibody levels throughout infancy.

Introduction: Training clinical skills is essential in medicine. Different models of clinical skills courses have been previously suggested. Here, we report an innovative approach adopted to train junior medical students in clinical skills in a multimodal fashion by near-peers, basic scientists with clinical background and senior clinicians., Methods: This quasi-experimental study was conducted at Alfaisal University College of Medicine at Riyadh. An electronic survey was conducted among year-2 and year-3 medical students seeking their perception about the (a) organization, (b) delivery, (c&d) self- and peer-assessment in clinical skills courses. Total 298 male and female medical students (91%), consisting of 164 from year 2 and 134 from year 3, participated by filling out a questionnaire (Cronbach's alpha 0.93)., Results: Out of maximum five, the average ratings for the course were 3.81, 3.72, 3.67 and 3.73 in organization, delivery, self-evaluation and peer-assessment respectively, with no significant difference between both subgroups. The in-campus sessions rated higher than hospital sessions (p < 0.001). As tutors, interns were rated higher than clinicians (p < 0.001). The qualitative analysis suggested high satisfaction., Conclusions: The clinical skills course that was conducted in a multimodal fashion utilizing diverse tutors showed a positive attitude of students toward the organization and delivery of the course.

Purpose: The cytotoxic drug cyclophosphamide (CP) is bioactivated into 4-hydroxy-cyclophosphamide (4-OH-CP) through cytochrome P450 enzymes and cleared through aldehyde dehydrogenase and glutathione S-transferase. This prospective study analyzes the influence of drug metabolizing enzyme genotype on (1) plasma 4-OH-CP:CP ratio and (2) myelotoxicity in breast cancer patients on 500 mg/m(2) cyclophosphamide., Methods: Sixty-eight female breast cancer patients on FAC (fluorouracil, adriamycin, cyclophosphamide) were included. Genotyping of cytochrome P450 enzymes CYP2B6, CYP2C9, CYP2C19, CYP3A5, aldehyde dehydrogenase (ALDH3A1), and glutathione S-transferase (GSTA1) was done either through RFLP or pyrosequencing. Plasma CP and 4-OH-CP were measured immediately and 1 and 2 h after the end of infusion through LC-MS. The leukocyte count was determined on day 10 and 20 after chemotherapy., Results: At CP dose of 500 mg/m(2), the 4-OH-CP:CP ratio was negatively affected by CYP2C19*2 genotype (p = 0.039) showing a gene-dose effect. Moreover ALDH3A1*2 genotype increased 4-OH-CP:CP ratio (p = 0.037). These effects did not remain significant in a univariate analysis of variance including all genotypes. GSTA1*B carriers were at increased risk of severe leucopenia (OR 6.94; 95% CI 1.75-27.6, p = 0.006)., Conclusion: The myelotoxicity in patients receiving FAC is related to the activity of the phase-II enzyme GSTA1 but is independent of the formation of 4-OH-CP.

Polymorphic genes of drug metabolizing enzymes and transporters may influence drug response. With some exemptions, single nucleotide polymorphisms in such genes, however, are not known to be susceptibility factors for breast cancer. This study explored genotype profiles for the breast cancer patients on fluorouracil, doxorubicin and cyclophosphamide (FAC) in a Pakistani set of population and their comparison with HapMap data. Sixty-eight female breast cancer patients were included. All received FAC chemotherapy. Relevant genotyping was done either through restriction fragment length polymorphism or pyrosequencing. The variant allele frequencies were: 5.1% for CYP2C9*2 (430C>T), 15.4% for CYP2C9*3 (1075A>C), 27.2% for CYP2C19*2 (681G>A), 33.1% for GSTA1*B (-69C>T, -52G>A), 62.5% for ALDH3A1*2 (985C>G), 58.8% and 4.4% for ABCB1 (2677 G>T/A), 64.7% for ABCB1 3435 C>T, and 15.4%, 33.1% and 39.7% for ABCC2 (-24 C>T, 1249 G>A and 3972 C>T). In comparison with HapMap, this first exploration in Pakistani samples shows higher frequency of (i) CYP2C9*3 carriers (p < 0.05) than in Hispanic, Chinese, Japanese and African samples, (ii) ALDH3A1*2 carriers (p < 0.01) than Caucasian, Hispanic, Chinese, Japanese and African samples. For ABC transporters, a higher frequency of variant allele was observed in (iii) ABCB1 2677 G>T/A (p < 0.01) than Caucasian, Hispanic and African, (iv) ABCB1 3435 C>T (p < 0.05) than Chinese, Japanese and African, (v) ABCC2 1249 G>A (p < 0.01) than Hispanic, Chinese and Japanese samples. In conclusion, cyclophosphamide activation and detoxification of reactive intermediates may be altered in the Pakistani. Though carriers of CYP2C19*2 were higher than in Caucasian and Hispanics, they did not reach statistical significance (p = 0.05).

Background: This study was planned to audit female breast cancers and their chemotherapy in a busy public sector institution. As a case-study, Pakistan provides an opportunity to explore the issue in a low-GDP, low-literacy, populous developing country., Method: Retrospective analysis of the records at Karachi Institute of Radiotherapy and Nuclear Medicine., Results: A total of 3,431 female breast cancer patients presented during 2001-2008, half being <45 years, mostly suffering from infiltrating ductal carcinoma of breast. Further analyzing a subgroup of 183 consecutive patients over six months revealed that only 1.6% were at stage-I, whereas 75% had node-positive disease, including 19.1% with distant metastases. Some 41.6% were either high grade or poorly differentiated. The low grade tumors showed a two-fold likelihood of ER and PR positivity as compared to high grade lesions. 5-Flourouracil, doxorubicin and cyclophosphamide (FAC) constituted the most common chemotherapy. Earlier diagnosis was associated with complete remission. Overall, 33% developed myelotoxicity, more often if age ≥ 45 years (p=0.012), out of which 60% needed active correction. All those patients who did not experience a drop in total leukocyte count (TLC) below 4 x 10⁹/L did not show complete remission., Conclusions: Infiltrating ductal carcinoma of the breast is the most common type. FAC is the most common chemotherapy. Tendency for late diagnosis, metastatic disease, treatment failure as well as leukopenia especially in ≥ 45 years is present. Failure to show leukopenia is suggestive of poor therapeutic outcome.

Objective: To observe the adverse effects of low dose combination contraceptive pills on blood coagulation in a set of local population., Methods: Between December 2002 to December 2003 a comparative cross-sectional study was conducted at the Department of Pharmacology, Ziauddin Medical University, Karachi and Aga Khan University Hospital, Karachi. Fifty women of reproductive age were divided in two equal groups; one being the users of combination oral contraceptive pills (ethinyl estradiol and levonorgestrel) and the other being matching controls not taking any hormonal contraceptives. We studied, CBC, PT and INR, APTT, BT and platelet aggregation against ADP, collagen, epinephrine and ristocetin., Results: PT, INR, and platelet aggregation response to ADP, collagen, epinephrine, and ristocetin were not significantly different among the groups. However, APTT was shortened in users of contraceptives (p = 0.003)., Conclusion: The referred oral contraceptive is associated with enhanced activity of intrinsic pathway of secondary haemostasis.

Background: Safe use of progestin-only hormonal preparations has remained quite controversial though they are being employed in various disorders very commonly. These hormones result in a number of adverse effects in the body, the most drastic being predisposition to higher risk of thromboembolism with reports of involvement of platelets. Despite a large number of studies, no definite inference had been derived regarding the effects of these agents on blood coagulation. It has been reported that the response in various ethnic groups may vary. Therefore this study is designed to observe the effects of progestin-only hormonal contraceptives regarding primary hemostasis in our population., Methods: We carried out this study on 50 women divided into two equal groups of 25 each, namely, a group of users of Progestin-only injectable hormonal contraceptive Norethisterone oenanthate 200 mg used as a 2-monthly injection and a control group and studied platelet aggregation against ADP, Collagen, Epinephrine and Ristocetin., Results: There was no statistical difference regarding the platelet aggregation studies against ADP, collagen, epinephrine and ristocetin between users and nonusers of progestin-only injectable contraceptive. The menstrual irregularities were found to be more frequent in users of injectable hormonal contraceptives than in non-users, especially amenorrhea and irregularities of menstrual flow. In users of injectable hormnonal contraceptives, hemoglobin and hematocrit were slightly better maintained as compared to non-users., Conclusion: This suggests that Norethisterone oenanthate at currently used doses does not increase the platelet aggregation against ADP, collagen, epinephrine and ristocetin in our population.

Objective: To observe the effects of progestin-only hormonal contraceptives in our population., Design: Cohort study., Place and Duration of Study: Department of Pharmacology, Ziauddin Medical University, Karachi and Department of Pathology, Faculty of Health Sciences, The Aga Khan University, Karachi from October 2002 to September 2003., Patients and Methods: The study comprised of 50 women of reproductive age group, divided into two equal and matched groups of 25 each, namely, a group of users of progestin-only injectable hormonal contraceptive Norethisterone oenanthate [NET EN] 200 mg used as a 2-monthly injection and a control group not using any hormonal contraception. Complete blood counts, prothrombin time (PT) and international normalized ratio (INR) as well as activated partial thromboplastin time (APTT) were monitored., Results: APTT and prothrombin time were not significantly different in both the groups. Menstrual irregularities were found out by more frequent in users of injectable hormonal contraceptives than in non-users (p= 0.001). Hemoglobin (p= 0.029) and hematocrit were slightly better preserved in the same group., Conclusion: Use of Norethisterone oenanthate does not predispose to thrombogenesis in current dose for contraception.