ZOLEDRONIC ACID: A MISCHIEVOUS SUSPECT FOR LIVER INJURY

ABSTRACTA 47-year-old male diagnosed as adenocarcinoma of the lung and received 8 cycles of chemotherapy comprising intravenous administration ofcisplatin 125 mg, pemetrexed 850 mg along with zoledronic acid 4 mg. After the completion of the 8 cycle, the liver enzymes were found to bemarkedly elevated, evincing zoledronic acid as the cause for hepatotoxicity. The case details were taken from the patient's medical record along withthe biochemical test reports and radiographic images. The causal association was confirmed using Naranjo's algorithm and Roussel Uclaf CausalityAssessment Method (RUCAM). After the uneventful chemotherapy, patient's liver function tests (LFT) were abnormal. There was an elevation in theaspartate aminotransferase, alanine transaminase, alkaline phosphatase, and direct bilirubin. The causal relationship was established using Naranjo'salgorithm (score-6) and RUCAM (score-5), displayed a probable†and possible†association. Hartwig's severity scale and Thornton's preventabilityscale displayed the adverse drug reaction to being moderately severe and not preventable, respectively. The zoledronic acid was stopped and neverreadministered. The LFTs assumed normal after a span of 2 months. The mechanism underlying hepatotoxicity due to zoledronic acid remains elusive.Zoledronic acid can induce acute phase response mediated by active production of interleukin-6, tumor necrosis factor alpha, and pro-inflammatorycytokines from the T-cells and macrophages. Vigilant monitoring along with timely assessment and management can prevent the occurrence ofirreversible liver damage. Henceforth, we would like to report the rare incidence of drug induced hepatic damage due to zoledronic acid. Henceforth,we would like to report the rare incidence of drug induced hepatic damage due to zoledronic acid.Keywords: Bisphosphonate, Dechallenge, Hepatotoxicity, Rechallenge.t

Synthesis, characterization, antimicrobial and DNA cleavage study of organoantimony(III) and organoarsenic(III) complexes with monofunctional bidentate Schiff base

341-347A series of mononuclear organoantimony(III) and organoarsenic(III) complexes of bidentate Schiff base [2-(2-fluorophenyl)methylene]hydrazinecarbothioamide (LH) have been synthesized by the reaction of Ph3Sb and Ph3As with ligand in 1:1 and 1:2 molar ratios. All the synthesized compounds were characterized by elemental analyses, melting point determinations and a combination of electronic, IR, 1H NMR, 13C NMR and X-ray diffraction studies. These studies have shown that the ligand coordinated to the antimony and arsenic in a monobasic bidentate manner through sulfur and nitrogen donor system. Thus, a tetra-coordinated and a penta-coordinated environment around the antimony and arsenic atom have been proposed for 1:1 and 1:2 complexes, respectively. All the complexes and parent ligand have been screened for their antimicrobial activity on several pathogenic fungi and bacteria and are found to possess appreciable fungicidal and bactericidal properties. Further, the ligand and its corresponding metal complexes have been tested for their DNA cleavage activity by the gel electrophoresis and the results revealed that the complexes are better cleaving agents than ligand

Causal relevance of blood lipid fractions in the development of carotid atherosclerosis: Mendelian randomization analysis.

BACKGROUND: Carotid intima-media thickness (CIMT), a subclinical measure of atherosclerosis, is associated with risk of coronary heart disease events. Statins reduce progression of CIMT and coronary heart disease risk in proportion to the reduction in low-density lipoprotein cholesterol. However, interventions targeting triglycerides (TGs) or high-density lipoprotein cholesterol (HDL-C) have produced inconsistent effects on CIMT and coronary heart disease risk, making it uncertain whether such agents are ineffective for coronary heart disease prevention or whether CIMT is an inadequate marker of HDL-C or TG-mediated effects. We aimed to determine the causal association among the 3 major blood lipid fractions and common CIMT using mendelian randomization analysis. METHODS AND RESULTS: Genetic scores specific for low-density lipoprotein cholesterol, HDL-C, and TGs were derived based on single nucleotide polymorphisms from a gene-centric array in ≈5000 individuals (Cardiochip scores) and from a genome-wide association meta-analysis in >100 000 individuals (Global Lipids Genetic Consortium scores). These were used as instruments in a mendelian randomization analysis in 2 prospective cohort studies. A genetically predicted 1 mmol/L higher low-density lipoprotein cholesterol concentration was associated with a higher common CIMT by 0.03 mm (95% confidence interval, 0.01-0.04) and 0.04 mm (95% confidence interval, 0.02-0.06) based on the Cardiochip and Global Lipids Genetic Consortium scores, respectively. HDL-C and TGs were not causally associated with CIMT. CONCLUSIONS: Our findings confirm a causal relationship between low-density lipoprotein cholesterol and CIMT but not with HDL-C and TGs. At present, the suitability of CIMT as a surrogate marker in trials of cardiovascular therapies targeting HDL-C and TGs is questionable and requires further study

Alcohol consumption and cognitive performance: a <scp>M</scp> endelian randomization study

Aims: To use Mendelian randomization to assess whether alcohol intake was causally associated with cognitive function. Design: Mendelian randomization using a genetic variant related to alcohol intake (ADH1B rs1229984) was used to obtain unbiased estimates of the association between alcohol intake and cognitive performance. Setting: Europe. Participants: More than 34000 adults. Measurements: Any versus no alcohol intake and units of intake in the previous week was measured by questionnaire. Cognitive function was assessed in terms of immediate and delayed word recall, verbal fluency and processing speed. Findings: Having consumed any versus no alcohol was associated with higher scores by 0.17 standard deviations (SD) [95% confidence interval (CI)=0.15, 0.20] for immediate recall, 0.17 SD (95% CI=0.14, 0.19) for delayed recall, 0.17 SD (95% CI=0.14, 0.19) for verbal fluency and 0.12 SD (95% CI=0.09, 0.15) for processing speed. The minor allele of rs1229984 was associated with reduced odds of consuming any alcohol (odds ratio=0.87; 95% CI=0.80, 0.95; P=0.001; R2=0.1%; F-statistic=47). In Mendelian randomization analysis, the minor allele was not associated with any cognitive test score, and instrumental variable analysis suggested no causal association between alcohol consumption and cognition: -0.74 SD (95% CI=-1.88, 0.41) for immediate recall, -1.09 SD (95% CI=-2.38, 0.21) for delayed recall, -0.63 SD (95% CI=-1.78, 0.53) for verbal fluency and -0.16 SD (95% CI=-1.29, 0.97) for processing speed. Conclusions: The Mendelian randomization analysis did not provide strong evidence of a causal association between alcohol consumption and cognitive ability

A systematic review and meta-analysis of 130,000 individuals shows smoking does not modify the association of APOE genotype on risk of coronary heart disease

Background: Conflicting evidence exists on whether smoking acts as an effect modifier of the association between APOE genotype and risk of coronary heart disease (CHD). Methods and results: We searched PubMed and EMBASE to June 11, 2013 for published studies reporting APOE genotype, smoking status and CHD events and added unpublished data from population cohorts. We tested for presence of effect modification by smoking status in the relationship between APOE genotype and risk of CHD using likelihood ratio test.In total 13 studies (including unpublished data from eight cohorts) with 10,134 CHD events in 130,004 individuals of European descent were identified. The odds ratio (OR) for CHD risk from APOE genotype (ε4 carriers versus non-carriers) was 1.06 (95% confidence interval (CI): 1.01, 1.12) and for smoking (present vs. past/never smokers) was OR 2.05 (95%CI: 1.95, 2.14). When the association between APOE genotype and CHD was stratified by smoking status, compared to non-ε4 carriers, ε4 carriers had an OR of 1.11 (95%CI: 1.02, 1.21) in 28,789 present smokers and an OR of 1.04 (95%CI 0.98, 1.10) in 101,215 previous/never smokers, with no evidence of effect modification (. P-value for heterogeneity=0.19). Analysis of pack years in individual participant data of >60,000 with adjustment for cardiovascular traits also failed to identify evidence of effect modification. Conclusions: In the largest analysis to date, we identified no evidence for effect modification by smoking status in the association between APOE genotype and risk of CHD

Sixty-five common genetic variants and prediction of type 2 diabetes.

We developed a 65 type 2 diabetes (T2D) variant-weighted gene score to examine the impact on T2D risk assessment in a U.K.-based consortium of prospective studies, with subjects initially free from T2D (N = 13,294; 37.3% women; mean age 58.5 [38-99] years). We compared the performance of the gene score with the phenotypically derived Framingham Offspring Study T2D risk model and then the two in combination. Over the median 10 years of follow-up, 804 participants developed T2D. The odds ratio for T2D (top vs. bottom quintiles of gene score) was 2.70 (95% CI 2.12-3.43). With a 10% false-positive rate, the genetic score alone detected 19.9% incident cases, the Framingham risk model 30.7%, and together 37.3%. The respective area under the receiver operator characteristic curves were 0.60 (95% CI 0.58-0.62), 0.75 (95% CI 0.73 to 0.77), and 0.76 (95% CI 0.75 to 0.78). The combined risk score net reclassification improvement (NRI) was 8.1% (5.0 to 11.2; P = 3.31 × 10(-7)). While BMI stratification into tertiles influenced the NRI (BMI ≤24.5 kg/m(2), 27.6% [95% CI 17.7-37.5], P = 4.82 × 10(-8); 24.5-27.5 kg/m(2), 11.6% [95% CI 5.8-17.4], P = 9.88 × 10(-5); >27.5 kg/m(2), 2.6% [95% CI -1.4 to 6.6], P = 0.20), age categories did not. The addition of the gene score to a phenotypic risk model leads to a potentially clinically important improvement in discrimination of incident T2D

Constraints on the χ_(c1) versus χ_(c2) polarizations in proton-proton collisions at √s = 8 TeV

The polarizations of promptly produced χ_(c1) and χ_(c2) mesons are studied using data collected by the CMS experiment at the LHC, in proton-proton collisions at √s=8  TeV. The χ_c states are reconstructed via their radiative decays χ_c → J/ψγ, with the photons being measured through conversions to e⁺e⁻, which allows the two states to be well resolved. The polarizations are measured in the helicity frame, through the analysis of the χ_(c2) to χ_(c1) yield ratio as a function of the polar or azimuthal angle of the positive muon emitted in the J/ψ → μ⁺μ⁻ decay, in three bins of J/ψ transverse momentum. While no differences are seen between the two states in terms of azimuthal decay angle distributions, they are observed to have significantly different polar anisotropies. The measurement favors a scenario where at least one of the two states is strongly polarized along the helicity quantization axis, in agreement with nonrelativistic quantum chromodynamics predictions. This is the first measurement of significantly polarized quarkonia produced at high transverse momentum