Acute leukemia associated with valproic acid treatment: A novel mechanism for leukemogenesis?

Valproic acid has been previously associated with hematologic toxicity, including a reversible myelodysplasia-like syndrome without chromosomal abnormalities. We now report three cases of acute leukemia with features of secondary leukemia associated with valproic acid therapy: two cases of acute myelogenous leukemia with multilineage dysplasia, one with trisomy 8 and one with monosomy 7, and one case of secondary acute lymphoblastic leukemia with del (7) (q22q34), del (9) (q21.11q22), del (11) (q12q23). One patient had a previous myelodysplastic syndrome while on valproic acid. Valproic acid has been previously shown to be a histone deacetylase inhibitor. Inhibition of histone deacetylase causes a relaxation of chromatin structure and thus increases susceptibility to DNA damage and sensitizes cells to radiation. We propose that valproic acid therapy may lead to secondary leukemia by increasing DNA damage through chronic inhibition of histone deacetylase.     

Plasma homocysteine levels and the left ventricular systolic function in coronary artery disease patients

BACKGROUND: Numerous studies have shown a relationship between hyperhomocysteinemia, atherothrombosis and cardiovascular mortality. However, an association between hyperhomocysteinemia and the extent of coronary artery disease (CAD) remains controversial whereas its relationship with left ventricular systolic function has not been established. METHODS: One hundred and fifty-seven patients with angiographically defined CAD were included. The relationships between hyperhomocysteinemia, severity of CAD and left ventricular systolic function were studied. Left ventricular systolic function was determined primarily by ventriculography. The severity of CAD was determined through coronary angiography using the Gensini score and the number of vessels with > or = 50% stenosis. RESULTS: The mean fasting plasma homocysteine level was 13.4 mumol/l+/-0.5 SE. Elevated levels of homocysteine correlated significantly with increased severity of CAD both by the Gensini scores (r-value = 0.344, P < 0.0005) and the total number of diseased vessels (r-value = 0.387, P < 0.0005). The patients with hyperhomocysteinemia were found to have significantly reduced left ventricular ejection fraction (r-value = -0.382, P < 0.0005). A multivariate regression analysis revealed homocysteine level to be an independent predictor of left ventricular systolic function. In addition, adjusted analysis revealed hyperhomocysteinemia to be associated with global left ventricular dysfunction. CONCLUSION: In patients with CAD, homocysteine levels correlate independently with left ventricular systolic function. The mechanism of this association between homocysteine and left ventricular systolic function is unknown but may be due to a direct effect of homocysteine on myocardial function separate from its effects on coronary atherosclerosis.     

Functionally aberrant dendritic cell subsets and expression of DC-SIGN differentiate acute from chronic HBV infection

Background

Dendritic cells (DCs) promote pathogen recognition, uptake and presentation of antigen through DC-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN) and toll-like receptors (TLRs).

Aims and Objectives

We aimed to study temporal changes in DCs, TLRs and DC-SIGN during acute viral hepatitis B (AVHB) infection and compare them to chronic (CHB) and to investigate the earliest time point of activated pathogen recognition receptors in hepatitis B viral infection.

Methods

We measured the frequencies of circulating myeloid (mDC) and plasmacytoid (pDC) dendritic cells and IFN-α production along with the expression of DC-SIGN and Toll Like Receptors (TLR's) in HBV patients at different time points. Also investigated in healthy volunteers, the dynamic changes in TLRs expression after receiving hepatitis B vaccine.

Results

On follow-up of AVHB patients, we found the mDC population was significantly higher at week 4 and 6 (p < 0.02, 0.01), whereas the pDC population was unchanged at week 6 compared with week 0. Whereas frequencies of mDCs and pDCs were found to be elevated in AVHB and CHB patients than HC (p < 0.00 and 0.01, respectively) but was comparable among AVHB vs CHB. The DCs in CHB patients were functionally impaired with significantly low IFN-α production and low DCSIGN expression (p < 0.04 and 0.00, respectively). Even after stimulation by TLR agonists, no change was found in IFN-α production in CHB patients. MyD88 and IL-6, IFN-α mRNA levels were also found down-regulated. Interestingly, on follow-up after HBV vaccine, TLRs expression was found high at day 3 after vaccination.

Discussion

The initial events of immune activation might be responsible for modulating immune response. These novel observations would pave the way for the development of antiviral strategies for chronic HBV infection.

     

Synthesis and biological evaluation of novel <Emphasis Type="SmallCaps">d</Emphasis>-glucose-derived 1,2,3-triazoles as potential antibacterial and antifungal agents

A series of novel d-glucose-derived 1,2,3-triazoles have been synthesized in excellent yields via Cu(I)-catalyzed 1,3-dipolar cycloaddition by using methyl α-d-glucopyranoside as starting material. All the new compounds were confirmed by ¹H NMR, ¹³C NMR, IR, MS, and HRMS spectra, and their antimicrobial activities were screened against Gram-Positive, Gram-Negative bacteria, and fungi. Bioactive assay manifested that some of the synthesized glucose-derived 1,2,3-triazoles exhibited good antibacterial and antifungal activities. Notably, compound 5k gave the most potent efficiency with MIC₅₀ value of 6 µM against Candida albicans, which was nine-fold more active than the reference drug Fluconazole. It also exhibited good antibacterial activity against Escherichia coli with the MIC₅₀ value of 10.8 µM compared to Chloramphenicol while the corresponding hydrochloride 4k revealed remarkable inhibitory against Bacillus subtilis with an MIC₅₀ value of 11 µM.     

Effectiveness and safety profiling of zolpidem and acupressure in CKD associated pruritus: An interventional study

Background:Chronic kidney disease (CKD)-associated pruritus (CKD-aP) contributes to poor quality of life, including reduced sleep quality and poor sleep quality is a source of patient stress and is linked to lower health-related quality of life. This study aimed to investigate the effectiveness of zolpidem 10 mg and acupressure therapy on foot acupoints to improve the sleep quality and overall quality of life among hemodialysis patients suffering from CKD-aP.Method:A multicenter, prospective, randomized, parallel-design, open label interventional study to estimate the effectiveness of zolpidem (10 mg) oral tablets versus acupressure on sleep quality and quality of life in patients with CKD-aP on hemodialysis. A total of 58 hemodialysis patients having sleep disturbance due to CKD-aP completed the entire 8-week follow-up. The patients were divided into a control (acupressure) group of 28 patients and an intervention (zolpidem) group of 30 patients.Results:A total of 58 patients having CKD-aP and sleep disturbance were recruited. In the control group there was a reduction in the PSQI score with a mean ± SD from 12.28 ± 3.59 to 9.25 ± 3.99, while in the intervention group the reduction in PSQI score with a mean ± SD was from 14.73 ± 4.14 to 10.03 ± 4.04 from baseline to endpoint. However, the EQ5D index score and EQ-visual analogue scale (VAS) at baseline for the control group with a mean ± SD was 0.49 ± 0.30 and 50.17 ± 8.65, respectively, while for the intervention group the values were 0.62 ± 0.26 and 47.17 ± 5.82, respectively. The mean EQ5D index score in the control group improved from 0.49 ± 0.30 to 0.53 ± 0.30, but in the intervention group there was no statistical improvement in mean EQ5D index score from 0.62 ± 0.26 to 0.62 ± 0.27 from baseline to week 8. The EQ 5D improved in both groups and the EQ-VAS score was 2.67 points higher at week 8 as compared to baseline in the control group, while in the intervention group the score was 3.33 points higher at week 8 as compared to baseline. Comparing with baseline, the PSQI scores were significantly reduced after week 4 and week 8 (P =  < .001). Furthermore, at the end of the study, the PSQI scores were significantly higher in the control as compared to the intervention group (P = .012).Conclusion:An improvement in sleep quality and quality of life among CKD-aP patients on hemodialysis has been observed in both the control and intervention groups. Zolpidem and acupressure safety profiling showed no severe adverse effect other that drowsiness, nausea and daytime sleeping already reported in literature of zolpidem.     

Human papillomavirus subtype 16 is common in Pakistani women with cervical carcinoma.

INTRODUCTION: Human papillomavirus (HPV) is recognized as a major causative agent for cervical carcinomas. Based on their oncogenic potential, HPV subtypes have been divided into high- and low-risk. In Pakistan, screening for HPV in female patients is not commonly practiced, and as a consequence, the degree of HPV prevalence and its correlation with cervical cancer is unknown. OBJECTIVE: In this study, we have attempted to estimate the prevalence of HPV infection, and also the HPV subtype profile, among Pakistani women with cervical cancer from varied geographical, racial, and social backgrounds within Pakistan. METHODOLOGY: Women visiting two tertiary care hospitals in Karachi, diagnosed with carcinoma of the cervix within the past 15 years, were analyzed for HPV subtypes in their cancer specimens. Retrospectively, 60 paraffin-embedded cervical cancer biopsies were examined for the presence of HPV DNA. After DNA extraction from these samples, polymerase chain reaction (PCR) was used to amplify the HPV L1 gene using the consensus (general) primers, and primers specific for subtypes 16 and 18. RESULTS: Of the 60 samples analyzed, only one sample was HPV negative; the rest of the samples were positive for the presence of HPV. Of the 59 HPV positive samples, 56 showed the presence of HPV16 and one sample was positive for HPV18; HPV subtype could not be determined in two samples. CONCLUSION: Our results show a strong relationship between HPV infection and cervical cancer among Pakistani women. These results underscore the need to implement regular HPV screening for Pakistani women. An early diagnosis of HPV infection will allow better health management to reduce the risk of developing cervical cancer.     

The effects of perinatal hypoxia on the behavioral,neurochemical, and neurohistological toxicity of the metabolic inhibitor 3-nitropropionic acid

3-nitropropionic acid (3-NPA) neurotoxicity and long-term effects of perinatal hypoxia were evaluated in 18 adult rats. Hypoxia-insulted (I) and noninsulted (NI) rats were delivered by cesarean section. Hypoxic insult was effected by submerging dissected uterine horns in warmed saline for 15 min. NI rats were delivered from the adjacent nonsubmerged horns. At postnatal day 90, I and NI rats were trained to perform tasks thought to measure behaviors dependent upon aspects of time estimation (TE), motivation, and learning. At 12 months of age, rats were injected i.p. with escalating doses of 3-NPA (5 mg/kg/day to a maximum of 30 mg/kg/day) immediately after each test session and sacrificed at the end of treatment. Additional male rats were used as untreated controls. Although 3-NPA produced a dose-dependent impairment of performance in each task, the effects were qualitatively similar for each group. A significant difference between I and NI rats was, however, observed in the TE task where NI rats completed less of the task at high doses of 3-NPA compared to I rats. Compared to untreated controls, dopamine concentrations were decreased in caudate nucleus of both I and NI rats after 3-NPA. Specific areas most frequently damaged included cerebral cortex, hippocampal subfield CA1, thalamus, caudate nucleus, and the cerebellum. Lesions usually were less extensive in the I rather than NI members of a littermate pair, suggesting a possible protective effect of perinatal hypoxia against subsequent 3-NPA neurotoxicity.