Uptake of anthracyclines in vitro and in vivo in acute myeloid leukemia cells in relation to apoptosis and clinical response

Aims  

To study anthracycline-induced apoptosis in leukemic cells isolated from patients with acute myelogenous leukemia (AML) in vitro and to compare intracellular anthracycline concentrations causing apoptosis in vitro with those obtained in vivo during anthracycline treatment.     

Association between anthropometric measures of obesity and subclinical atherosclerosis in Bangladesh

Background

Anthropometric measures such as waist–hip-ratio (WHR), waist-height-ratio (WHtR), waist circumference, Mid-upper arm circumference (MUAC), and upper thigh circumference, have been linked to the risk of cardiovascular disease (CVD). However, their relationships with subclinical atherosclerosis are unclear. Studies in normal-weight populations, especially in Asian countries where leanness is prevalent, are lacking.

Methods

We conducted a cross-sectional study to assess the associations of WHR, WHtR, waist circumference, hip circumference, body mass index (BMI), MUAC and upper thigh circumference with carotid intima-media thickness (cIMT) among 562 middle-aged participants free of CVD in rural Bangladesh.

Results

After adjusting for age and sex, WHR and waist circumference but not BMI showed a positive significant association with cIMT. In multivariate analysis, each standard deviation (SD) increase of WHR (0.08) or WHtR (0.07) was associated with an 8.96 μm (95% CI, 1.12–16.81) or 11.45 μm (95%CI, 0.86–22.04) difference in cIMT, respectively, after controlling for age, sex, BMI, smoking status, education level, and systolic blood pressure (SBP). The associations of WHR and WHtR with cIMT were independent of the influence of other anthropometric measures. The associations of other anthropometric measures and cIMT were not apparent.

Conclusions

In our relatively lean, healthy Asian population, WHR and WHtR appear to be better predictors of early atherosclerosis than other common surrogates of adiposity.     

Drug Addiction and Substance Use Among the Dalit Married Adolescent Girls in Bangladesh: a Cross-Sectional Survey

Dalits are referred to “shattered,” “outcasts,” and socially marginalized community in Bangladesh. In particular, Dalit adolescent girls are the most vulnerable owing to their caste and gender. Prior studies have looked at the prevalence and effects of drug addiction among the youths in mainstream population, but the Dalit adolescents were excluded from the samples. The study aimed to investigate the prevalence of drug addiction and substance use among the Dalit married adolescent girls (MAGs), and to identify the significant predictors associated with this addiction. A cross-sectional survey was carried out among 300 MAGs in the Dalit community. Involving systematic random sampling, participants were selected from both urban and rural settings located in Dhaka and Gaibandha districts. Bivariate and multivariate logistic regressions were performed to explore the significant factors associated with drug addiction. The prevalence of drug addiction was 11.3% among married Dalit adolescent girls. Multivariate analysis identified that participants’ habit of smoking (AOR=5.210, 95% CI=2.413–11.250), participant’s husband’s habit of smoking (AOR=10.415, 95% CI=3.911–27.739), and habit of using alcohol/highly risky substances (AOR=19.030, 95% CI=6.481–55.875) were significant associated with drug addiction. An alarming proportion of Dalit adolescent girls were recorded to be habituated in various forms of drugs use. Therefore, immediate policy measures focusing intensive campaigns, targeted counseling, and health education programs need to design to get over the risky health behaviors.

     

Multiply antibiotic-resistant Vibrio cholerae O1 biotype El Tor strains emerge during cholera outbreaks in Zambia

Antibiotic resistance data, made available from laboratory records during eight cholera outbreaks between 1990 and 2004 showed Vibrio cholerae serogroup O1 to have a low level of resistance (2-3%) to tetracycline during 1990-1991. Resistance increased for tetracycline (95%), chloramphenicol (78%), doxycycline (70%) and trimethoprim-sulphamethoxazole (97%) in subsequent outbreaks. A significant drop in resistance to tetracycline and chloramphenicol followed the adoption of a national policy to replace tetracycline with erythromycin for treating cholera. Sixty-nine strains from cholera outbreaks in Zambia between 1996 and 2004, were examined for antibiotic resistance and basic molecular traits. A 140 MDa conjugative, multidrug-resistant plasmid was found to encode tetracycline resistance in strains from 1996/1997 whereas strains from 2003/2004 were resistant to furazolidone, but susceptible to tetracycline, and lacked this plasmid. PCR revealed 25 of 27 strains from 1996/1997 harboured the intl1 class 1 integron but lacked SXT, a conjugative transposon element. Similar screening of 42 strains from 2003/2004 revealed all carried SXT but not the intl1 class 1 integron. All 69 strains, except two, one lacking ctxA and the other rstR and thus presumably truncated in the CTX prophage region, were positive for important epidemic markers namely rfbO1, ctxA, rstR2, and tcpA of El Tor biotype. Effective cholera management is dependent on updated reports on culture and sensitivity to inform the choice of antibiotic. Since the emergence of antibiotic resistance may significantly influence strategies for controlling cholera, continuous monitoring of epidemic strains is crucial.     

Failure of national guidelines to diagnose uncomplicated malaria in Bangladesh

During the mid 1990s, national guidelines were established in accordance with World Health Organization recommendations for the diagnosis of uncomplicated malaria in Bangladesh. Based on simple clinical and epidemiologic criteria these guidelines were designed to be applied outside of tertiary care centers where microscopy was not feasible. We evaluated the positive predictive value (PPV) of these criteria using microscopic slide examinations as the gold standard in 684 subjects diagnosed and treated for malaria, sampling from eight subdistrict centers. The PPV for malaria was 32% with 19% for falciparum and 14% for Plasmodium vivax. Medical officers assigned to the study also gave their own clinical impression of whether cases could have been malaria. With the additional criteria of a medical officers' diagnosis, the PPV increased negligibly to 37% with 23% and 14% for falciparum and vivax, respectively. Since the PPV of diagnosis is low and cannot be improved on clinical grounds alone, we recommend the incorporation of laboratory diagnosis. This is especially important as we detect resistance to the first-line therapy chloroquine and require more expensive, potentially more toxic, regimens.     

Plasma Leptin Levels in Children Hospitalized with Cholera in Bangladesh

Vibrio cholerae, the cause of cholera, induces both innate and adaptive immune responses in infected humans. Leptin is a hormone that plays a role in both metabolism and mediating immune responses. We characterized leptin levels in 11 children with cholera in Bangladesh, assessing leptin levels on days 2, 7, 30, and 180 following cholera. We found that patients at the acute stage of cholera had significantly lower plasma leptin levels than matched controls, and compared with levels in late convalescence. We then assessed immune responses to V. cholerae antigens in 74 children with cholera, correlating these responses to plasma leptin levels on day 2 of illness. In multivariate analysis, we found an association between day 2 leptin levels and development of later anti-cholera toxin B subunit (CtxB) responses. This finding appeared to be limited to children with better nutritional status. Interestingly, we found no association between leptin levels and antibody responses to V. cholerae lipopolysaccharide, a T cell–independent antigen. Our results suggest that leptin levels may be associated with cholera, including the development of immune responses to T cell–dependent antigens.     

Clinical and Immunological Aspects of Post–Kala-Azar Dermal Leishmaniasis in Bangladesh

We conducted active surveillance for kala-azar and post–kala-azar dermal leishmaniasis (PKDL) in a population of 24,814 individuals. Between 2002 and 2010, 1,002 kala-azar and 185 PKDL cases occurred. Median PKDL patient age was 12 years; 9% had no antecedent kala-azar. Cases per 10,000 person-years peaked at 90 for kala-azar (2005) and 28 for PKDL (2007). Cumulative PKDL incidence among kala-azar patients was 17% by 5 years. Kala-azar patients younger than 15 years were more likely than older patients to develop PKDL; no other risk factors were identified. The most common lesions were hypopigmented macules. Of 98 untreated PKDL patients, 48 (49%) patients had resolution, with median time of 19 months. Kala-azar patients showed elevated interferon-γ (IFNγ), tumor necrosis factor-α (TNFα), and interleukin 10 (IL-10). Matrix metalloproteinase 9 (MMP9) and MMP9/tissue inhibitor of matrix metalloproteinase-1 (TIMP1) ratio were significantly higher in PKDL patients than in other groups. PKDL is frequent in Bangladesh and poses a challenge to the current visceral leishmaniasis elimination initiative in the Indian subcontinent.     

Inhibition of HtrA2/Omi ameliorates heart dysfunction following ischemia/reperfusion injury in rat heart in vivo

High temperature requirement A2 (HtrA2)/Omi is a mitochondrial serine protease that is released into the cytosol from mitochondria and in turn promotes caspase activation by proteolyzing inhibitor of apoptosis proteins. Here we asked whether treatment with an HtrA2/Omi inhibitor, 5-[5-(2-nitrophenyl)furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid (UCF-101), restores heart dysfunction following ischemia/reperfusion injury in vivo. Rats underwent a 30-min ischemia by occluding the left anterior descending artery, followed by 24 h reperfusion. UCF-101 (0.75 or 1.5 micromol/kg, i.p.) was administered 10 min before reperfusion. UCF-101 treatment significantly recovered the mean arterial blood pressure and ameliorated contractile dysfunction of the left ventricle 72 h after reperfusion with concomitant reduction of infarct size. Cardio-protection mediated by UCF-101 was correlated with reduced X-linked inhibitor of apoptosis protein (XIAP) degradation and inhibition of Caspase-9, Caspase-3, and Caspase-7 processing. Furthermore, UCF-101 prevented loss of membrane integrity by inhibiting fodrin breakdown in cardiomyocytes. UCF-101-induced cytoprotection was also correlated with reduced Fas ligand expression and inhibition of FLIP degradation following ischemia/reperfusion. These results suggest that UCF-101 rescues cardiomyocytes from ischemia/reperfusion injury by inhibiting XIAP degradation and Fas/Fas-ligand-induced apoptosis, thereby ameliorating ischemia/reperfusion-induced myocardial dysfunction.