An inhibitor of the microsomal triglyceride transfer protein inhibits apoB secretion from HepG2 cells.

The microsomal triglyceride (TG) transfer protein (MTP) is a heterodimeric lipid transfer protein that catalyzes the transport of triglyceride, cholesteryl ester, and phosphatidylcholine between membranes. Previous studies showing that the proximal cause of abetalipoproteinemia is an absence of MTP indicate that MTP function is required for the assembly of the apolipoprotein B (apoB) containing plasma lipoproteins, i.e., very low density lipoproteins and chylomicrons. However, the precise role of MTP in lipoprotein assembly is not known. In this study, the role of MTP in lipoprotein assembly is investigated using an inhibitor of MTP-mediated lipid transport, 2-[1-(3, 3-diphenylpropyl)-4-piperidinyl]-2,3-dihydro-1H-isoindol-1-o ne (BMS-200150). The similarity of the IC50 for inhibition of bovine MTP-mediated TG transfer (0.6 microM) to the Kd for binding of BMS-200150 to bovine MTP (1.3 microM) strongly supports that the inhibition of TG transfer is the result of a direct effect of the compound on MTP. BMS-200150 also inhibits the transfer of phosphatidylcholine, however to a lesser extent (30% at a concentration that almost completely inhibits TG and cholesteryl ester transfer). When BMS-200150 is added to cultured HepG2 cells, a human liver-derived cell line that secretes apoB containing lipoproteins, it inhibits apoB secretion in a concentration dependent manner. These results support the hypothesis that transport of lipid, and in particular, the transport of neutral lipid by MTP, plays a critical role in the assembly of apoB containing lipoproteins.     

Outcomes of patients with Kaposi's sarcoma who start antiretroviral therapy under routine programme conditions in Malawi

AIDS-associated Kaposi's sarcoma (KS) is the most common AIDS-related malignancy in sub-Saharan Africa, with a generally unfavourable prognosis. We report on six-month and 12-month cohort treatment outcomes of human immunodeficiency virus (HIV)-positive KS patients and HIV-positive non-KS patients treated with antiretroviral therapy (ART) in public sector facilities in Malawi. Data were collected from standardized antiretroviral (ARV) patient master cards and ARV patient registers. Between July and September 2005, 7905 patients started ART-488 (6%) with a diagnosis of KS and 7417 with a non-KS diagnosis. Between January and March 2005, 4580 patients started ART-326 (7%) with a diagnosis of KS and 4254 with a non-KS diagnosis. At six-months and 12-months, significantly fewer KS patients were alive and significantly more had died or defaulted compared to non-KS patients. HIV-positive KS patients on ART in Malawi have worse outcomes than other patients on ART. Methods designed to improve these outcomes must be found.     

Availability, Utilisation and Quality of Basic and Comprehensive Emergency Obstetric Care Services in Malawi

Objective To establish a baseline for the availability, utilisation and quality of maternal and neonatal health care services for monitoring and evaluation of a maternal and neonatal morbidity/mortality reduction programme in three districts in the Central Region of Malawi. Methods Survey of all the 73 health facilities (13 hospitals and 60 health centres) that provide maternity services in the three districts (population, 2,812,183). Results There were 1.6 comprehensive emergency obstetric care (CEmOC) facilities per 500,000 population and 0.8 basic emergency obstetric care (BEmOC) facilities per 125,000 population. About 23% of deliveries were conducted in emergency obstetric care (EmOC) facilities and the met need for emergency obstetric complications was 20.7%. The case fatality rate for emergency obstetric complications treated in health facilities was 2.0%. Up to 86.7% of pregnant women attended antenatal clinic at least once and only 12.0% of them attend postnatal clinic at least once. There is a shortage of qualified staff and unequal distribution with more staff in hospitals leaving health centres severely understaffed. Conclusions The total number of CEmOC facilities is adequate but the distribution is unequal, leaving some rural areas with poor access to CEmOC services. There are no functional BEmOC facilities in the three districts. In order to reduce maternal mortality in Malawi and countries with similar socio-economic profile, there is a need to upgrade some health facilities to at least BEmOC level by training staff and providing equipment and supplies.     

Mechanism of action of DuP 721: inhibition of an early event during initiation of protein synthesis.

The mode of action of DuP 721 was investigated. This compound was active primarily against gram-positive bacteria, including multiply resistant strains of staphylococci. Although inactive against wild-type Escherichia coli, DuP 721 did inhibit E. coli when the outer membrane was perturbed by genetic or chemical means. Pulse-labeling studies with E. coli PLB-3252, a membrane-defective strain, showed that DuP 721 inhibited amino acid incorporation into proteins. The 50% inhibitory concentration of DuP 721 for protein synthesis was 3.8 micrograms/ml, but it was greater than 64 micrograms/ml for RNA and DNA syntheses. The direct addition of DuP 721 to cell-free systems did not inhibit any of the reactions of protein synthesis from chain initiation through chain elongation with either synthetic or natural mRNA as template. However, cell extracts prepared from DuP 721 growth-arrested cells were defective in initiation-dependent polypeptide synthesis directed by MS2 bacteriophage RNA. These cell-free extracts were not defective in polypeptide elongation or in fMet-tRNA(fMet)-dependent polypeptide synthesis stimulated by poly(G.U). We conclude, therefore, that DuP 721 exerts its primary action at a step preceding the interaction of fMet-tRNA(fMet) and 30S ribosomal subunits with the initiator codon.     

Nocturia and older people

Nocturia has been defined as one or more voids [of urine] at night, each of which is preceded and followed by sleep (Abrams et al, 2002; van Kerrebroeck et al, 2002). It is a condition that can influence health status and quality of life; for example, daytime sleepiness can occur as a result of loss of sleep at night, and the resultant loss of energy can render many older people prone to accidents, such as falls (Box 1).     

Reduction in Severity of All-Cause Gastroenteritis Requiring Hospitalisation in Children Vaccinated against Rotavirus in Malawi

Rotavirus is the major cause of severe gastroenteritis in children aged <5 years. Introduction of the G1P[8] Rotarix^® rotavirus vaccine in Malawi in 2012 has reduced rotavirus-associated hospitalisations and diarrhoeal mortality. However, the impact of rotavirus vaccine on the severity of gastroenteritis presented in children requiring hospitalisation remains unknown. We conducted a hospital-based surveillance study to assess the impact of Rotarix^® vaccination on the severity of gastroenteritis presented by Malawian children. Stool samples were collected from children aged <5 years who required hospitalisation with acute gastroenteritis from December 2011 to October 2019. Gastroenteritis severity was determined using Ruuska and Vesikari scores. Rotavirus was detected using enzyme immunoassay. Rotavirus genotypes were determined using nested RT-PCR. Associations between Rotarix^® vaccination and gastroenteritis severity were investigated using adjusted linear regression. In total, 3159 children were enrolled. After adjusting for mid-upper arm circumference (MUAC), age, gender and receipt of other vaccines, all-cause gastroenteritis severity scores were 2.21 units lower (p < 0.001) among Rotarix^®-vaccinated (n = 2224) compared to Rotarix^®-unvaccinated children (n = 935). The reduction in severity score was observed against every rotavirus genotype, although the magnitude was smaller among those infected with G12P[6] compared to the remaining genotypes (p = 0.011). Each one-year increment in age was associated with a decrease of 0.43 severity score (p < 0.001). Our findings provide additional evidence on the impact of Rotarix^® in Malawi, lending further support to Malawi’s Rotarix^® programme.     

Postoperative radiotherapy for elderly patients with stage III lung cancer

BACKGROUND:

The potential role of postoperative radiation therapy (PORT) for patients who have completely resected, stage III nonsmall cell lung cancer (NSCLC) with N2 disease remains controversial. By using population‐based data, the authors of this report compared the survival of a concurrent cohort of elderly patients who had N2 disease treated with and without PORT.

METHODS:

By using the Surveillance, Epidemiology, and End Results (SEER) registry linked to Medicare records, 1307 patients were identified who had stage III NSCLC with N2 lymph node involvement diagnosed between 1992 and 2005. Propensity scoring methods and instrumental variable analysis were used to compare the survival of patients who did and did not receive PORT after controlling for selection bias.

RESULTS:

Overall, 710 patients (54%) received PORT. Propensity score analysis indicated that PORT was not associated with improved survival in patients with N2 disease (hazard ratio [HR], 1.11; 95% confidence interval [CI], 0.97‐1.27). Analyses that were limited to patients who did or did not receive chemotherapy, who received intermediate‐complexity or high‐complexity radiotherapy planning, or adjusted for time trends produced similar results. The instrumental variable estimator for the absolute improvement in 1‐year and 3‐year survival with PORT was ?0.04 (95% CI, ?0.15 to 0.08) and ?0.08 (95% CI, ?0.24 to 0.15), respectively.

CONCLUSIONS:

The current data suggested that PORT is not associated with improved survival for elderly patients with N2 disease. These findings have important clinical implications, because SEER data indicate that a large percentage of elderly patients currently receive PORT despite the lack of definitive evidence about its effectiveness. The potential effectiveness of PORT should be evaluated further in randomized controlled trials. Cancer 2012. © 2012 American Cancer Society.