Effect of Moisture Sorption on Tabletting Characteristics of Spray Dried (15% Amorphous) Lactose

Spray dried (15% amorphous) lactose absorbs moisture when exposed to humidity. At 57% relative humidity (RH), the moisture uptake was 1.5%. It is suggested that the moisture is preferentially taken up in the amorphous regions, thereby increasing the actual moisture content in the amorphous parts up to 10%. The moisture uptake reduced the glass transition temperature below the operating temperature and thereby transformed the amorphous regions from a glassy to a rubbery state, setting up conditions for crystallisation of the lactose. Compaction of dry spray dried lactose led to a relatively low initial tablet strength. However, when pre-exposed to 57% RH for a short time period (2 to 4 hours) before compaction, the initial tablet strength increased markedly. This was due to moisture uptake which resulted in a higher molecular mobility of the amorphous spray dried lactose, and to an increase in plastic flow. Post compaction storage of tablets containing amorphous regions of spray dried lactose at 57% RH resulted in an increased tablet strength after 4 hours due to crystallisation. Spray dried lactose exposed to 57% RH for more than 6 hours before compaction led to the lowest initial tablet strength. Crystallisation of the amorphous regions of the spray dried lactose occurred before tabletting. No increase in tablet strength was noted on post compaction storage for these tablets.     

Role of angiotensin-converting enzyme gene polymorphisms in children with sepsis and septic shock

Background: Sepsis is characterized by a systemic inflammatory response. Its development and outcome are associated with host defense, pathogenicity of the microorganism and genetic polymorphisms. Genetic polymorphisms of the immune system genes have been shown to have a close relationship with the clinical outcomes of sepsis. Angiotensin-converting enzyme (ACE) plays a major role in the host defense against invading pathogens. It is therefore likely that polymorphisms in the ACE gene may have an important effect on determining the development and the outcome of sepsis.
Methods: Ninety-eight children diagnosed as having sepsis and 287 healthy children were included in the study. Insertion/deletion polymorphisms were analyzed using reverse-hybridization assay.
Results: The carriers of I allele (D/I genotype and I/I genotype) were found to have an increased risk of developing sepsis compared to the controls.
Conclusion: DD genotype may play a positive role against the development of sepsis in healthy children.     

Isolation and cultivation of bovine ephemeral fever virus in chickens and chicken embryos.

Unadapted bovine ephemeral fever (BEF) virus was isolated from cattle blood after intravenous inoculation into chicken embryos. Infected embryos died or hatched as abnormal chickens. The chick embryo was slightly less sensitive to unadapted BEF virus than were Vero cell cultures, but the use of embryos avoids the several blind passages that are required to isolate BEF virus in unweaned mice. Chick embryos were considerably less efficient than Vero cell culture or unweaned mice in detecting Vero cell-adapted and mouse-adapted BEF virus respectively. Viraemia was demonstrated in chicken embryos at 1-4 days and in one-day-old chickens at 1-3 days after intravenous inoculation of BEF virus. BEF virus was demonstrated by isolation and by immunofluoresence in heart, brain, lung and liver of chicken embryos at 1-5 days and in lung and liver of one-day-old chickens at 1-2 days, after intravenous inoculation. The isolated viruses were confirmed as BEF virus by neutralization with immune mouse ascitic fluid. BEF neutralizing antibodies were produced in 4-week-old and adult chickens after intravenous inoculation with BEF virus.     

Association between mannose binding lectin polymorphisms and predisposition to bacterial meningitis

The aim of this study was to examine the presence of any association between mannose binding lectin (MBL) gene variants and bacterial meningitis. Codon 54 (B allele) and codon 57 (C allele) polymorphisms in exon 1 of the MBL gene were investigated in 50 healthy controls and 31 patients diagnosed as purulent meningitis. Codon 57 polymorphism was not found in our patient and control groups. B allele frequency was significantly higher in the patient group (22%) compared to the control group (3%). AB genotype was determined in 39% and 6% of patient and healthy control groups, respectively, and the difference was statistically significant. AA genotype was determined in 61% of the patient group and in 94% of the control group, and it was statistically low in the patient group. These results suggest that codon 54 polymorphism in the MBL gene may play a role in susceptibility to bacterial meningitis in children.     

Aspirin for the Primary Prevention of Cardiovascular Events: A systematic review and meta-analysis comparing patients with and without diabetes

OBJECTIVE

The negative results of two randomized controlled trials (RCTs) have challenged current guideline recommendations for using aspirin for primary prevention of cardiovascular events among patients with diabetes. We therefore sought to determine if the effect of aspirin for primary prevention of cardiovascular events and mortality differs between patients with and without diabetes.

RESEARCH DESIGN AND METHODS

We conducted a systematic search of MEDLINE, EMBASE, Cochrane Library, Web of Science, and Scopus since their inceptions until November 2008 for RCTs of aspirin for primary prevention of cardiovascular events. Blinded pairs of reviewers evaluated studies and extracted data. Random-effects meta-analysis and Bayesian logistic regression were used to estimate the ratios of relative risks (RRs) of outcomes of interest among patients with and without diabetes. A 95% CI that crosses 1.00 indicates that the effect of aspirin does not differ between patients with and without diabetes.

RESULTS

Nine RCTs with moderate to high methodological quality contributed data to the analyses. The ratios of RRs comparing the benefit of aspirin among patients with diabetes compared with patients without diabetes for mortality, myocardial infarction, and ischemic stroke were 1.12 (95% CI 0.92–1.35), 1.19 (0.82–1.17), and 0.70 (0.25–1.97), respectively.

CONCLUSIONS

Whereas estimates of benefit among patients with diabetes remain imprecise, our analysis suggests that the relative benefit of aspirin is similar in patients with and without diabetes.Cardiovascular events including myocardial infarction and ischemic stroke are the leading causes of morbidity and mortality in patients with diabetes, and the population burden of cardiovascular disease attributed to diabetes appears to be increasing (1). Several guidelines, including those of the American Diabetes Association, recommend aspirin for the primary prevention of cardiovascular events in patients with diabetes (2,3). Given that trials of aspirin for primary prevention have enrolled too few patients with diabetes, guideline panels have applied indirect evidence from other high-risk groups to formulate this recommendation (4). In contrast, other guidelines such as those of the European Society of Cardiology and the European Association for the Study of Diabetes (5) and the most recent U.S. Preventive Services Task Force (6) provide no specific recommendations regarding the use of aspirin in patients with diabetes.The best available estimate of the effect of aspirin comes from the most recent study from the Antithrombotic Trialists'' Collaborative, an individual-level meta-analysis of randomized controlled trials (RCTs) that reported a 12% reduction in the rate ratio of serious vascular events in patients with diabetes randomized to aspirin prophylaxis, although this finding was not statistically significant (rate ratio 0.88, 95% CI 0.67–1.15) (7). However, this meta-analysis did not include data from the Early Treatment Diabetic Retinopathy Study (ETDRS) (8) nor two recent primary prevention RCTs, the Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) (9) and the Prevention of Progression of Arterial Disease and Diabetes (POPADAD) (10) studies. Results from both JPAD and POPADAD, however, were imprecise and unable to exclude a reduction in the risk for their composite end points of up to 42 and 24%, respectively.We, therefore, set out to conduct a systematic review of RCTs of aspirin for primary prevention in patients with diabetes to 1) estimate the efficacy of aspirin for the primary prevention of cardiovascular events among patients with diabetes and 2) estimate the extent to which the effect of aspirin differs in patients with and without diabetes.     

Curcumin inhibits the Sonic Hedgehog signaling pathway and triggers apoptosis in medulloblastoma cells

Medulloblastoma is an aggressive primary brain tumor that arises in the cerebellum of children and young adults. The Sonic Hedgehog (Shh) signaling pathway that plays important roles in the pathology of this aggressive disease is a promising therapeutic target. In the present report we have shown that curcumin has cytotoxic effects on medulloblastoma cells. Curcumin suppressed also cell proliferation and triggered cell‐cycle arrest at G₂/M phase. Moreover, curcumin inhibited the Shh–Gli1 signaling pathway by downregulating the Shh protein and its most important downstream targets GLI1 and PTCH1. Furthermore, curcumin reduced the levels of β‐catenin, the activate/phosphorylated form of Akt and NF‐κB, which led to downregulating the three common key effectors, namely C‐myc, N‐myc, and Cyclin D1. Consequently, apoptosis was triggered by curcumin through the mitochondrial pathway via downregulation of Bcl‐2, a downstream anti‐apoptotic effector of the Shh signaling. Importantly, the resistant cells that exhibited no decrease in the levels of Shh and Bcl‐2, were sensitized to curcumin by the addition of the Shh antogonist, cyclopamine. Furthermore, we have shown that curcumin enhances the killing efficiency of nontoxic doses of cisplatin and γ‐rays. In addition, we present clear evidence that piperine, an enhancer of curcumin bioavailability in humans, potentiates the apoptotic effect of curcumin against medulloblastoma cells. This effect was mediated through strong downregulation of Bcl‐2. These results indicate that curcumin, a natural nontoxic compound, represents great promise as Shh‐targeted therapy for medulloblastomas. © 2009 Wiley‐Liss, Inc.