Childhood TB epidemiology and treatment outcomes in Thailand: a TB active surveillance network, 2004 to 2006

Background

Hepatitis B virus (HBV) infection is a significant public health problem that may lead to chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). Approximately 30% of the world's population has been infected with HBV and approximately 350 million (5–6%) are persistent carriers. More than 120 million Chinese are infected with HBV. The role of host genetic factors and their interactions with environmental factors leading to chronic HBV infection and its complications are not well understood. We believe that a better understanding of these factors and interactions will lead to more effective diagnostic and therapeutic options.

Methods/Design

This is a population-based, case-control study protocol to enroll 2200 Han Chinese from medical centers in northern and western China. Adult subjects in the following groups are being enrolled: healthy donors (n = 200), HBV infected persons achieving virus clearance (n = 400), asymptomatic HBV persistent carriers (n = 400), chronic hepatitis B cases (n = 400), decompensated liver cirrhosis with HBV infection cases (n = 400), and hepatocellular carcinoma with HBV infection cases (n = 400). In addition, for haplotype inference and quality control of sample handling and genotyping results, children of 1000 cases will be asked to provide a buccal sample for DNA extraction. With the exception of adult patients presenting with liver cirrhosis or HCC, all other cases and controls will be 40 years or older at enrollment. A questionnaire is being administered to capture dietary and environmental risk factors. Both candidate-gene and genome-wide association approaches will be used to assess the role of single genetic factors and higher order interactions with other genetic or environmental factors in HBV diseases.

Conclusion

This study is designed and powered to detect single gene effects as well as gene-gene and environmental-gene interactions. The identification of allelic polymorphisms in genes involved in the pathway leading to chronic viral infection, liver cirrhosis and, ultimately, hepatocellular carcinoma would provide insights to those factors leading to HBV replication, liver inflammation, fibrosis, and the carcinogenic process. An understanding of the contribution of host genetic factors and their interactions may inform public health policy, improve diagnostics and clinical management, and provide targets for drug development.     

Cardiovascular Morbidity and Mortality in High-Risk Populations: Epidemiology and Opportunities for Risk Reduction

Despite significant growth in the number of drug classes and individual agents available to combat various cardiovascular (CV) risk factors in clinical practice, the prevalence of these risk factors, including hypertension, diabetes mellitus, and obesity, has remained largely unchanged and in some cases has even increased during the past decade. CV risk factors remain consistently undertreated across the world, despite consensus guidelines issued by national and international health care organizations. Given the earlier onset of obesity and diabetes mellitus in many national populations, beginning from childhood, it is desirable to implement a range of lifestyle and pharmacologic interventions intended to modify CV risk factors while also improving glucose tolerance. Drugs that block the renin-angiotensin system are associated with reduced incidence of diabetes compared with other antihypertensive agents and should be considered mainstays of therapy for patients with hypertension who are at high risk for diabetes, CV disease, or both.     

Botulinum neurotoxins and botulism: a novel therapeutic approach

Specific treatment is not available for human botulism. Current remedial mainstay is the passive administration of polyclonal antibody to botulinum neurotoxin (BoNT) derived from heterologous species (immunized animal or mouse hybridoma) together with supportive and symptomatic management. The antibody works extracellularly, probably by blocking the binding of receptor binding (R) domain to the neuronal receptors; thus inhibiting cellular entry of the holo-BoNT. The antibody cannot neutralize the intracellular toxin. Moreover, a conventional antibody with relatively large molecular size (150 kDa) is not accessible to the enzymatic groove and, thus, cannot directly inhibit the BoNT zinc metalloprotease activity. Recently, a 15-20 kDa single domain antibody (V(H)H) that binds specifically to light chain of BoNT serotype A was produced from a humanized-camel VH/V(H)H phage display library. The V(H)H has high sequence homology (>80%) to the human VH and could block the enzymatic activity of the BoNT. Molecular docking revealed not only the interface binding between the V(H)H and the toxin but also an insertion of the V(H)H CDR3 into the toxin enzymatic pocket. It is envisaged that, by molecular linking the V(H)H to a cell penetrating peptide (CPP), the CPP-V(H)H fusion protein would be able to traverse the hydrophobic cell membrane into the cytoplasm and inhibit the intracellular BoNT. This presents a novel and safe immunotherapeutic strategy for botulism by using a cell penetrating, humanized-single domain antibody that inhibits the BoNT by means of a direct blockade of the groove of the menace enzyme.     

Risk of Methylphenidate‐Induced Prehypertension in Normotensive Adult Smokers With Attention Deficit Hyperactivity Disorder

The authors studied predictors of methylphenidate‐induced increases in blood pressure (BP). In this secondary analysis of a randomized, double‐blind, placebo‐controlled smoking cessation trial, nonhypertensive adult smokers with attention deficit hyperactivity disorder randomized to osmotic‐release oral system methylphenidate (OROS‐MPH) (n=115) were matched one‐to‐one on baseline systolic BP (SBP) (±5 mm Hg) with participants randomized to placebo (n=115) and followed for 10 weeks. In adjusted mixed linear models of SBP and diastolic BP (DBP), baseline normal SBP (P<.0001) and DBP (P<.0001) were associated with significant OROS‐MPH–induced increases compared with placebo, whereas significant increases were not observed in participants with baseline prehypertensive SBP (P=.27) and DBP (P=.79). Participants randomized to OROS‐MPH with baseline normal BP had increased odds of developing either systolic (odds ratio [OR], 3.32; 95% confidence interval [CI], 1.41–8.37; P=.006) or diastolic prehypertension (OR, 4.32; 95% CI, 1.56–14.0; P=.004) compared with placebo using simple logistic regression. The authors demonstrated an augmented OROS‐MPH–induced BP elevation and risk of prehypertension in adults with baseline normal BP. Significantly increased BP was not observed in adults with baseline prehypertension. J Clin Hypertens (Greenwich). 2012; 00:00–00. ©2012 Wiley Periodicals, Inc.     

Estimating the burden of shigellosis in Thailand: 36-month population-based surveillance study

OBJECTIVE: To estimate incidence of shigellosis in the Kaengkhoi district, Saraburi Province, Thailand. METHODS: Population-based surveillance of shigellosis based in treatment centres. The detected rates of treated shigellosis were corrected for the number of cases missed due to the low sensitivity of microbiological culture methods and participants' use of health-care providers not participating in the study. FINDINGS: The overall uncorrected incidence of shigellosis was 0.6/1000 population per year (95% confidence interval (CI) = 0.5-0.8). The unadjusted incidence of treated shigellosis was highest among children less than 5 years old (4/1000 children per year; 95% CI = 3-6) and significantly lower among people aged > 5 years (0.3/1000 population per year; 95% CI = 0.2-0.5; P < 0.001). Adjusting for cases likely to be missed as a result of culture and surveillance methods increased estimates approximately five times. The majority of Shigella isolates (122/146; 84%) were S. sonnei; the rest were S. flexneri. Of the 22 S. flexneri isolates, the three most frequently encountered serotypes were 2a (36%), 1b (23%) and 3b (28%). A total of 90-95% of S. sonnei and S. flexneri isolates were resistant to tetracycline and co-trimoxazole. In contrast to S. sonnei isolates, more than 90% of the S. flexneri isolates were also resistant to ampicillin and chloramphenicol (P < 0.0001). CONCLUSION: Estimates of incidence of Shigella infection in the community are 10-fold to 100-fold greater than those found from routine government surveillance. The high prevalence of Shigella strains resistant to multiple antibiotics adds urgency to the development of a vaccine to protect against shigellosis in this region of Thailand.     

Novel biodegradable cholesterol-modified polyrotaxane hydrogels for cartilage regeneration

Cholesterol was introduced to a hydrolyzable polyrotaxane (PRx), not only to improve cell proliferation and glycosaminoglycan (GAG) production, but also to control the degradation rate of the hydrogels. The cholesterol was introduced to hydrolyzable PRx species by threading many alpha-cyclodextrins (alpha-CDs) on a poly(ethylene glycol) (PEG) chain having hydrolyzable ester linkages at the terminals; the PRx species were then cross-linked with other PEGs to prepare cholesterol-modified PRx hydrogels. The degree of cholesterol substitution was varied in the range of 1-25%. These hydrogels were examined to clarify the effect of cholesterol groups on mechanical properties, erosion time and chondrocyte proliferation. Highly porous biodegradable cholesterol-modified PRx hydrogels were fabricated using a combination of potassium hydrogen carbonate (as an effervescent salt) and citric acid. This fabrication process enabled the homogeneous expansion of pores within the polymer matrices, leading to well-interconnected macroporous hydrogels with a mean pore size of around 200-400 microm, ideal for high-density chondrocyte seeding. Time to complete degradation of the hydrogels was shortened by increasing the degree of substitution due to the aggregation of alpha-CDs through hydrophobic interaction of cholesterol groups. The presence of approx. 10% cholesterol improved the chondrocyte proliferation and GAG production. The modification of cholesterols to PRx is a good approach for creating new biodegradable hydrogels in terms of chondrocyte culture and controlling degradation time of the hydrogels.     

Inorganic-organic polymer hybrid scaffold for tissue engineering--II: partial enzymatic degradation of hydroxyapatite-chitosan hybrid

This article describes the preparation of porous chitosan, a hydroxyapatite hybrid, by partial enzymatic degradation. Two enzymes, chitosanase and lysozyme, were selected to hydrolyze a chitosan-reinforced matrix and create pores within the chitosan-hydroxyapatite composite. The degree of enzymatic hydrolysis of the chitosan-hydroxyapatite composite was determined by measuring the % weight loss of the chitosan matrix and the hydroxyapatite component. Hydroxyapatite loss from the chitosan matrix increased with the degree of enzymatic hydrolysis of the chitosan-reinforced matrix. After hydrolysis, the composite was further characterized by FTIR. Quantitative analysis revealed a decrease in the characteristic pyranose ring peak (1072 cm(-1)), compared with Po4(2-) (1110 cm(-1)), showing that the chitosan matrices were enzymatically hydrolyzed. The surface of the porous chitosan-hydroxyapatite composite, prepared by controlling enzymatic hydrolysis, was also observed by SEM.     

Management of hypertension in patients with coronary artery disease

Hypertension is present in three of four patients with coronary artery disease (CAD) but remains largely uncontrolled in most patients. Treating hypertension in these patients is complicated by the concern of precipitating coronary ischemia when diastolic blood pressure (DBP) is reduced excessively. However, an emerging body of evidence from recent clinical trials in high-risk hypertensive patients with or without CAD demonstrated the benefit of intensive drug therapy, even when DBP fell much lower than 80 mm Hg, in terms of reducing cardiovascular events and progression of coronary and carotid atherosclerosis. Accordingly, the American Heart Association has now set the target BP goal to less than 130/80 mm Hg in hypertensive patients with CAD. Given the enormous gap between current BP levels in patients with CAD and the new target BP goals, multiple drug therapy is essential to achieve BP control and improve cardiovascular outcomes.     

Immune responses of selected phagotopes from monoclonal antibodies of Burkholderia pseudomallei

Random peptide libraries displayed by bacteriophage T7 and M13 were employed to identify mimotopes from 4 monoclonal antibodies (MAbs) specific to Burkholderia pseudomallei. Insert DNA sequences of bound phages selected from four rounds of panning with each MAb revealed peptide sequences corresponding to B. pseudomallei K96243 hypothetical protein BPSL2046, hypothetical protein BpseP_02000035, B. pseudomallei K96243 hypothetical protein BPSS0784, B. pseudomallei 1710b hypothetical protein BURPS1710b_1104, and B. cenocepacia H12424 TonB-dependent siderophore receptor, all located at the outer membrane. The immune responses from all selected phagotopes were significantly higher than that of lipopolysaccharide. The study demonstrates the feasibility of identifying mimotopes through screening of phage-displayed random peptide libraries with B. pseudomallei MAbs.