Mining for SNPs: putting the common variants--common disease hypothesis to the test

Classical molecular genetic strategies have succeeded in identifying mutations responsible for numerous rare diseases with Mendelian patterns of inheritance, but have been largely unsuccessful in unravelling the (genetic basis of complex medical conditions like cardiovascular disease' diabetes and mental illness. These common disorders are shaped by multiple genes that exert weak allelic effects in the setting of confounding environmental variables. Association study designs provide statistical povwer to reveal the modest contributions of weak alleles, and evidence is mounting that common genetic polymorphisms play a role in complex diseases. Cataloguing genetic variation in human populations is a prerequisite for further validation of the 'common variants-common disease' hypothesis, and polymorphism discovery has begun in earnest in the academic and private sector. We will review several strategies for high-throughput polymorphism discovery and discuss the implications of early results from polymorphism screens for future genetic studies.     

Controlled Gastric Emptying. II. In Vitro Erosion and Gastric Residence Times of an Erodible Device in Beagle Dogs

An erodible gastric retention device fabricated from various polymeric blends was examined in vitro for its dissolution properties and in vivo in fasting dogs for assessment of its gastric retention potential. Dissolution studies were conducted with extruded rods of polymer blends to assess their potential as candidates for the erodible component of a gastrically retained device. Based on results from dissolution studies, rods of poly(ortho ester)/polyethylene blends (POE/PE) (45% erosion at pH 1.5 and 24 hr) were used to fabricate arms for tetrahedron-shaped devices. Corners for the tetrahedral device were fabricated from Silastic 382 loaded with 15% barium sulfate for X-ray visualization. Beagle dogs were dosed with tetrahedron-shaped test devices administered in gelatin capsules and gastric retention monitored by X ray over a 24-hr period. A comparison of in vitro erosion rates and in vivo performance of various polymer blends indicated a definite trend for increased gastric retention of devices made from the more slowly eroding blends. The results indicate that the blending of erodible and nonerodible polymers is a valid approach for obtaining materials that will provide the necessary structural properties to achieve gastric retention yet lose integrity within a desired time.     

Cardiopulmonary interactions of salbutamol and hypoxaemia in healthy young volunteers.

1. Nebulised salbutamol is frequently used in the treatment of asthma and chronic obstructive pulmonary disease. Its effects on the cardiovascular system have been extensively investigated although as yet little is known concerning its effects on the pulmonary circulation, particularly during hypoxaemia. We have therefore examined the effects of nebulised salbutamol on pulmonary haemodynamics to see if it modifies hypoxic pulmonary vasoconstriction. 2. Eight healthy normal volunteers were studied on two separate occasions. After resting to achieve baseline haemodynamics patients were randomised to receive 5 mg salbutamol or placebo via a nebuliser. They were restudied after 30 min and then rendered hypoxaemic by breathing an N2/O2 mixture to achieve an SaO2 of 75-80%. Doppler echocardiography was used to measure mean pulmonary artery pressure (MPAP), cardiac output (CO) and hence pulmonary vascular resistance (PVR). 3. Treatment with salbutamol significantly increased MPAP during normoxaemia and hypoxaemia compared with placebo at 12.0 +/- 1.2 vs 8.0 +/- 0.7 mm Hg and 28.6 +/- 0.9 vs 25.2 +/- 1.0 mm Hg, respectively (P < 0.05). Salbutamol caused a significant increase in heart rate compared with placebo and effects were additive to those of hypoxia at 74 +/- 2 vs 67 +/- 3 beats min-1 during normoxaemia and 84 +/- 3 vs 77 +/- 4 beats min-1 during hypoxaemia, respectively (P < 0.05). Whilst systemic vascular resistance fell in response to salbutamol, PVR was unchanged by salbutamol during either normoxaemia or hypoxaemia. Cardiac output was increased by salbutamol and by hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Object-relational databases: the next wave in pharmaceutical data management

Ontogen Corporation and Daylight Chemical Information Systems have recently integrated a molecule data type in an object-relational database management system. The authors explain how this innovation unites chemical and biological data management into a single universal database. All chemical information storage, searching and retrieval is performed using a standard structured query language. The authors describe using rapid application development methods for quickly building an application to access the database and they demonstrate that these techniques can simplify and standardize the management of pharmaceutical data.     

Comparative adrenal suppression with inhaled budesonide and fluticasone propionate in adult asthmatic patients.

BACKGROUND: A study was performed to compare the adrenal suppression caused by inhaled fluticasone propionate and budesonide on a microgram equivalent basis, each given by metered dose inhaler to asthmatic patients. METHODS: Twelve asthmatic patients of mean age 29.9 years, with a forced expiratory volume in one second (FEV1) 92.9% predicted and forced expiratory flow 25-75% (FEF25-75) 69.5% predicted, on less than or equal to 400 micrograms/day inhaled corticosteroid, were studied in a double blind placebo controlled crossover design comparing single doses of inhaled budesonide 400, 1000, 1600, 2000 micrograms and fluticasone propionate 500, 1000, 1500, 2000 micrograms. Doses were administered at 22.00 hours by metered dose inhaler with mouth rinsing and measurements were made in the laboratory 10 hours later. RESULTS: Serum cortisol levels compared with placebo (mean 325.2 nmol/l) were suppressed by fluticasone at doses of 1500 micrograms (211.6 nmol/l) and 2000 micrograms (112.3 nmol/l) and by budesonide at 2000 micrograms (243.4 nmol/l). Fluticasone propionate 2000 micrograms produced lower absolute serum cortisol levels than budesonide 2000 micrograms (95% CI for difference 42.9 to 219.2). The dose ratio (geometric mean) for the relative potency was 2.89 fold (95% CI 1.19 to 7.07). In terms of percentage suppression versus placebo, fluticasone propionate also produced greater effects (means and 95% CI for difference): budesonide 1600 micrograms (16.0) versus fluticasone propionate 1500 micrograms (40.9) (95% CI -0.6 to 50.6), budesonide 2000 micrograms (26.0) versus fluticasone 2000 micrograms (65.2) (95% CI 10.5 to 67.8). Individual serum cortisol levels at the two highest doses showed 15 of 24 patients below the normal limit of the reference range (150 nmol/l) for fluticasone and five of 24 for budesonide. Fluticasone propionate also caused greater ACTH suppression than budesonide (as % versus placebo): budesonide 1600 micrograms (12.0) versus fluticasone propionate 1500 micrograms (31.9) (95% CI 7.6 to 32.1), budesonide 2000 micrograms (13.5) versus fluticasone propionate 2000 micrograms (44.4) (95% CI 13.2 to 48.7). For overnight 10 hour urinary cortisol (nmol/10 hours) there was a difference between the lowest doses of the two drugs: budesonide 400 micrograms (37.2) versus fluticasone propionate 500 micrograms (19.9) (95% CI 6.9 to 27.8). CONCLUSIONS: Like budesonide the systemic bioactivity of fluticasone propionate is mainly due to lung vascular absorption. Fluticasone propionate exhibited at least twofold greater adrenal suppression than budesonide on a microgram equivalent basis in asthmatic patients.     

Incidence of red cell antibodies after multiple blood transfusion

A retrospective study was performed to estimate the frequency of alloimmunization against red cell (RBC) antigens in a multiply transfused group. Patients (n = 186) were studied who had received at least six blood transfusions during a period of at least 3 months. Some 6944 units of blood were transfused. One hundred forty patients had hematologic disorders. The patients' sera were investigated every 3 months with indirect antiglobulin tests and enzyme-treated RBCs. Twenty-two patients (11.8%) made 33 antibodies. Seven patients made more than one antibody. Eight of the 22 patients (36.4%) made their first antibody before or at the 10th transfusion. The risk of immunization increased with the number of transfusions. Influence of gender and age was not demonstrable. Nor was a relationship demonstrated between blood transfusion reactions and RBC antibody formation; no delayed hemolytic transfusion reactions occurred. Anti-E was demonstrated in 12 patients and anti-K in 15. When the gene frequencies were taken into account, it appeared that anti-E was made by 11.5 percent of E-negative patients, most of whom were immunized after an estimated three transfusions with E-positive blood. Anti-K was made by 8.7 percent of the K-negative patients, after an estimated 2.1 units of K-positive blood. It might be desirable to match red cell units for the E and K antigens in patients at relatively high risk. These are primarily patients who have already formed an antibody and are going to receive many transfusions and women of childbearing age who are to receive more than 4 units of blood.     

Naltrexone and disulfiram in patients with alcohol dependence and current depression

OBJECTIVE: Although disulfiram and naltrexone have been approved by the Food and Drug Administration for the treatment of alcoholism, no medications have been approved for individuals with alcohol dependence and comorbid psychiatric disorders. In particular, the effect of these medications on alcohol use outcomes and on specific psychiatric symptoms is still unknown in patients with the most common co-occurring disorder, major depression. METHOD: Two hundred fifty-four patients with a major Axis I psychiatric disorder and comorbid alcohol dependence were treated for 12 weeks in an outpatient medication study conducted at 3 Veterans Administration outpatient clinics. Randomization included (1) open randomization to disulfiram or no disulfiram, and (2) double-blind randomization to naltrexone or placebo. This resulted in 4 groups: (1) naltrexone alone, (2) placebo alone, (3) disulfiram and naltrexone, and (4) disulfiram and placebo. Primary outcomes were measures of alcohol use. Secondary outcomes included psychiatric symptoms assessed by the Hamilton Depression Rating Scale, alcohol craving, gamma-glutamyltransferase levels, and adverse events. RESULTS: One hundred thirty-nine subjects (54.7%) met the current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major depression. There was no relationship between the diagnosis of depression and medication treatment on alcohol use outcomes, psychiatric symptoms, or the reporting of side effects for these medications. There was a significant interaction between diagnosis, medication group, and craving, where subjects with depression on disulfram reported lower craving over time than subjects with depression on naltrexone. CONCLUSIONS: The results suggest that disulfiram and naltrexone are safe pharmacotherapeutic agents for dually diagnosed individuals with depression for the treatment of alcohol use disorders.     

Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities

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A randomised control trial of the effectiveness of personalised letters sent subsequent to school dental inspections in increasing registration in unregistered children

Background

The Child Perceptions Questionnaires (CPQ_8–10 and CPQ_11–14) are indicators of child oral health-related quality of life. The aim of this study was to assess the validity and reliability of the self-applied CPQ_8–10 and CPQ_11–14 in Brazilian children, after translations and cultural adaptations in the Brazilian Portuguese language.

Methods

Schoolchildren were recruited from general populations for pre-testing (n = 80), validity (n = 210), and test-retest reliability (n = 50) studies. They were also examined for dental caries, gingivitis, fluorosis, and malocclusion.

Results

Children with greater dental caries experience in primary dentition had higher impacts on CPQ domains. Girls had higher scores for CPQ_8–10 domains than boys. Mean CPQ_11–14 scores were highest for 11-year-old children and lowest for 14-year-old children. Construct validity was supported by significant associations between the CPQ_8–10 and CPQ_11–14 scores and the global rating of oral health (r = 0.38, r = 0.43) and overall well-being (r = 0.39, r = 0.60), respectively. The Cronbach's alpha was 0.95 for both questionnaires. The test-retest reliabilities of the overall CPQ_8–10 and CPQ_11–14 scores were both excellent (ICC = 0.96, ICC = 0.92).

Conclusion

The Brazilian Portuguese version of CPQ_8–10 and CPQ_11–14 was valuable and reliable for use in the Brazilian child population, although discriminant validity was sporadic due to the fact that impacts are mediated by others factors, such personal, social, and environmental variables.