The association of the composite IL-1 genotype with periodontitis progression and/or treatment outcomes: a systematic review

BACKGROUND: Genetically transmitted traits such as cytokine gene polymorphisms may accentuate the host inflammatory response to the bacterial challenge and influence susceptibility to periodontitis. OBJECTIVE: To systematically review the evidence of an association between the interleukin-1 (IL-1) composite genotype, i.e. presence of the allele 2 in the gene clusters IL-1A-889 and in IL-1B +3953, and periodontitis progression and/or treatment outcomes. Material and Methods: Based on the focused question, a search was conducted for longitudinal clinical trials comparing progression of periodontitis and/or treatment outcomes in IL-1 genotype-positive (carrying allele 2) and IL-1 genotype-negative (not carrying allele 2) subjects. A search in the National Library of Medicine computerized bibliographic database MEDLINE and a manual search were performed. Selection of publications, extraction of data and validity assessment were made independently by two reviewers. RESULTS: The search provided 122 titles of which 11 longitudinal publications were included. The heterogeneity of the data prevented the performance of a meta-analysis. While findings from some publications rejected a possible role of IL-1 composite genotype on progression of periodontitis after various therapies, other reported a prognostic value for disease progression of the positive IL-1 genotype status. When assessed on a multivariate risk assessment model, several publications concluded that the assessment of the IL-1 composite genotype in conjunction with other covariates (e.g. smoking and presence of specific bacteria) may provide additional information on disease progression. The small sample size of the available publications, however, requires caution in the interpretation of the results. CONCLUSION: Based on these findings, (i) there is insufficient evidence to establish if a positive IL-1 genotype status contributes to progression of periodontitis and/or treatment outcomes. Therefore, (ii) results obtained with commercially available tests should be interpreted with caution.

Success rate and efficiency of activator treatment

In a retrospective multicentre study, the success rate and efficiency of activator treatment were analysed. All patients from two University clinics (Giessen, Germany and Berne, Switzerland) that fulfilled the selection criteria (Class II division 1 malocclusion, activator treatment, no aplasia, no extraction of permanent teeth, no syndromes, no previous orthodontic treatment except transverse maxillary expansion, full available records) were included in the study. The subject material amounted to 222 patients with a mean age of 10.6 years. Patient records, lateral head films, and dental casts were evaluated. Treatment was classified as successful if the molar relationship improved by at least half to three-fourths cusp width depending on whether or not the leeway space was used during treatment. Group comparisons were carried out using Wilcoxon two-sample and Kruskal-Wallis tests. For discrete data, chi-square analysis was used and Fisher's exact test when the sample size was small. Stepwise logistic regression was also employed. The success rate was 64 per cent in Giessen and 66 per cent in Berne. The only factor that significantly (P < 0.001) influenced treatment success was the level of co-operation. In approximately 27 per cent of the patients at both centres, the post-treatment occlusion was an 'ideal' Class I. In an additional 38 per cent of the patients, marked improvements in occlusal relationships were found. In subjects with Class II division 1 malocclusions, in which orthodontic treatment is performed by means of activators, a marked improvement of the Class II dental arch relationships can be expected in approximately 65 per cent of subjects. Activator treatment is more efficient in the late than in the early mixed dentition.

Confidence Bands for Convex Median Curves using Sign-Tests

Suppose that one observes pairs (x1,Y1), (x2,Y2), ..., (xn,Yn), where x1 < x2 < ... < xn are fixed numbers while Y1, Y2, ..., Yn are independent random variables with unknown distributions. The only assumption is that Median(Yi) = f(xi) for some unknown convex or concave function f. We present a confidence band for this regression function f using suitable multiscale sign tests. While the exact computation of this band seems to require O(n4) steps, good approximations can be obtained in O(n2) steps. In addition the confidence band is shown to have desirable asymptotic properties as the sample size n tends to infinity.

Influence of ABCB1, ABCC1, ABCC2, and ABCG2 haplotypes on the cellular exposure of nelfinavir in vivo

OBJECTIVES: The human immunodeficiency virus protease inhibitor nelfinavir is substrate of polyspecific drug transporters encoded by ABCB1 (P-glycoprotein), ABCC1 (MRP1) and ABCC2 (MRP2), and an inhibitor of BCRP, encoded by ABCG2. Genetic polymorphism in these genes may be associated with changes in transport function. METHODS: A comprehensive evaluation of single nucleotide polymorphisms (39 SNPs in ABCB1, 7 in ABCC1, 27 in ABCC2, and 16 in ABCG2), and inferred haplotypes was done to assess possible associations of genetic variants with cellular exposure of nelfinavir in vivo. Analysis used peripheral mononuclear cells from individuals receiving nelfinavir (n=28). Key results were re-examined in a larger sample size (n=129) contributing data on plasma drug levels. RESULTS AND CONCLUSIONS: There was no significant association between cellular nelfinavir area under the curve (AUC) and SNPs or haplotypes at ABCC1, ABCC2, ABCG2. There was an association with cellular exposure for two loci in strong linkage disequilibrium: ABCB1 3435C>T; AUCTT>AUCCT>AUCCC (ratio 2.1, 1.4, 1, Ptrend=0.01), and intron 26 +80T>C; AUCCC> AUCCT > AUCTT (ratio 2.4, 1.3, 1, Ptrend=0.006). Haplotypic analysis using tagging SNPs did not improve the single SNP association values.

Isolated vertebral fractures give elevated serum protein S-100B levels

ABSTRACT: BACKGROUND: Serum protein S-100B determinations have been widely proposed in the past as markers of traumatic brain injury and used as a predictor of injury severity and outcome. The purpose of this prospective observational case series was therefore to determine S-100B serum levels in patients with isolated injuries to the back. METHODS: Between 1 February and 1 May 2008, serum samples for S-100B analysis were obtained within 1 hour of injury from 285 trauma patients. All patients with a head injury, polytrauma, and intoxicated patients were excluded to select isolated injuries to the spine. 19 patients with isolated injury of the back were included. Serum samples for S-100B analysis and CT spine were obtained within 1 hours of injury. RESULTS: CT scans showed vertebral fractures in 12 of the 19 patients (63%). All patients with fractures had elevated S-100B levels. Amongst the remaining 7 patients without a fracture, only one patient with a severe spinal contusion had an S-100B concentration above the reference limit. The mean S-100B value of the group with fractures was more than 4 times higher than in the group without fractures (0.385 vs 0.087 mug/L, p = 0.0097). CONCLUSION: Our data, although limited due to a very small sample size, suggest that S-100B serum levels might be useful for the diagnosis of acute vertebral body and spinal cord injury with a high negative predictive power. According to the literature, the highest levels of serum S-100B are found when large bones are fractured. If a large prospective study confirms our findings, determining the S-100B level may contribute to more selective use of CT and MRI in spinal trauma.

Publication and non-publication of clinical trials: longitudinal study of applications submitted to a research ethics committee

BACKGROUND: Not all clinical trials are published, which may distort the evidence that is available in the literature. We studied the publication rate of a cohort of clinical trials and identified factors associated with publication and nonpublication of results. METHODS: We analysed the protocols of randomized clinical trials of drug interventions submitted to the research ethics committee of University Hospital (Inselspital) Bern, Switzerland from 1988 to 1998. We identified full articles published up to 2006 by searching the Cochrane CENTRAL database (issue 02/2006) and by contacting investigators. We analyzed factors associated with the publication of trials using descriptive statistics and logistic regression models. RESULTS: 451 study protocols and 375 corresponding articles were analyzed. 233 protocols resulted in at least one publication, a publication rate of 52%. A total of 366 (81%) trials were commercially funded, 47 (10%) had non-commercial funding. 346 trials (77%) were multi-centre studies and 272 of these (79%) were international collaborations. In the adjusted logistic regression model non-commercial funding (Odds Ratio [OR] 2.42, 95% CI 1.14-5.17), multi-centre status (OR 2.09, 95% CI 1.03-4.24), international collaboration (OR 1.87, 95% CI 0.99-3.55) and a sample size above the median of 236 participants (OR 2.04, 95% CI 1.23-3.39) were associated with full publication. CONCLUSIONS: In this cohort of applications to an ethics committee in Switzerland, only about half of clinical drug trials were published. Large multi-centre trials with non-commercial funding were more likely to be published than other trials, but most trials were funded by industry.

Genetic association studies under the population stratification, family pedigree and application to genome-wide association studies

This dissertation has three separate parts: the first part deals with the general pedigree association testing incorporating continuous covariates; the second part deals with the association tests under population stratification using the conditional likelihood tests; the third part deals with the genome-wide association studies based on the real rheumatoid arthritis (RA) disease data sets from Genetic Analysis Workshop 16 (GAW16) problem 1. Many statistical tests are developed to test the linkage and association using either case-control status or phenotype covariates for family data structure, separately. Those univariate analyses might not use all the information coming from the family members in practical studies. On the other hand, the human complex disease do not have a clear inheritance pattern, there might exist the gene interactions or act independently. In part I, the new proposed approach MPDT is focused on how to use both the case control information as well as the phenotype covariates. This approach can be applied to detect multiple marker effects. Based on the two existing popular statistics in family studies for case-control and quantitative traits respectively, the new approach could be used in the simple family structure data set as well as general pedigree structure. The combined statistics are calculated using the two statistics; A permutation procedure is applied for assessing the p-value with adjustment from the Bonferroni for the multiple markers. We use simulation studies to evaluate the type I error rates and the powers of the proposed approach. Our results show that the combined test using both case-control information and phenotype covariates not only has the correct type I error rates but also is more powerful than the other existing methods. For multiple marker interactions, our proposed method is also very powerful. Selective genotyping is an economical strategy in detecting and mapping quantitative trait loci in the genetic dissection of complex disease. When the samples arise from different ethnic groups or an admixture population, all the existing selective genotyping methods may result in spurious association due to different ancestry distributions. The problem can be more serious when the sample size is large, a general requirement to obtain sufficient power to detect modest genetic effects for most complex traits. In part II, I describe a useful strategy in selective genotyping while population stratification is present. Our procedure used a principal component based approach to eliminate any effect of population stratification. The paper evaluates the performance of our procedure using both simulated data from an early study data sets and also the HapMap data sets in a variety of population admixture models generated from empirical data. There are one binary trait and two continuous traits in the rheumatoid arthritis dataset of Problem 1 in the Genetic Analysis Workshop 16 (GAW16): RA status, AntiCCP and IgM. To allow multiple traits, we suggest a set of SNP-level F statistics by the concept of multiple-correlation to measure the genetic association between multiple trait values and SNP-specific genotypic scores and obtain their null distributions. Hereby, we perform 6 genome-wide association analyses using the novel one- and two-stage approaches which are based on single, double and triple traits. Incorporating all these 6 analyses, we successfully validate the SNPs which have been identified to be responsible for rheumatoid arthritis in the literature and detect more disease susceptibility SNPs for follow-up studies in the future. Except for chromosome 13 and 18, each of the others is found to harbour susceptible genetic regions for rheumatoid arthritis or related diseases, i.e., lupus erythematosus. This topic is discussed in part III.

WATER ACCESS AND MAINTENANCE IN KARONGA, MALAWI

This report is a case study of how Mwangalala community accesses water and how that access is maintained. Mwangalala community is located in the northern tip of Karonga district in Malawi, Africa. The case study evaluates how close the community is to meeting target 10 of the Millennium Development Goals, sustainable access to safe drinking water, and evaluates the current water system through Human Centered Design’s criteria of desirability, feasibility, and viability. It also makes recommendations to improve water security in Mwangalala community. Data was collected through two years of immersive observation, interviews with 30 families, and observing two wells on three separate occasions. The 30 interviews provided a sample size of over 10% of the community’s population. Participants were initially self-selected and then invited to participate in the research. I walked along community pathways and accepted invitations to join casual conversations in family compounds. After conversing I asked the family members if they would be willing to participate in my research by talking with me about water. Data collected from the interviews and the observations of two wells were compared and analyzed for common themes. Shallow wells or open wells represented the primary water source for 93% of interview participants. Boreholes were also present in the community, but produced unpalatable water due to high concentrations of dissolved iron and were not used as primary water sources. During observations 75% of community members who used the shallow well, primarily used for consumptive uses like cooking or dinking, were females. Boreholes were primarily used for non-consumptive uses such as watering crops or bathing and 77% of the users were male. Shallow wells could remain in disrepair for two months because the repairman was a volunteer, who was not compensated for the skilled labor required to repair the wells. Community members thought the maintenance fee went towards his salary, so did not compensate the repairman when he performed work. This miscommunication provided no incentive for the repairman to make well repairs a priority, and left community members frustrated with untimely repairs. Shallow wells with functional pumps failed to provide water when the water table levels drop during dry season, forcing community members to seek secondary or tertiary water sources. Open wells, converted from shallow wells after community members did not pay for repairs to the pump, represented 44% of the wells originally installed with Mark V hand pumps. These wells whose pumps were not repaired were located in fields and one beside a church. The functional wells were all located on school grounds or in family compounds, where responsibility for the well’s maintenance is clearly defined. Mwangalala community fails to meet Millennium Development goals because the wells used by the community do not provide sustainable access to safe drinking water. Open wells, used by half the participants in the study, lack a top covering to prevent contamination from debris and wildlife. Shallow well repair times are unsustainable, taking longer than two weeks to be repaired, primarily because the repair persons are expected to provide skilled labor to repair the wells without compensation. Improving water security for Mwangalala can be achieved by improving repair times on shallow wells and making water from boreholes palatable. There are no incentives for a volunteer repair person to fix wells in a timely manner. Repair times can be improved by reducing the number of wells a repair person is responsible for and compensating the person for the skilled labor provided. Water security would be further improved by removing iron particulates from borehole water, thus rendering it palatable. This is possible through point of use filtration utilizing ceramic candles; this would make pumped water available year-round.

Human beta-defensin-2 and psoriasin are overexpressed in lesions of acne inversa

BACKGROUND: Acne inversa is a chronic inflammatory disorder of apocrine gland-bearing skin. The role of the innate immune system in the pathogenesis of the disease is controversial. OBJECTIVES: We investigated the expression of antimicrobial peptide/proteins in acne inversa. METHODS: Tissue samples were obtained from patients with acne inversa and compared with normal-appearing skin. The expression of psoriasin and human beta-defensin (hBD)-2 on messenger RNA and protein level was analyzed. RESULTS: Both messenger RNA and protein levels of psoriasin and hBD-2 were significantly increased in acne inversa. Macrophages expressing hBD-2 were found in the dermis. LIMITATIONS: Small sample size is a limitation. CONCLUSIONS: Antimicrobial peptide/proteins are overexpressed in acne inversa lesions as compared with normal-appearing skin. The site of the major expression depends on the particular antimicrobial peptide/protein. Psoriasin is overexpressed in epidermal keratinocytes whereas hBD-2 is produced mainly by dermal macrophages, leaving a relative deficiency of hBD-2 in the epidermis of acne inversa lesions.

Exercise for osteoarthritis of the hip

BACKGROUND: Current international treatment guidelines recommending therapeutic exercise for people with symptomatic hip OA report are based on expert opinion only. OBJECTIVES: To determine whether land-based therapeutic exercise is beneficial for people with hip OA in terms of reduced joint pain and/or improved physical function. SEARCH STRATEGY: Five databases were searched from 1966 up until August 2008. SELECTION CRITERIA: All randomised controlled trials (RCTs) recruiting people with hip OA and comparing some form of land-based therapeutic exercise (as opposed to exercises conducted in the water) with a non-exercise group. DATA COLLECTION AND ANALYSIS: Three reviewers independently extracted data and assessed methodological quality. All analyses were conducted on continuous outcomes. MAIN RESULTS: Combining the results of the five included RCTs demonstrated a small treatment effect for pain, but no benefit in terms of improved self-reported physical function. Only one of these five RCTs exclusively recruited people with symptomatic hip OA. AUTHORS' CONCLUSIONS: The limited number and small sample size of the included RCTs restricts the confidence that can be attributed to these results. Adequately powered RCTs evaluating exercise programs specifically designed for people with symptomatic hip OA need to be conducted.

The role of psychological stress in inflammatory bowel disease: quality assessment of methods of 18 prospective studies and suggestions for future research

BACKGROUND: Enquiries among patients on the one hand and experimental and observational studies on the other suggest an influence of stress on inflammatory bowel diseases (IBD). However, since this influence remains hypothetical, further research is essential. We aimed to devise recommendations for future investigations in IBD by means of scrutinizing previously applied methodology. METHODS: We critically reviewed prospective clinical studies on the effect of psychological stress on IBD. Eligible studies were searched by means of the PubMed electronic library and through checking the bibliographies of located sources. RESULTS: We identified 20 publications resulting from 18 different studies. Sample sizes ranged between 10 and 155 participants. Study designs in terms of patient assessment, control variables, and applied psychometric instruments varied substantially across studies. Methodological strengths and weaknesses were irregularly dispersed. Thirteen studies reported significant relationships between stress and adverse outcomes. CONCLUSIONS: Study designs, including accuracy of outcome assessment and repeated sampling of outcomes (i.e. symptoms, clinical, and endoscopic), depended upon conditions like sample size, participants' compliance, and available resources. Meeting additional criteria of sound methodology, like taking into account covariates of the disease and its course, is strongly recommended to possibly improve study designs in future IBD research.

Host genetic determinants of spontaneous hepatitis C clearance

Acute infection with the hepatitis C virus (HCV) induces a wide range of innate and adaptive immune responses. A total of 20-50% of acutely HCV-infected individuals permanently control the virus, referred to as 'spontaneous hepatitis C clearance', while the infection progresses to chronic hepatitis C in the majority of cases. Numerous studies have examined host genetic determinants of hepatitis C infection outcome and revealed the influence of genetic polymorphisms of human leukocyte antigens, killer immunoglobulin-like receptors, chemokines, interleukins and interferon-stimulated genes on spontaneous hepatitis C clearance. However, most genetic associations were not confirmed in independent cohorts, revealed opposing results in diverse populations or were limited by varying definitions of hepatitis C outcomes or small sample size. Coordinated efforts are needed in the search for key genetic determinants of spontaneous hepatitis C clearance that include well-conducted candidate genetic and genome-wide association studies, direct sequencing and follow-up functional studies.

Growth curves for cardio-metabolic risk factors in children and adolescents

OBJECTIVE: This study developed percentile curves for anthropometric (waist circumference) and cardiovascular (lipid profile) risk factors for US children and adolescents. STUDY DESIGN: A representative sample of US children and adolescents from the National Health and Nutrition Examination Survey from 1988 to 1994 (NHANES III) and the current national series (NHANES 1999-2006) were combined. Percentile curves were constructed, nationally weighted, and smoothed using the Lambda, Mu, and Sigma method. The percentile curves included age- and sex-specific percentile values that correspond with and transition into the adult abnormal cut-off values for each of these anthropometric and cardiovascular components. To increase the sample size, a second series of percentile curves was also created from the combination of the 2 NHANES databases, along with cross-sectional data from the Bogalusa Heart Study, the Muscatine Study, the Fels Longitudinal Study and the Princeton Lipid Research Clinics Study. RESULTS: These analyses resulted in a series of growth curves for waist circumference, total cholesterol, LDL cholesterol, triglycerides, and HDL cholesterol from a combination of pediatric data sets. The cut-off for abnormal waist circumference in adult males (102 cm) was equivalent to the 94(th) percentile line in 18-year-olds, and the cut-off in adult females (88 cm) was equivalent to the 84(th) percentile line in 18-year-olds. Triglycerides were found to have a bimodal pattern among females, with an initial peak at age 11 and a second at age 20; the curve for males increased steadily with age. The HDL curve for females was relatively flat, but the male curve declined starting at age 9 years. Similar curves for total and LDL cholesterol were constructed for both males and females. When data from the additional child studies were added to the national data, there was little difference in their patterns or rates of change from year to year. CONCLUSIONS: These curves represent waist and lipid percentiles for US children and adolescents, with identification of values that transition to adult abnormalities. They could be used conditionally for both epidemiological and possibly clinical applications, although they need to be validated against longitudinal data.

Evaluation of a Bayesian MCMC Random Effects Inference Methodology for Capture-Mark-Recapture Data

Monte Carlo simulation was used to evaluate properties of a simple Bayesian MCMC analysis of the random effects model for single group Cormack-Jolly-Seber capture-recapture data. The MCMC method is applied to the model via a logit link, so parameters p, S are on a logit scale, where logit(S) is assumed to have, and is generated from, a normal distribution with mean μ and variance σ2 . Marginal prior distributions on logit(p) and μ were independent normal with mean zero and standard deviation 1.75 for logit(p) and 100 for μ ; hence minimally informative. Marginal prior distribution on σ2 was placed on τ2=1/σ2 as a gamma distribution with α=β=0.001 . The study design has 432 points spread over 5 factors: occasions (t) , new releases per occasion (u), p, μ , and σ . At each design point 100 independent trials were completed (hence 43,200 trials in total), each with sample size n=10,000 from the parameter posterior distribution. At 128 of these design points comparisons are made to previously reported results from a method of moments procedure. We looked at properties of point and interval inference on μ , and σ based on the posterior mean, median, and mode and equal-tailed 95% credibility interval. Bayesian inference did very well for the parameter μ , but under the conditions used here, MCMC inference performance for σ was mixed: poor for sparse data (i.e., only 7 occasions) or σ=0 , but good when there were sufficient data and not small σ .

White matter microstructure alterations of the medial forebrain bundle in melancholic depression

BACKGROUND The medial forebrain bundle (MFB) is a key structure of the reward system and connects the ventral tegmental area (VTA) with the nucleus accumbens (NAcc), the medial and lateral orbitofrontal cortex (mOFC, lOFC) and the dorsolateral prefrontal cortex (dlPFC). Previous diffusion tensor imaging (DTI) studies in major depressive disorder point to white matter alterations of regions which may be incorporated in the MFB. Therefore, it was the aim of our study to probe white matter integrity of the MFB using a DTI-based probabilistic fibre tracking approach. METHODS 22 patients with major depressive disorder (MDD) (12 melancholic-MDD patients, 10 non-melancholic-MDD patients) and 21 healthy controls underwent DTI scans. We used a bilateral probabilistic fibre tracking approach to extract pathways between the VTA and NACC, mOFC, lOFC, dlPFC respectively. Mean fractional anisotropy (FA) values were used to compare structural connectivity between groups. RESULTS Mean-FA did not differ between healthy controls and all MDD patients. Compared to healthy controls melancholic MDD-patients had reduced mean-FA in right VTA-lOFC and VTA-dlPFC connections. Furthermore, melancholic-MDD patients had lower mean-FA than non-melancholic MDD-patients in the right VTA-lOFC connection. Mean-FA of these pathways correlated negatively with depression scale rating scores. LIMITATIONS Due to the small sample size and heterogeneous age group comparisons between melancholic and non-melancholic MDD-patients should be regarded as preliminary. CONCLUSIONS Our results suggest that the melancholic subtype of MDD is characterized by white matter microstructure alterations of the MFB. White matter microstructure is associated with both depression severity and anhedonia.