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AbstractHigher autism risk with valproate in pregnancy?Data from the north‐west of England suggest that use of sodium valproate during pregnancy is associated with an increased risk of autism spectrum disorders in infants (Neurology 2008;71: 1923–4).In a cohort of 632 children born between 2000 and 2006, 249 were exposed to an antiepileptic drug (AED) in early pregnancy. Ten children were diagnosed with autism, of whom seven were exposed to AEDs; four of these were exposed to valproate monotherapy and one to valproate plus lamotrigine. The incidence of autism in the control group was 0.9 per cent. The authors caution that their study was small and that the children are relatively young for a definitive diagnosis of autism.• The charity Epilepsy Action cautions many women with epilepsy are not receiving advice about AED use during pregnancy. Its evidence shows that 25 per cent of women who gave birth in the last five years did not receive preconception counselling and 68 per cent did not receive the joint care recommended by NICE. About 5000 women with epilepsy become pregnant each year.Pill over the counter?Pharmacies in south London will be supplying oral contraceptives without a prescription in a pilot scheme to start next summer (Pharm J 2008; 281:687).The DoH is keen to cut the number of unwanted pregnancies by increasing access to contraception. In a scheme planned by Southwark PCT, oral contraceptives will be supplied under a patient group direction. The RCGP said it would feel ‘more comfortable’ if GPs initiate supplies after taking a history, choosing a product and reviewing treatment options.MHRA safety concernsThe latest issue of the MHRA's Drug Safety Update (December 2008) includes warnings of the risk neurotoxicity associated with prolonged use of nitrous oxide, and progressive multifocal leucoencephalopathy with rituximab (Mabthera) and efalizumab (Raptiva).It also reminds prescribers that the tacrolimus brands Prograf and Advagraf have different dose schedules and are not interchangeable.Adding rituximab improves CLL survivalAdding rituximab (Mabthera) to standard chemotherapy increases median progression‐free survival in patients with chronic lymphocytic leukaemia (CLL) by 35–40 per cent, according to data presented at the Annual Meeting of the American Society of Hematology in San Francisco.Rituximab is a monoclonal antibody against the B‐cell protein CD20. The CLL8 trial in 817 previously untreated patients with CD20‐positive CLL showed that adding rituximab to treatment with fludarabine (Fludara) and cyclophosphamide increased progression‐free survival to 42.8 months compared with 32.3 months with chemotherapy alone. Complete remission rates were 52 and 27 per cent respectively.The REACH trial, in 552 previously‐treated patients, reported median progression‐free survival of 30.6 months with rituximab plus chemotherapy and 20.6 months with chemotherapy alone. Complete remission rates were 24 and 13 per cent.Tamsulosin POM to P?Consultations are underway on rescheduling tamsulosin to pharmacy‐only status under the brand Flomax Relief. Boehringer‐Ingelheim wants up to 10 weeks' supply at a dose of 400µg per day to be made available to men aged over 45 following a pharmacy assessment, continuing up to one year after confirmation of the diagnosis by a doctor.More data on fracture risk with glitazonesLong‐term treatment with rosiglitazone or pioglitazone doubles the risk of fracture in women with type 2 diabetes, say Canadian investigators (CMAJ 2009;180(1). DOI:10.1503/cmaj.080486).Their meta‐analysis comprised 10 RCTs and two observational studies. The overall odds ratio (OR) for fracture associated with at least one year's treatment was 1.45, but in five RCTs the OR was 2.23 for women and 1.00 for men. The observational studies showed a reduction in bone mineral density in the lumbar spine and hip, with a greater effect in women than men. The number needed to harm after one year's treatment was 55 for women aged 56 and 21 for women aged 72. Copyright © 2009 Wiley Interface Ltd

Alleles of alcohol and acetaldehyde metabolism genes modulate susceptibility to oesophageal cancer from alcohol consumption

Alleles of alcohol and acetaldehyde metabolism genes modulate susceptibility to oesophageal cancer from alcohol consumption

A systematic review and meta-analysis of the effects of clinical pathways on length of stay, hospital costs and patient outcomes

BackgroundTo perform a systematic review about the effect of using clinical pathways on length of stay (LOS), hospital costs and patient outcomes. To provide a framework for local healthcare organisations considering the effectiveness of clinical pathways as a patient management strategy.MethodsAs participants, we considered hospitalized children and adults of every age and indication whose treatment involved the management strategy "clinical pathways". We include only randomised controlled trials (RCT) and controlled clinical trials (CCT), not restricted by language or country of publication. Single measures of continuous and dichotomous study outcomes were extracted from each study. Separate analyses were done in order to compare effects of clinical pathways on length of stay (LOS), hospital costs and patient outcomes. A random effects meta-analysis was performed with untransformed and log transformed outcomes.ResultsIn total 17 trials met inclusion criteria, representing 4,070 patients. The quality of the included studies was moderate and studies reporting economic data can be described by a very limited scope of evaluation. In general, the majority of studies reporting economic data (LOS and hospital costs) showed a positive impact. Out of 16 reporting effects on LOS, 12 found significant shortening. Furthermore, in a subgroup-analysis, clinical pathways for invasive procedures showed a stronger LOS reduction (weighted mean difference (WMD) -2.5 days versus -0.8 days)).There was no evidence of differences in readmission to hospitals or in-hospital complications. The overall Odds Ratio (OR) for re-admission was 1.1 (95% CI: 0.57 to 2.08) and for in-hospital complications, the overall OR was 0.7 (95% CI: 0.49 to 1.0). Six studies examined costs, and four showed significantly lower costs for the pathway group. However, heterogeneity between studies reporting on LOS and cost effects was substantial.ConclusionAs a result of the relatively small number of studies meeting inclusion criteria, this evidence base is not conclusive enough to provide a replicable framework for all pathway strategies. Considering the clinical areas for implementation, clinical pathways seem to be effective especially for invasive care. When implementing clinical pathways, the decision makers need to consider the benefits and costs under different circumstances (e.g. market forces).

The angiotensinogen gene M235T polymorphism and development of preeclampsia/eclampsia: a meta-analysis and meta-regression of observational studies

The angiotensinogen gene M235T polymorphism is related to an increased risk of hypertension. Hypertension and pregnancy-induced hypertension have been suggested to share common etiologic factors. We examined whether this mutation also increases the risk of preeclampsia/eclampsia. Pubmed/Medline, Web of Science and EMBASE were searched and a hand search of bibliographies was conducted. In all, 17 studies (including 1446 cases and 3829 controls) published in English between 1993 and October 2006 on the association of angiotensinogen gene M235T polymorphism with preeclampsia/eclampsia were selected. The overall odds ratio (OR) under a random effects model revealed that individuals homozygous for the T allele were 1.62 times more likely to develop preeclampsia/eclampsia [95% confidence interval (CI), 1.12 to 2.33; P = 0.01) compared to individuals homozygous for the M allele. The relation in Caucasians (OR = 1.99; 95% CI, 1.18-3.36; P = 0.01) was similar to that in East Asian populations (OR = 1.74; 95% CI, 0.92-3.28; P = 0.09), although the latter was not statistically significant due to lower numbers of studies. Under additive, recessive and dominant genetic models positive associations were also found. A meta-regression analysis showed that ethnic background was a significant source of between-study heterogeneity (P = 0.04) but design of the study, study size and Hardy-Weinberg equilibrium deviation were not. There was a low probability of publication bias. Our meta-analysis expands the findings on hypertension by showing that the presence of the T allele of the angiotensinogen gene is associated with an increased risk to develop preeclampsia/eclampsia.

Prospective study of homocysteine and MTHFR 677TT genotype and risk for venous thrombosis in a general population – results from the HUNT 2 study

This case-cohort designed study prospectively investigated whether elevated homocysteine levels measured in blood samples drawn before the event and methylenetetrahydrofolate reductase (MTHFR) gene polymorphism (MTHFR C677T) were associated with subsequent first venous thrombosis (VT) in a general population. Between August 1995 and June 1997, blood was collected from 66 140 people in the second Norwegian Health Study of Nord-Trøndelag (HUNT2). During a seven-year follow-up, 505 VT cases were identified. 1458 age- and sex-matched controls were selected from the original cohort. Serum total homocysteine (tHcy) and MTHFR genotype were measured in stored samples that were drawn a median of 33 months before the events. The overall odds ratio (OR) was 1.50 [95% confidence interval (CI) 0.97-2.30] for homocysteine levels above versus below the 95th percentile. There was no graded association with VT over quintiles of homocysteine. In men the OR was 2.17 (95% CI 1.20-3.91) for levels above versus below the 95th percentile, but no association was found in women (OR 1.00). Stratification by age, predisposing risk factors or time to event did not change these results. The MTHFR 677TT genotype was not related to risk for VT. In conclusion, elevated homocysteine levels in the general population predicted subsequent first VT in men but not in women.

Toward a major risk factor for atopic eczema: Meta-analysis of filaggrin polymorphism data

With an impressive series of replication studies, filaggrin (FLG) has become the gene with the most widely replicated association to atopic eczema (AE). However, studies published to date demonstrate differences concerning study design and strength of associations. We sought to provide a general and overall estimate of FLG effect sizes and to estimate allele and carrier frequencies. We searched Medline and Institute for Scientific Information Web of Knowledge databases for relevant studies and abstracts from professional societies that were published through June 30, 2007. Initially, we accounted for different study types and evaluated an overall estimate for case-control and family studies. In a second step, we combined those 2 study types and used a random-effects analysis approach to calculate overall odds ratios (ORs). Tests of asymmetry were applied to detect potential publication bias. Nine studies that met the inclusion criteria were included in the meta-analysis. For the combined genotype (R501X or 2282del4), we found an overall OR of 4.09 (95% CI, 2.64-6.33) from the case-control studies and a summary OR of 2.06 (95% CI, 1.76-2.42) from the family studies. The powerful effect of FLG variation on AE risk exceeds that of any other investigated candidate gene for AE thus far and makes FLG one of the strongest genes known to date for complex diseases. These results underline the importance of a genetically determined epidermal barrier disruption in AE.

Initial T. gondii IgG Antibody Predicts Subsequent New-Onset Schizophrenia among Military Members

Purpose Several studies have documented an association between T. gondii IgG antibodies (Ab) and schizophrenia (SCZ) in serum specimens drawn after diagnosis. We report on a preliminary case-control study evaluating Ab in serum drawn before illness onset among service members medically discharged from the military with a diagnosis (Dx) of SCZ. Methods All cases had a mental health hospitalization (MHH) before medical discharge from the military; MHH date was assumed to mark illness onset. All cases were discharged from the military with SCZ Dx. We evaluated the association between initial Ab and subsequent new-onset SCZ. Two approaches were used to differentiate groups of subjects: those with ≥12 months from initial draw to onset, and those with Results 180 cases had an initial serum drawn followed by a MHH and subsequent medical discharge from the military with a SCZ Dx. There were 529 controls. The overall odds ratio (OR) for a positive IgG was 1.89 (p=0.077), and did not vary between those with ≥12 and Discussion This preliminary study documents that initial T.gondii IgG obtained before onset of illness predicts later SCZ. This association was strongest for those with ≥3 years of service, and this group had a higher proportion of affective psychoses from first MHH. SCZ associated with T. gondii may reflect a different disease process than other SCZ. This hypothesis will be explored and tested in a much larger case-control study now underway.

Amitriptyline for depression

For many years amitriptyline has been considered one of the reference compounds for the pharmacological treatment of depression. However, new tricyclic drugs, heterocyclic compounds and selective serotonin reuptake inhibitors have been introduced on the market with the claim of a more favourable tolerability/efficacy profile. The aim of the present systematic review was to investigate the tolerability and efficacy of amitriptyline in comparison with the other tricyclic/heterocyclic antidepressants and with the selective serotonin reuptake inhibitors. The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR-Studies) was searched on 28-11-2005. Reference lists of all included studies were checked. Only randomised controlled trials were included. Study participants were of either sex and any age with a primary diagnosis of depression. Included trials compared amitriptyline with another tricyclic/heterocyclic antidepressant or with one of the selective serotonin reuptake inhibitors. Data were extracted using a standardised form. The number of patients undergoing the randomisation procedure, the number of patients who completed the study and the number of improved patients were extracted. In addition, group mean scores at the end of the trial on Hamilton Depression Scale or any other depression scale were extracted. In the tolerability analysis, the number of patients failing to complete the study and the number of patients complaining of side-effects were extracted. A total number of 194 studies were included in the review. The estimate of the overall odds ratio (OR) for responders showed that more subjects responded to amitriptyline in comparison with the control antidepressant group (OR 1.12 to 95% confidence interval (CI) 1.02 to 1.23, number needed to treat to benefit (NNTB) = 50). The estimate of the efficacy of amitriptyline and control agents on a continuous outcome revealed an effect size which also significantly favoured amitriptyline (Standardised Mean Difference (SMD) 0.13, 95% CI 0.04 to 0.23). Whilst these differences are statistically significant, their clinical significance is less clear. When the efficacy analysis was stratified by drug class, no difference in outcome emerged between amitriptyline and either tricyclic or selective serotonin reuptake inhibitor comparators. The dropout rate in patients taking amitriptyline and control agents was similar; however, the estimate of the proportion of patients who experienced side-effects significantly favoured control agents in comparison with amitriptyline (OR 0.66, 95% CI 0.59 to 0.74). When the tolerability analysis was stratified by drug class, the dropout rate in patients taking amitriptyline and the selective serotonin reuptake inhibitors significantly favoured the latter (OR 0.84, 95% CI 0.75 to 0.95, number needed to treat to harm (NNTH) = 40). When the responder analysis was stratified by study setting amitriptyline was more effective than control antidepressants in inpatients (OR 1.22, 95% CI 1.04 to 1.42, NNTB = 24), but not in outpatients (OR 1.01, 95%CI 0.88 to 1.17, NNTB = 200). This present systematic review indicates that amitriptyline is at least as efficacious as other tricyclics or newer compounds. However, the burden of side-effects in patients receiving it was greater. In comparison with selective serotonin reuptake inhibitors amitriptyline was less well tolerated, and although counterbalanced by a higher proportion of responders, the difference was not statistically significant.

The GNB3 C825T polymorphism and essential hypertension: a meta-analysis of 34 studies including 14 094 cases and 17 760 controls

The C825T single nucleotide polymorphism of the G-protein beta3 (GNB3) has been implicated in susceptibility to essential hypertension, through the expression of an alternatively spliced truncated variant. In an effort to clarify earlier inconclusive results, we performed a meta-analysis of population-based case-control genetic association studies. Random-effects methods were applied on summary data in order to combine the results of the individual studies. We identified in total 34 studies, including 14,094 hypertensive cases and 17,760 controls. The TT versus CC + CT contrast yielded an overall odds ratio (OR) of 1.08 [95% confidence interval (CI): 1.01, 1.15], the contrast of TT + CT versus CC, an OR of 1.17 (95% CI: 1.06, 1.29), whereas that of the T allele versus C allele yielded a non-significant OR of 1.05 (95% CI: 0.98, 1.13). There was moderate evidence for a publication bias in the latter two contrasts, which was eliminated after excluding studies not in Hardy-Weinberg equilibrium and those performed on non-normal populations (those with a diagnosis of diabetes, obesity and myocardial infarction). Subgroup analyses revealed that non-significant estimates arose from studies on Asian populations, as opposed to the Caucasian ones. Furthermore, the frequency of the T allele was lower in Caucasians and these populations were found to inhabit higher latitudes. The findings are in agreement with a recently proposed causal model for systolic blood pressure, which correlates it with the T allele and the absolute latitude. Further studies are needed in order to fully address questions about the aetiological mechanism of the particular association, as well as to study the effect in populations of African descent.

Association of Angiotensin I-Converting Enzyme Gene Insertion/Deletion Polymorphism and IgA Nephropathy: A Meta-Analysis

Background/Aims: The angiotensin I-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism has been extensively examined for the association with immunoglobulin A (IgA) nephropathy (IgAN), however, conflicting results have occurred. We performed a meta-analysis to evaluate the association of ACE I/D polymorphism with IgAN in different ethnic groups. Methods: 11 studies testing the association between ACE I/D polymorphism and IgAN susceptibility, and 9 studies testing the association of ACE I/D with IgAN progression were used in this analysis. The overall odds ratio (OR) was estimated by a fixed or random effect model. Results: The overall OR for the risk of susceptibility and progression of IgAN in Asians for the DD genotype is 2.37 (95% CI 1.04–5.41) and 1.75 (95% CI 1.24–2.56). The overall OR for the D allele in Asians also showed a similar magnitude, though without statistical significance (p = 0.09, p = 0.13, respectively). In Caucasians, both the DD genotype and D allele were associated with IgAN progression (OR 1.90, 1.61, respectively), but not IgAN susceptibility (p = 0.30, p = 0.41, respectively). Conclusion: Our findings support the notion that ACE I/D polymorphism is associated with IgAN. Meanwhile, the role of ACE I/D polymorphism in Asians is different from that of Caucasians.

The PTPN22 C1858T functional polymorphism and autoimmune diseases--a meta-analysis

To assess whether combined evidence shows the association between the protein tyrosine phosphatase non-receptor 22 (PTPN22) C1858T polymorphism and autoimmune diseases, and to summarize the effect size of the polymorphism associated with susceptibility of autoimmune diseases. We surveyed studies on the PTPN22 C1858T polymorphism and autoimmune diseases using comprehensive Medline search and review of the references. Meta-analysis was performed for genotypes T/T (recessive effect), T/T + C/T (dominant effect) and T-allele in random effects models. Twenty-nine studies with 43 comparisons including 13 rheumatoid arthritis (RA), six systemic lupus erythematosus (SLE), six type-1 DM (T1D), three Grave's disease (GD), four inflammatory bowel diseases (IBD), three juvenile idiopathic arthritis (JIA), two psoriasis, two multiple sclerosis, two Addison's disease and two Celiac disease were available for the meta-analysis. The overall odds ratios (ORS) for T-allele, T/T and T/T + C/T genotypes were significantly increased in RA, SLE, GD and T1D (OR for T-allele = 1.58, 1.49, 1.85, 1.61, respectively, P < 0.00001). This meta-analysis showed the association between the T-allele and the T/T genotype and JIA (OR = 1.34, P = 0.03; OR = 1.97, P = 0.02) but did not reveal the association between the PTPN22 C1858T polymorphism and IBD, psoriasis, multiple sclerosis, Addison's disease and Celiac disease. This meta-analysis demonstrates that the PTPN22 1858T allele confers susceptibility to RA, SLE, GD, T1D and JIA, supporting evidence of association of the PTPN22 gene with subgroup of autoimmune diseases.

Comparison of European and U.S. results for cephalosporin versus penicillin treatment of group A streptococcal tonsillopharyngitis

The outcome of cephalosporin versus penicillin treatment of group A streptococcal tonsillopharyngitis may differ between Europe and the USA. In the present study, Medline, Embase, reference lists, and abstract searches were used to identify randomized, controlled trials of cephalosporin versus penicillin treatment of group A streptococcal (GAS) tonsillopharyngitis. The outcomes of interest were bacteriologic and clinical cure rates from investigations conducted in Europe versus those conducted in the USA. Forty-seven trials involving 11,426 patients were included in the meta-analyses. For the comparison of 10 days of treatment with cephalosporins versus 10 days of treatment with penicillin, there were ten European and 25 U.S. trials, all involving pediatric subjects. The overall odds ratio (OR) favored cephalosporins more strongly in bacteriologic cure rate in Europe (OR=4.27, p<0.00001) than in the USA (OR=2.70, p<0.00001). Studies of 4-5 days of cephalosporin treatment versus 10 days of penicillin treatment were also analyzed. For nine European trials, the OR significantly favored cephalosporins (OR=1.30, p=0.03) in bacteriologic cure rates, but not as strongly as in the USA, (OR=2.41, p<0.00001). When results for 4-5 days of cephalosporin treatment were divided into pediatric versus adult populations, the differences in bacteriologic eradication rates obtained with cephalosporins were more pronounced in children. The likelihood of bacteriologic and clinical failure of GAS tonsillopharyngitis treatment in both European and U.S. patients is significantly less if a 10-day course of oral cephalosporin is prescribed, and is at least similar, if not significantly less, with a 4- to 5-day course of oral cephalosporin compared with a 10-day course of oral penicillin.

Meta-analysis of TNF-α promoter −308 A/G polymorphism and SLE susceptibility

Alleles of tumor necrosis factor-alpha (TNF-alpha) gene have been inconsistently associated with systemic lupus erythematosus (SLE), particularly the 308-A/G functional promoter polymorphism. To generate large-scale evidence on whether 308-A/G promoter polymorphism is associated with SLE susceptibility we have conducted a meta-analysis. We have identified 21 studies of this polymorphism and SLE using MEDLINE search. Meta-analysis was performed for genotypes A/A (recessive effect), A/A+A/G (dominant effect), and A allele in fixed or random effects models. All control samples were in Hardy-Weinberg proportion. The overall odds ratio (OR) of the A/A genotype was 3.2 (95% CI=2.0-5.3, P<0.001). Stratification by ethnicity indicated that the A/A genotype was associated with SLE in European-derived population (OR=4.0, CI=2.5-6.4, P<0.001). No association was detected in Asian-derived population (OR, 1.3, CI=0.3-6.3, P=0.76). The overall OR for the risk genotypes (A/A and A/G) was 2.0 (CI=1.3-3.1, P<0.001). Similar results were found between the risk allele A and SLE where a significant association was found in European population (OR=2.1, CI=1.6-2.7, P<0.001), but not in Asian (OR=1.4, CI=0.8-2.3, P=0.2) or African (OR=1.2, CI=0.6-2.5, P=0.59) populations. In summary, this meta-analysis demonstrates that the TNF-alpha promoter -308 A/G polymorphism may confer susceptibility to SLE, especially in European-derived population.

Trends in the Prescribing of Antidepressants Following Acute Myocardial Infarction, 1993–2002

There has been a substantial increase in the prescribing of antidepressants on a population basis and in particular serotonin reuptake inhibitors (SSRIs). SSRIs have lower cardiac toxicity than tricyclic antidepressants (TCAs). We examined how the prescribing of antidepressants to patients post-myocardial infarction (MI) changed in the decade 1993 to 2002, including the proportion accounted for by TCAs. A population-based study cross-sectional time series analysis was conducted in which quarterly antidepressant prescription data were obtained for 1993 to 2002 for elderly Ontarians who had experienced an MI, as well as for age- and sex-matched controls with no history of MI. The number of patients varied per quarter, for a total of 68,870 post-MI patients and an equal number of matched controls. Covariates included age, gender, income, and number of medications dispensed in the past year. Post-MI patients were more likely to receive an antidepressant relative to controls, with an overall odds ratio (OR) of 1.34; 95% confidence interval (CI), 1.29-1.38. However, with adjustment for the number of medications received, post-MI patients were 20% less likely to receive an antidepressant relative to controls, adjusted OR = 0.81; 95% CI, 0.78-0.84. The proportion of antidepressants prescribed to post-MI patients accounted for by TCAs decreased, but the proportion of post-MI patients receiving a TCA remained stable at approximately 6%. Increases in the prescription of antidepressants, and in particular SSRIs, to post-MI patients reflect general population trends rather than any special importance attached to treating post-MI depression. The apparent greater likelihood that post-MI patients will receive an antidepressant is reversed when total number of medications is controlled, a proxy for medical utilization and comorbidity.

Genetic Polymorphisms of GlutathioneS-Transferases and the Risk of Adult Brain Tumors: A Meta-analysis

Studies investigating the association between genetic polymorphisms of glutathione S-transferases (GST) and risk of adult brain tumors have reported conflicting results. The rationale of this meta-analysis was to determine whether GST variants increase the susceptibility of adult brain tumors by pooling data. Two investigators independently searched the HuGENet database, MEDLINE, EMBASE, conference articles, and manually reviewed bibliographies of retrieved articles. Papers were included if they were observational studies investigating the influence of GSTM1, GSTT1, GSTP1 I105V, or GSTP1 A114V on the development of adult brain cancers. Potential sources of heterogeneity between studies were explored in a meta-regression. We identified eight eligible studies, which included 1,630 cases of glioma, 245 cases of meningioma, and 7,151 controls. Using the random effects model, there was no association between any of the GST variants and the risk of glioma [overall odds ratio (OR), 1.08; 95% confidence interval (95% CI), 0.95-1.22]. Subgroup analyses also showed no relationship between GST variants and histopathologic groups; the overall ORs were 1.13 (95% CI, 0.88-1.43) for high-grade glioma and 1.08 (95% CI, 0.76-1.55) for low-grade glioma. A random effects meta-regression suggested that the use of in-hospital controls produced larger effect estimates in glioma than the use of population controls (overall OR, 1.30; 95% CI, 1.03-1.65). The T1 null genotype was significantly associated with a risk of meningioma (OR, 1.95; 95% CI, 1.02-3.76), but the M1 variant was not. This study did not suggest any relationship between GST variants and risks of glioma; the T1 null genotype may influence the susceptibility of meningioma, but larger studies are needed to substantiate this relationship.

Glutathione S-transferase M1 status and breast cancer risk: a meta-analysis.

It is not yet clear whether Glutathione S-transferase M1 (GSTM1) polymorphisms affect the risk of breast cancer. The aim of this study is to provide a comprehensive meta-analysis of all the available, published case-control studies on the extent of the possible association between GSTM1 polymorphisms and susceptibility to breast cancer. Twenty case-control studies on GSTM1 and breast cancer were identified using both PUBMED and a manual search. Meta-analysis was conducted by the Peto method. Subgroup analyses were undertaken, in order to explore the relationship between effect sizes and the study characteristics. The overall odds ratio (OR) was found to be 1.06 (95% CI, 0.99-1.14). The OR for post-menopausal women with GSTM1 deficiency was determined to be 1.19 (95% CI, 1.05-1.34). In populations with a low frequency of GSTM1 deficiency, a greater increase was observed (OR, 1.20; 95% CI, 1.08-1.34). Furthermore, the highest associations were found in post-menopausal women with a low frequency of GSTM1 deficiency (OR, 1.44; 95% CI, 1.20-1.73). The fact that GSTM1 deficiency is not rare in the general population implies that the attributable risk for breast cancer could be sizable. Further studies focusing on the structure of haplotype blocks of GSTM1 are required in order to find a specific haplotype with a predisposing breast cancer susceptibility allele.

Polymorphism p53 codon-72 and invasive cervical cancer: a meta-analysis

Objectives: Although some studies have reported that the arginine isoform on codon 72 of p53 increases the susceptibility to invasive cervical cancer, such data remain controversial. The objective of this study was to quantitatively summarize the evidence for such a relationship. Methods: Our data sources consisted of a MEDLINE search of the literature published before December 2002, bibliography review, and expert consultation. Thirty-seven studies met the inclusion criteria. Information on sample size, study design, Hardy–Weinberg equilibrium, and method of genotype determination was abstracted by two reviewers using a standardized protocol. The overall odds ratio (OR) of the p53 gene on invasive cervical cancer was estimated using the Mantel–Haenzel method. Results: The overall OR (95% confidence interval) for cervical cancer among those with the homozygous mutant (Arg/Arg) was 1.2 (1.1–1.3, P=0.001) compared with those with the heterozygous mutant (Arg/Pro). By a cellular type of cervical cancer, the overall OR among those with Arg/Arg was statistically significant in adenocarcinomas (1.7, 1.1–2.6, P=0.024), but not in squamous cell carcinomas (1.1, 0.9–1.2, P=0.960), compared with Pro/Pro. Compared with Arg/Pro, the OR among those with Arg/Arg was statistically significant in HPV types 16 (1,5, 1.2–2.0, P=0.002). Conclusions: Overall, the p53 gene was associated with increased risk for invasive cervical cancer. However, the risk varied by country, cellular, and HPV type.

The plasminogen activator inhibitor-1 −675 4G/5G genotype influences the risk of myocardial infarction associated with elevated plasma proinsulin and insulin concentrations in men from Europe: the HIFMECH Study

Although the potential role of plasminogen activator inhibitor-1 (PAI-1) in the development of coronary artery disease is strongly supported by its biological characteristics, results of clinical studies remain controversial. To investigate whether plasma PAI-1 concentrations and the -675 4G/5G polymorphism located in the PAI-1 gene could constitute risk markers for myocardial infarction (MI). We used a European case-control study, the HIFMECH study, comparing 598 men with MI and 653 age-matched controls. Insulin resistance explained a major part of the variation in PAI-1 (24%) whereas inflammation had only a minor contribution (0.01%). For both cases and controls plasma PAI-1 concentrations were significantly higher in the North than the South, and in both regions were higher in individuals with MI compared with control subjects [overall odds ratio (OR) for a 1 SD increase=1.54, 95% confidence interval (CI) 1.34, 1.77]. This difference was observed in all the centers studied. Overall, the difference between cases and control subjects remained significant after controlling for inflammation variables (OR=1.30, 95% CI 1.08, 1.57), but lost significance after controlling for insulin resistance variables (OR=1.17, 95% CI 0.98, 1.40). The 4G allele was associated with significantly higher PAI-1 levels in cases but not controls and, taken independently, did not modify the risk of MI (P=0.9). However, a significant interaction was observed with both insulin or proinsulin and the risk of MI (P=0.05 and 0.02, respectively), but not with triglycerides or body mass index (BMI). The insulin or proinsulin effect on risk was observed only in the carriers of the 4G/4G genotype. This interaction appeared not to be mediated by plasma PAI-1 antigen concentrations (P=0.01 and 0.02 after adjustment for PAI-1 plasma levels). The interaction with proinsulin but not insulin remained statistically significant after further adjustment for other factors associated with insulin resistance (triglycerides and BMI) and C-reactive protein (P=0.01). This study suggests that PAI-1 has a role in risk of MI in the presence of underlying insulin resistance. A significant interaction between insulin or proinsulin and the -675 4G/5G polymorphism was observed in risk for MI. The mechanisms for these interactions remain to be determined.

A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders.

The different 5-HT (serotonin) receptors including the serotonin transporter (5-HTT) are candidate genes for affective disorders such as major depressive disorder (MDD) and bipolar disorder (BD). They have been investigated in a number of allelic association studies where the individual results have been inconsistent, and therefore, definite conclusions are difficult to make. Systematic reviews using meta-analytical techniques are a reliable method for objectively and reproducibly assessing individual studies and generating combined result. This study aimed at reviewing published studies investigating the association between affective disorders (MDD and BD) and variation at genes coding for serotonin receptors and the serotonin transporter. We performed National Library of Medicine database searches to identify potential studies. More than 430 articles were reviewed and 86 studies met the inclusion criteria for participation in our review. Of these, 41 studies investigated 45 different 5-HT receptor variants and 45 studies investigated at least one of two commonly studied 5-HTT polymorphisms in MDD. Many studies investigated the association between MDD and BD with the 5-HT2A 102 T/C, the 5-HTT promoter 44 bp insertion/deletion and the intron 2 VNTR polymorphisms, and thus, these could be pooled using meta-analytic techniques. The overall odds ratio (OR) for the combined individual results was significant for BD and the two 5-HTT polymorphisms: Mantel-Haenszel weighted OR=1.14, CI: 1.03-1.26, P=0.015 for the promoter locus (N=3467) and Mantel-Haenszel Weighted odds ratio OR=1.18, CI: 1.05-1.32, P=0.004 for the VNTR locus (N=3620). However, sensitivity analysis indicated that, in each case, the overall positive association could be mostly attributed to the large effect of one individual study. Therefore, these results suggest that, although promising, further studies are required to assess appropriately the evidence suggesting an association between BD and 5-HTT.

Meta-analysis of sero-epidemiologic studies of the relation between Chlamydia pneumoniae and atherosclerosis: Does study design influence results?

Background The results of sero-epidemiologic studies of the relation between Chlamydia pneumoniae and atherogenesis vary considerably. A meta-analysis was performed to calculate the overall odds ratio (OR) and to identify potential sources of variability. Methods The MEDLINE database was searched from January 1997 to December 2000 for studies describing the seroprevalence of IgG antibodies to C pneumoniae in relation to clinically manifest atherosclerosis. Data extracted included 1) the study design used, 2) the number of included patients, 3) the type of disease (or end point), 4) the number of control subjects, 5) the type of control subjects, 6) the follow-up duration, 7) the crude and adjusted ORs (and 95% CI), and 8) the extent of adjustment for potential confounders. Results Thirty-eight studies were included in the meta-analysis. The overall OR was 1.6 (95% CI 1.3-2.0). The overall OR of cross-sectional case-control studies (2.0, 95% CI 1.5-2.6) was higher than that of prospective (nested) case-control studies (1.1, 95% CI 0.8-1.4). Moreover, the duration of follow-up in prospective studies was inversely related to the strength of the relation (β = −0.04, 95% CI −0.08, −0.01). Adjustment of risk estimates for potentially confounding factors did not influence the strength of the relation. Conclusions The relation between C pneumoniae and clinically manifest atherosclerosis is not durable. This probably is due to a lack of causality, although results may have been influenced by the design of the component studies. (Am Heart J 2003;145:409-17.)