MET and autism susceptibility: family and case�Ccontrol studies

Autism is a common, severe and highly heritable neurodevelopmental disorder. The International Molecular Genetic Study of Autism Consortium (IMGSAC) genome screen for linkage in affected sib-pair families identified a chromosome 7q susceptibility locus (AUTS1), that has subsequently shown evidence of increased sharing in several independent multiplex samples and in two meta-analyses. Taking into account the location of the MET gene under this linkage peak, and the fact that it has recently been reported to be associated with autism, the gene was further analyzed as a promising autism candidate. The gene encodes a transmembrane receptor tyrosine kinase of the hepatocyte growth factor/scatter factor (HGF/SF). MET is best known as an oncogene, but its signalling also participates in immune function, peripheral organ development and repair, and the development of the cerebral cortex and cerebellum (all of which have been observed earlier as being disregulated in individuals with autism). Here we present a family-based association analysis covering the entire MET locus. Significant results were obtained in both single locus and haplotype approaches with a single nucleotide polymorphism in intron 1 (rs38845, P<0.004) and with one intronic haplotype (AAGTG, P<0.009) in 325 multiplex IMGSAC families and 10 IMGSAC trios. Although these results failed to replicate in an independent sample of 82 Italian trios, the association itself was confirmed by a case–control analysis performed using the Italian cohort (P<0.02). The previously reported positive association of rs1858830 failed to replicate in this study. Overall, our findings provide further evidence that MET may play a role in autism susceptibility.     

Predictors of incident atrial fibrillation and influence of medications: a retrospective case�Ccontrol study

Background

Atrial fibrillation (AF) is a common condition, associated with raisedmortality and risk of majormorbidity, and is predicted to increase due to an aging population.

Aim

To update earlier research of AF predictors using UK data.

Design and setting

Case–control analysis of adults aged 18 years and older with a diagnosis of AF in practices registered with the General Practice Research Database (GPRD) in the UK.

Method

Using the GPRD, a case.control analysis was performed using logistic regression to compare 55 412 incident AF cases to 216 400 controls, for medical history and prior use of drugs. The association between time since start of diagnosis or drug use and AF risk was summarised using Spline regression.

Results

The following were confirmed as risk factors for AF: heart failure (risk ratio [RR] 2.91 [95% CI = 2.59 to 3.27]); ischaemic heart disease (IHD) (RR 2.00 [95% CI = 1.78 to 2.24]); hypertension (RR 2.60 [95% CI = 2.32 to 2.92]); hyperthyroidism (RR 1.56 [95% CI = 1.39 to 1.75]); being a heavy drinker (RR 1.43 [95% CI = 1.27 to 1.60]); cerebrovascular accident (RR 1.48 [95% CI = 1.32 to 1.66]); and obesity (bodymass index ≥30 kg/m² RR 1.29 [95% CI = 1.15 to 1.45]). Current use of oral glucocorticoids (RR 1.62 [95% CI = 1.44 to 1.82]) and of beta-2 agonists (RR 1.30 [95% CI = 1.16 to 1.46]) were identified as significant risk factors, and statins (RR 0.82 [95% CI = 0.73 to 0.92]) as a significant protective factor. No effect was found for current use of bisphosphonates (RR 0.95 [95% CI = 0.85 to 1.07]), renin.angiotensin.aldosterone system (RAAS) agents (RR 1.04 [95% CI = 0.93 to 1.17]), or xanthine derivatives (RR 1.09 [95% CI = 0.97 to 1.22]). Spline regression analysis found the effect of heart failure, IHD, use of oral glucocorticoids, and use of statins on the likelihood of developing AF was sustained over a number of years.

Conclusion

These findings update the risk factors that are associated with AF, and confirmthe protective properties of statins and the risks of beta-2 agonists in developing AF, but not the supposed protective qualities of glucocorticoids and RAAS agents.     

The Non-covalent interaction between plasmin and α2-antiplasmin

The rate determining step of the reaction between plasmin and α₂-antiplasmin involves an interaction between a lysine binding site in the non-enzymatic chain of plasmin and a complementary site in the very carboxyterminal portion of the inhibitor. In this work we have studied the effect of synthetic peptides structurally related to this part of α₂-antiplasmin on the plasmin-α₂-antiplasmin reaction. The most effective peptide Leu₄₃₅-LYS₄₅₂ caused a reduction of the apparent rate constant to 50% at a concentration of 25 μmol/I. In order to evaluate the role of the COOH-terminal lysine residue, three tryptic peptides from the plasmin B-chain were also studied in such a kinetic system. Two of the peptides, which had a COOH-terminal lysine residue also inhibited theplasmin-α₂-antiplasmin reaction almost as effective as the α₂-antiplasmin peptide. In contrast, a peptide with C00H-terminal arginine did not display this capacity. However, one of the α₂-antiplasmin peptides studied, Leu₄₃₅-Tyr₄₄₅, without a COOH-terminal lysine was found to inhibit the reaction at higher concentrations. The data suggest that Lys₄₅₂ in α₂-antiplasmin is of major importance for the lysine binding site-mediated plasmin-α₂-antiplasmin interaction. But, most likely, also other structures in the COOH-terminal portion of α₂-antiplasmin are of importance for this interaction.     

The relationship between lateral epicondyle morphology and iliotibial band friction syndrome: A matched case–control study

BackgroundIliotibial band friction syndrome (ITBFS) is an overuse injury with pain at the level of the knee lateral epicondyle. We sought to determine whether there is greater knee lateral epicondyle prominence among patients with ITBFS versus matched controls.MethodsSeventy five patients with ITBFS and 75 age-, height-, and sex-matched controls (n = 150 total patients) with knee magnetic resonance imaging from 2015 to 2017 were included. All cases had a diagnosis of ITBFS and a lack of other identified lateral knee injuries on magnetic resonance imaging. Controls had medial knee pain with medial meniscus tear on MRI and no clinical evidence of ITBFS. Lateral knee epicondyle height in millimeters was measured.ResultsMean patient age was 39.1 years (SD 15.1), 57% were female, and mean height was 170.0 cm (SD 9.3) with no difference between cases and controls. Mean lateral epicondyle height for cases was 13.1 mm (SD 1.6) and for controls was 12.2 (SD 1.4) with a mean difference of 0.9 mm (95% CI 0.4–1.3 mm) between matched pairs (p < 0.001). Mean epicondyle height:condylar AP width ratio was 0.211 (SD 0.023) for cases and 0.198 (SD 0.020) for controls with a mean difference of 0.013 (95% CI 0.006–0.020) between matched pairs (p < 0.001).ConclusionsThere is a significant association between greater lateral epicondyle prominence and IT band friction syndrome, suggesting another anatomic risk factor for this multifactorial condition.     

Is there an interaction between interleukin-10 and interleukin-22?

Interleukin(IL)-10 and IL-22 are structurally related cytokines. Their heterodimeric receptors consist of the cytokine-specific chains IL-10R1 and IL-22R1, respectively, and the common chain IL-10R2. This study focused on the question of whether IL-10 modulates IL-22 effects and vice versa. This question is important because IL-10 and IL-22 exert anti- and proinflammatory effects, respectively, and, as we show here, are simultaneously present in both systemic and local inflammation. The revealed lacking concomitance of IL-10R1 and IL-22R1 on identical cells excluded any possible interaction between IL-10 and IL-22 apart from the competition for IL-10R2. To study this competition, monocytes and hepatocytes were chosen. The dependence of the cytokine action on IL-10R2 was verified. Interestingly, no influence of IL-22 on IL-10 effects was observed. The same was true when IL-22 was used in complex with IL-22-binding protein. Similarly, no influence of IL-10 was found on IL-22 action. This missing competition seemed to be due to a lack of binding between IL-10R2 and the native cytokines in the absence of their corresponding R1 chain. However, IL-10R2 interacted with defined IL-10- and IL-22-derived peptides supporting the hypothesis that cytokine binding to its corresponding R1 chain creates a binding site on this cytokine for IL-10R2.     

The macrophage and the apoptotic cell: an innate immune interaction viewed simplistically?

Macrophages play important roles in the clearance of dying and dead cells. Typically, and perhaps simplistically, they are viewed as the professional phagocytes of apoptotic cells. Clearance by macrophages of cells undergoing apoptosis is a non-phlogistic phenomenon which is often associated with actively anti-inflammatory phagocyte responses. By contrast, macrophage responses to necrotic cells, including secondarily necrotic cells derived from uncleared apoptotic cells, are perceived as proinflammatory. Indeed, persistence of apoptotic cells as a result of defective apoptotic-cell clearance has been found to be associated with the pathogenesis of autoimmune disease. Here we review the mechanisms by which macrophages interact with, and respond to, apoptotic cells. We suggest that macrophages are especially important in clearing cells at sites of histologically visible, high-rate apoptosis and that, otherwise, apoptotic cells are removed largely by non-macrophage neighbours. We challenge the view that necrotic cells, including persistent apoptotic cells are, of necessity, proinflammatory and immunostimulatory and suggest that, under appropriate circumstances, persistent apoptotic cells can provide a prolonged anti-inflammatory stimulus.     

The interaction between ischemia–reperfusion and immune responses in the kidney

Kidney ischemia–reperfusion injury (IRI) engages both the innate and adaptive immune responses. Cellular mediators of immunity, such as dendritic cells, neutrophils, macrophages, natural killer T, T, and B cells, contribute to the pathogenesis of renal injury after IRI. Postischemic kidneys express increased levels of adhesion molecules on endothelial cells and toll-like receptors on tubular epithelial cells. Soluble components of the immune system, such as complement activation proteins and cytokines, also participate in injury/repair of postischemic kidneys. Experimental studies on the immune response in kidney IRI have resulted in better understanding of the mechanisms underlying IRI and led to the discovery of novel therapeutic and diagnostic targets.     

Association between group A beta-haemolytic streptococci and vulvovaginitis in adult women: a case–control study

Guidelines for the management of vaginal discharge mention Candida albicans, Trichomonas vaginalis, bacterial vaginosis, Chlamydia trachomatis and Neisseria gonorrhoeae as causes and do not recommend full microbiological culture. The role of non-group B beta-haemolytic streptococci in vaginal cultures is unclear, except for group A streptococci that are known to cause vulvovaginitis in children. In a case–control study, we investigated the association between non-group B beta-haemolytic streptococci and vulvovaginitis in adult women. Cases were women with recurrent vaginal discharge from whom a sample was cultured. Controls were asymptomatic women who consented to submitting a vaginal swab. Group A streptococci were isolated from 49 (4.9%) of 1,010 cases and not from the 206 controls (P < 0.01). Isolation rates of group C, F and G streptococci were low and did not differ statistically between cases and controls. Group A beta-haemolytic streptococci are associated with vaginal discharge in adult women. The other non-group B streptococci require more study. For the adequate management of vaginal discharge, culturing is necessary if initial treatment fails. Guidelines should be amended according to these results.     

The arcade of Fröhse : an anatomic study

Summary An anatomic study of the appearance and consistency of the upper arcade of the superficial layer of the supinator m. was carried out on 106 elbow-joint dissections. A classification of the structure was drawn up in order to discern the criteria for normality. An arcade of a tendinous nature (arcade of Fröhse) was encountered in the majority of cases (64.1%). At first sight, it could not be ascribed a compressive role affecting the posterior branch of the radial n. Macroscopic examination of the nerve prior to its entry under the supinator arcade revealed the presence of macroscopic lesions in 42.9% of cases. This high incidence does not permit any conclusions regarding the pathologic significance of this type of lesion.

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L'arcade de Fröhse: étude anatomique

Résumé Une étude anatomique de l'aspect et de la consistance de l'arcade supérieure du faisceau superficiel du m. supinateur a été réalisée sur 106 préparations de coudes. Une classification basée sur la structure a été établie afin de dégager des critères de normalité. Une arcade tendineuse (arcade de Fröhse) est rencontrée dans la majorité des cas (64.1%). On ne peut lui attribuer à priori un rôle de compression du rameau profond du n. radial. L'observation macroscopique du nerf avant son passage sous l'arcade du m. supinateur révèle la présence d'altérations macroscopiques dans 42.9% des cas. Cette incidence élevée ne nous permet pas de conclure à la signification pathologique de ce type d'altération.

     

The anterior cruciate ligament–lateral meniscus complex: A histological study

The anterior root of the lateral meniscus (LM) dives underneath the tibial attachment of the anterior cruciate ligament (ACL). Although the distinct role of meniscal attachments has been investigated, the relationship between the LM anterior insertion (LMAI) and ACL tibial insertion (ACLTI) remains unclear. This study histologically analyzed the LMAI and ACLTI. Samples were divided into four regions in an anterior-to-posterior direction. Histological measurements of these insertion sites were performed using safranin O-stained coronal sections. Distribution and signal densities of type I and II collagen were quantified. The ACLTI and LMAI formed the ACL–LM complex via fiber connections. The anterior part of the ACLTI had a widespread attachment composed of dense fibers. Attachment fibers of the LMAI became dense and wide gradually at the middle-to-posterior region. The ACL–LM transition zone (ALTZ) was observed between the LMAI and the lateral border of the ACLTI at the middle part of the ACL tibial footprint. Type II collagen density of the LMAI was higher than that of the ACLTI and ALTZ. Our results can help create an accurate tibial bone tunnel within the dense ACL attachment during ACL reconstruction surgery.     

The apolipoprotein E polymorphism and cardiovascular diseases—an autopsy study

BackgroundNumerous studies have addressed the association between the apolipoprotein E polymorphism and cardiovascular disease, but only a few reports are based on findings at autopsy. In the present retrospective study, we have used autopsy findings from a general hospital population to further investigate this issue.Methods and resultsWe collected information from 1522 consecutive autopsy reports (886 men, mean age 65.7 years; 636 women, mean age 69.7 years) conducted at Oslo University Hospital, Norway, in the period from 1996 to 2000. Cause of death and signs related to cardiovascular disease including the degree of atherosclerosis in the aorta and the coronary arteries, signs of myocardial infarction, heart weight, and signs of cerebrovascular disease were recorded. The patients were genotyped, and the apolipoprotein E allele frequencies (?2, 8.0%; ?3, 72.6%; and ?4, 19.4%) were not statistically different from a group of healthy controls. Approximately 35% of the patients died from a cardiovascular disease. Genotypes differed significantly (P<.05), with more ?4-carriers (34.3% vs. 29.6%) and fewer ?2-carriers (11.8% vs. 13.9%) among patients who died from cardiovascular disease compared to those who died from other causes. A similar distribution of genotypes was seen in patients recorded with myocardial infarction or cerebrovascular disease. There was an association between the presence of ?4 and atherosclerosis in the aorta and coronary arteries, but this did not reach statistical significance. Among patients with signs of coronary heart disease, standardized heart weights were significantly higher in ?2-carriers compared to ?4-carriers.ConclusionThe present autopsy study suggests that the risk of developing and dying from cardiovascular disease, including coronary heart disease and cerebrovascular disease, is influenced by the apolipoprotein E polymorphism.     

Stressed out? Associations between perceived and physiological stress responses in adolescents: The TRAILS study

Studies regarding the interrelation of perceived and physiological stress indices have shown diverging results. Using a population sample of adolescents (N=715, 50.9% girls, mean age 16.11 years, SD=0.59), we tested three hypotheses: (1) perceived responses during social stress covary with concurrent physiological stress responses; (2) high pretest levels of perceived stress predict large physiological responses; and (3) large physiological responses to social stress predict low posttest perceived stress levels. Perceived arousal, unpleasantness, and dominance were related to heart rate, respiratory sinus arrhythmia, and cortisol responses to a laboratory social stress test. Although effect sizes were small, the results suggest covariation of perceived stress and concurrent physiological stress responses in both the ANS and the HPA axis, as well as inverse associations between heart rate responsiveness and the subsequent appraisal of stress.     

Periodontal infections and community-acquired pneumonia: a case–control study

The aim of this study was to evaluate if the presence of periodontal infections (PI) is associated with community-acquired pneumonia (CAP) in a group of patients admitted to a hospital. A total of 140 patients were enrolled in this case–control study, with 70 patients having CAP (case group) and the other 70 patients diagnosed with other systemic diseases (control group). A periodontal examination was carried out to assess pocket probing depth (PPD), clinical attachment loss (CAL), bleeding on probing (BOP), and presence of bacterial plaque (BP). CAL and BOP showed higher scores in the case group over the control group. They were, respectively, 3.16?±?2.43 mm and 0.33?±?0.24 % for the case group, and 1.99?±?2.23 mm and 0.25?±?0.24 % for the control group (p?<?0.05). High scores for BP were observed in both groups (case: 97.1 %; control: 98.6 %, p?=?1.0000). Chronic periodontitis (CP) was more frequent in patients with CAP (case: 61.4 %; control: 41.4 %). The presence of moderate or severe CP increased the risk for CAP [odds ratio (OR)?=?4.4, 95 % confidence interval (CI)?=?1.4–13.8], even when adjusted for age, ethnicity, gender, and smoking. Moderate and severe chronic periodontitis were associated with CAP in this study.     

Is the prevalence of adult asthma and allergic rhinitis still increasing? Results of an Italian study

BACKGROUND: The prevalence of asthma and allergic rhinitis has increased worldwide during the 1970s and 1980s. OBJECTIVE: This study was aimed at evaluating whether the increasing trend in prevalence persisted during the 1990s in the young adult Italian population. METHODS: In 1998 to 2000 a screening questionnaire was sent by mail to a general population sample aged 20 to 44 years; nonresponders were contacted again first by mail and then by phone, achieving a final response rate of 78.1% (6876 of 8800). Prevalence estimates, adjusted to correct for nonresponse bias, were compared with those recorded in Italy in 1991 to 1993 during the European Community Respiratory Health Survey, when response rate had been slightly higher (87.6%). Temporal variations in symptom prevalence were analyzed by a logistic regression model, controlling for sex, age, site of residence (urban vs suburban areas), season of response, response rate, and type of contact (mail vs phone). RESULTS: The prevalence of asthma attacks did not vary significantly from 1991 to 1993 (3.6%) to 1998 to 2000 (3.2%) (P =.188). The prevalence of asthma-like symptoms (wheezing, chest tightness, shortness of breath) tended to decrease in the age classes of 32.5 to 45 years, while increasing in the youngest age class (20 to 26 years). A clear-cut increase from 15.4% to 18.3% was observed for the prevalence of allergic rhinitis (P <.001), whereas the proportion of people under antiasthmatic treatment increased in suburban areas but not in urban areas (interaction time-site of residence, P <.001). CONCLUSION: Asthma prevalence has not increased during the last decade in Italy. The persistence of an increasing trend in allergic rhinitis prevalence deserves attention.     

Is there an association between pemphigus and hepatitis viruses? A population-based large-scale study

The association between pemphigus and hepatitis viruses has not been investigated sufficiently and remains unclear. Our objective was to assess the association between pemphigus and chronic hepatitis B (HBV) and hepatitis C (HCV) infections using a large-scale real-life computerized database. This study was conducted as a cross-sectional study utilizing the database of Clalit Health Services. The proportion of chronic HBV and HCV infections was compared between patients diagnosed with pemphigus and age-, sex-, and ethnicity-matched controls. Univariate analysis was performed using chi-square and Student’s t test, and multivariate analysis was performed using a logistic regression model. A total of 1985 pemphigus patients and 9874 controls were enrolled in the study. The prevalence of HBV chronic infection in patients with pemphigus was significantly higher than in control subjects (1.2 vs. 0.6%, respectively, p = 0.008). The prevalence rate of HCV carrier state was comparable between pemphigus patients and control subjects (1.1 vs. 1.0, respectively, p = 0.732). A multivariate analysis revealed a significant association between pemphigus and HBV with a multivariate odds ratio (OR) of 1.9 [95% confidence interval (CI), 1.2–3.90], whereas no association between pemphigus and HCV was identified (OR 1.1, 95% CI, 0.7–1.7). In conclusion, patients with pemphigus have a greater proportion of chronic HBV but not HCV infection relative to matched controls.