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Aim: To determine the effects of obesity in childhood on SARS‐CoV‐2 infection. Methods: A population‐based, cross‐sectional study combining the Israeli Growth Survey and COVID‐19 data for children with at least one SARS‐CoV‐2 test from 16 February 2020 to 20 December 2021. Overweight and obesity status were based on body mass index and the Center for Disease Control criteria. Multivariate logistics regression was performed to validate reliability for weight categories at the age of approximately 6 years compared with weights at approximately 12 years. Results: A total of 444 868 records for children with an overall positivity rate of 22% were studied. The mean age was 9.5 years. The odds ratios of children with obesity or overweight after controlling for sex at 6 years to test positive were 1.07–1.12 and 1.06–1.08 (depending on the model), respectively, compared to those with healthy range body mass index. Conclusion: Excess weight appears to increase the risk of SARS‐CoV‐2 infection. This finding should be considered for public health planning. For example, children with overweight and obesity should be prioritised for vaccination. Excess weight in childhood can be harmful at a young age and not only for long‐term health. [ABSTRACT FROM AUTHOR]

Background and purpose: Neuropsychological testing plays a key role in various clinical contexts. Even though a substantial number of adults suffer neurological disorders such as early‐onset dementia, stroke, traumatic brain injury or multiple sclerosis, most normative data do not include persons below 65. The aim of this study was to produce updated norms for the Mini‐Mental State Examination, the Free and Cued Selective Reminding Test, the Trail Making Test, verbal fluency tasks and the Digit Symbol Substitution Test for middle‐aged and older adults. Methods: The sample consisted of 51 879 participants aged 45–70 years from the CONSTANCES study. Norms are presented in percentiles stratified on age, education and gender. Results: The results illustrated the effect of age in all tests considered. For tests involving speed processing, the impact of age was observed including in tight age range categories (5 years). The results also showed the well‐known effect of education and an effect of gender in tests involving verbal memory and speed processing. Conclusions: The norms provided allow the variability of the cognitive performances of middle‐aged to older populations to be understood, with a high precision in age categories. The tests considered are broadly used in neuropsychological practice and should be helpful in a variety of clinical contexts. [ABSTRACT FROM AUTHOR]

Summary: Background: The prevalence of sesame food allergy (SFA) has increased over recent years, with the potential of anaphylactic reactions upon exposure. Oral food challenge (OFC) remains the diagnostic standard, yet its implementation may be risky. Commercial skin prick tests (SPT) have a low sensitivity. Investigation of alternate diagnostic methods is warranted. Objective: To evaluate the utility of SPT and the basophil activation test (BAT) for SFA diagnosis. Methods: Eighty‐two patients with suspected SFA completed an open OFC to sesame or reported a recent confirmed reaction. Patients were administered skin prick tests (SPT) with commercial sesame seed extract (CSSE) and a high protein concentration sesame extract (HPSE) (100 mg/mL protein). Whole blood from 80 patients was stimulated with sesame seed extract (40‐10 000 ng/mL protein) for BAT), assessing CD63 and CD203c as activation markers. Results: Sixty patients (73%) had IgE‐mediated reactions to sesame, and 22 (27%) did not react. Receiver operating characteristic (ROC) curve analysis demonstrated an area under the curve (AUC) of 0.87 for HPSE‐SPT and 0.66 for CSSE‐SPT. At 1000 ng/mL of sesame protein, induction of CD63 and CD203c was weakly but significantly associated with OFC eliciting dose by rank (Spearman's rho = −.42 (P < .01) and −.35 (P < .05) for CD63 and CD203c, respectively). By ROC analysis, the AUC was 0.86 for CD63 and was 0.81 for CD203c sesame‐induced basophil expression. Using HPSE‐SPT as a first test to definitively diagnose (n = 24) or rule‐out (n = 5) SFA and BAT as a second test to diagnose the remainder results in the correct classification of 73 of 80 (91%) patients, leaving one false negative and 4 false positive patients. Two BAT non‐responders remain unclassified by this algorithm. Conclusions & Clinical Relevance: While prospective cohort validation is necessary, joint utilization of BAT and SPT with HPSE extract may obviate the need for OFC in most SFA patients. [ABSTRACT FROM AUTHOR]

Abstract: Background: Ambiguities exist regarding the diagnosis of tree‐nut allergy, necessitating either their elimination or the performance of oral food challenges (OFCs). Objective: To examine the coincidences of allergies among tree‐nuts and improve diagnostic testing to minimize the need for OFC. Methods: Eighty‐three patients prospectively evaluated for walnut, pecan, cashew, pistachio, hazelnut, and almond allergy. A history of previous reactions was obtained, and standardized skin prick tests (SPTs) using finely ground tree‐nut solution and basophil activation tests (BAT) were performed. Patients underwent OFC for each tree‐nut they eliminated and to which a reaction in the previous 2 years was not documented. Results: While most patients were sensitized to 5‐6 tree‐nuts, over 50% were allergic to only 1‐2 tree‐nuts. The highest rate of allergy in sensitized patients was observed for walnut (74.6%) and cashew (65.6%). The rate of co‐allergy for most tree‐nuts was <30%. Two‐thirds of walnut‐ and cashew‐allergic patients were also allergic to pecan and pistachio, respectively, while all pecan‐ and pistachio‐allergic patients were allergic to walnut and cashew, respectively. Receiver‐operating characteristic analysis for SPT and BAT was tree‐nut dependent and yielded area under the curve (AUC) values ranging from 0.75 to 0.94. Knowledge of coincident allergies in these pairs along with the combination of SPT and BAT correctly distinguished allergic from tolerant patients for walnut (87%), pecan (66%), cashew (71%), and pistachio (79%). Conclusion: The data presented here should assist in differentiating between allergic and tolerant patients, decrease the need for OFC, and allow for appropriate elimination recommendations. [ABSTRACT FROM AUTHOR]

Background Quality of life ( QOL) is impaired in patients with food allergy and improves following oral immunotherapy ( OIT). However, the treatment itself is prolonged and demanding. We examined changes in patient QOL during OIT for food allergy. Methods The FAQLQ- PF was administered to children aged 4-12 years undergoing OIT for milk, peanut, or egg allergy, at the beginning and after 4 months of treatment. Patients were categorized as improved, unchanged, or diminished FAQLQ- PF (>0.5 point decrease, a change of ≤0.5 points, or >0.5 increase, respectively) and compared. Food-allergic patients not undergoing OIT served as controls. Results The Food Anxiety, Social and Dietary Limitation, and total FAQLQ- PF scores improved significantly during the study period ( P=.001, P=.018, and P=.01, respectively) in treated but not in control patients, while the Emotional Impact did not. The change in the FAQLQ- PF was independent of the maximal tolerated dose at baseline or following four months of treatment, the pace of dose increase, or the number or severity of reactions experienced. The total FAQLQ- PF score was inversely associated with the score at baseline on multivariate analysis (regression coefficient=−0.56, P<.001). That was driven primarily by improvement in QOL scores in patients with high score (worse QOL) at baseline. Some patients with low FAQLQ- PF score (better QOL) at baseline deteriorated. Conclusions QOL of patients with food allergy improves in some but deteriorates in others during OIT. Patients with impaired QOL at baseline improve significantly despite the treatment burden. Some patients with better QOL at baseline might deteriorate during OIT. [ABSTRACT FROM AUTHOR]

Background and purpose The aim of our study was to examine the effect sizes of different cognitive function determinants in middle and early old age. Methods Cognitive functions were assessed in 11 711 volunteers (45 to 75 years old), included in the French CONSTANCES cohort between January 2012 and May 2014, using the free and cued selective reminding test ( FCSRT), verbal fluency tasks , digit-symbol substitution test ( DSST) and trail making test ( TMT) , parts A and B. The effect sizes of socio-demographic (age, sex, education), lifestyle (alcohol, tobacco, physical activity), cardiovascular (diabetes, blood pressure) and psychological (depressive symptomatology) variables were computed as omega-squared coefficients ( ω2; part of the variation of a neuropsychological score that is independently explained by a given variable). Results These sets of variables explained from R2 = 10% (semantic fluency) to R2 = 26% ( DSST) of the total variance. In all tests, socio-demographic variables accounted for the greatest part of the explained variance. Age explained from ω2 = 0.5% (semantic fluency) to ω2 = 7.5% ( DSST) of the total score variance, gender from ω2 = 5.2% ( FCSRT) to a negligible part (semantic fluency or TMT) and education from ω2 = 7.2% ( DSST) to ω2 = 1.4% ( TMT-A). Behavioral, cardiovascular and psychological variables only slightly influenced the cognitive test results (all ω2 < 0.8%, most ω2 < 0.1%). Conclusion Socio-demographic variables (age, gender and education) are the main variables associated with cognitive performance variations between 45 and 75 years of age in the general population. [ABSTRACT FROM AUTHOR]

Aims To examine the extent to which adverse psychosocial factors, such as living alone, psychological distress, job strain and low support from supervisor, increase the risk of work disability (sickness absence and disability pension) among employees with diabetes. Methods In this pooled analysis of individual-participant data from three occupational cohort studies (the Finnish Public Sector Study, the British Whitehall II study, and the French GAZEL study), 1088 women and 949 men with diabetes were followed up to determine the duration (number of days) and frequency (number of spells) of work disability. The mean follow-up periods were 3.2 years in the GAZEL study, 4.6 years in the Whitehall II study and 4.7 years in the Finnish Public Sector Study. Psychosocial factors and potential confounding factors were assessed at baseline using standard questionnaires. Study-specific estimates were pooled using fixed-effects meta-analysis. Results In analysis adjusted for sociodemographic factors, health behaviours and comorbidities, participants with psychological distress had longer (rate ratio 1.66; 95% CI 1.31-2.09) and more frequent absences (rate ratio 1.33; 95% CI 1.19-1.49) compared with those with no psychological distress. Job strain was associated with slightly increased absence frequency (rate ratio 1.19 95% CI 1.05-1.35), but not with absence duration. Living alone and low supervisor support were not associated with absence duration or frequency. We observed no sex differences in these associations. Conclusions Psychological distress was associated with increased duration and frequency of work disability among employees with diabetes. Job strain was associated with increased absence frequency but not with absence duration. [ABSTRACT FROM AUTHOR]

Studies examining the long-term effect of oral immunotherapy in food-allergic patients are limited. We investigated cow's milk-allergic patients, >6 months after the completion of oral immunotherapy ( n = 197). Questionnaires, skin prick tests, and basophil activation assays were performed. Of the 195 patients contacted, 180 (92.3%) were consuming milk protein regularly. Half experienced adverse reactions, mostly mild. Thirteen patients (6.7%) required injectable epinephrine. Higher reaction rate after immunotherapy was associated with more anaphylactic episodes before treatment and a lower starting dose ( OR = 2.1, P = 0.035 and OR = 2.3, P = 0.035, respectively). Reaction rate in patients who were 6-15 months, 15-30 months, or >30 months post-treatment decreased from 0.28/month to 0.21/month to 0.15/month, respectively ( P < 0.01). Milk-induced % CD63 and % CD203c expression was significantly lower in patients >24 months vs in patients <24 months post-treatment ( P = 0.038 and P = 0.047, respectively). In conclusion, many patients experience mild adverse reactions after completing oral immunotherapy and some require injectable epinephrine. Progressive desensitization, both clinically and in basophil reactivity, occurs over time. [ABSTRACT FROM AUTHOR]

Aims To examine work disability trajectories among employees with and without diabetes and identify lifestyle-related factors associated with these trajectories. Methods We assessed work disability using records of sickness absence and disability pension among participants with diabetes and age- sex-, socio-economic status- and marital status-matched controls in the Finnish Public Sector Study (1102 cases; 2204 controls) and the French GAZEL study (500 cases; 1000 controls), followed up for 5 years. Obesity, physical activity, smoking and alcohol consumption were assessed at baseline and the data analysed using group-based trajectory modelling. Results Five trajectories described work disability: 'no/very low disability' (41.1% among cases and 48.0% among controls); 'low-steady' (35.4 and 34.7%, respectively); 'high-steady' (13.6 and 12.1%, respectively); and two 'high-increasing' trajectories (10.0 and 5.2%, respectively). Diabetes was associated with a 'high-increasing' trajectory only (odds ratio 1.90, 95% CI 1.47-2.46). Obesity and low physical activity were similarly associated with high work disability in people with and without diabetes. Smoking was associated with 'high-increasing' trajectory in employees with diabetes (odds ratio 1.88, 95% CI 1.21-2.93) but not in those without diabetes (odds ratio 1.32, 95% CI 0.87-2.00). Diabetes was associated with having multiple ( ≥ 2) risk factors (21.1 vs. 11.4%) but the association between multiple risk factors and the 'high-increasing' trajectory was similar in both groups. Conclusions The majority of employees with diabetes have low disability rates, although 10% are on a high and increasing disability trajectory. Lifestyle-related risk factors have similar associations with disability among employees with and without diabetes, except smoking which was only associated with poorer prognosis in diabetes. [ABSTRACT FROM AUTHOR]

Objective To examine whether non-psychiatric hospitalizations rates were higher in those with mental disorders. Method In a cohort of 15 811 employees, aged 35-50 years in 1989, mental disorder status was defined from 1989 to 2000. Hospitalizations for all-causes, myocardial infarction ( MI), stroke, and cancer, were recorded yearly from 2001 to 2011. Negative binomial regression models were used to estimate hospitalization rates over the follow-up. Results After controlling for baseline sociodemographic factors, health-related behaviors, self-rated health, and self-reported medical conditions, participants with a mental disorder had significantly higher rates of all-cause hospitalization [incidence rate ratio, IRR = 1.20 (95%, 1.14-1.26)], as well as hospitalization due to MI [ IRR = 1.44 (95%, 1.12-1.85)]. For stroke, the IRR did not reach statistical significance [ IRR = 1.37 (95%, 0.95-1.99)] and there was no association with cancer [ IRR = 1.01 (95%, 0.86-1.19)]. A similar trend was observed when mental disorders groups were considered (no mental disorder, depressive disorder, mental disorders due to psychoactive substance use, other mental disorders, mixed mental disorders, and severe mental disorder). Conclusion In this prospective cohort of employees with stable employment as well as universal access to healthcare, we found participants with mental disorders to have higher rates of non-psychiatric hospitalizations. [ABSTRACT FROM AUTHOR]

. Nyberg ST, Heikkilä K, Fransson EI, Alfredsson L, De Bacquer D, Bjorner JB, Bonenfant S, Borritz M, Burr H, Casini A, Clays E, Dragano N, Erbel R, Geuskens GA, Goldberg M, Hooftman WE, Houtman IL, Jöckel K-H, Kittel F, Knutsson A, Koskenvuo M, Leineweber C, Lunau T, Madsen IEH, Magnusson Hanson LL, Marmot MG, Nielsen ML, Nordin M, Oksanen T, Pentti J, Rugulies R, Siegrist J, Suominen S, Vahtera J, Virtanen M, Westerholm P, Westerlund H, Zins M, Ferrie JE, Theorell T, Steptoe A, Hamer M, Singh-Manoux A, Batty GD, Kivimäki M, for the IPD-Work Consortium (Finnish Institute of Occupational Health, Helsinki, Finland; Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Jönköping University, Jönköping, Sweden; Ghent University, Ghent, Belgium; National Research Centre for the Working Environment, Copenhagen, Denmark; Versailles-Saint Quentin University, Versailles, France; Centre for Research in Epidemiology and Population Health, Villejuif, France; Bispebjerg University Hospital, Copenhagen, Denmark; Centre for Maritime Health and Safety, Esbjerg, Denmark; Université Libre de Bruxelles, Brussels, Belgium; University Duisburg-Essen, Essen, Germany; West-German Heart Center Essen, University Duisburg-Essen, Essen, Germany; TNO, Hoofddorp, the Netherlands; Mid Sweden University, Sundsvall, Sweden; University of Helsinki, Helsinki, Finland; Stockholm University, Stockholm, Sweden; University College London, London, UK; Bispebjerg University Hospital, Copenhagen, Denmark; Umeå University, Umeå, Sweden; Finnish Institute of Occupational Health, Turku, Finland; Harvard School of Public Health, Boston, MA, USA; University of Copenhagen, Copenhagen, Denmark; University of Düsseldorf, Düsseldorf, Germany; University of Turku, Turku; Folkhälsan Research Center, Helsinki; Turku University Hospital, Turku, Finland; Uppsala University, Uppsala; Karolinska Institutet, Stockholm, Sweden; University of Bristol, Bristol; University of Edinburgh, Edinburgh, UK; and University of Helsinki, Helsinki, Finland). Job strain in relation to body mass index: pooled analysis of 160 000 adults from 13 cohort studies. J Intern Med 2012; 272: 65-73. Background. Evidence of an association between job strain and obesity is inconsistent, mostly limited to small-scale studies, and does not distinguish between categories of underweight or obesity subclasses. Objectives. To examine the association between job strain and body mass index (BMI) in a large adult population. Methods. We performed a pooled cross-sectional analysis based on individual-level data from 13 European studies resulting in a total of 161 746 participants (49% men, mean age, 43.7 years). Longitudinal analysis with a median follow-up of 4 years was possible for four cohort studies ( n = 42 222). Results. A total of 86 429 participants were of normal weight (BMI 18.5-24.9 kg m−2), 2149 were underweight (BMI < 18.5 kg m−2), 56 572 overweight (BMI 25.0-29.9 kg m−2) and 13 523 class I (BMI 30-34.9 kg m−2) and 3073 classes II/III (BMI ≥ 35 kg m−2) obese. In addition, 27 010 (17%) participants reported job strain. In cross-sectional analyses, we found increased odds of job strain amongst underweight [odds ratio 1.12, 95% confidence interval (CI) 1.00-1.25], obese class I (odds ratio 1.07, 95% CI 1.02-1.12) and obese classes II/III participants (odds ratio 1.14, 95% CI 1.01-1.28) as compared with participants of normal weight. In longitudinal analysis, both weight gain and weight loss were related to the onset of job strain during follow-up. Conclusions. In an analysis of European data, we found both weight gain and weight loss to be associated with the onset of job strain, consistent with a 'U'-shaped cross-sectional association between job strain and BMI. These associations were relatively modest; therefore, it is unlikely that intervention to reduce job strain would be effective in combating obesity at a population level. [ABSTRACT FROM AUTHOR]

Aliment Pharmacol Ther 2010; 32: 1102-1112 Background Velusetrag is an orally active 5-HT4 receptor agonist of potential benefit in treating chronic idiopathic constipation. Aim To evaluate the efficacy, safety and tolerability of velusetrag in chronic idiopathic constipation. Methods After a 2-week baseline period, patients [<3 spontaneous bowel movements (SBM)/week] received placebo or velusetrag (15, 30 or 50 mg) daily for 4 weeks in a randomized, double-blind design, followed by a 1-week follow-up period. The primary endpoint was the change from baseline in weekly SBM frequency averaged over the 4-week treatment period. Results Patients receiving velusetrag (15, 30 and 50 mg) achieved statistically and clinically significant increases in weekly SBM frequency relative to those receiving placebo. Mean increases were 3.6, 3.3 and 3.5 SBM/week respectively, compared with 1.4 SBM/week for placebo ( P < 0.0001). Statistically significant increases in the weekly frequency of complete SBM (CSBM) were also reported (mean increases of 2.3, 1.8 and 2.3 for 15, 30 and 50 mg velusetrag respectively, compared with 0.6 for placebo). Common adverse events associated with velusetrag were diarrhoea, headache, nausea and vomiting, generally occurring during the initial days of dosing. Conclusion Velusetrag was efficacious and well tolerated in patients with chronic idiopathic constipation (ClinicalTrials.gov identifier NCT00391820). [ABSTRACT FROM AUTHOR]

Velusetrag (TD-5108) is a potent, selective high intrinsic activity serotonin 5-HT4 receptor agonist. We assessed effects of Velusetrag on gastrointestinal transit and compared its pharmacokinetics in healthy volunteers (HV) and chronic constipation (CC) patients. Sixty HV were randomly assigned, double-blind to placebo, 5, 15, 30 or 50 mg Velusetrag (single and 6-day dosing). Primary endpoints were colonic transit (geometric centre at 24 h, GC24) and ascending colon emptying (ACE) T1/2 after first dose. Secondary endpoints included gastric emptying (GE) T1/2 and colonic filling at 6 h (CF6). Single dose Velusetrag significantly accelerated GC24, ACE T1/2, and CF6; 30 and 50 mg Velusetrag accelerated all three endpoints. With multiple doses, Velusetrag 30 mg accelerated GC24, and overall accelerated GE T1/2 at 15–50 mg. Pharmacokinetics studies showed dose proportionality in health, and no significant differences between health and chronic constipation with a 15 mg oral dose of Velusetrag. Stimulation of bowel function after15 mg Velusetrag was similar in CC and controls. There were no serious adverse events; notable adverse events were the predictable gastrointestinal effects such as diarrhoea or altered bowel movements. Velusetrag significantly accelerated intestinal and colonic transit after single dosing and accelerated gastric emptying after multiple dosing. Further studies of its potential as a gastrointestinal and colonic prokinetic are warranted. [ABSTRACT FROM AUTHOR]

Left-and right-handers have coexisted since the Palaeolithic age. Hand preference is heritable. Moreover, there is extensive evidence of an association between left-handedness and several fitness costs. In this context, the persistence of the polymorphism is interesting. Here, we explore the associations between socio-economic status and handedness, analysing data from two large cohorts of adult men and women. Such associations are relevant to an evolutionary approach, as the socio-economic and the reproductive value are related. Our results partly support the hypothesis that left-handers have a socio-economic status advantage, countervailing the health issues. Although the models explain a small proportion of the variance observed, the frequency of left-handedness is significantly higher: (1) among women of higher educational level; (2) among categories of higher income; and (3) among individuals who have a higher position in the company. The importance of these findings for the evolution of the polymorphism of handedness is discussed. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the outcome of 1-(OH) vitamin D and oral phosphate treatment on dentin structure in patients with familial hypophosphatemic rickets, and expression of SIBLINGs (a family of non-collagenous proteins involved in dentinogenesis) and osteocalcin. Patients and methods: Seven patients with familial hypophosphatemic rickets (age 3–16 years) were studied before or during treatment. Deciduous and permanent teeth were prepared for scanning electron microscopy (SEM) analysis and immunohistochemistry. Results: Untreated or inadequately treated patients had necrotic teeth with impaired dentin mineralization including unmerged calcospherites and accumulation of non-collagenous proteins in wide interglobular spaces. Most of the primary incisors analyzed displayed fissures linking enamel subsurface to pulp horn. These elements may explain the bacterial penetration and dental abscesses despite the absence of carious lesions. Well-treated patients had healthy teeth with good dentin mineralization and little evidence of calcospherites. Conclusion: Treatment of hypophosphatemic children with 1-(OH) vitamin D and oral phosphate insures good dentin development and mineralization, and prevents clinical anomalies such as the dental necrosis classically associated with the disease. Starting treatment during early childhood and good adherence to the therapy are mandatory to observe these beneficial effects. [ABSTRACT FROM AUTHOR]

To understand the value of computer-aided disproportionality analysis (DA) in relation to current pharmacovigilance signal detection methods, four products were retrospectively evaluated by applying an empirical Bayes method to Merck's post-marketing safety database. Findings were compared with the prior detection of labeled post-marketing adverse events. Disproportionality ratios (empirical Bayes geometric mean lower 95% bounds for the posterior distribution (EBGM05)) were generated for product–event pairs. Overall (1993–2004 data, EBGM05≥2, individual terms) results of signal detection using DA compared to standard methods were sensitivity, 31.1%; specificity, 95.3%; and positive predictive value, 19.9%. Using groupings of synonymous labeled terms, sensitivity improved (40.9%). More of the adverse events detected by both methods were detected earlier using DA and grouped (versus individual) terms. With 1939–2004 data, diagnostic properties were similar to those from 1993 to 2004. DA methods using Merck's safety database demonstrate sufficient sensitivity and specificity to be considered for use as an adjunct to conventional signal detection methods.Clinical Pharmacology & Therapeutics (2007) 82, 173–180. doi:10.1038/sj.clpt.6100233; published online 16 May 2007 [ABSTRACT FROM AUTHOR]

About 10–30% of primary liver cancers represent intrahepatic cholangiocarcinomas (IHCC). Since chromosomal losses of 3p are detectable in about 40% of cholangiocarcinomas our study aimed at the identification of mechanisms leading to functional deletion of tumor suppressor genes in this region. Our efforts focussed on genomic losses and epigenetic inactivation of two tumor suppressor genes, the fragile histidine triad (FHIT) and the ras association domain family 1 (RASSF1A) genes, both located on the short arm of chromosome 3. Methods: Methylation-specific PCR (MSP) and combined bisulfite-dependent restriction analysis (COBRA) were applied to detect epigenetic silencing of gene promoters. Genomic duplex PCR was used to identify exon losses of the FHIT gene. Nineteen paraffin-embedded samples of intrahepatic cholangiocarcinomas were studied. Results: Here we report for the first time that in addition to frequent losses of the exons 5 and 6, hypermethylation of the FHIT promoter occured in a significant portion of IHCC. Methylation specific PCR (MSP) detected epigenetic inactivation of the FHIT/FRA3B locus in 8 of 19 (42%) cases. Combined bisulfite restriction analysis (COBRA) revealed that high levels of methylated FHIT promoter sequences were present in 6 of the 8 methylation positive samples. In agreement with previous reports MSP identified hypermethylation of the RASSF1A gene in 13 of 19 (68%) IHCC specimens examined. Conclusions: Epigenetic silencing of the FHIT tumor suppressor gene is a novel inactivation mechanism to be considered in the development of intrahepatic cholangiocarcinomas. However, a statistically significant inverse correlation between K-Ras activation and RASSF1A inactivation was not found. [ABSTRACT FROM AUTHOR]

The aim of our study was to examine the absorption of insulin from the gastrointestinal (GI) tract, using a novel oral formulation—adding a delivery agent SNAC (sodium N-[8-(2-hydroxybenzoyl)amino] caprylate) in combination with insulin. Capsules containing insulin and SNAC, in various combinations, were administered orally, as a single dose, to 12 non-diabetic subjects and four control subjects (receiving SNAC or insulin only) in order to assess its biological effect and safety. Plasma glucose levels, insulin and C-peptide concentrations, as well as SNAC levels, were determined, at timed intervals up to 4 h. In all cases, a glucose-lowering effect was demonstrated, preceded by an increase in plasma insulin levels. The nadir of plasma glucose levels appeared after 30–50 min, following the ingestion of the mixture. The plasma insulin levels were found to parallel the blood SNAC levels. Plasma C-peptide levels were suppressed by the lowered glucose levels achieved concurrent with the increasing amount of exogenous insulin absorbed, indicating that the secretion of endogenous hormone was partially abolished. There were no biological effects regarding blood glucose levels upon administration of SNAC or insulin when given alone. No adverse effects were detected during the trial or several weeks after the trial. Insulin in combination with a novel delivery agent, SNAC, given orally, is absorbed through the GI tract in a biologically active form. This was demonstrated by a glucose lowering effect of the mixture as well as a suppression of an endogenous insulin secretion. Diabet. Med. 21, 354 –357 (2004) [ABSTRACT FROM AUTHOR]

Background: Complement receptor type 1 (CR1), which bears the Knops (Kn [KN]) blood group antigens, is involved in the rosetting of Plasmodium falciparum- infected RBCs with uninfected cells. As a first step in understanding this interaction, the molecular basis for the blood group antigens encoded by CR1 was investigated.Study Design and Methods: An antibody from a white donor who exhibited an apparent anti-Sl(a) was used for population studies of several racial groups. The donor's genomic DNA was sequenced to identify the Sl(a) mutation and other mutations.Results: The donor with anti-Sl(a) typed as Sl(a+) with some sera and had the CR1 genotype AA at bp 4828 (R1601). However, she was homozygous for a new mutation (GG) at bp 4855 changing amino acid 1610 from S1610 to T1610 (S1610T). This mutation occurred in heterozygous form in eight white and one Asian donor. The site is only nine amino acids from the previously described Sl(a) polymorphism and appears to produce a new conformational epitope.Conclusion: The antigen formerly known as Sl(a) can now be subdivided. A new terminology is proposed that recognizes both linear and conformational epitopes on the CR1 protein. At amino acid 1601, Sl 1 (Sl(a)) is represented by R, Sl 2 (Vil) is represented by glycine, and Sl 3 requires both R1601 and S1610. Sl 4 and Sl 5 are hypothetical epitopes represented by S1610 and T1610, respectively. [ABSTRACT FROM AUTHOR]

Virulence gene expression in enteropathogenic Escherichia coli (EPEC) is governed by a combination of environmental factors and virulence regulators. These factors control the expression of the bundle-forming pili (BFP), intimin, the type III secretion apparatus and the secreted proteins EspA, EspB, EspD and Tir. Expression of the bfp genes occurs for a short period in early exponential phase during growth in tissue culture medium. The nucleoid-associated regulator protein, Fis, is also expressed transiently during this period. To determine whether Fis was responsible for the growth phase-dependent expression of bfp, fis was deleted from the EPEC strain E2348/69S. Paradoxically, the Δfis mutant retained the ability to colonize HEp-2 cells in a characteristic localized adherence pattern, and Fis was found negatively to regulate the expression of BFP. However, the Δfis mutant failed to induce the accretion of filamentous actin, which is associated with attaching and effacing lesions. Using a combination of Western blotting and a novel multiplex primer extension assay (MPEA), we showed that, although the expression of intimin and Tir was not affected, transcription of the LEE4 operon encoding espADB and the virulence activator, Ler, were found to be Fis dependent. [ABSTRACT FROM AUTHOR]

Immunohistochemical studies using a polyclonal antibody, raised against the recombinant form of dentin matrix protein 1 (DMP1), show that DMP1 was detected mainly in odontoblasts in cultured mouse embryonic tooth germs. However, in restricted areas, DMP1 staining was also observed in secretory ameloblasts, in the stratum intermedium and stellate reticulum, but only when the odontoblasts located in front of them were unstained. When the embryonic tooth germs were cultured in the presence of inositol hexasulfate, a casein kinase I and II inhibitor, staining of odontoblasts was weak or nil, whereas, in contrast, ameloblasts and enamel organ were strongly immunolabelled, suggesting an enhanced translocation of DMP1 after secretion to the secretory ameloblasts and/or stratum intermedium and stellate reticulum. Moreover, DMP1 was shown to be a good substrate for gelatinase A (MMP‐2), but not to gelatinase B (MMP‐ 9). We hypothesized that DMP1 – or the sub‐fractions cleaved by the MMP – could behave as diffusible signaling molecule (s) rather than as a true dentin extracellular matrix component. [ABSTRACT FROM AUTHOR]

A Nigerian man had acute onset of headache and vertigo due to a cerebellar mass. A brain biopsy of the mass revealed toxoplasmosis despite repeated negative HIV-1 serology. The presence of an opportunistic infection and his country of origin raised the suspicion for HIV-2; this was confirmed by positive HIV-2 serology. Despite his preliminary pathological diagnosis, results of physiological magnetic resonance imaging (MRI) (perfusion MRI and proton magnetic resonance spectroscopy) were not typical for toxoplasmosis. The lesion showed a biochemical and perfusion pattern that was intermediate for infectious and neoplastic processes. Further neuropathology confirmed a secondary diagnosis of lymphomatoid granulomatosis. [ABSTRACT FROM AUTHOR]

Intrauterine growth retardation is frequently associated with intrauterine undernutrition, and can deleteriously affect brain function. Twenty-eight premature small for gestational age infants were compared with 28 premature appropriate for gestational age infants to determine whether intrauterine growth retardation was associated with abnormalities in the auditory pathway in the early neonatal period. The auditory pathway was studied between 4-18 wk of life by analysis of brainstem auditory-evoked potentials elicited by a 10/s 75 decibel above normal adult hearing level (dB nHL) click stimulus presented at the infants' ears. Peak latencies of components I, III and V, and interpeak latencies I-III, III-V and I-V, yielded no statistically significant differences between groups. The present study indicates that intrauterine growth-retarded premature infants may not have abnormalities of brainstem auditory-evoked response in the early neonatal period. [ABSTRACT FROM AUTHOR]

To identify the predictors of changes in alcohol intake among French men. Longitudinal study over a 2-year period. The GAZEL volunteer cohort comprising workers employed by Electricité de France-Gaz de France. The study included 11,613 men aged 40-50 years who had answered a self-administered questionnaire in 1989 and 1991. Subjects were defined according to initial levels of alcohol intake and changes in that intake (cessation, decrease and increase) and compared with subjects with corresponding levels but unchanged intake by logistic regression. The effects of individual characteristics and of occupational and health conditions were investigated. Different variables measured in 1989 were predictive of changes in alcohol consumption in 1991, depending on the change. Self-perception of bad health, consumption of sleeping pills and unmarried status were predictive of the cessation of alcohol consumption. Working under favourable conditions (with no specific occupational risks) and being a non-smoker tended to be associated with reduced consumption. Increased consumption was associated with the number of reported disease and the smoking status. Among abstainers or light daily drinkers, being exposed to more than one constraint enlarged the risk of increased consumption. For moderate drinkers, the risk of increased consumption was higher, irrespective of the number of physical constraints. These results highlight the fact that many inter-related factors help to determine changes in drinking habits. [ABSTRACT FROM AUTHOR]

The purpose of this paper is to investigate whether an antibody directed against the exocrine secretion, saliva, is able to induce a modification in vivo within the specific cells of the submaxillary glands which synthesize this secretion. The salivary antigens synthesized within the glandular acinar cells are secreted into they respective lumen and are not present in the general circulation or in the intercellular spaces of the gland. When heterologous anti-saliva antibodies are injected into mice, they induce marked lesions within the acinar cells of the submaxillary glands. When different antibodies recognizing different salivary components are injected, they ail induce similar modifications; it is not yet possible to distinguish whether different cells are involved in the synthesis of the different salivary components. The lesions described seem specific since other organs studied, such as the pancreas and the stomach, are unaffected. The different possible mechanisms of this cytotoxic effect are discussed. [ABSTRACT FROM AUTHOR]

Cyclosporin A (CsA), a widely used immunosuppressive drug, induces gingival overgrowth and modifications of bone remodelling. The scope of this study was to investigate the possible effect of CsA on dentin. Thirty mg/kg/day of CsA were administered orally to male Sprague-Dawley rats for nineteen weeks. The same number of control rats received oil-based vehicle solution. Rats were anesthetized, and tissues were fixed by an intracardiac perfusion of fixative solution. Mandibles were dissected, demineralized, and processed for Epon embedding. Semi-thin sections of the first molars revealed alterations at the secondary dentin-pulp interface in four out of six experimental animals. The changes consisted of the formation of: 1) osteodentin spurs, in which the volume and interface with the secondary dentin varied from about 25,000 to 75,000 microns 3 and from 1400 to 3530 microns 2, respectively; 2) abnormally shaped and irregularly spaced incremental lines; and 3) numerous globular formations embedded in dentin or free in the pulp. These results indicate that CsA induces abnormal mineralized matrix formation in dentin and in the peripheral part of the pulp in rat molars. [ABSTRACT FROM AUTHOR]

Replicas of unerupted and erupted human enamel submitted to protein-disrupting solutions showed: (1) an inequal distribution of porosities in the subsurface; (2) such porosities were restricted gradually in each enamel subunit (enamel segments limited by two perikymata). First the whole surface was covered by a network, reduced at a later stage to half of the surface and ultimately the porosities were present only in the perikymata. This paper confirms the occurrence of a late maturation at stage where cells are no longer active and details the time-dependent involution of these porosities. [ABSTRACT FROM AUTHOR]