A homozygous loss-of-function mutation in inositol monophosphatase 1 (IMPA1) causes severe intellectual disability.

The genetic basis of intellectual disability (ID) is extremely heterogeneous and relatively little is known about the role of autosomal recessive traits. In a field study performed in a highly inbred area of Northeastern Brazil, we identified and investigated a large consanguineous family with nine adult members affected by severe ID associated with disruptive behavior. The Genome-Wide Human SNP Array 6.0 microarray was used to determine regions of homozygosity by descent from three affected and one normal family member. Whole-exome sequencing (WES) was performed in one affected patient using the Nextera Rapid-Capture Exome kit and Illumina HiSeq2500 system to identify the causative mutation. Potentially deleterious variants detected in regions of homozygosity by descent and not present in either 59 723 unrelated individuals from the Exome Aggregation Consortium (Browser) or 1484 Brazilians were subject to further scrutiny and segregation analysis by Sanger sequencing. Homozygosity-by-descent analysis disclosed a 20.7-Mb candidate region at 8q12.3-q21.2 (lod score: 3.11). WES identified a homozygous deleterious variant in inositol monophosphatase 1 (IMPA1) (NM_005536), consisting of a 5-bp duplication (c.489_493dupGGGCT; chr8: 82,583,247; GRCh37/hg19) leading to a frameshift and a premature stop codon (p.Ser165Trpfs*10) that cosegregated with the disease in 26 genotyped family members. The IMPA1 gene product is responsible for the final step of biotransformation of inositol triphosphate and diacylglycerol, two second messengers. Despite its many physiological functions, no clinical phenotype has been assigned to this gene dysfunction to date. Additionally, IMPA1 is the main target of lithium, a drug that is at the forefront of treatment for bipolar disorder.

Is consuming yoghurt associated with weight management outcomes? Results from a systematic review.

BACKGROUND: Yoghurt is part of the diet of many people worldwide and is commonly recognised as a 'health food'. Epidemiological studies suggest that yoghurt may be useful as part of weight management programs. In the absence of comprehensive systematic reviews, this systematic review investigated the effect of yoghurt consumption by apparently healthy adults on weight-related outcomes. METHODS: An extensive literature search was undertaken, as part of a wider scoping review, to identify yoghurt studies. A total of 13 631 records were assessed for their relevance to weight-related outcomes. RESULTS: Twenty-two publications were eligible according to the review protocol. Cohort studies (n=6) and cross-sectional studies (n=7) all showed a correlation between yoghurt and lower or improved body weight/composition. Six randomised controlled trials (RCTs) and one controlled trial had various limitations, including small size and short duration. One RCT showed significant effects of yoghurt on weight loss, but was confounded by differences in calcium intake. One trial showed nonsignificant weight gain and the remaining five trials showed nonsignificant weight losses that were greater in yoghurt consumers. CONCLUSIONS: Yoghurt consumption is associated with lower body mass index, lower body weight/weight gain, smaller waist circumference and lower body fat in epidemiological studies. RCTs suggest weight reduction effects, but do not permit determination of a cause-effect relationship. Well-controlled, adequately powered trials in research and community settings appear likely to identify a modest but beneficial effect of yoghurt consumption for prevention of weight gain and management of obesity. The ready availability of yoghurt (a nutrient-dense food) and its ease of introduction to most diets suggests that educating the public to eat yoghurt as part of a balanced and healthy diet may potentially contribute to improved public health. Future carefully designed RCTs could provide proof of principle and large community-based studies could determine the practical impact of yoghurt on body weight/composition.

Registration and management of community patients with tuberculosis in north-west China.

OBJECTIVES: To describe the registration, management and characteristics of patients with tuberculosis (TB) in north-west China, and investigate whether patients with TB were diagnosed and treated in a timely manner. STUDY DESIGN: Health-facility-based retrospective data were collected from district patient registers and case reports for all patients with TB registered from January 2009 to December 2011 in Xinjiang Uygur Autonomous Region, north-west China. METHODS: Patient characteristics and clinical data were collected from the national TB epidemic reporting system using standardized case reporting forms for diagnosis, treatment and outcome. Data were collected and entered by trained health staff in the regional TB clinics. RESULTS: In total, data for 20,396 patients with TB were collected; of these, 78.5% were farmers. The age peaks were 20-44 years and 60-74 years. Average health-seeking and diagnostic delays were 32 days and two days, respectively. More than half (54.7%) of the patients with smear-negative TB were diagnosed by chest x-ray. Moreover, 94.3% of patients with TB were treated successfully. From 2009 to 2011, the health-seeking delay decreased significantly (P < 0.05), and the diagnostic delay increased significantly (P < 0.05). A significant decreasing trend in smear-positive TB was observed (P < 0.05), along with an increasing trend in treatment success (P < 0.05). CONCLUSIONS: In north-west China, there is a need to focus on key high-risk populations for prevention and control of TB, such as those aged 20-44 years and 60-74 years, males and farmers. Delays in diagnosis and treatment have a negative effect on cure rates and make it more difficult to control the propagation of TB.

PLP1 duplication at the breakpoint regions of an apparently balanced t(X;22) translocation causes Pelizaeus-Merzbacher disease in a girl.

PLP1 (proteolipid protein1 gene) mutations cause Pelizaeus-Merzbacher disease (PMD), characterized by hypomyelination of the central nervous system, and affecting almost exclusively males. We report on a girl with classical PMD who carries an apparently balanced translocation t(X;22)(q22;q13). By applying array-based comparative genomic hybridization (a-CGH), we detected duplications at 22q13 and Xq22, encompassing 487-546 kb and 543-611 kb, respectively. The additional copies were mapped by fluorescent in situ hybridization to the breakpoint regions, on the derivative X chromosome (22q13 duplicated segment) and on the derivative 22 chromosome (Xq22 duplicated segment). One of the 14 duplicated X-chromosome genes was PLP1.The normal X chromosome was the inactive one in the majority of peripheral blood leukocytes, a pattern of inactivation that makes cells functionally balanced for the translocated segments. However, a copy of the PLP1 gene on the derivative chromosome 22, in addition to those on the X and der(X) chromosomes, resulted in two active copies of the gene, irrespective of the X-inactivation pattern, thus causing PMD. This t(X;22) is the first constitutional human apparently balanced translocation with duplications from both involved chromosomes detected at the breakpoint regions.

Vitamin D: do we get enough? A discussion between vitamin D experts in order to make a step towards the harmonisation of dietary reference intakes for vitamin D across Europe.

UNLABELLED: On September 29, 2011, acknowledged experts in the field of vitamin D, mainly European, were brought together in order to discuss the recent scientific advances in relation to vitamin D: the current requirements and associations with various health outcomes. In this article, the discussions resulting from the meeting are summarized. INTRODUCTION: Several groups at risk for developing vitamin D insufficiency have been identified. Accordingly, reviews indicate that a significant percentage of the population worldwide have serum 25-hydroxyvitamin D levels below 50 nmol/l. In addition to the role of vitamin D in bone health, recent studies suggest that it may play a pivotal role in other systems, e.g., the cardiovascular system, pancreas, muscle, immune system and brain. Most evidence, however, is obtained from observational studies and yet inconclusive. METHODS: To exchange and broaden knowledge on the requirements for vitamin D and its effect on various health outcomes, a workshop entitled "Vitamin D Expert Meeting: Do we get enough?", was organized. RESULTS: Despite low vitamin D levels worldwide, consensus on the definition of deficiency is not yet reached. In order to define cut-off points for vitamin D whilst taking into account extraskeletal health effects, randomized controlled trials in these fields are warranted. The experts do emphasize that there is evidence to suggest an important role for vitamin D in the maintenance of optimal bone health at all ages and that vitamin D supplementation, in most studies co-administered with calcium, reduces fracture risk in the senior population. CONCLUSION: To reach a serum 25-hydroxyvitamin D level of 50 nmol/l older adults aged ≥65 years are therefore recommended to meet a mean daily vitamin D intake of 20 µg (800 IU), which is best achieved with a supplement.

A novel microdeletion syndrome at 3q13.31 characterised by developmental delay, postnatal overgrowth, hypoplastic male genitals, and characteristic facial features.

BACKGROUND: Congenital deletions affecting 3q11q23 have rarely been reported and only five cases have been molecularly characterised. Genotype-phenotype correlation has been hampered by the variable sizes and breakpoints of the deletions. In this study, 14 novel patients with deletions in 3q11q23 were investigated and compared with 13 previously reported patients. METHODS: Clinical data were collected from 14 novel patients that had been investigated by high resolution microarray techniques. Molecular investigation and updated clinical information of one cytogenetically previously reported patient were also included. RESULTS: The molecular investigation identified deletions in the region 3q12.3q21.3 with different boundaries and variable sizes. The smallest studied deletion was 580 kb, located in 3q13.31. Genotype-phenotype comparison in 24 patients sharing this shortest region of overlapping deletion revealed several common major characteristics including significant developmental delay, muscular hypotonia, a high arched palate, and recognisable facial features including a short philtrum and protruding lips. Abnormal genitalia were found in the majority of males, several having micropenis. Finally, a postnatal growth pattern above the mean was apparent. The 580 kb deleted region includes five RefSeq genes and two of them are strong candidate genes for the developmental delay: DRD3 and ZBTB20. CONCLUSION: A newly recognised 3q13.31 microdeletion syndrome is delineated which is of diagnostic and prognostic value. Furthermore, two genes are suggested to be responsible for the main phenotype.

Anti-aquaporin-4 antibodies in the context of assorted immune-mediated diseases.

BACKGROUND AND PURPOSES: Anti-aquaporin 4 antibodies are specific markers for Devic's disease. This study aimed to test if this high specificity holds in the context of a large spectrum of systemic autoimmune and non-autoimmune diseases. METHODS: Anti-aquaporin-4 antibodies (NMO-IgG) were determined by indirect immunofluorescence (IIF) on mouse cerebellum in 673 samples, as follows: group I (clinically defined Devic's disease, n=47); group II [inflammatory/demyelinating central nervous system (CNS) diseases, n=41]; group III (systemic and organ-specific autoimmune diseases, n=250); group IV (chronic or acute viral diseases, n=35); and group V (randomly selected samples from a general clinical laboratory, n=300). RESULTS: MNO-IgG was present in 40/47 patients with classic Devic's disease (85.1% sensitivity) and in 13/22 (59.1%) patients with disorders related to Devic's disease. The latter 13 positive samples had diagnosis of longitudinally extensive transverse myelitis (n=10) and isolated idiopathic optic neuritis (n=3). One patient with multiple sclerosis and none of the remaining 602 samples with autoimmune and miscellaneous diseases presented NMO-IgG (99.8% specificity). The autoimmune disease subset included five systemic lupus erythematosus individuals with isolated or combined optic neuritis and myelitis and four primary Sjögren's syndrome (SS) patients with cranial/peripheral neuropathy. CONCLUSIONS: The available data clearly point to the high specificity of anti-aquaporin-4 antibodies for Devic's disease and related syndromes also in the context of miscellaneous non-neurologic autoimmune and non-autoimmune disorders.

Effects of snack consumption for 8 weeks on energy intake and body weight.

BACKGROUND: Consumption of snacks might contribute to the obesity epidemic. It is not clear how the moment of consumption and energy density of snacks can influence the compensatory response to consumption of snacks in the long term. OBJECTIVE: To investigate the effects of snack consumption for 8 weeks on changes in body weight, emphasizing on moment of consumption and energy density. DESIGN: In total, 16 men and 66 women (mean age 21.9 years (s.d. 0.3 year), mean body mass index 20.7 kg m(-2) (s.d. 0.2 kg m(-2))) were randomly assigned to one of four parallel groups in a 2 x 2 design: snacks consumed with or between meals and snacks having a low (<4 kJ g(-1)) or high (>12 kJ g(-1)) energy density. For 8 weeks, subjects consumed mandatory snacks that provided 25% of energy requirements on each day. Body weight, body composition, physical activity level (PAL) and energy intake were measured in week 1 and week 8. RESULTS: There were no differences in changes in body weight between the four groups. Moment of consumption (P=0.7), energy density (P=0.8) and interaction (P=0.09) did not influence body weight. Similarly, there were no differences in changes in body composition, PAL and energy intake between the four groups. CONCLUSIONS: Body weight after 8 weeks of snack consumption was not affected by moment of consumption and energy density of snacks. This finding suggests that consuming snacks that are high or low in energy density does not necessarily contribute to weight gain. Healthy, nonobese young adults may be able to maintain a normal body weight through an accurate compensation for the consumption of snacks.

Recurrent neuromyelitis optica in Brazilian patients: clinical, immunological, and neuroimaging characteristics.

Neuromyelitis optica has not been thoroughly studied in Brazilian patients following the discovery of NMO-IgG and its specific antigen aquaporin-4. In this study we aimed to describe the clinical NMO-IgG immunological status and neuroimaging characteristics of recurrent neuromyelitis optica in a series Brazilian patients. We undertook a retrospective study of 28 patients with recurrent neuromyelitis optica, according to 1999 Wingerchuk's diagnostic criteria. Data on NMO-IgG status, clinical features, and MRI findings were analyzed. Three men and 25 women were evaluated. Median age at onset of disease was 26 years (range 7-55); median time of follow-up was 7 years (range 2-14). The mean time elapsed between the first and the second attack was 17 months (median 8.5; range 2-88). NMO-IgG was detected in 18 patients (64.3%). Four patients died due to respiratory failure. Most patients presented with cervical (36%) and cervical-thoracic myelitis (46.4%). Holocord lesion was the most common pattern of involvement (50%) on the axial plane. We did not find a statistical association between myelitis extension and NMO-IgG result. Our series of Brazilian patients showed a younger age of onset than previously reported. In our series, in contrast to previous reports, there was no correlation between the extension of myelitis and NMO-IgG positivity.

Reliability study of the sonographic measurement of the acromiohumeral distance in symptomatic patients.

BACKGROUND: The purpose of this study was to evaluate the inter- and intra-observer reliability and accuracy of sonographic (US) acromiohumeral distance (AHD) measurement for both experienced and novice operators in US in patients suffering from subacromial impingement syndrome. METHOD: A total of 43 patients (50 shoulders) diagnosed with subacromial impingement syndrome were recruited from an orthopedic outpatient clinic. The US measurement of AHD was obtained consecutively in a neutral position and in a 60 degrees abduction position. A total of 300 blinded measurements were taken. RESULT: In the neutral abduction group the intra- observer interclass correlation coefficient (ICC) was 0.94 for the experienced operator and 0.92 for the novice operator. The inter-observer ICC was 0.70 and the accuracy was 1.1 mm. In the 60 degrees abduction group, the intra-observer ICC was 0.90 for the experienced operator and 0.87 for the novice operator. The inter-observer ICC was 0.64 and the accuracy was 1.4 mm. All ICCs were significant at a level of p < 0.0001. CONCLUSION: The inaccuracy of the method was 1 mm regardless of the experience of the observer. US AHD measurement in patients with shoulder complaints is not as accurate as reported in healthy subjects. This may have important implications for the clinical use of this parameter.

Chromosome imbalances in syndromic hearing loss.

The cause of hearing impairment has not been elucidated in a large proportion of patients. We screened by 1-Mb array-based comparative genomic hybridization (aCGH) 29 individuals with syndromic hearing impairment whose clinical features were not typical of known disorders. Rare chromosomal copy number changes were detected in eight patients, four de novo imbalances and four inherited from a normal parent. The de novo alterations define candidate chromosome segments likely to harbor dosage-sensitive genes related to hearing impairment, namely 1q23.3-q25.2, 2q22q23, 6p25.3 and 11q13.2-q13.4. The rare imbalances also present in normal parents might be casually associated with hearing impairment, but its role as a predisposition gene remains a possibility. Our results show that syndromic deafness is frequently associated with chromosome microimbalances (14-27%), and the use of aCGH for defining disease etiology is recommended.

Children's hard-wired aversion to pure vegetable tastes. A 'failed' flavour-nutrient learning study.

Conditioning is an important mechanism for establishing food preferences. Although the basic principles for conditioning are well-known, less is known about the conditions under which this type of learning takes place. This paper aims to add to the knowledge of the essential conditions for flavour-nutrient learning with vegetable flavours. We describe a study which aimed to investigate whether flavour-nutrient learning is effective in increasing 7-8-year-old children's preference for vegetables. Their preference for, and consumption of, two different vegetable drinks was measured before and after a 14-day-conditioning period, using a within-subject design. Flavour-nutrient learning could not occur, due to insufficient consumption during the conditioning period: 2.4 g (S.D.=5.6) for the high energy (HE) drink and 3.0 g (S.D.=9.3) for the low energy (LE) drink. The high taste intensity may have caused the insufficient consumption. We hypothesize that the pure taste of vegetables in itself is not acceptable. Mixing vegetables with other foods may lead to gradual acceptance of vegetables through flavour-flavour and flavour-nutrient learning. Future flavour-nutrient learning studies with children should use less intense vegetable flavours.

Effect of moderate alcohol consumption on adipokines and insulin sensitivity in lean and overweight men: a diet intervention study.

OBJECTIVE: Moderate alcohol consumption is associated with a decreased risk of type II diabetes. This study investigates the effect of moderate alcohol consumption on adipokines and insulin sensitivity. SUBJECTS: Twenty healthy, lean (body mass index (BMI) 18.5-25 kg/m(2); n=11) or overweight (BMI>27 kg/m(2); n=9) men (18-25 years). METHODS: Three cans of beer (40 g alcohol) or alcohol-free beer daily during 3 weeks. RESULTS: Adiponectin and ghrelin concentrations increased (P<0.01) by 11 and 8%, while acylation-stimulating protein (ASP) concentrations decreased by 12% (P=0.04) after moderate alcohol consumption. Concentrations of leptin and resistin remained unchanged. Insulin sensitivity by an oral glucose tolerance test (OGTT) was not affected by moderate alcohol consumption, but 2 h glucose concentrations were lower (P=0.01) after beer (4.5+/-0.1 mmol/l) than alcohol-free beer (4.9+/-0.1 mmol/l). Both free fatty acids and glucagon concentrations showed a stronger increase (P<0.01) after 90 min during OGTT after beer than alcohol-free beer. Changes of adiponectin were positively correlated (r=0.69, P<0.001), and changes of leptin (r=-0.53, P=0.016) and ASP (r=-0.43, P=0.067) were negatively correlated with changes of insulin sensitivity index. All these results did not differ between lean and overweight men. CONCLUSIONS: Moderate alcohol consumption increased adiponectin and ghrelin, while it decreased ASP concentrations both in lean and overweight men. These changes are in line with the hypothesized improvement of insulin sensitivity, but did not affect insulin sensitivity within 3 weeks of moderate alcohol consumption.

Associations between dietary factors and markers of NAFLD in a general Dutch adult population.

BACKGROUND/OBJECTIVES: The objective of this sudy was to assess the relationship between dietary intake and fatty liver as scored by the validated Fatty Liver Index (FLI) in a large cross-sectional study among a general Dutch adult population. Diet is known to affect liver fat accumulation in humans. SUBJECTS/METHODS: 1128 men and women aged 20-70 years were included. Dietary intake was assessed using a validated semiquantitative food frequency questionnaire. FLI was derived from body mass index (BMI), waist circumference, triglycerides and gamma-glutamyltransferase. Associations were adjusted for energy intake, alcohol intake, age, sex, education, smoking and prevalence of hypertension and diabetes. RESULTS: In this population (mean age 53.0±11.4 years; BMI 25.9±4.0 kg/m2; FLI 35.0±27.7), the prevalence of fatty liver as indicated by an FLI>60 was 21.5%. Subjects in the highest FLI category were more likely to be male, older and less physically active. Total protein intake and animal protein intake were positively associated with the highest FLI score versus the lowest (odds ratio (OR) 1.25 per 1 en%, 95% confidence interval (CI) 1.15-1.37 and OR 1.27, 95% CI 1.17-1.38, respectively); for vegetable protein, an inverse association was observed (OR 0.81, 95% CI 0.69-0.94). A similar positive association with FLI was observed when carbohydrates and fat were iso-calorically exchanged for total and animal proteins. CONCLUSIONS: Subjects in the high FLI group consumed more protein, especially from animal origin, less carbohydrates and less dietary fibre. The presence of fatty liver was associated with a higher intake of animal protein and total fat, soft drinks and snacks.

Phytate intake and molar ratios of phytate to zinc, iron and calcium in the diets of people in China.

OBJECTIVE: To assess the phytate intake and molar ratios of phytate to calcium, iron and zinc in the diets of people in China. DESIGN: 2002 China Nationwide Nutrition and Health Survey is a cross-sectional nationwide representative survey on nutrition and health. The information on dietary intakes was collected using consecutive 3 days 24 h recall by trained interviewers. SUBJECTS: The data of 68 962 residents aged 2-101 years old from 132 counties were analyzed. RESULTS: The median daily dietary intake of phytate, calcium, iron and zinc were 1186, 338.1, 21.2 and 10.6 mg, respectively. Urban residents consumed less phytate (781 vs 1342 mg/day), more calcium (374.5 vs 324.1 mg/day) and comparable amounts of iron (21.1 vs 21.2 mg/day) and zinc (10.6 vs 10.6 mg/day) than their rural counterparts. A wide variation in phytate intake among residents from six areas was found, ranging from 648 to 1433 mg/day. The median molar ratios of phytate to calcium, iron, zinc and phytate x calcium/zinc were 0.22, 4.88, 11.1 and 89.0, respectively, with a large variation between urban and rural areas. The phytate:zinc molar ratios ranged from 6.2 to 14.2, whereas the phytate x calcium/zinc molar ratios were from 63.7 to 107.2. The proportion of subjects with ratios above the critical values of phytate to iron, phytate to calcium, phytate to zinc and phytate x calcium/zinc were 95.4, 43.7, 23.1 and 8.7%, respectively. All the phytate/mineral ratios of rural residents were higher than that of their urban counterparts. CONCLUSIONS: The dietary phytate intake of people in China was higher than those in Western developed countries and lower than those in developing countries. Phytate may impair the bioavailability of iron, calcium and zinc in the diets of people in China.

Decreased cellular uptake and metabolism in Allan-Herndon-Dudley syndrome (AHDS) due to a novel mutation in the MCT8 thyroid hormone transporter.

We report a novel 1 bp deletion (c.1834delC) in the MCT8 gene in a large Brazilian family with Allan-Herndon-Dudley syndrome (AHDS), an X linked condition characterised by severe mental retardation and neurological dysfunction. The c.1834delC segregates with the disease in this family and it was not present in 100 control chromosomes, further confirming its pathogenicity. This mutation causes a frameshift and the inclusion of 64 additional amino acids in the C-terminal region of the protein. Pathogenic mutations in the MCT8 gene, which encodes a thyroid hormone transporter, results in elevated serum triiodothyronine (T3) levels, which were confirmed in four affected males of this family, while normal levels were found among obligate carriers. Through in vitro functional assays, we showed that this mutation decreases cellular T3 uptake and intracellular T3 metabolism. Therefore, the severe neurological defects present in the patients are due not only to deficiency of intracellular T3, but also to altered metabolism of T3 in central neurones. In addition, the severe muscle hypoplasia observed in most AHDS patients may be a consequence of high serum T3 levels.

Alcohol, smoking, and physical activity related to respiratory infections in elderly people.

OBJECTIVE: Elderly people show an increased risk of acute respiratory infections and their complications. This increased susceptibility may be the result of immunosenescence. If lifestyle factors could influence the risk of the infections, this could result in great public health relevance. We investigated the relation between alcohol consumption, smoking, and physical activity with acute respiratory infections. DESIGN: Prospective observational analysis. SETTING: The study took place between September 1998 - June 2000, in the Wageningen area of The Netherlands. PARTICIPANTS: In total 652 relatively healthy elderly people participated. Participants were noninstitutionalized and 60 years and older. MEASUREMENTS: The lifestyle factors were assessed at baseline by means of standardized and validated questionnaires in the participants. Self-reported respiratory infections were assessed from 1998-2000 by nurse telephone contact, and home visits, and were evaluated by microbiological tests in a subset. RESULTS: We detected 1024 acute respiratory infections among 443 participants, the overall incidence rate (IR) was 1.6 infections per person per year. IR ratio (95% confidence interval) of the infections was 1.31 (1.01, 1.70) for occasional (superior 0 glasses/day < 1), 1.22 (0.92, 1.64) for light (1 < glasses/day < 3 (men) and 1< glasses/day < 2 (women)), and 1.33 (1.04, 1.83) at moderate/heavy (superior 3 (men) or superior 2 (women) glasses/day) alcohol consumption after adjustment for age and sex. Alcohol intake was not related to illness severity. Smoking and physical activity were not related to the incidence and severity of the infections. All results remained unaltered after adjustment for lifestyle factors and for other potential risk factors for respiratory infections. CONCLUSION: Our findings suggest that only alcohol intake may be unfavorably associated with the frequency of acute respiratory infections in apparently healthy elderly people. Until our results are confirmed in trials, it is not warranted to recommend elderly people to change their habits of life, such as alcohol consumption, smoking and physical activity in order to reduce the risk of acute respiratory infections.

Whole-genome array-CGH screening in undiagnosed syndromic patients: old syndromes revisited and new alterations.

We report array-CGH screening of 95 syndromic patients with normal G-banded karyotypes and at least one of the following features: mental retardation, heart defects, deafness, obesity, craniofacial dysmorphisms or urogenital tract malformations. Chromosome imbalances not previously detected in normal controls were found in 30 patients (31%) and at least 16 of them (17%) seem to be causally related to the abnormal phenotypes. Eight of the causative imbalances had not been described previously and pointed to new chromosome regions and candidate genes for specific phenotypes, including a connective tissue disease locus on 2p16.3, another for obesity on 7q22.1-->q22.3, and a candidate gene for the 3q29 deletion syndrome manifestations. The other causative alterations had already been associated with well-defined phenotypes including Sotos syndrome, and the 1p36 and 22q11.21 microdeletion syndromes. However, the clinical features of these latter patients were either not typical or specific enough to allow diagnosis before detection of chromosome imbalances. For instance, three patients with overlapping deletions in 22q11.21 were ascertained through entirely different clinical features, i.e., heart defect, utero-vaginal aplasia, and mental retardation associated with psychotic disease. Our results demonstrate that ascertainment through whole-genome screening of syndromic patients by array-CGH leads not only to the description of new syndromes, but also to the recognition of a broader spectrum of features for already described syndromes. Furthermore, on the technical side, we have significantly reduced the amount of reagents used and costs involved in the array-CGH protocol, without evident reduction in efficiency, bringing the method more within reach of centers with limited budgets.

Blood pressure response to calcium supplementation: a meta-analysis of randomized controlled trials.

Calcium plays a role in blood pressure (BP) regulation, but the importance of supplemental calcium intake for the prevention of hypertension is still debated. We conducted a meta-analysis of randomized controlled trials to determine the effect of calcium supplementation on BP. A systematic search for randomized trials of calcium supplementation and BP in non-pregnant subjects was performed in Medline from 1966 to June 2003. Seventy-one trials were identified, 40 of which met the criteria for meta-analysis (total of 2492 subjects). Two persons independently extracted data from original publications on changes in calcium intake and BP. In addition, data were collected on subjects' characteristics, that is, age, gender, initial BP and initial calcium intake. A random effects model was used to obtain the effect of calcium supplementation on BP, overall and in predefined population subgroups. Calcium supplementation (mean daily dose: 1200 mg) reduced systolic BP by -1.86 mm Hg (95% confidence interval: -2.91 to -0.81) and diastolic BP by -0.99 mm Hg (-1.61 to -0.37). In people with a relatively low calcium intake (< or =800 mg per day) somewhat larger BP estimates were obtained, that is, -2.63 (-4.03 to -1.24) for systolic BP and -1.30 (-2.13 to -0.47) for diastolic BP. Our study suggests that an adequate intake of calcium should be recommended for the prevention of hypertension. More research on BP in people with calcium-deficient diets is warranted.