Clinical and course characteristics of depression and all-cause mortality: A prospective population-based study.

BACKGROUND: Given the large heterogeneity of depressive disorders (DD), studying depression characteristics according to clinical manifestations and course is a more promising approach than studying depression as a whole. The purpose of this study was to determine the association between clinical and course characteristics of DD and incident all-cause mortality. METHODS: CoLaus|PsyCoLaus is a prospective cohort study (mean follow-up duration=5.2 years) including 35-66 year-old randomly selected residents of an urban area in Switzerland. A total of 3668 subjects (mean age 50.9 years, 53.0% women) underwent physical and psychiatric baseline evaluations and had a known vital status at follow-up (98.8% of the baseline sample). Clinical (diagnostic severity, atypical features) and course characteristics (recency, recurrence, duration, onset) of DD according to the DSM-5 were elicited using a semi-structured interview. RESULTS: Compared to participants who had never experienced DD, participants with current but not remitted DD were more than three times as likely to die (Hazard Ratio: 3.2, 95% CI: 1.1-10.0) after adjustment for socio-demographic and lifestyle characteristics, comorbid anxiety disorders, antidepressant use, and cardiovascular risk factors and diseases. There was no evidence for associations between other depression characteristics and all-cause mortality. LIMITATIONS: The small proportion of deceased subjects impeded statistical analyses of cause-specific mortality. CONCLUSIONS: A current but not remitted DD is a strong predictor of all-cause mortality, independently of cardiovascular or lifestyle factors, which suggests that the effect of depression on mortality diminishes after remission and further emphasizes the need to adequately treat current depressive episodes.

An analysis of protocols and publications suggested that most discontinuations of clinical trials were not based on preplanned interim analyses or stopping rules.

OBJECTIVES: To investigate the frequency of interim analyses, stopping rules, and data safety and monitoring boards (DSMBs) in protocols of randomized controlled trials (RCTs); to examine these features across different reasons for trial discontinuation; and to identify discrepancies in reporting between protocols and publications. STUDY DESIGN AND SETTING: We used data from a cohort of RCT protocols approved between 2000 and 2003 by six research ethics committees in Switzerland, Germany, and Canada. RESULTS: Of 894 RCT protocols, 289 prespecified interim analyses (32.3%), 153 stopping rules (17.1%), and 257 DSMBs (28.7%). Overall, 249 of 894 RCTs (27.9%) were prematurely discontinued; mostly due to reasons such as poor recruitment, administrative reasons, or unexpected harm. Forty-six of 249 RCTs (18.4%) were discontinued due to early benefit or futility; of those, 37 (80.4%) were stopped outside a formal interim analysis or stopping rule. Of 515 published RCTs, there were discrepancies between protocols and publications for interim analyses (21.1%), stopping rules (14.4%), and DSMBs (19.6%). CONCLUSION: Two-thirds of RCT protocols did not consider interim analyses, stopping rules, or DSMBs. Most RCTs discontinued for early benefit or futility were stopped without a prespecified mechanism. When assessing trial manuscripts, journals should require access to the protocol.

Laboratory automation in clinical bacteriology: what system to choose?

Automation was introduced many years ago in several diagnostic disciplines such as chemistry, haematology and molecular biology. The first laboratory automation system for clinical bacteriology was released in 2006, and it rapidly proved its value by increasing productivity, allowing a continuous increase in sample volumes despite limited budgets and personnel shortages. Today, two major manufacturers, BD Kiestra and Copan, are commercializing partial or complete laboratory automation systems for bacteriology. The laboratory automation systems are rapidly evolving to provide improved hardware and software solutions to optimize laboratory efficiency. However, the complex parameters of the laboratory and automation systems must be considered to determine the best system for each given laboratory. We address several topics on laboratory automation that may help clinical bacteriologists to understand the particularities and operative modalities of the different systems. We present (a) a comparison of the engineering and technical features of the various elements composing the two different automated systems currently available, (b) the system workflows of partial and complete laboratory automation, which define the basis for laboratory reorganization required to optimize system efficiency, (c) the concept of digital imaging and telebacteriology, (d) the connectivity of laboratory automation to the laboratory information system, (e) the general advantages and disadvantages as well as the expected impacts provided by laboratory automation and (f) the laboratory data required to conduct a workflow assessment to determine the best configuration of an automated system for the laboratory activities and specificities.

Systemic lupus erythematosus in the elderly: Clinical and immunological characteristics.

Systemic lupus erythematosus (SLE) predominantly affects young women in their 20s. In 40 out of 250 (16%) patients with SLE seen in our hospital disease onset occurred after the age of 50. The interval between the time of onset and diagnosis was five years in this older group compared with three years in the younger group. Arthritis, as a first symptom, was less common in the older onset group. During the follow up a lower incidence of arthritis, malar rash, photosensitivity, and nephropathy was found in the older onset group. In contrast, this group showed an increased incidence of myositis. High titres of anti-dsDNA tended to occur less often and the incidence of anti-Ro antibodies was lower in the older onset group. These features seem to distinguish patients with older onset SLE as a particular subset.

Systemic lupus erythematosus in men: clinical and immunological characteristics.

Although systemic lupus erythematosus (SLE) has traditionally been considered a disease of women, men may also be affected. Thirty of 261 patients (12%) with SLE seen in this hospital were men. Arthritis was less common as a first symptom in the men, although this group of patients had discoid lesions and serositis more often than the women. During the follow up a lower incidence of arthritis and malar rash and a higher incidence of other skin complications including discoid lesions and subcutaneous lupus erythematosus was found in the men. The incidence of nephropathy, neurological disease, thrombocytopenia, vasculitis, and serositis, was similar in the two groups. No significant immunological differences were found between men and women. These features indicate that several gender associated clinical differences may be present in patients with SLE.

Clinical and molecuar characterization of Brazilian patients with growth hormone gene deletions

Genomic DNA from 23 patients with isolated growth hormone (GH) deficiency (12 males and 11 females: heights -4.9 ± 1.4 SDS) was screened for GH gene deletions by restriction endonuclease analysis of polymerase chain reaction amplification products. Three unrelated patients had typical features of severe GH deficiency and deletions (6.7 kb in two and 7.6 kb in one) of the GH gene. The two patients with 6.7-kb deletions developed growth-attenuating anti-GH antibodies whereas the patient with the 7.6-kb deletion continued to grow with GH replacement therapy. Our finding that 3/23 (~13%) Brazilian subjects had GH gene deletions agrees with previous studies of severe isolated GH deficiency subjects in other populations. Two of three subjects (67%) with deletions developed blocking antibodies despite administration of exogenous GH at low doses. Interestingly, only 1/10 of cases with affected relatives or parental consanguinity had GH-1 gene deletions

Acute leukemias in Piauí: comparison with features observed in other regions of Brazil

Differences in age and sex distribution as well as FAB (French-American-British classification) types have been reported for acute leukemias in several countries. We studied the demographics and response to treatment of patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) between 1989 and 2000 in Teresina, Piauí, and compared these results with reports from Brazil and other countries. Complete data concerning 345 patients (230 ALL, 115 AML) were reviewed. AML occurred predominantly in adults (77%), with a median age of 34 years, similar to that found in the southeast of Brazil but lower than the median age in the United States and Europe (52 years). FAB distribution was similar in children and adults and FAB-M2 was the most common type, as also found in Japan. The high frequency of FAB-M3 described in most Brazilian studies and for Hispanics in the United States was not observed. Overall survival for adults was 40%, similar to other studies in Brazil. A high mortality rate was observed during induction. No clinical or hematological parameter influenced survival in the Cox model. ALL presented the characteristic peak of incidence between 2-8 years. Most of the cases were CD10+ pre-B ALL. In 25%, abnormal expression of myeloid antigens was observed. Only 10% of the patients were older than 30 years. Overall survival was better for children. Age and leukocyte count were independent prognostic factors. These data demonstrate that, although there are regional peculiarities, the application of standardized treatments and good supportive care make it possible to achieve results observed in other countries for the same chemotherapy protocols.

Oculo-facio-cardio-dental syndrome in three succeeding generations: genotypic data and phenotypic features

Oculo-facio-cardio-dental (OFCD) syndrome is a rare X-linked disorder mainly manifesting in females. Patients show ocular, facial, cardiac, and dental abnormalities. OFCD syndrome is caused by heterozygous mutations in the BCOR gene, located in Xp11.4, encoding the BCL6 co-repressor. We report a Croatian family with four female members (grandmother, mother and monozygotic female twins) diagnosed with OFCD syndrome who carry the novel BCOR mutation c.4438C>T (p.R1480*). They present high intrafamilial phenotypic variability with special regard to cardiac defect and cataract that showed more severe disease expression in successive generations. Clinical and radiographic examination of the mother of the twins revealed a talon cusp involving the permanent maxillary right central incisor. This is the first known report of a talon cusp in OFCD syndrome with a novel mutation in the BCOR gene.

Correlation of cadherin-17 protein expression with clinicopathological features and prognosis of patients with sporadic gastric cancer

This study aimed to explore the correlations between cadherin-17 (CDH17) protein expression and the clinicopathological features and prognosis of patients with sporadic gastric cancer (GC). Nine relevant studies of 1,960 patients were identified using electronic database searches supplemented with a manual search in strict accordance with inclusion and exclusion criteria. Statistical analyses were conducted using STATA 12.0 statistical software. Relative risks and 95% confidence intervals were determined, and Z test was used to measure the significance of the overall effect size. A total of nine eligible cohort studies were included in this meta-analysis. The expression of CDH17 in patients with diffuse GC was significantly higher than in those with intestinal-type GC. Moreover, the tumor depth of invasion differed significantly between patients with positive CDH17 (CDH17+) and negative CDH17 (CDH17-) GC. However, there were no significant differences between CDH17+ and CDH17- GC patients with respect to tumor node metastasis clinical stages, histological grades, or lymph node metastasis. Despite the differences in invasive depth, there was no significant difference in 5-year survival rates between CDH17+ and CDH17- GC patients. Our meta-analysis provides evidence that CDH17 protein expression may be associated with the development of GC, suggesting that CDH17 is an important biomarker that could be useful for the early diagnosis of GC. However, CDH17 levels do not appear to impact overall survival.

Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features

The recent identification of multiple dominant mutations in the gene encoding β-catenin in both humans and mice has enabled exploration of the molecular and cellular basis of β-catenin function in cognitive impairment. In humans, β-catenin mutations that cause a spectrum of neurodevelopmental disorders have been identified. We identified de novo β-catenin mutations in patients with intellectual disability, carefully characterized their phenotypes, and were able to define a recognizable intellectual disability syndrome. In parallel, characterization of a chemically mutagenized mouse line that displays features similar to those of human patients with β-catenin mutations enabled us to investigate the consequences of β-catenin dysfunction through development and into adulthood. The mouse mutant, designated batface (Bfc), carries a Thr653Lys substitution in the C-terminal armadillo repeat of β-catenin and displayed a reduced affinity for membrane-associated cadherins. In association with this decreased cadherin interaction, we found that the mutation results in decreased intrahemispheric connections, with deficits in dendritic branching, long-term potentiation, and cognitive function. Our study provides in vivo evidence that dominant mutations in β-catenin underlie losses in its adhesion-related functions, which leads to severe consequences, including intellectual disability, childhood hypotonia, progressive spasticity of lower limbs, and abnormal craniofacial features in adults

Epstein-Barr virus: clinical and epidemiological revisits and genetic basis of oncogenesis

Epstein-Barr virus (EBV) is classified as a member in the order herpesvirales, family herpesviridae, subfamily gammaherpesvirinae and the genus lymphocytovirus. The virus is an exclusively human pathogen and thus also termed as human herpesvirus 4 (HHV4). It was the first oncogenic virus recognized and has been incriminated in the causation of tumors of both lymphatic and epithelial nature. It was reported in some previous studies that 95% of the population worldwide are serologically positive to the virus. Clinically, EBV primary infection is almost silent, persisting as a life-long asymptomatic latent infection in B cells although it may be responsible for a transient clinical syndrome called infectious mononucleosis. Following reactivation of the virus from latency due to immunocompromised status, EBV was found to be associated with several tumors. EBV linked to oncogenesis as detected in lymphoid tumors such as Burkitt's lymphoma (BL), Hodgkin's disease (HD), post-transplant lymphoproliferative disorders (PTLD) and T-cell lymphomas (e.g. Peripheral T-cell lymphomas; PTCL and Anaplastic large cell lymphomas; ALCL). It is also linked to epithelial tumors such as nasopharyngeal carcinoma (NPC), gastric carcinomas and oral hairy leukoplakia (OHL). In vitro, EBV many studies have demonstrated its ability to transform B cells into lymphoblastoid cell lines (LCLs). Despite these malignancies showing different clinical and epidemiological patterns when studied, genetic studies have suggested that these EBV- associated transformations were characterized generally by low level of virus gene expression with only the latent virus proteins (LVPs) upregulated in both tumors and LCLs. In this review, we summarize some clinical and epidemiological features of EBV- associated tumors. We also discuss how EBV latent genes may lead to oncogenesis in the different clinical malignancies

In vitro and clinical evaluation of specific dentifrices for complete denture hygiene

To study the physical properties of two experimental dentifrices for complete denture hygiene, their effect on denture biofilm removal and antimicrobial properties by means of a clinical trial. The experimental dentifrices comprised two compositions. One was based on the addition of 1% chloramine T (D1) and the other on the presence of 0.01% fluorosurfactant (D2). Measurements of density, pH, consistency, rheological features and abrasiveness were conducted. Sixty complete denture wearers were randomly assigned to three groups and were instructed to brush their dentures with a specific toothbrush: (1) Water (control); (2) D1; or (3) D2. Each method was used for 21 days. Denture biofilm was disclosed by a 1% neutral red solution and quantified by means of digital photos taken from the internal surface. Microbiological assessment was conducted to quantify Candida sp. and mutans streptococci. Data were evaluated by one-way anova and Tukey HSD, or Kruskal-Wallis (alpha = 0.05). Both dentifrices decreased biofilm coverage when compared with the control group. D1 was the most efficacious treatment to reduce mutans streptococci, whereas D2 showed an intermediate outcome (anova, p < 0.040). No treatment influenced Candida albicans or non-albicans species (Kruskal-Wallis, p = 0.163 and 0.746, respectively). It can be concluded that brushing complete dentures with the experimental dentifrices tested could be effective for the removal of denture biofilm.

Clinical evaluation and COL2A1 gene analysis in 21 Brazilian families with Stickler syndrome: Identification of novel mutations, further genotype/phenotype correlation, and its implications for the diagnosis

We present clinical and molecular evaluation from a large cohort of patients with Stickler syndrome: 78 individuals from 21 unrelated Brazilian families. The patients were selected in a Hospital with a craniofacial dysmorphology assistance service and clinical diagnosis was based on the presence of cleft palate associated to facial and ocular anomalies of Stickler syndrome. Analysis of COL2A1 gene revealed 9 novel and 4 previously described pathogenic mutations. Except for the mutation c.556G>T (p.Gly186X), all the others were located in the triple helical domain. We did not find genotype/phenotype correlation in relation to type and position of the mutation in the triple helical domain. However, a significantly higher proportion of myopia in patients with mutations located in this domain was observed in relation to those with the mutation in the non-tripe helical domain (c.556G>T; P < 0.04). A trend towards a higher prevalence of glaucoma, although not statistically significant, was observed in the presence of the mutation c.556G>T. It is possible. that this mutation alters the splicing of the mRNA instead of only creating a premature stop codon and therefore it can lead to protein products of different ocular effects. One novel DNA variation (c.1266+7G>C) occurs near a splice site and it was observed to co-segregate with the phenotype in one of the two families with this DNA variation. As in silico analysis predicted that the c.1266+7G>C DNA variation can affect the efficiency of the splicing, we still cannot rule it out as non-pathogenic. Our study also showed that ascertainment through cleft palate associated to other craniofacial signs can be very efficient for identification of Stickler syndrome patients. Still, high frequency of familial cases and high frequency of underdevelopment of distal lateral tibial epiphyses observed in our patients suggested that the inclusion of this information can improve the clinical diagnosis of Stickler syndrome. (C) 2008 Elsevier Masson SAS. All rights reserved.

Consensus Statement: Chromosomal Microarray Is a First-Tier Clinical Diagnostic Test for Individuals with Developmental Disabilities or Congenital Anomalies

Chromosomal microarray (CMA) is increasingly utilized for genetic testing of individuals with unexplained developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), or multiple congenital anomalies (MCA). Performing CMA and G-banded karyotyping on every patient substantially increases the total cost of genetic testing. The International Standard Cytogenomic Array (ISCA) Consortium held two international workshops and conducted a literature review of 33 studies, including 21,698 patients tested by CMA. We provide an evidence-based summary of clinical cytogenetic testing comparing CMA to G-banded karyotyping with respect to technical advantages and limitations, diagnostic yield for various types of chromosomal aberrations, and issues that affect test interpretation. CMA offers a much higher diagnostic yield (15%-20%) for genetic testing of individuals with unexplained DD/ID, ASD, or MCA than a G-banded karyotype (similar to 3%, excluding Down syndrome and other recognizable chromosomal syndromes), primarily because of its higher sensitivity for submicroscopic deletions and duplications. Truly balanced rearrangements and low-level mosaicism are generally not detectable by arrays, but these are relatively infrequent causes of abnormal phenotypes in this population (<1%). Available evidence strongly supports the use of CMA in place of G-banded karyotyping as the first-tier cytogenetic diagnostic test for patients with DD/ID, ASD, or MCA. G-banded karyotype analysis should be reserved for patients with obvious chromosomal syndromes (e.g., Down syndrome), a family history of chromosomal rearrangement, or a history of multiple miscarriages.

Clinical and molecular delineation of the 17q21.31 microdeletion syndrome

Background: The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high resolution genome analyses in patients with unexplained mental retardation. Aim: We report the molecular and/or clinical characterisation of 22 individuals with the 17q21.31 microdeletion syndrome. Results: We estimate the prevalence of the syndrome to be 1 in 16 000 and show that it is highly underdiagnosed. Extensive clinical examination reveals that developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour are the most characteristic features. Other clinically important features include epilepsy, heart defects and kidney/urologic anomalies. Using high resolution oligonucleotide arrays we narrow the 17q21.31 critical region to a 424 kb genomic segment (chr17: 41046729-41470954, hg17) encompassing at least six genes, among which is the gene encoding microtubule associated protein tau (MAPT). Mutation screening of MAPT in 122 individuals with a phenotype suggestive of 17q21.31 deletion carriers, but who do not carry the recurrent deletion, failed to identify any disease associated variants. In five deletion carriers we identify a <500 bp rearrangement hotspot at the proximal breakpoint contained within an L2 LINE motif and show that in every case examined the parent originating the deletion carries a common 900 kb 17q21.31 inversion polymorphism, indicating that this inversion is a necessary factor for deletion to occur (p< 10(25)). Conclusion: Our data establish the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognisable genomic disorder.