A pharmacogenetic investigation of intravenous furosemide in decompensated heart failure: a meta-analysis of three clinical trials.

We conducted a meta-analysis of pharmacogenomic substudies of three randomized trials conducted in patients with decompensated heart failure (HF) that were led by National Heart Lung and Blood Institute (NHLBI)-funded HF Network to test the hypothesis that candidate genes modulate net fluid loss and weight change in patients with decompensated HF treated with a furosemide-based diuretic regimen. Although none of the genetic variants previously shown to modulate the effects of loop diuretics in healthy individuals were associated with net fluid loss after 72 h of treatment, a set of rare variants in the APOL1 gene, which codes for apolipoprotein L1 (P=0.0005 in the random effects model), was associated with this end point. Moreover, a common variant in the multidrug resistance protein-4 coding gene (ABCC4, rs17268282) was associated with weight loss with furosemide use (P=0.0001). Our results suggest that both common and rare genetic variants modulate the response to a furosemide-based diuretic regimen in patients with decompensated HF.

Methylomic changes during conversion to psychosis.

The onset of psychosis is the consequence of complex interactions between genetic vulnerability to psychosis and response to environmental and/or maturational changes. Epigenetics is hypothesized to mediate the interplay between genes and environment leading to the onset of psychosis. We believe we performed the first longitudinal prospective study of genomic DNA methylation during psychotic transition in help-seeking young individuals referred to a specialized outpatient unit for early detection of psychosis and enrolled in a 1-year follow-up. We used Infinium HumanMethylation450 BeadChip array after bisulfite conversion and analyzed longitudinal variations in methylation at 411 947 cytosine-phosphate-guanine (CpG) sites. Conversion to psychosis was associated with specific methylation changes. Changes in DNA methylation were significantly different between converters and non-converters in two regions: one located in 1q21.1 and a cluster of six CpG located in GSTM5 gene promoter. Methylation data were confirmed by pyrosequencing in the same population. The 100 top CpGs associated with conversion to psychosis were subjected to exploratory analyses regarding the related gene networks and their capacity to distinguish between converters and non-converters. Cluster analysis showed that the top CpG sites correctly distinguished between converters and non-converters. In this first study of methylation during conversion to psychosis, we found that alterations preferentially occurred in gene promoters and pathways relevant for psychosis, including oxidative stress regulation, axon guidance and inflammatory pathways. Although independent replications are warranted to reach definitive conclusions, these results already support that longitudinal variations in DNA methylation may reflect the biological mechanisms that precipitate some prodromal individuals into full-blown psychosis, under the influence of environmental factors and maturational processes at adolescence.

[Congenital myasthenic syndromes in childhood: Drug therapeutic strategies]. / Syndromes myasthéniques congénitaux de l'enfant : stratégies thérapeutiques médicamenteuses.

Congenital myasthenia syndromes (CMS) are a group of genetic disorders responsible for neuromuscular junction dysfunction. Usually beginning before 2 years of age, they are revealed by fatigability and muscle weakness, especially after stress, and often prevent the child's normal development. Over recent years, major advances in therapeutic strategies have been made following the discovery of numerous mutations responsible for CMS and the understanding of their pathogenic role. Here we report a pediatric CMS case caused by a mutation of the ɛ subunit of the acetylcholine receptor. The initial treatment with acetylcholinesterase inhibitor rapidly showed its limits in terms of both effectiveness and tolerance. The association with 3.4 diaminopyridine (DAP), a new drug available to treat such conditions, has transformed the motor outcome of our patient and allowed psychomotor development. In addition to 3.4 DAP, other molecules adapted to other types of CMS are now available. Three major groups of CMS can be distinguished depending on whether the deficit is at the presynaptic, synaptic, or postsynaptic level of the neuromuscular junction. Depending on the type of CMS, therapeutic management may include acetylcholinesterase inhibitors, 3.4 DAP, fluoxetine, quinidine sulfate, or ephedrine. With the case report, we provide a recent review of the literature on such new therapeutic options, their indications and restrictions, their mechanism of action, and prescription modalities. Knowing the precise CMS type and the appropriate therapeutic options available is essential for the proper management of such chronic and severe but relatively treatable childhood disorders.

CCM3 Mutations Are Associated with Early-Onset Cerebral Hemorrhage and Multiple Meningiomas.

Mutations of CCM3/PDCD10 cause 10-15% of hereditary cerebral cavernous malformations. The phenotypic characterization of CCM3-mutated patients has been hampered by the limited number of patients harboring a mutation in this gene. This is the first report on molecular and clinical features of a large cohort of CCM3 patients. Molecular screening for point mutations and deletions was used to identify 54 CCM3-mutated index patients. Age at referral and clinical onset, type of inaugural events and presence of extra-axial lesions were investigated in these 54 index patients and 22 of their mutated relatives. Mean age at clinical onset was 23.0 ± 16 years. Clinical onset occurred before 10 years in 26% of the patients, and cerebral hemorrhage was the initial presentation in 72% of these patients. Multiple extra-axial, dural-based lesions were detected in 7 unrelated patients. These lesions proved to be meningiomas in 3 patients who underwent neurosurgery and pathological examination. This 'multiple meningiomas' phenotype is not associated with a specific CCM3 mutation. Hence, CCM3 mutations are associated with a high risk of early-onset cerebral hemorrhage and with the presence of multiple meningiomas.

Integration of visual and proprioceptive afferents in kinesthesia.

Proprioceptive signals are of prime importance in kinesthesia. However, in conditions of visuo-proprioceptive conflicts, strong visual-evoked biases can be observed. In three experiments, we parsed the interaction between visual and proprioceptive afferents using the 'mirror box' paradigm. Participants' left arm, the image of which was reflected in a mirror, was passively moved into flexion/extension or remained static. In Experiment 1 proprioceptive afferents of the unseen static right arm were masked with diffuse arm vibration. In Experiments 2 and 3, afferent signals were enhanced by muscle vibration of biceps or triceps stretch receptors. Illusory arm movements were evaluated with subjective reports and matching adjustments. Results revealed that participants did not experience kinesthetic illusions when the mirror reflected the image of a static arm while proprioceptive afferents conveyed signals of a moving arm (Experiment 2). In this specific case, vision apparently contributed much more strongly to the final percept than proprioceptive signals. However, in most circumstances, the percept reflected integration of both afferent signals (Experiments 1-3). For instance, when both sensory channels conveyed signals of arm displacement but in the opposite direction, kinesthetic illusions occurred but were either proprioceptively (vibration illusion) or visually driven (mirror illusion), according to individual sensorial preferences (Experiments 2 and 3). These results indicate that kinesthesia is the product of cooperative integration processes in which the final percept strongly depends on the experimental conditions as well as sensorial preferences. The observed changes in the relative contribution of each input across experimental conditions likely reflect reliability-dependent weights.

The influence of primary health care organizational models on patients' experience of care in different chronic disease situations.

OBJECTIVES: To examine the extent to which experience of care varies across chronic diseases, and to analyze the relationship of primary health care (PHC) organizational models with the experience of care reported by patients in different chronic disease situations. METHODS: We linked a population survey and a PHC organizational survey conducted in two regions of Quebec. We identified five groups of chronic diseases and contrasted these with a no-chronic-disease group. RESULTS: Accessibility of care is low for all chronic conditions and shows little variation across diseases. The contact and the coordination-integrated models are the most accessible, whereas the single-provider model is the least. Process and outcome indices of care experience are much higher than accessibility for all conditions and vary across diseases, with the highest being for cardiovascular-risk-factors and the lowest for respiratory diseases (for people aged 44 and under). However, as we move from risk factors to more severe chronic conditions, the coordination-integrated and community models are more likely to generate better process of care, highlighting the greater potential of these two models to meet the needs of more severely chronically ill individuals within the Canadian health care system.

Differential expression of SMAD3 transcripts is not regulated by cis-acting genetic elements but has a gender specificity.

As a key component of the transforming growth factor-beta (TGF-beta) pathway, SMAD3 plays an essential role in development and maintenance of self-tolerance. Furthermore, a recent study based on gene-expression profiling in donors of allogeneic hematopoietic cell grafts revealed that the level of expression of several components of the TGF-beta pathway can predict the occurrence of graft-versus-host disease (GVHD) in recipients. The gene with the best GVHD predictive accuracy was SMAD3: no recipients suffered from GVHD when their donor cells expressed high levels of SMAD3 transcripts. The present study had two specific aims: to validate differential expression of SMAD3 transcripts in an independent and larger cohort of subjects and to determine whether interindividual differences were dictated by cis-acting genetic elements. In a cohort of 397 subjects, we found that SMAD3 transcript levels varied over a sixfold range. Analyses of SMAD3 single nucleotide polymorphisms and of SMAD3 promoter methylation patterns provide compelling evidence that interindividual differences in SMAD3 transcript levels do not result from in-cis genetic variations. Of note, part of the variance in SMAD3 expression was gender related as women expressed lower levels of SMAD3 transcripts than men.

Telomere length is severely and similarly reduced in JAK2V617F-positive and -negative myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterized by chronic proliferation of hematopoietic progenitors. We studied the telomere length (TL) of 335 MPN patients and 93 gender- and age-matched controls using a quantitative PCR method (relative TL calculated as the ratio of the amount of telomere DNA vs single-copy DNA: T/S ratio). TL was markedly reduced in MPN patients compared with controls (T/S 0.561 vs 0.990, P<0.001). In JAK2V617F MPN patients, TL correlated inversely with allelic burden (P<0.001). Patients homozygous for the mutation (allelic burden 90-100%) had the shortest TL, even when compared with patients with lower allele burdens consistent with a dominant heterozygous population (allelic burden 55-65%) (T/S 0.367 vs 0.497, P=0.037). This suggests that the high degree of proliferation of the MPN clone reduces TL and suggests the possibility that TL shortening may be indicative of progressive genomic instability during MPN progression. The TL of JAK2V617F-negative MPN patients was similar to JAK2V617F-positive counterparts (T/S 0.527 vs 0.507, P=0.603), suggesting that the yet-to-be-discovered causative mutation(s) impact the mutated stem cell similarly to JAK2V617F, and that TL measurement may prove useful in the diagnostic workup of JAK2V617F-negative MPN.

An intraventricular clear cell meningioma revealed by an inflammatory syndrome in a male adult: a case report.

Intraventricular meningiomas are infrequent intracranial tumors. Clinical symptoms are mainly due to an increased intracranial pressure or a direct pressure on the surrounding brain structures. Inflammatory syndrome was described in some patients with chordoid meningiomas. Here we report a case of right intraventricular clear cell meningioma in a 50-year-old man who presented with fever, headache, and inflammatory syndrome. Clinical and biological normalization was rapidly obtained after tumor removal. Immunohistochemical examination showed tumor cells and lymphocytes positivity for the pyrogenic cytokine interleukin-6, with a same intensity. To our knowledge, this is the first case described in the literature concerning an adult man with an intraventricular clear cell meningioma associated with a systemic inflammatory syndrome.

A novel autosomal dominant restless legs syndrome locus maps to chromosome 20p13.

The authors investigated genetic factors contributing to restless legs syndrome (RLS) by performing a 10-cM genome-wide scan in a large French-Canadian pedigree. They detected an autosomal-dominant locus mapping to chromosome 20p13, with a maximum multipoint lod score of 3.86 at marker D20S849. This is the third reported autosomal-dominant locus for RLS and the first autosomal-dominant RLS locus in the French-Canadian population.

[Fatal toxic respiratory epitheliolysis. Subacute tracheo-bronchial desquamation in Stevens-Johnson syndrome]. / Epithéliolyse respiratoire toxique fatale. Desquamation suraiguë trachéo-bronchique lors d'un syndrome de Stevens-Johnson.

Acute bronchial mucosal sloughing related to Toxic Epidermal Necrolysis (Lyell syndrome) is widely reported in literature. On the contrary severe respiratory involvement is rare in post-infectious or toxic Epitheliolysis (Stevens-Johnson syndrome). There is no well-known predictive sign of bronchial epithelium involvement. An 18-year-old patient was admitted for Stevens-Johnson syndrome related to sulfasalazine (salazosulfapyridine). There were no respiratory signs. An acute respiratory failure occurred 36 hours after from admission due to an obstructive and desquamative necrosis of the tracheobronchial epithelium. We purpose that a fiberoptic laryngoscopy should be performed even in non-dyspneic patients suffering from Stevens-Johnson syndrome if hypersecretion is present. Fiberoptic bronchoscopy can be helpful in these cases.

Predictors of pretravel consultation in tourists from Quebec (Canada).

BACKGROUND: Although many tourists from Quebec (Canada) each year visit destinations at risk for infectious diseases, only a few of them seek travel health advice. To identify the determinants of travel health consultation, we conducted a study among Quebec's tourists visiting two popular sun destinations. METHODS: A conceptual model based on psychosocial determinants of human behavior was constructed. A cross-sectional survey was carried out, from January to April 1999, on two samples of travelers planning to visit Mexico and the Dominican Republic. One sample was composed of people who did not consult a travel clinic (cluster sampling in seven flights), and the other sample was one of clients of travel clinics (purposive selection of 13 specialized clinics located in Quebec). A 34-item self-administered bilingual questionnaire was distributed to travelers. Statistical analysis included a multivariate approach (logistic regression). RESULTS: A total of 2,242 travelers were surveyed (response rate in flight 75% and in clinics 99%). We present only results reported by French-speaking tourists: 1,152 who did not consult a travel clinic and were reached in flight, and 449 who were reached in clinics. Multivariate analyses indicated that travel agent recommendation was the most important predictor of consultation among travelers (OR 8.0, 95% CI 5.1-13), especially among those under 45 years of age and those who never sought pretravel consultation before (OR 21, 95% CI 11-41). Other important predictors were: traveling for the first time, traveling with children, previous consultation, perception about efficacy of immunization, risk perception, and information from travel agent, family doctor, and pharmacist. CONCLUSIONS: Despite its limitations, this study provides data that should help improve public health interventions aimed at encouraging travelers to get a pretravel consultation.

Quality measures for mental health care: results from a national inventory.

The National Inventory of Mental Health Quality Measures was funded by the Agency for Healthcare Research and Quality to (1) inventory process measures for assessing the quality of mental health care; (2) identify clinical, administrative, and quality domains where measures have been developed; and (3) identify areas where further research and development is needed. Among the 86 measures identified, most evaluated treatment of major mental disorders, for example, schizophrenia (24 percent) and major depression (21 percent). A small proportion focused on children (8 percent) or the elderly (9 percent). Domains of quality included treatment appropriateness (65 percent), continuity (26 percent), access (26 percent), coordination (13 percent), detection (12 percent), and prevention (6 percent). Few measures were evaluated for reliability (12 percent) or validity (3 percent). Measures imposing a lower burden were more likely to be in use (chi 2 = 4.41, p = .036). Further measures are needed to assess care for several priority clinical and demographic groups. Research should focus on measure validity, reliability, and implementation costs. In order to foster quality improvement activities and use of common measures and specifications for mental health care, the inventory of quality measures will be made available at www.challiance.org/cqaimh.

Human motor units in health and disease.

Recent advances in clinical neurophysiology have made it possible to non-invasively stimulate single motor axons and determine the physiological characteristics of the associated motor units. Some motor units lend themselves to longitudinal studies of their electrical and contractile characteristics. The former include the conduction velocities of their motor axons and the sizes and shapes of their motor unit action potentials and the latter such contractile characteristics of the motor unit as their contractile speeds, twitch and tetanic tensions, and resistance to fatigue. The feasibility of serially examining the same motor unit has made it possible to study the responses of single motor units to conditioning as well as changes in the responses of single motor units to diseases such as amyotrophic lateral sclerosis. The non-invasive character of these approaches offers an attractive means of studying the responses of single human cells, in these cases motor neurons, in health and disease.

Spontaneous mutation in lacI transgenic mice: a comparison of tissues.

The nature of spontaneous mutations in the lacI transgene of Big Blue mice was determined in selected tissues. The mutant frequencies ranged from 2.5 x 10(-5) to 7.1 x 10(-5) for liver, spleen, bladder, stomach, kidney, bone marrow, lung and skin. We also determined the DNA sequence alterations in the mutants recovered from these tissues. In all tissues the predominant class of mutations was G:C-->A:T transitions, most of which occurred at 5'-CpG-3' dinucleotide sequences. Bladder, kidney and skin display the highest contribution of G:C-->A:T transitions. The second most common class of mutations was G:C-->T:A transversions. All other base substitution classes contributed < 10% each. Of the non-substitution events, the loss of a single base pair was the most frequently occurring event (< 10%). The similarity of mutational spectra (in terms of kinds of mutations detected by the lacI transgenic system) in all tissues examined supports the idea that similar mutational pathways function in these tissues in the absence of chemical or physical stimulus.

Vitamin D3 enhances mood in healthy subjects during winter.

Mood changes synchronised to the seasons exist on a continuum between individuals, with anxiety and depression increasing during the winter months. An extreme form of seasonality is manifested as the clinical syndrome of seasonal affective disorder (SAD) with carbohydrate craving, hypersomnia, lethargy, and changes in circadian rhythms also evident. It has been suggested that seasonality and the symptoms of SAD may be due to changing levels of vitamin D3, the hormone of sunlight, leading to changes in brain serotonin. Forty-four healthy subjects were given 400 IU, 800 IU, or no vitamin D3 for 5 days during late winter in a random double-blind study. Results on a self-report measure showed that vitamin D3 significantly enhanced positive affect and there was some evidence of a reduction in negative affect. Results are discussed in terms of their implications for seasonality, SAD, serotonin, food preference, sleep, and circadian rhythms.

Analysis of allele distribution for six short tandem repeat loci in the French Canadian population of Québec.

Short tandem repeat (STR) loci represent a rich source of highly polymorphic markers in the human genome which are useful for the purposes of forensic identification and determination of biological relatedness of individuals. Here, as a part of an ongoing extensive study, we report the analysis of a multilocus genotype survey of 642 to 870 chromosomes in the French Canadian Caucasian population of Québec at six STR loci. The loci HUMCSF1PO, HUMTPOX, HUMTH01, HUMF13A01, HUMFESFPS, and HUMvWA were typed using two multiplex polymerase chain reactions (PCR). Amplified DNA samples were subsequently analyzed by polyacrylamide gel electrophoresis followed by silver staining. The heterozygote frequencies of the loci range from 0.614 to 0.820 (0.661 to 0.818 expected) and the number of alleles from 7 to 12 per locus. Although statistically significant deviation from Hardy-Weinberg expectations of genotype frequencies was noted at some loci by one or more tests, in general, the genotype frequencies are well estimated from the product of allele frequencies at all loci. The most frequent six-locus genotype is expected to occur in the French Canadian population with a frequency of 3.50 by 10(-5) and together, these six loci have an average probability of discrimination of 0.9999985. The study presented here indicates that these six STR loci are informative genetic markers for identity testing purposes in the French Canadian Caucasian population of Québec.

Job sharing at the managerial level.

Job sharing restructures a full-time position-two individuals share the responsibilities and the benefits of the position. If nurses are committed to making it work, this arrangement can succeed at the managerial level.