SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system.

Charcot-Marie-Tooth disease type 4C (CMT4C) is an early-onset, autosomal recessive form of demyelinating neuropathy. The clinical manifestations include progressive scoliosis, delayed age of walking, muscular atrophy, distal weakness, and reduced nerve conduction velocity. The gene mutated in CMT4C disease, SH3TC2/KIAA1985, was recently identified; however, the function of the protein it encodes remains unknown. We have generated knockout mice where the first exon of the Sh3tc2 gene is replaced with an enhanced GFP cassette. The Sh3tc2(DeltaEx1/DeltaEx1) knockout animals develop progressive peripheral neuropathy manifested by decreased motor and sensory nerve conduction velocity and hypomyelination. We show that Sh3tc2 is specifically expressed in Schwann cells and localizes to the plasma membrane and to the perinuclear endocytic recycling compartment, concordant with its possible function in myelination and/or in regions of axoglial interactions. Concomitantly, transcriptional profiling performed on the endoneurial compartment of peripheral nerves isolated from control and Sh3tc2(DeltaEx1/DeltaEx1) animals uncovered changes in transcripts encoding genes involved in myelination and cell adhesion. Finally, detailed analyses of the structures composed of compact and noncompact myelin in the peripheral nerve of Sh3tc2(DeltaEx1/DeltaEx1) animals revealed abnormal organization of the node of Ranvier, a phenotype that we confirmed in CMT4C patient nerve biopsies. The generated Sh3tc2 knockout mice thus present a reliable model of CMT4C neuropathy that was instrumental in establishing a role for Sh3tc2 in myelination and in the integrity of the node of Ranvier, a morphological phenotype that can be used as an additional CMT4C diagnostic marker.

Improving the Understanding and the Reliability of the Concept of "Sufficiency" in Friction Ridge Examination

The National Academies has stressed the need to develop quantifiable measures for methods that are currently qualitative in nature, such as the examination of fingerprints. Current protocols and procedures to perform these examinations rely heavily on a succession of subjective decisions, from the initial acceptance of evidence for probative value to the final assessment of forensic results. This project studied the concept of sufficiency associated with the decisions made by latent print examiners at the end of the various phases of the examination process. During this 2-year effort, a web‐based interface was designed to capture the observations of 146 latent print examiners and trainees on 15 pairs of latent/control prints. Two main findings resulted from the study: The concept of sufficiency is driven mainly by the number and spatial relationships between the minutiae observed on the latent and control prints. Data indicate that demographics (training, certification, years of experience) or non‐minutiae based features (such as level 3 features) do not play a major role in examiners' decisions; Significant variability was observed between detecting and interpreting friction ridge features and at all levels of details, as well as for factors that have the potential to influence the examination process, such as degradation, distortion, or influence of the background and the development technique.

P value and the theory of hypothesis testing: an explanation for new researchers.

In the 1920s, Ronald Fisher developed the theory behind the p value and Jerzy Neyman and Egon Pearson developed the theory of hypothesis testing. These distinct theories have provided researchers important quantitative tools to confirm or refute their hypotheses. The p value is the probability to obtain an effect equal to or more extreme than the one observed presuming the null hypothesis of no effect is true; it gives researchers a measure of the strength of evidence against the null hypothesis. As commonly used, investigators will select a threshold p value below which they will reject the null hypothesis. The theory of hypothesis testing allows researchers to reject a null hypothesis in favor of an alternative hypothesis of some effect. As commonly used, investigators choose Type I error (rejecting the null hypothesis when it is true) and Type II error (accepting the null hypothesis when it is false) levels and determine some critical region. If the test statistic falls into that critical region, the null hypothesis is rejected in favor of the alternative hypothesis. Despite similarities between the two, the p value and the theory of hypothesis testing are different theories that often are misunderstood and confused, leading researchers to improper conclusions. Perhaps the most common misconception is to consider the p value as the probability that the null hypothesis is true rather than the probability of obtaining the difference observed, or one that is more extreme, considering the null is true. Another concern is the risk that an important proportion of statistically significant results are falsely significant. Researchers should have a minimum understanding of these two theories so that they are better able to plan, conduct, interpret, and report scientific experiments.

Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure. The Cardiovascular Health study.

OBJECTIVES: The goal of this study was to determine whether subclinical thyroid dysfunction was associated with incident heart failure (HF) and echocardiogram abnormalities. BACKGROUND: Subclinical hypothyroidism and hyperthyroidism have been associated with cardiac dysfunction. However, long-term data on the risk of HF are limited. METHODS: We studied 3,044 adults>or=65 years of age who initially were free of HF in the Cardiovascular Health Study. We compared adjudicated HF events over a mean 12-year follow-up and changes in cardiac function over the course of 5 years among euthyroid participants, those with subclinical hypothyroidism (subdivided by thyroid-stimulating hormone [TSH] levels: 4.5 to 9.9, >or=10.0 mU/l), and those with subclinical hyperthyroidism. RESULTS: Over the course of 12 years, 736 participants developed HF events. Participants with TSH>or=10.0 mU/l had a greater incidence of HF compared with euthyroid participants (41.7 vs. 22.9 per 1,000 person years, p=0.01; adjusted hazard ratio: 1.88; 95% confidence interval: 1.05 to 3.34). Baseline peak E velocity, which is an echocardiographic measurement of diastolic function associated with incident HF in the CHS cohort, was greater in those patients with TSH>or=10.0 mU/l compared with euthyroid participants (0.80 m/s vs. 0.72 m/s, p=0.002). Over the course of 5 years, left ventricular mass increased among those with TSH>or=10.0 mU/l, but other echocardiographic measurements were unchanged. Those patients with TSH 4.5 to 9.9 mU/l or with subclinical hyperthyroidism had no increase in risk of HF. CONCLUSIONS: Compared with euthyroid older adults, those adults with TSH>or=10.0 mU/l have a moderately increased risk of HF and alterations in cardiac function but not older adults with TSH<10.0 mU/l. Clinical trials should assess whether the risk of HF might be ameliorated by thyroxine replacement in individuals with TSH>or=10.0 mU/l.

Application in the STRATHE trial of a score system to compare the efficacy and the tolerability of different therapeutic strategies in the management of hypertension

A score system integrating the evolution of efficacy and tolerability over time was applied to a subpopulation of the STRATHE trial, a trial performed according to a parallel group design, with a double-blind, random allocation to either a fixed-dose combination strategy (perindopril/indapamide 2 mg/0.625 mg, with the possibility to increase the dose to 3 mg/0.935 mg, and 4 mg/1.250 mg if needed, n = 118), a sequential monotherapy approach (atenolol 50 mg, followed by losartan 50 mg and amlodipine 5 mg if needed, n = 108), or a stepped-care strategy (valsartan 40 mg, followed by valsartan 80 mg and valsartan 80 mg+ hydrochlorothiazide 12.5 mg if needed, n = 103). The aim was to lower blood pressure below 140/90 mmHg within a 9-month period. The treatment could be adjusted after 3 and 6 months. Only patients in whom the study protocol was strictly applied were included in this analysis. At completion of the trial the total score averaged 13.1 +/- 70.5 (mean +/- SD) using the fixed-dose combination strategy, compared with -7.2 +/- 81.0 using the sequential monotherapy approach and -17.5 +/- 76.4 using the stepped-care strategy. In conclusion, the use of a score system allows the comparison of antihypertensive therapeutic strategies, taking into account at the same time efficacy and tolerability. In the STRATHE trial the best results were observed with the fixed-dose combination containing low doses of an angiotensin enzyme converting inhibitor (perindopril) and a diuretic (indapamide).

Cigarette smoking and the risk of endometrial cancer.

The risk of endometrial cancer in relation to cigarette consumption was evaluated in a hospital-based case-control study of breast and genital neoplasms conducted in Milan, northern Italy. For the present analysis, 357 women (cases) with histologically confirmed endometrial cancer were compared to a group of 1122 women (controls) admitted for a large spectrum of acute conditions unrelated to smoking or to any of the known or potential risk factors for endometrial cancer. Compared with never-smokers, the multivariate relative risk estimates were for current 0.45 [95% confidence interval (CI) = 0.30-0.70] and 0.86 (95% CI = 0.50-1.46) for ex-smokers. The negative association of endometrial cancer with current smoking was not influenced by menopausal status as well as by other major identified potential confounding factors, i.e. menstrual and reproductive history, body mass index, oral contraceptive or estrogen replacement therapy use and family gynecologic cancer history. However, there was no evidence of a dose-risk effect, since the relative risks were similar in moderate and heavy smokers. The present study confirms that smoking is less frequent in cases hospitalized for endometrial cancer than in a comparison group of patients with non-smoking-related acute conditions. This negative association is perhaps explained in terms of reduced estrogen levels in smokers, though the influence and the importance of some uncontrolled selection bias (due, for instance, to longer hospital stay of smokers even when admission diagnosis was for non-smoking-related conditions) cannot be ruled out.

Social network architecture and the maintenance of deleterious cultural traits.

How have changes in communications technology affected the way that misinformation spreads through a population and persists? To what extent do differences in the architecture of social networks affect the spread of misinformation, relative to the rates and rules by which individuals transmit or eliminate different pieces of information (cultural traits)? Here, we use analytical models and individual-based simulations to study how a 'cultural load' of misinformation can be maintained in a population under a balance between social transmission and selective elimination of cultural traits with low intrinsic value. While considerable research has explored how network architecture affects percolation processes, we find that the relative rates at which individuals transmit or eliminate traits can have much more profound impacts on the cultural load than differences in network architecture. In particular, the cultural load is insensitive to correlations between an individual's network degree and rate of elimination when these quantities vary among individuals. Taken together, these results suggest that changes in communications technology may have influenced cultural evolution more strongly through changes in the amount of information flow, rather than the details of who is connected to whom.

Insularity and the evolution of melanism, sexual dichromatism and body size in the worldwide-distributed barn owl.

Abstract Island biogeography has provided fundamental hypotheses in population genetics, ecology and evolutionary biology. Insular populations usually face different feeding conditions, predation pressure, intraspecific and interspecific competition than continental populations. This so-called island syndrome can promote the evolution of specific phenotypes like a small (or large) body size and a light (or dark) colouration as well as influence the evolution of sexual dimorphism. To examine whether insularity leads to phenotypic differentiation in a consistent way in a worldwide-distributed nonmigratory species, we compared body size, body shape and colouration between insular and continental barn owl (Tyto alba) populations by controlling indirectly for phylogeny. This species is suitable because it varies in pheomelanin-based colouration from reddish-brown to white, and it displays eumelanic black spots for which the number and size vary between individuals, populations and species. Females are on average darker pheomelanic and display more and larger eumelanic spots than males. Our results show that on islands barn owls exhibited smaller and fewer eumelanic spots and lighter pheomelanic colouration, and shorter wings than on continents. Sexual dimorphism in pheomelanin-based colouration was less pronounced on islands than continents (i.e. on islands males tended to be as pheomelanic as females), and on small islands owls were redder pheomelanic and smaller in size than owls living on larger islands. Sexual dimorphism in the size of eumelanic spots was more pronounced (i.e. females displayed much larger spots than males) in barn owls living on islands located further away from a continent. Our study indicates that insular conditions drive the evolution towards a lower degree of eumelanism, smaller body size and affects the evolution of sexual dichromatism in melanin-based colour traits. The effect of insularity was more pronounced on body size and shape than on melanic traits.

Merkel cells and the individuality of friction ridge skin

There is no definite theory yet for the mechanism by which the pattern of epidermal ridges on fingers, palms and soles forming friction ridge skin (FRS) patterns is created. For a long time growth forces in the embryonal epidermis have been believed to be involved in FRS formation. More recent evidence suggests that Merkel cells play an important part in this process as well. Here we suggest a model for the formation of FRS patterns that links Merkel cells to the epidermal stress distribution. The Merkel cells are modeled as agents in an agent based model that move anisotropically where the anisotropy is created by the epidermal stress tensor. As a result ridge patterns are created with pattern defects as they occur in real FRS patterns. As a consequence we suggest why the topology of FRS patterns is indeed unique as the arrangement of pattern defects is sensitive to the initial configuration of Merkel cells.

Patterns of Adherence to Raltegravir-Based Regimens and the Risk of Virological Failure Among HIV-Infected Patients: The RALTECAPS Cohort Study.

ABSTRACT:: Adherence patterns and their influence on virologic outcome are well characterized for protease inhibitor (PI)- and non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. We aimed to determine how patterns of adherence to raltegravir influence the risk of virological failure. We conducted a prospective multicenter cohort following 81 HIV-infected antiretroviral-naive or experienced subjects receiving or starting twice-a-day raltegravir-based antiretroviral therapy. Their adherence patterns were monitored using the Medication Events Monitoring System. During follow-up (188 days, ±77), 12 (15%) of 81 subjects experienced virological failure. Longer treatment interruption [adjusted odds ratio per 24-hour increase: 2.4; 95% confidence interval: 1.2 to 6.9; P < 0.02] and average adherence (odds ratio per 5% increase: 0.68; 95% confidence interval: 0.46 to 1.00, P < 0.05) were both independently associated with virological failure controlling for prior duration of viral suppression. Timely interdose intervals and high levels of adherence to raltegravir are both necessary to control HIV replication.

Tumor-host interactions Part 1: Stromal signatures of breast and prostate cancer Part 2: GLG1 and the control of the secretory pathway in tumor cells

Tumor-host interaction is a key determinant during cancer progression, from primary tumor growth to metastatic dissemination. At each step, tumor cells have to adapt to and subvert different types of microenvironment, leading to major phenotypic and genotypic alterations that affect both tumor and surrounding stromal compartments. Understanding the molecular mechanisms that govern tumor-host interplay may be essential for better comprehension of tumorigenesis in an effort to improve current anti-cancer therapies. The present work is composed of two projects that address tumor-host interactions from two different perspectives, the first focusing on the characterization of tumor-associated stroma and the second on membrane trafficking in tumor cells. Part 1. To selectively address stromal gene expression changes during cancer progression, oligonucleotide-based Affymetrix microarray technology was used to analyze the transcriptomes of laser-microdissected stromal cells derived from invasive human breast and prostate carcinoma. Comparison showed that invasive breast and prostate cancer elicit distinct, tumor-specific stromal responses, with a limited panel of shared induced and/or repressed genes. Both breast and prostate tumor-specific deregulated stromal gene sets displayed statistically significant survival-predictive ability for their respective tumor type. By contrast, a stromal gene signature common to both tumor types did not display prognostic value, although expression of two individual genes within this common signature was found to be associated with patient survival. Part 2. GLG1 is known as an E-selectin ligand and an intracellular FGF receptor, depending on cell type and context. Immunohistochemical and immunofluorescence analyses showed that GLG1 is primarily localized in the Golgi of human tumor cells, a central location in the biosynthetic/secretory pathways. GLG1 has been shown to interact with and to recruit the ARF GEF BIGI to the Golgi membrane. Depletion of GLG1 or BIGI markedly reduced ARF3 membrane localization and activation, and altered the Golgi structure. Interestingly, these perturbations did not impair constitutive secretion in general, but rather seemed to impair secretion of a specific subset of proteins that includes MMP-9. Thus, GLG1 coordinates ARF3 activation by recruiting BIGI to the Golgi membrane, thereby affecting secretion of specific molecules. - Les interactions tumeur-hôte constituent un élément essentiel à la progression tumorale, de la croissance de la tumeur primaire à la dissémination des métastases. A chaque étape, les cellules tumorales doivent s'adapter à différents types de microenvironnement et les détourner à leur propre avantage, donnant lieu à des altérations phénotypiques et génotypiques majeures qui affectent aussi bien la tumeur elle-même que le compartiment stromal environnant. L'étude des mécanismes moléculaires qui régissent les interactions tumeur-hôte constitue une étape essentielle pour une meilleure compréhension du processus de tumorigenèse dans le but d'améliorer les thérapies anti cancer existantes. Le travail présenté ici est composé de deux projets qui abordent la problématique des interactions tumeur-hôte selon différentes perspectives, le premier se concentrant sur la caractérisation du stroma tumoral et le second sur le trafic intracellulaire des cellules tumorales. Partie 1. Pour examiner les changements d'expression des gènes dans le stroma en réponse à la progression du cancer, des puces à ADN Affymetrix ont été utilisées afin d'analyser les transcriptomes des cellules stromales issues de carcinomes invasifs du sein et de la prostate et collectées par microdissection au laser. L'analyse comparative a montré que les cancers invasifs du sein et de la prostate provoquent des réponses stromales spécifiques à chaque type de tumeur, et présentent peu de gènes induits ou réprimés de façon similaire. L'ensemble des gènes dérégulés dans le stroma associé au cancer du sein, ou à celui de la prostate, présente une valeur pronostique pour les patients atteints d'un cancer du sein, respectivement de la prostate. En revanche, la signature stromale commune aux deux types de cancer n'a aucune valeur prédictive, malgré le fait que l'expression de deux gènes présents dans cette liste soit liée à la survie des patients. Partie 2. GLG1 est connu comme un ligand des sélectines E ainsi que comme récepteur intracellulaire pour des facteurs de croissances FGFs selon le type de cellule dans lequel il est exprimé. Des analyses immunohistochimiques et d'immunofluorescence ont montré que dans les cellules tumorales, GLG1 est principalement localisé au niveau de l'appareil de Golgi, une place centrale dans la voie biosynthétique et sécrétoire. Nous avons montré que GLG1 interagit avec la protéine BIGI et participe à son recrutement à la membrane du Golgi. L'absence de GLG1 ou de BIGI réduit drastiquement le pool d'ARF3 associé aux membranes ainsi que la quantité d'ARF3 activés, et modifie la structure de l'appareil de Golgi. Il est particulièrement intéressant de constater que ces perturbations n'ont pas d'effet sur la sécrétion constitutive en général, mais semblent plutôt affecter la sécrétion spécifique d'un sous-groupe défini de protéines comprenant MMP-9. GLG1 coordonne donc l'activation de ARF3 en recrutant BIGI à la membrane du Golgi, agissant par ce moyen sur la sécrétion de molécules spécifiques.