Regional and bilateral MRI and gene signatures in facioscapulohumeral dystrophy: implications for clinical trial design and mechanisms of disease progression.

Identifying the aberrant expression of DUX4 in skeletal muscle as the cause of facioscapulohumeral dystrophy (FSHD) has led to rational therapeutic development and clinical trials. Several studies support the use of MRI characteristics and the expression of DUX4-regulated genes in muscle biopsies as biomarkers of FSHD disease activity and progression. We performed lower-extremity MRI and muscle biopsies in the mid-portion of the tibialis anterior (TA) muscles bilaterally in FSHD subjects and validated our prior reports of the strong association between MRI characteristics and expression of genes regulated by DUX4 and other gene categories associated with FSHD disease activity. We further show that measurements of normalized fat content in the entire TA muscle strongly predict molecular signatures in the mid-portion of the TA, indicating that regional biopsies can accurately measure progression in the whole muscle and providing a strong basis for inclusion of MRI and molecular biomarkers in clinical trial design. An unanticipated finding was the strong correlations of molecular signatures in the bilateral comparisons, including markers of B-cells and other immune cell populations, suggesting that a systemic immune cell infiltration of skeletal muscle might have a role in disease progression.

Longitudinal measures of RNA expression and disease activity in FSHD muscle biopsies.

Advances in understanding the pathophysiology of facioscapulohumeral dystrophy (FSHD) have led to the discovery of candidate therapeutics, and it is important to identify markers of disease activity to inform clinical trial design. For drugs that inhibit DUX4 expression, measuring DUX4 or DUX4-target gene expression might be an interim measure of drug activity; however, only a subset of FHSD muscle biopsies shows evidence of DUX4 expression. Our prior study showed that MRI T2-STIR-positive muscles had a higher probability of showing DUX4 expression than muscles with normal MRI characteristics. In the current study, we performed a 1-year follow-up assessment of the same muscle with repeat MRI and muscle biopsy. There was little change in MRI characteristics over the 1-year period and, similar to the initial evaluation, MRI T2-STIR-postive muscles had a higher expression of DUX4-regulated genes, as well as genes associated with inflammation, extracellular matrix and cell cycle. Compared to the initial evaluation, overall the level of expression in these gene categories remained stable over the 1-year period; however, there was some variability for each individual muscle biopsied. The pooled data from both the initial and 1-year follow-up evaluations identified several FSHD subgroups based on gene expression, as well as a set of genes-composed of DUX4-target genes, inflammatory and immune genes and cell cycle control genes-that distinguished all of the FSHD samples from the controls. These candidate markers of disease activity need to be replicated in independent datasets and, if validated, may provide useful measures of disease progression and response to therapy.

MRI-informed muscle biopsies correlate MRI with pathology and DUX4 target gene expression in FSHD.

Facioscapulohumeral muscular dystrophy (FSHD) is a common, dominantly inherited disease caused by the epigenetic de-repression of the DUX4 gene, a transcription factor normally repressed in skeletal muscle. As targeted therapies are now possible in FSHD, a better understanding of the relationship between DUX4 activity, muscle pathology and muscle magnetic resonance imaging (MRI) changes is crucial both to understand disease mechanisms and for the design of future clinical trials. Here, we performed MRIs of the lower extremities in 36 individuals with FSHD, followed by needle muscle biopsies in safely accessible muscles. We examined the correlation between MRI characteristics, muscle pathology and expression of DUX4 target genes. Results show that the presence of elevated MRI short tau inversion recovery signal has substantial predictive value in identifying muscles with active disease as determined by histopathology and DUX4 target gene expression. In addition, DUX4 target gene expression was detected only in FSHD-affected muscles and not in control muscles. These results support the use of MRI to identify FSHD muscles most likely to have active disease and higher levels of DUX4 target gene expression and might be useful in early phase therapeutic trials to demonstrate target engagement in therapies aiming to suppress DUX4 expression.

Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy.

The autosomal dominant myopathy facioscapulohumeral muscular dystrophy (FSHD1, OMIM 158900) is caused by contraction of the D4Z4 repeat array on 4qter. We show that this contraction causes marked hypomethylation of the contracted D4Z4 allele in individuals with FSHD1. Individuals with phenotypic FSHD1, who are clinically identical to FSHD1 but have an unaltered D4Z4, also have hypomethylation of D4Z4. These results strongly suggest that hypomethylation of D4Z4 is a key event in the cascade of epigenetic events causing FSHD1.

Validation of the association between MRI and gene signatures in facioscapulohumeral dystrophy muscle: implications for clinical trial design.

Identifying the aberrant expression of DUX4 in skeletal muscle as the cause of facioscapulohumeral dystrophy (FSHD) has led to rational therapeutic development and clinical trials. Several studies support the use of MRI characteristics and the expression of DUX4-regulated genes in muscle biopsies as biomarkers of FSHD disease activity and progression, but reproducibility across studies needs further validation. We performed lower-extremity MRI and muscle biopsies in the mid-portion of the tibialis anterior (TA) muscles bilaterally in FSHD subjects and validated our prior reports of the strong association between MRI characteristics and expression of genes regulated by DUX4 and other gene categories associated with FSHD disease activity. We further show that measurements of normalized fat content in the entire TA muscle strongly predict molecular signatures in the mid-portion of the TA. Together with moderate-to-strong correlations of gene signatures and MRI characteristics between the TA muscles bilaterally, these results suggest a whole muscle model of disease progression and provide a strong basis for inclusion of MRI and molecular biomarkers in clinical trial design.

Calcium polysulfide remediation of hexavalent chromium contamination from chromite ore processing residue.

Past disposal of high-lime chromite ore processing residue (COPR) from a chemical works in S.E. Glasgow, UK, has led to continuing release of toxic and carcinogenic hexavalent chromium (Cr(VI)) to groundwaters which are highly contaminated with Cr(VI)O4(2-). Traditional methods of remediating Cr(VI)-contaminated land, e.g. using ferrous sulfate and organic matter, have had limited success in converting Cr(VI) to less harmful and insoluble Cr(III). This paper describes the first application of calcium polysulfide (CaS(x)) to the remediation of contaminated groundwater and high-lime COPR in a series of laboratory experiments, which have demonstrated the effectiveness of the treatment in quantitatively and rapidly reducing Cr(VI) to Cr(III) over the pH range (8-12.5) typically found at the sites. Cr(III)-organic complexes, present in groundwater at one location, were also effectively precipitated upon treatment with CaS(x). The potential for large-scale use of CaS(x) in the remediation of Cr(VI) from COPR is also discussed.

Double SMCHD1 variants in FSHD2: the synergistic effect of two SMCHD1 variants on D4Z4 hypomethylation and disease penetrance in FSHD2.

Facioscapulohumeral muscular dystrophy (FSHD) predominantly affects the muscles in the face, trunk and upper extremities and is marked by large clinical variability in disease onset and progression. FSHD is associated with partial chromatin relaxation of the D4Z4 repeat array on chromosome 4 and the somatic expression of the D4Z4 encoded DUX4 gene. The most common form, FSHD1, is caused by a contraction of the D4Z4 repeat array on chromosome 4 to a size of 1-10 units. FSHD2, the less common form of FSHD, is most often caused by heterozygous variants in the chromatin modifier SMCHD1, which is involved in the maintenance of D4Z4 methylation. We identified three families in which the proband carries two potentially damaging SMCHD1 variants. We investigated whether these variants were located in cis or in trans and determined their functional consequences by detailed clinical information and D4Z4 methylation studies. In the first family, both variants in trans were shown to act synergistically on D4Z4 hypomethylation and disease penetrance, in the second family both SMCHD1 function-affecting variants were located in cis while in the third family one of the two variants did not affect function. This study demonstrates that having two SMCHD1 missense variants that affect function is compatible with life in males and females, which is remarkable considering its role in X inactivation in mice. The study also highlights the variability in SMCHD1 variants underlying FSHD2 and the predictive value of D4Z4 methylation analysis in determining the functional consequences of SMCHD1 variants of unknown significance.

[Study of the categorization process among patients with eating disorders: a new cognitive approach to psychopathology]. / Etude du processus de catégorisation chez des patientes aux troubles des conduites alimentaires: une nouvelle approche cognitive de la psychopathologie.

Anorexic and bulimic patients have a highly distorted relationship with food and eating, even though they tend to be knowledgeable about diet and nutrition. The progress of this disease, as well as its complications and associated difficulties, are increasingly understood, while the etiopathogeny of eating disorders remains obscure. The approach that we are proposing involves the study of one of the most fundamental cognitive functions of human reasoning--the cognitive process of categorization. The purpose of this study is to understand the procedures used by these patients to construct representations of food. Categorization, one of the basic features of human cognition, allows individuals to organize their subjective experience of the surrounding environment by structuring its contents. This ability to group different objects into the same category based on their common characteristics is important for explaining the major cognitive activities of planning, memorization, communication and perception. Indeed, our categories reflect our conceptions of the world. They depend on our experiences and representations, as well as the expertise acquired in a specific field. The differences that appear in the categories created by subjects when they are asked to classify objects reveal the properties that are most salient to them and, as a result, the interests, values and ideas associated with these properties. There are three types of properties: perceptive properties, which describe the object's shape, color, odor and texture; structural properties, which relate to the object's components; and functional properties, which specify the way in which the object is used and provide an answer to the question, "What is it used for?". Subjects attribute these functional properties by means of knowledge or inference according to their representation of the object's role; such properties are especially likely to emerge during top-down (theory-driven) processing. The type of processing used (bottom-up or top-down) is dependent on a certain number of factors. We hypothesize, within the context of food product categorization, that patients suffering from eating disorders largely resort to processing based on acquired information or beliefs about the objects, i.e. top-down processing. We present two studies: a naturalistic and exploratory pilot study whose goal is to identify whether the various categorization processes used by eating disorder patients differ from those employed by subjects not suffering from an eating disorder. A second study aims to identify the different categorization procedures. During the first experiment, 68 women (17 control subjects, 17 anorexics, 17 anorexic bulimics and 17 bulimics) aged 18-39 (average age: 26.6) verbalize all representations that come to mind during a limited time period as the name of a food item is read. Eighty-nine food items are presented in alphabetical order. The list is read out loud and all comments are recorded. The data is processed in three ways : an analysis based on the positive or negative valence of each representation, an analysis based on each categories of food and an analysis of representations based on themes expressed. The three analyses (valence, categories of food and theme assigned to the representations) show differences between the representations of the four experimental groups. In fact, the anorexics and anorexic bulimics mainly express strongly negative representations about food, whereas bulimics and control produce representations whose positive and negative valences balances. These negative cognitions concern mainly meat for the control subjects and cakes for the subjects reached of TCA. Concerning theme assigned to the representations, the control subjects produce mainly cognitions relating to the hedonism, the flavor of food and their purpose on health. The anorexics and anorexics-bulimics evoke mainly the fat and sugar content of the foods. The bulimics evoke mainly cognitions relating to the effect on health and the intestinal transit time of food. These results lead one to believe that it is not the bulimic binging and purging of these patients, but rather their restrictive behavior that is the determining factor in the differences in food representations observed between the two experimental groups. During the second experiment, 60 women (15 controls, 15 anorexics, 15 anorexic bulimics and 15 bulimics) aged 18-32 (average age: 25.6) classified 27 food names according to their similarities and differences, and then explained the reasons for their categorizations. The data were analyzed in terms of similarity/difference, and the verbalizations were analyzed by content. The results indicate that 10 of the 27 foods were categorized differently by the controls and the subjects with eating disorders. Subjects classified the following foods: camembert cheese, cold cuts, cheese spread, fruit in syrup, whole milk, mayonnaise, bread, fresh fish, potatoes and plain yogurt. Bulimics and controls use similar classifications for food names, while anorexics and atypical bulimics classify foods in a similar way. Examining the categorization criteria used during verbalizations allows us to better understand these differences. The control group's major criterion seems to be the succession of dishes. These subjects group into separate categories entry foods (beef, eggs, fish, etc.), vegetables, cheese or dairy foods, and finally desserts. Additional foods, like bread and mayonnaise, belong to the same category. Other categories are nutritional criteria (for example, dairy products contain calcium) and biological criteria (for example, bananas and apples are fruits). These categorization criteria include structural properties (which describe what the object is made of) and functional, "academic" properties, those which describe how foods are used, "as in cookbooks or diet books." On the other hand, the categorization criteria expressed by anorexic patients are very different from those used by control subjects: foods that are hard to eliminate, rich, high-fat and therefore indigestible are considered to be similar. Some examples are cold cuts, potatoes, mayonnaise and prepared desserts. A second categorization criterion involves the concept of natural foods : certain foods "are unhealthy because they're processed, so they're bad for you"--one such example is cheese spread. A third criterion concerns the notion of familiar foods: poultry and eggs, for example, are "familiar to us." We are clearly seeing here the importance of functional properties in the categorization of food names: certain foods are indigestible, hard to eliminate, cause heartburn or reflux, are not natural, and thus are avoided. The categorization criteria mentioned by bulimic patients also clearly take into account the functional properties of foods. The criteria are of the following type: "it's filling, it relieves a bulimic attack, it helps prevent heartburn and constipation, etc." It appears that bulimics' categorization criteria are solely associated with these foods' imagined or real effect on the body. The categorization criteria used by anorexic bulimics seem to be especially associated with weight gain or the consumption of such foods during bulimia attacks because "they make you feel full." On the other hand, light foods, which patients allow themselves to eat, are placed in the same category. This study, which seeks to understand the cognitive functioning of eating disorder patients with anorexia and bulimia, has brought new elements to light. All patients exhibit food categorization processes that differ greatly from those displayed by control subjects. Patients also attribute greater significance to the functional properties of foods as compared to controls, who give priority to structural properties. Anorexic and bulimic patients base their food categorizations on the consequences of ingestion, in terms of health, digestion and weight gain. Their processing of food stimuli is therefore radically different and gives a dominating place to top-down processes. Additional studies should supplement these findings in order to gain a better understanding of patients' disturbed processing of information.

[Characteristics of the population hospitalized for advanced and terminal heart failure and experiences in palliative caring in the Intensive Care Unit of cardiology]. / Caractéristiques et prise en charge des patients hospitalisés pour insuffisance cardiaque terminale ayant fait l'objet d'une limitation de soins en unité de soins intensifs cardiologiques.

PURPOSE: Advanced heart failure incidence is in progression. Palliative care access remains difficult due to its unpredictable course. The aim of this study was to describe the characteristics of patients admitted in Cardiology Intensive Care Unit for advanced heart failure who received palliative care and compare them to the whole population of acute heart failure hospitalized in the same period. PATIENTS AND METHODS: The patients hospitalized for acute heart failure were retrospectively included from 2009 to 2013. We identified among them those who received palliative care. Specific caring was decided in pluridisciplinary meeting. RESULTS: On 940 patients included, 42 patients (4.5%) receive palliative care. Ischemic heart disease was the main etiology (n=19; 45.2%). Right ventricular dysfunction (n=34; 80.9%) was associated with supra-ventricular arrhythmia (n=28; 66.7%). Twenty-eight patients (57.1%) have died in hospital, 9 (21.4%) were referred to a palliative care unit and 8 (19.1%) was discharged or referred to a rehabilitation center. Time between inclusion and death was 6 days on average. Intra-hospital mortality in control group was 6.8%. CONCLUSION: Palliative care in cardiology is uncommon and has often been too late because of its poor adaptability to advanced heart failure. It is, as consequence, necessary to identify the prognostic factors of these patients in order to propose a personalized care and to adjust the intensity of care ahead of the terminal evolution of heart failure.

Analogical transfer as guided by an abstraction process: the case of learning by doing in text editing.

The authors proposed that not only are the first attempts to solve a problem made by analogy but also that progress in learning can be guided by referring to more abstract knowledge, which affords new possibilities. Two experiments investigated this view in a situation of learning how to use a text editor. Experiments 1A to 1C identified the knowledge associated with 3 domains hypothesized as sources of transfer at increasing levels of abstraction (typewriting, writing in general, manipulating objects). Experiment 2 tested whether participants first use their knowledge about typewriting, then about writing in general, and then about manipulating objects. The data showed that the order of acquisition of text editor functions appeared to be strongly related to this hierarchy, supporting the idea that part of learning consists of discovering properties of objects by accessing increasingly general domains.

Polypoid formations at the anal margin in infants less than two years old.

Polypoid formations in the anal canal and at the anal margin are sometimes observed in the newborn and in infants less than 2 years old. Unlike hamartomatous polyps, which are commonly reported in infantile proctology, these growths are rare in early childhood. Only by performing a pathological anatomy examination is it possible to determine the nature of the numerous affections encountered to assess prognosis and to decide on suitable therapeutic management.

[Antral exclusion. A complement to palliative gastrojejunal shunt in pancreatic cancer]. / L'exclusion antrale. Un complément à l'anastomose gastro-jéjunale palliative dans le cancer du pancréas.

OBJECTIVES: Prophylactic gastrojejunostomy remains a controversial issue in the management of unresectable pancreatic cancer. The main disadvantage of the gastrojejunostomy being the postoperative delayed gastric emptying (gastroparesia and circulus vitiosus through the nonobstructed duodenum). In the aim to reduce the effects of delayed gastric emptying we advocated the adjunct of an antral exclusion to simplify antrectomy by eliminating antral dysfunction and duodenal circulus vitiosus. METHODS: The procedure of antral exclusion was performed using a 4-row linear stapler. The gastrojejunostomy was immediately proximal to the staples row. RESULTS: Preliminary results in 6 patients, evaluated by clinical follow up, radiologic and radionucleide studies, showed no delayed gastric emptying nor other postoperative complications related to this technique. CONCLUSION: These preliminary results are encouraging and suggest that this procedure could improve the functional results of the prophylactic gastrojejunostomy.

[Actinomycosis: value of percutaneous drainage of intra-abdominal abscesses]. / Actinomycose: intérêt du drainage per-cutané des abcès intra-abdominaux.

Abdominal actinomycosis was localized in the liver with intra-abdominal abscesses. The disease had evolved for several years before diagnosis. Percutaneous interventional radiology allowed taking biopsies which confirmed the diagnosis. Percutaneous drainage of the intra-abdominal abscesses with antibiotherapy was successful without iterative surgery.

Cytokine and chemokine production by human pancreatic islets upon enterovirus infection.

Enteroviruses of the human enterovirus B species (HEV-Bs) (e.g., coxsackie B viruses [CVBs] and echoviruses) have been implicated as environmental factors that trigger/accelerate type 1 diabetes, but the underlying mechanism remains elusive. The aim of this study was to gain insight into the cytokines and chemokines that are produced by human pancreatic islets upon infection with CVBs. To this end, we studied the response of human islets of Langerhans upon mock or CVB3 infection. Using quantitative PCR, we showed that upon CVB3 infection, transcription of interferon (IFN), IFN-stimulated genes, and inflammatory genes was induced. Analysis of secreted cytokines and chemokines by Luminex technology confirmed production and secretion of proinflammatory cytokines (e.g., interleukin [IL]-6 and tumor necrosis factor-α) as well as various chemotactic proteins, such as IFN-γ-induced protein 10, macrophage inflammatory protein (MIP)-1α, MIP-1ß, and IL-8. Infection with other HEV-Bs induced similar responses, yet their extent depended on replication efficiency. Ultra violet-inactivated CVB3 did not induce any response, suggesting that virus replication is a prerequisite for antiviral responses. Our data represent the first comprehensive overview of inflammatory mediators that are secreted by human islets of Langerhans upon CVB infection and may shed light on the role of enteroviruses in type 1 diabetes pathogenesis.

A lead isotopic study of the human bioaccessibility of lead in urban soils from Glasgow, Scotland.

The human bioaccessibility of lead (Pb) in Pb-contaminated soils from the Glasgow area was determined by the Unified Bioaccessibility Research Group of Europe (BARGE) Method (UBM), an in vitro physiologically based extraction scheme that mimics the chemical environment of the human gastrointestinal system and contains both stomach and intestine compartments. For 27 soils ranging in total Pb concentration from 126 to 2160 mg kg(-1) (median 539 mg kg(-1)), bioaccessibility as determined by the 'stomach' simulation (pH ~1.5) was 46-1580 mg kg(-1), equivalent to 23-77% (mean 52%) of soil total Pb concentration. The corresponding bioaccessibility data for the 'stomach+intestine' simulation (pH ~6.3) were 6-623 mg kg(-1) and 2-42% (mean 22%) of soil Pb concentration. The soil (206)Pb/(207)Pb ratios ranged from 1.057 to 1.175. Three-isotope plots of (208)Pb/(206)Pb against (206)Pb/(207)Pb demonstrated that (206)Pb/(207)Pb ratios were intermediate between values for source end-member extremes of imported Australian Pb ore (1.04)--used in the manufacture of alkyl Pb compounds (1.06-1.10) formerly added to petrol--and indigenous Pb ores/coal (1.17-1.19). The (206)Pb/(207)Pb ratios of the UBM 'stomach' extracts were similar (<0.01 difference) to those of the soil for 26 of the 27 samples (r=0.993, p<0.001) and lower in 24 of them. A slight preference for lower (206)Pb/(207)Pb ratio was discernible in the UBM. However, the source of Pb appeared to be less important in determining the extent of UBM-bioaccessible Pb than the overall soil total Pb concentration and the soil phases with which the Pb was associated. The significant phases identified in a subset of samples were carbonates, manganese oxides, iron-aluminium oxyhydroxides and clays.

Determination of the bioaccessibility of chromium in Glasgow soil and the implications for human health risk assessment.

The Unified Bioaccessibility Method (UBM), which simulates the fluids of the human gastrointestinal tract, was used to assess the oral bioaccessibility of Cr in 27 Glasgow soils. These included several contaminated with Cr(VI), the most toxic form of Cr, from the past disposal of chromite ore processing residue (COPR). The extraction was employed in conjunction with the subsequent determination of the bioaccessible Cr by ICP-OES and Cr(VI) by the diphenylcarbazide complexation colorimetric procedure. In addition, Cr(III)-containing species were determined by (i) HPLC-ICP-MS and (ii) ICP-OES analysis of gel electrophoretically separated components of colloidal and dissolved fractions from centrifugal ultrafiltration of extracts. Similar analytical procedures were applied to the determination of Cr and its species in extracts of the <10 µm fraction of soils subjected to a simulated lung fluid test to assess the inhalation bioaccessibility of Cr. The oral bioaccessibility of Cr was typically greater by a factor of 1.5 in the 'stomach' (pH ~1.2) compared with the 'stomach+intestine' (pH ~6.3) simulation. On average, excluding two COPR-contaminated soil samples, the oral bioaccessibility ('stomach') was 5% of total soil Cr and, overall, similar to the soil Cr(VI) concentration. Chromium(VI) was not detected in the extracts, a consequence of pH- and soil organic matter-mediated reduction in the 'stomach' to Cr(III)-containing species, identified as predominantly Cr(III)-humic complexes. Insertion of oral bioaccessible fraction data into the SNIFFER human health risk assessment model identified site-specific assessment criteria (for residential land without plant uptake) that were exceeded by the soil total Cr (3680 mg kg(-1)) and Cr(VI) (1485 mg kg(-1)) concentration at only the most COPR-Cr(VI)-contaminated location. However, the presence of measurable Cr(VI) in the <10 µm fraction of the two most highly Cr(VI)-contaminated soils demonstrated that inhalation of Cr(VI)-containing dust remains the most potentially harmful exposure route.