AMP-activated protein kinase mediates glucocorticoid-induced metabolic changes: a novel mechanism in Cushing's syndrome.

Chronic exposure to glucocorticoid hormones, resulting from either drug treatment or Cushing's syndrome, results in insulin resistance, central obesity, and symptoms similar to the metabolic syndrome. We hypothesized that the major metabolic effects of corticosteroids are mediated by changes in the key metabolic enzyme adenosine monophosphate-activated protein kinase (AMPK) activity. Activation of AMPK is known to stimulate appetite in the hypothalamus and stimulate catabolic processes in the periphery. We assessed AMPK activity and the expression of several metabolic enzymes in the hypothalamus, liver, adipose tissue, and heart of a rat glucocorticoid-excess model as well as in in vitro studies using primary human adipose and primary rat hypothalamic cell cultures, and a human hepatoma cell line treated with dexamethasone and metformin. Glucocorticoid treatment inhibited AMPK activity in rat adipose tissue and heart, while stimulating it in the liver and hypothalamus. Similar data were observed in vitro in the primary adipose and hypothalamic cells and in the liver cell line. Metformin, a known AMPK regulator, prevented the corticosteroid-induced effects on AMPK in human adipocytes and rat hypothalamic neurons. Our data suggest that glucocorticoid-induced changes in AMPK constitute a novel mechanism that could explain the increase in appetite, the deposition of lipids in visceral adipose and hepatic tissue, as well as the cardiac changes that are all characteristic of glucocorticoid excess. Our data suggest that metformin treatment could be effective in preventing the metabolic complications of chronic glucocorticoid excess.

A Heterozygous Deletion Mutation in the Cardiac Sodium Channel Gene SCN5A with Loss- and Gain-of-Function Characteristics Manifests as Isolated Conduction Disease, without Signs of Brugada or Long QT Syndrome.

BACKGROUND: The SCN5A gene encodes for the α-subunit of the cardiac sodium channel NaV1.5, which is responsible for the rapid upstroke of the cardiac action potential. Mutations in this gene may lead to multiple life-threatening disorders of cardiac rhythm or are linked to structural cardiac defects. Here, we characterized a large family with a mutation in SCN5A presenting with an atrioventricular conduction disease and absence of Brugada syndrome. METHOD AND RESULTS: In a large family with a high incidence of sudden cardiac deaths, a heterozygous SCN5A mutation (p.1493delK) with an autosomal dominant inheritance has been identified. Mutation carriers were devoid of any cardiac structural changes. Typical ECG findings were an increased P-wave duration, an AV-block I° and a prolonged QRS duration with an intraventricular conduction delay and no signs for Brugada syndrome. HEK293 cells transfected with 1493delK showed strongly (5-fold) reduced Na(+) currents with altered inactivation kinetics compared to wild-type channels. Immunocytochemical staining demonstrated strongly decreased expression of SCN5A 1493delK in the sarcolemma consistent with an intracellular trafficking defect and thereby a loss-of-function. In addition, SCN5A 1493delK channels that reached cell membrane showed gain-of-function aspects (slowing of the fast inactivation, reduction in the relative fraction of channels that fast inactivate, hastening of the recovery from inactivation). CONCLUSION: In a large family, congregation of a heterozygous SCN5A gene mutation (p.1493delK) predisposes for conduction slowing without evidence for Brugada syndrome due to a predominantly trafficking defect that reduces Na(+) current and depolarization force.

Le syndrome du tunnel carpien [Carpal tunnel syndrome]

The carpal tunnel syndrome is very frequent. The authors insist on some points of surgical technique. The results of a Swiss study on the problem of the recurrent carpal tunnel syndrome are described (96 cases); the etiology of the recurrency, the surgical technique and the results after operative revision are analysed.

Nécroses cutanées au chaud : une forme de syndrome antiphospholipide primaire?

INTRODUCTION : Le syndrome antiphospholipide primaire est caractérisé par des thromboses, des avortements a répétition associés à une thrombocytopénie, un PTT prolongé et la présence d'anticorps antiphospholipides, en I'absence d'autres maladies de type immunologique, comme le lupus érythémateux dissémine. PRESENTATION DE CAS: Une fillette de 7 ans s'est présentée avec des douleurs intenses, persistant pendant plusieurs heures, aux extrémités des membres, suite a I'exposition à un temps caniculaire. II n'y avait aucune évidence de photosensibilité. C'est une fillette en bonne santé habituelle et aucun autre signe ou symptôme ne semblait suggérer une maladie auto-immune ou infectieuse. Le status clinique était parfaitement normal exception faite des nécroses aux extrémités des orteils et des doigts. Les paramétrés paracliniques ne montraient pas de signes inflammatoires, pas d'anémie, pas de leucocytose et les plaquettes étaient dans la norme. Nous avons exclu la présence d'anticorps antinucléaire et anti-DNA, ainsi que la présence de cryo-et pyroglobulines. Les test de la crase ont montre un PTT prolongé et des anticorps antiphospholipides spécifiques de la P2-glycoprotéine I, mais aucune autre anomalie susceptible de favoriser des thromboses. Le diagnostic de syndrome antiphospholipide primaire a été pose sur la base des épisodes de thromboses des extrémités, associes a un PTT prolonge et à la présence d'anticorps antiphospholipides. Le risque pour I'enfant de présenter un nouvel épisode thrombotique étant élevé, nous avons propose une anticoagulation par dicoumarine. CONCLUSION: La présentation de ce cas de syndrome antiphospholipide primaire est atypique. Ce syndrome est rare chez I'enfant, mais iI est responsable d'un tiers des thromboses pédiatriques. La rareté de ce syndrome est due au fait que I'enfant n'a pas d'autres facteurs thrombogènes par opposition a I'adulte. La raison pour laquelle I'exposition à la chaleur est Ie facteur déclenchant chez cette patiente reste inexpliquée. Ce cas démontre la nécessité de contrôler les anticorps antiphospholipides chez tous les patients pédiatriques présentant des thromboses.

Visceral leishmaniasis and hemophagocytic syndrome

A 11 months old female infant from Portugal, free of family history, consults for apathy, weight loss, tachycardia, tachypnea, petechiae, pallor without icterus and hepatoslenomegaly. Seven months earlier, while being in Portugal, she presented a persistent bluish pimple on her buttock. Laboratory results showed anemia (35 g/l), leucopenia (3.3 G/l), thrombocytopenia (13 G/l), impaired coagulation (INR 1.4, PTT 41 sec.), hyponatremia (124 mmol/l), elevated CRP (139 mg/l), high ferritin (34.775 μg/l) and high triglycerides (5.22 mmol/l). After correction of vital parameters, a bone marrow aspiration and biopsy (BMB) revealed both the etiological diagnosis, namely a visceral leishmaniasis (VL) as well as one of its potential complications, the hemophagocytic syndrome (HS). Transfusions of whole blood, platelets and fresh frozen plasma were immediately started. Dexamethasone (10 mg/m2) and amphotericin B (3 mg/kg/day) have also been administrated. Visceral leishmaniasis is caused by a protozoan (Leishmania donovani) transmitted by the female sandfly. It is endemic in the Mediterranean basin (including France, Italy, Spain and Portugal), South America, sub-Saharan Africa as well as in India and Bangladesh. The parasite infects macrophages and, after several weeks of incubation, the disease occurs by affection of bloodlines (anemia, leucopenia, thrombocytopenia), hepatosplenomegaly, cachexia, gastrointestinal damage. The complications of the disease may lead to death. Liposomal amphotericin B is the currently recommended treatment. HS is caused by the proliferation and activation of macrophages in the marrow in response to a cytokine storm. It may be of primary cause. When it is secondary, it may be related to infections such as leishmaniasis. Patients present with fever and laboratory diagnostic criteria include cytopenia, hypertriglyceridemia, high ferritin and hemophagocytosis in the BMB. The treatment consists among other in the administration of high doses corticosteroids and, in secondary cases, in the treatment of the underlying cause. In conclusion, the clinical and biological features of VL may mimic haematological disorders as leukemia, but an enlargement of the liver and especially of the spleen should remind in this parasitic infection and its potential fatal complication, the HS.

Validity of Charlson Comorbidity Index in patients hospitalised with acute coronary syndrome. Insights from the nationwide AMIS Plus registry 2002-2012.

OBJECTIVE: This study aimed to assess the impact of individual comorbid conditions as well as the weight assignment, predictive properties and discriminating power of the Charlson Comorbidity Index (CCI) on outcome in patients with acute coronary syndrome (ACS). METHODS: A prospective multicentre observational study (AMIS Plus Registry) from 69 Swiss hospitals with 29 620 ACS patients enrolled from 2002 to 2012. The main outcome measures were in-hospital and 1-year follow-up mortality. RESULTS: Of the patients, 27% were female (age 72.1 ± 12.6 years) and 73% were male (64.2 ± 12.9 years). 46.8% had comorbidities and they were less likely to receive guideline-recommended drug therapy and reperfusion. Heart failure (adjusted OR 1.88; 95% CI 1.57 to 2.25), metastatic tumours (OR 2.25; 95% CI 1.60 to 3.19), renal diseases (OR 1.84; 95% CI 1.60 to 2.11) and diabetes (OR 1.35; 95% CI 1.19 to 1.54) were strong predictors of in-hospital mortality. In this population, CCI weighted the history of prior myocardial infarction higher (1 instead of -0.4, 95% CI -1.2 to 0.3 points) but heart failure (1 instead of 3.7, 95% CI 2.6 to 4.7) and renal disease (2 instead of 3.5, 95% CI 2.7 to 4.4) lower than the benchmark, where all comorbidities, age and gender were used as predictors. However, the model with CCI and age has an identical discrimination to this benchmark (areas under the receiver operating characteristic curves were both 0.76). CONCLUSIONS: Comorbidities greatly influenced clinical presentation, therapies received and the outcome of patients admitted with ACS. Heart failure, diabetes, renal disease or metastatic tumours had a major impact on mortality. CCI seems to be an appropriate prognostic indicator for in-hospital and 1-year outcomes in ACS patients. ClinicalTrials.gov Identifier: NCT01305785.

Metabolic syndrome is associated with colorectal cancer in men.

AIM OF THE STUDY: We assessed the relation between metabolic syndrome (MetS) and its components and colorectal cancer. METHODS: We analysed data from a multicentre case-control study conducted in Italy and Switzerland, including 1378 cases of colon cancer, 878 cases of rectal cancer and 4661 controls. All cases were incident and histologically confirmed. Controls were subjects admitted to the same hospitals as cases with acute non-malignant conditions. MetS was defined according to the International Diabetes Federation criteria. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were estimated by multiple logistic regression models, including terms for major identified confounding factors for colorectal cancer. RESULTS: With reference to each component of the MetS, the ORs of colorectal cancer in men were 1.27 (95% CI, 0.95-1.69) for diabetes, 1.24 (95% CI, 1.03-1.48) for hypertension, 1.14 (95% CI, 0.93-1.40) for hypercholesterolaemia and 1.26 (95% CI, 1.08-1.48) for overweight at age 30. The corresponding ORs in women were 1.20 (95% CI, 0.82-1.75), 0.87 (95% CI, 0.71-1.06), 0.83 (95% CI, 0.66-1.03) and 1.06 (95% CI, 0.86-1.30). Colorectal cancer risk was increased in men (OR=1.86; 95% CI, 1.21-2.86), but not in women (OR=1.13; 95% CI, 0.66-1.93), with MetS. The ORs were 2.09 (95% CI, 1.38-3.18) in men and 1.15 (95% CI, 0.68-1.94) in women with > or =3 components of the MetS, as compared to no component. Results were similar for colon and rectal cancers. CONCLUSION: This study supports a direct association between MetS and both colon and rectal cancers in men, but not in women.

SET translocation is associated with increase in caspase cleaved amyloid precursor protein in CA1 of Alzheimer and Down syndrome patients.

Caspase cleaved amyloid precursor protein (APPcc) and SET are increased and mislocalized in the neuronal cytoplasm in Alzheimer Disease (AD) brains. Translocated SET to the cytoplasm can induce tau hyperphosphorylation. To elucidate the putative relationships between mislocalized APPcc and SET, we studied their level and distribution in the hippocampus of 5 controls, 3 Down syndrome and 10 Alzheimer patients. In Down syndrome and Alzheimer patients, APPcc and SET levels were increased in CA1 and the frequency of both localizations in the neuronal cytoplasm was high in CA1, and low in CA4. As the increase of APPcc is already present at early stages of AD, we overexpressed APPcc in CA1 and the dentate gyrus neurons of adult mice with a lentiviral construct. APPcc overexpression in CA1 and not in the dentate gyrus induced endogenous SET translocation and tau hyperphosphorylation. These data suggest that increase in APPcc in CA1 neurons could be an early event leading to the translocation of SET and the progression of AD through tau hyperphosphorylation.

Prevalence of Joint Hypermobility and Joint Hypermobility Syndrome in a Swiss population with Chronic Low Back Pain

Objective¦Joint hypermobility (JH) and Joint Hypermobility Syndrome (JHS) are often underdiagnosed¦and were never specifically assessed in a selected population of chronic low back pain¦(LBP). This study aimed to assess JH and JHS among a population with chronic LBP using the¦Beighton and the Brigthon criteria.¦Methods¦We conducted a retrospective cross-sectional study based on a prospective data base¦among 143 patients with non-specific chronic LBP. Patients were seen by the same rheumatologist,¦who looked for JH and JHS and took their medical history. Data were analysed using logistic¦regression.¦Results¦We found a JH prevalence of 33,3% (CI 95% 22.0-44.6) among women and 21,4% (11.7-¦31.2) among men, and for JHS, of 37,9% (26.0-49.8) among women and 30,9% (19.7-42.0) among¦men. JH was less frequent among people older than fifty (P < 0.02). JHS was more prevalent among¦Swiss individuals (P < 0.01) and among individuals having a non-manual job (P<0.03) compared to¦there opposites. Patients having an important limitation for daily living activities were four times¦more likely to have JHS. Degenerative spinal disorders were negatively associated with JH (OR¦0.31 (0.13-0.73) and JHS (OR 0.31 (0.14-0.68).¦Conclusion¦A high prevalence of joint hypermobility was found in our population. JHS should be¦part of differential diagnosis in individuals with chronic non-specific LBP.

Discriminating Irritable Bowel Syndrome fromInflammatory Bowel Disease: what is the Role of Biomarkers in Daily Practice?

Background a nd A ims: D iscriminating irritable bowelsyndrome (IBS) from inflammatory bowel disease (IBD) can bea clinical c hallenge as s ymptoms c an overlap. We a nd othershave recently shown that fecal c alprotectin ( FC) is moreaccurate for d iscriminating IBS f rom IBD compared to C -reactive p rotein ( CRP) and b lood leukocytes. We a imed toassess which b iomarkers are used by g astroenterologists intheir daily practice for discriminating IBS from IBD.Methods: A q uestionnaire was sent to all board certifiedgastroenterologists in Switzerland in July 2010.Results: Response rate was 57% (153/270). Mean physician'sage was 50±9years, mean duration o f gastroenterologicpractice 1 4±8years, 52% of them were working in p rivatepractice a nd 48% in h ospitals. T he following biomarkers weredetermined for discriminating IBS from IBD: CRP 100%, FC79%, hematogram (red blood cells and leukocytes) 70%, ironstatus ( ferritin, t ransferrin s aturation) 59%, e rythrocytesedimentation rate 2.7%, protein electrophoresis 0.7%, andalpha-1 antitrypsin clearance 0.7%. There was a trend for usingFC more often in p rivate practice t han in h ospital ( P = 0.08).Eighty-nine percent of gastroenterologists considered FC to besuperior to CRP for discriminating IBS from IBD, 8 7% thoughtthat patient's compliance for fecal sampling is high, and 51%judged the fee of USD 60 for a FC test as appropriate.Conclusions: F C is widely used in c linical practice t odiscriminate IBS from IBD. In accordance with the scientificevidence, the majority of gastroenterologists consider FC to bemore accurate than CRP for discriminating IBS from IBD.

Prioritizing genetic testing in patients with kallmann syndrome using clinical phenotypes.

Context: The complexity of genetic testing in Kallmann syndrome (KS) is growing and costly. Thus, it is important to leverage the clinical evaluations of KS patients to prioritize genetic screening. Objective: The objective of the study was to determine which reproductive and nonreproductive phenotypes of KS subjects have implications for specific gene mutations. Subjects: Two hundred nineteen KS patients were studied: 151 with identified rare sequence variants (RSVs) in 8 genes known to cause KS (KAL1, NELF, CHD7, HS6ST1, FGF8/FGFR1, or PROK2/PROKR2) and 68 KS subjects who remain RSV negative for all 8 genes. Main Outcome Measures: Reproductive and nonreproductive phenotypes within each genetic group were measured. Results: Male KS subjects with KAL1 RSVs displayed the most severe reproductive phenotype with testicular volumes (TVs) at presentation of 1.5 ± 0.1 mL vs 3.7 ± 0.3 mL, P < .05 vs all non-KAL1 probands. In both sexes, synkinesia was enriched but not unique to patients with KAL1 RSVs compared with KAL1-negative probands (43% vs 12%; P < .05). Similarly, dental agenesis and digital bone abnormalities were enriched in patients with RSVs in the FGF8/FGFR1 signaling pathway compared with all other gene groups combined (39% vs 4% and 23% vs 0%; P < .05, respectively). Hearing loss marked the probands with CHD7 RSVs (40% vs 13% in non-CHD7 probands; P < .05). Renal agenesis and cleft lip/palate did not emerge as statistically significant phenotypic predictors. Conclusions: Certain clinical features in men and women are highly associated with genetic causes of KS. Synkinesia (KAL1), dental agenesis (FGF8/FGFR1), digital bony abnormalities (FGF8/FGFR1), and hearing loss (CHD7) can be useful for prioritizing genetic screening.

Complex regional pain syndrome type I affects brain structure in prefrontal and motor cortex.

The complex regional pain syndrome (CRPS) is a rare but debilitating pain disorder that mostly occurs after injuries to the upper limb. A number of studies indicated altered brain function in CRPS, whereas possible influences on brain structure remain poorly investigated. We acquired structural magnetic resonance imaging data from CRPS type I patients and applied voxel-by-voxel statistics to compare white and gray matter brain segments of CRPS patients with matched controls. Patients and controls were statistically compared in two different ways: First, we applied a 2-sample ttest to compare whole brain white and gray matter structure between patients and controls. Second, we aimed to assess structural alterations specifically of the primary somatosensory (S1) and motor cortex (M1) contralateral to the CRPS affected side. To this end, MRI scans of patients with left-sided CRPS (and matched controls) were horizontally flipped before preprocessing and region-of-interest-based group comparison. The unpaired ttest of the "non-flipped" data revealed that CRPS patients presented increased gray matter density in the dorsomedial prefrontal cortex. The same test applied to the "flipped" data showed further increases in gray matter density, not in the S1, but in the M1 contralateral to the CRPS-affected limb which were inversely related to decreased white matter density of the internal capsule within the ipsilateral brain hemisphere. The gray-white matter interaction between motor cortex and internal capsule suggests compensatory mechanisms within the central motor system possibly due to motor dysfunction. Altered gray matter structure in dorsomedial prefrontal cortex may occur in response to emotional processes such as pain-related suffering or elevated analgesic top-down control.