The diet of the Alpine mouse Apodemus alpicola in the Swiss Alps

In this study, we used faecal analysis to determine the diet of the alpine mouse Apodemus alpicola in the field for the first time. This species consumes mainly insects in spring and fruits and seeds of small herbaceous dicotyledons in summer and autumn. Compared to the two congeneric species A. flavicollis and A. sylvaticus, which also occur in the Alps, the diet of A. alpicola is rich in contrasts, with a very pronounced difference between spring and summer. The absence of tree seeds also suggests a mostly terrestrial behaviour. We explain these facts by the specificity of the habitat of A. alpicola: the extreme weather conditions produce great seasonal changes in the vegetation, and the rocky ground favours the adaptation to rock climbing rather than to arboreal Living. (c) 2005 Elsevier GmbH. All rights reserved.

Electric bicycles as a new active transportation modality to promote health.

GOJANOVIC, B., J. WELKER, K. IGLESIAS, C. DAUCOURT, and G. GREMION. Electric Bicycles as a New Active Transportation Modality to Promote Health. Med. Sci. Sports Exerc., Vol. 43, No. 11, pp. 2204-2210, 2011. Electrically assisted bicycles (EAB) are an emerging transportation modality favored for environmental reasons. Some physical effort is required to activate the supporting engine, making it a potential active commuting option. Purpose: We hypothesized that using an EAB in a hilly city allows sedentary subjects to commute comfortably, while providing a sufficient effort for health-enhancing purposes. Methods: Sedentary subjects performed four different trips at a self-selected pace: walking 1.7 km uphill from the train station to the hospital (WALK), biking 5.1 km from the lower part of town to the hospital with a regular bike (BIKE), or EAB at two different power assistance settings (EAB(high), EAB(std)). HR, oxygen consumption, and need to shower were recorded. Results: Eighteen sedentary subjects (12 female, 6 male) age 36 +/- 10 yr were included, with (V) over dotO(2max) of 39.4 +/- 5.4 mL.min(-1).kg(-1). Time to complete the course was 22 (WALK), 19 (EAB(high)), 21 (EAB(std)), and 30 (BIKE) min. Mean %(V) over dotO(2max) was 59.0%, 54.9%, 65.7%, and 72.8%. Mean%HR(max) was 71.5%, 74.5%, 80.3%, and 84.0%. There was no significant difference between WALK and EAB(high), but all other comparisons were different (P < 0.05). Two subjects needed to shower after EAB(high), 3 needed to shower after WALK, 8 needed to shower after EAB(std), and all 18 needed to shower after BIKE. WALK and EAB(high) elicited 6.5 and 6.1 METs (no difference), whereas it was 7.3 and 8.2 for EAB(std) and BIKE. Conclusions: EAB is a comfortable and ecological transportation modality, helping sedentary people commute to work and meet physical activity guidelines. Subjects appreciated ease of use and mild effort needed to activate the engine support climbing hills, without the need to shower at work. EAB can be promoted in a challenging urban environment to promote physical activity and mitigate pollution issues.

Contribution of genetic background, traditional risk factors, and HIV-related factors to coronary artery disease events in HIV-positive persons.

BACKGROUND: Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection. METHODS: In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort. RESULTS: A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9 × 10(-4)). In the final multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval [CI], 1.05-2.04). This effect was similar to hypertension (OR = 1.36; 95% CI, 1.06-1.73), hypercholesterolemia (OR = 1.51; 95% CI, 1.16-1.96), diabetes (OR = 1.66; 95% CI, 1.10-2.49), ≥ 1 year lopinavir exposure (OR = 1.36; 95% CI, 1.06-1.73), and current abacavir treatment (OR = 1.56; 95% CI, 1.17-2.07). The effect of the genetic risk score was additive to the effect of nongenetic CAD risk factors, and did not change after adjustment for family history of CAD. CONCLUSIONS: In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD.

Defective nitric oxide synthesis: a link between metabolic insulin resistance, sympathetic overactivity and cardiovascular morbidity.

Epidemiological studies demonstrate an association between insulin resistance, hypertension and cardiovascular morbidity. In addition to its metabolic effects, insulin also has important cardiovascular actions. The sympathetic nervous system and the nitric oxide-l-arginine pathway have emerged as central players in the mediation of these actions. Over the past decade, the underlying mechanisms and the factors that may govern the interaction between insulin and these two major cardiovascular regulatory systems have been studied extensively in healthy people and insulin-resistant individuals. Here we summarize the current understanding and gaps in knowledge on these interactions. We propose that a genetic and/or acquired defect of nitric oxide synthesis could represent a central defect triggering many of the metabolic, vascular and sympathetic abnormalities characteristic of insulin-resistant states, all of which may predispose to cardiovascular disease.

Mid-gut ACTH-secreting neuroendocrine tumor unmasked with (18)F-dihydroxyphenylalanine-positron emission tomography.

Ectopic ACTH Cushing's syndrome (EAS) is often caused by neuroendocrine tumors (NETs) of lungs, pancreas, thymus, and other less frequent locations. Localizing the source of ACTH can be challenging. A 64-year-old man presented with rapidly progressing fatigue, muscular weakness, and dyspnea. He was in poor condition and showed facial redness, proximal amyotrophy, and bruises. Laboratory disclosed hypokalemia, metabolic alkalosis, and markedly elevated ACTH and cortisol levels. Pituitary was normal on magnetic resonance imaging (MRI), and bilateral inferior petrosal sinus blood sampling with corticotropin-releasing hormone stimulation showed no significant central-to-periphery gradient of ACTH. Head and neck, thoracic and abdominal computerized tomography (CT), MRI, somatostatin receptor scintigraphy (SSRS), and (18)F-deoxyglucose-positron emission tomography (FDG-PET) failed to identify the primary tumor. (18)F-dihydroxyphenylalanine (F-DOPA)-PET/CT unveiled a 20-mm nodule in the jejunum and a metastatic lymph node. Segmental jejunum resection showed two adjacent NETs, measuring 2.0 and 0.5 cm with a peritoneal metastasis. The largest tumor expressed ACTH in 30% of cells. Following surgery, after a transient adrenal insufficiency, ACTH and cortisol levels returned to normal values and remain normal over a follow-up of 26 months. Small mid-gut NETs are difficult to localize on CT or MRI, and require metabolic imaging. Owing to low mitotic activity, NETs are generally poor candidates for FDG-PET, whereas SSRS shows poor sensitivity in EAS due to intrinsically low tumor concentration of type-2 somatostatin receptors (SST2) or to receptor down regulation by excess cortisol. However, F-DOPA-PET, which is related to amine precursor uptake by NETs, has been reported to have high positive predictive value for occult EAS despite low sensitivity, and constitutes a useful alternative to more conventional methods of tumor localization. LEARNING POINTS: Uncontrolled high cortisol levels in EAS can be lethal if untreated.Surgical excision is the keystone of NETs treatment, thus tumor localization is crucial.Most cases of EAS are caused by NETs, which are located mainly in the lungs. However, small gut NETs are elusive to conventional imaging and require metabolic imaging for detection.FDG-PET, based on tumor high metabolic rate, may not detect NETs that have low mitotic activity. SSRS may also fail, due to absent or low concentration of SST2, which may be down regulated by excess cortisol.F-DOPA-PET, based on amine-precursor uptake, can be a useful method to localize the occult source of ACTH in EAS when other methods have failed.

Status epilepticus: impact of therapeutic coma on outcome.

OBJECTIVES: Therapeutic coma is advocated in guidelines for management of refractory status epilepticus; this is, however, based on weak evidence. We here address the specific impact of therapeutic coma on status epilepticus outcome. DESIGN: Retrospective assessment of a prospectively collected cohort. SETTING: Academic hospital. PATIENTS: Consecutive adults with incident status epilepticus lasting greater than or equal to 30 minutes, admitted between 2006 and 2013. MEASUREMENTS AND MAIN RESULTS: We recorded prospectively demographics, clinical status epilepticus features, treatment, and outcome at discharge and retrospectively medical comorbidities, hospital stay, and infectious complications. Associations between potential predictors and clinical outcome were analyzed using multinomial logistic regressions. Of 467 patients with incident status epilepticus, 238 returned to baseline (51.1%), 162 had new disability (34.6%), and 67 died (14.3%); 50 subjects (10.7%) were managed with therapeutic coma. Therapeutic coma was associated with poorer outcome in the whole cohort (relative risk ratio for new disability, 6.86; 95% CI, 2.84-16.56; for mortality, 9.10; 95% CI, 3.17-26.16); the effect was more important in patients with complex partial compared with generalized convulsive or nonconvulsive status epilepticus in coma. Prevalence of infections was higher (odds ratio, 3.81; 95% CI, 1.66-8.75), and median hospital stay in patients discharged alive was longer (16 d [range, 2-240 d] vs 9 d [range, 1-57 d]; p < 0.001) in subjects managed with therapeutic coma. CONCLUSIONS: This study provides class III evidence that therapeutic coma is associated with poorer outcome after status epilepticus; furthermore, it portends higher infection rates and longer hospitalizations. These data suggest caution in the straightforward use of this approach, especially in patients with complex partial status epilepticus.

TRANSITION IN ENDOCRINOLOGY: Hypogonadism in adolescence.

Puberty is a remarkable developmental process with the activation of the hypothalamic-pituitary-gonadal axis culminating in reproductive capacity. It is accompanied by cognitive, psychological, emotional, and sociocultural changes. There is wide variation in the timing of pubertal onset, and this process is affected by genetic and environmental influences. Disrupted puberty (delayed or absent) leading to hypogonadism may be caused by congenital or acquired etiologies and can have significant impact on both physical and psychosocial well-being. While adolescence is a time of growing autonomy and independence, it is also a time of vulnerability and thus, the impact of hypogonadism can have lasting effects. This review highlights the various forms of hypogonadism in adolescence and the clinical challenges in differentiating normal variants of puberty from pathological states. In addition, hormonal treatment, concerns regarding fertility, emotional support, and effective transition to adult care are discussed.

Experience-based Auditory Predictions Modulate Brain Activity to Silence as Do Real Sounds.

Interactions between stimuli's acoustic features and experience-based internal models of the environment enable listeners to compensate for the disruptions in auditory streams that are regularly encountered in noisy environments. However, whether auditory gaps are filled in predictively or restored a posteriori remains unclear. The current lack of positive statistical evidence that internal models can actually shape brain activity as would real sounds precludes accepting predictive accounts of filling-in phenomenon. We investigated the neurophysiological effects of internal models by testing whether single-trial electrophysiological responses to omitted sounds in a rule-based sequence of tones with varying pitch could be decoded from the responses to real sounds and by analyzing the ERPs to the omissions with data-driven electrical neuroimaging methods. The decoding of the brain responses to different expected, but omitted, tones in both passive and active listening conditions was above chance based on the responses to the real sound in active listening conditions. Topographic ERP analyses and electrical source estimations revealed that, in the absence of any stimulation, experience-based internal models elicit an electrophysiological activity different from noise and that the temporal dynamics of this activity depend on attention. We further found that the expected change in pitch direction of omitted tones modulated the activity of left posterior temporal areas 140-200 msec after the onset of omissions. Collectively, our results indicate that, even in the absence of any stimulation, internal models modulate brain activity as do real sounds, indicating that auditory filling in can be accounted for by predictive activity.

"Live High-Train Low and High" Hypoxic Training Improves Team-Sport Performance.

PURPOSE: This study aims to investigate physical performance and hematological changes in 32 elite male team-sport players after 14 d of "live high-train low" (LHTL) training in normobaric hypoxia (≥14 h·d at 2800-3000 m) combined with repeated-sprint training (six sessions of four sets of 5 × 5-s sprints with 25 s of passive recovery) either in normobaric hypoxia at 3000 m (LHTL + RSH, namely, LHTLH; n = 11) or in normoxia (LHTL + RSN, namely, LHTL; n = 12) compared with controlled "live low-train low" (LLTL; n = 9) training. METHODS: Before (Pre), immediately after (Post-1), and 3 wk after (Post-2) the intervention, hemoglobin mass (Hbmass) was measured in duplicate [optimized carbon monoxide (CO) rebreathing method], and vertical jump, repeated-sprint (8 × 20 m-20 s recovery), and Yo-Yo Intermittent Recovery level 2 (YYIR2) performances were tested. RESULTS: Both hypoxic groups similarly increased their Hbmass at Post-1 and Post-2 in reference to Pre (LHTLH: +4.0%, P < 0.001 and +2.7%, P < 0.01; LHTL: +3.0% and +3.0%, both P < 0.001), whereas no change occurred in LLTL. Compared with Pre, YYIR2 performance increased by ∼21% at Post-1 (P < 0.01) and by ∼45% at Post-2 (P < 0.001), with no difference between the two intervention groups (vs no change in LLTL). From Pre to Post-1, cumulated sprint time decreased in LHTLH (-3.6%, P < 0.001) and LHTL (-1.9%, P < 0.01), but not in LLTL (-0.7%), and remained significantly reduced at Post-2 (-3.5%, P < 0.001) in LHTLH only. Vertical jump performance did not change. CONCLUSIONS: "Live high-train low and high" hypoxic training interspersed with repeated sprints in hypoxia for 14 d (in season) increases the Hbmass, YYIR2 performance, and repeated-sprint ability of elite field team-sport players, with benefits lasting for at least 3 wk postintervention.

Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations.

PURPOSE: Congenital hypogonadotropic hypogonadism (CHH) and split hand/foot malformation (SHFM) are two rare genetic conditions. Here we report a clinical entity comprising the two. METHODS: We identified patients with CHH and SHFM through international collaboration. Probands and available family members underwent phenotyping and screening for FGFR1 mutations. The impact of identified mutations was assessed by sequence- and structure-based predictions and/or functional assays. RESULTS: We identified eight probands with CHH with (n = 3; Kallmann syndrome) or without anosmia (n = 5) and SHFM, seven of whom (88%) harbor FGFR1 mutations. Of these seven, one individual is homozygous for p.V429E and six individuals are heterozygous for p.G348R, p.G485R, p.Q594*, p.E670A, p.V688L, or p.L712P. All mutations were predicted by in silico analysis to cause loss of function. Probands with FGFR1 mutations have severe gonadotropin-releasing hormone deficiency (absent puberty and/or cryptorchidism and/or micropenis). SHFM in both hands and feet was observed only in the patient with the homozygous p.V429E mutation; V429 maps to the fibroblast growth factor receptor substrate 2α binding domain of FGFR1, and functional studies of the p.V429E mutation demonstrated that it decreased recruitment and phosphorylation of fibroblast growth factor receptor substrate 2α to FGFR1, thereby resulting in reduced mitogen-activated protein kinase signaling. CONCLUSION: FGFR1 should be prioritized for genetic testing in patients with CHH and SHFM because the likelihood of a mutation increases from 10% in the general CHH population to 88% in these patients.Genet Med 17 8, 651-659.

Plasma cell and terminal B-cell differentiation in mantle cell lymphoma mainly occur in the SOX11-negative subtype.

Mantle cell lymphoma is a mature lymphoid neoplasm characterized by the t(11;14)(q13;q32) and cyclin D1 overexpression. SOX11 is a transcription factor commonly overexpressed in these tumors but absent in most other mature B-cell lymphomas whose function is not well understood. Experimental studies have shown that silencing of SOX11 in mantle cell lymphoma cells promotes the shift from a mature B cell into an early plasmacytic differentiation phenotype, suggesting that SOX11 may contribute to tumor development by blocking the B-cell differentiation program. The relationship between SOX11 expression and terminal B-cell differentiation in primary mantle cell lymphoma and its relationship to the plasmacytic differentiation observed in occasional cases is not known. In this study we have investigated the terminal B-cell differentiation phenotype in 60 mantle cell lymphomas, 41 SOX11-positive and 19 SOX11-negative. Monotypic plasma cells and lymphoid cells with plasmacytic differentiation expressing cyclin D1 were observed in 7 (37%) SOX11-negative but in none of 41 SOX11-positive mantle cell lymphomas (P<0.001). Intense cytoplasmic expression of a restricted immunoglobulin light chain was significantly more frequent in SOX11-negative than -positive tumors (58 vs 13%) (P=0.001). Similarly, BLIMP1 and XBP1 expression was also significantly more frequent in SOX11-negative than in -positive cases (83 vs 34% and 75 vs 11%, respectively) (P=0.001). However, no differences in the expression of IRF4/MUM1 were observed among these subtypes of mantle cell lymphoma. In conclusion, these results indicate that SOX11-negative mantle cell lymphoma may be a particular subtype of this tumor characterized by more frequent morphological and immunophenotypic terminal B-cell differentiation features that may be facilitated by the absence of SOX11 transcription factor.

Diagnosis of endocrine disease: High-yield thyroid fine-needle aspiration cytology: an update focused on ancillary techniques improving its accuracy.

Thyroid fine-needle aspiration (FNA) cytology is a fast growing field. One of the most developing areas is represented by molecular tests applied to cytological material. Patients that could benefit the most from these tests are those that have been diagnosed as 'indeterminate' on FNA. They could be better stratified in terms of malignancy risk and thus oriented with more confidence to the appropriate management. Taking in to consideration the need to improve and keep high the yield of thyroid FNA, professionals from various fields (i.e. molecular biologists, endocrinologists, nuclear medicine physicians and radiologists) are refining and fine-tuning their diagnostic instruments. In particular, all these developments aim at increasing the negative predictive value of FNA to improve the selection of patients for diagnostic surgery. These advances involve terminology, the application of next-generation sequencing to thyroid FNA, the use of immunocyto- and histo-chemistry, the development of new sampling techniques and the increasing use of nuclear medicine as well as molecular imaging in the management of patients with a thyroid nodule. Herein, we review the recent advances in thyroid FNA cytology that could be of interest to the 'thyroid-care' community, with particular focus on the indeterminate diagnostic category.