Distinct populations of GABAergic neurons in mouse rhombomere 1 express but do not require the homeodomain transcription factor PITX2

Hindbrain rhombomere 1 (r1) is located caudal to the isthmus, a critical organizer region, and rostral to rhombomere 2 in the developing mouse brain. Dorsal r1 gives rise to the cerebellum, locus coeruleus, and several brainstem nuclei, whereas cells from ventral r1 contribute to the trochlear and trigeminal nuclei as well as serotonergic and GABAergic neurons of the dorsal raphe. Recent studies have identified several molecular events controlling dorsal r1 development. In contrast, very little is known about ventral r1 gene expression and the genetic mechanisms regulating its formation. Neurons with distinct neurotransmitter phenotypes have been identified in ventral r1 including GABAergic, serotonergic, and cholinergic neurons. Here we show that PITX2 marks a distinct population of GABAergic neurons in mouse embryonic ventral r1. This population appears to retain its GABAergic identity even in the absence of PITX2. We provide a comprehensive map of markers that places these PITX2-positive GABAergic neurons in a region of r1 that intersects and is potentially in communication with the dorsal raphe.     

Cardiorespiratory and cerebrovascular responses to head-up tilt I: Influence of age and training status

The purpose of this study was to examine the combined cardiorespiratory and cerebrovascular responses to head-up tilt (HUT) in young (27 ± 4 years) and older (65 ± 5 years) trained and untrained humans. Middle cerebral artery blood velocity (MCAv; transcranial Doppler ultrasound), blood pressure (BP; Finometer) and cardiac output (Q?) were measured continuously whilst supine and during 60° HUT for 15 min or to pre-syncope in 41 participants [nine young trained; eleven young untrained; twelve older trained; nine older untrained]. Thirty seven of forty one participants completed 15 min HUT, and orthostatic tolerance did not differ with age or fitness (P = 0.66). Supine MCAv was 30% lower in the older participants but the HUT-induced drop in MCAv was not altered by age [− 18% (young) vs. − 17% (older)], or fitness. Mean arterial BP was maintained during HUT and not altered by age or fitness. In the untrained, peripheral resistance was elevated [11% vs. − 2% (trained); P = 0.01], and Q? was reduced [− 10% vs. − 5% (trained); P = 0.04] with HUT. Despite these age- and fitness-associated differences in some cardiovascular responses to HUT, orthostatic tolerance was similar across groups. Thus, at least in this healthy population, neither age nor fitness impacts on the ability to adapt to postural change.     

Prevalence and clinical profile and management of peripheral arterial disease in elderly patients with diabetes

Introduction

Peripheral arterial disease (PAD) increases with age and diabetes. The aim of this study was to assess the prevalence of PAD in an elderly population with diabetes.

Methods

This multicenter and cross-sectional study included patients > 70 years, with an established diagnosis of diabetes. PAD was defined as those patients with a history of revascularization or amputation due to ischemia, or a pathological ankle-brachial index (ABI). Adequate blood pressure (BP), LDL cholesterol and HbA1c control were considered as < 130/80 mm Hg, < 100 mg⁄dL and < 7.0%, respectively.

Results

A total of 1462 patients were included. The most frequent cardiovascular risk factor and cardiovascular disease were hypertension (80.37%) and PAD (60.60% overall; 83.2% of those assisted by vascular surgeons vs 31.9% of those attended by other medical specialists; p < 0.001), respectively. However, when ABI was measured, 70.99% of the study population had PAD (80.2% of those assisted by vascular surgeons vs 59.6% of those attended by other medical specialists; p < 0.001). The predictors for a pathological ABI included male gender, smoking, dyslipidemia, family history of premature cardiovascular disease, sedentary lifestyle, diabetic-related complications, heart and cerebrovascular diseases. Although risk factors control was very poor, it was even lower in patients with PAD.

Conclusions

The prevalence of PAD is high in diabetic elderly patients. The concomitance with other risk factors and cardiovascular diseases was very high. The ABI allowed increasing the diagnosis of PAD.     

A new telemonitoring system intended for chronic heart failure patients using mobile telephone technology — Feasibility study

Background

Remote monitoring is one modality of structured care in chronic heart failure. The purpose of this study was to evaluate the feasibility of a new wireless telemonitoring system via a mobile phone network.

Methods

Portable home devices for electrocardiogram, blood pressure, body weight and self-assessment measurements were connected (via Bluetooth®) to a personal digital assistant (PDA) that performs automated encrypted transmission via mobile phone. Two telemedical centres were set-up.

Results

30 healthy volunteers were enrolled and followed for 26 days. A total of 4002 single measurements were taken, 133 ± 37 per person. No data was lost or incorrectly allocated. 880 of 937 (94%) of the ECG recordings had sufficient diagnostic quality for rhythm analysis and single beat measurements. 50 continuous ECG-streams (312 min) without disruption were performed. Total system availability was 96.6%, including that of the mobile phone network.

Conclusions

Mobile phone technology is suitable for continuous and secure medical data transmission. To evaluate the clinical use in chronic heart failure patients, a large multicentre randomized controlled trial (ClinicalTrials.gov Identifier: NCT00543881) was started.     

The loss of asymmetry and reduced interhemispheric connectivity in adolescents with autism: A study using diffusion spectrum imaging tractography

Evidence from neuroimaging and neurobiological studies suggests that abnormalities in cortical-cortical connectivity involving both local and long-distance scales may be related to autism. The present study analyzed the microstructural integrity of the long-range connectivity related to social cognition and language processing with diffusion tractography among adolescents with autism compared with neurotypical adolescents. Tract-specific analyses were used to study the long-range connectivity responsible for integrating social cognition and language processing. Specifically, three pairs of association fibers and three portions of callosal fiber tracts were analyzed. Generalized fractional anisotropy (GFA) values were measured along individual targeted fiber tracts to investigate alterations in microstructure integrity. The asymmetry patterns were also assessed in three pairs of association fibers. In neurotypical participants, we found a consistent leftward asymmetry in three pairs of association fibers. However, adolescents with autism did not demonstrate such asymmetry. Moreover, adolescents with autism had significantly lower mean GFA in three callosal fiber tracts than neurotypical participants. The loss of leftward asymmetry and reduction of interhemispheric connection in adolescents with autism suggest alterations of the long-range connectivity involved in social cognition and language processing. Our results warrant further investigation by combining developmental and neurocognitive data.     

Hemispheric comparisons of neuron density in the planum temporale of schizophrenia and nonpsychiatric brains

Postmortem and in vivo studies of schizophrenia frequently reveal reduced cortical volume, but the underlying cellular abnormalities are incompletely defined. One influential hypothesis, especially investigated in Brodmann's area 9 of prefrontal cortex, is that the number of neurons is normal, and the volume change is caused by reduction of the surrounding neuropil. However, studies have differed on whether the cortex has the increased neuron density that is predicted by this hypothesis. In a recent study of bilateral planum temporale (PT), we reported smaller volume and width of the outer cortex (layers I-III), especially in the left hemisphere, among subjects with schizophrenia. In the present study, we measured neuron density and size in the same PT samples, and also in prefrontal area 9 of the same brains. In the PT, separate stereological measurements were made in layers II, IIIc, and VI, whereas area 9 was sampled in layer IIIb-c. In both cortical regions, there was no significant effect of schizophrenia on neuronal density or size. There was, nevertheless, a trend-level right > left hemispheric asymmetry of neuron density in the PT, which may partially explain the previously reported left > right asymmetry of cortical width. In schizophrenia, our findings suggest that closer packing of neurons may not always explain reduced cortical volume, and subtly decreased neuron number may be a contributing factor.     

Shape alterations in the striatum in chorea-acanthocytosis

Chorea-acanthocytosis (ChAc) is an uncommon autosomal recessive disorder due to mutations of the VPS13A gene, which encodes for the membrane protein chorein. ChAc presents with progressive limb and orobuccal chorea, but there is often a marked dysexecutive syndrome. ChAc may first present with neuropsychiatric disturbance such as obsessive-compulsive disorder (OCD), suggesting a particular role for disruption to striatal structures involved in non-motor frontostriatal loops, such as the head of the caudate nucleus. Two previous studies have suggested a marked reduction in volume in the caudate nucleus and putamen, but did not examine morphometric change. We investigated morphometric change in 13 patients with genetically or biochemically confirmed ChAc and 26 age- and gender-matched controls. Subjects underwent magnetic resonance imaging and manual segmentation of the caudate nucleus and putamen, and shape analysis using a non-parametric spherical harmonic technique. Both structures showed significant and marked reductions in volume compared with controls, with reduction greatest in the caudate nucleus. Both structures showed significant shape differences, particularly in the head of the caudate nucleus. No significant correlation was shown between duration of illness and striatal volume or shape, suggesting that much structural change may have already taken place at the time of symptom onset. Our results suggest that striatal neuron loss may occur early in the disease process, and follows a dorsal-ventral gradient that may correlate with early neuropsychiatric and cognitive presentations of the disease.     

Validation of the Edinburgh Depression Scale during pregnancy

Background

Untreated depression during pregnancy may have adverse outcomes for the mother and her child. Screening for depression in the general pregnant population is thus recommended. The Edinburgh Depression Scale (EDS) is widely used for postpartum depression screening. There is no consensus on which EDS cutoff values to use during pregnancy. The aim of the current study was to examine the predictive validity and concurrent validity of the EDS for all three trimesters of pregnancy.

Methods

In a large unselected sample of 845 pregnant women, the sensitivity, specificity, and validity of the EDS were evaluated. The Composite International Diagnostic Interview (depression module) was used to examine the predictive validity of the EDS. The anxiety and somatization subscales of the Symptom Checklist 90 (SCL-90) were used to examine its concurrent validity. Only women with a major depressive episode were considered as cases.

Results

The prevalence of depression decreased toward end term: 5.6%, 5.4%, and 3.4%. The EDS scores also decreased toward end term, while the SCL-90 subscale anxiety scores increased. The EDS showed high test-retest reliability and high concurrent validity with the SCL-90 anxiety and somatization subscales. The area under the receiver operating characteristic curve was high and varied between 0.93 and 0.97. A cutoff value of 11 in the first trimester and that of 10 in the second and third trimesters gave the most adequate combination of sensitivity, specificity, and positive predictive value.

Conclusions

The EDS is a reliable instrument for screening depression during pregnancy. A lower cutoff than commonly applied in the postpartum period is recommended.     

Higher levels of fatigue are associated with higher CRP levels in disease-free breast cancer survivors

Objective

To investigate the associations between level of fatigue and various potential inflammatory biomarkers for fatigue after multivariate adjustments for possible confounders in a sample of 299 disease-free survivors of breast cancer (BCSs) at a mean of 4 years post diagnosis.

Methods

Medical record data were used for cancer-related information, and a follow-up mailed survey collected data on fatigue, depression, anxiety and insomnia symptoms as well as information on demographics, physical health, medication and lifestyle. Blood samples drawn at an outpatient examination were analyzed for leukocyte count, high sensitivity C-reactive Protein (CRP), interleukin 1 receptor antagonist (IL-1ra), interleukin-6 (IL-6), soluble tumor necrosis factor receptor type 1 (sTNF-R1) and neopterin.

Results

Fatigue levels were significantly and positively associated with hsCRP (p<.001) and leukocyte count (p=.018), but not with levels of IL-1ra, IL-6, sTNF-R1 or neopterin in unadjusted analyses. Only hsCRP remained significantly associated with fatigue levels in the fully adjusted models (p=.020). Depression and self-rated health also remained independently associated with fatigue; however these variables were not significantly associated with hsCRP in multivariate analyses.

Conclusion

In general, and after adjustment for potential confounders, our hypotheses of positive associations between fatigue and several inflammatory markers were not confirmed. However, a small but independent association between level of fatigue and hsCRP was observed and supports the hypothesis that low-grade inflammation could play a role in the pathogenesis of fatigue in BCSs.