Neuroendocrine and behavioral effects of CRH blockade and stress in male rats.

Our previous data have shown that restraint (RT), a mild nonpainful stressor, acutely impairs nonsocial and social behavior in male rats. Corticotropin-releasing hormone (CRH) is a regulator of these behavioral responses. To evaluate whether CRH mediates the neuroendocrine and behavioral alterations present 24 h after restraint stress, we administered the CRH antagonist alpha-helical CRH(9-41) (alpha-hCRH) intracerebroventricularly to male rats and we compared its effects with those of saline. Twenty-four hours after treatment, nonsocial behaviors were significantly decreased by alpha-hCRH, this effect being independent of RT. Among social behaviors, only introductory activity showed significant differences as a result of both RT and alpha-hCRH. The concentrations of ACTH in the plasma and those of beta-endorphin in the anterior and neurointermediate lobes of the pituitary were affected by alpha-hCRH treatment. The effect on ACTH was simply related to the administration of the alpha-hCRH, while for beta-endorphin, significant interactions between alpha-hCRH and RT were found. On the whole, these results point to the role played by CRH in the control of neuronal mechanisms involved in the stress-induced effects.     

Structural connectivity differences in motor network between tremor‐dominant and nontremor Parkinson's disease

Motor phenotypes of Parkinson's disease (PD) are recognized to have different prognosis and therapeutic response, but the neural basis for this clinical heterogeneity remains largely unknown. The main aim of this study was to compare differences in structural connectivity metrics of the main motor network between tremor‐dominant and nontremor PD phenotypes (TD‐PD and NT‐PD, respectively) using probabilistic tractography‐based network analysis. A total of 63 PD patients (35 TD‐PD patients and 28 NT‐PD patients) and 30 healthy controls underwent a 3 T MRI. Next, probabilistic tractography‐based network analysis was performed to assess structural connectivity in cerebello‐thalamo‐basal ganglia‐cortical circuits, by measuring the connectivity indices of each tract and the efficiency of each node. Furthermore, dopamine transporter single‐photon emission computed tomography (DAT‐SPECT) with ¹²³I‐ioflupane was used to assess dopaminergic striatal depletion in all PD patients. Both PD phenotypes showed nodal abnormalities in the substantia nigra, in agreement with DAT‐SPECT evaluation. In addition, NT‐PD patients displayed connectivity alterations in nigro‐pallidal and fronto‐striatal pathways, compared with both controls and TD‐PD patients, in which the same motor connections seemed to be relatively spared. Of note, in NT‐PD group, rigidity‐bradykinesia score correlated with fronto‐striatal connectivity abnormalities. These findings demonstrate that structural connectivity alterations occur in the cortico‐basal ganglia circuit of NT‐PD patients, but not in TD‐PD patients, suggesting that these anatomical differences may underlie different motor phenotypes of PD. Hum Brain Mapp 38:4716–4729, 2017. © 2017 Wiley Periodicals, Inc.     

A newly distal hereditary motor neuropathy caused by a rare <Emphasis Type="Italic">AIFM1</Emphasis> mutation

In two siblings, who suffer from an early childhood-onset axonal polyneuropathy with exclusive involvement of motor fibers, the c.629T>C (p.F210S) mutation was identified in the X-linked AIFM1 gene, which encodes for the apoptosis-inducing factor (AIF). The mutation was predicted as deleterious, according to in silico analysis. A decreased expression of the AIF protein, altered cellular morphology, and a fragmented mitochondrial network were observed in the proband’s fibroblasts. This new form of motor neuropathy expands the phenotypic spectrum of AIFM1 mutations and therefore, the AIFM1 gene should be considered in the diagnosis of hereditary motor neuropathies.     

Commotio Cordis and complete heart block: Where is the block level?

Ventricular fibrillation is typically the initial arrhythmia in commotio cordis following precordium impacts that occur within an electrically vulnerable period of the cardiac cycle. Conversely, complete heart block is very rare in this context, and its mechanism and temporal course are poorly understood. The presented case concerns a 12-year-old boy, athletic skier, who developed a transient complete heart block following commotio cordis. The electrocardiographic features, the proposed block level and mechanisms of complete heart block following commotio cordis are discussed.     

Missing HLA C group 1 ligand in patients with AML and MDS is associated with reduced risk of relapse and better survival after allogeneic stem cell transplantation with fludarabine and treosulfan reduced toxicity conditioning

Reduced‐toxicity conditioning with fludarabine and treosulfan is a dose‐intensive regimen with enhanced anti‐leukemia effect and acceptable toxicity in AML/MDS. HLA‐C regulates natural‐killer (NK) cell function by inhibiting Killer immunoglobulin‐like receptors (KIR) and is divided into C1 and C2 epitopes. The missing‐ligand theory suggests that missing recipient KIR ligands drives NK‐alloreactivity after SCT, in the absence of HLA‐mismatch by activating unlicensed donor NK cells. We analyzed SCT outcomes in 203 patients with AML/MDS, median age 58 years, given SCT from matched‐siblings (n = 97) or matched‐unrelated donors (n = 106), using two treosulfan doses (total 36 or 42 g/m²). 34% expressed one HLA‐C group 1 allele (C1C1), 19% one HLA‐C group 2 allele (C2C2), and 48% both KIR ligands (C1C2). Median follow‐up was 48 months. 5‐year relapse, nonrelapse mortality (NRM) and leukemia‐free survival (LFS) rates were 38%, 27%, and 36%, respectively. Relapse rates were 43%, 45%, and 26% in patients expressing C1C1, C1C2, and C2C2 ligands, respectively (P = .03). Multivariate‐analysis identified chemo‐refractory disease (HR 3.1, P = .003), poor cytogenetics (HR 1.7, P = .08), female donor to male recipient (HR 0.4, P = .01) and C2C2 ligands (HR 0.4, P = .04) as independent factors predicting relapse. HLA‐C ligands were not associated with GVHD or NRM. LFS was 33%, 30%, and 46%, respectively (P = .07). Chemorefractory disease (HR 3.1, P = .0004) and C2C2 group ligand (HR 0.6, P = .06) independently predicted LFS. Treosulfan dose did not predict any SCT outcome. In conclusion, missing HLA‐C group 1 ligand is associated with reduced relapse risk, similar NRM and improved LFS, after HLA‐matched SCT with treosulfan conditioning in AML/MDS.     

The Emerging Role of Nutraceuticals in Cardiovascular Calcification: Evidence from Preclinical and Clinical Studies

Cardiovascular calcification is the ectopic deposition of calcium-phosphate crystals within the arterial wall and the aortic valve leaflets. This pathological process leads to increased vascular stiffness, reduced arterial elasticity, and aortic valve stenosis, increasing the risk of cardiovascular diseases. Although cardiovascular calcification is an increasing health care burden, to date no medical therapies have been approved for treating or preventing it. Considering the current lack of therapeutic strategies and the increasing prevalence of cardiovascular calcification, the investigation of some nutraceuticals to prevent this pathological condition has become prevalent in recent years. Recent preclinical and clinical studies evaluated the potential anti-calcific role of nutraceuticals (including magnesium, zinc, iron, vitamin K, and phytate) in the progression of vascular calcification, providing evidence for their dietary supplementation, especially in high-risk populations. The present review summarizes the current knowledge and latest advances for nutraceuticals with the most relevant preclinical and clinical data, including magnesium, zinc, iron, vitamin K, and phytate. Their supplementation might be recommended as a cost-effective strategy to avoid nutritional deficiency and to prevent or treat cardiovascular calcification. However, the optimal dose of nutraceuticals has not been identified and large interventional trials are warranted to support their protective effects on cardiovascular disease.     

A novel delins mutation in the alpha-TTP gene in a family segregating ataxia with isolated vitamin E deficiency

Ataxia with isolated vitamin E deficiency is a rare autosomal recessive neurodegenerative disease due to mutations in the alpha-tocopherol transfer protein gene. In ataxia with isolated vitamin E deficiency, the biochemical hallmark is the low plasmatic levels of vitamin E and, in most of the patients, vitamin E supplementation allows a stabilization of the neurologic conditions. We have investigated the genetic cause of ataxia and reduced levels of vitamin E, and apolipoproteins A1 and B in a 16-y-old patient. Results revealed that our propositus is a compound heterozygote for the c.227_229delinsATT/c.744delA mutations in the alpha-tocopherol transfer protein gene, each inherited from one of the two parents. His sister is also a compound heterozygote for both mutations, and she presents a biochemical pattern similar to that of his brother. After receiving the vitamin E supplementation, plasmatic levels of vitamin E and apolipoprotein A1 have been normalized in the propositus. The detected mutations would justify the undetectable levels of vitamin E, but would not explain the also decreased levels of the apolipoproteins, as neither that after treatment with vitamin E, the levels of apolipoprotein B do not become normal. These findings suggest that other genes may play a role in producing this atypical biochemical profile.