A hematopoietic growth factor, thrombopoietin, has a proapoptotic role in the brain

Central nervous and hematopoietic systems share developmental features. We report that thrombopoietin (TPO), a stimulator of platelet formation, acts in the brain as a counterpart of erythropoietin (EPO), a hematopoietic growth factor with neuroprotective properties. TPO is most prominent in postnatal brain, whereas EPO is abundant in embryonic brain and decreases postnatally. Upon hypoxia, EPO and its receptor are rapidly reexpressed, whereas neuronal TPO and its receptor are down-regulated. Unexpectedly, TPO is strongly proapoptotic in the brain, causing death of newly generated neurons through the Ras-extracellular signal-regulated kinase 1/2 pathway. This effect is not only inhibited by EPO but also by neurotrophins. We suggest that the proapoptotic function of TPO helps to select for neurons that have acquired target-derived neurotrophic support.     

Basics of Coronary Thermodilution

Coronary microvascular dysfunction is a highly prevalent condition in both obstructive and nonobstructive coronary artery disease. Intracoronary thermodilution is a promising technique to investigate coronary microvascular (dys)function in vivo and to assess its most important metric: microvascular resistance. Here, the authors provide a practical review of bolus and continuous thermodilution for the measurement of coronary flow and microvascular resistance. The authors describe the basic principles of indicator-dilution theory and of coronary thermodilution and detail the practicalities of their application in the catheterization laboratory. Finally, the authors discuss contemporary clinical applications of coronary thermodilution–based microvascular assessment in humans and future perspectives.     

Assessment of renal flow and flow reserve in humans.

OBJECTIVES: The purpose of this work was to establish the normal range of maximal renal hyperemic response in humans and to identify the ideal renal vasodilatory stimuli. BACKGROUND: Stenotic renovascular atherosclerosis is increasingly treated by percutaneous transluminal renal intervention but with an unpredictable outcome. This may be due to hemodynamically non-significant stenosis or the presence of irreversible damage to the glomerular circulation. We propose that the renovascular hyperemic response may help identify appropriate patients. METHODS: In 28 normotensive patients, quantitative angiographic measurements of the renal artery were obtained, and renal artery pressure and flow velocity were continuously recorded after various hyperemic agents. RESULTS: In a first group of 11 patients, a significant increase in renal artery average peak velocity (APV) was observed after intrarenal (IR) bolus injection of 600 microg isosorbide dinitrate (41 +/- 19%), 30 mg papaverine (50 +/- 34%), 50 microg dopamine (94 +/- 54%), 0.8 microg x kg(-1) fenoldopam (80 +/- 25%), and during IR infusion of 1 microg x kg(-1) x min(-1) fenoldopam (86 +/- 28%). A second group of 17 patients received intravenous infusion of dopamine (3, 5, 10, 20, 30, and 40 microg x kg(-1) x min(-1)). The 3 and 5 microg x kg(-1) x min(-1) of dopamine modestly reduced renal resistance index (RI) (-13 +/- 15% and -25 +/- 20%, respectively). At higher dosages, no further decline in RI was observed. No significant change in vessel diameter was observed before and after the administration of the pharmacological stimuli suggesting that changes in APV corresponded with changes in absolute renal blood flow. CONCLUSIONS: The normal renal flow reserve averages approximately 2 in humans with normal renal function. An IR bolus injection of 50 microg x kg(-1) of dopamine is the most convenient means to elicit maximal renal hyperemia.     

Common variants in the CLDN2-MORC4 and PRSS1-PRSS2 loci confer susceptibility to acute pancreatitis

Background/Objectives

Acute pancreatitis (AP) is one of the most common gastrointestinal disorders often requiring hospitalization. Frequent aetiologies are gallstones and alcohol abuse. In contrast to chronic pancreatitis (CP) few robust genetic associations have been described. Here we analysed whether common variants in the CLDN2-MORC4 and the PRSS1-PRSS2 locus that increase recurrent AP and CP risk associate with AP.

Dysautonomia in Narcolepsy: Evidence by Questionnaire Assessment

Background and Purpose

Excessive daytime sleepiness and sudden sleep attacks are the main features of narcolepsy, but rapid-eye-movement sleep behavior disorder (RBD), hyposmia, and depression can also occur. The latter symptoms are nonmotor features in idiopathic Parkinson''s disease (IPD). In the present study, IPD-proven diagnostic tools were tested to determine whether they are also applicable in the assessment of narcolepsy.

Methods

This was a case-control study comparing 15 patients with narcolepsy (PN) and 15 control subjects (CS) using the Scales for Outcomes in Parkinson''s Autonomic Test (SCOPA-AUT), Parkinson''s Disease Nonmotor Symptoms (PDNMS), University of Pennsylvania Smell Test, Farnsworth-Munsell 100 Hue test, Beck Depression Inventory, and the RBD screening questionnaire.

Results

Both the PN and CS exhibited mild hyposmia and no deficits in visual tests. Frequent dysautonomia in all domains except sexuality was found for the PN. The total SCOPA-AUT score was higher for the PN (18.47±10.08, mean±SD) than for the CS (4.40±3.09), as was the PDNMS score (10.53±4.78 and 1.80±2.31, respectively). RBD was present in 87% of the PN and 0% of the CS. The PN were more depressed than the CS. The differences between the PN and CS for all of these variables were statistically significant (all p<0.05).

Conclusions

The results of this study provide evidence for the presence of dysautonomia and confirm the comorbidities of depression and RBD in narcolepsy patients. The spectrum, which is comparable to the nonmotor complex in IPD, suggests wide-ranging, clinically detectable dysfunction beyond the narcoleptic core syndrome.     

Clinical,biochemical and molecular analysis of 13 Japanese patients with β-ureidopropionase deficiency demonstrates high prevalence of the c.977G > A (p.R326Q) mutation

β-ureidopropionase (βUP) deficiency is an autosomal recessive disease characterized by N-carbamyl-β-amino aciduria. To date, only 16 genetically confirmed patients with βUP deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 13 Japanese βUP deficient patients. In this group of patients, three novel missense mutations (p.G31S, p.E271K, and p.I286T) and a recently described mutation (p.R326Q) were identified. The p.R326Q mutation was detected in all 13 patients with eight patients being homozygous for this mutation. Screening for the p.R326Q mutation in 110 Japanese individuals showed an allele frequency of 0.9 %. Transient expression of mutant βUP enzymes in HEK293 cells showed that the p.E271K and p.R326Q mutations cause profound decreases in activity (≤ 1.3 %). Conversely, βUP enzymes containing the p.G31S and p.I286T mutations possess residual activities of 50 and 70 %, respectively, suggesting we cannot exclude the presence of additional mutations in the non-coding region of the UPB1 gene. Analysis of a human βUP homology model revealed that the effects of the mutations (p.G31S, p.E271K, and p.R326Q) on enzyme activity are most likely linked to improper oligomer assembly. Highly variable phenotypes ranging from neurological involvement (including convulsions and autism) to asymptomatic, were observed in diagnosed patients. High prevalence of p.R326Q in the normal Japanese population indicates that βUP deficiency is not as rare as generally considered and screening for βUP deficiency should be included in diagnosis of patients with unexplained neurological abnormalities.     

Effects of yoga on cardiovascular disease risk factors: A systematic review and meta-analysis

Background

The aim of this review was to systematically assess and meta-analyze the effects of yoga on modifiable biological cardiovascular disease risk factors in the general population and in high-risk disease groups.

Methods

MEDLINE/PubMed, Scopus, the Cochrane Library, and IndMED were screened through August 2013 for randomized controlled trials (RCTs) on yoga for predefined cardiovascular risk factors in healthy participants, non-diabetic participants with high risk for cardiovascular disease, or participants with type 2 diabetes mellitus. Risk of bias was assessed using the Cochrane risk of bias tool.

Results

Forty-four RCTs with a total of 3168 participants were included. Risk of bias was high or unclear for most RCTs. Relative to usual care or no intervention, yoga improved systolic (mean difference (MD) = − 5.85 mm Hg; 95% confidence interval (CI) = − 8.81, − 2.89) and diastolic blood pressure (MD = − 4.12 mm Hg; 95%CI = − 6.55, − 1.69), heart rate (MD = − 6.59 bpm; 95%CI = − 12.89, − 0.28), respiratory rate (MD = − 0.93 breaths/min; 95%CI = − 1.70, − 0.15), waist circumference (MD = − 1.95 cm; 95%CI = − 3.01, − 0.89), waist/hip ratio (MD = − 0.02; 95%CI = − 0.03, − 0.00), total cholesterol (MD = − 13.09 mg/dl; 95%CI = − 19.60, − 6.59), HDL (MD = 2.94 mg/dl; 95%CI = 0.57, 5.31), VLDL (MD = − 5.70 mg/dl; 95%CI = − 7.36, − 4.03), triglycerides (MD = − 20.97 mg/dl; 95%CI = − 28.61, − 13.32), HbA1c (MD = − 0.45%; 95%CI = − 0.87, − 0.02), and insulin resistance (MD = − 0.19; 95%CI = − 0.30, − 0.08). Relative to exercise, yoga improved HDL (MD = 3.70 mg/dl; 95%CI = 1.14, 6.26).

Conclusions

This meta-analysis revealed evidence for clinically important effects of yoga on most biological cardiovascular disease risk factors. Despite methodological drawbacks of the included studies, yoga can be considered as an ancillary intervention for the general population and for patients with increased risk of cardiovascular disease.