Mutant huntingtin fragmentation in immune cells tracks Huntington’s disease progression

Huntington’s disease (HD) is a fatal, inherited neurodegenerative disorder caused by an expanded CAG repeat in the gene encoding huntingtin (HTT). Therapeutic approaches to lower mutant HTT (mHTT) levels are expected to proceed to human trials, but noninvasive quantification of mHTT is not currently possible. The importance of the peripheral immune system in neurodegenerative disease is becoming increasingly recognized. Peripheral immune cells have been implicated in HD pathogenesis, but HTT levels in these cells have not been quantified before. A recently described time-resolved Förster resonance energy transfer (TR-FRET) immunoassay was used to quantify mutant and total HTT protein levels in leukocytes from patients with HD. Mean mHTT levels in monocytes, T cells, and B cells differed significantly between patients with HD and controls and between pre-manifest mutation carriers and those with clinical onset. Monocyte and T cell mHTT levels were significantly associated with disease burden scores and caudate atrophy rates in patients with HD. mHTT N-terminal fragments detected in HD PBMCs may explain the progressive increase in mHTT levels in these cells. These findings indicate that quantification of mHTT in peripheral immune cells by TR-FRET holds significant promise as a noninvasive disease biomarker.     

Transapical minimally invasive aortic valve implantation and conventional aortic valve replacement in octogenarians

Objective Transcatheter aortic valve implantation (TAVI) has been developed to minimize the operative trauma in high-risk patients. Patient selection for TAVI is still subject to debate and octogenarians are often regarded as high-risk patients.Methods In this single-center study, data of 169 octogenarians who received conventional AVR (90) or TAVI (79) have been analyzed retrospectively according to the endpoint definitions of the Valve Academic Research Consortium to answer the following questions: (a) Should patients due to their age of 80 years or older be considered as high risk? (b) Is the EuroSCORE a suitable tool for estimating mortality after AVR or TAVI in octogenarians? (c) Is TAVI the procedure of choice for octogenarians?Results TAVI patients showed higher comorbid conditions concerning an existing renal dysfunction (31 vs. 56%, p = 0.001), peripheral vascular disease (6 vs. 30%, p < 0.001), diabetes (19% vs. 49%, p < 0.001), a decreased ejection fraction (LVEF < 30%: 2 vs. 13%, p < 0.05), and pulmonary hypertension (23 vs. 48%; p < 0.005) with an increase of the perioperative risk represented by logistic EuroSCORE (AVR 11% ± 1.27 vs. TAVI 38% ± 1.35; p < 0.0005) and STS Score (7% ± 0.52 vs. 14% ± 0.56; p < 0.0005). All-cause and cardiovascular-cause in-hospital or 30-day mortality was 5.6% (n = 5) and 3.4% (n = 3) in the AVR cohort and 8.8% (n = 7) and 7.6% (n = 6) in TAVI-patients (p = 0.55; p = 0.31), respectively. The overall combined safety endpoint at 30 days was 22.2% (n = 20) in AVR patients and 29.1% (n = 23) with regard to the TAVI group (p = 38). Analysis of cerebrovascular complications, vascular complications, and pacemaker revealed no significant differences. In the AVR group, actuarial survival at 6 months and 1 and 2 years was 89, 78, and 74%, respectively. Data of the TAVI patients are only available for a follow-up of 6 months and revealed a survival of 85%.Conclusion AVR and TAVI in octogenarians show comparable results, but the analyzed cohorts differ significantly in their risk profile. The results indicate an overrated perioperative mortality using the EuroSCORE but on the other hand logistic EuroSCORE represents articulately the different risk profile of the two groups. For this reason, we consider the EuroSCORE still to be a useful tool for preoperative risk assessment. Moreover, octogenarians cannot per se be considered as "true high risk" patients. Differentiated clinical judgment is most important for reasonable decision making.     

The immunoproteasome as a target in hematologic malignancies

Suppression of proteasome function with the first-in-class small molecule inhibitor bortezomib is a rational therapeutic strategy against several hematologic malignancies, including multiple myeloma and mantle cell lymphoma. Second-generation inhibitors such as carfilzomib, ixazomib, and marizomib that, like bortezomib, target both the constitutive proteasome and the immunoproteasome, are also in clinical trials and showing encouraging activity. While the efficacy of these agents is well documented, toxicities associated with their use, such as peripheral neuropathy and gastrointestinal effects, can necessitate dose reductions or even discontinuations, possibly hampering their anti-neoplastic effects. These findings suggested that it could be possible to improve the therapeutic index of this class of drugs by specifically targeting only the immunoproteasome. Since the immunoproteasome is a unique target found in lymphoid-derived cells, immunoproteasome-specific inhibitors (IPSIs) could preserve efficacy while reducing treatment-emergent toxicities since they would spare other tissues with little to no immunoproteasome expression. This review discusses the current state of development of IPSIs, and the potential of using such agents for the treatment of hematologic malignancies.     

Expression of the melanoma cell adhesion molecule in human mesenchymal stromal cells regulates proliferation,differentiation, and maintenance of hematopoietic stem and progenitor cells

The melanoma cell adhesion molecule defines mesenchymal stromal cells in the human bone marrow that regenerate bone and establish a hematopoietic microenvironment in vivo. The role of the melanoma cell adhesion molecule in primary human mesenchymal stromal cells and the maintenance of hematopoietic stem and progenitor cells during ex vivo culture has not yet been demonstrated. We applied RNA interference or ectopic overexpression of the melanoma cell adhesion molecule in human mesenchymal stromal cells to evaluate the effect of the melanoma cell adhesion molecule on their proliferation and differentiation as well as its influence on co-cultivated hematopoietic stem and progenitor cells. Knockdown and overexpression of the melanoma cell adhesion molecule affected several characteristics of human mesenchymal stromal cells related to osteogenic differentiation, proliferation, and migration. Furthermore, knockdown of the melanoma cell adhesion molecule in human mesenchymal stromal cells stimulated the proliferation of hematopoietic stem and progenitor cells, and strongly reduced the formation of long-term culture-initiating cells. In contrast, melanoma cell adhesion molecule-overexpressing human mesenchymal stromal cells provided a supportive microenvironment for hematopoietic stem and progenitor cells. Expression of the melanoma cell adhesion molecule increased the adhesion of hematopoietic stem and progenitor cells to human mesenchymal stromal cells and their migration beneath the monolayer of human mesenchymal stromal cells. Our results demonstrate that the expression of the melanoma cell adhesion molecule in human mesenchymal stromal cells determines their fate and regulates the maintenance of hematopoietic stem and progenitor cells through direct cell-cell contact.     

Emergency department ultrasound scanning for abdominal aortic aneurysm: accessible, accurate, and advantageous

STUDY OBJECTIVE: This study was conducted to determine whether emergency physicians with relatively limited training and experience can accurately identify the presence or absence of abdominal aortic aneurysms (AAAs) by performing bedside ultrasound scanning, and to assess the potential impact of ultrasound scanning on clinical management. METHODS: Patients in whom AAAs were suspected, including those patients older than 50 years presenting with abdominal/back pain of unclear origin or presumed renal colic, were eligible for study entry. Consenting adults had ultrasound scanning by an emergency physician who was not responsible for their primary care. Treating physicians remained blinded to the results unless an unexpected AAAs was discovered. Scan accuracy was ascertained by comparing our ultrasound results with preselected gold standards. The clinical impact of the ultrasound studies was determined by comparing the preultrasound and postultrasound assessment sheets that detailed the presumed diagnosis, proposed investigations and therapies, and patient disposition. RESULTS: Our convenience sample includes 68 scans for AAAs; findings of 26 scans were positive, 40 scans yielded negative findings, and 2 scans were indeterminate. Scan interpretations were 100% accurate. The ultrasound results would have improved the care of 46 patients without adverse sequelae. Ultrasound scanning served primarily to exclude AAA in patients who proved not to have aneurysms; however, scans also provided significant benefits for those with AAAs and improved patient management plans. CONCLUSION: Relative neophytes can perform aortic ultrasound scans accurately. These scans appear useful as a screening measure in high-risk emergency department patients; they may also aid in rapidly verifying the diagnosis in patients who require immediate surgical intervention.     

Modulation of the intracellular calcium concentration in photoreceptor terminals by a presynaptic metabotropic glutamate receptor.

Fast excitatory neurotransmission in the central nervous system is mediated through glutamate acting on ionotropic glutamate receptors. However, glutamate acting on metabotropic glutamate receptors (mGluRs) can also exert an inhibitory action. Here, we report by immunocytochemistry and physiology, to our knowledge, the first glutamate receptor to be found in terminals of photoreceptors in the mammalian retina-the group III metabotropic glutamate receptor mGluR8. Glutamate is the transmitter of photoreceptors, and thus mGluR8 functions as an autoreceptor. Activation of mGluR8 by the group III mGluR agonists L-2-amino-4-phosphonobutyrate and L-serine-O-phosphate, or by glutamate itself, evokes a decrease in the intracellular calcium ion concentration ([Ca(2+)](i)) in isolated photoreceptors. This effect is blocked by the group III mGluR antagonists (RS)-alpha-methyl-4-phosphonophenylglycine and (RS)-alpha-methylserine-O-phosphate. Agonists for other classes of glutamate receptors-N-methyl-D-aspartic acid, quisqualic acid, kainic acid, or (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-have no effect on the [Ca(2+)](i) in isolated photoreceptors. The down-regulation of the [Ca(2+)](i) in photoreceptors by mGluR8 provides evidence for an inhibitory feedback loop at the photoreceptor synapse in the mammalian retina. This negative feedback may be a mechanism for the fine adjustment of the light-regulated release of glutamate from photoreceptors and may serve as a safety device against excitotoxic levels of release at this tonic synapse. Such a mechanism may provide a model for feedback inhibition in other parts of the central nervous system.     

Nouveaux mécanismes physiopathologiques du Syndrome Métabolique : implication des récepteurs nucléaires orphelins ?

This review focuses on a number of new data on biology and pathophysiology of the metabolic syndrome (MetS) and the involvement of nuclear receptors that have been presented during the last Endocrine Society meeting, held in Houston in June 2012. Several studies have reported beneficial effects of various orphan nuclear receptors, including SHP (Small Heterodimeric Partner, NR0B2) and LXR (Liver X Receptor, NR1H3 and NR1H2), on various components of MetS. By using an inactivation model of SHP, David Moore has shown that SHP exerts “antidiabetic” effects but associated with hepatic steatosis development. He also showed that DLPC (dilauroyl phosphatidylcholine), an unconventional phospholipid, exhibited anti-diabetic properties through its binding to LRH-1 (Liver Receptor Homolog-1, NR5A2), a molecular partner of SHP. Interestingly, Carolyn Cummins investigated LXR α and β isoforms knock-out mice and provided experimental evidence for the detailed mechanisms involved in the deleterious metabolic effects of glucocorticoids, pointing out to the functional interaction between LXRβ, and the glucocorticoid receptor. These new and original studies open new therapeutic opportunities for the management of metabolic disorders in humans by selective modulators of these receptors.     

Prospective study comparing human albumin vs. reinfusion of ultrafiltrate-ascitic fluid after total paracentesis in cirrhotic patients with tense ascites

Although, total paracentesis associated with human albumin substitution has shown to be a rapid, effective and safe treatment of diuretic refractory ascites in advanced liver cirrhosis, it implies high costs and has a limited availability. Therefore an alternative procedure the reinfusion of concentrated ascites has gained popularity in recent years (Smart et al. 1990; Grazioto et al. 1997). It was the aim of the study to compare human albumin substitution vs. reinfusion of ascitic-ultrafiltrate after total paracentesis. 35 patients with cirrhosis and tense ascites received total paracentesis associated with either human albumin (5-8 g/l ascites) (= group A) or reinfusion of an ascitic-ultrafiltrate fluid by means of hemofiltration technique (= group B). The mean volume of ascites removed was 9.41 (2.1-20.0) in group A and 11.41 (6.5-21.0) in group B. No significant differences in serum electrolytes, liver and renal function, coagulation profiles and hormones of the renin-angiotensin-aldosterone system were observed during hospitalization. In both groups sodium excretion increased significantly. 43% of the patients in group B developed pyrexia and chill after reinfusion of the ascitic-ultrafiltrate fluid. In one patient an anaphylactic bronchospasm occurred requiring IUC-treatment. The treatment cost in case of human albumin were 326.-DM vs. 290.-DM for each patient treated with ascitic-ultrafiltrate fluid reinfusion. The probabilities of hospital readmission and survival were similar in both groups during follow-up. The results indicate that i.v. infusion of ascitic-ultrafiltrate fluid is as effective as total paracentesis and albumin infusion in case of diuretic refractory ascites. However, according to the costs of instruments and staff and due to the significant allergic reactions caused by ascitic fluid it cannot be considered as a real alternative to albumin substitution.     

Hemodynamic and antiischemic effects of intravenous elgodipine,a new dihydropyridine calcium channel blocker,in patients with chronic stable angina

Summary Elgodipine is a new second-generation dihydropyridine calcium antagonist. Its hemodynamic and antiischemic properties were evaluated in a single-blind, placebocontrolled trial in 22 males with chronic stable angina. Coronary artery disease was angiographically confirmed. Measurements were performed with a Swan-Ganz thermodilution catheter during a 30-minute period of rest and before the end of a 4-minute bicycle exercise test at maximum individual workload, both with placebo (IV infusion of 5 ml saline over 30 minutes) and elgodipine (10 µg/kg/2 min bolus IV, then IV infusion of 1 µ/kg/min for 28 minutes. Elgodipine caused very similar hemodynamic changes at rest and during exercise. Its major hemodynamic modification was the marked decrease in systemic vascular resistance, which was accompanied by an increase in cardiac index and stroke volume. Mean arterial blood pressure was slightly reduced, whereas the opposite small increase in heart rate meant that the double product remained unchanged. Contrary to resting conditions, pulmonary capillary wedge pressure, pulmonary artery pressures, pulmonary vascular resistance, and mean right atrial pressure remained normal or increased to a lesser extent during exercise after elgodipine. After elgodipine ischemic ST depression during exercise was diminished, and 11 of 16 assessable patients remained free from angina pectoris. We conclude that elgodipine is an efficacious antianginal drug. Its major mechanism of action is lowering of systemic vascular resistance. Thus elgodipine improves systolic cardiac function in patients with chronic stable angina and may delay the onset of ischemic diastolic dysfunction during exercise, as indicated by a normal left ventricular end-diastolic pressure (LVEDP). The data also suggest an improvement in coronary blood flow during exercise.