Glia cell line‐derived neurotrophic factor mediates survival of murine sympathetic precursors

During embryonic development, neurons are first produced in excess, and final numbers are adjusted by apoptosis at later stages. Crucial to this end is the amount of target‐derived growth factor available for the neurons. By this means, the target size correctly matches the innervating neuron number. This target‐derived survival has been well studied for sympathetic neurons, and nerve growth factor (NGF) was identified to be the crucial factor for maintaining sympathetic neurons at late embryonic and early postnatal stages, with a virtual complete loss of sympathetic neurons in NGF knockout (KO) mice. This indicates that all sympathetic neurons are dependent on NGF. However, also different glia cell line‐derived neurotrophic factor (GDNF) KO mice consistently presented a loss of sympathetic neurons. This was the rationale for investigating the role of GDNF for sympathetic precursor/neuron survival. Here we show that GDNF is capable of promoting survival of 30% sympathetic precursors dissociated at E13. This is in line with data from GDNF KOs in which a comparable sympathetic neuron loss was observed at late embryonic stages, although the onset of the phenotype was unclear. We further present data showing that GDNF ligand and canonical receptors are expressed in sympathetic neurons especially at embryonic stages, raising the possibility of an autocrine/paracrine GDNF action. Finally, we show that GDNF also maintained neonatal sympathetic neurons (40%) cultured for 2 days. However, the GDNF responsiveness was lost at 5 days in vitro. © 2013 Wiley Periodicals, Inc.     

Mutational analysis of N-Bak reveals different structural requirements for antiapoptotic activity in neurons and proapoptotic activity in nonneuronal cells

N-Bak, a neuron-specific BH3-only splice variant of Bak, is proapoptotic when overexpressed in nonneuronal cells, but antiapoptotic in NGF-deprived sympathetic neurons. We generated mutants of N-Bak and compared their activities in COS-7 or Neuro2A cells to those in NGF-deprived sympathetic neurons. A C-terminal deletion shortly after the BH3 domain of N-Bak compromised its neuroprotective activity but had little effect on its cytotoxic activity in nonneuronal cells. Amino acid changes in the BH3 domain of N-Bak differently affected its function in nonneuronal cells and in neurons. The same changes in the BH3 domain of longer Bak isoform affected its function similarly in nonneuronal cells and neurons. C-terminally truncated Bax, a structural analogue of N-Bak, was also neuroprotective, whereas Blk, a different BH3-only protein was apoptotic in neurons. Thus, neuron-specific antiapoptotic interactions require a "N-Bak-type" conformation, not just a BH3 domain, whereas the presence of a BH3 domain in the Bak protein is sufficient to kill nonneuronal cells.     

The loop diuretic bumetanide blocks posttraumatic p75NTR upregulation and rescues injured neurons

Injured neurons become dependent on trophic factors for survival. However, application of trophic factors to the site of injury is technically extremely challenging. Novel approaches are needed to circumvent this problem. Here, we unravel the mechanism of the emergence of dependency of injured neurons on brain-derived neurotrophic factor (BDNF) for survival. Based on this mechanism, we propose the use of the diuretic bumetanide to prevent the requirement for BDNF and consequent neuronal death in the injured areas. Responses to the neurotransmitter GABA change from hyperpolarizing in intact neurons to depolarizing in injured neurons. We show in vivo in rats and ex vivo in mouse organotypic slice cultures that posttraumatic GABA(A)-mediated depolarization is a cause for the well known phenomenon of pathological upregulation of pan-neurotrophin receptor p75(NTR). The increase in intracellular Ca(2+) triggered by GABA-mediated depolarization activates ROCK (Rho kinase), which in turn leads to the upregulation of p75(NTR). We further show that high levels of p75(NTR) and its interaction with sortilin and proNGF set the dependency on BDNF for survival. Thus, application of bumetanide prevents p75(NTR) upregulation and neuronal death in the injured areas with reduced levels of endogenous BDNF.     

Comparison of 5 days of extended-release clarithromycin versus 10 days of penicillin V for the treatment of streptococcal pharyngitis/tonsillitis: results of a multicenter,double-blind,randomized study in adolescent and adult patients

OBJECTIVE: This study compared a short-course of clarithromycin with a standard course of penicillin V in patients with tonsillopharyngitis caused by Streptococcus pyogenes. Research design and methods: A total of 539 patients, aged 12-75 years, were randomized to receive either clarithromycin extended-release (ER) 500 mg once daily for 5 days or penicillin V 500 mg three times daily for 10 days in this multicenter, double-blind, parallel-group trial. Eligibility required a positive antigen test for group A beta-hemolytic streptococcus (GABHS) followed by confirmatory culture. MAIN OUTCOME MEASURES: Bacteriological and clinical assessments were conducted at each study visit (visit 1: study day 1; visit 2: study day 3; visit 3: study days 8-12; visit 4: study days 13-20; and visit 5: study days 40-50). RESULTS: At the test-of-cure visit (visit 3 for clarithromycin ER patients and visit 4 for penicillin V patients) in per-protocol patients, 5 days of clarithromycin ER was comparable to 10 days of penicillin V in eradicating S. pyogenes (89% (157/177) vs 90% (139/154) respectively; 95% CI for difference (-8.2, 5.1)). Bacterial eradication was sustained in both treatment groups at the follow-up visit (88% (135/153) vs 91% (112/123) respectively; 95% CI for difference (-10.0, 4.4)). Clinical cure was achieved in > or = 94% of patients in each treatment group. The most commonly reported study drug-related adverse events (< or = 3% in either treatment group) were abdominal pain, diarrhea, dyspepsia and nausea. CONCLUSION: Clarithromycin ER 500 mg once daily for 5 days is equally effective as penicillin V 500 mg three times daily for 10 days in the treatment of adolescent and adult patients with streptococcal tonsillopharyngitis.     

Chronic pain after open inguinal hernia repair

Following the widespread use of mesh repairs, recurrence rates after inguinal hernia surgery have become acceptable and focus has shifted from recurrence to chronic pain. Although pain can be controlled with analgesics, chronic postsurgical pain is a major clinical problem, which can significantly influence the patient’s quality of life. The rate of chronic pain after inguinal hernia mesh repair can reach 51.6%. The reasons for posthernioplasty chronic pain are often unclear. It has been linked to nerve injury and nerve entrapment, but there is also association between the rate of chronic pain and the type of mesh used for hernia repair. As there are >160 meshes available in the market, it is difficult to choose a mesh whose usage would result in the best outcome. Different mesh characteristics have been studied, among them weight of mesh has probably gained the most attention. The choice of adequate therapy for chronic groin pain after inguinal hernia repair is controversial. The European Hernia Society recommends that a multidisciplinary approach at a pain clinic should be considered for the treatment of chronic postoperative pain. Although surgical treatment of chronic posthernioplasty pain is limited because of the lack of relevant research data, resection of entrapped nerves, mesh removal in the case of mesh related pain or removal of fixation sutures can be beneficial for the patient with severe pain after inguinal hernia surgery. One drawback of published studies is the lack of consensus over definition of chronic pain, which makes it complicated to compare the results of different studies and to conduct meta-analyses and systematic reviews. Therefore, a uniform definition of chronic pain and its best assessment methods should be developed in order to conduct top quality multicenter randomized trials. Further research to develop meshes with optimal parameters is of vital importance and should be encouraged.     

Nanoporous Carbide-Derived Carbon Material-Based Linear Actuators

Devices using electroactive polymer-supported carbon material can be exploited as alternatives to conventional electromechanical actuators in applications where electromechanical actuators have some serious deficiencies. One of the numerous examples is precise microactuators. In this paper, we show for first time the dilatometric effect in nanocomposite material actuators containing carbide-derived carbon (CDC) and polytetrafluoroetylene polymer (PTFE). Transducers based on high surface area carbide-derived carbon electrode materials are suitable for short range displacement applications, because of the proportional actuation response to the charge inserted, and high Coulombic efficiency due to the EDL capacitance. The material is capable of developing stresses in the range of tens of N cm^-2. The area of an actuator can be dozens of cm², which means that forces above 100 N are achievable. The actuation mechanism is based on the interactions between the high-surface carbon and the ions of the electrolyte. Electrochemical evaluations of the four different actuators with linear (longitudinal) action response are described. The actuator electrodes were made from two types of nanoporous TiC-derived carbons with surface area (S_A) of 1150 m² g^-1 and 1470 m² g^-1, respectively. Two kinds of electrolytes were used in actuators: 1.0 M tetraethylammonium tetrafluoroborate (TEABF₄) solution in propylene carbonate and pure ionic liquid 1-ethyl-3-methylimidazolium trifluoromethanesulfonate (EMITf). It was found that CDC based actuators exhibit a linear movement of about 1% in the voltage range of 0.8 V to 3.0 V at DC. The actuators with EMITf electrolyte had about 70% larger movement compared to the specimen with TEABF₄ electrolyte.     

Prevalence of cardiovascular disorders among the elderly in primary care in Estonia

OBJECTIVE: To assess the prevalence of diagnoses of cardiovascular disorders among the elderly in family practice. DESIGN: Cross-sectional study. SETTING: Estonia, population aged 65 years or older (206,915 persons). SUBJECTS: 811 elderly persons selected randomly from the lists of family practitioners. MAIN OUTCOME MEASURES: Prevalence of hypertension, hypotension, coronary heart disease (CHD), myocardial infarction (MI), heart failure (HF) and cardiac arrhythmias; differences between the genders and age groups. RESULTS: The prevalence of cardiovascular disorders was as follows: hypertension 63.2%, hypotension 11.1%, CHD 56.5%, MI 9.8%, HF 41.4% and arrhythmias 37.5%. Women had a significantly higher prevalence of hypertension and men of MI. The prevalence of CHD and hypotension was significantly higher in the oldest elderly persons. CONCLUSION: Among the older population in Estonia, cardiovascular disorders that have broader diagnostic criteria and need expensive methods for verifying (CHD, HF) have a high prevalence and are most likely over-diagnosed. The need for strict and simple diagnostic methods for these disorders in primary care practice continues to be serious.