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.     

Intraoperative cholangiography can be safely omitted during laparoscopic cholecystectomy: a prospective study of 413 consecutive patients.

BACKGROUND AND AIMS: The aim of the study was to show that laparoscopic cholecystectomy (LC) can be performed safely without intraoperative cholangiography (IOC). MATERIAL AND METHODS: We conducted a prospective study of 413 consecutive patients with symptomatic gallstone disease, who underwent LC. According to the preoperative clinical, laboratory and ultrasound criteria, 38 patients (9.2%) were selected for preoperative endoscopic retrograde cholangiography (ERC). All patients were followed postoperatively for symptoms and signs of common bile duct (CBD) stones. RESULTS: Preoperative ERC allowed to make a diagnosis of choledocholithiasis in 22 (58%) of the 38 selected patients. Stone clearance was achieved with endoscopic sphincterotomy (ES) in all cases. Three patients (7.9%) had an episode of mild self-limited pancreatitis after the procedure. Eight patients (1.9%) of 413 required conversion from LC to open cholecystectomy. There were no CBD injuries and no death cases. Of the postoperative complications, 1.5% were recorded during hospital stay. During the follow-up period, for at least 2 years after surgery, retained CBD stones were verified in 6 patients (1.5%); however, the supposed rate of residual stones was 2.4%. CONCLUSIONS: This study demonstrates that performance of selective preoperative ERC with ES when necessary, followed by LC, is an appropriate and safe approach to the treatment of patients with cholecystolithiasis and unsuspected choledocholithiasis. This approach allows to omit IOC and to perform LC safely without biliary duct injuries, ensuring low rate of retained CBD stones in the late follow-up period.     

Three-year results of randomised clinical trial comparing lightweight mesh with heavyweight mesh for inguinal hernioplasty

Purpose

The aim of the present randomised study was to find out whether usage of lightweight mesh in inguinal hernia repair, compared with heavyweight mesh, results in decreased incidence of chronic groin pain and foreign body feeling, as well as to evaluate the risk factors for chronic pain development and hernia recurrences.

Methods

The patients were randomised into the heavyweight mesh (HW) group and lightweight mesh (LW) group. A tension-free mesh repair using the Lichtenstein technique was performed on all patients. Pain scores during different activities were measured on visual analogue scale. All patients underwent a clinical examination for any evidence of hernia recurrence.

Results

Of the patients, 17.2?% in the HW group and 29.3?% in the LW group reported that they experienced pain at 3-year follow-up (P?=?0.1323). Pain was most often reported during physical activity. The median VAS score of all studied activities was 30.5 in the HW group and 30.0 in the LW group. There were more patients in the HW group than in the LW group who stated that they could feel the mesh in the groin (27.6 vs. 20.7?%, P?=?0.3967). Among all patients, 42.9?% who had severe pain preoperatively also reported pain during different activities and 19.6?% of the patients who did not have severe pain preoperatively reported pain during different activities (P?=?0.0481). At 3-year follow-up, there was 1 hernia recurrence in the HW group and 1 hernia recurrence in the LW group.

Conclusions

Our study shows that compared with HW mesh, LW mesh has no advantage in reducing chronic groin pain and foreign body feeling at the operation site after inguinal hernioplasty at 3-year follow-up. Severe preoperative pain was correlated with the development of chronic pain. There was no difference between the two study groups in the recurrence rates.     

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.     

Population-Based Autopsy Study of Traumatic Fatalities

Background

Injuries result in 5.8 million global fatalities annually and are the leading cause of death in younger individuals. Nevertheless, population-based autopsy investigations on traumatic deaths are scarce. We set out to study all consecutive autopsies on traumatic fatalities performed in a 5-year time segment in Estonia.

Methods

After the ethics review board approval, all consecutive autopsies after blunt or penetrating deaths occurring in prehospital or in-hospital settings between January 1, 2009, and December 31, 2013, were retrospectively reviewed using the National Forensic Medicine Database. Fatalities due to suffocation, intoxication, burns, or freezing were excluded. Data collection included demographics, mechanism of injuries, cause of death, and a detailed injury profile. Primary outcome was cause of death. Secondary outcomes included injury patterns.

Results

Overall, 1344 autopsies were included. 75.7% of deaths were following blunt trauma. Mean age was 50.4 ± 18.5 years, and 77.1% were male. A total of 71.8% of deaths occurred in the prehospital setting. Accidents, assaults, and suicides constituted 64.4, 20.5, and 15.2% of deaths, respectively. A total of 51.1% of injury fatalities had a positive blood alcohol level (BAL). Mean injury severity score was 39.7 ± 23.9. Most common cause of death was due to head injuries at 50.5% followed by hemorrhage at 30.4%. Cardiac and aortic injuries were the predominant cause of hemorrhage-related fatalities.

Conclusions

The current population-based investigation documented brain injury as the predominant cause of death followed by cardiac and aortic injuries. High incidence of positive BAL among injury fatalities requires national initiatives for alcohol harm reduction and law enforcement efforts.

     

Randomised clinical trial comparing lightweight mesh with heavyweight mesh for inguinal hernioplasty

Purpose  

The aim of the present randomised clinical study was to compare the incidence of post-operative chronic groin pain and the feeling of a foreign body after inguinal hernioplasty with lightweight (LW) and heavyweight (HW) mesh, as well as to evaluate the patient’s quality of life after inguinal hernia repair.     

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.