MET inhibition in tumor cells by PHA665752 impairs homologous recombination repair of DNA double strand breaks

Abnormal activation of cellular DNA repair pathways by deregulated signaling of receptor tyrosine kinase systems has broad implications for both cancer biology and treatment. Recent studies suggest a potential link between DNA repair and aberrant activation of the hepatocyte growth factor receptor Mesenchymal-Epithelial Transition (MET), an oncogene that is overexpressed in numerous types of human tumors and considered a prime target in clinical oncology. Using the homologous recombination (HR) direct-repeat direct-repeat green fluorescent protein ((DR)-GFP) system, we show that MET inhibition in tumor cells with deregulated MET activity by the small molecule PHA665752 significantly impairs in a dose-dependent manner HR. Using cells that express MET-mutated variants that respond differentially to PHA665752, we confirm that the observed HR inhibition is indeed MET-dependent. Furthermore, our data also suggest that decline in HR-dependent DNA repair activity is not a secondary effect due to cell cycle alterations caused by PHA665752. Mechanistically, we show that MET inhibition affects the formation of the RAD51-BRCA2 complex, which is crucial for error-free HR repair of double strand DNA lesions, presumably via downregulation and impaired translocation of RAD51 into the nucleus. Taken together, these findings assist to further support the role of MET in the cellular DNA damage response and highlight the potential future benefit of MET inhibitors for the sensitization of tumor cells to DNA damaging agents.

Late results after percutaneous closure of patent foramen ovale for secondary prevention of paradoxical embolism using the amplatzer PFO occluder without intraprocedural echocardiography: effect of device size

OBJECTIVES: We sought to assess the safety and clinical efficacy of patent foramen ovale (PFO) closure under fluoroscopic guidance only, without intraprocedural echocardiography. BACKGROUND: Percutaneous PFO closure has been shown to be safe and feasible using several devices. It is generally performed using simultaneously fluoroscopic and transesophageal or intracardiac echocardiographic guidance. Transesophageal echocardiography requires sedation or general anesthesia and intubation to avoid aspiration. Intracardiac echocardiography is costly and has inherent risks. Both lengthen the procedure. The Amplatzer PFO Occluder (AGA Medical Corporation, Golden Valley, Minnesota) can be safely implanted without echocardiographic guidance. METHODS: A total of 620 patients (51 +/- 12 years; 66% male) underwent PFO closure using the Amplatzer PFO Occluder for secondary prevention of presumed paradoxical embolism. Based on size and mobility of the PFO and the interatrial septum, an 18-mm device was used in 50 patients, a 25-mm device in 492, and a 35-mm device in 78. RESULTS: All procedures were successful, with 5 procedural complications (0.8%): 4 arteriovenous fistulae requiring elective surgical correction, and 1 transient ischemic attack. Contrast transesophageal echocardiography at 6 months showed complete closure in 91% of patients, whereas a minimal, moderate, or large residual shunt persisted in 6%, 2%, and 1%, respectively. During a mean follow-up period of 3.0 +/- 1.9 years (median: 2.6 years; total patient-years: 1,871), 5 ischemic strokes, 8 transient ischemic attacks, and no peripheral emboli were reported. Freedom from recurrent ischemic stroke, transient ischemic attack, or peripheral embolism was 99% at 1 year, 99% at 2 years, and 97% at 5 years. CONCLUSIONS: The Amplatzer PFO Occluder affords excellent safety and long-term clinical efficacy of percutaneous PFO closure without intraprocedural echocardiography.

1,25-(OH)2-16ene-23yne-D3 reduces secondary hyperparathyroidism in uremic rats with little calcemic effect

To compare the effects of vitamin D analogs versus calcitriol on serum levels of Ca, P and parathyroid hormone (PTH). A compound better than calcitriol should increase the Ca x P product less than calcitriol for an equivalent decrease in PTH levels.

Secondary skull fractures in head wounds inflicted by captive bolt guns: autopsy findings and experimental simulation

Apart from one article published by Rabl and Sigrist in 1992 (Rechtsmedizin 2:156-158), there are no further reports on secondary skull fractures in shots from captive bolt guns. Up to now, the pertinent literature places particular emphasis on the absence of indirect lesions away from the impact point, when dealing with the wounding capacity of slaughterer's guns. The recent observation of two suicidal head injuries accompanied by skull fractures far away from the bolt's path gave occasion to experimental studies using simulants (glycerin soap, balls from gelatin) and skull brain models. As far as ballistic soap was concerned, the dimensions of the bolt's channel were assessed by multi-slice computed tomography before cutting the blocks open. The test shots to gelatin balls and to skull-brain models were documented by means of a high-speed motion camera. As expected, the typical temporary cavity effect of bullets fired from conventional guns could not be observed when captive bolt stunners were discharged. Nevertheless, the visualized transfer of kinetic energy justifies the assumption that the secondary fractures seen in thin parts of the skull were caused by a hydraulic burst effect.

Effect of intravenous tropisetron on modulation of pain and central hypersensitivity in chronic low back pain patients

The activation of 5-hydroxytryptamine-3 (5-HT-3) receptors in spinal cord can enhance intrinsic spinal mechanisms of central hypersensitivity, possibly leading to exaggerated pain responses. Clinical studies suggest that 5-HT-3 receptor antagonists may have an analgesic effect. This randomized, double-blind, placebo-controlled crossover study tested the hypothesis that the 5-HT-3 receptor antagonist tropisetron attenuates pain and central hypersensitivity in patients with chronic low back pain. Thirty patients with chronic low back pain, 15 of whom were women (aged 53 ± 14 years) and 15 men (aged 48 ± 14 years), were studied. A single intravenous injection of 0.9% saline solution, tropisetron 2mg, and tropisetron 5mg was administrated in 3 different sessions, in a double-blind crossover manner. The main outcome was the visual analogue scale (VAS) score of spontaneous low back pain before, and 15, 30, 60, and 90 minutes after drug administration. Secondary outcomes were nociceptive withdrawal reflexes to single and repeated electrical stimulation, area of reflex receptive fields, pressure pain detection and tolerance thresholds, conditioned pain modulation, and area of clinical pain. The data were analyzed by analysis of variance and panel multiple regressions. All 3 treatments reduced VAS scores. However, there was no statistically significant difference between tropisetron and placebo in VAS scores. Compared to placebo, tropisetron produced a statistically significant increase in pain threshold after single electrical stimulation, but no difference in all other secondary outcomes was found. A single-dose intravenous administration of tropisetron in patients with chronic low back pain had no significant specific effect on intensity of pain and most parameters of central hypersensitivity.

The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT)

Zoledronic acid 5 mg (ZOL) annually for 3 years reduces fracture risk in postmenopausal women with osteoporosis. To investigate long-term effects of ZOL on bone mineral density (BMD) and fracture risk, the Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) was extended to 6 years. In this international, multicenter, double-blind, placebo-controlled extension trial, 1233 postmenopausal women who received ZOL for 3 years in the core study were randomized to 3 additional years of ZOL (Z6, n = 616) or placebo (Z3P3, n = 617). The primary endpoint was femoral neck (FN) BMD percentage change from year 3 to 6 in the intent-to-treat (ITT) population. Secondary endpoints included other BMD sites, fractures, biochemical bone turnover markers, and safety. In years 3 to 6, FN-BMD remained constant in Z6 and dropped slightly in Z3P3 (between-treatment difference = 1.04%; 95% confidence interval 0.4 to 1.7; p = 0.0009) but remained above pretreatment levels. Other BMD sites showed similar differences. Biochemical markers remained constant in Z6 but rose slightly in Z3P3, remaining well below pretreatment levels in both. New morphometric vertebral fractures were lower in the Z6 (n = 14) versus Z3P3 (n = 30) group (odds ratio = 0.51; p = 0.035), whereas other fractures were not different. Significantly more Z6 patients had a transient increase in serum creatinine >0.5 mg/dL (0.65% versus 2.94% in Z3P3). Nonsignificant increases in Z6 of atrial fibrillation serious adverse events (2.0% versus 1.1% in Z3P3; p = 0.26) and stroke (3.1% versus 1.5% in Z3P3; p = 0.06) were seen. Postdose symptoms were similar in both groups. Reports of hypertension were significantly lower in Z6 versus Z3P3 (7.8% versus 15.1%, p < 0.001). Small differences in bone density and markers in those who continued versus those who stopped treatment suggest residual effects, and therefore, after 3 years of annual ZOL, many patients may discontinue therapy up to 3 years. However, vertebral fracture reductions suggest that those at high fracture risk, particularly vertebral fracture, may benefit by continued treatment.

Severe signs of hyponatremia secondary to desmopressin treatment for enuresis: A systematic review

OBJECTIVE: Dilutional hyponatremia is a serious adverse effect of desmopressin, a vasopressin analog that is widely prescribed to manage monosymptomatic enuresis. The presentation of hyponatremia, largely related to cerebral dysfunction, can include severe signs like altered mental status and seizures. METHODS: We reviewed the literature dealing with altered mental status or seizures in enuretic subjects on desmopressin. The retained publications included patients who were described individually, revealing data on mode of administration, further identifiable factors predisposing to hyponatremia, presentation and clinical course. RESULTS: We found 54 cases of hyponatremia secondary to desmopressin treatment presenting with altered mental status or seizures. In most cases the complication developed 14 days or less after starting desmopressin. An intranasal formulation had been used in 47 patients. Excess fluid intake was documented as a contributing factor in at least 22 cases. In 6 cases severe signs of hyponatremia developed in the context of intercurrent illnesses. CONCLUSION: Altered mental status or seizures are very rare but recognized complications of desmopressin in enuresis. This complication mostly develops in subjects managed with the intranasal formulation 14 days or less after starting the medication, following excess fluid intake and during intercurrent illnesses.

rCBF in hemorrhagic, non-hemorrhagic and mixed contusions after severe head injury and its effect on perilesional cerebral blood flow

Intracerebral contusions can lead to regional ischemia caused by extensive release of excitotoxic aminoacids leading to increased cytotoxic brain edema and raised intracranial pressure. rCBF measurements might provide further information about the risk of ischemia within and around contusions. Therefore, the aim of the presented study was to compare the intra- and perilesional rCBF of hemorrhagic, non-hemorrhagic and mixed intracerebral contusions. In 44 patients, 60 stable Xenon-enhanced CT CBF-studies were performed (EtCO2 30 +/- 4 mmHg SD), initially 29 hours (39 studies) and subsequent 95 hours after injury (21 studies). All lesions were classified according to localization and lesion type using CT/MRI scans. The rCBF was calculated within and 1-cm adjacent to each lesion in CT-isodens brain. The rCBF within all contusions (n = 100) of 29 +/- 11 ml/100 g/min was significantly lower (p < 0.0001, Mann-Whitney U) compared to perilesional rCBF of 44 +/- 12 ml/100 g/min and intra/perilesional correlation was 0.4 (p < 0.0005). Hemorrhagic contusions showed an intra/perilesional rCBF of 31 +/- 11/44 +/- 13 ml/100 g/min (p < 0.005), non-hemorrhagic contusions 35 +/- 13/46 +/- 10 ml/100 g/min (p < 0.01). rCBF in mixed contusions (25 +/- 9/44 +/- 12 ml/100 g/min, p < 0.0001) was significantly lower compared to hemorrhagic and non-hemorrhagic contusions (p < 0.02). Intracontusional rCBF is significantly reduced to 29 +/- 11 ml/100 g/min but reduced below ischemic levels of 18 ml/100 g/min in only 16% of all contusions. Perilesional CBF in CT normal appearing brain closed to contusions is not critically reduced. Further differentiation of contusions demonstrates significantly lower rCBF in mixed contusions (defined by both hyper- and hypodense areas in the CT-scan) compared to hemorrhagic and non-hemorrhagic contusions. Mixed contusions may evolve from hemorrhagic contusions with secondary increased perilesional cytotoxic brain edema leading to reduced cerebral blood flow and altered brain metabolism. Therefore, the treatment of ICP might be individually modified by the measurement of intra- and pericontusional cerebral blood.

Effect of once-yearly zoledronic acid 5 mg on fracture risk and change in femoral neck bone mineral density

Context: In the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly - Pivotal Fracture Trial (HORIZON-PFT), zoledronic acid (ZOL) 5 mg significantly reduced fracture risk. Objective: To identify factors associated with greater efficacy during ZOL 5 mg treatment. Design, Setting and Patients: Subgroup analysis (preplanned and post hoc) of a multicenter, double-blind, placebo-controlled, 36-month trial in 7765 women with postmenopausal osteoporosis. Intervention: Single infusion of ZOL 5 mg or placebo at baseline, 12 and 24 months. Main Outcome Measures: Primary endpoints: new vertebral fracture and hip fracture. Secondary endpoints: non-vertebral fracture, change in femoral neck bone mineral density (BMD). Baseline risk factor subgroups: age, BMD T-score and vertebral fracture status, total hip BMD, race, weight, geographical region, smoking, height loss, history of falls, physical activity, prior bisphosphonates, creatinine clearance, body mass index (BMI), concomitant osteoporosis medications. Results: Greater ZOL induced effects on vertebral fracture risk with younger age (treatment-by-subgroup interaction P=0.05), normal creatinine clearance (P=0.04), and BMI >/=25 kg/m(2) (P=0.02). There were no significant treatment-factor interactions for hip or non-vertebral fracture or for change in BMD. Conclusions: ZOL appeared more effective in preventing vertebral fracture in younger women, overweight/obese women and women with normal renal function. ZOL had similar effects irrespective of fracture risk factors or femoral neck BMD.

Suburothelial myofibroblasts in the human overactive bladder and the effect of botulinum neurotoxin type A treatment

BACKGROUND: An increasing body of evidence suggests a possible role of suburothelial myofibroblasts (MFs) in bladder mechanosensation and in the pathophysiology of detrusor overactivity (DO). OBJECTIVE: To determine whether markers of MFs, including gap junction protein connexin43 (Cx43) and c-kit have altered immunohistochemical expression in the suburothelium of patients with neurogenic DO (NDO) or idiopathic DO (IDO) and whether this is affected by successful treatment of DO with botulinum neurotoxin type A (BoNTA). DESIGN, SETTING, AND PARTICIPANTS: Patients with NDO (n=10) or IDO (n=11) were treated in a single-centre, open-label study of intradetrusor BoNTA injections. Control tissue was obtained from 10 patients undergoing pelvic-floor repair procedures who had no overactive bladder (OAB) symptoms. This study is registered with ClinicalTrials.gov, number NCT00662064. INTERVENTIONS: Bladder biopsies performed with flexible cystoscopes were obtained from control subjects and from NDO and IDO patients before BoNTA treatment and at 4 wk and 16 wk after treatment. They were studied with quantitative immunofluorescence using antibodies to connexin 43 (Cx43), vimentin, and c-kit. MEASUREMENTS: Differences in Cx43, vimentin, and c-kit immunoreactivity between control subjects and NDO or IDO patients (primary outcomes). Changes in NDO or IDO, Cx43 immunoreactivity, and c-kit immunoreactivity after BoNTA treatment (secondary outcomes). RESULTS AND LIMITATIONS: Cx43 immunoreactivity was increased in both IDO and NDO patients compared to controls, but remained unchanged after BoNTA treatment. C-kit immunoreactivity was similar in NDO/IDO patients and controls and remained unchanged after BoNTA treatment. CONCLUSIONS: Increased gap junction formation in the suburothelium has been demonstrated in biopsies from humans with DO. It is hypothesised that this change could have a significant role in the pathogenesis of the detrusor abnormality. Successful treatment of NDO or IDO does not appear to be associated with changes in the expression of Cx43 or c-kit on suburothelial MFs.

Effect of calcium-channel blockers on calcium-phosphate metabolism in patients with end-stage renal disease

After EDTA-induced hypocalcaemia, healthy volunteers treated with diltiazem display more severe hyperparathyroidism than subjects on felodipine studied under identical conditions. Therefore patients with end-stage renal disease (ESRD) and severe secondary hyperparathyroidism might be particularly sensitive to this side-effect.

Educational Expansion and Persistent Inequalities of Education: Utilizing the Subjective Expected Utility Theory to Explain the Increasing Participation Rates in Upper Secondary School in the Federal Republic Of Germany

This investigation attempts to answer the question why more and more parents have chosen the Gymnasium for their children's secondary school education in post‐war West Germany. Based on the theory of subjective expected utility, the crucial mechanisms of parental educational decisions have been emphasized. From this perspective it is assumed that increasing educational motivation coupled with changes in the subjective evaluation of the cost–benefit of education were important conditions for an increasing participation in upper secondary schools. These were, however, in turn, the result of educational expansion. The empirical analyses for three time‐periods in the 1960s, 1970s, and 1980s confirm these assumptions to a large degree. Additionally, empirical evidence was found to suggest that in addition to the intentions of parents and the educational career of their children, structural moments of educational expansion and their own inertia played an important role in the pupils' transition from one educational level to the next. Finally, evidence was found that persistent class‐specific educational inequality stems from a constant balance in the relative cost–benefit advantages between social classes as well as from an increasing difference of primary origin effect between social classes in the realization of their educational choice.

Effect of comprehensive cardiac rehabilitation after heart valve surgery (CopenHeartVR): study protocol for a randomised clinical trial

Background Heart valve diseases are common with an estimated prevalence of 2.5% in the Western world. The number is rising due to an ageing population. Once symptomatic, heart valve diseases are potentially lethal, and heavily influence daily living and quality of life. Surgical treatment, either valve replacement or repair, remains the treatment of choice. However, post surgery, the transition to daily living may become a physical, mental and social challenge. We hypothesise that a comprehensive cardiac rehabilitation programme can improve physical capacity and self-assessed mental health and reduce hospitalisation and healthcare costs after heart valve surgery. Methods A randomised clinical trial, CopenHeartVR, aims to investigate whether cardiac rehabilitation in addition to usual care is superior to treatment as usual after heart valve surgery. The trial will randomly allocate 210 patients, 1:1 intervention to control group, using central randomisation, and blinded outcome assessment and statistical analyses. The intervention consists of 12 weeks of physical exercise, and a psycho-educational intervention comprising five consultations. Primary outcome is peak oxygen uptake (VO2 peak) measured by cardiopulmonary exercise testing with ventilatory gas analysis. Secondary outcome is self-assessed mental health measured by the standardised questionnaire Short Form 36. Also, long-term healthcare utilisation and mortality as well as biochemistry, echocardiography and cost-benefit will be assessed. A mixed-method design is used to evaluate qualitative and quantitative findings encompassing a survey-based study before the trial and a qualitative pre- and post-intervention study. Discussion The study is approved by the local regional Research Ethics Committee (H-1-2011-157), and the Danish Data Protection Agency (j.nr. 2007-58-0015).

Migrant Background and Higher Education Participation in Europe. The Effect of the Educational Systems

The main aim of this article is to shed light on the extent to which differences in higher education participation between people with and without a migrant background of low/higher social origin can be explained by two macro-level characteristics of national educational institutions: stratification of the secondary school system and provision of alternative access to higher education. General assumptions are that people with a migrant background of low social origin benefit in low-stratified secondary school systems and in systems that provide alternative access to institutions of higher education more than their native peers in the same social stratum, owing to primary and secondary effects of migrant background. Database is a pooled dataset of the five waves of the European Social Survey. Results of logistic multi-level analyses indicate that a low-stratified secondary school system improves the probability of people with a migrant background/low social origin attaining a higher education degree. On the other hand, a stratified secondary school system reduces their chances regarding this educational stage. The provision of alternative access to an institution of higher education improves their likelihood of becoming higher education graduates.