Acute cocaine exposure alters spine density and long-term potentiation in the ventral tegmental area

Growing evidence indicates that the expression of synaptic plasticity in the central nervous system results in dendritic reorganization and spine remodeling. Although long-term potentiation of glutamatergic synapses after cocaine exposure in the ventral tegmental area (VTA) has been proposed as a cellular mechanism underlying addictive behaviors, the relationship between long-term potentiation and dendritic remodeling induced by cocaine on the dopaminergic neurons of the VTA has not been demonstrated. Here we report that rat VTA cells classified as type I and II showed distinct morphological responses to cocaine, as a single cocaine exposure significantly increased dendritic spine density in type I but not in type II cells. Further, only type I cells had a significant increase in the AMPA receptor:NMDA receptor ratio after a single cocaine exposure. Taken together, our data provide evidence that increased spine density and synaptic plasticity are coexpressed within the same VTA neuronal population and that only type I neurons are structurally and synaptically modified by cocaine.     

The schizophrenia brain exhibits low-level aneuploidy involving chromosome 1

OBJECTIVE: Genetic instability manifested as loss or gain of whole chromosomes (aneuploidy) is a newly described feature of the human brain. Aneuploidy in the brain was hypothesized to be involved in schizophrenia pathogenesis. To gain further insights into the relationship between aneuploidy in the brain and schizophrenia pathogenesis, a molecular-cytogenetic study of chromosome 1 aneuploidy was performed. METHODS: Interphase multiprobe fluorescence in situ hybridization (FISH) with quantitative FISH (QFISH) and interphase chromosome-specific multicolor banding (ICS-MCB) were used to define aneuploidy rate in 12 unaffected and 12 schizophrenia brains. RESULTS: In the unaffected brain (n=12; 22,794 cells analyzed), average frequencies of stochastic chromosome 1 loss and gain were 0.3% (95%CI 0.2-0.4%) and 0.3% (95%CI 0.2-0.4%), respectively. The threshold level for stochastic chromosome gain and loss (the mean+3SD) in the normal brain was 0.7%. Average rate of aneuploidy in the schizophrenia brain (n=12; 28,482 cells analyzed) was 0.9% (95%CI 0.3-1.5%) for chromosome 1 loss and 0.9% (95%CI 0.2-1.7%) for chromosome 1 gain. Significantly increased level of mosaic aneuploidy involving chromosome 1 was revealed in two schizophrenia brains (3.6% and 4.7% of cells with chromosome 1 loss and gain, respectively). Stochastic aneuploidy rate for chromosome 1 in the schizophrenia brain without two outliers (n=10) reached 0.6% (95%CI 0.3-0.9%) for loss and 0.5% (0.2-0.9%) for gain and was higher than in controls (P=0.005 and P=0.001, respectively). CONCLUSIONS: Our findings support the hypothesis suggesting that subtle genomic imbalances manifesting as low-level mosaic aneuploidy may contribute to schizophrenia pathogenesis.     

Transfemoral endovascular treatment of proximal common carotid artery lesions: a single-center experience on 153 lesions

PURPOSE: To assess primary success and safety of percutaneous transluminal angioplasty (PTA) and/or stenting of ostial/proximal common carotid artery lesions (pCCA) and to compare its 30-day stroke/mortality level with the literature data for surgical options. METHODS: A total of 147 patients (153 stenoses, 6 recurrent) (71 female; 121 left) with significant diameter stenosis (>70% in symptomatic, n = 46; >85% in asymptomatic, n = 101 patients) of pCCA treated between 1994 and 2006 were retrospectively reviewed. With the exception of one, all procedures were performed using a transfemoral approach. A stent was implanted in 108 (70.5%) of cases. Stents were not available in the early years of our experience, but gradually became a routine practice. Embolic protection devices were used in 16 cases. Follow-up included neurological examination, carotid duplex scan, and office/telephone interview. RESULTS: Primary technical success was 98.7% (151/153 stenoses). There were no deaths. Periprocedural (<48 hours) neurological complications included 3/153 (2.0%) ipsilateral major strokes and 4/153 (2.6%) TIAs (including one contralateral TIA). There were 8/153 (5.2%) access site hematomas, 1/153 (0.7%) bradycardia, and 1/153 (0.7%) acute left ventricular failure with respiratory distress. Follow-up was achieved in 115/147 patients (78.2%) undergoing 120 procedures for a mean of 24.7 months and revealed one additional contralateral TIA and one additional minor stroke in an asymptomatic patient. In patients with follow-up, the 30-day procedural death/all-stroke rate was 3/120 (2.5%) The cumulative primary patency rate in the 115 patients with follow-up was 97.9% +/- 2.1% at 1 year, 82.0% +/- 7.1% at 4-years, and 73.5% +/- 12.7% at 7 years. The cumulative secondary patency rate was 100% at 1 year, 88.0% +/- 7.0% at 4 years, and 88.0% +/- 11% at 7 years. Log-rank test showed no statistical difference (P = .82) in primary cumulative patency between PTA alone (n = 34) or PTA/stent (n = 86). CONCLUSION: Transfemoral PTA/stenting appears to be appropriate treatment option for ostial/proximal common carotid artery significant stenoses. This study should also draw attention to the lack of data on natural history or effect of best medical treatment alone for these lesions, making evidence-based decision currently impossible for treatment of symptomatic or asymptomatic ostial and proximal common carotid artery significant stenoses.     

Prevention of ulnar nerve injury during fixation of supracondylar fractures in children by 'flexion-extension cross-pinning' technique

No consensus exists concerning the best pin configuration for displaced supracondylar fractures of the humerus in children. Although cross-pinning is the most stable biomechanically, this configuration may cause iatrogenic ulnar nerve palsy. For the last 7 years, we have been using a three-pin fixation technique with insertion of two K wires from the lateral side (elbow in full flexion) and the third wire through the medial side (elbow in full extension). We used this technique in 67 displaced supracondylar fractures without any complications related to the ulnar nerve. The technique provides excellent stability and eliminates the risk of iatrogenic ulnar nerve palsy.     

Factors affecting fluid requirement on the first day after severe burn trauma

BACKGROUND: Parkland formula (PF) is the most often used schema for calculating intravenous resuscitation fluid requirement in burn patients. Some studies have reported that PF underestimates the fluid requirement in 45-63% of patients. The aim of this retrospective study was to analyse factors influencing first-day intravenous fluid replacement set for a targeted urinary output in severely burnt patients. METHODS: Data of 47 patients with burn injury affecting equal or more than 15% of body surface area were retrieved from the archived files. The local intensive care protocol rendered the infusion rate of lactated Ringer's solution to achieve a urinary output of 0.5-1.0 mL/kg per hour in the first 24 h after burn trauma. RESULTS: First-day i.v. infusion volume was significantly higher than PF preferred. In the first 24 h the hourly volume of intravenous fluid resuscitation per bodyweight per burnt surface area showed significant negative correlation to the burnt body surface area and body mass index, (r = -0.553, P < 0.001; r = -0.570, P < 0.001, respectively) no correlation was found to bodyweight, height or patient age. Patients having deep-burn injury required higher intravenous fluid resuscitation rate than patients having superficial injury only (P < 0.01). CONCLUSION: Our data suggest that fluid requirement is higher than predicted by PF if the extent of burn or body mass index is low and less if the extent of burn or body mass index is high. The presence of deep burn increases fluid requirement.     

Targeting vascular endothelial growth factor (VEGF)-receptor-signaling in renal cell carcinoma

Metastatic renal cell carcinoma (RCC) is resistant to conventional chemotherapy. Combined data for a variety of immunotherapies resulted in an overall chance of partial (PR) or complete remission (CR) of only 12.9%. There is a clear need for novel, more effective therapies to prevent relapse, control metastases and improve overall survival. Improved understanding of RCC disease biology has led to the introduction of molecularly targeted treatment strategies in these cancers. Von Hippel-Lindau (VHL) gene inactivation is observed in most clear cell renal carcinoma, resulting in vascular endothelial growth factor (VEGF) over-expression and driving the malignant phenotype. This review discusses the efficacy of novel therapies targeting the VEGF receptor (VEGFR) (e.g. anti-VEGF antibodies, VEGFR tyrosine kinase inhibitors, mTOR inhibitors), some of which were recently approved by the Food and Drug Administration/European Medicines Evaluation Agency (FDA/EMEA) and represent the new treatment standards in RCC patients.     

A peroxynitrite decomposition catalyst counteracts sensory neuropathy in streptozotocin-diabetic mice

Whereas an important role of free radicals and oxidants in peripheral diabetic neuropathy is well established, the contribution of nitrosative stress and, in particular, of the highly reactive oxidant peroxynitrite, has not been properly explored. Our previous findings implicate peroxynitrite in diabetes-associated motor and sensory nerve conduction deficits and peripheral nerve energy deficiency and poly(ADP-ribose) polymerase activation associated with Type 1 diabetes. In this study the role of nitrosative stress in diabetic sensory neuropathy is evaluated. The peroxynitrite decomposition catalyst Fe(III) tetrakis-2-(N-triethylene glycol monomethyl ether)pyridyl porphyrin (FP15) was administered to control and streptozotocin (STZ)-diabetic mice at the dose of 5 mg kg(-1) day(-1) (FP15), for 3 weeks after initial 3 weeks without treatment. Mice with 6-week duration of diabetes developed clearly manifest thermal hypoalgesia (paw withdrawal, tail-flick, and hot plate tests), mechanical hypoalgesia (tail pressure Randall-Sellito test), tactile allodynia (flexible von Frey filament test), and approximately 38% loss of intraepidermal nerve fibers. They also had increased nitrotyrosine and poly(ADP-ribose) immunofluorescence in the sciatic nerve, grey matter of spinal cord, and dorsal root ganglion neurons. FP15 treatment was associated with alleviation of thermal and mechanical hypoalgesia. Tactile response threshold tended to increase in response to peroxynitrite decomposition catalyst treatment, but still remained approximately 59% lower compared with non-diabetic controls. Intraepidermal nerve fiber density was 25% higher in FP15-treated than in untreated diabetic rats, but the difference between two groups did not achieve statistical significance (p=0.054). Nitrotyrosine and poly(ADP-ribose) immunofluorescence in sciatic nerve, spinal cord, and dorsal root ganglion neurons of peroxynitrite decomposition catalyst-treated diabetic mice were markedly reduced. In conclusion, nitrosative stress plays an important role in sensory neuropathy associated with Type 1 diabetes. The findings provide rationale for further studies of peroxynitrite decomposition catalysts in a long-term diabetic model.     

Additional surgical intervention after radical prostatectomy, radiation therapy, androgen-deprivation therapy, or watchful waiting

OBJECTIVES: The amount of additional surgical procedures that cancer patients undergo following their initial treatment is one means of measuring the impact that cancer and cancer treatment has on their quality of life. In this study we looked for treatment-related differences in the need for additional surgical intervention among men with nonmetastatic prostate cancer within 66 mo of their initial treatment. METHODS: Data for this study were from the National Cancer Institutes Surveillance, Epidemiology, and End Results (SEER) program and from the Medicare claims database. We searched the claims database for procedure codes indicating artificial urinary sphincter procedures, cystoscopy, urethral dilation, transurethral resection of the prostate (TURP) and bladder-neck incision, bladder irrigation/cystotomy, or nephrostomy. RESULTS: Of the 12,711 patients in our study, 3940 (31.0%) were initially treated by radical prostatectomy (RP), 3950 (31.1%) by radiation therapy (RT), 1209 (9.5%) by androgen-deprivation therapy (ADT), and 3612 (28.4%) by watchful waiting (WW). The percentage of patients who underwent cystoscopy 6-66 mo after their initial treatment ranged narrowly from 22% to 24% among members of the four treatment groups. In the RP group, 5.2% had artificial urinary sphincter procedures; 6.8% of the RT group, 8.2% of the ADT group, and 10.1% of the WW group had TURP/bladder-neck procedures compared with 3.7% of the RP group; and 12.5-16.2% of members in the four groups had urethral dilation procedures. CONCLUSIONS: Over one third of prostate cancer patients needed surgical intervention within 66 mo of their initial treatment despite the type of initial treatment.     

Surgery for transposition of the great arteries, ventricular septal defect and left ventricular outflow tract obstruction: European Congenital Heart Surgeons Association multicentre study

Objectives: Optimal surgical management for patients with transposition of the great arteries (TGA), ventricular septal defect (VSD) and left ventricular outflow obstruction (LVOTO) remains controversial. Although the Rastelli operation has been the most widely performed surgical procedure during the past decades, several studies have shown its suboptimal long-term prognosis. Other operations have been developed to improve results. This study was performed to compare the outcomes of the different surgical approaches for patients with TGA, VSD and LVOTO, as well as to determine risk factors for mortality and re-intervention. Methods: Records from 146 patients undergoing surgery from 1980 to 2008 from eight European hospitals were reviewed. Median age at operation was 21.5 months (range 0.2–165.1 months), and median weight was 10.0 kg (range 2.0–41.0 kg). Surgical procedures involved were the Rastelli procedure (82), arterial (24) and atrial (5) switch operation with relief of LVOTO, Réparation à l’Etage ventriculaire (REV) procedure (7) and the Metras modification (24), as well as the Nikaidoh procedure (4). Results: The overall survival was 88%, 88% and 58% at 1, 10 and 20 years, respectively. The overall event-free survival was 80%, 45% and 26% at 1, 10 and 20 years, respectively. The REV procedure and the Metras modification were found to have the best long-term results in both survival and event-free survival rates. Multivariate analysis revealed year of operation, non-commitment of the VSD and prolonged cardiopulmonary bypass (CPB) time as risk factors for mortality while age at surgery, year of operation and type of corrective surgery were risk factors for re-intervention. Conclusions: Different surgical approaches have been developed for patients with TGA, VSD and LVOTO. The REV procedure and the Metras modification were observed to have favourable long-term results in survival and event-free survival rates. Aortic translocation techniques such as the Nikaidoh procedure seem promising, but further studies will be needed to confirm this in the long term.