Alpha-synuclein potentiates Ca2+ influx through voltage-dependent Ca2+ channels

Alpha-synuclein localized in synaptic terminals plays an important role in the pathogenesis of neurodegenerative diseases. The central domain of the protein, the nonamyloid component, is probably responsible for alpha-synuclein toxicity. Here, we report that alpha-synuclein and its nonamyloid component induced Ca2+ influx in rat synaptoneurosomes. The effect of alpha-synuclein was eliminated by the N-type specific Ca2+ channel blocker, omega-conotoxin GVIA. The antioxidant, resveratrol, and the nitric oxide synthase inhibitor, Nomega-nitro-L-arginine, did not prevent alpha-synuclein-induced Ca2+ influx. Our findings indicate that alpha-synuclein stimulated Ca2+ influx through N-type voltage-dependent Ca2+ channels by a mechanism other than free radicals. A direct interaction between alpha-synuclein and N-type Ca2+ channels could be responsible for their effects on Ca2+ influx through voltage-dependent Ca2+ channels.     

Genetic background of ADHD: genes of the serotonergic system, other candidate genes, endophenotype

Recent studies have shown that in the aetiology of attention-deficit hyperactivity disorder (ADHD) genetic factors may be of importance. Biochemical and pharmacological studies reveal a connection between abnormalities of dopaminergic, adrenergic and serotonergic system and ADHD. Therefore genes for enzymes synthesizing or degrading proper neurotransmitters, genes for adequate transporters and receptors and genes for other substances, which altered the level of neurotransmitters, are studied. Many authors describe the connection between ADHD development and the synaptosomal-associated protein 25 (SNAP-25) gene. This protein plays a role in catecholamine secretion. Its higher expression is specific for neurones. SNAP-25 gene mutation may change this protein level, function of synapse and neurotransmitters storage. Acetylcholine receptor alpha4 subunit gene stimulation increases the dopamine level. Therefore this receptor gene may be important in the aetiology of ADHD studies. Other possible factors in ADHD background are substance influence on brain maturation, including N-methyl-D aspartate glutamate receptor 2A gene polymorphism (GRIN2A) and brain derived neurotrophic factor (BDNF) gene. One of the greatest challenges in studying the genetic basis of psychiatric disorders is to find appropriate ways to define the relevant endophenotype. ADHD often coexists with other psychiatric disorders, including specific developmental disorders, conduct disorders, obsessive-compulsive disorder and early onset of bipolar disorder.     

Comparison of Brain Glucose Metabolism and Monoamine Oxidase B (MAO B) in Traumatic Brain Injury

OBJECTIVE: Positron emission tomography (PET) studies in patients with temporal lobe epilepsy have reported that hypometabolism in temporal regions is associated with elevated monoamine oxidase B (MAO B) probably reflecting gliosis. The purpose of this study was to examine a group of head trauma patients suffering from seizures and memory loss to determine whether hypometabolic regions show correspondingly elevated MAO B.METHODS: Seven patients with traumatic brain injury received PET scans with (18)FDG and [(11)C]L-deprenyl-D2 to measure regional glucose metabolism (LCMRglu) and MAO B respectively. Results were compared to a group of nine age-matched healthy controls. Hypometabolic regions were identified and MAO B values corresponding to these brain regions were determined. Averaged brain images for temporal regions for LCMRglu and MAO were also compared.RESULTS: LCMRglu values for temporal regions were reduced in patients relative to normal subjects. Of the 13 hypometabolic brain regions, 6 (46%) showed a corresponding elevation in MAO B. There was a trend for a significant inverse relationship between normalized LCMRglu and normalized MAO B values for medial temporal cortex. Glucose metabolism was significantly higher in lateral than medial temporal regions whereas the pattern was reversed for MAO B.CONCLUSION: MAO B images provide a markedly better delineation of the medial temporal regions than LCMRglu. There was not a consistent inverse relationship between metabolism and MAO B as had been reported in PET studies of epileptogenic temporal lobes with [(11)C]L-deprenyl-D2 and (18)FDG indicating that prospective studies are needed to determine the pathophysiology of hypometabolic lesions in head trauma.     

Retrograde (reverse) jejunal intussusception might not be such a rare problem: a single group’s experience of 23 cases

BACKGROUND: Retrograde (reverse) intussusception of the jejunum is thought to be a very rare occurrence, having been reported approximately 15 times (21 patients) in medical studies. A review of our own experience of >15,000 Roux-en-Y gastric bypass patients found 23 cases treated since 1996. This is the largest single-center report to date. METHODS: A chart review dating back to 1996 revealed 23 patients with retrograde intussusception involving the jejunum. Their charts were reviewed. A variety of data was reviewed to identify the risk factors for developing intussusception, as well as the presentation, findings, and treatment. RESULTS: We identified 23 patients with retrograde intussusception involving the jejunum. Of these 23 patients, 22 had undergone Roux-en-Y gastric bypass. One patient had undergone Roux-en-Y choledochojejunostomy. Of the 23 patients, 1 (4%) had a gastrojejunal intussusception and 22 (96%) jejunojejunal intussusceptions. All patients were women, with a median age of 32 years (range 20-50). The mean body mass index at gastric bypass was 45.2 kg/m2 (range 39.4-55). Of the 23 patients, 19 (83%) had undergone open and 4 (17%) laparoscopic gastric bypass. The median duration from gastric bypass to the diagnosis of intussusception was 51 months (range 6-288). Of the 23 patients, 8 (35%) presented with gangrene, perforation, or nonreducable obstruction, 9 (39%) had a spontaneous reduction, and in 6 (26%), the obstruction was successfully reduced at surgery. The treatment was surgical resection in 16 (70%) with 2 recurrences (12.5%), simple reduction in 2 (9%) with 100% recurrence, and plication in 5 patients (22%) with 2 recurrences (40%). CONCLUSION: Retrograde intussusception of the jejunum after gastric bypass is probably more common than previously believed. Although resection and revision of the area of intussusception appears to be effective, more information is needed about the treatment and possible prevention of this disorder.     

Bromodeoxyuridine Labeling Index as an Indicator of Early Tumor Response to Preoperative Radiotherapy in Patients with Rectal Cancer

Purpose Assessment of tumor proliferation rate using Bromodeoxyuridine labeling index (BrdUrdLI) as a possible predictor of rectal cancer response to preoperative radiotherapy (RT). Methods and material Ninety-two patients were qualified either to short RT (5 Gy/fraction/5 days) and surgery about 1 week after RT (schedule I), or to short RT and 4–5 weeks interval before surgery (schedule II). Tumor samples were taken twice from each patient: before RT and at the time of surgery. The samples were incubated with BrdUrd for 1 h at 37°C, and the BrdUrdLI was calculated as a percentage of BrdUrd-labeled cells. Results Thirty-eight patients were treated according to schedule I and 54 patients according to schedule II. Mean BrdUrdLI before RT was 8.5% and its value did not differ between the patients in the two compared groups. After RT tumors showed statistically significant growth inhibition (reduction of BrdUrdLI). As the pretreatment BrdUrd LI was not predictive for early clinical and pathologic tumor response, prognostic role of the ratio of BrdUrdLI after to BrdUrdLI before RT was considered. The ratios were calculated separately for fast (BrdUrd LI > 8.5%) and slowly (BrdUrd LI ≤ 8.5%) proliferating tumors and correlated with overall treatment time (OTT, i.e., time from the first day of RT to surgery). One month after RT, accelerated proliferation was observed only in slowly proliferating tumors. Conclusions Pretreatment BrdUrdLI was not predictive for early clinical and pathologic tumor response. The ratio after/before RT BrdUrdLI was correlated to inhibition of proliferation in responsive tumors. The paper was presented at ECCO 13, October 30 to November 03, 2005 in Paris, France     

Cross-infection in cystic fibrosis: the knowledge and behaviour of adult patients.

INTRODUCTION: The knowledge and behaviour of adult patients with cystic fibrosis (CF) regarding cross-infection are ill understood. METHODS: A questionnaire was designed to investigate this at the West Midlands Adult CF Centre. RESULTS: 94 patients completed the questionnaire. 54%, 36% and 46% had "no idea" of the lifetime risk of contracting Burkholderia cepacia complex, epidemic strains of Pseudomonas aeruginosa, and MRSA, respectively. 25-33% did not know the consequences of infection with these bacteria. 35% mixed with other people with CF, 6.5% during physiotherapy or nebulizer use. Most respondents did not think quality of life was significantly linked with segregation from other patients with CF. CONCLUSIONS: Adults with CF, at least in the West Midlands, have poor knowledge of the risk and consequences of cross-infection. A significant proportion ignored advice not to mix with other patients, although segregation was not thought to impact upon quality of life. This suggests that more education about the risks of cross-infection would be beneficial.     

Ischemia-reperfusion of small liver remnant promotes liver tumor growth and metastases--activation of cell invasion and migration pathways.

Elucidating the mechanism of liver tumor growth and metastasis after hepatic ischemia-reperfusion (I/R) injury of a small liver remnant will lay the foundation for the development of therapeutic strategies to target small liver remnant injury, and will reduce the likelihood of tumor recurrence after major hepatectomy or liver transplantation for liver cancer patients. In the current study, we aimed to investigate the effect of hepatic I/R injury of a small liver remnant on liver tumor development and metastases, and to explore the precise molecular mechanisms. A rat liver tumor model that underwent partial hepatic I/R injury with or without major hepatectomy was investigated. Liver tumor growth and metastases were compared among the groups with different surgical stress. An orthotopic liver tumor nude mice model was used to further confirm the invasiveness of the tumor cells from the above rat liver tumor model. Significant tumor growth and intrahepatic metastasis (5 of 6 vs. 0 of 6, P=0.015), and lung metastasis (5 of 6 vs. 0 of 6, P=0.015) were found in rats undergoing I/R and major hepatectomy compared with the control group, and was accompanied by upregulation of mRNA levels for Cdc42, ROCK (Rho kinase), and vascular endothelial growth factor, as well as activation of hepatic stellate cells. Most of the nude mice implanted with liver tumor from rats under I/R injury and major hepatectomy developed intrahepatic and lung metastases. In conclusion, hepatic I/R injury of a small liver remnant exacerbated liver tumor growth and metastasis by marked activation of cell adhesion, invasion, and angiogenesis pathways.     

Pathological Evaluation of Nipple‐Sparing Mastectomies with Emphasis on Occult Nipple Involvement: The Weill‐Cornell Experience with 325 Cases

Nipple‐sparing mastectomy (NSM) is an increasingly utilized surgical option in managing breast carcinoma; however, data on malignant involvement of a separately submitted nipple margin are scant. Consecutive NSM, including those performed for therapeutic and prophylactic purposes, over a 4‐year period (2007–2011), were studied. A separately submitted nipple margin was evaluated by permanent H&E preparations and via frozen section evaluation whenever requested. 325 consecutive NSM specimens, 208 (64%) therapeutic‐NSM, and 117 (36%) prophylactic‐NSM were studied. All nipples were clinically unremarkable. 86% (179/208) of nipple margins from therapeutic‐NSM and 100% (117/117) from prophylactic‐NSM showed no histopathologic abnormality. 14% (29/208) of nipple margins from therapeutic‐NSM and no nipple margin from prophylactic‐NSM showed malignancy. Frozen section evaluation was performed in 188/325 NSM (58%) with a sensitivity of 64% and specificity of 99%. Central tumor location and stage N2/N3 lymph node status were significantly associated with nipple margin positivity (χ² ≤ 0.05). Subsequent nipple resection was performed in 69% (20/29) of nipple margin‐positive cases with residual malignancy found in 40% (8/20, including three cases of invasive carcinoma). In a mean follow‐up of 33 months, one invasive carcinoma recurred in the “saved” nipple, 36 months after therapeutic‐NSM. 14% (29/208) of nipple margins in therapeutic‐NSM and no nipple margin (0/117) in prophylactic‐NSM showed malignancy. Central tumor location and N2/N3 stage were significantly associated with nipple margin positivity (χ² ≤ 0.05).     

Collagen type III alpha 1 polymorphism (rs1800255, COL3A1 2209 G>A) assessed with high-resolution melting analysis is not associated with pelvic organ prolapse in the Dutch population

Introduction and hypothesis

The rs1800255, COL3A1 2209 G>A polymorphism in the alpha 1 chain of collagen type III has been associated with an increased risk of pelvic organ prolapse (POP). In one of our previous studies however, polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) misdiagnosed rs1800255, COL3A1 2209 G>A in 6 % of cases. The high-resolution melting (HRM) analysis on the contrary obtained a 100 % accordance for this specific polymorphism and was used in the present study to validate this risk factor for POP.

Methods

In this case–control study, women with and without symptoms of POP were included and compared. DNA was extracted from blood samples. HRM analysis was used to assess for the presence of the homozygous rs1800255. Groups were compared using the Pearson chi-square, Mann–Whitney, and t tests. The discrepancy between HRM and PCR-RFLP results was investigated using PCR-RFLP results available from our previous study.

Results

The study included 354 women: 272 patients with POP and 82 controls; 18 (7 %) cases versus 3 (4 %) controls had a homozygous rs1800255, COL3A1 2209 G>A polymorphism (odds ratio 1.9, 95 % confidence interval 0.5–6.9, compared to the wild type), and thus no association between POP and the homozygous polymorphism could be demonstrated. A discrepancy between HRM and PCR-RFLP results was found in 8 % of the samples.

Conclusions

The previously found statistically significant association between the rs1800255, COL3A1 2209 G>A polymorphism as measured with PCR-RFLP and POP could no longer be demonstrated. This raises concerns regarding the results of other association studies using PCR-RFLP.