Protein kinase Cδ mediates trimethyltin-induced neurotoxicity in mice in vivo via inhibition of glutathione defense mechanism

We investigated whether protein kinase C (PKC) is involved in trimethyltin (TMT)-induced neurotoxicity. TMT treatment (2.8 mg/kg, i.p.) significantly increased PKCδ expression out of PKC isozymes (i.e., α, βI, βII, δ, and ?) in the hippocampus of wild-type (WT) mice. Consistently, treatment with TMT resulted in significant increases in cleaved PKCδ expression. Genetic or pharmacological inhibition (PKCδ knockout or rottlerin) was less susceptible to TMT-induced seizures than WT mice. TMT treatment increased glutathione oxidation, lipid peroxidation, protein oxidation, and levels of reactive oxygen species. These effects were more pronounced in the WT mice than in PKCδ knockout mice. In addition, the ability of TMT to induce nuclear translocation of Nrf2, Nrf2 DNA-binding activity, and upregulation of γ-glutamylcysteine ligase was significantly increased in the PKCδ knockout mice and rottlerin (10 or 20 mg/kg, p.o. × 6)-treated WT mice. Furthermore, neuronal degeneration (as shown by nuclear chromatin clumping and TUNEL staining) in WT mice was most pronounced 2 days after TMT. At the same time, TMT-induced inhibition of phosphoinositol 3-kinase (PI3K)/Akt signaling was evident, thereby decreasing phospho-Bad, expression of Bcl-xL and Bcl-2, and the interaction between phospho-Bad and 14-3-3 protein, and increasing Bax expression and caspase-3 cleavage were observed. Rottlerin or PKCδ knockout significantly protected these changes in anti- and pro-apoptotic factors. Importantly, treatment of the PI3K inhibitor LY294002 (0.8 or 1.6 µg, i.c.v.) 4 h before TMT counteracted protective effects (i.e., Nrf-2-dependent glutathione induction and pro-survival phenomenon) of rottlerin. Therefore, our results suggest that down-regulation of PKCδ and up-regulations of Nrf2-dependent glutathione defense mechanism and PI3K/Akt signaling are critical for attenuating TMT neurotoxicity.     

Is handedness related to health status?

Handedness is the most important behavioural asymmetry due to its intimate association with the specialisation of the brain for language. It exists in 3 forms, namely right, left and mixed. Left-handers constitute the biggest minority group in the world and in many aspects they are in a disadvantaged position compared to right-handers. Numerous studies demonstrated association between left-handedness and different health problems ranging from learning disorders to breast cancer and decreased longevity. This paper reviews the relevant literature on the genesis of handedness and connection between handedness and health. Deviations from the “normal” pattern of braininess observed in some left-handers might contribute to developmental, cognitive and some mental disorders. However increased incidence of some of pathological conditions among sinistrals could hardly be explained by the “abnormal” pattern of braininess or by the action of a gene or genes responsible for handedness determination. Review of literature suggests that many of health problems of left-handers develop due to environmental, developmental and other mechanisms related to genesis of handedness.     

Long-term results of the Cox-Maze III procedure for persistent atrial fibrillation associated with rheumatic mitral valve disease: 10-year experience.

OBJECTIVE: We evaluated the long-term results of the Cox-Maze III procedure (CM-III) for persistent atrial fibrillation (AF) associated with rheumatic mitral valve (MV) disease. METHODS: We analyzed 127 patients who underwent the CM-III combined with a rheumatic MV procedure between 1994 and 2004. In-hospital mortalities were excluded from the study. RESULTS: There were 10 late deaths and the mean follow-up duration was 7.1+/-2.8 years (range, 13 months to 11.5 years). Normal sinus rhythm was restored in 88.2% (112/127) after the CM-III. Right atrial contractility was demonstrable in 100% (112/112) and left atrial contractility in 68.8% (77/112) of the patients restored to sinus rhythm. Fifteen patients never regained sinus rhythm after the CM-III (AF treatment failure). Permanent pacemakers were implanted in 4.7% (6/127) of the patients during the follow-up. Late recurrence of AF developed in 34 of 112 patients at 44+/-27 months postoperatively, and sinus rhythm was restored in 29 of 34 patients by administration of an antiarrhythmic medication. Independent risk factors for late AF recurrence were longer duration of AF (>60 months) (odds ratio (OR)=2.758, p=0.025), increased left atrial size (OR=1.113, p=0.004). Freedom from AF recurrence was 93% at 1-year, 82% at 3 years, 71% at 5 years, and 63% at 7 years. Risk factors for AF treatment failure were longer duration of AF (>60 months) (p<0.001) and increased patient age (p=0.030). A higher prevalence of significant late tricuspid regurgitation was observed in patients with AF treatment failure and those with late AF recurrence. CONCLUSIONS: The CM-III for persistent AF associated with rheumatic MV disease demonstrated a progressively decreased cure rate during the follow-up period. Early surgical therapy, aggressive left atrial reduction, and correction of tricuspid regurgitation at the time of surgery may increase the long-term success rate.     

Reversible Verbal and Visual Memory Deficits after Left Retrosplenial Infarction

The retrosplenial cortex is a cytoarchitecturally distinct brain structure located in the posterior cingulate gyrus and bordering the splenium, precuneus, and calcarine fissure. Functional imaging suggests that the retrosplenium is involved in memory, visuospatial processing, proprioception, and emotion.We report on a patient who developed reversible verbal and visual memory deficits following a stroke. Neuropsychological testing revealed both anterograde and retrograde memory deficits in verbal and visual modalities. Brain diffusion-weighted and T2-weighted magnetic resonance imaging (MRI) demonstrated an acute infarction of the left retrosplenium.     

A SLAP lesion associated with calcific tendinitis of the long head of the biceps brachii at its origin

Calcific tendinitis is a common condition with characteristic clinical and radiological findings. Although we do not know which condition initiated the pathologic cascade, we present a rare case of calcific tendinitis of the long head of the biceps brachii at its origin, associated with a SLAP lesion. The calcium deposit was removed and the SLAP lesion was repaired with a suture anchor arthroscopically.     

多索茶碱及其片剂的高效液相色谱分析

多索茶碱及其片剂的高效液相色谱分析刘春胜，何秀峰，王云萍，谷士杰，周同惠（中国医学科学院、中国协和医科大学药物研究所，北京１０００５０）多索茶碱（ｄｏｘｏｆｙｌｌｉｎｅ）是用于治疗支气管哮喘合并支气管痉挛的慢性阻塞性肺部疾病的新一代黄嘌吟衍生物，其药...     

Extensive Aberrant Mongolian Spot

A 9-month-old male infant had generalized diffuse blue-gray pigmentation over most of his body, sparing the scalp, face, neck, palms, soles, periumbilical area, genital area, and nipples. Within the lesion, there were several conspicuous macules of considerably darker hue. Histologic examination revealed numerous dermal melanocytes. By 16 months of age, the child's blue-gray pigmentation had decreased substantially.     

Comparison of the biomechanical effect of posterior condylar offset and kinematics between posterior cruciate-retaining and posterior-stabilized total knee arthroplasty

Background

The effect of the changes in the femoral posterior condylar offset (PCO) on anterior–posterior (AP) translation and internal–external (IE) rotation in cruciate-retaining (CR) and posterior-stabilized (PS) total knee arthroplasty (TKA) remains unknown. The purpose of this study was to compare the kinematics in CR and PS TKA with respect to the difference in prosthetic design and PCO change through a computational simulation.