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.     

Fast CT-PRESS-based spiral chemical shift imaging at 3 Tesla.

A new sequence is presented that combines constant-time point-resolved spectroscopy (CT-PRESS) with fast spiral chemical shift imaging. It allows the acquisition of multivoxel spectra without line splitting with a minimum total measurement time of less than 5 min for a field of view of 24 cm and a nominal 1.5x1.5-cm2 in-plane resolution. Measurements were performed with 17 CS encoding steps in t1 (Deltat1=12.8 ms) and an average echo time of 151 ms, which was determined by simulating the CT-PRESS experiment for the spin systems of glutamate (Glu) and myo-inositol (mI). Signals from N-acetyl-aspartate, total creatine, choline-containing compounds (Cho), Glu, and mI were detected in a healthy volunteer with no or only minor baseline distortions within 14 min on a 3 T MR scanner.     

Prognostic factors for surgical resection in patients with multidrug-resistant tuberculosis.

Although surgical lung resection could improve prognosis in some patients with multidrug-resistant tuberculosis (MDR-TB), there are no reports on the optimal candidates for this surgery. The aim of the present study was to elucidate the prognostic factors for surgery in patients with MDR-TB. Patients who underwent lung resection for the treatment of MDR-TB between March 1993 and December 2004 were included in the present study. Treatment failure was defined as greater than or equal to two of the five cultures recorded in the final 12 months of treatment being positive, any one of the final three cultures being positive, or the patient having died during treatment. The variables that affected treatment outcomes were identified through univariate and multivariate logistic regression analysis. In total, 79 patients with MDR-TB were included in the present study. The treatment outcomes of 22 (27.8%) patients were classified as failure. A body mass index <18.5 kg x m(-2), primary resistance, resistance to ofloxacin and the presence of a cavitary lesion beyond the range of the surgical resection were associated with treatment failure. Low body mass index, primary resistance, resistance to ofloxacin and cavitary lesions beyond the range of resection are possible poor prognostic factors for surgical lung resection in multidrug-resistant tuberculosis patients.     

Effects of magnetic resonance imaging diffusion gradient recalled echo on a patient with an intracranial hemorrhage presenting to the emergency department.

Generally, a computed tomography scan is conducted for the diagnosis of stroke in the emergency department, because these scans are easier and faster in the detection of stroke. If there are no signs of hemorrhage on computed tomography scan, an ischemic stroke is diagnosed and treated accordingly. A magnetic resonance imaging scan may be taken in order to verify ischemic stroke. This process may lead to improper treatment and is time consuming. To address this situation, case studies are presented in which magnetic resonance imaging diffusion-weighted imaging and gradient recalled echo were performed to detect hemorrhagic and ischemic stroke and particularly, subarachnoid hemorrhage, which is undetectable with a computed tomography scan.     

Use of paracervical analgesia for outpatient hysteroscopic surgery: A randomized, double-blind, placebo-controlled study

Twenty-five women receiving sedation for outpatient hysteroscopic polypectomy were injected with 0.25% bupivacaine 10 mL (paracervical group) and another 25 received the same volume of saline (control group) at the cervical fornix. Both groups were given target-controlled propofol sedation during the procedure. More propofol (mg/min) was needed for adequate anesthesia in the control group compared to the paracervical group (6.5 versus 4.6). In addition, the postoperative pain scores were lower in the paracervical group than in the control group. Hemodynamic changes and postoperative side effects were similar in the two groups. This prospective, randomized, double-blind, placebo-controlled study confirmed the effective use of paracervical blocks. This approach has the effect of reducing the amount of intraoperative propofol and decreasing postoperative pain in outpatient hysteroscopic surgery.     

A survey: conscious sedation with epidural and zygapophyseal injections: is it necessary?

BACKGROUND CONTEXT: Substantial variation exists regarding the use of sedation before interventional spine techniques. Patient preference should play an important role in decision making regarding the need for sedation. However, little is known about patients' anxiety levels before spinal injections and their perceptions about the necessity of sedation. PURPOSE: To determine patient perception for need for sedation before epidural steroid injections and zygapophyseal joint injections. STUDY DESIGN/SETTING: Survey of consecutive spinal injection patients in an outpatient spine center. PATIENT SAMPLE: 500 consecutive lumbar, thoracic, and cervical patients receiving spinal injections. OUTCOME MEASURES: A 12-item questionnaire assessing patients' perceived anxiety before to a spinal injection. METHODS: Subjects were given the questionnaire after their spinal injection. Percentages requesting sedation for a first and potential second procedure were assessed. Additionally, anxiety level and pain rating, location of injection, age, sex, and other medication use were analyzed to determine the effect on the request for sedation. RESULTS: 17% of patients questioned requested sedation before an injection, and 28% would request sedation if they were to have a second injection. CONCLUSIONS: Routine sedation before diagnostic and therapeutic injections is not necessary as the majority of patients would not request sedation before the procedure when given the option. However, in some patients sedation is indicated, and all patients would benefit from educational material on sedation before the injection.     

Nonselective cation channels activated by the stimulation of muscarinic receptors in mammalian gastric smooth muscle.

Muscarinic receptors play key roles in the control of gastrointestinal smooth muscle activity. However, specific physiological functions of each subtype remain to be determined. Single cell RT-PCR experiments showed that all five subtypes of muscarinic receptors were present in circular smooth muscle cells of the guinea-pig gastric antrum. Nonselective cation channels (NSCC) activated by ACh or CCh are coupled to pertussis toxin (PTX)-sensitive Go protein through m4 subtype as well as m2 and m3 subtypes in guinea-pig stomach. CCh-activated currents (I(CCh)), especially the steady-state I-V relationship of I(CCh) showed a chracteristic U-shaped curve; reversal potential of around 0 mV and inward rectification at around +15 mV and a negative slope conductance at negative potential range. Under physiological conditions, the measured single channel conductance of NSCC was approximately 25 pS. The single channel conductance was modulated by external monovalent and divalent cations including Na+, Cs+, Li+, and Ca2+ through changing both the open probability and unitary conductance. Through the NSCC, Ca2+ can move into the cell from extracellular solution as well as Na+. Calculated fractional Ca2+ current of I(CCh) (f(Ca)) was around 1% at the 2 mM [Ca2+]o and at the 4 mM [Ca2+]o, f(Ca) was 2.3%. Quinidine blocked I(CCh) potently in a reversible manner; IC50 was 0.25 microM. There were two kinds of I(CCh) modulations through Ca(2+)-dependent pathways in guinea-pig gastric smooth muscle cells; 1) Facilitation of I(CCh) via Ca2+/CaM-dependent MLCK pathway, 2) Desensitization of I(CCh) via Ca(2+)-dependent PKC pathway. In the mouse stomach, all seven types of TRPC mRNA were detected with RT-PCR. On the basis of electrophysiological, pharmacological, and molecular biological experiments, we reported the mTRPC5 as a candidate for the NSCC activated by muscarinic stimulation in mouse stomach.