Altered subthreshold sodium currents and disrupted firing patterns in Purkinje neurons of Scn8a mutant mice

Sodium currents and action potentials were characterized in Purkinje neurons from ataxic mice lacking expression of the sodium channel Scn8a. Peak transient sodium current was approximately 60% of that in normal mice, but subthreshold sodium current was affected much more. Steady-state current elicited by voltage ramps was reduced to approximately 30%, and resurgent sodium current, an unusual transient current elicited on repolarization following strong depolarizations, was reduced to 8%-18%. In jolting mice, with a missense mutation in Scn8a, steady-state and resurgent current were also reduced, with altered voltage dependence and kinetics. Both spontaneous firing and evoked bursts of spikes were diminished in cells from null and jolting mice. Evidently Scn8a channels carry most subthreshold sodium current and are crucial for repetitive firing.     

Metalloregulatory properties of the ArsD repressor

The plasmid-encoded arsenical resistance (ars) operon of plasmid R773 produces resistance to trivalent and pentavalent salts of the metalloids arsenic and antimony in cells of Escherichia coli. The first two genes in the operon, arsR and arsD, were previously shown to encode trans-acting repressor proteins. ArsR controls the basal level of expression of the operon, while ArsD controls maximal expression. Thus, action of the two repressors form a homeostatic regulatory circuit that maintains the level of ars expression within a narrow range. In this study, we demonstrate that ArsD binds to the same site on the ars promoter element as ArsR but with 2 orders of magnitude lower affinity. The results of gel shift assays demonstrate that ArsD is released from the ars DNA promoter by phenylarsine oxide, sodium arsenite, and potassium antimonyl tartrate (in order of effectiveness), the same inducers to which ArsR responds. Using the quenching of intrinsic tryptophan fluorescence to measure the affinity of the repressor for inducers, apparent Kd values for Sb(III) and As(III) of 2 and 60 microM, respectively, were obtained. These results demonstrate that the arsR-arsD pair provide a sensitive mechanism for sensing a wide range of environmental heavy metals.     

Transforming region of 243R E1A contains two overlapping but distinct transactivation domains

Conserved regions 1 and 2 as well as the amino terminus of E1A are required for the transforming activity of the E1A oncoprotein. We show here that the amino terminus of 243R E1A has transactivation activity when brought to a promoter in yeast. Recruitment to a specific promoter is essential. Mutagenesis studies correlated the transactivation function with the extreme amino terminus and the conserved region 1 of E1A. Cotransfection assays in rodent cells confirmed that two overlapping but distinguishable domains, amino acids 1-65 and 37-80, can transactivate independently when targeted to a promoter. We also observed that when recruited to the proliferating cell nuclear antigen (PCNA) promoter, the amino-terminal region was sufficient to transactivate the PCNA promoter. On the other hand, deletion of the amino terminus of E1A resulted in failure to induce PCNA expression. Fusion of VP16 with the amino-terminal-deleted E1A mutant was able to restore the ability to induce the PCNA promoter. We further show that the amino-terminal region also is required for 243R E1A to repress the transactivation mediated by a universal transactivator DBD.VP16 and DBD.E1A. This repression could be specifically relieved by overexpression of TBP but not TFIIB. In addition, we show that the amino terminus of E1A is involved in in vitro interaction with the TATA binding protein (TBP). Thus the amino-terminal transforming region of E1A may regulate cellular gene expression in species that are distant in evolution via a common mechanism, functionally targeting TBP.     

Naming decline after left anterior temporal lobectomy correlates with pathological status of resected hippocampus

PURPOSE: To evaluate the determinants of postoperative change in visual confrontation naming ability and the differential sensitivity of two common tests of confrontation naming. METHODS: In a group of 99 patients undergoing lobectomy of the left, language-dominant anterior temporal lobe, we examined naming ability using two measures: the 60 item Boston Naming Test (BNT), and the Visual Naming (VN) subtest of the Multilingual Aphasia Examination (MAE). ATL entailed resection of lateral temporal lobe followed by microsurgical complete removal of hippocampus. Language mapping was not performed. The status of the resected hippocampus was graded on a scale 0-4 of hippocampal sclerosis (HS). A dichotomous grouping HS- (grades 0 and 1, n = 34) and HS+ (grades 3 and 4, n = 61) was effected. Age at surgery, age of epilepsy onset, sex, extent of lateral temporal resection, Full-Scale IQ (FSIQ), and preoperative naming scores were also examined as potential predictors of pre- versus postoperative naming change. RESULTS: Preoperative BNT and VN scores were significantly worse for HS+ than for HS- (BNT, p < 0.05; VN, p = 0.001). Postoperatively, BNT and VN scores significantly declined for HS- as compared with HS+ patients (p < 0.001). For individual risk, the 90th centile of reliable change index (RCI) was used. By this criterion, of the total sample, 39% evidenced decline on the BNT and 17% evidenced decline on the VN. Logistic regression analysis with backward elimination showed HS to be the only predictor of decline in BNT and HS and sex to be the only predictors of VN decline. Males were more at risk than females. Age, age at onset, extent of lateral resection, preoperative scores, and FSIQ were not predictors. Using age at onset as a proxy for HS+/HS- we calculated probabilities for naming decline for given onset age. CONCLUSIONS: Both preoperative and postoperative change in naming ability are associated with the pathological status of the hippocampus. The potential interpretations and implications of these findings are discussed.     

Immunomodulatory effects of linomide in animals immunized with immunopathogenic retinal antigens: dissociation between different immune functions

Linomide (LS-2616, quinoline-3-carboxamide) has been reported to exert a diverse range of effects on the immune system. On one hand, this drug was found to stimulate the immune system and to enhance activities such as DTH or allograft rejection. On the other hand, linomide was shown to inhibit the induction of experimental autoimmune encephalomyelitis and myasthenia gravis, as well as the development of diabetes in non-obese diabetic (NOD) mice. Here we report the effects of linomide in animals immunized with uveitogenic retinal antigens. Treatment with linomide completely inhibited the development of experimental autoimmune uveoretinitis (EAU) in mice immunized with interphotoreceptor retinoid-binding protein and markedly suppressed EAU in rats immunized with S-antigen (S-Ag). In addition, linomide-treated rats exhibited reduced antibody production and lymphocyte proliferative response to S-Ag. In contrast to these suppressive activities, linomide treatment did not affect the development of adoptively transferred EAU in rats and moderately enhanced the DTH reactions to S-Ag in immunized rats in which EAU and other immune responses to this antigen were suppressed.     

Learned helplessness, attributional style, and depression in epilepsy. Bozeman Epilepsy Surgery Consortium

PURPOSE: We wished to examine the relevance of the theory of learned helplessness in general, and attributional style in particular, to the understanding of depression among patients with epilepsy. METHODS: Patients with lateralized temporal lobe epilepsy (TLE) (right = 73, left = 70) were administered two self-report depression inventories [Beck Depression Inventory (BDI), Center for Epidemiological Studies-Depression scale (CES-D)]. Depression scores were examined in relation to a key component of the revised theory of learned helplessness (attributional style) using the Optimism/Pessimism Scale. RESULTS: Attributional style was significantly associated with increased self-reported depression and remained significant when the effects of several confounding variables were controlled [age, age at onset, laterality of TLE, sex, and method variance]. CONCLUSIONS: The results indicate that the concept of learned helplessness in general, and attributional style in particular, are related to the genesis of depression in epilepsy. Because they are known to be related to depression in the general population, and because specific techniques for intervention and prevention are available, greater consideration of learned helplessness and attributional style in the genesis of depression in epilepsy may be worthwhile.     

Predicting recovery from common whiplash

Epididymo-orchitis (EO) is said to be extremely rare in infants and children. It is usually diagnosed after scrotal exploration for symptoms which mimic manifestations between EO and torsion of the cord and its appendage. The pathophysiologic mechanisms for the development of EO are not well known. Although some causative agents of EO have been reported, in most cases there was no clear etiology. We report a 3-month-old male infant who had been well until the day prior to admission when irritability, left testicular swelling, scrotal erythema with a hot sensation were noted by his mother. He was treated medically after excluding the possibility of an emergent surgical condition (such as torsion of the cord and its appendage, or incarcerated hernia) by means of physical examinations, abdominal and inguino-scrotal sonography, laboratory studies, and testicular radionuclide scintigraphy. A catheterized sample of urine for culture yielded Escherichia coli. There was the possibility that the EO was caused by hematogenous rather than local spread from an infection of the urinary tract. He was treated with a 10-day course of intravenous cefazolin and amikacin. Following this, he improved clinically and a repeat catheterized urine sample remained sterile on culture. In addition, a bilateral inguinal hernia and hydrocele were detected by inguino-scrotal sonography and were operated on the 11th hospital day. He was discharged on the 16th day of hospitalization and remained well 11 months after discharge.