Current-distance relations of axons mediating circling elicited by midbrain stimulation

Stimulation of mediocaudal midbrain in rats produces ipsiversive circling due to the stimulation of longitudinal axons. The refractory periods of these axons were measured by delivering trains of conditioning and testing pulses via a single electrode at various conditioning-testing (C-T) intervals. As C-T interval increased from 0.3 to 2.0 ms, the frequency required to produce a constant amount of circling halved. The current-distance relations of these axons were measured by placing two electrodes lateral to one another, and delivering conditioning pulses via one electrode and testing pulses via the second electrode. The required frequency decreased less at C-T intervals in the refractory period range using two electrodes rather than using a single electrode. This partial refractoriness suggests that only part of the axons were stimulated by both electrodes. The refractoriness increased as current increased or as interelectrode distance decreased. The overlap in the fields of stimulation at each current was calculated from the refractoriness observed in single and double electrode experiments. The results suggest that the axons mediating circling have a wide range of thresholds rather than a single threshold. The current required to activate an axon is roughly equal to K X r2, were K is a constant and r is the radial distance from electrode to axon. K must range from 400 to at least 3000 microA/mm2, to account for the circling data. For axons mediating medial forebrain bundle self-stimulation3, K must range from 1000 to at least 6400 microA/mm2. Estimation of the K distribution allows calculation of the effects of electrode size, placement and current on the recruitment of axons with different thresholds.     

An evaluation of symptom and chest radiographic screening in tuberculosis prevalence surveys.

SETTING: A tuberculosis (TB) prevalence survey was performed in 2002 in two urban communities in Cape Town, South Africa. The population was 36,334 in 2001, and the TB notification rate was 341 per 100,000 population for new smear-positive TB in 2002. OBJECTIVE: To evaluate the relative contributions of symptom and chest radiographic (CXR) screening in the detection of subjects with smear- and/or culture-positive TB in prevalence surveys. DESIGN: Information on symptoms, CXR abnormalities, sputum smear and culture was gathered from a random cluster sample of 1170 adults (aged > or = 15 years). Smear and/or culture-positive TB was used as the gold standard. RESULTS: Of 1170 adults, 29 had bacteriologically positive TB (smear- and/or culture-positive). The presence of any abnormalities on CXR had the highest sensitivity for detecting subjects with bacteriologically positive TB (0.97, 95%CI 0.90-1.00). Specificity for any abnormalities on CXR was 0.67 (95%CI 0.64-0.70). The specificity of any of five TB-related symptoms was 0.68 (95%CI 0.65-0.71). Individual symptoms had low sensitivities, ranging from 0.10 for fever to 0.54 for cough of > or = 2 weeks. CONCLUSION: In this TB prevalence survey, CXR screening, but not symptom screening, was a sensitive alternative to sputum examination of all participants.     

Reduced stimulation of helper T cells by Ki-ras transformed cells.

A number of viral genes and cellular oncogenes inhibit major histocompatibility complex (MHC) antigen expression at the cell surface. In the case of inhibition of class I MHC antigens by viral genes this results in a reduced recognition by antigen-specific cytotoxic T cells. The activated Ki-ras cellular oncogene carried by the Ki-murine sarcoma virus (Ki-MuSV) in contrast inhibits class II MHC (or Ia) antigen expression on transformed cells. We have studied how transformation with Ki-ras affects recognition by alloreactive helper T cells. We found that the Ki-ras inhibition of class II MHC antigen expression led to greatly reduced stimulation of alloreactive T cells to proliferate and to secrete interferon-gamma (IFN-gamma). These findings support our hypothesis that the ability of an oncogene to reduce class II MHC antigen expression is crucial to its ability to produce tumour cells.     

Influence of TNFalpha and LTalpha single nucleotide polymorphisms on susceptibility to and prognosis in cutaneous malignant melanoma in the British population.

Cutaneous malignant melanoma (CMM) is a potentially fatal malignancy in which exposure to UV light is the most important risk factor. Several lines of evidence suggest that increased expression of tumour necrosis factor (TNF) alpha, upregulated by UV exposure, may contribute to tumour escape from the immune response. In this study, we addressed whether single nucleotide polymorphisms (SNPs) in the TNFalpha promoter and lymphotoxin (LT) alpha gene are associated with susceptibility to or known prognostic indicators (e.g. initial tumour growth phase, Breslow thickness, mitotic count in vertical growth phase tumours, and tumour regression) in CMM. One hundred and forty-six British Caucasian CMM patients and 220 controls were typed for TNFalpha-376, -308 and -238 and LTalpha+252 SNPs by ARMS-PCR. Only the TNFalpha -238 GG (P = 0.05) and GA (P = 0.03) genotypes showed slight, but significant, associations with CMM, while LTalpha+252 AA was associated with a higher mitotic count in vertical growth phase tumours (P = 0.02). Both TNFalpha-238 and LTalpha+252 SNPs showed linkage disequilibrium with HLA-DQB1*0303 and *0301 alleles, variably implicated in CMM susceptibility/prognosis. In addition, TNFalpha-238, -308, LTalpha+252 haplotypes were assigned and compared. The GGA haplotype showed a modest association with CMM (P = 0.04) and with stage of disease (P = 0.03) and initial growth phase in CMM (P = 0.02), but these associations were only significant when P-values were uncorrected. Unlike basal cell carcinoma, these preliminary findings suggest that genetic variation associated with differential TNFalpha and LTalpha production is unlikely to play a major, independent role in susceptibility to, and perhaps prognosis in, CMM.     

Gene expression of LDL receptor, HMG-CoA reductase, and cholesterol-7 alpha-hydroxylase in chronic renal failure

BACKGROUND: Chronic renal failure (CRF) is associated with an atherogenic lipid profile and an increased risk of ischaemic cardiovascular disease. The associated hyperlipidaemia is reportedly ameliorated by erythropoietin (Epo) therapy. According to a recent report, rats studied 3 weeks after 5/6 nephrectomy and fed a high- protein diet exhibited increased activities of hepatic HMG-CoA reductase (HMG-CoAR) and cholesterol 7 alpha-hydroxylase (Ch-7 alpha- H), despite normal corresponding mRNA values. DESIGN AND METHODS: This study was designed to examine the effects of naturally progressing CRF of longer duration as well as those of Epo therapy on gene expressions of the key factors involved in hepatic cholesterol metabolism, i.e., LDL receptor (LDLR), HMG-CoAR, and Ch-7 alpha-H. Sprague-Dawley rats were randomized to the CRF group (5/6 nephrectomy), Epo-treated CRF group (given Epo 150 U/kg/twice weekly) and sham-operated, placebo- treated normal controls. They were allowed free access to regular rat chow and studied 6 weeks after surgery. Liver mRNAs and protein mass or activities of the above factors were studied. RESULTS: Plasma cholesterol concentration was significantly increased in the CRF group (P < 0.001) and was modestly lowered (P < 0.05) by Epo therapy. However, microsomal cholesterol concentration and LDLR, HMG-CoAR, and Ch-7 alpha-H mRNA as well as HMG-CoAR activity, and Ch-7 alpha-H and LDLR protein mass measurements were virtually identical in the three groups. Thus, hepatic LDLR, HMG-CoAR, and Ch-7 alpha-H mRNA and protein measurements in rats with CRF were similar to those of the normal control group representing an inappropriate response to the associated hypercholesterolemia. Epo therapy led to partial amelioration of CRF- associated hypercholesterolaemia with no discernible effect on hepatic tissue expression of the above factors.