Autonomic Regulation of Voltage-Gated Cardiac Ion Channels

Altering voltage-gated ion channel currents, by changing channel number or voltage-dependent kinetics, regulates the propagation of action potentials along the plasma membrane of individual cells and from one cell to its neighbors. Functional increases in the number of cardiac sodium channels (Na_V1.5) at the myocardial sarcolemma are accomplished by the regulation of caveolae by β adrenergically stimulated G-proteins. We demonstrate that Na_V1.5, Ca_V1.2a, and K_V1.5 channels specifically localize to isolated caveolar membranes, and to punctate regions of the sarcolemma labeled with caveolin-3. In addition, we show that Na_V1.5, Ca_V1.2a, and K_V1.5 channel antibodies label the same subpopulation of isolated caveolae. Plasma membrane sheet assays demonstrate that Na_V1.5, Ca_V1.2a, and K_V1.5 cluster with caveolin-3. This may have interesting implications for the way in which adrenergic pathways alter the cardiac action potential morphology and the velocity of the excitatory wave.     

High-grade T-cell lymphoma following treatment with cyclosporin A

A 47-year-old man with persistent severe oropharyngeal ulceration developed a high-grade T-cell lymphoma soon after commencing treatment with cyclosporin A. Using Southern blotting to identify T-cell beta-chain gene rearrangements, evidence of clonal restriction was found both in blood and lymph node DNA samples. Two BamH1 rearranged bands were demonstrated in both samples. In the blood a 16 Kb band predominated, with a weaker 28 kb band. In the lymph node sample this pattern was reversed. The findings suggest that a bi-clonal population of T-lymphocytes or clonal evolution of an existing T-cell monoclone had developed, and that cyclosporin contributed to the emergence of a high-grade T-cell lymphoma.     

Protective immunity to malaria: studies with cloned lines of Plasmodium chabaudi chabaudi in CBA/Ca mice. III. Protective and suppressive responses induced by immunization with purified antigens

The protective effect of affinity purified antigen has been investigated in an experimental model for malaria which shows a well marked recrudescence of parasitaemia, a feature of the disease in man. A monoclonal antibody (MoAb) recognizing an epitope common to two genetically distinct cloned lines of Plasmodium chabaudi (AS and CB), was used to purify a Mr250,000 polymorphic schizont antigen (PSA) from these parasites. The purified preparations were then examined for the presence of specific and cross-reactive epitopes by immunoprecipitation with a panel of MoAb raised against P. chabaudi AS. When tested previously on smears of parasitized blood by immunofluorescence, or against lysates of parasitized erythrocytes by immunoprecipitation, most of these MoAb had been found to be AS specific. When either AS or CB affinity purified Mr250,000 PSA was used as the target, these same MoAb immunoprecipitated both antigens, and in some cases, a number of associated polypeptides (AP) which copurify with the Mr250,000 PSA. Subsequently, mice were immunized with either the purified AS or CB antigens in Freund's complete adjuvant (FCA). Prechallenge sera were compared by indirect immunofluorescence and immunoprecipitation. Sera from mice immunized with AS antigen reacted strongly with AS and cross-reacted with CB parasite preparations. Pre-challenge serum from CB antigen immunized mice reacted well with CB, but only faintly with AS preparations. In mice immunized with the AS antigen and then challenged with either AS or CB parasites, the initial parasitaemias were delayed in appearance and the height of the peak parasitaemia reduced, an effect which was most pronounced after challenge with homologous parasites. Only homologous challenge of the mice immunized with CB antigen produced statistically significant modification of the initial parasitaemia. In the immunized mice challenged with homologous parasites, the delayed appearance and slightly reduced peak of the primary parasitaemia was associated with delayed resolution of the patent parasitaemia and significant enhancement of the recrudescence.     

Results of the tension-free vaginal tape procedure for stress incontinence: Patient''s perspective

BACKGROUND: To evaluate the results of the tension-free vaginal tape procedure (TVT) from a patient's perspective. METHODS: Between May 1999 and January 2002, 90 patients underwent a TVT for genuine stress incontinence (GSI) and mixed incontinence. Prior to the procedure, GSI was confirmed by clinical examination and urodynamic studies. Results were then audited from patient notes and the same patients were sent questionnaires to examine results from a patient perspective. RESULTS: Overall response rate to the questionnaire was 70 (77%). The mean age of the patients was 50.4 years (range 31-83 years). Sixty-one patients had spinal anesthesia, seven had general anesthesia and two had local anesthesia. Mean hospital stay was 3.36 days (range 2-14 days) and mean period from the operation to the time of the survey and audit was 16.34 months (range 3-28; SD 6.92). Thirty-nine (56%) of the 70 patients who answered said that the operation had cured their incontinence, 16 (23%) had an improvement in their symptoms, 7 (10%) had worsening of their symptoms and 8 (11%) felt that the operation did not make any difference. The overall success rate according to the patients' perspective was 79%, whereas our audit showed an overall success rate of 86% (77% and 82%, respectively, when we compared only the 66 patients who had both notes and replies available for analysis). CONCLUSION: Although a patient's perception regarding the success of TVT tends to differ from that of a clinician, it was not found to be statistically significant (P = 0.22, McNemar test). The TVT is a very successful operation, but realistic cure rates should be offered to patients.     

A hypothesis on the cause of chronic epidermal hyperproliferation in asebia mice

We compared the skin of the mutant mouse asebia (ab/ab) with that of normal BALB/c mice by examining dermal cell counts, epidermal thickness, epidermal cell labelling index and ultrastructure. In asebia we found epidermal hyperproliferation and dermal inflammation, with much cell debris in the dermis. The very numerous macrophages, both intact and disintegrating, contained electron-lucent crystals, apparently composed of lipid. We hypothesize that these crystals cause macrophage lysis followed by dermal inflammation and finally hyperproliferation in the overlying epidermis.     

The Association of Different Measures of Insulinaemia with Vascular Risk Factors in Healthy Normoglycaemic Normotensive Non-obese Men and Women

Hyperinsulinaemia is said to be a risk factor for cardiovasculardisease, but the extent to which different insulinaemic measuresare associated with vascular risk factors in ostensibly healthyindividuals, and whether they operate independently in men andwomen, remains uncertain. The association between risk factors and various insulinaemicmeasures was examined in 148 men and 118 women who were normoglycaemic,normotensive, and non-obese (body mass index in men <27,in women <25). A 75 g glucose tolerance test was administeredafter blood sampling for fibrinogen, lipids, lipoproteins andinsulin. Insulin was also measured after 1 and 2 hours. Significantunivariate correlations (p<0.01) were most consistently recordedbetween insulinaemic measures and fasting serum triglyceridesin men and women, whilst systolic blood pressure only correlatedwith insulinaemia in women, and diastolic blood pressure correlatedwith fasting and 2 hour insulinaemic measures in men and women.Inconsistent associations were noted with total serum cholesterolin men and women, with high density lipoprotein cholesterol,body mass index, apoprotein B and A1 in men, and with fibrinogenin women. Age was not correlated with any insulinaemic measurein men or women. Differences in vascular risk factors between quintiles of theinsulinaemic measures were examined, after correction for bodymass index. The dominant association with fasting and post-glucoseload insulinaemic measures was with triglycerides, especiallyin women, with less frequent graded differences between quintilesobserved for total cholesterol, and diastolic and systolic bloodpressures in men and women. The incidence of other risk factors often only differed in thelowest or highest quintile in comparison to other quintiles,suggesting a threshold rather than a graded effect. Furthermore,differences in HDL cholesterol and apoprotein B were only recordedfor top quintiles of post-glucose challenge/integrated insulinaemicmeasures in men, whilst serum fibrinogen concentrations onlydiffered significantly in women in the top insulinaemic areaunder the curve quintile. In the absence of additional risk factors such as diabetes,hypertension and obesity, insulinaemic measures are not consistentlyrelated to blood pressure and measures of lipid metabolism andcoagulation, and are thus a weak predictor of other cardiovascularrisk factors. The vascular risk profile associated with insulinappears somewhat different in apparently healthy men and women.