Hyperexcitability and reduced low threshold potassium currents in auditory neurons of mice lacking the channel subunit Kv1.1

A low voltage-activated potassium current, I _KL, is found in auditory neuron types that have low excitability and precisely preserve the temporal pattern of activity present in their presynaptic inputs. The gene Kcna1 codes for Kv1.1 potassium channel subunits, which combine in expression systems to produce channel tetramers with properties similar to those of I _KL, including sensitivity to dendrotoxin (DTX). Kv1.1 is strongly expressed in neurons with I _KL, including auditory neurons of the medial nucleus of the trapezoid body (MNTB). We therefore decided to investigate how the absence of Kv1.1 affected channel properties and function in MNTB neurons from mice lacking Kcna1 . We used the whole cell version of the patch clamp technique to record from MNTB neurons in brainstem slices from Kcna1 -null (−/−) mice and their wild-type (+/+) and heterozygous (+/−) littermates. There was an I _KL in voltage-clamped −/− MNTB neurons, but it was about half the amplitude of the I _KL in +/+ neurons, with otherwise similar properties. Consistent with this, −/− MNTB neurons were more excitable than their +/+ counterparts; they fired more than twice as many action potentials (APs) during current steps, and the threshold current amplitude required to generate an AP was roughly halved. +/− MNTB neurons had excitability and I _KL amplitudes identical to the +/+ neurons. The I _KL remaining in −/− neurons was blocked by DTX, suggesting the underlying channels contained subunits Kv1.2 and/or Kv1.6 (also DTX-sensitive). DTX increased excitability further in the already hyperexcitable −/− MNTB neurons, suggesting that −/− I _KL limited excitability despite its reduced amplitude in the absence of Kv1.1 subunits.     

Myositis associated with a newly described microsporidian, Trachipleistophora hominis, in a patient with AIDS.

Microsporidia are zoonotic protozoa which were rare human pathogens prior to 1985, when Enterocytozoon bieneusi was described in human immunodeficiency virus-infected patients with chronic diarrhea. Another species, Encephalitozoon (Septata) intestinalis, is associated with diarrhea and chronic sinusitis, and approximately 25 cases have been reported in the literature. However, other microsporidial infections in human immunodeficiency virus-infected patients remain extremely rare. We report the first case of a Pleistophora sp.-like microsporidian infection presenting as a progressive severe myosotis associated with fever and weight loss. The organism was demonstrated by light microscopy and electron microscopy in corneal scrapings, skeletal muscle, and nasal discharge. Electron microscopy showed an electron-dense surface coat with "sunflare"-like projections surrounding all stages of development of meronts (two to four nuclei, dividing by binary fission), sporonts, and sporoblasts. Division of sporonts, in which sporonts separate from the thick outer coat, creating a sporophorous vesicle, is by binary fission, differentiating this organism from Pleistophora sp. The spore measures 4.0 by 2.5 microns and has a rugose exospore. A new genus and species, Trachipleistophora hominis, has been established for this parasite. The patient was treated with albendazole, sulfadiazine, and pyrimethamine, and the clinical symptoms resolved.     

T-cell receptor heterogeneity of gamma delta T-cell clones from human female reproductive tissues.

gamma delta T cells were isolated from human decidua parietalis, decidua basalis and cervix and cloned in the presence of interleukin-2 (IL-2). T-cell receptor (TcR) expression was then analysed and compared with that of a panel of gamma delta T-cell clones from peripheral blood. Only 17/40 (42.5%) clones from decidua parietalis were V gamma 9+/V delta 2+ as compared to 68/94 (72%) of peripheral blood clones (P < 0.005). Conversely, 50% of clones from decidua parietalis but only 15% of clones from peripheral blood were V delta 1+ (P < 0.001). At least seven distinct TcR types were identified among the panel of clones from decidua parietalis and at least six different types were expressed by the panel of 17 clones from cervix. This receptor heterogeneity was not a result of interdonor variation as in all instances where more than one clone was obtained from a single sample, individual clones having between two and five receptor types were identified. However, 23/24 (95.8%) of clones from decidua basalis were V gamma 9+/V delta 2+. Most clones from decidua parietalis and cervix, whether V gamma 9+/V delta 2+ or V delta 1+, were positive for the mucosal lymphocyte marker, HML-1, but expression was often heterogeneous within a single clone. In contrast, almost all gamma delta T-cell clones from peripheral blood were HML-1-. Thus, unlike the mouse, gamma delta T cells within these human female reproductive tissues have a diverse TcR repertoire which, in decidua parietalis, is distinct from that of peripheral blood.     

Nitric oxide synthetase and Helicobacter pylori in patients undergoing appendicectomy

BACKGROUND: This study was designed to determine whether Helicobacter pylori forms part of the normal microenvironment of the appendix, whether it plays a role in the pathogenesis of acute appendicitis, and whether it is associated with increased expression of inducible nitric oxide synthetase (iNOS) in appendicular macrophages. METHODS: Serology for H. pylori was performed on 51 consecutive patients undergoing emergency appendicectomy. Appendix samples were tested for urease activity, cultured and stained for H. pylori, graded according to the degree of inflammatory infiltrate, and probed immunohistochemically for iNOS expression. RESULTS: The mean age of the patients was 21 (range 7-51) years. Seventeen patients (33 per cent) were seropositive for H. pylori but no evidence of H. pylori was found in any appendix specimen. However, an enhanced inflammatory cell infiltration was observed in seropositive patients (P < 0.04) and the expression of macrophage iNOS in the mucosa of normal and inflamed appendix specimens was increased (P < 0.01). CONCLUSION: H. pylori does not colonize the appendix and is unlikely to be a pathogenic stimulus for appendicitis. Priming effects on mucosal immunology downstream from the foregut may occur after infection with H. pylori.     

Recurrence of progressive multifocal leukoencephalopathy despite immune recovery in two HIV seropositive individuals

We present two cases of recurrent progressive multifocal leukoencephalopathy (PML) in patients with long standing virally suppressed human immunodeficiency virus (HIV) and normal CD4+ T cell count who were taking stable regimens of highly active antiretroviral therapy (HAART). This has significant implications for other patients with a past history of PML, not just those with HIV but also those on medications such as natalizumab or fumarates.     

Alcohol and Brain Damage

In this review, two forms of alcohol-related brain damage and their possible pathogenesis are discussed. These are the Wernicke-Korsakoff syndrome and alcoholic dementia. There is little doubt that thiamine deficiency is the factor responsible for Wernicke's encephalopathy. However, additional factors might play a role in the development of Korsakoff's psychosis. Many cases of Wernicke's encephalopathy are undiagnosed by clinicians whose awareness of the various manifestations of this disease needs to be increased. Thiamine deficiency may lead to brain damage by blocking the oxidative metabolism of glucose, ammo acids and fatty acids. There is no definite evidence that marginal thiamine deficiency causes disease. Certain individuals may be especially prone to the effects of thiamine deficiency for genetic reasons. There is clearly a spectrum of mental impairment in alcoholics which cannot be attributed to thiamine deficiency. Some of these abnormalities correlate with the neuroradiological and pathological signs of cerebral atrophy. Mental impairment and atrophy in alcoholics are partly reversible with abstinence. Alcohol itself might be neurotoxic which would explain some of these phenomena.     

Effect of the alpha-adrenergic blocker, doxazosin, on endothelial function and insulin action

Essential hypertension is associated with impairment of both endothelial function and insulin action, and this has provided rationale for the use of antihypertensive agents that are at least neutral, if not beneficial, in these areas. This study examines the effect of the alpha-adrenergic blocker, doxazosin, on endothelial function and insulin action. Sixteen patients with essential hypertension were recruited with 13 (3 men/10 women; median age, 55 years; range, 38 to 65 years) completing the study. A double-blind, placebo-controlled crossover study design was used. After a 6-week placebo run-in, there were two 12-week treatment periods of either placebo or doxazosin, separated by a 6-week wash out period. Subjects were studied at the end of each treatment period with endothelial function assessed by forearm plethysmography and insulin action by the hyperinsulinemic clamp technique. Blood pressure was significantly lowered by doxazosin (doxazosin 144 +/-3/86 +/- 2 mm Hg; placebo 159 +/- 3/96 +/- 1 mm Hg, P <.005 for both systolic and diastolic pressure; mean +/- SEM). Baseline forearm blood flow (FBF) was unchanged (doxazosin 4.9 +/- 0.9; placebo 4.0 +/- 0.7 mL x 100 mL(-1) x min(-1), P >.05), however, FBF responses (area under dose response curve, percentage change in infused:control arm ratio) to acetylcholine (endothelium-dependent vasodilation) were improved by doxazosin (doxazosin 58.6 +/- 11.7 standard units [SU]; placebo 22.1 +/- 7.0 SU, P =.03) with responses to sodium nitroprusside (endothelium-independent vasodilation) unchanged (doxazosin 40.3 +/- 5.5 SU; placebo 46.3 +/- 8.1 SU, P >.05). Exogenous glucose infusion rates to maintain euglycemia during hyperinsulinemia were not significantly different (doxazosin 30.4 +/- 0.9; placebo 32.3 +/- 1.0 micromol x kg(-1) min(-1), P >.05). Suppression of postabsorptive endogenous glucose production by insulin was also unchanged by treatment (doxazosin 65.6% +/- 7.5% suppression; placebo 68.3% +/- 11.2% suppression, P >.05). Doxazosin has a neutral effect on both peripheral and hepatic insulin action, but improves endothelium-dependent vasodilation. These results indicate that doxazosin can be used safely in patients with insulin resistance, while its positive effect on endothelial function may lessen the subsequent incidence of atherosclerosis.     

A pilot randomised controlled trial of the management of systolic blood pressure during endovascular thrombectomy for acute ischaemic stroke

It is unknown whether systolic blood pressure augmentation during endovascular thrombectomy improves clinical outcomes. This pilot randomised controlled trial aimed to assess the feasibility of differential systolic blood pressure targeting during endovascular thrombectomy procedures for anterior circulation ischaemic stroke. Fifty-one eligible patients fulfilling the national criteria for endovascular thrombectomy were randomly assigned to receive either standard or augmented systolic blood pressure management from the start of anaesthesia to recanalisation of the target vessel. Systolic blood pressure targets for the standard and augmented groups were 130–150 mmHg and 160–180 mmHg, respectively. The study achieved all feasibility targets, including a recruitment rate of 3.5 participants per week and median (IQR [range]) of mean systolic blood pressure separation between groups of 139 (135–143 [115–154]) vs. 167 (150–175 [113–188]) mmHg, p < 0.001. Data completeness was 99%. Independent functional recovery at 90 days (modified Rankin Scale 0, 1 or 2) was achieved in 30 (59%) patients, which is consistent with previously published data. There were no safety concerns with trial procedures. In conclusion, a large randomised controlled efficacy trial of standard vs. augmented systolic blood pressure management during endovascular thrombectomy is feasible.     

Changes in Cathepsin D and Beclin-1 mRNA and protein expression by the excitotoxin quinolinic acid in human astrocytes and neurons

Quinolinic acid (QUIN) is an excitotoxin that has been implicated in the pathogenesis of several neurodegenerative diseases including Alzheimer’s disease (AD). While QUIN has been shown to induce neuronal and astrocytic apoptosis as well as excitotoxic cell death, other mechanisms such as autophagy remain unexplored. We investigated the role of Cathepsin D (CatD) and Beclin-1 (Bc1) in QUIN-treated primary human astrocytes and neurons. We demonstrated that the expression patterns of CatD, a lysosomal aspartic protease associated with autophagy, are increased at 24 h after QUIN treatment. However, unlike CatD, the expression patterns of Bc1, a tumour suppressor protein, are significantly reduced at 24 h after QUIN treatment in both brain cell types. Furthermore, we showed that the NMDA ion channel blockers, MK801, can attenuate QUIN-induced changes CatD and Bc1 expression in both astrocytes and neurons. Taken together, these results suggest that induction of deficits in CatD and Bc1 is a significant mechanism for QUIN toxicity in glial and neuronal cells. Maintenance of autophagy may play a crucial role in neuroprotection in the setting of AD.