Excitation of rat hippocampal interneurons via modulation of endogenous agonist activity at the α7 nicotinic ACh receptor

The α7 subtype of the nicotinic acetylcholine receptor (α7 nAChR) is prominently expressed in the hippocampus where it is thought to play a role in the regulation of cognitive function. In this study, we have investigated the effects of 5-hydroxyindole (5-HI), a positive modulator of the α7 nAChR, on GABAergic activity in hippocampal CA1 stratum radiatum interneurons in acute rat brain slices. Superfusion of 5-HI (100 μ m ) increased the mean frequency and amplitude of spontaneous IPSCs (sIPSCs). The potentiation was occluded by pretreatment of slices with: (1) a high concentration of the broad-spectrum agonist nicotine to desensitize the α7 receptor, (2) an α7 nAChR antagonist, and (3) tetrodotoxin to block action potential firing. These results indicate that facilitation by 5-HI was mediated by the α7 nAChR and required neuronal excitation. In contrast, 5-HI had no effect on sIPSCs recorded in hippocampal slices from younger animals, even though the expression of functional α7 nAChRs was confirmed by agonist application experiments. In these slices, 5-HI only enhanced sIPSCs after pretreatment with the acetylcholinesterase inhibitor Bw284c51. Taken together, our results suggest that 5-HI facilitates GABAergic transmission via excitation of the α7 nAChR, and that this effect requires the presence of the endogenous agonist ACh in the extracellular environment of the receptor.     

High throughput protein expression screening in the nervous system – needs and limitations

The cellular complexity of the brain (some estimate that there are up to 10³ different cell types) is exceeded by the synaptic complexity, with each of the ∼10¹¹ neurons in the brain having around 10³–10⁴ synapses. Proteomic studies of the synapse have revealed that the postsynaptic density is the most complex multiprotein structure yet identified, with ∼10³ different proteins. Such studies, however, use brain tissue with many different regions and therefore different cell types, and there is clear potential for heterogeneity of protein content at different synapses within and between brain regions. Although large-scale mRNA-based assays are in progress to map this sort of complexity at the cellular level, and indeed all brain-expressed genes, analysis of protein distribution (at synapses and other structures) is still in the very early stages. We review existing large-scale protein expression studies and the specific technical obstacles that need to be overcome before applying the scaling used in nucleic acid based approaches.     

Antibodies to fibroblasts in idiopathic and scleroderma-associated pulmonary hypertension.

The aim of the present study was to investigate the presence of anti-fibroblast antibodies in patients with idiopathic or scleroderma-associated pulmonary arterial hypertension (PAH) and healthy controls. PAH was documented by right-heart catheterisation (mean pulmonary artery pressure at rest >25 mmHg). Serum immunoglobulin (Ig)G and IgM reactivities of patients with idiopathic PAH (n = 35), scleroderma-associated PAH (n = 10), diffuse (n = 10) or limited cutaneous (n = 10) scleroderma without PAH and age- and sex-matched healthy individuals (n = 65) were analysed by cell-based ELISA and immunoblotting on normal human fibroblasts. As assessed by ELISA, 14 out of 35 (40%) patients with idiopathic PAH and three out of 10 (30%) patients with scleroderma-associated PAH expressed anti-fibroblast IgG antibodies. IgG from all individuals bound to one major 40-kDa protein band. IgG from patients with idiopathic PAH bound to two 25- and 60-kDa bands with a higher intensity than IgG from other individuals. In conclusion, immunoglobulin G anti-fibroblast antibodies are present in the serum of patients with pulmonary arterial hypertension. Immunoglobulin G from patients with idiopathic pulmonary arterial hypertension or scleroderma-associated pulmonary arterial hypertension express distinct reactivity profiles with fibroblasts antigens, suggesting distinct target antigens.     

A single-season prospective study of respiratory viral infections in lung transplant recipients.

The frequency and complications of respiratory viral infections (RVI) were studied in 50 ambulatory lung transplant patients during a single winter season, using viral antigens, viral cultures and PCR of nasal washes or bronchoalveolar lavages. Patients' survival, episodes of acute rejection and occurrence of bronchiolitis obliterans (BO) or BO syndrome (BOS) were monitored for 1 yr after the study. Overall, 32 (64%) patients had 49 symptomatic episodes. Documented infections included eight due to respiratory syncytial virus (RSV), one due to parainfluenza virus (PIV) and 10 due to influenza (FLU). Four of the FLU infections were serological rises without symptoms. Overall, 17 (34%) patients had documented viral infection; four patients had lower respiratory involvement and two (one RSV, one PIV) were hospitalised for aerosolised ribavirin treatment. After 1 yr there were three (6%) deaths unrelated to RVI. BO or BOS had occurred in one (6%) out of 17 patients with and three (12%) out of 33 without RVI. Respiratory viruses infected one-third of ambulatory lung transplant recipients in a single season. In conclusion, respiratory viral infection was not associated with subsequent graft dysfunction. Larger prospective studies are required to better define the acute and long-term morbidity of these infections.     

Linear atrophoderma of Moulin together with leuconychia: a case report

Linear atrophoderma of Moulin has a distinctive disease pattern characterized by hyperpigmented atrophoderma and was described originally in 1992. It follows the line of Blaschko, and occurs without preceding inflammation, subsequent induration or scleroderma. The lesions usually develop during childhood or adolescence, and the prognosis is good. The diagnosis is made clinically and histopathologically. In our 18-year-old male patient, there were atrophic plaques unilaterally located on the trunk and arm, and white discoloration on all finger nails. Histopathological examination revealed epidermal atrophy together with disruption of collagen fibres.     

Monophasic action potentials and activation recovery intervals as measures of ventricular action potential duration: experimental evidence to resolve some controversies.

BACKGROUND: Activation recovery intervals (ARIs) and monophasic action potential (MAP) duration are used as measures of action potential duration in beating hearts. However, controversies exist concerning the correct way to record MAPs or calculate ARIs. We have addressed these issues experimentally. OBJECTIVES: To experimentally address the controversies concerning the correct way to record MAPs or calculate ARIs. METHODS: Left ventricular local electrograms were recorded in isolated pig hearts with an exploring electrode grid, with a KCl reference electrode on the left ventricular myocardium, the aortic root, or the left atrium. Local activation was determined from calculated Laplacian electrograms. RESULTS: With the KCl electrode on the aortic root, local electrograms represented local activation. However, with the KCl electrode on the myocardium remote from the exploring electrode, a combined electrogram emerged consisting of local activation recorded from the grid and remote activation recorded from the reference electrode. The remote, inverted monophasic component did not show propagation and did not correlate with the Laplacian complex. When the KCl electrode was placed on the atrium during AV block, remote atrial monophasic components were completely dissociated from local, ventricular deflections. At left ventricular sites with a positive T wave, the Laplacian signal showed that the end of the T wave was caused by remote repolarization. During cooling-induced regional action potential prolongation, the T wave became negative, whereby the positive flank of the T wave remained correlated with repolarization (recorded with a MAP at the same site). CONCLUSIONS: MAPs are recorded from the depolarizing electrode. In both negative and positive T waves, the moment of maximum dV/dt corresponds to local repolarization.     

Evaluation of the thyroid nodule.

BACKGROUND: Thyroid nodules are common, yet treatment modalities range from observation to surgical resection. Because thyroid nodules are frequently found incidentally during routine physical examination or imaging performed for another reason, physicians from a diverse range of specialties encounter thyroid nodules. Clinical decision making depends on proper evaluation of the thyroid nodule. METHODS: The current literature was reviewed and synthesized. RESULTS: Current evidence allows the formulation of recommendations and a general algorithm for evaluating the incidental thyroid nodule. CONCLUSIONS: Only a small percentage of thyroid nodules require surgical management. Diagnosis and treatment selection require a risk stratification by history, physical examination, and ancillary tests. Nodules causing airway compression or those at high risk for carcinoma should prompt evaluation for surgical treatment. In nodules larger than 1 cm, fine-needle aspiration biopsy is central to the evaluation as it is accurate, low risk, and cost effective. Subcentimeter nodules, often found incidentally on imaging obtained for another purpose, can usually be evaluated by ultrasonography. Other laboratory and imaging evaluations have specific and more limited roles. An algorithm for the evaluation of the thyroid nodule is presented.     

Arsenic trioxide–loaded, microemulsion-enhanced cytotoxicity on MDAH 2774 ovarian carcinoma cell line

The antiproliferative effect of As(2)O(3)-loaded microemulsion (As(2)O(3)-M) on human MDAH 2774 ovarian cancer cells was compared with a regular solution of the As(2)O(3). We used MDAH 2774 as model cell lines for ovarian cancer. The (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide) (XTT) and trypane blue dye exclusion tests were used to evaluate cytotoxicity. Apoptotic effect of solutions was evaluated using cell death detection kit. Standard microemulsion formulation used in this experiment contains 5 x 10(-6) M As(2)O(3). It was clearly demonstrated that As(2)O(3)-M had a significant cytotoxic effect on MDAH 2774 cell line, and the cytotoxic effect of As(2)O(3)-M was significantly higher than that of regular As(2)O(3) solutions. Even approximately 6000 times diluted microemulsion formulation loaded with 5 x 10(-6) M As(2)O(3) showed a cytotoxic effect. As a result, this diluted concentration (approximately 8 x 10(-10) M) was found to be approximately 6000 times more effective than regular As(2)O(3) solutions (5 x 10(-6) M). Moreover, this diluted concentration resulted in 1.5-fold enhancement of apoptosis. According to the in vitro cytotoxicity studies, we concluded that by incorporating As(2)O(3) into the microemulsion (As(2)O(3)-M), which is a new drug carrier system, it is possible to increase antiproliferative effect of regular As(2)O(3) on MDAH 2774 cells. Translating these results to in vivo conditions would open new windows in the treatment of ovarian cancer.