Regeneration of human auditory nerve. In vitro/in video demonstration of neural progenitor cells in adult human and guinea pig spiral ganglion

Time lapse video recordings of cultured adult human and guinea pig spiral ganglion (hSG and gpSG) show that mitogen responsive progenitor/stem cells develop in the form of spheres that proliferate and differentiate into mature neurons and glia cells. Neurospheres, cultured with EGF and bFGF showed expression of nestin and incorporation of 5'-Bromo-2-deoxyuridine (BrdU). Newly formed BrdU labelled cells were positive for beta-tubulin, and also for GFAP demonstrating that neuronal cells were derived from a dividing population of progenitor cells. Dissociated spheres cultured either with glia cell line-derived neurotrophic factor (GDNF) or brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), induced differentiation of the progenitor cells. Video microscopy showed that neurons develop from subcultured spheres maintained for up to four weeks. Neurons showed fasciculation and migration with a speed of 10-30 microm/h, and some cells had up to 6 mm long neurites coexpressing TrkB and TrkC receptors. Precise dissection suggests that the neurons formed are cochlea-specific. The results suggest that the mammalian auditory nerve has the capability for self-renewal and replacement. Transplantation of progenitor cells together with established means to induce neural differentiation and fiber growth may facilitate strategies for better repair and treatment of auditory neuronal damage.     

Left ventricular remodeling after infarction: sequential MR imaging with oral nicorandil therapy in rat model

PURPOSE: To use magnetic resonance (MR) imaging in quantification of the short- and long-term effects of therapy with orally administered nicorandil on left ventricular (LV) geometry and function independent of infarction size. MATERIALS AND METHODS: Forty-six rats were subjected to reperfused infarction and randomly divided into two groups. Group 1 rats (n = 21) were treated with nicorandil (3 mg/kg/day in drinking water) for 4 days before infarction and 8 weeks after infarction (hereafter, the nicorandil group). Group 2 rats (n = 25) received tap water for the same period and served as the control group. Mesoporphyrin- (as a necrosis-specific agent) enhanced MR imaging was used to define necrotic myocardium on day 2 after infarction in all 46 animals. Contrast material-enhanced MR images showed large but identical infarction size in 11 control and 11 nicorandil rats. Only these 22 rats underwent repeat MR imaging at 8 weeks after infarction. The following variables were measured: LV volumes, ejection fraction, mass, wall thickness, and infarction size. Student t test and analysis of variance for repeated measurements were used for statistical analysis. RESULTS: The size of the necrotic region on mesoporphyrin-enhanced MR images was 39% +/- 3 of the size of the left ventricle in the control group and 41% +/- 2 in the nicorandil group (difference not significant, unpaired Student t test). Pretreatment with nicorandil for 6 days before imaging did not reduce LV dilation or improve function compared with those in control animals with identical infarction size. Eight weeks after infarction, control animals showed deterioration in LV function, wall thinning, and gradient in regional dysfunction (analysis of variance test). Nicorandil produced significant salutary effects on LV ejection fraction (37% +/- 3 in the nicorandil group vs 24% +/- 3 in the control group), end-diastolic volume (0.53 mL +/- 0.03 vs 0.65 mL +/- 0.04), end-systolic volume (0.36 mL +/- 0.03 vs 0.49 mL +/- 0.05), LV wall thickening in remote noninfarcted myocardium (28% +/- 2 vs 19% +/- 1), and a rim of infarction (16% +/- 2 vs 8% +/- 1) (P <.05 for all parameters). The increase in LV mass was reduced in the nicorandil group (0.73 g +/- 0.03) compared with that in the control group (0.89 g +/- 0.04) (P <.05). CONCLUSION: In animals studied longitudinally, MR imaging demonstrated the deleterious changes in LV geometry and function in the period after infarction and the salutary effects of medical therapy.     

Clinical variants of lichen planus

Lichen planus is characterized by lichenoid, polygonal papules with fine white lines, called Wickham striae. Lesions most commonly occur on the limbs and on the dorsal aspect of the trunk. At the same time often leukoplakia of mucous membranes as well as nail disorders are seen. There are numerous variants of lichen planus which can be distinguished from the classical form on the basis of morphology and distribution of the lesions. The typical primary lesion of lichen planus may be replaced by other forms, such as patches, hyperkeratoses, ulcerations, or bullous lesions. Moreover, distribution patterns of these lesions may vary and include erythrodermic, inverse or linear arrangements. In contrast to these numerous clinical features, histologic findings remain characteristic in the variants, so that the diagnosis can be made securely. Differential diagnoses of lichen planus include diverse dermatoses such as bullous pemphigoid or paronychia.     

Multiple neuroectodermal abnormalities in pheochromocytoma patients

A series of 80 consecutive pheochromocytoma patients operated on from 1956 to 1985 were investigated for other neuroectodermal abnormalities. Such abnormalities were found in 23 (29%) patients. Medullary thyroid carcinoma was the most common associated neuroectodermal abnormality followed by von Recklinghausen's neurofibromatosis. Other abnormalities were intracranial tumors, midgut carcinoid, and parathyroid hyperplasia. All 6 patients with multiple pheochromocytomas had other neuroectodermal abnormalities. In the total series, the 14 patients with hereditary disease had multiple neuroectodermal abnormalities (MNA). Hypertension occurred significantly less often in MNA patients (p<0.05). All the MNA patients had benign adrenal pheochromocytoma. In 7 of 9 normotensive patients, pheochromocytoma was suspected because of the presence of other neuroectodermal abnormalities. None of these 9 patients had any cardio- or cerebrovascular complications, but these occurred in 22% of the hypertensive patients. No patient in the series died from pheochromocytoma, but 4 of 5 deceased MNA patients died as a result of their associated neuroectodermal disease. During the last decade, 40% of the pheochromocytoma patients had MNA diagnosed compared to 20% during the previous period. An increased observation for other neuroectodermal abnormalities in pheochromocytoma patients and for pheochromocytoma in patients with neuroectodermal abnormalities should lead to earlier diagnosis and a better prognosis for the patients concerned.

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Resumen Una serie de 80 pacientes con feocromocitoma operados entre 1956 y 1985 fueron investigados para establecer la presencia de otras anomalías neuroectodérmicas, las cuales fueron halladas en 23 pacientes (29%). La más frecuente fue el carcinoma medular de tiroides, seguida de neurofibromatosis de von Recklinghausen. Otras anomalías encontradas fueron tumores intracraneales, carcinomas del intestino medio, e hiperplasia paratiroidea. La totalidad de los 6 pacientes con feocromocitomas múltiples poseían otras anomalías neuroectodérmicas. Los 14 pacientes con enfermedad hereditaria presentaban también anomalías neuroectodérmicas múltiples (ANM). La hipertensión se presentó con incidencia significativamente menor en los pacientes con ANM (p<0.05). Todos los pacientes con ANM tenían feocromocitoma adrenal benigno. En 7 de los 9 pacientes normotensos se sospechó el feocromocitoma por la presencia de otras anomalías neuroectodérmicas. Ninguno de los 9 pacientes exhibió complicaciones cardiovasculares o neurovasculares, pero éstas ocurrieron en 22% de los pacientes hipertensos. Ningún paciente de la serie falleció por causa de su feocromocitoma, pero 4 de los 5 pacientes fallecidos con ANM murieron como resultado de la enfermedad neuroectodérmica asociada. En el curso del último decenio, 40% de los pacientes con feocromocitoma tuvieron diagnóstico de ANM, contra 20% en el período previo. La creciente conciencia sobre la posibilidad de otras anomalías neuroectodérmicas en pacientes con feocromocitoma y de feocromocitoma en pacientes con anomalías neuroectodérmicas debe resultar en diagnósticos más tempranos y mejor pronóstico en estos pacientes.

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Résumé Chez 80 patients consécutifs porteurs de phéochromocytome, opérés de 1956 à 1985, on a recherché des signes d'autres anomalies neuroectodermiques. On en a trouvé chez 23 patients (29%). L'anomalie associée la plus fréquente était le cancer médullaire de thyroïde, puis venait la neurofibromatose de von Recklinghausen. Les autres anomalies retrouvées étaient les tumeurs intracrâniennes, les tumeurs carcinoïdes de l'intestin moyen et l'hyperplasie parathyroïdienne. Les 6 patients ayant des phéochromocytomes multiples avaient des anomalies neuroectodermiques associées. Quatorze patients avec une maladie héréditaire avaient des anomalies neuroectodermiques multiples associées (ANM). Il y avait significativement moins d'hypertension parmi les patients avec des ANM (p<0.05). Tous les patients présentant une ANM, avaient aussi un phéochromocytome surrénalien bénin. Chez 1 patient parmi les 9 patients normotensifs, on a soupçonné un phéochromocytome en raison de l'association d'anomalies neuroectodermiques. Parmi ces 9 patients, il n'y a pas eu de complications cardio- ou cérébrovasculaires, mais celles-ci se sont produites chez 22% des patients hypertendus. Aucun patient dans cette série n'est mort de son phéochromocytome, mais 4 sur 5 patients avec une ANM sont morts de leur maladie neuroectodermique associée. Pendant ces 10 dernières années, on a fait le diagnostic d'ANM chez 40% des patients avec un phéochromocytome, alors qu'au cours des 10 précédentes années, ce diagnostic n'a été fait que chez 20%. Une recherche approfondie des anomalies neuroectodermiques associées chez le patient avec phéochromocytome ainsi que la recherche de phéochromocytome chez le patient présentant des anomalies neuroectodermiques devraient aider à poser le diagnostic plus précocément et ainsi à améliorer le pronostic.

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Presented at the International Association of Endocrine Surgeons in Paris, France, September, 1985.

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Supported by grants from the University of Göteborg, the Göteborg Medical Society, and the Swedish Medical Research Council (B87-17X-06534-05A).     

Long-Term Risk of Infective Endocarditis After Transcatheter Aortic Valve Replacement

Background

Patients undergoing surgical aortic valve replacement (SAVR) are considered at high risk of infective endocarditis (IE). However, data on the risk of IE following transcatheter aortic valve replacement (TAVR) are sparse and limited by the lack of long-term follow-up as well as a direct comparison with patients undergoing SAVR.

Endoscopic biopsies in Ussing chambers evaluated for studies of macromolecular permeability in the human colon

OBJECTIVE: Studies of mucosal permeability to protein antigens in humans are limited to in vitro techniques. The use of surgical specimens for such studies has major shortcomings. Endoscopic biopsies in Ussing chambers have been introduced as a means of studying secretion and transepithelial permeability, but have not been evaluated for studies of protein antigen uptake in human intestine. MATERIAL AND METHODS: Standard forceps biopsies from the sigmoid colon of 24 healthy volunteers were mounted in Ussing chambers with an exposed tissue area of 1.76 mm2. 51Cr-EDTA (paracellular probe) and horseradish peroxidase (HRP; 45 kDa protein antigen) were used as permeability markers. Mucosal permeability, electrophysiology, histology and energy contents of the biopsies were studied over time. To evaluate the ability of the technique to detect permeability changes, the mucosa was modulated with capric acid, a medium-chain fatty acid, known to affect tight junctions. RESULTS: In the Ussing chamber the mucosal biopsies were viable for 160 min with stable levels of ATP and lactate, and only minor changes in morphology. Steady-state permeability with low variability was seen for both markers during the 30-90 min period. Exposure to capric acid induced a rapid decrease in short-circuit current (Isc) and a slower reversible decrease in transepithelial resistance (TER), as well as an increased permeability to 51Cr-EDTA and HRP. CONCLUSIONS: Endoscopic biopsies of human colon are viable in Ussing chambers and are reliable tools for studies of mucosal permeability to protein antigens. The technique offers a broad potential for studies of mucosal function in the pathophysiology of human gastrointestinal diseases.     

Interface connections of a transmembrane voltage sensor

Voltage-sensitive ion channels open and close in response to changes in transmembrane (TM) potential caused by the motion of the S4 voltage sensors. These sensors are alpha-helices that include four or more positively charged amino acids, most commonly arginine. The so-called paddle model, based on the high-resolution structure of the KvAP K+ channel [Jiang, et al. (2003) Nature 423, 33-41], posits that the S4 sensors move within the membrane bilayer in response to TM voltage changes. Direct exposure of S4 sensors to lipid is contrary to the classical expectation that the dielectric contrast between the membrane hydrocarbon core and water presents an insurmountable energetic penalty to burial of electric charges. Nevertheless, recent experiments have shown that a helix with the sequence of KvAP S4 can be inserted across the endoplasmic reticulum membrane. To reconcile this result with the classical energetics argument, we have carried out a molecular dynamics simulation of an isolated TM S4 helix in a lipid bilayer. The simulation reveals a stabilizing hydrogen-bonded network of water and lipid phosphates around the arginines that reduces the effective thickness of the bilayer hydrocarbon core to approximately 10 A in the vicinity of the helix. It suggests that bilayer phospholipids can adapt locally to strongly perturbing protein elements, causing the phospholipids to become a structural extension of the protein.