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.     

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.     

Changes and progress in surgical treatment of fractures of the pelvic ring and acetabulum

The diagnosis and treatment of pelvic fractures and dislocations demand that the pelvic girdle and the acetabulum be examined separately. Fractures of the pelvic girdle are present in more than 60% of cases but have to be stabilized only in 9%, in contrast to acetabular fractures, which need to be reduced and internally fixated in 55%. Combined fractures need surgical management in 66% of cases. Fractures of the pelvic girdle are best diagnosed by means of plain radiograms and computed tomograms to distinguish posterior instability. These techniques are the basis of the treatment plan for external or internal fixation. External fixation is an effective method from the aspect of hemorrhage control but not sufficient to avoid postoperative pain. Early open reduction and internal anterior and posterior fixation is the treatment of choice if good rehabilitation is to be achieved. Acetabular fractures occur mostly in young patients. Only accurate articular reduction of displaced fractures can bring about a good functional result, as this minimizes posttraumatic arthritis. Radiological evaluation is done with three standard views: 1. A. P. X-ray of the pelvis; 2. oblique view of the obturator; 3. oblique view of the ilium. When those are considered in combination with a CT scan, acetabular fractures can be classified. The Letournel classification is extremely important for reduction and fixation, as no one surgical approach has been found that is satisfactory for all acetabular fractures. Internal stabilization is provided with single screws and plates.     

Genetic variations in cytokines and cytokine receptors associated with psoriasis found by genome-wide association

Genetic variants have long been suspected to be important in psoriasis. Recent work has suggested that HLA-Cw6 on chromosome 6 is the risk variant in the PSORS1 [MIM 177900] susceptibility locus that confers the greatest risk for early onset of psoriasis. Although numerous minor susceptibility loci have been identified by linkage analysis, few biologically relevant candidates have been discovered within these intervals. Recent large-scale genome-wide association studies have yielded new candidates in genes encoding cytokines with functional relevance to psoriasis. Polymorphisms within the genes encoding the IL-12 p40 subunit, IL12B, and one of the IL-23 receptor subunits, IL23R, have been replicated in US and European populations and overlap with risk of Crohn's disease. Polymorphisms within the gene encoding IL-13, a Th2 cytokine, also confer risk for psoriasis. Variants of the gene IL15 encoding IL-15 have been identified that associate with psoriasis in a Chinese population. These discoveries pose the challenge of elucidating the role of common genetic variants in susceptibility to and manifestations of psoriasis.     

Low-dose mitomycin C as a prophylaxis for corneal haze in myopic surface ablation

PURPOSE: To evaluate the efficacy of low-dose (0.002%) mitomycin C (MMC) vs no prophylactic MMC (control) in reducing corneal haze after surface laser ablation. DESIGN: Two-year retrospective follow-up study performed in Jaipur, India. METHODS: Ninety-two eyes with no MMC application and 83 eyes with 0.002% MMC application during laser epithelial keratomileusis (LASEK) were analyzed in a retrospective chart review with one month, two months, three months, six months, one year, and two years of postoperative follow-up. Postoperative haze, visual acuity, and efficacy ratio (EFFR) then were analyzed statistically. RESULTS: The no-dose MMC and low-dose MMC groups were statistically similar except for a thinner corneal pachymetry (P < .001), higher spherical equivalent error (P = .006), and smaller ablation zone (P = .009) in eyes not treated with MMC when subjected to univariate analysis. Multivariate analysis was used to overcome the preoperative statistical differences among the two groups. Eyes treated with low-dose MMC (0.002%) demonstrated statistically less haze at all postoperative time points and in each myopic subgroup (P < .001). The postoperative uncorrected visual acuity (UCVA) and EFFR, however, showed no difference between the groups, except for better EFFR with MMC at one month (P < .001) and two months (P = .034). CONCLUSIONS: Low-dose MMC (0.002%) in eyes after LASEK results in less corneal haze than in eyes not receiving this agent. Concerns regarding the potential toxicity of MMC make a 10-fold less concentration more desirable in refractive surgery. Further comparative study of low- vs higher-dose MMC is recommended to characterize its clinical benefit fully.     

Effects of Zernike wavefront aberrations on visual acuity measured using electromagnetic adaptive optics technology

PURPOSE: This study measured the changes in visual acuity induced by individual Zernike ocular aberrations of various root-mean-square (RMS) magnitudes. METHODS: A crx1 Adaptive Optics Visual Simulator (Imagine Eyes) was used to modify the wavefront aberrations in nine eyes. After measuring ocular aberrations, the device was programmed to compensate for the eye's wavefront error up to the 4th order and successively apply different individual Zernike aberrations using a 5-mm pupil. The generated aberrations included defocus, astigmatism, coma, trefoil, and spherical aberration at a level of 0.1, 0.3, and 0.9 microm. Monocular visual acuity was assessed using computer-generated Landolt-C optotypes. RESULTS: Correction of the patients' aberrations improved visual acuity by a mean of 1 line (-0.1 logMAR) compared to best sphero-cylinder correction. Aberrations of 0.1 microm RMS resulted in a limited decrease in visual acuity (mean +0.05 logMAR), whereas aberrations of 0.3 microm RMS induced significant visual acuity losses with a mean reduction of 1.5 lines (+0.15 logMAR). Larger aberrations of 0.9 microm RMS resulted in greater visual acuity losses that were more pronounced with spherical aberration (+0.64 logMAR) and defocus (+0.62 logMAR), whereas trefoil (+0.22 logMAR) was found to be better tolerated. CONCLUSIONS: The electromagnetic adaptive optics visual simulator effectively corrected and generated wavefront aberrations up to the 4th order. Custom wavefront correction significantly improved visual acuity compared to best-spectacle correction. Symmetric aberrations (eg, defocus and spherical aberration) were more detrimental to visual performance.     

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).     

Recessive dystrophic epidermolysis bullosa skin displays a chronic growth-activated immunophenotype. Implications for carcinogenesis.

Epidermolysis bullosa represents a grouping of inherited skin diseases characterized by epidermal fragility and frequently wounded skin. The recessive dystrophic subtype of epidermolysis bullosa (RDEB) is characterized by extensive dermal scarring after healing of repeated epidermal injuries and by an unusually high incidence of squamous cell carcinoma occurring in chronically wounded skin. In contrast, the simplex form of epidermolysis bullosa usually heals without scarring and does not predispose to malignant neoplasms of the skin. The differences in scarring and the neoplastic potential of these two forms of epidermolysis bullosa prompted us to investigate growth activation and differentiation characteristics in epidermal keratinocytes in individuals with these disorders. The expression of filaggrin, involucrin, cytokeratins, and the growth activation marker psi-3 was examined by immunohistochemistry in skin biopsy specimens from four individuals with epidermolysis bullosa simplex and six individuals with RDEB. Previous experiments using this technique have demonstrated that these antibodies are good markers for identifying growth-activated keratinocytes in wounded and hyperplastic epidermis. All biopsy specimens of healed wounds in skin from patients with RDEB showed epidermis that reacted with antibodies to filaggrin, involucrin, specific cytokeratins, and psi-3 in a growth-activated pattern. This growth-activated phenotype was maintained in keratinocytes from previously wounded skin that had been healed for more than 2 years. The RDEB growth-activated phenotype detected by immunohistochemistry was not associated with microscopically detectable epidermal hyperplasia. In contrast, all cases of epidermolysis bullosa simplex examined showed an epidermal phenotype similar to that of keratinocytes in normal skin. Thus, healing with dermal scar formation in RDEB is associated with a persistent growth-activated immunophenotype of epidermal keratinocytes. This chronic growth activation state or failure of cells to differentiate in a normal fashion may be directly linked to the high incidence of squamous cell cancers in individuals with RDEB.