Genotype-phenotype correlations in Rubinstein-Taybi syndrome.

Rubinstein-Taybi syndrome (RTS) is a rare multiple congenital anomaly/intellectual impairment syndrome. Loss of function in CREBBP or EP300 genes has been found in about 50% of patients with RTS. Genotype-phenotype correlations were investigated in 93 patients meeting diagnostic criteria for RTS during 2 international RTS family conferences. Mutation analysis of CREBBP was performed on all 31 coding exons and exon-intron junctions; a subset of patients had FISH analysis for large deletions. A total of 64 different variations were observed in the DNA sequence, and determined to be definitive mutations in 52 patients (56%). Mutations detected included: 10 missense mutations; 36 truncating or splice-site mutations; and 6 large deletions detectable by FISH. Fourteen patients had synonymous changes of unknown significance. The majority of mutations affected the HAT domain of CREBBP or predicted termination of the protein before the HAT region. Extensive phenotypic data were collected on each patient and analyzed to determine correlations with mutation types, that is, truncating, large deletions, single amino acid substitutions, or no CREBBP mutation. All four groups displayed the characteristic facial and thumb dysmorphology. Growth retardation in height and weight was seen more frequently in patients with no CREBBP mutation; seizure disorder was more frequent in those with CREBBP mutations. Degree of mental retardation was similar in all groups, although there was a trend toward lower IQ and autistic features in patients with large deletions. Similarity in phenotype between the groups implies that the several genes involved in causing RTS likely have effects through the same pathway.

Results of surgical procedures for the correction of foot-drop and of lagophthalmus due to leprosy.

Leprosy mutilations of the muscles and skeleton can be relieved by reconstructive surgery, but evaluation of the results of these operations is seldom undertaken. Between 1975 and 1984, 59 leprosy patients were operated on at the Marie Adelaide Leprosy Centre, Karachi, Pakistan, for lagophthalmus with the transposition of the posterior tibial muscle. We were able to re-examine 39 patients: tibialis posterior transposition was performed 25 times, and temporalis transposition was carried out 33 times; 18 of the 25 patients with the tibialis posterior transposition were pleased with the result, 7 were not: 21 patients could extend their feet above the neutral position; 24 of the patients with the temporalis transposition were satisfied, 9 were not: complete closure was demonstrated in 21 eyes; Persistent corneal damage was noted in 15 eyes; 12 of the 23 male patients cared for themselves, 16 lived with their families; 7 of the 8 female patients lived with their families. The results of the rehabilitation, in relation to the degree of mutilation, are considered satisfactory for a developing country. These surgical procedures give a good result, provided they are followed by intensive physiotherapy.

Genetic diversity of the major histocompatibility complex of cotton rats (Sigmodon hispidus) inhabiting an oil refinery complex.

We examined genetic diversity of an immune-response gene within the major histocompatibility complex in cotton rats (Sigmodon hispidus) inhabiting an oil refinery complex. Genetic diversity of MHC-DQA exon-2 was examined within and among contaminated and noncontaminated reference grids. The level of gene diversity within contaminated grids (0.748) was lower than within reference grids (0.818), but the difference was not statistically significant (p > 0.5). Analysis of molecular variance, pairwise FST values, and hierarchical clustering failed to reveal population genetic structure related to contamination. Results of this study indicate either that the level of contaminant-induced selection is insignificant at this major histocompatibility complex (MHC) locus or that gene flow from surrounding areas has obliterated the effects of selection.

A method for estimating weight in children from femoral midshaft diameter and age.

In this investigation, we relate transverse midshaft diameter of the femur, age, and weight in a sample of 183 children from Central Ohio. Age and femur diameter considered separately are similar in their ability to predict weight. Considering all sex and ancestry groupings (male, female, white, black), age explains between 90% to 96.8% of the variation in weight while femur diameter explains between 93% to 97.4%. However, estimates of individual weight from age or femur diameter have very large 95% prediction limits. Using age and femur diameter together results in a greater proportion of the variation in weight explained, 97.7% for the total sample, but the 95% prediction limits are similar to those using femur diameter alone.

A method for establishing the age of subadults.

Accurate estimates of age-at-death of subadult human skeletal remains are limited because of the dearth of information on the covariance among reliable indicators in recent samples of children. To obtain these kinds of data, namely patterns of maturation among dental development, epiphyseal union, and long bone growth, we focused on a radiographic method using recently decreased children. A total of 183 subadult cadavers were examined using X-radiographs of the six long bones and the mandibular dentition with measurements and evaluations thereof. The results of this study show that cadaver samples can relatively inexpensively, provide accurate and precise information on the covariance of subadult age indicators and thus can contribute to the formation of age standards for population lacking such data.

Galactosamine-induced cell death in primary cultures of rat hepatocytes.

Primary cultures of rat hepatocytes were exposed to 0.5 mM D-galactosamine. After 36 hours, only 10-20% of the original cells were viable, as assessed by trypan blue exclusion. In the absence of galactosamine, there was no loss of viability over this same period. The addition of 3 mM uridine to the culture medium completely prevented the cell death produced by galactosamine. Glucosamine had no effect on the viability of the hepatocytes. The extent of galactosamine-induced cell death was dependent upon the concentration of Ca++ ions in the culture medium. With the only source of Ca++ that added with the fetal calf serum, galactosamine had only a very slight effect on viability. With higher Ca++ than with the fetal calf serum, galactosamine had only a very slight effect on viability. With higher Ca++ concentrations, from 0.9 to 3.6 mM, the viability ranged from 75% to 31% 18 hours after treatment with galactosamine. The addition of 1.4 microM chlorpromazine to culture medium containing 1.8 mM Ca++ decreased the extent of the galactosamine-induced cell death. This protective effect was progressively reduced by raising the Ca++ concentration to 3.6 and 5.4 mM. Chlorpromazine given to intact rats 2 hours after treatment with 400 mg/kg galactosamine prevented the appearance of liver cell necrosis. At the same time, chlorpromazine prevented the increases in liver cell Ca++ content. These results indicate that many of the features of the effect of galactosamine on intact rat liver cells can be reproduced in primary cultures of these same cells. The data also support the hypothesis that a disturbance in intracellular Ca++ homeostasis leading to accumulations of these ions is causally related to the cell death produced by galactosamine.

Photoageing: the role of UVB, solar-simulated UVB, visible and psoralen UVA radiation.

We have studied the morphological and histological effects of chronic exposure of two strains of haired mice (albino Balb/c and pigmented C3H-) to various types of radiation. UVB (280-320 nm) radiation from unfiltered sunlamp bulbs for 20 and 30 weeks produced marked epidermal acanthosis and dyskeratosis which was reversible in mice exposed for 20 weeks followed by a 20-week rest. In the dermis the elastic fibres were altered and in the pigmented mice these changes had almost completely reversed 29 weeks after cessation of exposure. Cellulose acetate-filtered sunlamp bulbs (greater than 289 nm) produced similar but less marked changes. Chronic exposure to UVA (320-400 nm) radiation produced minimal alterations in the dermis while the epidermis was normal. Visible (greater than 400 nm) radiation in large doses produced no degenerative changes. Methoxsalen/UVA radiation produced epidermal acanthosis, dermal sclerosis, and alteration of elastic fibres, which was prominent in both strains at 40 weeks. These findings suggest that the UVB component of sunlight is largely responsible for photoageing of the skin. Furthermore, chronic exposure to methoxsalen/UVA therapy is likely to potentiate solar-induced photoageing.

Pediatric cutaneous malignant fibrous histiocytoma.

Malignant fibrous histiocytoma (MFH) is an aggressive soft-tissue sarcoma that most commonly occurs in the skeletal muscle of the extremities or retroperitoneum of adults. Although the majority of MFH is located beneath the fascia, the tumor occasionally occurs in the subcutaneous tissue. MFH rarely occurs in children and the disease course, prognosis, and outcome in younger patients has not been well described. We report a case of cutaneous MFH presenting on the thigh of a 12-year-old boy.

Prevention by chlorpromazine of ischemic liver cell death.

Ischemic liver tissue was produced by clamping the portal venous and hepatic arterial blood supply to the left lateral and median lobes of rat liver. If, after 2 to 3 hours of ischemia, reflow to the liver was established by removing the clamp, two-thirds or more of the liver cells were histologically dead 24 hours later. Pretreatment with chlorpromazine (20 mg/kg) 30 minutes before inducing ischemia for up to 3 hours virtually completely prevented this ischemic cell death. If the animals were kept alive for an additional 24 hours with no further treatment, the extent of liver cell necrosis at 48 hours was still markedly less than that seen in the untreated ischemic controls. Administration of chlorpromazine after induction of ischemia and immediately prior to the onset of reflow reduced but did not completely prevent ischemic cell death as determined at 24 hours. This protective action of chlorpromazine was confirmed by the ability of the treated animals to regenerate cellular ATP levels after 3 hours of ischemia. In addition, chlorpromazine was shown to significantly reduce the increases in total liver cell and mitochondrial calcium ion contents that accompany the return of blood flow to irreversibly injured liver cells. The protective effect of chlorpromazine could not be attributed to any effect either on the rate or extent to which the liver cells became ischemic or on the perfusion patterns following release of the obstruction, and it is concluded that the action of chlorpromazine must be on some component(s) of the reaction of the cells to the ischemia itself. The possible basis of this action is discussed.

An acquired form of epidermolysis bullosa without immunoreactants. Report of a case.

A patient with a 10-year history of an acquired, scarring bullous eruption localized to the anterior surfaces of the lower extremities is described. Clinical, histologic, and electron microscopic features of an acquired form of epidermolysis bullosa are shown to occur in the absence of immune deposits, a finding not previously documented.