Synthesis and biological evaluation of prostaglandin-F alkylphosphinic acid derivatives as bone anabolic agents for the treatment of osteoporosis.

A series of novel C(1) alkylphosphinic acid analogues of the prostaglandin-F family have been evaluated at the eight human prostaglandin receptors for potential use in the treatment of osteoporosis. Using molecular modeling as a tool for structure-based drug design, we have discovered that the phosphinic acid moiety (P(O)(OH)R) behaves as an isostere for the C(1) carboxylic acid in the human prostaglandin FP binding assay in vitro and possesses enhanced hFP receptor selectivity when compared to the parent carboxylic acid. When evaluated in vivo, the methyl phosphinic acid analogue (4b) produced a bone anabolic response in rats, returning bone mineral volume (BMV) [corrected], to intact levels in the distal femur in the ovariectomized rat (OVX) model. These results suggest that prostaglandins of this class may be useful agents in the treatment of diseases associated with bone loss.

Medium-chain acyl coenzyme A dehydrogenase deficiency: occurrence in an infant and his father.

BACKGROUND: Autosomal recessive inborn errors of metabolism often present as life-threatening disease in infancy and have adverse effects on the nervous system. Parents are usually heterozygotes. This is true of most disorders of fatty acid oxidation, which are rare and present with hypoketotic hypoglycemia. However, the gene for medium-chain acyl coenzyme A dehydrogenase (MCAD) deficiency is common in white people, raising the possibility that a parent may be homozygous. OBJECTIVE: To document the occurrence of MCAD deficiency in a 12-month-old boy and his father, both of whom were homozygous for the A985G mutation. DESIGN: Clinical observations and definitive biochemical testing. SETTING: Children's hospital and university laboratory. PARTICIPANTS: One child and one adult. INTERVENTIONS: Diagnosis and treatment. MAIN OUTCOME MEASURES: Clinical outcome; analysis results of plasma and urine for carnitine and organic acids. RESULTS: An infant admitted with an acute illness requiring intensive care was found to have carnitine deficiency and dicarboxylic aciduria; MCAD deficiency was diagnosed by assay of his DNA for the common mutation. Test results of the father revealed him also to be homozygous. CONCLUSION: In MCAD deficiency, as opposed to the usual rare autosomal recessive metabolic disease, a parent may also be an affected homozygote.

Miscellaneous nail presentations.

A variety of individual nail dystrophies that are not categorized easily in other articles are reviewed. Onychoatrophia, anonychia, onychorrhexis, leukonychia, Beau's lines, onycholysis, onychomadesis, onychoschizia, haplonychia, longitudinal melanonychia, and ventral pterygium are included and pictured clinically. Their clinical description, etiology, associated conditions, differential diagnoses, and treatments are discussed and tabulated.

Superficial white onychomycosis.

A study on the incidence and causative organisms of pedal superficial white onychomycosis within several patient populations is presented. Early recognition, debridement, and topical antifungal therapy for several weeks with attention to biomechanical factors should resolve the infection and prevent progression to a more destructive form of onychomycosis.

Interleukin-1 pretreatment prevents interleukin-1-induced lung leak in rats.

We found that rats pretreated with interleukin-1 (IL-1) intraperitoneally did not develop the acute oxidative, neutrophil-dependent lung leak that occurs after administration of IL-1 intratracheally (IL-1-induced tolerance). IL-1-pretreated rats also had increased lung catalase and glucose-6-phosphate dehydrogenase (G6PDH) activity and increased plasma catalase activity compared with sham-pretreated rats. In contrast to reducing lung leak, IL-1 pretreatment did not reduce the numbers of neutrophils that are increased in lung lavages of rats given IL-1 intratracheally. IL-1-induced tolerance to IL-1-mediated lung leak and the associated increases in lung catalase, lung G6PDH, and serum catalase activities were all prevented by treating rats with the IL-1-receptor antagonist or with N-acetyl-L-cysteine, an agent that increases intracellular glutathione levels. Our results indicate that IL-1 pretreatment confers tolerance to IL-1-mediated lung leak without decreasing IL-1-induced increases in lung neutrophils. The possible protective actions of IL-1 should be considered in experiments and clinical trials where IL-1 activity is reduced pharmacologically.

Post-insult treatment with interleukin-1 receptor antagonist decreases oxidative lung injury in rats given intratracheal interleukin-1.

Systemic administration of recombinant human interleukin-1 receptor antagonist (IL-1Ra) caused a rapid and sustained elevation of plasma IL-1Ra levels and decreased the leak of intravascularly injected 125I-labeled albumin into lungs of rats given human recombinant interleukin-1 intratracheally. IL-1Ra treatment decreased leak when given 0.5 h before, 1.25 h after, or 2.5 h after IL-1 administration. Similarly, IL-1Ra treatment decreased lavage leukocytes and neutrophils when given 0.5 h before, 1.25 h after, or 2.5 h after IL-1 administration. Pretreatment with IL-1Ra also decreased lung myeloperoxidase activity and breath H2O2 concentration increases in rats given IL-1 intratracheally. Our results suggest that IL-1Ra treatment may decrease acute lung injury and neutrophil influx even when given after an IL-1 inciting insult.

Interleukin-1-induced lung neutrophil accumulation and oxygen metabolite-mediated lung leak in rats.

We found that intratracheal administration of recombinant interleukin-1 alpha (IL-1) into rats rapidly (< 5 h) increased neutrophils in lung lavages and caused an acute edematous lung injury which was reflected by lung albumin accumulation (lung leak) and histological abnormalities (perivascular cuffing). These IL-1-dependent processes were inhibited by prior administration of recombinant IL-1 receptor antagonist and did not occur following administration of heated IL-1. Several lines of evidence suggested that neutrophil-derived oxygen metabolites contributed to lung leak. First, lung leak did not occur in rats rendered neutropenic by vinblastine treatment 4 days before IL-1 administration but did occur in neutrophil-replete rats given vinblastine 1 day before IL-1 administration and control rats given IL-1. Second, treatment with a hydroxyl radical scavenger, dimethyl sulfoxide (DMSO) or a superoxide anion scavenger, manganese superoxide dismutase, decreased lung leak, lung lavage neutrophils, and histological abnormalities in rats given IL-1 intratracheally. Third, intratracheal IL-1 administration increased lung oxidized glutathione (GSSG) levels and expired H2O2 concentrations, and these two indices of oxidative stress were decreased by dimethyl sulfoxide or manganese superoxide dismutase treatment. We conclude that intratracheal administration of IL-1 increases neutrophils in the lung and causes a neutrophil and oxygen metabolite-dependent acute edematous lung injury.

Liposome-entrapped PGE1 posttreatment decreases IL-1 alpha-induced neutrophil accumulation and lung leak in rats.

We found that treatment with liposome-entrapped prostaglandin E1 (Lip-PGE1), but not with empty liposomes and/or free PGE1, decreased the leak of intravascularly administered 125I-labeled albumin into lungs of rats given interleukin-1 alpha (IL-1 alpha) intratracheally. Lip-PGE1 treatment also decreased lung myeloperoxidase activity, lung lavage neutrophil increases, and lung histological abnormalities found in rats given IL-1 alpha intratracheally. Interestingly, decreased lung leak and lung neutrophil accumulation occurred when Lip-PGE1 was given intravenously 2.5 h after, but not immediately before, intratracheal IL-1 alpha administration. When Lip-PGE1 treatment was given both before and 2.5 h after IL-1 alpha administration, lung leak was decreased to baseline levels. Lip-PGE1 treatment given 2.5 h after IL-1 alpha administration also decreased lung oxidized glutathione levels, which increased in rats given IL-1 alpha intratracheally. We conclude that postinsult treatment with Lip-PGE1 decreases lung leak, neutrophil recruitment, and oxidative responses in lungs of rats given IL-1 alpha intratracheally.

Bullosis diabeticorum. A report of two cases with a review of the literature.

Bullosis diabeticorum is a rare complication of long-standing diabetes mellitus. Bullous lesions, which appear like burn-induced blisters, occur suddenly without trauma in the feet. These bullae heal spontaneously without scarring; however, recurrence is common. The etiology of bullosis diabeticorum remains unknown. Several theories exist as to causal and contributory factors related to this cutaneous manifestation of diabetes mellitus.