Doxycycline prophylaxis for shigellosis.

The efficacy of oral doxycycline, 100 mg/d for 14 days, in reducing the incidence of shigellosis in newcomers to an area hyperendemic for the disease was examined in a double-blind, placebo-controlled trial. Of 107 entrants, 100 completed the study; 50 received the drug and 50 received a placebo. Diarrheal disease and associated symptoms were monitored for 8 weeks. Starting on the 3rd day of the trial, an outbreak was observed, and Shigella flexneri type 2a was isolated from 6 subjects. Eight of the subjects in the treatment group had diarrhea (16%) compared with 37 in the placebo group (74%), providing a 79% protection rate. There was no significant difference in the occurrence of accompanying symptoms between the subjects suffering from diarrhea in both groups, but the duration of disease was shorter in the treatment group. Serologic study of the outbreak showed no significant difference in antibody response to S flexneri between the treatment (14 of 43) and placebo (18 of 39) groups. Doxycycline prophylaxis apparently is effective and probably does not prevent subclinical infection.

Interstitial 7q deletion [46,XY,del (7) (pter----cen::q112----qter)] in a retarded quadriplegic boy with normal beta glucuronidase.

A 14-year-old severely retarded male with deletion of chromosomal band 7 cen----q112 is described. Clinical features include short stature, microcephaly, unusual facies with narrow forehead, short nose, malar hypoplasia, protruding alveolar ridges and incisors, receding chin, relatively long philtrum, and large ears. In addition, he had bilateral inguinal herniae cryptorchidism with hypogonadism, pulmonic stenosis, and spastic quadriplegia. Normal activity of beta-glucuronidase was found in the patient's leukocytes. This finding suggests that the gene is not in the deleted region, narrowing the smallest region of overlap to 7q112----q22.

Hypodipsic hypernatremia and hypertriglyceridemia associated with cleft lip and cleft palate: a new hypothalamic dysfunction syndrome?

We report on a 4-month-old girl with congenital hypodipsic hypernatremia resulting from decreased sensitivity of the hypothalamic osmoreceptors with increased tonicity in association with hyperlipemia and cleft lip and cleft palate. We postulate that the link among these various derangements is hypothalamic dysfunction.

Cross resistance to esters of methotrexate in a doxorubicin-resistant subline of P388 murine leukemia.

Resistance to methotrexate was developed by continuous exposure of P388 murine leukemia cells in vitro to increasing concentrations of methotrexate up to 1 X 10(-7) M. Once established, the resistance to methotrexate was stable. This was also found in methotrexate-resistant cells that were maintained in methotrexate-free medium for more than 4 months. The sensitivity of the methotrexate-resistant P388 cells to doxorubicin was comparable to the sensitivity measured in the parental cell line. Another methotrexate-resistant cell line was developed, in a similar way, from doxorubicin-resistant P388 cells. This methotrexate-resistant cell line maintained its original resistance to doxorubicin. In methotrexate-sensitive cells, the dimethyl and dibutyl esters of methotrexate were 18.3- and 2.7-fold less active, respectively, than the free methotrexate in inhibiting cell growth. In methotrexate-resistant cells, the inhibitory effect of the methotrexate dimethyl ester was similar to its effect on the methotrexate-sensitive cell line. The activity of the methotrexate dibutyl ester was 3.3-fold lower than its activity in the parental cell line. However, both esters of methotrexate were much more active than free methotrexate in the methotrexate-resistant cell line. In the doxorubicin-resistant cell line, the activity of free methotrexate was comparable to its activity in the doxorubicin-sensitive parent cell line. However, this cell line was remarkably resistant to the ester analogs of methotrexate. The clinical implications of these findings are discussed.

Transport into brain of buthionine sulfoximine, an inhibitor of glutathione synthesis, is facilitated by esterification and administration of dimethylsulfoxide.

Buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis, is poorly transported into the brain of adult mice, and only a slight decrease (approximately 10%) in the level of brain glutathione is found 30-60 min after intraperitoneal administration of BSO. When BSO is given as the ethyl ester, the brain level of BSO increases substantially after 5-15 min, and the glutathione level decreases by about 25% after 30-60 min. When BSO or its ester is given in 15% dimethylsulfoxide solution the brain levels of BSO are increased significantly and the brain glutathione levels are decreased by 20-35%. These observations suggest procedures that may be useful in decreasing the glutathione levels of the brains of adult animals. The finding that administration of BSO ethyl ester led to about a 25% decrease in the brain level of glutathione within 15 min suggests that a fraction of brain glutathione turns over very rapidly and may therefore be of special physiological significance.

Effects of cysteamine and other thiols on cystine egress from isolated lysosome-rich fractions of cystinotic and normal leucocytes.

After loading isolated normal and cystinotic white blood cell lysosomes with radioactive amino acid methyl esters, egress of the corresponding amino acids was measured in the presence or absence of reducing agents. Cysteamine greatly enhanced disposal of cystine- and, to a lesser extent, cysteine-loaded lysosomes, resulting in final similar rates of radioactive clearance. Cysteamine did not alter leucine egress. Cysteamine comparably accelerated cystine egress from normal and cystinotic lysosomes. Reduced glutathione, ascorbic acid, coenzyme A and acetylcoenzyme A, which are much less effective cystine-depleting agents on intact cystinotic cells than cysteamine, failed to increase egress rates from isolated lysosomes loaded with cystine. We believe this in vitro system can help in the future in evaluating drug efficacy in reducing cystine content in cystinotics in addition to the already existing tissue culture technique.

Cystine accumulation and clearance in normal and cystinotic fibroblasts exposed to cystine dimethyl ester.

Exposure of cultured skin fibroblasts of normals and cystinotic patients to 0.5 mmol/l[35S]cystine dimethyl ester for 30 min resulted in an accumulation of cystine in excess to that naturally occurring in cystinotic skin fibroblasts. These equal levels of cystine accumulation achieved in both cystinotic and normal cells, permitted comparative experiments to look for differences in cystine disposal between normal and cystinotic cells. Cystinotic fibroblasts demonstrated very low cystine clearance with a lower ratio of cysteine-N-ethylmaleimide to cystine than normal. The results on cystinotic fibroblasts are consistent with those observed in leucocytes, suggesting that fibroblasts can be useful in further studies to elucidate the clearance defect of cystine in cystinosis as well as its potential in antenatal diagnosis.

A comparison of insulin receptors in the developing fetal lung in normal and in streptozotocin-induced diabetic pregnancies.

Insulin receptors from fetal rat lungs of normal and streptozotocin-induced diabetic pregnancies were examined for their binding capacities and association constants. Sprague-Dawley rats, given a single dose of streptozotocin at 7 days' gestation, became hypoinsulinemic and hyperglycemic within 48 hours, although they remained healthy enough to carry fetuses to term. The fetuses of the streptozotocin-treated pregnancies had hyperglycemia (3,750 +/- 400 micrograms glucose/ml vs 390 +/- glucose/ml for control subjects), but were not hyperinsulinemic. Insulin receptor binding capacities of fetal lungs from control pregnancies increased as a function of gestational age from 16 to 21 days. Receptor binding capacities of lungs from streptozotocin-treated pregnancies also increased with gestational age until 21 days, when they dropped to 50% of control values. It was demonstrated in organ culture that fetal lung receptors from normal pregnancies of 20 days' gestation could be down-regulated in the presence of insulin and that this down-regulation is coupled to a biologic effect of insulin, hexose transport. It was concluded that fetal lung insulin receptors can be regulated by insulin concentrations in vitro and by experimental diabetic pregnancies in vivo.

Cystinosis phenotypes have identical defective cystine clearance pattern.

Exposure of cultured skin fibroblast of normal, infantile nephropathic, juvenile-late-onset and adult type cystinotic patients and their corresponding obligate heterozygotes to 0.5 mmol/l of 35S cystine dimethyl ester for 30 minutes, resulted in an accumulation of cystine within the cells, and was used to look for differences in cystine clearance between the different cell types. The results suggested that all cystinotic variants are defective in their capacity to eliminate cystine to the same extent. The presented data imply that, separate clinical phenotypic variants of cystinosis, cannot be differentiated biochemically by the assay of cystine egress.

Reason for referrals among military primary care physicians.

In order to assess the reasons for high referral rates to secondary medical care services in the Israel Defence Force-Medical Corps, we conducted a study in which 28 physicians in five primary care clinics took part. Seven hundred thirty-seven patients were referred to specialists. The referral reasons were learned from questionnaires filled in for each of these patients. The study shows that factors related to the physicians are important in determining when referral is made: Israeli medical graduates showed less confidence than their peer graduates outside of Israel. A possible explanation is that the Israeli graduates are better prepared for working in a scientific, sophisticated medical environment rather than the ambulatory primary care environment.

The radiographic manifestations of bone changes in copper deficiency.

The bone changes in infants with copper deficiency are typified by osteopenia and the symmetrical appearance of sickle-shaped metaphyseal spurs. Four examples are demonstrated and the differential diagnosis is extensively discussed.

Possible Waardenburg syndrome with gastrointestinal anomalies.

We describe a patient with possible Waardenburg syndrome associated with anal atresia and oesophageal atresia with tracheooesophageal fistula. Three other published cases with atretic gastrointestinal anomalies associated with the Waardenburg syndrome are reviewed. We conclude that the association between atretic lesions of the gastrointestinal tract and the Waardenburg syndrome may be a significant one.

Noonan's syndrome and neurofibromatosis.

A child with Noonan syndrome and multiple cafe au lait spots, compatible in size and number with von Recklinghausen's neurofibromatosis, is presented. These features may represent a distinct genetic entity rather than the coincidence of two diseases.

Hypernatremic dehydration as a sign leading to the diagnosis of glucose-galactose malabsorption in breast-fed neonates.

Hypernatremic dehydration is described in a case of a breast-fed infant with glucose-galactose malabsorption. Hypernatremic dehydration in general is uncommon in normal breast-fed infants. The finding of hypernatremic dehydration in breast-fed infants with watery diarrhea and sugar in the stool should lead to the consideration of monosaccharide intolerance such as glucose-galactose malabsorption.

Glutathione ester prevents buthionine sulfoximine-induced cataracts and lens epithelial cell damage.

Treatment of newborn rats and mice with buthionine sulfoximine, an inhibitor of glutathione synthesis, leads to development of cataracts, which are not prevented by treatment with glutathione, but they are prevented by treatment with glutathione monoester. Cataracts are associated with glutathione deficiency in the lens epithelium, which undergoes severe degeneration. The findings indicate that glutathione normally functions in the protection of the lens and lens epithelium against oxidative injury, suggesting that procedures that increase lens glutathione levels might be useful for prevention of other types of cataracts. Relatively low doses of buthionine sulfoximine produce cataracts in newborn animals, and treatment of pregnant mice with buthionine sulfoximine during the last part of gestation leads to cataract formation in the offspring. The high sensitivity of the developing lens to the effects of glutathione deficiency suggests that this tissue may be a useful model for studies on glutathione function.

Unusual ophthalmological findings in a case of partial trisomy 15.

The clinical and pathological findings in a two-month old girl having partial trisomy 15, are presented. The patient showed bilateral microphthalmia accompanied by a retrolental mass in her left eye. She underwent vitrectomy, lensectomy and accidental retinectomy. During the course of the operation, persistent hyperplastic primary vitreous (PHPV) was found with findings of retinal dysplasia on the pathologic examination.