Biomedical subjects
Publications and source records attributed to A Etzioni.
A child with a germ cell tumor involving the pineal region had marked suppression of melatonin secretion associated with severe insomnia. Exogenous melatonin (3 mg in the evening) for 2 weeks restored sleep continuity, as demonstrated by objective monitoring of rest-activity cycles. This case report provides direct evidence of the essential role of melatonin in normal sleep.
OBJECTIVE: To investigate two related children with congenital permanent diabetes. SUBJECTS AND METHODS: Two related male patients of Arab origin with congenital permanent diabetes were studied for immunological and genetic markers, insulin and glucagon secretion, thiamine levels, pancreatic ultrasounds studies and developmental characteristics. RESULTS: Both patients developed normally. The immunological markers were negative, there was no ketosis at diagnosis, and both patients were negative for diabetes susceptibility alleles at the HLA locus. Insulin levels were undetectable, glucagon secretion, thiamine levels and pancreatic ultrasound studies were normal. CONCLUSIONS: Congenital permanent diabetes is an extremely rare entity that differs from type I or type II diabetes. Our patients have a unique disorder with isolated beta cell defect and no additional manifestations. Autosomal recessive inheritance is suggested.
The occurrence of recurrent bacterial infections, neutrophil motility dysfunction and normal expression of beta 2 integrins (CD18) in two unrelated children suggested an as yet undescribed adhesion deficiency. The fact that both children exhibited the rare Bombay blood group and were Lewis negative, each involving carbohydrates with different fucose linkages, suggested a possible defect in the fucose-containing ligand for E- and P-selectin, sialyl Lewis X (SLe(x)). Using a monoclonal anti-SLe(x) antibody, we did not detect expression of SLe(x) on the neutrophils of the patients. Adhesion of neutrophils to endothelial cells activated with interleukin-1 beta or histamine was markedly decreased ( < 5% of control). The observation that the neutrophils did not bind to recombinant E-selectin and purified P-selectin confirmed the SLe(x) deficiency as the basis for adhesion deficiency. Using several in vivo techniques, we were able to show that neutrophil rolling, the first step in their adhesion, is markedly decreased, and therefore neutrophil emigration through the endothelium and arrival at site of inflammation is significantly diminished (1-2% of normal). Low binding of fucose-specific lectins to the patients' B lymphocytes transformed with Epstein-Barr virus was observed, while the binding of mannose-specific lectins was normal, providing further evidence for a general fucose deficiency as the primary defect. The existence of the patients and their deficiency emphasizes the essential role of the endothelial cell selectins and their ligand, SLe(x), in recruitment of neutrophils to sites of infection.
BACKGROUND: The rare Bombay phenotype is usually due to a primary genetic defect in an alpha-2- or alpha-4-fucosyltransferase. The present study was done to investigate a patient with normal transferases, who exhibits the Bombay phenotype. CASE REPORT: Red cells of the patient, his parents, and siblings were phenotyped for A, B, and H antigens. The presence of B, H, and Le transferases in serum and saliva was measured. RESULTS: The parents and siblings were all group B, Le(a-b-). The propositus was typed as Oh, Le(a-b-). His serum contained anti-A, anti-B, and anti-H. Normal levels of B, H, and Le transferases were found in all family members including the patient. CONCLUSION: In an unusual case, a person has the Bombay phenotype, but normal levels of transferases in serum and saliva. A general defect in fucose metabolism seems to be the primary abnormality in this case.
There are conflicting results regarding the role of autoantibodies in the pathogenesis of vitiligo. To examine their in vivo effect, human skin was transplanted onto nude mice injected with purified IgG obtained from patients with vitiligo and from controls. The effect was evaluated by several techniques. Dihydroxyphenylalanine staining revealed a marked decrease in the number of melanocytes in skin grafted onto mice injected with patients' IgG. Direct immunofluorescence staining demonstrated the presence of human IgG throughout the epidermis in specimens injected with purified IgG from vitiligo patients. No staining was observed when control IgG was injected. Electron microscopy studies demonstrated a marked decrease in melanin pigmentation with only rare melanosomes and melanocytes detected in grafts injected with patients' IgG. Thus all three techniques showed the destructive effect of vitiligo patients' serum on melanocytes. Our study highlights the important role of autoantibodies in the pathogenesis of vitiligo.
We report on a 12-year-old boy who suffered from staphylococcal pyomyositis in both arms following vigorous exercise. No trauma or skin lesions were observed. In non-tropical areas, the etiology of pyomyositis can be related to muscle injury caused merely by exercise, without any other predisposing factors.
BACKGROUND: Failure of aged human epidermis to induce HLA-DR antigens after intradermal administration of gamma-interferon (IFN-gamma) has recently been observed. OBJECTIVE: The purpose of the study was to find out whether this observation reflects an intrinsic impairment in the aged skin or is rather due to an environmental factor. METHODS: Aged and young human skin grafted onto nude mice were injected with IFN-gamma, and the induction of HLA-DR, intercellular adhesion molecule-1 (ICAM-1) and Langerhans cell (LC) migration patterns were studied. RESULTS: Increased surface expression of both HLA-DR and ICAM-1 molecules by epidermal cells was observed in all grafts, after IFN-gamma injections, whereas a decrease in LC was found only in the young grafts. CONCLUSION: This study may indicate that the lack of response of aged skin to IFN-gamma is due to both intrinsic impairment in epidermal cell function and changes in function of cells outside the epidermis such as lymphocytes and endothelial cells.
We have previously reported a newly discovered congenital disorder of neutrophil adhesion, leukocyte adhesion deficiency syndrome type 2 (LAD II). The clinical manifestations of this syndrome are similar to those seen in the classic leukocyte adhesion deficiency syndrome, now designated type 1 (LAD I), but the two syndromes differ in the molecular basis of their adhesion defects. LAD I is caused by a deficiency in the CD18 integrin adhesion molecules while LAD II patients are deficient in expression of sialyl-Lewis X (SLeX), a carbohydrate ligand for selectins. In this report we demonstrate that neutrophils from a LAD II patient bind minimally or not at all to recombinant E-selectin, purified platelet P-selectin, or P-selectin expressed on histamine-activated human umbilical vein endothelial cells, but have normal levels of L-selectin and CD11b/CD18 integrin, and adhere to and migrate across endothelium when CD11b/CD18 is activated. We compare LAD I and LAD II patient neutrophil function in vitro, demonstrating that integrin and selectin adhesion molecules have distinct but interdependent roles in neutrophil adhesion during an inflammatory response.
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BACKGROUND AND DESIGN: In recent studies on the behavior of aged skin transplanted onto nude mice, the epidermis of aged and young skin showed an increase in proliferation and thickness following engraftment, and became almost identical. The aim of this study was to ascertain a possible role for the release of local cytokines in this phenomenon. Grafted human skin was injected intradermally with anti-interleukin-6 (IL) and anti-IL-1 alpha, and comparisons of epidermal thymidine incorporation and thickness were made. Grafts injected with irrelevant antibodies served as control. RESULTS: Interleukin-6 and IL-1 alpha expression were studied in grafts by immunoperoxidase staining. Only IL-6 expression was found in the 1-month grafts. Intradermal injections of anti-IL-1 alpha and anti-IL-6 showed an inhibitory effect on cellular proliferation in the epidermis. A significant difference in the response of epidermal proliferation and, consequently, in thickness was found in samples injected with anti-IL-1 alpha and anti-IL-6 compared with those injected with irrelevant antibodies. CONCLUSIONS: These data may indicate that local cytokines released by the keratinocytes are involved in the cellular proliferative activity in skin engrafted onto the mice.
We investigated in vivo neutrophil and lymphocyte function in a patient who lacks Sialyl-Lewis-X, a ligand for the selectin family of leukocyte adhesion molecules (leukocyte adhesion deficiency II, LAD II). As assessed by skin chamber and skin window techniques, in vivo chemotaxis of neutrophils was markedly impaired (less than 6% of normal values). A marginal pool was present as determined by an increase in circulating neutrophils after epinephrine injection and calculated recovery of infused radiolabeled autologous neutrophils. Kinetic studies showed a reduced half-life of 3.2 hours (normal 7 hours) and markedly increased turnover rate (cells/kg/d) of approximately eight times the normal value. A normal antibody response to the T-cell-dependent antigen bacteriophage phi X174 showed that T/B-cell interaction is not affected in LAD II. These findings provide direct evidence that the selectin family and its ligands play an important role in neutrophil function.
Since the first description by Elliot et al. [1970, Am J Dis Child 119:72-73] of a probable partial deletion of chromosome 10p, 17 other cases have been reported. The phenotypic expression is variable, but the craniofacial malformations constitute a more consistent finding. The 10p deletion syndrome has been associated with the DiGeorge anomaly in several patients. We report on an additional case of 10p deletion syndrome and review the literature.
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Pruritus associated with hepatic cholestasis may cause significant morbidity and its correlation to retention of bile acids in skin is inconsistent. Available treatment modalities are only partially effective and can have several adverse effects. Phototherapy has recently been reported to improve cholestatic pruritus, but has not been evaluated previously in children, and its mechanism is still unclear. We report the outcome of multiple Daylite phototherapy treatments over two years in a seven-year-old child with chronic hepatic cholestasis that was resistant to other therapeutic modalities. Bile acid levels in urine were used as markers of effectiveness in parallel with clinical response. Night phototherapy alone increased the bile acids/creatinine ratio in urine from 1.54 +/- 0.04 mumol/mg at baseline to 2.07 +/- 0.29 mumol/mg. Continuous phototherapy combined with night diuresis raised the ratio further to 2.28 +/- 0.55 mumol/mg. Night diuresis alone had no effect. Continuous phototherapy combined with night diuresis raised the bile acids/creatinine ratio by 44% on the first day and by 61% on the second day, but declined to baseline on the third day of treatment. A marked clinical improvement was noted for one week following two days of phototherapy. This schedule has been repeatedly effective in improving pruritus for approximately one year and may be due to the ability of phototherapy to enhance excretion of bile acids and other possible pruritogens into urine.
In the last 10 years, Ethiopian Jews have immigrated to Israel in large numbers. Up to 1990 they came directly from their remote villages in northern Ethiopia and no HIV infection was detected in the several thousands that came. In contrast, 1.74% of approximately 14,000 new immigrant Ethiopians who arrived in 1991-92, after spending more than a year in Addis Ababa, were HIV positive. Several infants born in Israel following the latter immigration were found to be infected, whereas more than 2500 children born in Ethiopia were negative. Sexual transmission during their stay in Addis Ababa is thought to be the only route of infection, and therefore this is a newly infected population. Immunological studies revealed very low CD4 count in HIV-infected people. HIV-negative Ethiopian immigrants to Israel also have a lower CD4 count than the general Israeli population. Further studies are currently under way to look at the natural history of this particular HIV-infected group.
In 1991, more than 15,000 Ethiopian Jews immigrated to Israel after spending more than a year in Addis Ababa. They came from remote villages and had had no contact with modern medicine for centuries. About 2% of these new immigrants were found to be HIV positive. Their completely different background forced the Israeli government to develop a special educational program explaining about the modes of HIV infection and prevention measures. The staff participating in the program were mainly Ethiopian Jews who immigrated to Israel before 1990 and were employed as nurses or social workers. The goal of the study was to prevent the spread of the virus; thus the target population was those who were infected with HIV. As most of them were illiterate, posters with pictures were used to explain risk factors, and lectures were given explaining what a virus is and, especially, the "carrier state". Using this program the spread of HIV inside the Ethiopian community seems to have diminished.
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Normal human skin grafted onto the nude mouse can be maintained without any signs of rejection throughout the life-span of the animal. Indeed, the nude mouse model is a powerful tool for understanding the pathological process of the skin. Until now many skin diseases such as psoriasis, cutaneous lupus, pemphigus and vitiligo have been looked at using the nude mouse model, which has helped to clarify the role of the various factors involved.