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S J Orlow

Publications and source records attributed to S J Orlow.

At least 73 records · Page 4Linked to original sources
PubMed1993

AIDS-associated Kaposi's sarcoma in Romanian children.

BACKGROUND: Kaposi's sarcoma (KS) is commonly associated with the acquired immunodeficiency syndrome (AIDS) in adults. Little is known regarding its occurrence in children. OBJECTIVE: Our purpose was to report the clinical and epidemiologic characteristics of KS in three Romanian children with AIDS and to compare them with previously reported AIDS-associated KS in children. METHODS: This was a clinicopathologic study and computer-based literature review. RESULTS: All three Romanian children had skin involvement; two had involvement of lymph nodes and internal organs. All had acquired human immunodeficiency virus (HIV) infection postnatally. Including these children, 33 cases of AIDS-associated KS in children have been reported. Thirteen of 30 evaluable patients had acquired HIV infection postnatally; nine of these children (69%) had cutaneous involvement by KS. A perinatal route of transmission was present in the remaining 17 cases; only two of these children (12%) with KS had cutaneous involvement. No case was noted in which intravenous drug use was the sole parental HIV risk factor. CONCLUSION: The data support the contention that KS is caused by a second infectious agent prevalent only in certain HIV-infected populations. Children of parents in high-risk groups for KS and children who acquire HIV via contaminated blood or blood products are at highest risk for KS. The route of acquisition of HIV infection may also be associated with different clinical manifestations of KS in children.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Syndromes associated with melanocytic nevi.

Melanocytic nevi have been reported in association with several congenital syndromes. This review describes the clinical and cutaneous manifestations of six syndromes associated with congenital melanocytic nevi, two associated with acquired nevi, and six associated with melanocytic nevi in which insufficient evidence exists to classify them as congenital or acquired. It is important to recognize these associations to evaluate and counsel patients with melanocytic nevi. Early recognition will also facilitate timely intervention.

Abnormalities, Multiple↗
PubMed1993

Subcellular distribution of tyrosinase and tyrosinase-related protein-1: implications for melanosomal biogenesis.

Are tyrosinase, encoded at the albino locus, and tyrosinase-related protein-1 (TRP-1), encoded at the brown locus, similarly distributed in melanocytes? We determined the subcellular distribution of tyrosinase and TRP-1 using density fractionation of postnuclear supernatants from mouse melanoma cells of defined genotype followed by immunoblotting with specific antipeptide sera. In highly melanized cells, the majority of tyrosinase cosedimented on Percoll density gradients with visible melanin and with the peak of DOPA incorporation, confirming its presence predominantly in stage III-IV melanosomes. In contrast, the distribution of TRP-1 was limited to a less-dense melanosomal compartment, devoid of melanin. In amelanotic or minimally melanized cells, the majority of tyrosinase shifted into these lighter peaks. To explore a suspected relationship between lysosomes and melanosomes, we analyzed the distribution of lysosome-associated membrane protein-1 (LAMP-1). An overlap in the distribution of LAMP-1 and TRP-1 was demonstrated by immunomicroscopy and confirmed by immunoisolation. LAMP-1 was not present in the dense, melanin-rich melanosomal peak on gradient analysis. TRP-1 from melanoma cells homozygous for the brown mutation is not fully glycosylated, is more rapidly degraded, and is restricted in its distribution compared to its wild-type counterpart. In these mutant cells, all melanosomal compartments contain LAMP-1. Our results demonstrate that in wild-type cells the majority of tyrosinase eventually localizes to stage III-IV melanosomes. TRP-1 is limited to a less dense melanosomal compartment that is also LAMP-1 positive. The existence of this compartment suggests that it may represent a common step in the biogenesis of melanosomes and lysosomes.

Antigens, CD↗
PubMed1993

Pathogenesis of the platinum (cp) mutation, a model for oculocutaneous albinism.

The platinum mutation at the C (albino) locus in the mouse is a potential model for oculocutaneous albinism in humans other than type IA (tyrosinase-negative) albinism. Although tissues from mice homozygous for the mutation display substantial tyrosinase activity, cutaneous and ocular pigmentation is severely restricted in affected animals. Using specific antipeptide antisera, we demonstrate that ocular extracts from wild-type mice contain two isoforms of tyrosinase bearing either the amino-terminal PEP5 epitope or the carboxy-terminal PEP7 epitope. The latter isoform participates in a high-molecular-weight complex detectable on sucrose density gradients. In platinum mice, antiserum to the PEP7 epitope fails to recognize any protein species, and the high-molecular-weight form of tyrosinase is not detectable. Our results support a key role for this high-molecular-weight complex in melanogenesis, and suggest that mutations that interfere with the ability of tyrosinase to participate in a multimeric complex may be a cause of oculocutaneous albinism in people.

Albinism, Oculocutaneous↗
PubMed1993

Identification of a mammalian melanosomal matrix glycoprotein.

Antiserum raised in rabbits against the Triton X-100 insoluble fraction of melanosomes from mouse melanoma cells specifically decorates the internal matrix of melanosomes in immunoelectron microscopy. In metabolic labeling studies, the antiserum recognizes a protein of 94 kDa, which is processed to a band of 53 kDa. Whereas the precursor is relatively soluble in buffers containing Triton X-100, the processed protein requires the addition of sodium dodecyl sulfate for effective solubilization, as would be expected for a melanosomal matrix constituent. Tunicamycin reduces the Mr of the nascent protein to 75 kDa, but deoxymannojirimycin and swainsonine have no effect, suggesting that following initial glycosylation in the endoplasmic reticulum, the protein is not subject to processing by glycosidases in the Golgi apparatus or may bypass it entirely. Subcellular fractionation followed by immunoblotting confirms that the protein is present in the melanosome-rich, large granule fraction. Expression of the protein is regulated differently from that of the tyrosinase-related protein family. Conditions that greatly stimulate expression of tyrosinase-related proteins do not affect matrix protein expression, nor is the protein immunologically related to the tyrosinase-related protein family. Our results suggest that we have identified an authentic component of the mammalian melanosomal matrix, and that its characteristics lend support to a bipartite pathway for melanosomal biogenesis.

Animals↗
PubMed1993

Lysosome-associated membrane protein-1 (LAMP-1) is the melanocyte vesicular membrane glycoprotein band II.

Coated vesicles play a critical role in the process of melanogenesis. Antisera raised against a coated vesicle fraction from mouse melanoma cells recognize two major glycoprotein antigens, band I (47-55 kd) and band II (90-120 kd). We demonstrate that band II is lysosome-associated membrane protein 1 (LAMP-1) by the following criteria: 1) the molecular weight and abundance of LAMP-1 varies among tissues but is always identical to that of band II; 2) band II and LAMP-1 co-migrate in sucrose gradient sedimentation studies; 3) immunodepletion of cell extracts with antivesicle serum removes all LAMP-1; and 4) intact organelles immunoisolated with antivesicle serum contain band II and LAMP-1. Our results further confirm the long-suspected relationship between melanosomes and the lysosomal lineage of organelles.

Animals↗
PubMed1993

Supraumbilical midabdominal raphe, sternal atresia, and hemangioma in an infant: response of hemangioma to laser and interferon alfa-2a.

We cared for an infant girl with the clinical constellation of supraumbilical midabdominal raphe, sternal atresia, and cutaneous facial and upper trunk hemangioma. This is the first report of this clinical association in the dermatologic literature. The vascular component of the disorder responded to flashlamp-pumped pulsed dye laser therapy and to systemic interferon alfa-2a (Roferon-A).

Abdominal Muscles↗
PubMed1993

Varicella-zoster virus infection in Romanian children infected with the human immunodeficiency virus.

OBJECTIVE: Varicella-zoster virus (VZV) infections can cause severe disease in immunocompromised individuals. To evaluate the spectrum of VZV infections in human immunodeficiency virus (HIV)-infected children, we retrospectively analyzed all the cases of VZV infection in a cohort of children cared for at a hospital for infectious diseases in Bucharest, Romania. METHODS: The records of 391 HIV-infected children admitted to the acquired immunodeficiency syndrome pavilion of Colentina Hospital during the period January 1, 1991, through March 31, 1992, were reviewed for evidence of VZV infection. The diagnosis of varicella or zoster was made clinically and information was collected concerning course of the illness, number of skin lesions, and clinical evidence of complications. Lymphocyte subpopulation typing, as an estimate of immune function, was performed by either a standard fluorescent activated flow cytometric method or by immunofluorescent technique. RESULTS: Thirty-eight cases of varicella (9.7%) and seven cases of zoster (1.8%) were adequately documented among the 391 records reviewed. The duration of varicella was prolonged; in 57% of the children it was greater than 10 days. Forty percent of children with varicella developed a complication, including superinfection of the skin, pneumonia, or thrombocytopenia. None of the children developed clinical hepatitis or encephalitis. Two children (5%) died during varicella, both of respiratory failure. None of the 7 children with zoster had chronic, recurrent, or disseminated lesions. Lymphocyte subset analysis was available for 22 of 38 children with varicella and 3 of 7 children with zoster. Fifteen of the 22 children had normal, age-adjusted, absolute CD4 counts within 3 months of the diagnosis of varicella. All 3 children with zoster who had lymphocyte subset analysis had low CD4 counts and absolute numbers. None of the 45 children received antiretroviral therapy and only 1 child with varicella and 1 with zoster received acyclovir. CONCLUSIONS: The spectrum of VZV infection in this hospitalized group of HIV-infected children was broad. The majority (57%) experienced a prolonged course of disease and a higher rate of complications than normal children hospitalized with varicella.

CD4-Positive T-Lymphocytes↗
PubMed1992

Evidence that dopachrome tautomerase is a ferrous iron-binding glycoprotein.

Dopachrome tautomerase (DT) (EC 5.3.2.3) is a melanocyte-specific, membrane-associated, heat-labile, non-dialyzable, protease-sensitive factor which catalyzes the isomeric rearrangement of dopachrome to 5,6-dihydroxyindole-2-carboxylic acid (DHICA), apparently through a tautomerization reaction. Metal ions such as Cu, Ni, Co, Zn, Mn, Ca, Al, and Fe can also catalyze the dopachrome/DHICA isomerization. How is the reaction regulated in vivo? An attractive possibility would be that DT is a metalloenzyme. Here we present evidence that this may indeed be the case. Purified preparations of DT and tyrosinase, obtained from Cloudman S91 mouse melanoma cells, were assayed in the presence of a variety of metal chelators including EDTA (predominantly Ca and Mg), EGTA (predominantly Ca), phenylthiourea (PTU) (predominantly Cu), 2,2'-dipyridyl (predominantly Fe); 1,10-phenanthroline (predominantly Fe), and 2,3-dihydroxybenzoic acid (predominantly Fe). In addition, DT activity was assayed in the presence of two non-chelating structural analogs of 1,10-phenanthroline. Results were as follows: (i) iron chelators inhibited DT activity with no effects on tyrosinase activity; (ii) inhibition by the chelators was reversible with the addition of ferrous iron; (iii) 1,10-phenanthroline pre-complexed to ferrous iron was not inhibitory to DT; (iv) non-chelating analogs of phenanthroline were not inhibitory to DT; (v) PTU was inhibitory to tyrosinase but not DT; (vi) Ca2+ and Mg2+ chelators had little effect on either enzyme activity. Finally, studies with glycosylation inhibitors, glycosylase enzymes, and immobilized lectins, indicated that DT is a glycoprotein. The results suggest that DT is a metal-containing glycosylated enzyme, possibly with ferrous iron at its catalytic center.

2,2'-Dipyridyl↗
PubMed1992

Induction of B16 melanoma melanogenesis by a serum-free synthetic medium.

Cultured murine B16 melanoma cells normally grow as spindle-shaped cells firmly attached to tissue culture flasks. Pellets obtained from harvested B16 melanoma cells are white to grey in color. When the same cells were grown in synthetic, serum-free AIM V medium, cellular morphology and pigmentation were radically altered. Within 3 days of subculture in AIM V, cells rounded up and grew in clusters in suspension. Melanin content increased to greater than 30 times and tyrosinase activity was found to be 10-50 times higher in cells grown in AIM V medium compared to those cultured in normal medium. A concomitant increase in the level of immunoreactive tyrosinase was also induced. The individual growth factors and hormones present in AIM V medium were examined to determine which component(s) stimulates melanogenesis. Only those cells grown in the presence of 2.5% human albumin were stimulated to synthesize melanin. These findings suggest that albumin, or a component associated with albumin, has a major effect upon the regulation of melanogenesis in these cells.

Animals↗
PubMed1992

Fatal disseminated infection with human herpesvirus-6.

A 13-month-old immunocompetent girl had fever, rash, and multisystem disease, and she eventually died of cardiac failure. Autopsy revealed intracellular viral inclusions of the herpesvirus group, with results of in situ hybridization positive for human herpesvirus-6. This is apparently the first case of fatal disseminated herpesvirus-6 infection.

Exanthema Subitum↗
PubMed1992

Multiple subcutaneous leiomyosarcomas in an adolescent with AIDS.

The case of 17-year-old boy with thalassemia major who contracted the human immunodeficiency virus (HIV) through multiple transfusions is described. Eight years after the onset of generalized lymphadenopathy, and 5 years after the documentation of HIV infection on serologic grounds, he developed the first of multiple, painful, subcutaneous nodules, which proved to be leiomyosarcomas of vascular origin. The histopathology and possible pathogenesis of these unusual tumors are discussed.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Synthesis and characterization of melanins from dihydroxyindole-2-carboxylic acid and dihydroxyindole.

Several studies have confirmed that a melanocyte-specific enzyme, dopachrome tautomerase (EC 5.3.2.3), catalyzes the isomerization of dopachrome to 5,6-dihydroxyindole-2-carboxylic acid (DHICA) (Pawelek, 1991). Here we report that DHICA, produced either enzymatically with dopachrome tautomerase or through chemical synthesis, spontaneously polymerized to form brown melanin that was soluble in aqueous solutions above pH 5. Under the same reaction conditions, solutions of either DOPA, DOPAchrome, or 5,6-dihydroxyindole (DHI) formed black, insoluble melanin precipitates. When DHICA and DHI were mixed together, with DHICA in molar excess, little or no precipitation of DHI-melanin occurred and the rate and extent of soluble melanin formation was markedly enhanced over that achieved with DHICA alone, suggesting co-polymerization of DHICA and DHI. With or without DHI, DHICA-melanins absorbed throughout the ultraviolet and visible spectra (200-600 nm). The DHICA-melanins precipitated below pH 5, at least in part because of protonation of the carboxyl groups. DHICA-melanins could be passed through 0.22 micron filters but could not be dialyzed through semi-permeable membranes with exclusion limits of 12,000-14,000 daltons. HPLC/molecular sieve analyses revealed apparent molecular weights ranging from 20,000 to 200,000 daltons, corresponding to 100-1,000 DHICA monomers per molecule of melanin. DHICA-melanins were stable to boiling, lyophilization, freezing and thawing, and incubation at room temperature for more than 1 year. The natural occurrence of oligomers of DHICA was first reported by Ito and Nichol (1974) in their studies of the brown tapetal pigment in the eye of the sea catfish (Arius felis L.).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Molecular cascades in UV-induced melanogenesis: a central role for melanotropins?

When human skin is exposed to ultraviolet (UV) light, a highly complex cascade of events ensues that culminates, among other things, in increased skin melanin content. From analyses at the tissue and cellular level, it has been shown that following exposure to UV light there is an increase in the number of active melanocytes in the basal layer of the epidermis, and individual melanocytes are stimulated to produce more melanin. In addition, the rate of transfer of melanosomes from melanocytes to keratinocytes is apparently increased, although the role of UV light in this process remains to be demonstrated. Recent biochemical evidence is reviewed on factors that regulate these processes. A plausible explanation for the effects of UV on pigmentation is that there are mechanisms in the skin for the orderly, regulated reception of UV signals that are then transduced to initiate the cascade. The signals involve both melanocytes and keratinocytes, and available evidence supports a model in which melanotropins and their receptors play a central role in the process.

Humans↗