Biomedical subjects
Publications and source records attributed to G Scott.
We describe how a novel mirror-based laser handpiece device allows for the pinpoint coincidence of aiming and surgical beams during uvulopalatoplasty and other laser ablation procedures.
Epidemiological studies have shown an increased risk of breast cancer in obligate ataxia telangiectasia (A-T) heterozygotes. We analyzed 100 samples from young breast cancer patients for mutations in ataxia-telangiectasia mutated (ATM), the gene responsible for the autosomal recessive condition, A-T, to determine whether A-T heterozygosity predisposes such individuals to develop breast cancer. These patients were selected from families with a moderate or absent family history of breast cancer and included a subset of 16 radiosensitive patients. Forty-four germline sequence variants were detected by fluorescent chemical cleavage of mismatch of RT-PCR products. These included seven rare variants found in nine patients (three described for the first time), but no truncating mutations. Although three variants were detected in the radiosensitive subset, this was not statistically significant compared to the nonradiosensitive group. One variant, G2765S, is likely to be a missense mutation, but the other six variants probably represent rare polymorphisms. However, five of the seven rare germline variants detected showed loss of heterozygosity of the wild-type ATM allele for one or more markers close to the ATM locus in matched tumor DNA. This high rate of somatic inactivation of ATM may indicate either that these rare variants play a role in breast cancer development or alternatively that a neighboring tumor suppressor gene is important for tumorigenesis. We found germline truncating ATM mutations to be rare in these young breast cancer patients and therefore they are unlikely to play a role in the etiology of their disease. Genes Chromosomes Cancer 26:286-294, 1999.
A new CC chemokine, designated CKbeta-8 or myeloid progenitor inhibitor factor-1, was recently identified in a large scale sequencing effort and was cloned from a human aortic endothelial library. CKbeta-8 cDNA encodes a signal sequence of 21 amino acids, followed by a 99-amino acid predicted mature form. CKbeta-8 was expressed and purified from a baculovirus insect cell expression system, which resulted in the identification of different N-terminal variants of the secreted chemokine. The three major forms (containing amino acids 1-99, 24-99, and 25-99 of the secreted chemokine) showed a large variation in potency. CKbeta-8 activated both monocytes and eosinophils to mobilize intracellular calcium; however, the shortest form of CKbeta-8 (25-99) was >2 orders of magnitude more potent than the longest form. Cross-desensitization experiments in both monocytes and eosinophils suggested that the CCR1 receptor was probably the predominant receptor that mediates this chemokine's physiologic response. However, incomplete desensitization was encountered in both cell systems, suggesting involvement of an additional receptor(s). Interestingly, the short form of CKbeta-8 was the most potent chemotactic chemokine that we have ever evaluated in the monocyte system (EC50 = 54 pM). However, in contrast to its action on monocytes, CKbeta-8 was a very poor chemotactic factor for eosinophils.
A series of biaryl acids has been found to show micromolar inhibition of the HIV reverse transcriptase (RT) from types 1 and 2 with IC50S in the micromolar range. The series was discovered by consideration of the polymerase active site and sub-structure searching of the company compound collection. Synthesis of analogues to investigate the SAR is described. Two of these compounds have shown inhibition of HIV-2 RT only.
OBJECTIVE: To determine the safety of the zidovudine (ZDV) regimen utilized in the Pediatric AIDS Clinical Trial Group (ACTG) 076 study. DESIGN: ACTG 076 was a randomized, double-blind, placebo-controlled trial which demonstrated that a ZDV regimen could prevent mother-to-child HIV-1 transmission. Infants were followed through 18 months of age and women were followed through 6 months postpartum. METHODS: Maternal complications, pregnancy outcomes, growth and development of the uninfected infants, and HIV-1 disease progression in the women were monitored prospectively. RESULTS: Maternal therapy was well tolerated. There was no serious pattern of adverse pregnancy outcomes associated with ZDV use. Amongst the ZDV-exposed infants, the only recognized toxicity was anemia within the first 6 weeks of life; the risk for anemia was not associated with premature delivery, duration of maternal treatment, degree of maternal immunosuppression, or maternal anemia. ZDV treatment was not associated with an increased incidence of newborn structural abnormalities. At 18 months of age, uninfected infants did not differ in growth parameters or immune function. No childhood neoplasias were reported in either group. In the women, at 6 months postpartum, there were no differences in clinical, immunologic, or virologic disease progression. CONCLUSION: There were no identified problems that would alter current recommendations for the routine use of ZDV for the prevention of mother-child HIV-1 transmission.
Poly(ADP-ribose) synthetase (PARS) activation, a downstream event of nitric oxide (NO) neurotoxicity has been implicated in cerebral reperfusion injury. The aim of our study was to identify the trigger of PARS activation during stroke. Formation of poly(ADP-ribose) profoundly increased in the early phase of reperfusion. Poly(ADP-ribose) formation was attenuated in mice deficient for neuronal NO synthase (nNOS). We next tested in glioma cells whether NO, or peroxynitrite (a cytotoxic oxidant formed from NO and superoxide) is the actual trigger of PARS activation. Peroxynitrite, but not various NO donors, activated PARS and suppressed cellular viability in a PARS-dependent fashion. Thus, nNOS is responsible for PARS activation in stroke. PARS activation, however, is not a direct result of NO production, but it occurs via peroxynitrite formation.
Previous studies have suggested a role for histamine in mediating effects of light on rodent circadian systems. We combined behavioural and neuroanatomical studies to analyze the potential role of histamine in circadian rhythm regulation of Syrian hamsters. The effects of histamine and the selective H2 receptor agonist dimaprit on free-running locomotor activity rhythms were monitored. In addition, histamine projections were mapped immunohistochemically. Histamine (0.5 microl of 1 mM) microinjected into the region of the suprachiasmatic nucleus induced very small delay phase-shifts, which were significantly greater than those elicited by vehicle at circadian time (CT) 18. No other significant differences were observed. Dimaprit (0.5 microl of 1 mM) microinjected into the region of the suprachiasmatic nucleus at CT 6 and CT 18, induced very small phase-shifts which were significantly different from the effects of vehicle, but did not resemble those of light. Numerous cell bodies immunopositive for histamine were found in the tuberomammillary nucleus of the posterior hypothalamus, while histamine immunoreactive fibres were seen in the periventricular nucleus and paraventricular nucleus of the anterior hypothalamus. The suprachiasmatic nuclei were largely devoid of immunostaining. Finally, preliminary electrophysiological studies demonstrated that ionophoretic application of histamine and the H2 receptor agonist dimaprit elicit inconsistent and weak responses in the hamster suprachiasmatic nucleus in vitro. The results presented here show that microinjections of HA or dimaprit into the SCN region do not mimic the effects of light on hamster circadian rhythms, and the SCN of the Syrian hamster is almost devoid of histaminergic fibres. These studies suggest that histamine does not play a prominent role in circadian rhythm regulation in this species.
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The essential elements controlling trigeminal motoneurons during feeding lie between the trigeminal and facial motor nuclei. These include populations of neurons in the medial reticular formation and pre-motoneurons in the lateral brainstem that reorganize to generate various patterns. Orofacial sensory feedback, antidromic firing in spindle afferents and intrinsic properties of motoneurons also contribute to the final masticatory motor output.
Cryofibrinogenemia is a disorder characterized by cryoprecipitation with variable clinical presentation that was first described by Korst and Kratochvil in 1955. Cryofibrinogen is a cold insoluble complex of fibrin, fibrinogen, and fibrin split products with albumin, cold insoluble globulin, factor VIII, and plasma proteins. Cryofibrinogenemia is associated with metastatic malignancies, collagen vascular diseases, and thromboembolic disorders and may be clinically asymptomatic or present with thromboembolic phenomena of skin and viscera. The pathogenesis of cryofibrinogenemia is unknown. It may be caused by the inhibition of fibrinolysis, leading to an accumulation of cryofibrinogen. Treatment of cryofibrinogenemia may include Stanozolol, plasmapheresis, and fibrinolytics. Cryofibrinogenemia simulates calciphylaxis clinicopathologically, because both may present with skin necrosis. Calciphylaxis has been reported in end-stage renal disease, but we report the first case of cryofibrinogen in a chronic dialysis patient. We suggest that in the appropriate clinical setting, cryofibrinogenemia should be considered in the differential diagnosis of calciphylaxis, and serum cryofibrinogen levels should be measured in end-stage renal disease patients presenting with skin necrosis.
Ultraviolet (UV) light has been associated with the development of human non-melanoma skin cancers (NMSC). Such cancers often exhibit mutations in the p53 tumour suppressor gene. In order to determine the UV-induced p53 mutation spectrum, a yeast expression vector that harbours a human wild-type p53 cDNA was UV-irradiated in vitro and transfected into a yeast strain that contained the ADE2 gene regulated by a p53-responsive promoter. Forty-five mutant clones contained 51 mutations. Seven mutations were tandem base pair substitutions, four of which being CC-->TT, hallmark mutations of UV mutagenesis. Eighty percent (41/51) of the mutations were single or non-tandem base pair substitutions, the majority of which (27/41) were C-->T transitions. Ninety-five percent of such mutations occurred at dipyrimidine sites. Through a rigorous statistical test, the UV-induced p53 mutation spectrum appears to differ significantly (P < 0.008) from the one induced by the antineoplastic drug chloroethyl-cyclohexyl-nitrosourea, and to be indistinguishable from the one observed in NMSC (P = 0.4). These results demonstrate that the assay allows the determination of carcinogen-specific p53 mutation fingerprints and represents a new tool for molecular epidemiology.
BACKGROUND: Since 1991, unlinked anonymous HIV testing of homosexual/bisexual males attending genitourinary clinics in Edinburgh and Glasgow has been conducted and resulting prevalence data have been published annually. More detailed information which provides an understanding of what proportion of HIV infected men attending genitourinary clinics in central Scotland (i) remain undetected, (ii) acquire sexually transmitted infections following HIV diagnosis, and (iii) possibly become HIV infected either abroad or following sex with someone from abroad, is reported by the authors. METHODS: Unlinked anonymous HIV testing of syphilis serology specimens from homosexual/bisexual males attending genitourinary clinics during 1991-5. RESULTS: Of 3468 specimens tested, 165 (4.8%) were HIV positive. Thirty five per cent (57) of all HIV positive specimens were from men whose infection remained undetected following clinic attendance. Of the 80 attenders who knew themselves to be HIV positive before their clinic visit, 13 had clinical and/or laboratory evidence of a sexually transmitted infection. Men who had a sexual risk associated with America or who were American, had a 2.4-fold greater risk of being HIV infected than those with United Kingdom only connections. CONCLUSION: Increased efforts should be made to ensure that HIV infected men are diagnosed early after infection and do not engage in high risk sexual behaviour, and that all homosexual men are educated about the particular risks of acquiring HIV infection abroad. More effective interventions to prevent indigenous HIV transmissions need to be developed.
OBJECTIVE: To identify cerebral aneurysmal arteriopathy in children with longstanding AIDS. BACKGROUND: Five cases are described from the authors' experience, and eight additional cases are reviewed from the literature. Details are presented in regard to the clinical picture as well as brain imaging with cerebral angiography and magnetic resonance angiography in some cases. Autopsy information is available in four cases, including one of the authors' patients. RESULTS: Seven patients acquired HIV infection perinatally, five patients were infected by blood transfusions, and one patient had both risk factors. In the four postmortem patients, the vascular pathology was similar, showing ectasia and aneurysmal dilatation confined to the large arteries of the circle of Willis. Medial fibrosis and loss of muscularis with destruction of the internal elastic lamina and intimal hyperplasia was common. The latency period following infection varied from 2 to 11 years. Once a diagnosis of aneurysmal arteriopathy was made, the patients deteriorated rapidly, with death occurring in less than 6 months. CONCLUSIONS: The development of cerebral aneurysmal arteriopathy in childhood AIDS tends to occur after a prolonged delay and is usually followed by death in a short period of time. The etiology for the vasculitis is unknown. Varicella zoster virus may be the etiology in some of the cases because of its potential to cause this pathology and the striking unilateral arterial involvement found in Case 5. HIV vasculitis is also a possibility, as suggested by the detection of HIV protein or genomic material in two of the four autopsy cases.
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The cloning of the breast and ovarian cancer susceptibility gene, BRCA1, allows direct estimation of the proportion of these cancers in the general population which can be attributed to germline mutations in this gene. We have used a combination of SSCP, heteroduplex analysis, and chemical cleavage of mismatch to screen the BRCA1 gene for mutations in the germline of 42 patients with breast or ovarian cancer who either have a moderate family history of these cancers, or have no family history of malignancy but a very early onset of the disease. A total of 30 sequence variants were observed, eight of which have not been described previously. Three sequence changes detected by chemical cleavage or heteroduplex analysis were missed by SSCP. The variants included 13 missense mutations, which were assessed for their pathogenic implications. Two of these (M18T and A1708E) are nonconservative substitutions which are located in evolutionarily conserved regions of the gene: M18T lies just upstream of the RING finger motif, and A1708E abolishes the transcriptional transactivation activity of the carboxy-terminal region of BRCA1. Mutations were observed in eight patients overall (19.0%), and protein-truncating mutations occurred in five of 27 (18.5%) families with 1-3 cases of breast or ovarian cancer. The data suggest that a significant proportion of patients with a modest or no family history of these cancers may carry germline mutations in BRCA1.
OBJECTIVE: To break the link between drug use and the human immunodeficiency virus (HIV), in 1992 the state of Connecticut rescinded a 14-year ban on pharmacy sales of syringes without a physician's prescription. In 1993, the Center for Disease Control and Prevention (CDC) evaluated the impact of the new legislation on access to syringes among injecting drug users (IDUs) and found an initial pattern of expanded access. However, it also found that some pharmacies, after negative experiences with IDU customers, reverted to requiring a prescription. This chapter reports findings from a four-year follow-up study of current IDU access to over-the-counter (OTC) pharmacy syringes in Hartford, Connecticut. METHODS: Through structured interviews, brief telephone interviews, and mailed surveys, data on nonprescription syringe sale practices were collected on 27 pharmacies, including 18 of the 21 pharmacies in Hartford and none from pharmacies in contiguous towns, during June and July 1997. Interview data on pharmacy syringe purchase from two sample of IDUs, a group of out-of-treatment injectors recruited through street outreach, and a sample of users of the Hartford Needle Exchange Program, also are reported. RESULTS: The study found that, while market trends as well as negative experiences have further limited pharmacy availability of nonprescription syringes, pharmacies remain an important source of sterile syringes for IDUs. However, the distribution of access in not even; in some areas of the city it is much easier to purchase nonprescription syringes than in other. All of the seven pharmacies located on the north end of Hartford reported that they had a policy of selling OTC syringes, whereas only six (54.5%) of the II pharmacies located on the south end have such a policy. Overt racial discrimination was not found to be a barrier to OTC access to syringes. CONCLUSIONS: To further decrease acquired immunodeficiency syndrome (AIDS) risk among IDUs, there is a need for public education to counter empirically unsupported stereotypes about IDUs that diminish their access to health care and AIDS prevention resources and services. In states or cities where pharmacy sale of nonprescription syringes is illegal, policy makers should examine the benefits of removing existing barriers to sterile syringe acquisition. In cases in which pharmacy sale of nonprescription syringes is legal, local health departments should implement educational programs to inform pharmacy staff and management about the critically important role low-cost (or cost-free), sterile syringe access can play in HIV prevention.
Recent reports show that alpha-MSH (melanocyte-stimulating hormone) is mitogenic and melanogenic for normal human melanocytes, and that this effect is mediated through binding to the melanocortin receptor (MC1R) and activation of cAMP formation. alpha-MSH has also been shown to induce changes in cell shape in melanocytes and melanoma cells, particularly increased dendricity, suggesting a potential role for alpha-MSH in melanocyte-matrix interactions and pigment transfer through reorganization of the melanocyte actin filament cytoskeleton. In this report we show that the potent alpha-MSH analog (Nle4, D-Phe7)-alpha-MSH (NDP-MSH) induces reorganization of the actin stress fiber cytoskeleton in treated human melanocytes and that this reorganization is associated with increased adhesion to fibronectin (FN). Because most melanocyte growth factors act synergistically on melanocyte mitogenesis, we also sought to determine the effect of the melanocyte mitogen endothelin-1 (ET-1) on the melanocyte actin cytoskeleton, melanocyte adhesion, and melanocyte migration. We show that ET-1, which increases melanocyte migration on FN, has opposite effects on melanocyte adhesion to FN compared with NDP-MSH and that endothelin-1-induced actin reorganization is distinct from that observed following NDP-MSH treatment. Finally, we show that focal adhesion kinase (pp125FAK), a nonreceptor tyrosine kinase associated with focal contact formation and cell migration, is phosphorylated on tyrosine residues after treatment of melanocytes with ET-1, but not NDP-MSH. These data indicate that while alpha-MSH and ET-1 act synergistically to modulate melanocyte proliferation, they have opposite effects on melanocyte-matrix interactions.
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