Life insurance and HIV antibody testing.
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HIV Seropositivity↗
Biomedical subjects
B A Evans
Publications and source records attributed to B A Evans.
Fusobacterium nucleatum bacteraemia with multiple liver abscesses in an HIV-I antibody positive man with IgG2 deficiency.
Liver abscess formation due to Fusobacterium nucleatum is rare. We describe an HIV-I antibody positive man, with normal surrogate markers of cell-mediated immunity, who presented with F. nucleatum bacteraemia and liver abscess formation. He was found to have IgG2 subclass deficiency. This case illustrates the clinical importance of altered B-cell function in patients who are at an early stage of HIV disease.
Adult↗
Androgen receptor gene mutations identified by SSCP in fourteen subjects with androgen insensitivity syndrome.
The androgen insensitivity syndrome (AIS) is a disorder of male sexual development resulting in a wide range of clinical phenotypes. AIS is classified into two phenotypic forms: complete (CAIS) and partial (PAIS). To determine the molecular basis of the phenotypic diversity in AIS, we have studied 27 subjects (13 CAIS, 14 PAIS), spanning the full range of AIS phenotypes. We report the results of a mutation screen of the androgen receptor gene. The coding regions of the gene were amplified by the polymerase chain reaction and screened for single strand conformation polymorphisms to identify mutations. This was followed by DNA sequencing of putative mutant segments. Androgen receptor gene mutations were identified in nine CAIS and five PAIS subjects. Two of the CAIS mutations in exon A resulted in frameshifts. A third CAIS mutation resulted in the deletion of a single amino acid from the ligand binding domain of the receptor. All other mutations caused single amino acid substitutions in the ligand binding domain. These results suggest that mutations affecting the ligand binding domain of the androgen receptor are the most frequent cause of AIS, although some cases of PAIS may be the result of other, as yet undefined, genetic lesions.
Androgens↗
Increased incidence of cervical cytological abnormalities in women with genital warts.
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Condylomata Acuminata↗
A colposcopic case-control study of cervical squamous intraepithelial lesions in women with anogenital warts.
OBJECTIVE: To assess whether anogenital warts, present or past, are an indication for women to be referred for colposcopy. DESIGN: A case control study comparing patients with and without a history of anogenital warts. SETTING: A department of genitourinary medicine in West London. PATIENTS: 468 patients examined by colposcopy between January 1985 and December 1987 of whom 147 (31%) had abnormal cytology, 163 (35%) had anogenital warts and 158 (34%) had both. MAIN OUTCOME MEASURES: Colposcopic findings and histology of cervical biopsies compared with behavioural and disease variables. RESULTS: Human papillomavirus infection (HPVI) of the cervix showed no relationship with a life time history of vulval warts, or with the presence of anogenital warts on clinical examination, or with any parameter of sexual behaviour included in the study. Cervical intraepithelial neoplasia (CIN) was strongly associated with current IUCD usage (RR = 7.75) and coitarche under 16 years of age (RR = 3.72), but a history of vulval warts yielded a negative association (RR = 0.34), suggesting a protective effect. This relationship held true when cytological dyskaryosis was made the dependent variable (RR = 0.24). CONCLUSIONS: Anogenital warts are not a risk for subclinical cervical HPVI or for CIN and therefore not an indication for colposcopy.
Adult↗
Role of the androgen receptor in male sexual differentiation.
The two androgens responsible for all aspects of male sexual differentiation are testosterone and dihydrotestosterone. The action of both these steroids is mediated by a specific intracellular receptor, the androgen receptor, which is a member of the nuclear receptor superfamily. The androgen receptor gene has been cloned and is located on the X chromosome at Xq11-12. Mutations of this gene have been found in subjects with both complete and partial androgen insensitivity. In a study of 27 subjects with the androgen insensitivity syndrome, we have identified mutations in 14, using a rapid mutation screening assay. The same technique has also been used to determine carrier status in an affected family. We have also identified a mutation in two brothers who show perineal hypospadias as the only evidence of undervirilisation. Familial severe hypospadias should therefore be included as part of the phenotypic spectrum of partial androgen insensitivity. The study of naturally occurring mutations of the androgen receptor gene is providing further information on the function of the androgen receptor and its role in normal male sexual differentiation.
Dihydrotestosterone↗
Complete androgen insensitivity due to deletion of exon C of the androgen receptor gene highlights the functional importance of the second zinc finger of the androgen receptor in vivo.
Androgen-dependent gene transcription is mediated by the androgen receptor (AR) through interaction of its central zinc finger region with specific DNA sequences on target genes. Failure of this receptor-mediated gene transcription results in end organ resistance to androgens-the androgen insensitivity syndromes. In a pair of siblings with complete androgen insensitivity who had supranormal levels of androgen binding in genital skin fibroblasts, polymerase chain reaction and Southern blot analysis of the androgen receptor gene confirmed by polymerase chain reaction and sequence analysis of AR cDNA, revealed an in-frame deletion of exon C encoding the second zinc finger of the receptor. The mutant receptor in cultured genital skin fibroblasts had normal androgen binding affinity and was localized in the nucleus but had markedly reduced DNA-binding affinity. When recreated in vitro and tested in a cotransfection assay system the mutant receptor failed to activate transcription of an androgen-responsive reporter gene. This naturally occurring mutation highlights the functional dependence of the AR upon its second zinc finger in vivo and explains the complete insensitivity to androgen manifest by the affected individuals despite increased androgen binding. The elevated AR levels in the subjects' genital skin fibroblasts further suggests a possible role for the second zinc finger in autoregulation of receptor levels in vivo.
Androgen-Insensitivity Syndrome↗
'Diaphragmlike' stricture and ulcer of the colon during diclofenac treatment.
Diclofenac sodium is a widely used enteric-coated nonsteroidal anti-inflammatory drug. We describe a woman with Hemoccult-positive stools and iron deficiency anemia who developed both a colonic ulcer and a "diaphragm-like" colonic stricture while taking enteric-coated diclofenac. These lesions were evident on colonoscopy but not on barium studies. Biopsy specimens of the ulcer and stricture revealed particulate matter that was indistinguishable from diclofenac pill fragments by electron microscopy. Discontinuation of diclofenac therapy resulted in resolution of anemia and Hemoccult-positive stools. We conclude that (1) enteric-coated diclofenac is associated with both colonic ulcers and diaphragm-like colonic strictures; (2) the pathophysiologic mechanism for the development of both ulcers and strictures may involve a direct action of diclofenac within these lesions; (3) colonoscopy may be superior to barium studies in evaluating patients receiving diclofenac who have iron deficiency anemia and/or Hemoccult-positive stools.
Anemia, Hypochromic↗
Bioavailability studies of drugs with nonlinear pharmacokinetics: I. Tracer dose AUC varies directly with serum concentration.
The authors show that for a drug cleared by one enzyme the area under the serum concentration-time curve from time 0 to infinity (AUC0-INF) of a test dose can be expressed as AUC0-INF = TD x F x (Km + C)/Vmax where TD is test dose size, F is fraction absorbed, C is drug serum concentration at the time of the study, and Km and Vmax are the Michaelis constant and maximum velocity of the enzyme. This equation predicts the AUC0-INF produced by a given tracer dose of drug will vary directly with C in drugs with nonlinear pharmacokinetic properties (i.e., drugs whose value for C approaches or exceeds Km) if C is held constant by administration of tracer and maintenance doses of drug. The AUC0-INF produced by intravenous tracer doses of 150 mg of 13C15N2-sodium phenytoin was determined in 15 subjects at 30 different values of C. AUC0-INF showed a high degree of direct linear correlation with C (AUC0-INF (ug x hr/mL) = 35.4 + 8.1 x C (ug/mL), r = 0.885, P < .0001). Consequences of this observation for relative bioavailability studies of drugs with nonlinear pharmacokinetic properties are discussed.
Adolescent↗
Plasma exchange in polyneuropathy associated with monoclonal gammopathy of undetermined significance.
BACKGROUND: Polyneuropathy associated with monoclonal gammopathy of undetermined significance (MGUS) has been treated with plasma exchange, intravenous immune globulin, and chemotherapy, but the effectiveness of these treatments remains uncertain. METHODS: We randomly assigned 39 patients with stable or worsening neuropathy and MGUS of the IgG, IgA, or IgM type to receive either plasma exchange twice weekly for three weeks or sham plasma exchange, in a double-blind trial. The patients who initially underwent sham plasma exchange subsequently underwent plasma exchange in an open trial. RESULTS: In the double-blind trial, the average neuropathy disability score improved by 2 points from base line (from 62.5 to 60.5) in the sham-exchange group and by 12 points (from 58.3 to 46.3) in the plasma-exchange group (P = 0.06). A similar difference was observed in the weakness score, a component of the neuropathy disability score (improvement, 1 and 10 points, respectively; P = 0.07). After treatment the summed compound muscle action potentials of motor nerves were 1.2 mV lower (worse) than at base line in the sham-exchange group and 0.4 mV higher (better) in the plasma-exchange group (P = 0.07). The greater degree of improvement with plasma exchange was equal in magnitude to or greater than the difference between not being able to walk on the heels or toes and being able to perform these activities. Changes in the vibratory detection threshold, summed motor-nerve conduction velocity, and sensory-nerve action potentials did not differ significantly between the treatment groups. In the open trial, in which patients who initially underwent sham exchange were treated with plasma exchange, the neuropathy disability score (P = 0.04), weakness score (P = 0.07), and summed compound muscle action potentials (P = 0.07) improved more with plasma exchange than they had with sham exchange. In both the double-blind and the open trial, those with IgG or IgA gammopathy had a better response to plasma exchange than those with IgM gammopathy. CONCLUSIONS: Plasma exchange appears to be efficacious in neuropathy associated with MGUS, especially of the IgG or IgA type.
Action Potentials↗
The relaxin gene is located on chromosome 19 in the mouse.
Relaxin is a polypeptide hormone that exerts a variety of physiological effects during pregnancy. To investigate the possibility that known genetic mutations affecting aspects of reproductive physiology result in alterations in the structure or production of relaxin, we have determined the chromosomal location of the mouse gene. The finding of a BamHI restriction fragment length polymorphism in AKR mice enabled us to use recombinant inbred strains to make an assignment to chromosome 19. This was confirmed by Southern analysis of DNA from microcell hybrids.
Animals↗
Changing disease patterns in AIDS.
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Acquired Immunodeficiency Syndrome↗
Magnetic stimulation of the peripheral nervous system.
Following a review of general aspects of magnetic stimulation pertaining to the peripheral nervous system, the reported performance of currently available magnetic stimulation systems in various critical areas of peripheral clinical neurophysiology is evaluated. The author suggests techniques for the use of the magnetic stimulator in the clinical study of the peripheral nervous system, where its use has been shown to be appropriate or to have advantages over other currently used techniques.
Brachial Plexus↗
Androgen dependent stimulation of aromatase activity in genital skin fibroblasts from normals and patients with androgen insensitivity.
OBJECTIVE: To measure the effect of androgens or aromatase activity as an index of androgen responsiveness in patients with androgen insensitivity. DESIGN: Genital skin fibroblasts were established in culture using primary skin explants obtained from normal males at the time of circumcision and from androgen insensitive patients who had surgery either for gonadectomy (complete androgen insensitivity syndrome) or for reconstruction of the external genitalia (partial androgen insensitivity syndrome). PATIENTS: Foreskin samples were obtained at the time of circumcision in 27 normal males. Scrotal or labia majora skin was obtained at the time of surgery from 14 patients with the complete and 22 with the partial forms of the androgen insensitivity syndrome. MEASUREMENTS: Basal and stimulated levels of aromatase activity were measured in genital skin fibroblasts following preincubation with natural and synthetic, nonmetabolizable androgens. RESULTS: Following a 48-hour preincubation with testosterone or dihydrotestosterone, there was a five to six-fold stimulation of aromatase activity in normal fibroblasts. Mibolerone, a synthetic androgen, produced similar results. The stimulatory effect was blocked by anti-androgens. Seven patients with partial androgen insensitivity, of whom four were either receptor deficient or showed a qualitative defect in androgen binding, had reduced mibolerone induced stimulation of aromatase activity. All ten patients with receptor negative complete androgen insensitivity had an absent response. There was no aromatase induction in a further three patients with complete androgen insensitivity who were receptor positive. Two siblings in the latter group had an exon deletion encoding for part of the DNA binding domain of the androgen receptor. CONCLUSIONS: Androgens stimulate aromatase activity in genital skin fibroblasts from normals. The response is mediated via the androgen receptor and can be decreased or absent in patients with the androgen insensitivity syndrome. This may be a useful in-vitro marker of androgen responsiveness in such patients.
Androgens↗
Normal postnatal androgen production and action in isolated micropenis and isolated hypospadias.
To try and find out if a defect in androgen biosynthesis or action could be responsible for the incomplete virilisation seen in boys with isolated hypospadias and isolated micropenis, androgen receptor binding was studied in genital skin fibroblasts established from 18 boys with isolated micropenis and 19 boys with isolated hypospadias. The production of gonadotrophins and testosterone was also measured in the boys with micropenis. There was no evidence of gonadotrophin deficiency, or of a defect in testosterone biosynthesis in the boys with micropenis, and there was no evidence of a quantitative or qualitative defect of androgen binding in either group. These isolated abnormalities may be the result of transient defects in androgen synthesis or action, or both, during a critical phase of embryogenesis.
Adolescent↗
Trends in sexual behaviour and HIV testing among women presenting at a genitourinary medicine clinic during the advent of AIDS.
Changes in female sexual behaviour with the advent of AIDS and safer sex campaigns were studied. Subjects were drawn from a wide social spectrum of women attending an STD clinic in West London where there is a high prevalence of HIV infection among homosexual men. Between 1982 and 1989, 4224 women answered a self-administered questionnaire: women who reported more than one sexual partner in the previous year fell from 56.9% in 1982 to 51.8% in 1989 (p = 0.003). Anal intercourse showed no change and was reported by 8.8% in 1982 and 9.4% in 1989 (p = 0.8). Oral intercourse increased from 36.9% in 1982 to 44.7% in 1989 (p = 0.001). Condom use for contraception increased from 3.6% in 1982 to 16.2% in 1989 (p less than 0.001). Between 1987 and 1989, 35.6% of 3199 women reported having non-regular partners with no significant trend over this period; these women had earlier coitarche (17.0 years cf 17.9 years), many more partners (p less than 0.0001) and more practised anal (p = 0.007) and oral (p less than 0.0001) intercourse. However, frequent use of condoms doubled from 23.6% in 1987 to 47.6% in 1989. During this period, the prevalence of antibody to HIV (anti-HIV) remained unchanged (0.27-0.37%), but more women declined to be tested. Anonymised testing showed that none of those who refused consent for named testing was anti-HIV positive. It is concluded that significant changes in female sexual behaviour have taken place with the advent of AIDS but there has been no evidence of heterosexual spread beyond the confines of well defined risk behaviours. Risks of the magnitude reported in homosexual men were not found in heterosexual women.
AIDS Serodiagnosis↗
New pharmacokinetic methods. II: Determination of the presence or absence of product inhibition in drugs with nonlinear pharmacokinetics.
We show that for drugs metabolized by one enzyme the slope of a plot of serum concentration (C) versus 1/clearance (CL) is linear with a value of 1/Vmax in the presence of substrate saturation and may be linear (rarely) or curved (usually) with a slope always greater than 1/Vmax in the presence of substrate saturation and product inhibition (competitive, noncompetitive, or uncompetitive) when the serum concentration of product varies with the serum concentration of substrate. Serum concentration, CL, and Vmax were determined for a group of six subjects receiving phenytoin monotherapy using three approaches. With each approach: 1) a plot C versus 1/CL was linear (r greater than or equal to 0.738, P less than .01); 2) the slope of this regression line did not differ significantly (P greater than .30) from 1/Vmax. We conclude: 1) our method is a simple and useful method for determination of mechanism of a drug's nonlinear pharmacokinetics (substrate saturation versus substrate saturation and product inhibition), 2) phenytoin has nonlinear pharmacokinetics due to substrate saturation only in man.
Humans↗
New pharmacokinetic methods: I. Estimation of mean serum concentration from trough serum concentration.
An equation is derived to estimate mean steady state serum concentration (Css) from trough steady state serum concentration (Cmin) which can be used for drugs with either linear or nonlinear pharmacokinetic properties. In 15 subjects receiving phenytoin monotherapy, estimated Css did not differ significantly from measured Css, while Cmin differed significantly (P less than .0001) from measured Css and estimated Css. Clearance (CL) and elimination half-life (t1/2) values determined by stable isotope tracer methods or by standard equations and measured Css or estimated Css did not differ significantly, while CL and t1/2 values calculated with standard equations and Cmin differed significantly (P less than .02) from values obtained by any of the other three methods. We conclude: 1) Cmin values and CL and t1/2 values calculated with Cmin values may differ significantly from Css values and CL and t1/2 values calculated with Css; 2) accurate estimates of Css and of CL and t1/2 can be obtained using our procedure to correct a Cmin value to an estimated Css value.
Half-Life↗