The value of anal cytology and human papillomavirus typing in the detection of anal intraepithelial neoplasia: a review of cases from an anoscopy clinic.

BACKGROUND: Previous studies have reached differing conclusions about the utility of anal cytology as a screening tool for anal intraepithelial neoplasia (AIN). There is a need also to establish whether HPV typing offers a useful adjunct to screening. METHODS: We analysed data from 99 consecutive homosexual/bisexual male patients (89 HIV-1 positive) who underwent high resolution anoscopy. Follow up visits for these patients were also included, giving a total of 160 anoscopic procedures. Comparison was made between results of anal cytology using the sampling method of Palefsky, and histological findings of biopsies taken from abnormal areas seen on high resolution anoscopic examination of the anal canal. Swabs taken concurrently with the cytology were analysed for the presence of human papillomavirus (HPV) DNA and compared with the cytological and histological findings. RESULTS: The sensitivity of the cytology was 83%, and the specificity 38% when compared with histology. At screening of 34 asymptomatic men, 83% had anal cytological dysplasia and 78% had AIN. There were no significant differences in the prevalence of hrHPV genotypes between different cytological or histological grades of abnormalities. CONCLUSION: Anal cytology by the Palefsky method is simple to undertake, has a sensitivity and specificity comparable with cervical cytology, and can therefore be used as the basis of a pilot screening project in centres with large cohorts of HIV positive homosexual men who have a high risk of developing anal carcinoma. HPV genotyping is not a useful adjunct to cytological screening.

Chronic erosive herpes simplex virus infection of the penis, a possible immune reconstitution disease.

OBJECTIVE: To report a novel clinical presentation: a chronic erosive herpes simplex virus (HSV) infection of the penis which developed in AIDS patients following the commencement of highly active antiretroviral therapy (HAART). The lesions were unresponsive to antiviral treatments which had previously been effective, and this could not be accounted for in terms of increased antiviral resistance. DESIGN: Detailed case-note review and investigation of three cases which presented at two large HIV units in London. METHODS: Review of all histology with immunohistochemistry for HSV, HSV drug susceptibility assays, tissue typing and measurement of in vitro lymphocyte functional activity against HSV. RESULTS: The histology of the lesions was the same in each case, with the presence of HSV on immunohistochemistry and an unusual prominence of plasma cell and eosinophils in the inflammatory infiltrate. HSV-specific lymphoproliferative responses were normal in two cases, but subnormal in a third case. All individuals shared the HLA class I molecules B72 and Cw0202 and the class II allele DRB4. CONCLUSION: We believe this to be a previously unreported adverse consequence of HAART, the result of partial immune restoration, reminiscent of the the recently described syndrome of immune recovery vitritis.

Disposition of milrinone in patients after cardiac surgery.

We have evaluated the disposition of milrinone in seven patients with low cardiac output after elective cardiac surgery involving cardiopulmonary bypass. Patients received a loading dose of milrinone 50 micrograms kg-1 given over 10 min followed immediately by an infusion of 0.5 microgram kg-1 min-1, continued for a minimum of 5 h. Plasma concentrations of milrinone were measured at designated intervals during the infusion and for 6 h after its termination, by high pressure liquid chromatography. Concentrations greater than 100 ng ml-1 were produced in all patients within 2 min of starting the loading dose and were maintained for the duration of the infusion. Volume of distribution, clearance and terminal half-life were similar to those found in patients with chronic cardiac failure.

A unique epithelial basement membrane antigen defined by a monoclonal antibody (KF-1).

The basement membrane zone (BMZ) of human skin is a complex structure which contains several well-defined components including bullous pemphigoid antigen, laminin, type IV collagen, and proteoglycan. Characterization of additional basement membrane (BM) constituents has been limited by their relative inaccessibility, insolubility, and low tissue concentration. We have produced a murine monoclonal antibody that has enabled us to define a unique constituent of the BMZ of human stratified squamous epithelia. The monoclonal antibody (KF-1) was raised by standard techniques using suction blister-derived trypsinized human epidermal cells as the antigen. Indirect immunofluorescence and immunoperoxidase staining of human and rhesus monkey tissues with KF-1 produced linear BMZ staining of stratified squamous epithelia. Glandular and vascular BMs were not stained. Immunoelectron microscopic studies of normal human skin and esophagus showed specific binding of KF-1 to the lamina densa of the BMZ, a localization identical to that of type IV collagen. However, unlike type IV collagen, which is not species specific and is found in all BMs, the antigen defined by KF-1 is collagenase-resistant and is specific for primate stratified squamous epithelia. These findings confirm the existence of regional variation in BM composition, and demonstrate for the first time that the lamina densa of stratified squamous epithelial BMs contains a constituent other than type IV collagen.

Biological and biochemical properties of the 2-hydroxyl metabolites of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea.

The lethal and bone marrow toxicity and antitumor activity of the cis- and trans-2-hydroxylated metabolites of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) have been correlated with their relative in vitro alkylating and carbamoylating activities. Both the isomers have considerably greater alkylating activity and shorter chemical half-lives than the parent compound and on a molar basis have greater antitumor activity against i.p. L1210 leukemia. However, in terms of molar doses resulting in the death of 10% of normal mice, the cis- and trans-2 isomers were 2- and 3-fold more toxic than was CCNU in normal mice. In comparing the antitumor activity produced by a maximum nonlethal dose for each compound, we found that the trans isomer had activity identical to that of CCNU (413 and 410% increased life span compared to control), and the cis isomer had considerably less (152%). Like chlorozotocin, both isomers possess low carbamoylating activity and increased water solubility, two features that have been considered possible contributors to the bone marrow-sparing character of chlorozotocin. However, in the murine model the human bone marrow colony formation (CFU-C) assay neither hydroxylated metabolite of CCNU was associated with reduced myelotoxicity.

Biological and biochemical properties of 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea (NSC D 254157), a nitrosourea with reduced bone marrow toxicity.

1-(2-Chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea (GANU), a water-soluble nitrosourea, differs from 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose (chlorozotocin) by the placement of the cytotoxic group on C-1 of glucose. Its biological and biochemical properties are compared with those of chlorozotocin. At a 10% lethal dose (10 mg/kg i.p.), GANU demonstrates minimal myelosuppression. This dose failed to depress normal bone marrow DNA synthesis, in contrast to a 96% inhibition in L1210 DNA synthesis. In L1210 cell suspension, equimolar doses of GANU and chlorozotocin produced equivalent degrees of inhibition in DNA synthesis. GANU has significant L1210 activity in BALB/c X DBA/2 F1 mice treated on Day 2 of tumor growth. A 117% increased life-span and 15% 45-day survivors are atained with 15 mg/kg i.p., a 50% lethal dose. However, in concurrent studies using randomly selected littermate groups of mice, GANU proved less active than chlorozotocin which produced a 306% increased life-span (15 mg/kg i.p.). GANU and chlorozotocin have similar in vitro alkylating activity but the in vitro carbamoylating activity of GANU is sevenfold that of chlorozotocin. On a molar basis, the lethal toxicity of GANU is twice that of chlorozotocin. The significant carbamoylating activity of GANU may contribute to its greater toxicity and therefore limit the mumoles of alkylating agent that can be administered to the tumor. These structure-activity studies further confirm that the addition of a glucose carrier to a cytotoxic nitrosourea moiety can selectively reduce bone marrow toxicity while retaining antitumor activity.