The use of telemedicine in the management of vascular surgical referrals.

We have performed a feasibility study of telemedicine as an alternative to conventional outpatient appointments for the making of diagnostic and management decisions for patients referred for vascular surgery. Twenty-two sequential patients referred by a single general practice to a vascular centre were offered a telemedicine clinic appointment as an alternative to a conventional hospital outpatient appointment. A referral pro forma and digital photograph (where appropriate) were transmitted in advance of the videoconference. The videoconference involved patient, practice nurse and vascular consultant. All patients opted for the teleconsultation. The majority had leg ulceration or leg pain. Six patients required only the initial teleconsultation and were managed thereafter in the community. Thirteen were referred to the vascular laboratory for investigation. Three proceeded to angioplasty and four to surgery. Two patients had a conventional outpatient appointment for follow-up but all others were followed up via telemedicine. Overall 27 conventional outpatient appointments were replaced by a teleconsultation.

Recurrent primary vulvovaginal malignant melanoma arising in melanoma in situ--the natural history of lesions followed for 23 years.

Multifocal melanoma and melanoma in situ of the vulva and vagina are uncommon lesions, and our understanding of their natural history is limited. Vulvovaginal melanoma appears to be biologically different from cutaneous melanoma and has more in common with mucosal melanoma. A 60-year-old woman presented in 1977 with a pigmented vulvar lesion. Histologic examination revealed melanoma in situ associated with focal invasive melanoma. She re-presented with recurrent primary melanomas arising in melanoma in situ in 1990 and 1998 and died of widespread metastatic melanoma in 2000. Melanoma in situ of the vulva and vagina is rare and appears to have a relatively slow but definite progression to invasive melanoma. All suspicious pigmented lesions in this region should be biopsied, and if multifocal in situ melanoma is identified, vulvo(vagin)ectomy should be considered.

Abnormal splicing of hepatocyte nuclear factor-1 beta in the renal cysts and diabetes syndrome.

AIMS/HYPOTHESIS: Mutations in the hepatocyte nuclear factor-1 beta ( HNF-1 beta) gene result in disorders of renal development, typically involving renal cysts and early-onset diabetes (the RCAD syndrome/ MODY5). Sixteen mutations have been reported, including three splicing mutations of the intron 2 splice donor site. Because tissues showing abundant expression (kidney, liver, pancreas, gut, lung and gonads) are not easily accessible for analysis in living subjects, it has previously proven difficult to determine the effect of HNF-1 beta mutations at the mRNA level. This is the aim of the present study. METHODS: We have developed a nested RT-PCR assay that exploits the presence of ectopic HNF-1 beta transcripts in Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines derived from subjects carrying HNF-1 beta splice site mutations. RESULTS: We report a fourth mutation of the intron 2 splice donor site, IVS2nt+2insT. Sequence analysis of ectopic HNF-1 beta transcripts showed that both IVS2nt+2insT and IVS2nt+1G>T result in the deletion of exon 2 and are predicted to result in premature termination of the HNF-1 beta protein. Mutant transcripts were less abundant than the normal transcripts but there was no evidence of nonsense-mediated decay. CONCLUSIONS/INTERPRETATION: This is the first study to define the pathogenic consequences of mutations within the HNF-1 beta gene by mRNA analysis. This type of approach is a useful and important tool to define mutational mechanisms and determine pathogenicity.

Mapping genes for resistance to Verticillium albo-atrum in tetraploid and diploid potato populations using haplotype association tests and genetic linkage analysis.

Verticillium wilt disease of potato is caused predominantly by Verticillium albo-atrum and V. dahliae. StVe1 -a putative QTL for resistance against V. dahliae -was previously mapped to potato chromosome 9. To develop allele-specific, SNP-based markers within the locus, the StVe1 fragment from a set of 30 North American potato cultivars was analyzed. Three distinct and highly diverse haplotypes can be distinguished at the StVe1 locus. These were detected in 97%, 33%, and 10% of the cultivars analyzed. We tested for haplotype association and for genetic linkage between the StVe1 haplotypes and resistance of tetraploid potato to V. albo-atrum. Moreover, field resistance was assessed in diploid populations with known molecular linkage maps in order to identify novel QTLs. Resistance QTLs against V. albo-atrum were detected on four chromosomes (2, 6, 9, and 12) at the diploid level, with one QTL on chromosome 2 contributing over 40% to the total phenotypic variation of the trait. At the tetraploid level, a significant association between the StVe1-839-C haplotype and susceptibility to the disease was detected, suggesting that resistance-related genes directed against V. albo-atrum and V. dahliae are located in the same genomic region of chromosome 9. However, on the basis of the present analysis, we cannot determine whether these genes are closely linked or if a single gene provides resistance against both Verticillium species. To assess the usefulness of the StVe1-839-C haplotype for marker-assisted selection, we subjected the resistance data to Bayesian analysis, and calculated positive (0.65) and negative (0.75) predictive values, and overall predictive accuracy (0.72). Our results indicate that tagging of additional genes for resistance to Verticillium with molecular markers will be required for efficient marker-assisted selection.

Linkage disequilibrium mapping of a Verticillium dahliae resistance quantitative trait locus in tetraploid potato ( Solanum tuberosum) through a candidate gene approach.

We have used the linkage disequilibrium mapping method to test for an association between a candidate gene marker and resistance to Verticillium dahliae in tetraploid potato. A probe derived from the tomato Verticillium resistance gene ( Ve1) identified homologous sequences ( StVe1) in potato, which in a diploid population map to chromosome 9, in a position analogous to that of the tomato resistance gene. When a molecular marker closely linked (1.5 cM) to the homologues was used as a candidate gene marker on 137 tetraploid potato genotypes (mostly North American cultivars), the association between the marker and resistance was confirmed ( P<0.001). The amount of phenotypic variation in resistance explained by the allele of the STM1051 marker was greater than 10% and 25% in two subpopulations that were inferred from coancestry data matrix. Cloning of homologues from the highly resistant potato cv. Reddale indicates that the resistance quantitative trait locus (QTL) comprises at least an eleven-member family, encoding plant-specific leucine-rich repeat proteins highly similar to the tomato Ve genes. The sequence analysis shows that all homologues are uninterrupted open reading frames and thus represent putative functional resistance genes. This is the first time that the linkage disequilibrium method has been used to find an association between a resistance gene and a candidate gene marker in tetraploid potato. We have shown that it is possible to map QTL directly on already available potato cultivars, without developing a new mapping population.

Characterization of the glucose-6-phosphate isomerase gene in Phytophthora infestans reveals the presence of multiple alleles.

Glucose-6-phosphate isomerase (GPI) plays a key role in both glycolysis and gluconeogenesis. Isoforms of GPI are common, and therefore, its isozyme pattern is widely used to characterize isolates of Phytophthora infestans. Despite the importance of GPI in P. infestans studies, the gene encoding this enzyme has not yet been characterized. Furthermore, it has been suggested that P. infestans contains multiple copies of the gene but this hypothesis remains to be demonstrated. We have cloned and characterized GPI in various isolates of P. infestans as well as in several species of the genus Phytophthora. The gene contains 1671bp and encodes a protein with a predicted molecular weight of 60.8kDa. Multiple different alleles were identified and Southern analysis indicated certain P. infestans isolates carry several copies of the gene. Phylogenetic analysis revealed that P. infestans GPI is most closely related to sequences from Toxoplasma gondii, Arabidopsis thaliana, and Clarkia lewisii.

An UK myeloma forum phase II study of thalidomide; long term follow-up and recommendations for treatment.

Myeloma remains incurable with conventional treatment in the vast majority of patients. The introduction of thalidomide in 1999 for the treatment of relapsed disease offers the opportunity to treat patients who have developed myelotoxicity or who are refractory to conventional chemotherapy. The optimal schedule remains unresolved and only two studies have reported long term follow-up data. We report a phase II low dose escalation study of thalidomide with long term follow-up showing overall survival (OS) of 19 months and progression free survival (PFS) of 14 months. In addition we report on the side effects and toxicity and give recommendations for the use of thalidomide in the relapsed setting based upon these findings.

Vaginal adenosis with adenocarcinoma in situ in a woman with no recognised antecedent factors.

We present a case of vaginal adenosis with adenocarcinoma in situ in a woman with no recognised antecedent factors. This case demonstrates the importance of continuing thorough colposcopic assessment of the entire lower genital tract with repeated biopsies of all abnormal epithelium in women with persistent or recurrent cervical cytology abnormalities. Successful management requires accurate definition of the vaginal lesion.

Vulval intraepithelial neoplasia: current perspectives.

The heterogeneous clinical features of vulval intraepithelial neoplasia (VIN), its uncertain and variable natural history, difficulties in the management of certain cases and the frequency of recurrences provide a continuing challenge for gynaecologists. Patients with VIN present to a diverse range of physicians, all of whom provide differing perspectives on the multifarious issues relating to the condition. The importance of VIN relates principally to the symptoms it causes and its potential to progress to invasive vulval cancer. Both the International Society for the Study of Vulvovaginal Diseases and the International Society of Gynaecological Pathologists have stressed the importance of eliminating eponymous terminology and recommend only the term vulval intraepithelial neoplasia (VIN). This terminology includes both squamous and non-squamous varieties (Table 1). The latter includes both Paget's disease of the vulva and melanoma in situ. Non-squamous VIN will not be considered in this paper. Until 30 years ago VIN was an uncommon condition, seen principally in middle and later life. The incidence particularly in younger women has increased significantly since then [1-3]. Since that time the mean age in our unit has fallen from 52.7 years to 35.8 years (Figure 1) [2]. The increasing incidence of the condition parallels similar trends in cervical intraepithelial neoplasia (CIN) and relates at least in part to changing sexual morés, human papilloma virus (HPV) infection, and cigarette smoking.

Loss of fhit expression in invasive cervical carcinomas and intraepithelial lesions associated with invasive disease.

Allelic losses involving chromosome 3p are frequently observed in cervical cancers. Deletion mapping studies of primary cervical carcinomas have localized common regions of deletion to 3p14.2 and 3p21. The candidate tumor suppressor gene FHIT has been mapped to 3p14.2, and previous studies have demonstrated reduced or aberrant FHIT transcripts and reduced or absent Fhit protein expression in a large percentage of cervical cancer-derived cell lines and primary cervical carcinomas. To expand these observations to preinvasive cervical epithelial lesions and to determine whether loss of Fhit protein expression might be associated with tumor progression, immunohistochemical methods were used to examine Fhit expression in 95 invasive cervical carcinomas, 33 high-grade squamous intraepithelial lesions (HSILs) associated with concurrent invasive cancer, 38 HSILs unassociated with invasive cancer, 24 low-grade squamous intraepithelial lesions, and 22 normal cervix samples. All normal cervical epithelia and low-grade squamous intraepithelial lesions exhibited diffuse cytoplasmic immunostaining of moderate to strong intensity. Fhit protein expression was markedly reduced or absent in 67 of 95 (71%) invasive cancers, 17 of 33 (52%) HSILs associated with invasive cancer, and 8 of 38 (21%) HSILs without associated invasive cancer. The results confirm that Fhit protein expression is reduced or absent in the majority of cervical carcinomas and suggest that loss of Fhit expression often accompanies cervical tumor progression. Moreover, absent or reduced Fhit protein is observed at a significantly higher frequency in HSILs associated with progression to invasive cancer than in HSILs with unknown risk for progression (P = 0.012). These findings suggest that loss of Fhit expression in HSILs could serve as a useful marker of high-grade preinvasive lesions that have an increased likelihood of progression to invasive carcinoma.

Spontaneous regression of vulvar intraepithelial neoplasia 2-3.

OBJECTIVE: To determine the background and clinical features of a group of women who experienced spontaneous regression of vulvar intraepithelial neoplasia (VIN) 2-3 before treatment was undertaken. METHODS: A retrospective review was made of the records of 14 women who experienced spontaneous regression of VIN 2-3. RESULTS: The women were 15-27 years of age (median 19.5 years). Ninety-three percent were non-white. All women were seen initially in a sexual health clinic, and with one exception, all had been treated previously for genital condyloma acuminata. Four of the 14 cases were pregnancy-associated. Half of the women were asymptomatic. The transit time to regression of VIN 2-3 was 3-30 months (median 9.5 months). The median follow-up was 3 years. All lesions were multiple and pigmented. CONCLUSION: Spontaneous regression of VIN 2-3 can occur in young women with multifocal pigmented lesions.

Guidelines for the management of women with abnormal cervical smears 1998.

Four important changes have been introduced in the revised guidelines for the management of women with abnormal cervical smears, 1998. 1. For the purposes of management, atypical squamous cells of undetermined significance (ASCUS) and atypical glandular cells of undetermined significance (AGUS) have been included with low grade squamous intraepithelial lesions (LSIL/CIN1/HPV) except where the smear raises the possibility of a high grade squamous intraepthelial lesion (HSIL) or favours glandular dysplasia. 2. Women with low grade cytological and histological intraepithelial abnormalities will, after initial follow-up, revert to three yearly screening. 3. Requirements for those practising colposcopy have been defined. 4. A formal review of all cases of invasive cervical cancer is advocated.

The AIDMAN project--a telemedicine approach to cardiology investigation, referral and outpatient care.

The AIDMAN pilot project will connect health clinics on remote Greek islands with a mainland hospital. We have developed a virtual consultation workstation for the project, together with a satellite communication network. A UK pilot site has been used to test the concepts and applications between a surgery in Chorleywood and St Mary's Hospital in London.

Analyzing prior clinical events at presentation in 102 women with vulvar carcinoma. Evidence of diagnostic delays.

OBJECTIVE: To evaluate the clinical events preceding the diagnosis of squamous cell carcinoma of the vulva. STUDY DESIGN: One hundred two women presenting with squamous cell carcinoma of the vulva to a gynecologic oncology unit between 1989 and 1996 were prospectively evaluated by a single investigator. History, clinical findings, previous physician contact, investigations and treatment were analyzed. RESULTS: Vulvar symptoms were present for more than six months in 88% and for more than five years in 28% of women. Eighty-five percent of patients had clinical evidence of abnormal skin adjacent to the cancer. Thirty-one percent of women had three or more medical consultations for vulvar symptoms prior to the diagnosis of cancer. Twenty-five percent of women had had a previous diagnostic vulvar biopsy, and 27% gave a history of having applied topical estrogen or corticosteroid to the vulva. Patients with a history of a preceding biopsy were more likely to present with stage 1 disease. CONCLUSION: Avoidable factors appear to be present in many women who present with vulvar cancer. A more active approach to the diagnosis and management of precursor lesions may often prevent the development of vulvar cancer.