Women with congenital factor VII deficiency: clinical phenotype and treatment options from two international studies.

INTRODUCTION: A paucity of data exists on the incidence, diagnosis and treatment of bleeding in women with inherited factor VII (FVII) deficiency. AIM: Here we report results of a comprehensive analysis from two international registries of patients with inherited FVII deficiency, depicting the clinical picture of this disorder in women and describing any gender-related differences. METHODS: A comprehensive analysis of two fully compatible, international registries of patients with inherited FVII deficiency (International Registry of Factor VII deficiency, IRF7; Seven Treatment Evaluation Registry, STER) was performed. RESULTS: In our cohort (N = 449; 215 male, 234 female), the higher prevalence of mucocutaneous bleeds in females strongly predicted ensuing gynaecological bleeding (hazard ratio = 12.8, 95% CI 1.68-97.6, P = 0.014). Menorrhagia was the most prevalent type of bleeding (46.4% of patients), and was the presentation symptom in 12% of cases. Replacement therapies administered were also analysed. For surgical procedures (n = 50), a receiver operator characteristic analysis showed that the minimal first dose of rFVIIa to avoid postsurgical bleeding during the first 24 hours was 22 µg kg(-1) , and no less than two administrations. Prophylaxis was reported in 25 women with excellent or effective outcomes when performed with a total weekly rFVIIa dose of 90 µg kg(-1) (divided as three doses). CONCLUSION: Women with FVII deficiency have a bleeding disorder mainly characterized by mucocutaneous bleeds, which predicts an increased risk of ensuing gynaecological bleeding. Systematic replacement therapy or long-term prophylaxis with rFVIIa may reduce the impact of menorrhagia on the reproductive system, iron loss and may avoid unnecessary hysterectomies.

Implementation of a hepatitis A prevention policy in haemophiliacs: results from the French cohort.

In the early nineties, the occurrence of hepatitis A outbreaks in some patients with haemophilia in some countries led French health authorities to recommend hepatitis A virus (HAV) vaccination in HAV-seronegative haemophiliacs. The French 'Suivi thérapeutique National des Hémophiles' cohort permitted to assess the implementation of this recommendation by the analysis of the vaccinal process, i.e. HAV seropositivity assessment and vaccination of HAV-seronegative patients, in a survival approach. In a subgroup of 812 patients diagnosed earlier than 1990 (prevalent cohort), the implementation of vaccinal process increased quickly from 0% in 1993 to 41.8% in 1994 and to 71.2% in 1996, suggesting a 'notification effect'. The vaccinal process was associated to three cofactors in a Cox model analysis (age, severity of haemophilia, centre of treatment). No infection was observed during the survey in this group. In another subgroup of 201 boys born since 1993 (incident cohort), 27.5% and 15.4% patients remained exposed to the risk at 3 and 5 years from diagnosis respectively, again with a 'centre effect', which might be linked to various factors such as regain in confidence for products or economic reasons. Only five infectious seroconversions were assessed over the 7-year survey, which represents 14.5 cases per 1000 person-year incidence without any relationship with products. Our data combined with the contemporary hepatitis A epidemiology and the current safety of anti-haemophilic concentrates, should lead to a new assessment of the risk of hepatitis A in haemophiliacs. We suggest that among patients with bleeding disorder, as well as in other populations, HAV prevention policy might be stressed on those who already suffer from chronic liver disease and/or travel in endemic countries.

Factor VIII recovery after a single infusion of recalibrated ReFacto in 14 severe haemophilia A patients.

A recent multicentre collaborative study showed higher estimates of ReFacto potency when assayed with ReFacto Laboratory Standard(TM) (RLS) in comparison when standards consisting of full-length factor VIII (FVIII) were used. The RLS was hence recalibrated, leading to a 20% increase in the amount of ReFacto per vial without change in the labelled potency. The primary objective of this study was to determine the incremental and in vivo recovery of the recalibrated ReFacto in patients with severe haemophilia A. Fourteen male severe haemophilia A patients (FVIII < 1 IU dL(-1)) with a cumulative previous exposure days to any FVIII product >150 were administered an intravenous infusion 50 +/- 5 IU kg(-1) of ReFacto over a 5-min period. Blood samples were collected before infusion and after 15, 30 and 60 min. FVIII clotting activity (FVIII:C) was assessed in a central laboratory by the chromogenic substrate assay. After ReFacto infusion, peak FVIII:C was obtained within 15 min for 10 patients and within 30 min for the remaining four. Mean FVIII:C at peak was 117.7 +/- 17.3 IU dL(-1). Mean incremental recovery was 2.22 +/- 0.27 IU dL(-1) per IU kg(-1) while mean in vivo recovery was 105.9 +/- 14.6%. One patient reported three mild adverse events rated as 'unrelated' to the study drug. FVIII recovery after recalibrated ReFacto infusion falls within the expected range and is similar to the values reported for other FVIII concentrates.

Analysis of biological phenotypes from 42 patients with inherited factor VII deficiency: can biological tests predict the bleeding risk?

BACKGROUND AND OBJECTIVES: Inherited factor VII (FVII) deficiency is a rare bleeding disorder characterized by a poor relationship between reported FVII clotting activity (FVII:C) and bleeding tendency. Our study was aimed at defining biological parameters that are possibly predictive for bleeding risk in this condition. DESIGN AND METHODS: Forty-two FVII-deficient patients (FVII:C <30%) were classified into two opposite clinical groups defined as severe and non-or-mild bleeders. For each patient, plasma samples were collected and then investigated for FVII:C (using a sensitive method and human recombinant thromboplastin as the reagent), FVII antigen, activated FVII coagulant activity (FVIIa:C) and the free-form of tissue factor pathway inhibitor. RESULTS: None of these tests could be used as highly accurate predictors of bleeding. Nevertheless, both FVII:C and FVIIa:C differed significantly between the two clinical groups. Using ROC-curve analysis, two critical values of 8% and 3mIU/mL for FVII:C and FVIIa:C, respectively, could be proposed to discriminate between severe bleeders and non-or-mild bleeders. INTERPRETATION AND CONCLUSIONS: A highly accurate diagnostic test for predicting bleeding tendency in inherited FVII deficiency still eludes definition, highlighting the fact that factors other than FVII itself interfere with the expression of bleeding phenotypes in this condition. Nevertheless, potential critical values using sensitive FVII:C and FVIIa:C methods may be useful in clinical laboratories for FVII-deficient patients. Those patients with FVII:C levels higher than 8% FVII:C or FVIIa:C higher than 3 mIU/mL, with no other hemostatic defect, seem to have a minimal risk of severe bleeding. Extended clinical studies are needed to support these findings.

An analysis of 84244 patients from the British Columbia cytology-colposcopy program.

OBJECTIVE: To determine the diagnostic correlation between referral cytology, initial biopsies and colposcopic impression in patients assessed in a provincial cytology screening program. METHODS: A retrospective review of the computerized cytology screening database for British Columbia (BC), to identify all patients having their first colposcopy between 1986 and 2000 in 24 participating clinics constituted the study population. 84244 patient records were identified for analysis. Colposcopies were performed mainly by 37 general gynecologists as part of a province-wide colposcopy program. Correlation of cytology, colposcopic impression and directed biopsies was performed. RESULTS: The colposcopic impression correlated with the referral cytology within one degree in over 90% of cases. Colposcopists felt cytology underestimated disease in 1.5% and overestimated disease in 8.3%. Cytology-histology correlation within one degree occurred in 82%. Cytology underestimated the result of the biopsies in 2.3% and appeared to overestimate disease in 16.1% of patients. Patients with HSIL cytology had corresponding lesions in 77%, with a further 4.9% having LSIL disease. The predictive accuracy of colposcopy increased with advancing severity of disease expected. As the degree of cytological abnormality worsened, the predictive accuracy of colposcopic diagnosis increased. CONCLUSIONS: Both cytology and colposcopy have high sensitivity but low to moderate specificity. Colposcopy is most accurate in identifying high-grade diseases. Colposcopic impression correlates closely with the cytology diagnosis and combining the two produces optimum results.

Cost related to replacement therapy during hospitalization in haemophiliacs with or without inhibitors: experience of six French haemophilia centres.

Replacement therapy in haemophiliacs has a major economic impact on health establishments. We assessed in this prospective study the cost of clotting factor concentrate therapy for haemophilia A or B patients. We compared the overall costs of treated patients with or without inhibitors. In six French haemophilia centres, 278 consecutive hospitalizations were collected and analysed between June 97 and June 99. Haemophilia must be considered as the main cost factor during hospitalization. The severity of bleeds and surgical procedures increase the total cost. Furthermore, the daily and total costs are closely linked to the presence or the absence of inhibitors. This study should enable the hospital administration to evaluate the necessary resources to the clotting factor therapy in haemophiliacs with or without inhibitors during hospitalization.

Interferon alpha therapy in haemophilic patients with chronic hepatitis C: a French multicentre pilot study of 58 patients.

BACKGROUND AND OBJECTIVES: Information about the long-term efficacy of interferon alpha (interferon-alpha) in haemophilic patients with chronic hepatitis not co-infected with the human immunodeficiency virus (HIV-1) is still limited. Previous studies seemed to indicate a low rate of response. The aim of this study was to evaluate the safety and long-term efficacy of interferon treatment in multi-transfused haemophiliacs. METHODS: Fifty-eight haemophiliacs were scheduled to receive 3 MU of interferon-alpha 2b three times a week for 12 months. The patients were followed up for at least 24 months post-treatment. Response was assessed by measurements of serum hepatitis C virus (HCV) RNA. RESULTS: Twenty-four patients (41.4%) dropped out. Except for seven patients, the symptoms that led to interrupting interferon treatment would probably not have resulted in the same decision in non-haemophilic patients. One patient developed an inhibitor to the deficient clotting factor without haemorrhagic consequences. In an intent to treat, the sustained virological response rate was 14%. However, when considering only the 34 patients who received the full treatment, HCV-RNA was cleared in eight patients (23%). CONCLUSIONS: This study suggests that multi-transfused haemophiliacs with chronic hepatitis not co-infected with HIV-1 respond to prolonged treatment with interferon-alpha in a similar proportion to that observed in non-haemophiliacs. There was a high rate of patients who did not complete the interferon-alpha treatment, and this seems to be characteristic of this patient population.

Urachal abscess and infected bladder diverticulum.

Urachal abscess is an uncommon condition with protean features and often presents a diagnostic challenge to clinicians. This case report describes a 41-year-old woman with severe multiple sclerosis who was referred to a gynaecological oncology service with the presumed diagnosis of advanced ovarian cancer. A diagnosis of urachal abscess and infected bladder diverticulum was made by a combination of imaging modalities and a percutaneous biopsy. It is important to be aware of this entity, as the presentation varies widely and when diagnosed early the condition may be treated appropriately by relatively minor surgical intervention.

Basal cell carcinoma of the vulva: clinical features and treatment results in 28 patients.

OBJECTIVE: To review our experience and that in the recent literature regarding basal cell carcinoma of the vulva to see whether current management guidelines are appropriate. METHODS: Twenty-eight women with basal cell carcinoma of the vulva were seen over 25 years at the BC Cancer Agency. The clinical-pathologic features were tabulated and the outcome was analyzed. RESULTS: The mean age was 74 years, and almost two-thirds were over the age of 70 at diagnosis. Patients typically presented with an irritation or soreness, with a symptom duration ranging from a few months to several years. Most lesions were confined to the anterior half of the vulva, and 23 of the 28 patients had T1 lesions. Wide local excision was the treatment method used most commonly. Only one patient was known to have died from disease metastasis. Ten women had other basal cell carcinomas, either before or after the diagnosis of their vulvar lesions, and in ten patients 11 other malignancies were diagnosed. CONCLUSION: Basal cell carcinoma of the vulva is an extremely uncommon tumor that rarely metastasizes or spreads. Primary treatment should consist of wide local excision and continued follow-up.

Detecting structural changes at the molecular level with Fourier transform infrared spectroscopy. A potential tool for prescreening preinvasive lesions of the cervix.

OBJECTIVE: To study cervical exfoliated cells with Fourier transform infrared spectroscopy (FTIR). STUDY DESIGN: Consecutive samples from 133 women attending the Dysplasia Clinic, Ottawa Civic Hospital, were collected in balanced electrolyte solution. After centrifugation, two smears were prepared for routine screening. The remainder of the pellet was frozen for FTIR spectroscopic study. RESULTS: In 120 samples, adequate material was available for spectroscopic study. All smears from 17 women with normal spectra were within normal limits (WNL). One hundred three spectra were abnormal. The corresponding smears were interpreted as: 41 low grade squamous intraepithelial lesions, 20 high grade squamous intraepithelial lesions, 6 atypical squamous cells of undetermined significance, 17 cases with benign cellular changes, and 19 WNL. Ten of 17 cases with benign cellular changes had characteristic spectra consistent with inflammatory changes. CONCLUSION: FTIR spectroscopy is a highly sensitive technique for detecting cervical abnormalities and a potential tool for prescreening preinvasive lesions of the cervix.

Bilateral primary ovarian squamous cell carcinoma associated with human papilloma virus infection and vulvar and cervical intraepithelial neoplasia. A case report with review of the literature.

Primary squamous cell carcinoma of the ovary is rare. Most cases represent malignant transformation of ovarian teratomas. Other cases are associated with preexisting Brenner tumor or ovarian endometriosis. We report a primary ovarian squamous cell carcinoma in a 40-year-old woman. The patient had recurrent high-grade intraepithelial neoplasia of the vulva (VIN) and recurrent high-grade cervical intraepithelial neoplasia (CIN). Human papilloma virus (HPV) DNA 16/18 was identified in an in situ and invasive carcinoma in the left ovary; CIN and VIN were identified with in situ hybridization with biotinylated DNA probes. Review of the literature revealed nine cases of primary ovarian squamous cell carcinoma not associated with a preexisting ovarian lesion. Three cases were not associated with CIN and occurred in women who ranged in age from 64 to 90 years and did not have carcinoma in situ component. Six cases were associated with CIN, had a carcinoma in situ, and occurred in younger women ranging from 33 to 54 of age. Our case belonged to the latter category. This report raises the possible causal relationship of HPV with primary ovarian squamous carcinoma in the group of middle-aged patients with CIN.

Molecular analysis by pulsed-field gel electrophoresis of penicillin-resistant Streptococcus pneumoniae from Toulouse, France.

A sample of 28 penicillin-resistant Streptococcus pneumoniae strains isolated between 1991 and 1993 in a large hospital in Toulouse, France, was characterized by pulsed-field gel electrophoresis of genomic DNA. Also included were 6 penicillin-susceptible clinical isolates from Toulouse and 12 penicillin-resistant strains from different parts of the world. The restriction endonucleases ApaI and SmaI were used to digest intact chromosomes, and the fragments were resolved by field-inversion gel electrophoresis. Seven major pattern types could be recognized among the penicillin-resistant isolates from Toulouse. Nine of these isolates could be assigned to two clones that were also found in Spain and were associated with serotypes 6B and 9V. A third clone was isolated in South Africa and in Spain and contained serotype 23F isolates. The profiles obtained by field-inversion gel electrophoresis suggested that 15 of the 16 penicillin-resistant serogroup 23 isolates from Toulouse belonged to the same Spanish 23F clone. The molecular test profiles of penicillin-susceptible strains differed from those of resistant strains of the same serotype except those of 9V strains. These data underline the importance of the geographic spread of resistant clones from Spain in the emergence of penicillin-resistant pneumococci in France.

The interaction of various cholesterol 'ancestors' with lipid membranes: a 2H-NMR study on oriented bilayers.

The effect of putative cholesterol 'precursors' on model membranes has been studied by deuterium nuclear, magnetic resonance (2H-NMR) spectroscopy. Oriented bilayers were prepared from 1-myristoyl-2-[2H27 myristoyl-sn-glycero-3-phosphocholine (DMPC-d27) and tricyclohexaprenols or octaprenediols. Order parameter profiles were determined and showed that tricyclohexaprenols and octaprenediols increase the acyl chain order in DMPC bilayers, but to a smaller extent than cholesterol. The order parameter increases, depending on the chain position, from 5% to 7% in the presence of ditertiary octaprenediol, and from 16% to 21% in the presence of tricyclohexaprenol-Z,Z. Aqueous multilamellar dispersions of DMPC-d27 and of DMPC-d27 containing 30 mol% tricyclohexaprenol-E,E were prepared, and the first moments calculated from 2H-NMR spectra over the temperature range 5-55 degrees C. Tricyclohexaprenol-E,E almost abolishes the phase transition of DMPC. Thus, as predicted, tricyclohexaprenols and octaprenediols have a cholesterol-like behaviour in lipid membranes; however their effect on the model DMPC system is weak. On the contrary, isoarborinol has no effect on the lipid chain order in the liquid-crystalline phase of DMPC bilayers. 2H-NMR spectra of aqueous dispersions of DMPC-d27 and 30 mol% isoarborinol between 25 and 60 degrees C showed the coexistence of two lamellar phases over a wide temperature range, which was confirmed by differential scanning calorimetry (DSC) and 31P-NMR spectroscopy. This absence of ordering effect of isoarborinol might be related to some inherent structural features.

Clinical and microbiologic features of urethritis in men in Toulouse, France.

On hundred twenty-six men who attended a hospital microbiology laboratory and 99 men who attended a private laboratory in Toulouse, France, for symptoms of urethritis were examined during 1988, for evidence of urethral pathogens. The following incidences were found: Neisseria gonorrhoeae: 24 (10.7%); Chlamydia trachomatis: 58 (25.8%); Ureaplasma urealyticum: 46 (20.4%); Gardnerella vaginalis: 21 (9.3%); Haemophilus parainfluenzae: 21 (9.3%); Streptococcus agalactiae: 15 (6.7%); Candida albicans: 10 (4.4%); and Trichomonas vaginalis: 4 (1.8%). The prevalence of these microorganisms was similar in the two groups of patients. No pathogen was isolated from 71 patients (31.6%). Mixed infections with at least two pathogens were found in 49 men (21.8%). Another goal of this study was to determine the relative prevalence of urethral pathogens in relation to clinical findings. N. gonorrhoeae was isolated significantly more often in patients who had a urethral discharge (P less than .05) that contained five or more polymorphonuclear cells per high-power field (PMN/HPF) (P less than .001). G. vaginalis was isolated significantly more often in patients who did not have an urethral discharge (P less than .05) and in men with less than five PMN/HPF (P less than .05). Isolation of C. albicans was significantly associated with pruritus (P less than .05) and balanitis (P less than .001). Like the clinical features, the gram-stained urethral smear was of limited value in diagnosis and therapeutic decision-making regarding non-gonococcal urethritis. In contrast, this study underlines the importance of full identification of urethral isolates in the management of urethritis in men.

Evaluation of the Captia enzyme immunoassays for detection of immunoglobulins G and M to Treponema pallidum in syphilis.

Two new enzyme-linked immunosorbent assays (ELISA), one for the measurement of immunoglobulin G (IgG) (Captia Syphilis-G) and one for the measurement of IgM (Captia Syphilis-M), were evaluated for detecting antibodies to Treponema pallidum. Serum samples from 169 patients, 96 with various stages of untreated syphilis, 63 with treated syphilis, and 10 who were noninfected, were investigated. All sera were also examined by traditional treponemal and cardiolipin tests and by the fluorescent treponemal antibody absorption (FTA-ABS) test for 19S(IgM). The overall sensitivity of Captia Syphilis-G was 98.3%. The IgG ELISA was very sensitive (100%) in all stages of untreated syphilis, except in primary syphilis (82%). In all diagnostic groups of syphilis, the reactivity of Captia Syphilis-M was similar to that of the 19S(IgM) FTA-ABS test, except in reinfections, in which the IgM capture ELISA was less sensitive. False-positive IgM capture ELISA results were not found in the 10 neonates born to mothers adequately treated for syphilis. However, of six serum samples containing rheumatoid factor, two were reactive in the Captia Syphilis-M test but not in the 19S(IgM) FTA-ABS test. This indicated that the specificity of the IgM capture ELISA was not absolute. All serum samples from treated patients were reactive in the IgG ELISA, but only 15 samples were reactive in the IgM capture ELISA, which appeared to be as effective as the 19S(IgM) FTA-ABS test in monitoring the effect of treatment. Simultaneous measurement of IgG and IgM antibodies for T. pallidum by the Captia immunoassays appears to be an efficient and simple method for confirming the diagnosis of syphilis as well as for indicating whether active disease is present.