Efficacy of a Carrageenan gel Against Transmission of Cervical HPV (CATCH): interim analysis of a randomized, double-blind, placebo-controlled, phase 2B trial.

OBJECTIVES: To evaluate the efficacy of a carrageenan-based lubricant gel in reducing the risk of genital human papillomavirus (HPV) infections in women. METHODS: We conducted a planned interim analysis of a randomized, double-blind, placebo-controlled, phase 2B trial. Women aged 18 years and older were randomly assigned (1:1) to a carrageenan-based gel or a placebo gel to be self-applied every other day for the first month and before and after each intercourse during follow-up. Assessments were performed at 0.5, 1, 3, 6, 9 and 12 months. The primary outcome was incidence of a new infection by an HPV type that was not present at baseline. Intention-to-treat analyses were performed. RESULTS: Between January 2013 and June 2017, a total of 280 participants were randomly assigned to the carrageenan (n = 141) or the placebo (n = 139) arm. All participants were included in safety analyses, but three (1%) were excluded from efficacy analyses (HPV results unavailable for two participants in the carrageenan and one participant in the placebo arm). The median follow-up time was 9.2 months (interquartile range, 1.9-13.2 months). A total of 59 (42%) of 139 participants in the carrageenan arm and 78 (57%) of 138 participants in the placebo arm became infected by at least one new HPV type (hazard ratio = 0.64, 95% confidence interval = 0.45-0.89, p 0.009). A total of 62 (44%) of 141 participants in the carrageenan arm versus 43 (31%) of 139 participants in the placebo arm reported an adverse event (p 0.02), none of which was deemed related to the gels. CONCLUSIONS: Our trial's interim analysis suggests that using a carrageenan-based lubricant gel can reduce the risk of genital HPV infections in women.

Lower-limb vascularization in diabetic patients. Assessment by thallium-201 scanning coupled with exercise myocardial scintigraphy.

OBJECTIVE: To investigate, by thallium-201 scanning, circulation in the muscles of the lower limb (LL) in diabetic patients without clinical peripheral vascular disease but with a high cardiovascular risk profile. RESEARCH DESIGN AND METHODS: A total of 80 diabetic patients (76 patients with type 2 diabetes, mean age 57.3 years, duration of diabetes 13.0 +/- 7.5 years) with more than one additional cardiovascular risk factor but no claudication were investigated. After stress testing, 1.5 MBq/kg thallium-201 was administered to perform myocardial single-photon emission computed tomography followed by LL scanning. Muscle blood flow was considered abnormal if the asymmetry in thallium-201 uptake between the two buttocks and/or thighs and/or calves was > 10%. RESULTS: Muscle perfusion defects were found in 42% of the patients, mainly in the calves. These defects correlated with retinopathy (P = 0.042) and the HbA1c level (P = 0.044). In patients with defects in the buttock and/or thigh, the prevalence of nephropathy and retinopathy was higher than in those with isolated defects in the calf (P = 0.032 and 0.023, respectively). CONCLUSIONS: This study suggests that LL scanning coupled with myocardial scintigraphy is a convenient method of investigating peripheral muscle circulation. Proximal perfusion defects in patients without clinical arterial disease are associated with increased prevalence of retinopathy and nephropathy and, therefore, may be due to microvascular disease of LL muscle. Distal defects may indicate silent macrovascular disease of the LL.

Fenfluramines, idiopathic pulmonary primary hypertension and cardiac valve disorders: facts and artifacts.

The fenfluramines saga began in 1963 and ended in 1997. Fenfluramines are anorexigenic agents recommended, in April 1996, for the long-term treatment of obesity in USA, before being suddenly withdrawn from the market in September 1997. Over 34 years, about 60 million people were exposed to these drugs worldwide, mainly in Europe. The aim of this critical review is not to attempt to rehabilitate these appetite suppressants but to launch a plea for a more rational and rigorous approach to what might be called objective medical knowledge. Idiopathic primary pulmonary hypertension and cardiac valve disorders which have been both associated with fenfluramines have in common many puzzling features. The metamorphosis of facts into artifacts is only a hypothesis, but seems conceivable from a scientific point of view. Medicine is not only an art, it is also a science, which, like the others, implies adhesion to certain fundamental rules, such as refutation or verification of all experimental results by rigorous and standardized methods, before considering them as established facts. Firstly, a single study, moreover a case-control study like the International Primary Pulmonary Hypertension Study, is not sufficient to establish a causal relationship between exposure to appetite-suppressants and idiopathic pulmonary hypertension, because of the numerous biases which characterize even the best analytical research. Secondly, Doppler-echocardiography cannot be considered as a laboratory test, because of the poor interoperator reproducibility observed in obese patients. The use of this technique in pharmaco-epidemiology implies standardized procedures concerning not only reading data, but also their acquisition, because of possible uncontrolled interactions between sonographers, patients and sophisticated machines. In the case of the fenfluramines saga, numerous methodological artifacts concerning acquisition, processing and interpretation of epidemiologic and echocardiographic data might have contributed to distortion of reality. Let us recall how Webster's dictionary defines artifact: "a spurious observation or result arising from preparatory or investigative procedures or any feature that is not naturally present but is a product of an extrinsic agent, method, or the like".

[Menopause and hormone replacement]. / Ménopause et hormonothérapie substitutive.

INTRODUCTION: Considered until recently as a biological fate, menopause has evolved within a decade into a major public health issue at stake. Such an evolution results from various factors that deserve an exhaustive critical approach because the situation is much more complex than it appears to be at first analysis. CURRENT KNOWLEDGE AND KEY POINTS: 1) Ninety-five percent of the available epidemiological information relies on observation or cohort studies, such as case-control studies that do not allow any certitude in regard to therapy. 2) Chronic estrogen deficiency probably plays a pathogenic role in various symptoms or pathological conditions that are associated to menopause. 3) However, behind the paradigm of menopause, there is a whole psychosocial construct that classifies what remains a physiological condition within major risk factors, just as for the most serious chronic diseases. 4) Indeed, menopause cannot be considered as a well-characterized disease, and hormone replacement therapy is undeniably a complex therapeutic intervention that requires proper prescription and careful evaluation of the benefit:risk ratio. 5) While such a treatment is now considered as the gold standard for the prevention of post-menopausal osteoporosis, this does not hold true regarding cardiovascular diseases. 6) Although hormone replacement therapy may lead to the relief of various symptoms associated with menopause, it may also result in side-effects that extreme medication cannot prevent, especially since some of them are not fully known, particularly in the case of either long-term or very long-term treatments. FUTURE PROSPECTS AND PROJECTS: A more rigorous evaluation of side-effects of hormone replacement therapy in the framework of long-term controlled trials is therefore clearly required. The indications of such a treatment should only rely on objective data and not on questionable studies or impressions at clinical examination.

Determinants of low-risk and high-risk cervical human papillomavirus infections in Montreal University students.

BACKGROUND: Previous studies have been inconsistent about the degree of sexual transmissibility of cervical human papillomavirus (HPV) infection. The authors hypothesize that risk factors for HPV infection vary according to HPV type. GOAL: To estimate the prevalence of HPV infection in asymptomatic women and to identify risk factors for overall HPV infection and HPV infection by oncogenic and nononcogenic type. STUDY DESIGN: A cross-sectional survey was conducted at the McGill University clinic in Montreal. Cervical specimens were collected from 489 female students presenting at the clinic for a routine Papanicolaou test. Data on potential risk factors was obtained by questionnaire. Human papillomavirus DNA was detected by the polymerase chain reaction using consensus primers (MY09/11) followed by hybridization with generic and type-specific probes using Southern blot and dot blot techniques. RESULTS: The overall HPV prevalence was 21.8%. A low-risk HPV infection was found in 6.2% of the women, 11.8% had a high-risk HPV infection (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58), 7.1% had an unknown HPV type, and 2.7% had a multiple type infection. Two profiles emerged for sexual activity and risk of HPV infection according to oncogenic risk after multivariate analysis. Lifetime frequency of sexual intercourse and lifetime number of oral sex partners was associated with high-oncogenic-risk HPV infections; however, HPV infection with low-oncogenic-risk types was invariant with respect to markers of sexual activity. CONCLUSION: These results suggest that there are differences in epidemiologic correlates of transmission between low-risk and high-oncogenic-risk HPV types based on oncogenicity. This finding has important implications for primary prevention of HPV infection and cervical cancer precursors.

Comparison between exercise whole body thallium imaging and ankle-brachial index in the detection of peripheral arterial disease.

BACKGROUND: Exercise whole body thallium imaging and rest/exercise ankle-brachial index can provide evidence of peripheral artery disease at the stage of intermittent claudication. The aim of this study was to compare both methods in the detection of asymptomatic peripheral artery disease. EXPERIMENTAL DESIGN: prospective non-randomised study. SETTING AND PATIENTS: general community, private practice, ambulatory patients referred in a Nuclear Medicine Department for exercise myocardial scintigraphy. Intermittent claudication was present in 8% of the whole study population. Coronary artery disease and diabetes were respectively present in 70% and 16% of the same population. MEASURES: rest/exercise ankle-brachial index and exercise whole body thallium imaging were measured in 105 patients (76 men and 29 women, mean age +/- 1 SD= 61 +/- 10 year) who performed a near-maximal or maximal treadmill test. Normal values of regional blood supply and indices of asymmetry at different levels of legs were determined in 14 patients with a very low probability of peripheral artery disease. RESULTS: The probability of peripheral artery disease was very high in 19 patients (group 1), because of abnormal rest and/or exercise ankle-brachial index, whereas in the 86 remaining patients, the index at rest and exercise was quite normal (group 2).With respect to rest and/or exercise ankle-brachial index, the sensitivity, specificity, positive and predictive negative value of exercise scintigraphy abnormalities were respectively 89%, 62%, 34% and 96%. The false positive scan group differed from the true positive group only by sex and redistribution of thallium 201. The proportion of diabetic patients was the same (15%) in both groups. CONCLUSIONS: Exercise whole body thallium imaging might contribute without additional cost to the detection, functional evaluation and/or risk stratification of peripheral artery disease in patients who perform exercise myocardial scintigraphy.

Characterization of amino acid substitutions that severely alter the DNA repair functions of Escherichia coli endonuclease IV.

Escherichia coli endo IV is a bifunctional DNA repair protein, i.e., possessing both apurinic/apyrimidinic (AP) endonuclease and 3'-diesterase activities. The former activity cleaves AP sites, whereas the latter one removes a variety of 3'-blocking groups present at single-strand breaks in damaged DNA. However, the precise reaction mechanism by which endo IV cleaves DNA lesions is unknown. To probe this mechanism, we have identified eight amino acid substitutions that alter endo IV function in vivo. Seven of these mutant proteins are variably expressed in E. coli and, when purified, show a 10-60-fold reduction in both AP endonuclease and 3'-diesterase activities. The most severe defect was observed with the one remaining mutant (E145G) that showed normal protein expression. This mutant has lost the ability to bind double-stranded DNA and showed a dramatic 150-fold reduction in enzymatic activities. We conclude that the AP endonuclease and the 3'-diesterase activities of endo IV are associated with a single active site, that is perhaps remote from the DNA binding domain.

Effect of oral probenecid coadministration on the chronic toxicity and pharmacokinetics of intravenous cidofovir in cynomolgus monkeys.

In animals and humans, intravenous administration of the antiviral nucleotide analogue cidofovir results in a dose-limiting nephrotoxicity characterized by damage to the proximal tubular epithelial cells. Probenecid, a competitive inhibitor of organic anion transport in the proximal tubular epithelial cells, was evaluated for its effect on the chronic toxicity and pharmacokinetics of cidofovir. Cynomolgus monkeys (5/sex/group) received cidofovir for 52 consecutive weeks as a once weekly intravenous bolus injection at 0 (saline), 0.1, 0.5, or 2.5 mg/kg/dose alone or at 2.5 mg/kg/dose in combination with probenecid (30 mg/kg/dose via oral gavage 1 h prior to cidofovir administration). Cidofovir-associated histopathological changes were seen only in the kidneys, testes, and epididymides. Nephrotoxicity (mild to moderate cortical tubular epithelial cell karyomegaly, tubular dilation, basement membrane thickening) was present only in monkeys receiving 2.5 mg/kg/dose cidofovir without probenecid. The incidence and severity of testicular (hypo- and aspermatogenesis) and epididymal (severe oligo- and aspermia) changes were increased in monkeys administered cidofovir at 2.5 mg/kg/dose, either alone or in combination with oral probenecid. Renal drug clearance was decreased between Weeks 1 and 52 in the 2.5 mg/kg/dose groups and resulted in an increased systemic exposure to cidofovir (as measured by AUC) that was significantly greater in monkeys administered cidofovir alone (312% increase in males, 98% in females) than in those coadministered probenecid (32% increase in males, 3% in females). These results demonstrate that oral probenecid coadministration protects against the morphological evidence of nephrotoxicity and the accompanying decrease in renal clearance in monkeys receiving chronic intravenous cidofovir treatment.

Whole-body exercise thallium imaging in smokers.

Whole-body exercise thallium imaging (WBEI) can show abnormalities of leg muscle perfusion in patients with symptomatic peripheral artery disease (PAD). This study compared the exercise distribution of thallium-201 at different levels of the legs in asymptomatic smokers and non-smokers who performed a maximal graded treadmill test. A group of 74 smokers (more than 20 pack-years) with (n = 51) or without coronary artery disease (CAD) (n = 23) were included in group 1 and 64 non-smokers with a low probability of PAD and CAD in group 2. Patients in group 1 were older than the patients in group 2 (58 +/- 9 versus 48 +/- 12 years, p < 0.0001). Indexes of asymmetry were significantly higher in group 1, at each level of the legs, both in anterior and posterior views (0.001 < p < 0.05), except at thigh level in anterior view. Fractional uptake indexes of thallium-201 were significantly lower in group 1 than in group 2 at calf level (p = 0.0001 in anterior and posterior views) and buttocks (p = 0.006 and p = 0.009 in anterior view only). Interextremity asymmetry was four to six times more frequent at calf level in smokers than in non-smokers. These WBEI abnormalities in smokers are highly suggestive of silent PAD or at least decreased vascular reactivity in clinically uninvolved vessels.

Neoplastic and nonneoplastic hepatic changes in lake whitefish (Coregonus clupeaformis) from the St. Lawrence River, Quebec, Canada.

As part of a survey of fish diseases, lake whitefish (Coregonus clupeaformis) were collected in fall 1995 from the St. Lawrence River 15 km upstream of Quebec City, Quebec, Canada, to assess the prevalence of liver lesions. A total of 141 fish were captured and necropsied, and three standard sections of liver were taken for histological examination. Prevalences of altered hepatocyte foci, hepatocellular carcinoma, cholangioma, and cholangiocarcinoma were 0.7%, 2.1%, 0.7%, and 2.1%, respectively. Thus, the overall prevalence of liver neoplasia was 4.9% (7/141). Hepatic tumors were only observed in fish 7 years old or older. Fish age was significantly and positively correlated with the index assessing the number and size of macrophage aggregates (p<0.001; rs = 0.16). Hepatocyte vacuolation, anisokaryosis, lymphocytic infiltration, and bile duct hyperplasia were also observed but were not related to the age, length, sex, or condition factor of the fish. These results represent the first report on a series of hepatic tumors in a wild salmonid species.

Predicting who will choose a family medicine residency.

PURPOSE: To create and evaluate a screening instrument and a revised interview format for use in the selection of family medicine residents at the McGill University Faculty of Medicine. METHOD: The screening tool consisted of two sections an assessment of academic performance (the TASS) and an evaluation of applicants' generalist versus specialist orientation (the GSSS); each applicant's file was assessed by two raters. The revised interview included specific questions and scenarios related to family medicine. All three parts were tested on 143 applicants from outside the region of Quebec in 1994-95. The results on both parts of the screening tool and the interview were compared with the students' first choices of residency and then were compared with the performances of the 24 accepted into the program as reflected in their first six-month summative evaluation forms. Data were analyzed through several statistical methods. RESULTS: Only the GSSS accurately predicted the applicants' first choices (for agreement between both raters: sensitivity, 81%; specificity, 70%; accuracy, 78%). No significant association was found when comparing matching applicants' scores obtained during the selection process with their scores on the six-month evaluation forms. CONCLUSION: The GSSS may prove useful as a tool in the review of applicants' files. More studies are needed to reevaluate the use of the interview in the selection process and to help determine whether any selection instrument can accurately predict applicants' subsequent performances in a residency.

Inhalation toxicity of aerosolized pentamidine isethionate in rats and dogs.

The toxicity of inhaled aerosolized pentamidine isethionate solutions in rats and dogs was evaluated. Nose-only exposure equipment and a mass mean aerodynamic particle size of < or = 2 microns were employed. Rats received either a single inhaled dose estimated at 0, 1.4, 2.1, or 6.0 mg/kg/exposure day or 4 inhaled doses evenly spaced over 13 weeks estimated at 0, 0.35, 0.7, or 1.4 mg/kg/exposure day. Dogs were administered a single inhaled dose estimated at 0, 1.1, 3.4, or 5.0 mg/kg/exposure day. Rats administered a single inhaled dose of 6.0 mg/kg/exposure day exhibited respiratory distress. The lung-with-trachea weights of these animals were elevated relative to controls. The histopathology of acutely exposed rats consisted of dose-related neutrophil infiltration in the turbinates, larynx, and bronchi; erosion of epithelium in the turbinates and larynx; thickening of the alveoli walls with alveolar accumulation of mononuclear cells and neutrophils; and rhinitis. Rats in the highest dose group in the subchronic evaluation exhibited decreased body weight gains and reduced lung-with-trachea-to-body weight ratios relative to controls. Hematology, clinical chemistry, and urinalysis values were within normal ranges. Microscopic pulmonary tissue changes were similar to those found in acute exposure with certain lesions (e.g., mucous cell hyperplasia) suggestive of a more chronic process. In addition, lung fibrosis was seen at the highest dose. In dogs, pentamidine isethionate did not cause a change in the respiratory minute volume (not measured in rats). Elevated lung-with-trachea weights were noted in the high- dose females. Hematology, clinical chemistry, and urinalysis values were within normal ranges.(ABSTRACT TRUNCATED AT 250 WORDS)

Whole-body thallium imaging in coronary artery disease.

The aim of this study was to evaluate the incidence, type, and severity of asymptomatic leg perfusion abnormalities in 116 male patients with proven coronary artery disease (CAD) who performed near-maximal treadmill test. Interextremity asymmetry was observed in 60% of patients, but the incidence of this sign increased with age (from 35% below forty-five years of age to 72% over sixty-one years). Asymmetry was very marked or marked in 61% of all segments and moderate in 39% of them. A significant decrease in fractional uptake was observed in 21% of patients with CAD and in 25% of those with interextremity asymmetry. Myocardial ischemia, which was defined by reversible defects on myocardial tomoscintigraphy, was three times more frequent in patients with interextremity asymmetry than in patients with normal results from exercise whole-body thallium scintigraphy. This observation, combined with type, extent, and location of asymmetry, is highly suggestive of silent peripheral arterial disease in most cases. Whole-body scan could easily be performed following an exercise myocardial thallium scan so as to provide information on multifocal atherosclerosis in patients with CAD or multiple and severe vascular risk factors. The prognostic value of these silent peripheral muscle perfusion abnormalities remains to be established.

[Preoperative localization of parathyroid adenoma with technetium and thallium double-labeling scintigraphy. Difficulties related to associated thyroid lesions]. / Localisation préopératoire des adénomes parathyroïdiens par la scintigraphie en double marquage, technétium et thallium. Difficulties liées aux lésions thyroïdiennes associées.

Technetium and thallium double-labeling scintigraphy with image subtraction was carried out on 63 patients suspected of having primary hyperparathyroidism, with or without thyroid involvement. Forty-four patients had a normal thyroid image with technetium. The positive foci located by double-labeling in patients who were to undergo surgery always coincided with parathyroid adenoma. In the 16 cases where the initial diagnosis of hyperparathyroidism was not substantiated, the double-labeling test was normal. Thus for these 44 patients, scintigraphy sensitivity was 75% and specificity was 100%. Nineteen patients had an abnormal thyroid image with technetium. In 7 cases, image subtraction following double-labeling yielded uninterpretable data. In 12 other patients, the positive foci located outside the thyroid by double-labeling coincided with a parathyroid adenoma, whereas this was true for only one patient whose positive foci were located inside the thyroid; a parathyroid adenoma was not detected preoperatively in 4 patients. This double-labeling test is thus useful in locating parathyroid adenomas when technetium scintigraphy of the thyroid is normal; when it is abnormal, double-labeling is advantageous only in cases of extra-thyroid foci.

[Study of dilated cardiomyopathies using gallium 67 myocardial scintigraphy]. / Exploration des myocardiopathies dilatées par la scintigraphie myocardique au gallium 67.

Twenty-seven patients were diagnosed as having dilated cardiomyopathies, based on increases in the cardiothoracic index greater than 0.50, in the diastolic and systolic diameters of the left ventricle, and in the telediastolic volume of the left ventricle, which was indexed by body surface determined by contrast ventriculography. They underwent gallium 67 scintigraphic examination of the myocardium, in order to non-invasively detect the presence of an inflammatory infiltrate. Fifteen of them also had endomyocardial biopsies and all had virology check-up. The results were disappointing. Only in one case was the scintigraphic image undeniably positive; in 20 other patients the findings were dubious or negative. This technique did not demonstrate the presence of an inflammatory infiltrate and thus we could not establish an association between myocarditis and dilated cardiomyopathy.