The feasibility of fertility preservation in adolescents with Klinefelter syndrome.

STUDY QUESTION: Is fertility preservation feasible after the onset of puberty in adolescents with Klinefelter syndrome (KS)? SUMMARY ANSWER: Fertility preservation counseling should be an integral part of the care of XXY adolescents. Frozen ejaculated or testicular spermatozoa and even frozen immature germ cells can give them the potential to conceive their genetic progeny. However, no biological or clinical parameters were predictive of mature or immature germ cell retrieval. WHAT IS KNOWN ALREADY: KS is the commonest sex chromosome disorder observed in azoospermic infertile males. Testicular sperm extraction success decreases with age and after testosterone therapy. Arguably, spermatozoa should be retrieved from KS males at the onset of puberty and before testosterone therapy to increase the chance of success. STUDY DESIGN, SIZE, DURATION: A retrospective study was performed in eight KS adolescents, aged between 15 and 17 years, who were referred for counseling about their future fertility to the center CECOS (Centre d'Etude et de Conservation des Oeufs et du Sperme humain) at Rouen University Hospital between October 2008 and December 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: The patients were first seen with their parents and then separately. It was proposed to them that they should provide a semen sample, if this was azoospermic, two other semen samples spaced by 3 months were collected. If azoospermia was confirmed, a bilateral testicular biopsy was proposed for sperm retrieval and testicular tissue preservation. Each adolescent met the psychologist before undergoing testicular biopsy. Paraffin-embedded testicular tissue was evaluated after staining with hematoxylin-eosin and saffron and immunostaining using vimentin, anti-Müllerian hormone, androgen receptor and MAGE-A4 antibodies. Sertoli cell maturity, germ cell identification and lamina propria alteration were assessed on seminiferous tubules. MAIN RESULTS AND THE ROLE OF CHANCE: KS adolescents were not deeply concerned about their future fertility and only became involved in the process of fertility preservation after at least three medical consultations. The parents agreed immediately that fertility preservation should be attempted. Seven non-mosaic XXY adolescents presented with azoospermia and one XXY/XY adolescent had oligozoospermia. Increased plasma levels of FSH and LH as well as bilateral testicular hypotrophy were observed in all patients. The XXY/XY adolescent banked four semen samples before testosterone replacement therapy. Two patients refused testicular biopsy. Five patients accepted a bilateral testicular biopsy. Spermatozoa were retrieved in one patient, elongated spermatids and spermatocytes I in a second patient. LIMITATIONS, REASONS FOR CAUTION: The number of patients enrolled in our study was low because the diagnosis of KS is only rarely made before or at the onset of puberty. Most XXY males are diagnosed in adulthood within the context of male infertility. WIDER IMPLICATIONS OF THE FINDINGS: Spermatozoa can be retrieved in semen sample and in testicular tissue of adolescent Klinefelter patients. Furthermore, the testis may also harbor spermatogonia and incompletely differentiated germ cells. However, the physician should discuss with the patient and his parents over a period of several months before collecting a semen sample and performing bilateral testicular biopsy. Fertility preservation might best be proposed to adolescent Klinefelter patients just after the onset of puberty when it is possible to collect a semen sample and when the patient is able to consider alternative options to achieve fatherhood and also to accept the failure of spermatozoa or immature germ cell retrieval.

[Prognosis factors in donor semen insemination: a 10-years follow-up study of 188 patients]. / Facteurs pronostiques en insémination avec sperme de donneur : suivi rétrospectif d'une cohorte de 188 patientes.

OBJECTIVES: Improving our practice by a constant evaluation is essential in the field of donor semen insemination (DI). Our center examined the prognosis factors for DI success in order to standardize patient treatment options. PATIENTS AND METHODS: We retrospectively analysed all couples referred for DI from January 2000 till December 2010. RESULTS: We analysed 551 cycles among 188 patients. Pregnancy rate by stimulation cycle was 19,8% with birth rate of 16.7%. The rate of pregnancy was improved till the fourth trial then plateau. On a patient-based analysis, success factors were age (P=0.04), previous successful DSI (P=0.02), and no previous failure of an ICSI-C (P=0.035). On a cycle-based analysis, success factors were the number of follicles greater than 15mm (P=0.04) and than 18mm (P=0.001). The percentage of 68.1 patients obtained a child by IVF-D after a failed DI. CONCLUSION: There are two predictive factors for DI success: the age of the patient and the number of mature follicles. It seems accurate to referred patients to IVF-D after four unsuccessful cycles of DSI. This recommendation may be adapted according to patient's age and hormonal evaluation.

Modification of chromosomal architecture in human spermatozoa with large vacuoles.

Human normal spermatozoa present a specific chromatin organization, illustrated particularly by the non-random chromosome positioning. Spermatozoa with large vacuoles, described using motile sperm organelle morphology organization (MSOME), are associated with nuclear alterations, such as abnormal chromatin condensation and aneuploidy. To question a probable association between large nuclear vacuoles and chromatin disorganization, we evaluated chromosomes X, Y and 18 topography in normal spermatozoa (NS) compared with spermatozoa with large vacuoles (SLV). After centrifugation on a gradient density system, 229 NS (spermatozoa presenting a normal nuclear shape and a vacuole area <6.5% of head area) from 10 normal semen samples and 221 SLV (spermatozoa presenting a vacuole area >13% of head area) from 10 semen samples with teratozoospermia were selected using MSOME. A three-colour FISH was carried out using α-satellite centromeric probes for chromosomes X, Y and 18. For each chromosome, longitudinal and spatial positioning of centromeres was analysed. Distribution of each chromosome was non-random in NS and in SLV, whatever the methodology used. Using longitudinal positioning, distribution of chromosome 18 and chromosome Y centromeres did not differ significantly between SLV and NS. On the contrary, chromosome X centromeres were more frequently positioned in the posterior region of sperm nucleus in SLV (p = 0.01). Considering spatial positioning, distributions differed significantly between SN and SLV for chromosome Y (p = 0.02) and chromosome 18 (p < 10(-4) ) and marginally for chromosome X (p = 0.08). Our study concluded to a modification in chromosomes X, Y and 18 centromere topography between NS and SLV, representing a novel and supplementary evidence to argue chromatin disorganization in SLV.

[ICSI treatment in severe asthenozoospermia]. / Asthénozoospermie sévère à vitalité normale et ICSI.

In the management of asthenozoospermia, the spermogram-spermocytogram plays an important role during diagnosis. It is of major importance to distinguish between necrozoospermia and sperm vitality. An ultrastructural study of spermatozoa is processed in the case of primary infertility without female implication, severe, unexplained and irreversible asthenozoospermia, sperm vitality at least 50 % and normal concentration of spermatozoa. Ultrastructural flagellar abnormalities are numerous and involve most spermatozoa. ICSI provides a suitable solution for patients with sperm flagellar defects to conceive children with their own gametes but the rate of ICSI success may be influenced by the type of flagellar abnormality. Some fertilization and birth rate failures which are related to some flagellar abnormalities might occur.

[Male gamete spermatozoon or spermatid?]. / Gamète mâle un spermatozoïde ou une spermatide?

Normal spermatogenesis results from a balance between process of cell proliferation, cell differentiation and apoptosis that concern somatic cells and germ cells. Dysfunction of spermatogenesis may be the result of constitutional or acquired abnormalities of spermatogonia stem cells or somatic cells. To overcome these problems, it seems necessary to implement preventive measures for germ stem cell preservation or substitute measures to replace them, the objective being to replicate in vivo or in vitro the process of spermatozoa production. This article will discuss the different experimental strategies for considering the in vivo or in vitro production of spermatozoa, outside the physiological process.

[Assisted reproductive technologies with sperm donation]. / Assistance médicale à la procréation avec don de spermatozoïdes.

INTRODUCTION: The purpose of this review is to relate to the operating rules of CECOS in France and the legal, medical and ethical issues raised by sperm donation. MATERIAL AND METHODS: Review of articles and consensus conferences on this subject published in Medline (PubMed) selected from 1973 and 2011 according to their relevance and Acts recorded on official legislative French websites. RESULTS: The operating rules of CECOS were established by the Act of July 29, 2004, revised 6 August 2004 and July 7, 2011. Of the 21,759 children born of ART in France in 2009, 5.1% are from a sperm donation. From 1973 to 2006, 44,045 children are born after a sperm donation. Between 1973 and 2006, 16,971 donors are presented in the CECOS and only 10,347 donors have completely made their donation process. The main indication for use of donor sperm (75% of applications) is represented by men of infertile couples with nonobstructive azoospermia, the second indication is infertile men with oligospermia. In azoospermia, the application is usually performed after failure of testicular or epididymal surgical specimen. In oligozoospermia, claims made most often after several failures of intraconjugal ART. CONCLUSION: Many questions are still present around the conception of children by sperm donation. The legitimacy of maintaining anonymity in the gift remains widely debated.

Relationship between conventional sperm parameters and motile sperm organelle morphology examination (MSOME).

With the motile sperm organelle morphology examination (MSOME), spermatozoa morphology may be assessed directly on motile spermatozoa at high magnification (up to 6600×). This procedure describes more precisely spermatozoa abnormalities, especially head vacuoles. However, no consensus has been established concerning normal or abnormal MSOME criteria. The aim of our study was to define MSOME vacuole criteria assessed objectively with a digital imaging system software to establish a potential relationship between conventional semen parameters. A total of 440 semen samples were obtained from males consulting in Rouen University Hospital Reproductive Biology Laboratory. Conventional semen analysis (volume, sperm concentration, progressive motility, vitality and morphology) and MSOME assessment {sperm head length, width and area as well as vacuole number, vacuole area and relative vacuole area to sperm head [RVA (%) = [vacuole area (µm(2))/head area (µm(2))] × 100)]} were performed for each semen sample. Among our 440 males, 109 presented normal conventional semen parameters and 331 abnormal ones. Sperm head vacuoles were significantly larger in abnormal semen samples (p < 0.0001). RVA was the most discriminative MSOME criterion between normal and abnormal semen samples according to ROC curves analysis, and was negatively correlated with poor sperm morphology (r = -0.53, p < 0.0001). We concluded to (i) the normal occurrence of vacuoles in sperm head whatever the normality or abnormality of semen parameters, (ii) the discriminative function of the RVA to distinguish semen samples with normal and abnormal parameters, and (iii) the strong correlation between high RVA and poor sperm morphology.

Assessment of freezing procedures for rat immature testicular tissue.

Fertility preservation has been included in the management of childhood cancer treatment. Cryopreservation of immature testicular tissue is the only available solution for pre-pubertal boys. Different freezing protocols have been developed in several species but without a clearly identified procedure. We tried to evaluate several protocols for cryopreservation of rat immature testicular tissue. Twelve different freezing protocols using different (i) cryoprotectant (dimethylsulphoxide [DMSO] or 1,2-propanediol [PROH]), (ii) cryoprotectant concentration (1.5M or 3M), (iii) equilibration time (30 or 60 min), (iv) equilibration temperature (4 °C or room temperature), (v) size of testicular fragment (7.5mg or 15 mg), (vi) package (straws or cryovials), were compared using cord morphological damage evaluation. A testicular tissue piece of 7.5mg cryopreserved in cryovial using 1.5M DMSO, an equilibration time of 30 min at 4 °C showed fewer morphological alterations than the other protocols tested. The selected freezing protocol was able to maintain rat immature testicular tissue architecture, functionality after testicular pieces organotypic culture, and could be proposed in a human application.

[Conventional in vitro fertilization and intracytoplasmic sperm injection in sibling oocytes following intrauterine inseminations failure]. / Fécondation in vitro mixte après échecs d'inséminations intra-utérines intraconjugales. Étude de cohorte au CHU de Rouen.

OBJECTIVES: To evaluate the results of the initial in vitro fertilization (IVF) procedure after intrauterine insemination (IUI) failure where half of the oocytes were inseminated as for conventional IVF and half of the oocytes where treated for intra cytoplasmic sperm injection (ICSI). PATIENTS AND METHODS: From the first of January 2001 to the 31st of December 2008, 75 couples failing to conceive with ovarian stimulation and IUI were included in this retrospective study. RESULTS: Among the 75 couples, 53 had IVF and ICSI in sibling oocytes and 22 had just ICSI because of an insufficient oocyte cohort. No significant difference was observed in fertilization, implantation and pregnancy rates between the different groups; however, a total fertilization failure was observed more frequently when conventional IVF was used compared to ICSI (11.3% vs 3.8%). These patients with fertilization failure on conventional IVF had a lower sperm count than those who obtained embryos but sperm parameters were normal according to World Health Organisation (WHO) criteria and our study did not find any predictive factor of fertilization failure. DISCUSSION AND CONCLUSION: Couples failing to conceive after controlled ovarian hyperstimulation and IUI may be proposed a mixed in vitro fertilization procedure (with conventional IVF and ICSI) in order to avoid a total fertilization failure. Moreover, this procedure will indicate the better IVF technology (conventional or ICSI) for the subsequent attempt.

Assessment of acrosome and nuclear abnormalities in human spermatozoa with large vacuoles.

BACKGROUND: Spermatozoa with large vacuoles (SLV) may have a negative impact on embryo development. The origin of these vacuoles is unknown. We evaluated acrosome and nucleus alterations in isolated SLV, versus unselected spermatozoa. METHODS: We studied 20 patients with teratozoospermia. Spermatozoa from the native semen sample and spermatozoa presenting a vacuole occupying >13.0% total head area, isolated under high magnification (×6600), were assessed. Confocal and transmission electron microscope evaluations were performed on SLV and native sperm, respectively. Acrosome morphology and DNA fragmentation were analysed using proacrosin immunolabelling (monoclonal antibody 4D4) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling assay. Chromatin condensation was evaluated with aniline blue staining. Sperm aneuploidy was assessed using fluorescence in situ hybridization. RESULTS: SLV represented 38.0 ± 5.10% of motile spermatozoa obtained after gradient density centrifugation. Vacuoles were mainly in the anterior and median sperm head (45.7 ± 2.90 and 46.1 ± 3.00%, respectively). Abnormal acrosomes were increased in SLV compared with unselected spermatozoa (77.8 ± 2.49 versus 70.6 ± 2.62%; P = 0.014). Microscopic observations showed an exclusively nuclear localization of large vacuoles. Complete DNA fragmentation was higher in native spermatozoa (P < 0.0001) than SLV, while chromatin condensation was altered in SLV (P < 0.0001). Aneuploidy and diploidy rates were increased in SLV (P < 0.0001). CONCLUSIONS: Sperm vacuoles were exclusively nuclear. In our selected teratozoospermic population, aneuploidy and chromatin condensation defects were the main alterations observed in SLV. Based on results from this small sample of spermatozoa, we propose a global impairment of the spermatogenesis process as a common origin of the morphological alterations.

[How do we reduce the under-reporting of occupational primary lung cancer]. / Sous-déclaration des cancers bronchiques professionnels.

UNLABELLED: The under-reporting of occupational lung cancer is due to insufficient recognition of occupational exposure and inadequate medico-legal action. MATERIALS AND METHODS: All cases of primary bronchial carcinoma seen at the University Hospital of Grenoble between October 1996 and December 1998 completed a standardised questionnaire set by a physician in occupational medicine. When evidence of exposure to occupational carcinogens was established a claim for occupational disease was made and the outcomes of these claims were obtained from the Department of Social Security at the end of 2000. RESULTS: Asbestos was the most common carcinogenic agent found, followed by crystalline silica, diesel fumes, metals, paints and ionising radiation. Among the 305 patients in the study with primary bronchial carcinoma 20% were able to make a claim for occupational disease whereas only 2% would have claimed otherwise. The Department of Social Security accepted 77% of the 39 claims for occupational disease submitted, thus giving a 12% incidence of occupational bronchial carcinoma in this group. CONCLUSION: It is important to inform and instruct doctors of the environmental risks that are additional to those of tobacco smoking and of the need of inquire into any exposure to carcinogenic agents in order to ensure that the victims receive the appropriate medico-legal benefits. Improved primary prevention alone might eventually avoid the development of up to 3 500 cases of occupation bronchial carcinoma per year in France.

Lung cancer mortality in a site producing hard metals.

OBJECTIVES: To study the mortality from lung cancer from exposures to hard metal dust at an industrial site producing hard metals--pseudoalloys of cobalt and tungsten carbide--and other metallurgical products many of which contain cobalt. METHODS: A historical cohort was set up of all subjects who had worked for at least 3 months on the site since its opening date in the late 1940s. A full job history could be obtained for 95% of the subjects. The cohort was followed up from January 1968 to December 1992. The exposure was assessed by an industry specific job exposure matrix (JEM) characterising exposure to hard metal dust from 1 to 9 and other possibly carcinogenic exposures as present or absent. Smoking information was obtained by interview of former workers. Standard lifetable methods and Poisson regression were used for the statistical analysis of the data. RESULTS: Mortality from all causes was close to the expected (standardised mortality ratio (SMR) 1.02, 399 deaths) whereas mortality from lung cancer was significantly increased among men (SMR 1.70; 46 deaths, 95% confidence interval (95% CI) 1.24 to 2.26). By workshop, lung cancer mortality was significantly higher than expected in hard metal production before sintering (SMR 2.42; nine deaths; 95%CI 1.10 to 4.59) and among maintenance workers (SMR 2.56; 11 deaths; 95%CI 1.28 to 4.59), whereas after sintering the SMR was lower (SMR 1.28; five deaths; 95%CI 0.41 to 2.98). The SMR for all exposures to hard metal dust at a level >1 in the JEM was in significant excess (SMR 2.02; 26 deaths; 95%CI 1.32 to 2.96). The risks increased with exposure scores, duration of exposure, and cumulative dose reaching significance for duration of exposure to hard metal dust before sintering, after adjustment for smoking and known or suspected carcinogens. CONCLUSION: Excess mortality from lung cancer was found among hard metal production workers which cannot be attributed to smoking alone. This excess occurred mostly in subjects exposed to unsintered hard metal dust.

[Relationships between air conditioning, airborne microorganisms and health]. / Etude des relations entre climatisation, micro-organismes aéroportés et santé.

Concurrently with the increase of air-conditioning, potentially severe or frequent new diseases have emerged, giving rise to social and economical consequences. The first part of this work is a state of the art review of the relationships between air-conditioning, airborne microorganisms and health, through a technical, metrological and medical approach. The second part presents four studies performed in this field. Two of them deal with the relationship between airborne microorganisms and technical features of air-conditioning. Measurements performed on actual sites demonstrated the benefit of using high efficiency filters and low risk components in air-conditioning systems. The third study was aimed to look for a relationship between airborne microorganisms and sick building syndrome symptoms. Statistical analyses of individual data revealed significant associations between airborne bacteria or fungi and symptoms. These results may be the first step in determining a dose-response relationship, in order to define threshold limit values in this field. In the fourth study, the contribution of particle counting in assessing exposure to airborne microorganisms was explored by monitoring simultaneous variations of microbial and particle concentrations. The results showed that associating particle counting may allow to detect microbial variations instantaneously, and therefore improve the assessment of exposure to airborne microorganisms.

[Exposure to asbestos: role of respiratory function tests as tools for screening and follow-up]. / Exposition à l'amiante: la place des épreuves fonctionnelles respiratoires comme outil de dépistage et de suivi.

Among pulmonary function tests, spirometries and flow-volume curves are used in occupational or environmental field. They require the compromise between simple and sufficiently performance to be useful. Limitation factors explain the low sensitivity and the absence of specificity related to asbestos (tobacco...). The wide interindividual variation compared to standards limits meaning for early detection. A significant epidemiological difference makes no sense for individual detection. The carbon monoxide diffusing capacity, even classical, has restricted uses. Unlike diffuse pleural thickening, the worst cases with circumscribed pleural plaques lead to limited lung capacity decline. If not, they are associated to pulmonary abnormalities or tobacco. The early asbestos-related parenchyma diseases are associated to restrictive ventilator disorders, small airway obstruction or isolated single breath carbon monoxide diffusing limitation, leading to great difficulties for specific early detection criteria validation. Comparative pulmonary changes over time greater than the physiological pulmonary slope should be a good alert indicator.

Lung cancer risk in hard-metal workers.

An industry-wide mortality study on the association between lung cancer and occupational exposure to cobalt and tungsten carbide was carried out in the French hard-metal industry. This case-control study was nested in the historical cohort of workers ever employed in this industry's 10 facilities, most of which are located in eastern France. Workers were followed up from 1968 to 1991. Occupational exposure was assessed using a job-exposure matrix that provided semiquantitative scores for 320 job periods. These scores were significantly correlated with the levels of cobalt measured in 744 historical air samples. In this cohort, which comprised 5,777 males and 1,682 females, the death rate from lung cancer was significant (63 deaths, standardized mortality ratio=1.30, 95% confidence interval (CI) 1.00-1.66) when compared with national death rates. Sixty-one cases and 180 controls were included in the study. When the exposures during the last 10 years were ignored, a twofold lung cancer risk was observed among workers simultaneously exposed to cobalt and tungsten carbide (odds ratio (OR)=1.93, 95% CI 1.03-3.62) adjusted for other cobalt exposure (OR=2.21, 95% CI 0.99-4.90). The odds ratios increased with cumulative exposure (first quartile, OR=1.00; second quartile, OR=2.64; third quartile, OR=2.59; fourth quartile, OR=4.13) and, to a lesser degree, with duration of exposure (one decade, OR=1.00; two decades, OR=1.61; three decades, OR=2.77; four decades, OR=2.03). Adjustments for smoking and for exposures to known or suspected carcinogens did not change the results, yet the odds ratio for smoking (3.38) was lower than expected, suggesting the possibility of some misclassification. Occupational risk was highest among smokers. This study supports the hypothesis that workers who manufacture hard metals have an increased mortality from lung cancer due to simultaneous exposure to cobalt and tungsten carbide.

[Development of a job-exposure matrix in the heavy-metal industry in France]. / Elaboration d'une matrice emplois-expositions dans l'industrie productrice de métaux durs en France.

A job exposure matrix (JEM) was developed by a committee of experts using the DELPHI method, in the French hard metal industry, in order to assess occupational exposures to cobalt along with tungsten carbide resulting from the industrial process. This JEM is part of a nested case-control study, carried out within the historical cohort of workers ever employed in these factories, aimed at assessing lung cancer risk. The committee included 8 experts: hygienists, chemical engineers, occupational physicians and epidemiologists. The JEM was developed in four stages: (i) visit of factories, (ii) definition of lines (job-periods) and columns (exposures) of the JEM, (iii) definition of coding procedures, (iv) coding the cells of the JEM. This last stage used a method derived from the DELPHI method. Throughout the study period 1945-1994. 320 job-periods and 21 agents were defined. A quantitative assignment (level 0 to level 9) along with a frequency code (1 to 3) was attempted for 4 agents, whereas only a qualitative assignment (non exposed/exposed, i.e. 0/l) was done for the other agents. An additional probability code (1 to 3) was assigned to all agents. This procedure led to 46 columns and 14,720 cells in the JEM. When applying the DELPHI method, the consensus of the committee was obtained for 85% of all cells after the first individual assignment of experts, 88% after the second individual assignment and 100% after the third assignment by the experts all together. In order to validate the JEM, these expert assignments will be brought together with the results of exposure measurements that were performed in some workplaces of these factories. The JEM will also be linked with the data base of the case-control study for the exposure assessment of cases and controls.

Urinary hexane diamine as an indicator of occupational exposure to hexamethylene diisocyanate.

The occupational exposure of 19 men to hexamethylene diisocyanate (HDI) vapour was monitored during one 8-h shift. It ranged from 0.30 to 97.7 micrograms/m3. This was compared with the urinary output of hexane diamine (HDA) liberated by acid hydrolysis from its conjugates in post-shift samples. The excretion varied from 1.36 to 27.7 micrograms g creatinine, and there was a linear association of HDI air concentration with urinary HDA excretion. The validity of the urinary analysis was confirmed by simultaneous blind analysis in another laboratory. The results had an excellent linear concordance. Thus, it seems that while the gas chromatographic-mass spectrometric detection method requires sophisticated apparatus, the results are very useful to occupational health practices. A biological exposure index limit of 19 micrograms HDA/g creatinine in a post-shift urine specimen is proposed as an occupational limit level of HDI monomer (time-weighted average = 75 micrograms/m3). Most importantly, biological monitoring of HDA is sensitive enough to be used at and below the current allowable exposure limit levels.

[Detection of alcoholism in the medical office: applicability of the CAGE questionnaire by the practicing physician. Group of Medical Practitioners PMU]. / Dépistage de l'alcoolisme en cabinet médical: applicabilité du questionnaire "CAGE" par le médecin praticien. Groupe des praticiens PMU.

INTRODUCTION: The general practitioner (GP) plays a very important role in early detection of alcoholism. Clinical evaluation is often the only method used, although it has been suggested that any systematic patient history should include the CAGE test. We compare the effectiveness of these two approaches and attempt to determine the applicability of the CAGE test in a general practitioner's usual practice. METHOD: 12 GPs took part in this study during 6 months. They looked for possible alcohol abuse in each new patient by a standard patient history and clinical examination. Patients were randomized into 2 groups, one of which was given the CAGE test and the other not. For each patient in the CAGE group the applicability of the test was quantified by the GP. RESULTS: 416 patients were included; 214 were randomized into the "CAGE group" and 202 into the control group. On a clinical basis, 15 patients in the control group and 16 in the "CAGE group" (14 men, 2 women) were suspected of alcohol abuse. The CAGE test was positive in 15 patients (7%); among these, 6 were not suspect on a clinical basis. In patients aged 18-34, the detection rate of alcohol-related problems more than doubled when the CAGE test was used. The age of the patients influenced performance of the CAGE test and clinical evaluation. Only 2% of women had a positive CAGE test. Administration of the CAGE test was considered easy in 112 patients and average to difficult in 50, while the test was inapplicable with 52 patients. The latter proportion was higher than that observed in institutions (hospitals, outpatient departments) of the same region. Applicability was influenced neither by the sex nor the age of the patients, but varied greatly according to the physician (from 38% to 100%). CONCLUSION: The CAGE test increases the number of patients detected with alcohol problems by 37% and seems to be especially useful when administered to young people. The number of women with alcohol problems is probably underestimated by both clinical evaluation and the CAGE test. Furthermore, physicians in private practice are more reluctant to use the CAGE test systematically than those in a public institution.

Biological monitoring of occupational exposure to toluene diisocyanate.

The study validated the use of urinary toluene diamine (TDA) in postshift samples as an indicator of preceding 8-h exposure to toluene diisocyanate (TDI). Nine workers exposed in TDI-based polyurethane foam production were studied. Their exposure levels varied in 8-h time-averaged samples from 9.5 to 94 micrograms/m3. The urinary TDA concentrations varied from 6.5 to 31.7 micrograms/g creatinine and they were linearly related to the atmospheric TDI levels. Approximately 20% of TDI is metabolized to diamines but their specificity is remarkable to the extent that by analysis for the 2,4- and 2,6-diamino isomers an idea of the percutaneous absorption may be had.