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The prevalence of radiation-induced nausea and vomiting varies between 40% and 80%. They have many consequences on treatment and comorbidities. This work thus aimed to define clinical practice guidelines for the management of radiation-induced nausea and vomiting.XXXXX, XXXX, XXX, XXXXX, XXXX and XXXX compiled a working group who draft these recommendations.The assessment of the emetogenic risk found two main predictive factors: 1) the irradiated anatomical location, 2) an associated concomitant chemotherapy. In the case of exclusive radiotherapy, primary antiemetic prophylaxis depends on the emetogenic risk (the irradiated anatomical location). In the case of concomitant chemotherapy, the emetogenic risk is generally higher and the primary antiemetic prophylaxis corresponds to that of chemotherapy-induced nausea and vomiting. In cases where symptoms persist, remedial treatments are poorly codified.Radiation-induced nausea and vomiting remains underdiagnosed and undertreated, its rapid detection and treatment are essential to reinstate good clinical practice.

The screening of patients who are at-risk drinkers, which means exceeding the thresholds defined by health authorities or associated with a specific situation (taking psychotropic drugs, having an organic pathology, driving a vehicle, drinking during pregnancy), represents a major issue in primary care. Few studies have offered perspective from the patients' standpoint. The main purpose of this study was to describe general practitioners at-risk drinking screening from their patients point of view. The secondary objective was to identify the factors associated with perception of satisfactory general practitioner knowledge about alcohol consumption.A quantitative cross-sectional study was launched in 9 general practitioner offices over 6 months. Patients older than 18 were recruited to answer a questionnaire blinded from their general practitioner, indicating the level of their alcohol consumption and their perception regarding their general practitioner's screening methods. Descriptive, univariate and multivariate logistic regression analyses were performed.All in all, 445 patients were analyzed. Sixty-two at-risk drinkers were screened (13.9 %). Most of the patients declared they had not been interviewed about their alcohol consumption by their general practitioner either during initial consultations (86.1 %) or over time (83.3 %). Only 4.2 % of patients had previously initiated discussion about their consumption. Patients were not ashamed to talk about alcohol (99.2 %) and found their general practitioner to be competent on this topic (100 %). In multivariate analysis, independent factors associated with a good general practitioner knowledge about their patients' current consumption were the questions put forward by their general practitioner about alcohol consumption during their first visit (P0.001) and during subsequent visits (P0.001).This study showed a low general practitioner screening rate of their patients' at-risk drinking. Only a minority of patients, including at-risk drinkers, declared that their general practitioner was aware of their level of alcohol consumption. Screening could be improved by being systematized during initial consultations and regularly scheduled during subsequent visits, especially in at-risk situations.

International audience; The health, environmental and socio-economic issues related to the massive use of plant protection products are a concern for all the stakeholders involved in the agricultural sector. These stakeholders, including farmers and territorial actors, have expressed a need for decision-support tools for the management of diffuse pollution related to plant protection practices and their impacts. To meet the needs expressed by the public authorities and the territorial actors for such decision-support tools, we have developed a technical-economic model “OptiPhy” for risk mitigation based on indicators of pesticide toxicity risk to applicator health (IRSA) and to the environment (IRTE), under the constraint of suitable economic outcomes. This technical-economic optimisation model is based on linear programming techniques and offers various scenarios to help the different actors in choosing plant protection products, depending on their different levels of constraints and aspirations. The health and environmental risk indicators can be broken down into sub-indicators so that management can be tailored to the context. This model for technical-economic optimisation and management of plant protection practices can analyse scenarios for the reduction of pesticide-related risks by proposing combinations of substitution PPPs, according to criteria of efficiency, economic performance and vulnerability of the natural environment. The results of the scenarios obtained on real ITKs in different cropping systems show that it is possible to reduce the PPP pressure (TFI) and reduce toxicity risks to applicator health (IRSA) and to the environment (IRTE) by up to approximately 50 %.

International audience; Diffuse phytosanitary pollution is a complex phenomenon to manage. Reducing this type of pollution is one of today’s key socio-economic and environmental challenges. At the regional level, few approaches enable the actors concerned to implement agricultural management strategies to reduce the use and impact of phytosanitary products. Our research problem focused on the consequences of intensive agriculture and, in particular, how to evaluate the impact of phytosanitary products on human health and the environment. In this article, we present the SimPhy simulation game which places the actors from a given region directly into a situation in which they manage farms whilst under pressure to reduce phytosanitaries (quantity and toxicity). The application focused on the Merja Zerga catchment area in Morocco. The region is dominated by intensive agriculture which is located upstream from a Ramsar-classified wetland area. The SimPhy simulation game is based on a decision support system-type tool. It allows us to anticipate the impact of regulations on farming systems. It also enables us to analyse the consequences of the actors’ strategies on farm economies, human health and the quality of ecosystems. Initial results from the SimPhy simulation game enabled the technicians from Agricultural Development Center (CDA) themselves to learn about managing agricultural production systems in a dynamic and interactive fashion. With the simulation game, it was possible to learn about the farmer's ability to adapt to new regulatory constraints, and the involved consequences for toxicity risks for human health and the environment.

The blood-brain barrier (BBB) is composed of tightly bound endothelial cells (ECs) and perivascular astrocytes that regulate central nervous system (CNS) homeostasis. We showed that astrocytes secrete Sonic hedgehog and that BBB ECs express Hedgehog (Hh) receptors, which together promote BBB formation and integrity during embryonic development and adulthood. Using pharmacological inhibition and genetic inactivation of the Hh signaling pathway in ECs, we also demonstrated a critical role of the Hh pathway in promoting the immune quiescence of BBB ECs by decreasing the expression of proinflammatory mediators and the adhesion and migration of leukocytes, in vivo and in vitro. Overall, the Hh pathway provides a barrier-promoting effect and an endogenous anti-inflammatory balance to CNS-directed immune attacks, as occurs in multiple sclerosis.

In order to heat the whole volume of a tumour by microwave interstitial hyperthermia it is necessary to use an antenna array. The antenna modelization and the numerical solution of the bidimensional bioheat transfer equation allow determination of temperature evolution during a heating session. The calculations are taken for four antennas fed in phase and the theory is then proven by experiments on gel and on patients. Results are presented on cross-section heating patterns and their time evolution. Temperature distribution is calculated when feeding one antenna by a feeding current out of phase with the other currents. The phase difference value is optimized and it is then demonstrated that the heated volume is increased by successively feeding each antenna with an out-of-phase current. The time taken to feed each antenna one after the other is optimized.

Microwave radiometry, used routinely since 1984 for non-invasive temperature measurements during hyperthermia sessions for superficial tumours treatment has proven its efficiency for temperature control. From radiometric temperature measurements in two frequency ranges (around 1 and 3 GHz) and superficial (or cutaneous) temperature measurements achieved during hyperthermia sessions, a numerical method to obtain the two-dimensional thermal profile has been developed and implemented. This method is based on hyperthermia simulation from the bioheat equation, the absorbed microwave power calculation in the medium taking into account the radiative diagram of the applicator, and the calculation of radiometric temperatures. From these experimental measurements (radiometric and superficial temperatures, heating power, dielectric and thermal characteristics), a program to determine the bidimensional distribution of temperature during the hyperthermia session has been developed, tested and used during and after clinical treatments.

Microwave interstitial hyperthermia now plays an increasing part in the various hyperthermia techniques used in cancer treatment. This paper will present the design, construction and theoretical as well as experimental study of miniature coaxial antennas designed to heat tumours of various volumes and sizes. Monitoring temperature using multifrequency radiometry during hyperthermia stems naturally from the very design of these antennas. Experiments on phantoms, animals and patients in phase I clinical assessment have demonstrated that microwave interstitial hyperthermia can be achieved with temperature control and monitoring by microwave radiometry.

The pattern of contralaterally and ipsilaterally projecting retinal ganglion cell (RGC) axons at the optic chiasm is essential for the establishment of binocular vision. Contralateral axons cross the chiasm midline as they progress from the optic nerve to the optic tract. In contrast, ipsilateral axons deviate from the chiasm and continue in the ipsilateral optic tract, avoiding the chiasm midline. The molecular mechanism underlying this phenomenon is not completely understood. Here we show that the Sonic Hedgehog (Shh) receptor Boc is enriched in ipsilateral RGCs of the developing retina. Together with the presence of Shh at the midline, this complementary expression pattern led us to hypothesize that Shh might repel ipsilateral RGC axons at the chiasm. Consistent with this hypothesis, we found that only Boc-positive RGC axons retractin vitroin response to Shh and that this response is lost in Boc mutant RGCs.In vivo, we show that Boc is required for the normal segregation of ipsilateral axons at the optic chiasm and, conversely, that Boc expression in contralateral RGCs prevents their axons from crossing the optic chiasm. Together, these results suggest that Shh repels ipsilateral RGC axons at the optic chiasm via its receptor Boc. This work identifies a novel molecular pathway required for the segregation of axons at the optic chiasm.

Health organizations worldwide have advocated that treatment records be required to show that antibiotics are used prudently by veterinarians and farmers alike. In 2000, the French government passed legislation making a farm register mandatory for all farms that raise animals for food production. The farm register is a comprehensive record designed to track all animal movements, treatments, and veterinary interventions on the farm. We conducted a survey to assess the knowledge, attitudes, and behaviors of dairy farmers toward the farm register, with particular emphasis on recording of antibiotic treatments. The 43 farmers interviewed belonged to veterinary health cooperatives. All farmers correctly named an antibiotic or antibiotic preparation, yet only 2 recognized the 5 components of the farm register. Farmer attitudes toward the register were globally positive, even though they named a wide variety of constraints. Nevertheless, 72% of farmers interviewed had a permanent health record, and approximately half had recorded either the last treatment (irrespective of drug class) or the last intramammary tube administered. Results were discussed in the light of health behavior change models that are applied in human medicine. We suggest that programs that seek compliance with the farm register should focus on educational interventions and bonus incentives.

The most frequent side-effects due to nevirapine (Viramune), the first non-nucleoside HIV reverse transcriptase inhibitor introduced for clinical use, are cutaneous hypersensitivity reactions. In non-serious cases, tolerance induction can be proposed.Describe the long-term safety and efficacy of tolerance induction to nevirapine.Six HIV-infected patients started a tolerance 1 to 2 months after an episode of nevirapine hypersensitivity. Increasing doses of nevirapine (2.5, 10, 25, 100, 250 and 750 microg and 2.5, 5, 10, 25, 50 and 100 mg) were given orally at half-hour intervals under strict medical surveillance and patients were followed up regularly.All but two of the patients tolerated this induction well. One had a mild and transient reaction on day 1; nevirapine was not stopped. One had a moderate to severe reaction one month later; nevirapine was stopped and he recovered fully. All other patients have been taking nevirapine for more than 3 months without any adverse reaction.Therefore, when no alternatives are available in severely ill and hypersensitive HIV-infected patients, tolerance induction is a possible therapeutic option.

Distomatosis is a parasite infection following ingestion of food contaminated by Fasciola hépatica, the tropism of which is essentially hepatic. The mechanism of this exceptional complication is discussed in two cases of pneumothorax.Two 35 and 60 year-old patients presenting spontaneous pneumothorax during distomatosis, the first revealing the disease, the second suggesting the evolution of a severe form of the disease. The surgical biopsy in the first patient revealed a granulomatous pleuro-pneumopathy rich in giant cells.Pulmonary manifestations of distomatosis are frequent during the invasive phase. Their immunoallergic origin can be questioned and emphasis should be placed on lesions secondary to aberrant parasite migrations.

Alterations of body fat distribution have been recently reported in HIV-infected patients. We aimed to investigate whether the hormones modulating adipose tissue metabolism could be implicated.We investigated twenty-eight HIV-infected patients who had developed abdominal fat, combined with peripheral lipodystrophy in 25 cases and 'buffalo hump' in 2 cases, but who had otherwise improved on antiretroviral therapies. Twelve patients with no change in body fat, matched for age, disease control and treatment, were studied as controls.Body composition was assessed by bioelectrical impedance analysis. Subcutaneous (SAT) and visceral (VAT) compartments of total abdominal adipose tissue (TAT) were measured by computed tomography. Resting metabolic rate (RMR) was assessed by indirect calorimetry. Endocrine investigations included plasma thyroid hormones, cortisol, testosterone, oestradiol and 24-hour urinary free cortisol (UFC) and catecholamines.Despite similar body mass index, the patients with body fat alterations showed significantly larger VAT and higher VAT:TAT ratio than controls (P = 0.002 and 0.0001, respectively). In these patients, RMR was significantly higher than estimated according to the Harris-Benedict formula (+ 19.7 +/- 11.6 %, P = 0.0001) and correlated with VAT (r = 0.58, P = 0.003) and 24-hour urinary output of catecholamines (r = 0.67, P = 0.002), that was significantly increased in comparison with controls (1737 +/- 1228 vs 476 +/- 292 nmol, P = 0.013). We also found a significant correlation between VAT and UFC (r = 0.41, P = 0.042) that was absent in controls, although levels of UFC were similar in the two groups.Our data suggest that body fat redistribution may involve cortisol and catecholamine actions. While high release of catecholamines may enhance RMR through increased lipolysis, cortisol may promote central fat storage. These effects might be related both to persistent hormonal responses to stress becoming inappropriate while disease control improved and to an increased sensitivity of visceral adipose tissue to cortisol in affected patients.

Does communication with terminal cancer patients about their disease influence their psychological well-being? The degree of patient-carer consensus about the disease was compared to psychological well-being related to acceptance of the disease, emotional state, and hope. These were evaluated and scored from 6 (good) to 0 (poor) through a semi-structured interview of 10 open-ended questions. Nineteen palliative care patients were studied, 18 of whom were suffering from advanced cancer. Overall, 57 interviews were conducted with the patients, staff nurses, and medical doctors. The answers of the carers (staff nurses and doctors) were compared to the patients' answers to determine the degree of consensus in terms of communication about disease, aim of treatment, and ultimate objective of hospitalization. The consensus between patients and carers was scored from 6 (satisfactory) to 0 (unsatisfactory). A significant positive correlation between the scores of consensus and those of psychological well-being (r = 0.90, p0.001) was found. These results suggest that good and truthful communication may improve patients' psychological well-being.

Nephrotoxicity of carboplatin is rare, especially in children with normal renal function. A 3-year-old boy had localized esthesioneuroblastoma and received 2 courses of carboplatin (200 mg/m2/day during a 1-hour infusion for 3 consecutive days) associated with etoposide (150 mg/m2/day after carboplatin). Because of a good tumor response, a second course was given 21 days later. Complete surgical excision and local irradiation were performed. However, the tumor recurred a few months later, and the patient subsequently died of the disease.Renal function initially was assessed by standard baseline chemistry and technetium-panetetic acid (Tc-DTPA) clearance. Follow-up included ionic controls and tubular exploration during the episodes of hyponatremia.Hyponatremia occurred 4 days after completion of the first course and resolved after intravenous supplementation. It recurred 20 days after the second course despite salt and magnesium prehydration and posthydration and resolved 17 days later. No glomerular dysfunction was noticed. The association of urinary bicarbonate loss with elevated N-acetyl-beta-glucosaminidase suggested a proximal tubular damage.Standard doses of carboplatin may lead to recurrent renal salt wasting in children with initially normal renal function.

This study was designed to examine whether concomitant administration of anti-free radicals with donorcore cooling on cardiopulmonary bypass (CPB) and hypothermic storage of the heart and lung, could provide successful extended cardiopulmonary preservation. Fourteen sheep heart-lung blocks harvested after core-cooling and cardioplegic arrest were preserved at 4 degrees C for 8.5 hr. Before and during CPB, the animals were perfused with Prostaglandin E1 (PGE1), superoxide dismutase (SOD), catalase (CAT) and deferoxamine (DEF). Cardioplegic arrest was induced with St. Thomas' Hospital solution (Plegisol) to which SOD, CAT and DEF had been added. The preservation solution consisted of Plegisol modified by the addition of K-lactobionate, raffinose, mannitol, SOD, CAT, DEF, a phosphate buffer and penicillin. Histological examination performed on 3 donor heart-lung blocks before and after CPB and cardioplegia, then immediately following cold storage, produced no clear evidence of structural damage in cardiac myocytes and lung parenchyma. Eleven donor organs were therefore transplanted in size-matched recipients with a total mean ischemic time of 12 hr. The combined administration of SOD, CAT, DEF, insulin and glucose during the initial period of reperfusion had no beneficial effect on cardiopulmonary performance. A progressive fall in Pa O2 and mean aortic pressure was observed post-operatively in the 7 animals that were weaned from CPB. Five of them died within 3 to 5 hr after CPB weaning, the remaining 2 animals died of cardiac arrest within the fourth hour. The results of this experiment seem to indicate that: 1. better organ function and improved survival could have been obtained if the duration of anti-radical treatment had been prolonged after reperfusion and, 2. physical manipulation of the donor grafts during harvesting and transplantation may have been partly responsible for the poor post-transplantation cardiopulmonary performance.

Between June 1988 and February 1993, combined heart-lung transplantation was performed in 30 children and adolescents aged 3.6 to 18.6 years (mean, 12.2 years) at The Hospital for Sick Children in London. Original diagnoses included cystic fibrosis (n = 25), Eisenmenger's syndrome (n = 4), and chronic graft-versus-host disease of the lung (n = 1). Posttransplantation maintenance immunosuppression comprised a triple regimen, with methylprednisolone and antithymocyte globulin given perioperatively and for episodes of allograft rejection. Actuarial survival was 63% (95% confidence interval: 42%-78%) at 1 year and 48% (95% confidence interval: 27%-66%) at 3 years. Obliterative bronchiolitis has been diagnosed in 13 patients (43%). Actuarial freedom from obliterative bronchiolitis in survivors was 76%, 59%, and 37% at 12, 24, and 36 months after transplantation, respectively. Recipients in whom obliterative bronchiolitis developed within the first year (n = 6) had more episodes of pulmonary rejection during the first 6 months after transplantation (mean, 5.7 episodes per patient) than those in whom "premature" obliterative bronchiolitis did not develop (mean, 3.2 episodes per patient). Infection of the pulmonary allograft was implicated to a lesser extent in predisposing to obliterative bronchiolitis. At 2, 3, and 6 months, tracheal stenosis developed in three patients, all of whom died with obliterative bronchiolitis within 10 months of transplantation. Noncompliance with therapy was considered a contributory factor in producing obliterative bronchiolitis in four adolescent recipients. The high incidence of obliterative bronchiolitis observed in this pediatric cohort may have a multifactorial cause.

From October 1989 to October 1991, 16 patients (17 tumours) with locally advanced carcinomas of the oral tongue and eight patients with second carcinomas of the base of tongue in previously irradiated areas, have been treated by means of an interstitial hyperthermia-brachytherapy combination in a phase II clinical trial. Each miniature microwave antenna of our hyperthermia system, called HIMCAR, is used both for heating and for thermal measurements by microwave radiometry at 3 and 9 GHz (see Part I). Among these 25 lesions (21 T2, 4 T3), 21 showed a complete response (15/17 locally advanced carcinomas and 6/8 second carcinomas in previously irradiated areas). The toxicity was not severe (less than 10%). A French multicentre phase III study is now under way.

Keratoconus, a bilateral corneal disease, is characterized by modifications in corneal shape and thinning of the stroma. It affects young people. From a biochemical point of view, a decrease in collagen content, probably due to the high collagenase activity, has been reported. In these experiments, we have studied the membrane receptors for interleukin 1 alpha, and the corresponding dissociation constant (KD). We also investigated synthesis of prostaglandin E2 (PGE2) and collagen, as well as kinetics of cyclooxygenase. Data from normal human corneas and from keratoconus were compared. Fibroblasts from keratoconus proved to bear four fold more IL1 binding sites than those from normal cornea, with similar KD. Both types of cells synthesize prostaglandin E2, even if IL1 is not added to the medium, but the keratoconus cells produce ten times more than the normal cornea cells. When the cells are stimulated with IL1, synthesis of PGE2 strongly increases and the amounts produced by keratoconus cells are always higher than those of the normal cornea cells. Kinetics of the cyclooxygenase show that Vmax. is 10 times higher in keratoconus than in normal cornea cells; Km's are the same. The amounts of collagen synthesized by keratoconus cells are slightly lower than those of normal cornea cells. Addition of IL1 to the cultures enhances synthesis of collagenase by the cells and decreases collagen found in the culture media. The drop of collagen is more important in keratoconus than in normal cornea cell cultures.

Young high-level athletes are frequently exposed to deficiencies, the most frequent origin of which is dietary. Supervision must be clinical, biological and dietary. Recommendations should be made individually, based on the nature and intensity of the exercise, and are calculated from the recommended supplements for the paediatric population. Protein, glucid and lipid supplements must represent approximately 12, 60 and 28% of the daily energetic intake respectively, the glucid ratio reaching 70% under certain conditions of prolonged exercise. Liquids must be controlled when exercise takes place in a warm atmosphere because young athletes are rapidly exposed to dehydration, the osmolarity of the selected drink being below 250 mosm/l. Mineral and vitamin supplementations are recommended. For minerals, perspiration losses may be associated with dietary deficiency. Possible vitamin deficiencies concern B1, B2, B6, B9, B12, C and D vitamins. The daily mineral supplements are estimated at 10 mg for iron, 5 mg for zinc and 1 mg for copper, and have to be prescribed in regular treatment after biological control.

Approximately one half of the patients takes prescribed medications irregularly or omits these altogether. On the basis of our own observations and published reports we analyze the factors influencing compliance. The motivation of the patients plays a decisive role, it is rooted in the meaning the patient gives to his existence, to where the strength of his family bonds and the confidence in the care-taking persons lays as well as the possibility to express himself which is most important. The better guidance and training of the doctors in the difficult task of strengthening such motivation may contribute to substantially improve this situation.

There is a wealth of evidence that more psychotropic drugs are prescribed to female than to male patients. We studied the psychotropic drug prescription of 15 male and 9 female physicians to 2493 patients in the Ambulatory Care Clinic of a University hospital. The relative odds (RO) of benzodiazepine prescription to a female compared to a male patient was the same when the physician was a male or a female (adjusted RO: 1.8; 95% CL: 1.5-2.1). But female patients were significantly more likely to be prescribed psychotropic drugs of all types from a female than from a male physician (adjusted RO: 1.3; 95% CL: 1.0-1.7). Information on patient diagnosis or on severity of symptoms would be needed to determine whether the present results reflect gender differences in medical care needs, overprescription of psychotropic drugs to females or underprescription of psychotropic drugs to males.

Keratoconus, a bilateral corneal disease, is characterized by modifications in corneal shape and thinning of the stroma. From a biochemical point of view, a decrease in collagen content, probably due to the high collagenase activity, has been reported. Gamma Interferon (gamma-IFN), Tumor Necrosis Factor (TNF), and Interleukin 1 (IL1) are peptide regulatory factors involved in immunological responses, but they also play a role in the synthesis of collagen and prostaglandin E2 by fibroblasts. In these experiments, we have determined the number of membrane binding sites for gamma-IFN, TNF, and IL1, and the dissociation constant (Kd) for each radiolabelled ligand. All experiments were carried out on cultured corneal stromal cells. Data from normal human corneas and from keratoconus were compared. No differences were found concerning gamma-IFN and TNF binding sites between normal corneas and keratoconus, while fibroblasts from keratoconus proved to bear four fold more IL1 binding sites than normal fibroblasts, with similar Kd.

Portal hypertension consecutive to hypervitaminosis A has seldom been well documented. Two cases are reported here. The first case concerns a 39-year old woman who had taken meladinine (8-methoxypsoralen) for the purpose of tanning. In the second case, a 43-year old woman had absorbed Plethoryl (a combination of tiratricol, cyclovalone and retinol) in order to lose weight. Both patients had histological hepatic lesions, such as hypertrophic Ito cells, perisinusoidal cirrhosis and spontaneous autofluorescence, suggestive of vitamin A overload, associated with a hepatic vein pressure gradient of 10 mmHg or more and high liver concentrations of vitamin A. The responsibility of Plethoryl in case 2 is beyond any doubt, but the mechanism of hypervitaminosis in case 1 is controverted. A review of the literature has provided detailed information on the signs of vitamin A overload, the frequency of which is probably underestimated. Patients with portal hypertension of unknown origin should be investigated for hypervitaminosis A.

We studied the effect of rat rec-IFN-gamma, human rec-IL-2, and an IgG1 monoclonal antibody (DB1) directed against rat IFN-gamma on allograft survival in the rat in various experimental conditions. The DB1 monoclonal antibody did not prolong heart allograft survival in the (LEW/BN)F1 to LEW combination, even when used at high doses (2 mg/rat x 9 days). Rec-IFN-gamma induced major histocompatibility antigen expression in vivo, but its administration had no effect on the graft survival either of untreated LEW recipients of (LEW x BN)F1 heart allografts or of donor blood-transfused LEW recipients. In addition, rec-IFN-gamma alone had no effect on graft survival in cyclosporine-treated rats. In contrast, rec-IL-2 shortened heart allograft survival both in untreated and in cyclosporine-treated recipients. Rec-IFN-gamma partially reversed the effects of rec-IL-2 in cyclosporine-treated rats. The data suggest that in vivo administration of IFN-gamma in allograft recipients may have a suppressor effect, in addition to the postulated augmenting effect on the immune response by increasing MHC antigen expression.

A 48 year old woman presented peripheral eosinophilia and neurologic symptoms which were related to a right parietal hypodense lesion. Further investigation led to the discovery of a left atrial cardiac tumor which had been incompletely resected and diagnosed as sarcoma. Eosinophilia than decreased. Two months after cardiac surgery, intracranial hypertension appeared and another expansive cerebral mass was discovered on CT scan. The patient was treated by radiotherapy. Two years later, the patient presented left abdominal pain. An increase of eosinophilic rate was noted. Abdominal CT scan revealed an heterogenous mass in the spleen. Splenectomy was performed and the tumor was diagnosed as a metastasis of the cardiac sarcoma. This case illustrates a rare tumor which is distinctive by its clinical signs: peripheral eosinophilia and neurologic signs. There were no cardiac symptoms. The clinical evolution was good after more than two years from initial diagnosis. This implies that a surgical attitude is recommended in such cases.

Opinions diverge on the ethics of preventive medicine. A balance needs to be struck between nihilism (doing nothing) and fanaticism (doing too much). The authors consider the ethical aspects of preventive medicine from the practising physician's viewpoint. Various aspects can be identified: SCIENTIFIC AND METHODOLOGICAL: Like any medical act, preventive practice relies on good scientific data. The epidemiologic studies should be clinically relevant and their recommendations must be interpreted critically before being incorporated into clinical practice. It should not be forgotten that we are dealing with patients and their behaviour. Tactful dialogue and personalized intervention are essential. DEONTOLOGICAL: Modern medicine is oriented toward health maintenance and promotion, thus including prevention. Although the community has drawn obvious benefits from preventive practices such as the use of vaccines, prevention must not be allowed to become a medical tyranny. Respect for the individual should remain its central concern. ETHICAL: The "meaning of life" must not be forgotten. Factors such as quality of life should always be kept in mind in measuring the benefits of prevention. By providing objective information and tailored counselling, the aim of prevention is to encourage expression of the individual's own responsibility for her/his own health. FINANCIAL: Preventive medicine is not covered by health insurance schemes. Cost-benefit analysis should consider not only the economic aspects of prevention but also its positive impacts on the entire social field. SOCIAL AND CULTURAL: The findings of epidemiologic studies must be adapted to precise socio-cultural environments. In our culture, for example, caregivers should be the first to practise what they preach. It must also be remembered that at the present time the basic preventive measures are still not accessible to everyone.

Fifteen patients with neoplastic meningitis received a single intrathecal injection of between 11 and 60 mCi of a 131I radiolabelled monoclonal antibody (MoAb), chosen for its immunoreactivity to tumour. Major toxicity was manifest as nausea, vomiting and headache (7/15 patients), reversible bone marrow suppression (3/8 patients) and seizures (2/15 patients). Nine patients were evaluable for either a tumour or clinical response. Six of these demonstrated an event-free response that was maintained for periods of between 7 and 26 months.

The diagnosis of smoking-related chronic obstructive pulmonary disease (COPD) is often made too late. Could the study of breathing pattern during exercise testing help in earlier detection. In order to test this hypothesis, we studied 34 asymptomatic smokers (S) compared to 55 nonsmoking controls (NS). The subjects, divided into 3 age groups (30-60 yr), were comparable in terms of anthropometric and spirometric characteristics. The smokers from 30-50 yr had a lower VO2max than the controls (p less than 0.01) whereas the older smokers (50-60 yr) had a VO2max comparable to that of the controls. The study of breathing pattern indicated rapid, shallow breathing by all smokers. Thus exercise testing, and the abnormalities observed in breathing pattern, would seem to help in early detection of COPD in asymptomatic smokers.

Six maturity onset diabetic patients took glibenclamide 5 mg by mouth, every morning 10 min before a standard breakfast. Serum levels of immunoreactive glibenclamide, glucose and immunoreactive insulin were measured repeatedly on the first and 15th days of treatment. Measured glibenclamide blood levels were in close agreement with an analogue computer simulation of data obtained from healthy volunteers: there was no accumulation of drug in the blood, but there was strong evidence for the existence of a slowly equilibrating "deep" compartment. Considerable insulin release and correction of the breakfast-induced hyperglycaemia were observed immediately after administration of the drug, as well as 5 h later, at lunch time. The clinical significance of blood levels of glibenclamide, as well as the correlation of pharmacokinetics with pharmacodynamics, are discussed in the light of these results.

Sodium dodecyl sulphate—acrylamide gel electrophoresis (SDS-AGE) separates proteins according to their molecular weight (MW) without being influenced by their electrostatic charge. It was carried out on the urine of 17 healthy control subjects and 92 ambulatory patients with suspected or known renal impairment. The SDS-AGE patterns were classified as physiological, low MW predominance, middle MW predominance, high MW predominance, or mixed low and high MW. Patients were separately classified as having either normal kidneys or glomerular, tubular or mixed renal lesions according to the results of clinical investigation. Comparison of both classifications revealed that SDS-AGE allowed a correct diagnosis of the site of renal involvement in 83 per cent of cases. Predominantly low MW protein excretion correlated with tubular damage. Middle and high MW patterns correlated with glomerular disease, and a relationship between nephrotic syndrome with minimal glomerular changes and middle MW pattern was found in two cases, suggesting that SDS-AGE could be used to evaluate the selectivity of proteinuria. However, the estimation of selectivity by SDS-AGE should be studied in a sufficient number of cases and compared with measurements of selectivity by the protein clearance method.

This study was carried out to determine the take rate of malignant lymphomas transplanted subcutaneously in nude mice. Lymphoid tissue from patients with a variety of lymphoproliferative and lymphomatous disorders was employed, but only four (8.3% of total) non-Hodgkin's lymphomas of various types grew in the nude mice. These transplants were from patients with lymphoplasmacytic, lymphoblastic, immunoblastic and centroblastic lymphomas; two of them were serially transferred. High grade malignant lymphomas seem easier to transplant than low grade ones. In each case, the tumor growing in nude mice was similar to the patient's tumor. In one case, metastases were found in mesenteric lymph nodes and lung. Electron microscopic study showed that neoplastic cells were associated with peculiar dark cells the nature of which is discussed. Furthermore, in two transplanted lymphomas, neoplastic cells contained C type virus particles, indicating contamination by the murine xenotropic type C virus.

Bufuralol (Ro 3 - 4787, Angium) is a non selective beta-adrenoceptor blocking drug with some degree of sympathomimetic action and a longer duration of action than propranolol. Plasma concentrations of bufuralol and 1'-hydroxybufuralol, its main blood derivative which shows similar beta-adrenoceptor blocking properties, were determined in healthy volunteers after a 60 mg oral and a 20 mg intravenous dose. Peak plasma concentrations were higher for the parent drug but due to a longer elimination half-life, the metabolite concentrations became higher after a few hours (bufuralol t 1/2 = 2.7 +/- 0.9 h, metabolite t 1/2 = 6.1 +/- 1.5h). The bioavailability of the tablet tested was 46 +/- 15%. The occurrence of side-effects in a subject with abnormal pharmacokinetics of the drug in this study and in a previous study with this drug suggested the possibility of a pharmacogenetic anomaly. Determination of the plasma metabolic ratio in the family of this subject and in a larger population confirmed that aliphatic hydroxylation of bufuralol is under polymorphic control. Phenotyping of our volunteers with debrisoquine showed the present pharmacogenetic anomaly to be the same as the one reported for debrisoquine alicyclic hydroxylation. The occurrence of side-effects in poor metabolizers as seen with bufuralol illustrates the clinical relevance of the hydroxylation polymorphism. In Switzerland the frequency of poor metabolizers is about 9% as previously reported for caucasian British subjects.

Microwave radiometry has been used during the last few years in some clinical centres (Lille, Freiburg, Strasbourg, Brussels) for the non-invasive control of temperature during microwave hyperthermia. The principal objective of this paper is to present an atraumatic thermal dosimetry system based on numerical simulations of hyperthermia and radiometric temperature measurements for TEM propagation. To gauge the feasibility and performance of the method, a one-dimensional model in a homogeneous medium is considered, neglecting the curvature of the tissue layer. The good correlation between the theoretical and experimental values obtained allowed the likely thermal profile on the probe axis to be computed using the dielectric and thermal properties of the medium and measurement of the radiometric and cutaneous temperatures.

Patients with renal insufficiency often react abnormally to a number of drugs. Small doses that are safe under normal conditions may cause severe and even fatal side-effects. As a consequence, modification of the usual drug dosage of these drugs in required in renal insufficiency. Since the risk of retention concerns only those drugs which are mainly excreted by the kidney, it is possible to establish a mathematical relationship between glomerular filtration rate and the rate of drug elimination. These relationships serve as a basis for the determination of the proper dosage regimen for the individual patient. Such dosage adaptation for intermitten drug administration can be obtained by two methods and a series of compromises between them: (1) increase of the dosage interval without changing the dose, and (2) reduction of the does without changing the frequency of administration. One must however, not only consider inadequate drug elimination but also a number of other factors. Some of these modify the behaviour of the drug, such as hypoalbumineamia, which causes an increase of the unbound portion of the drug; anomalies of the volume of distribution, as found in patients with oedema; metabolic disturbance; alteration of absorption from the gastro-intestinal tract, etc. Other factors are related only indirectly to the pharmacokinetic behaviour of the drug. Frequently, there is an increased sensitivity to the undesirable side-effects of certain drugs in patients with renal insufficiency, causing the level of tolerance to be lowered compared with normal patients. Such an effect probably involves functional or morphological modifications of the drug receptors, or interaction with substance retained in renal insufficiency. Furthermore, drugs may accentuate the consequences of the nephropathy or have increased nephrotoxicity for those with diseased kidneys. It is with these important reservations that a critical analysis of the proposed methods of adapting drug dosage in renal insufficiency is presented. An appendix tabulates the effects of renal insufficiency on the behaviour of 117 drugs. Irrespective of the method used to calculate drug dosage, all patients with renal disease must be monitored closely, particularly for signs of unexpected drug toxicity.

The beta-blocking agent bufuralol is subject to first-pass metabolism and is eliminated from the body almost entirely by biotransformation. Its major metabolite in plasma (1'-hydroxy-bufuralol) is biologically active and may contribute to the pharmacological effect of the drug. The effect of renal failure on the behavior of the parent compound and three of its metabolites was studied by comparing their kinetics in normal volunteers and in patients with severe renal insufficiency. Bufuralol was given orally to all subjects (20 mg); some of the healthy volunteers also received the drug intravenously (5 mg). Renal failure was found to be associated with a marked increase of the areas under the plasma concentration-time curves of the parent compound, whereas its halflife of elimination was not markedly influenced. The behavior of 1'-hydroxy-bufuralol was consistent with a decreased renal clearance. The behavior of bufuralol in patients with renal failure was analyzed using the clearance approach. From this analysis it appears that the presystemic biotransformation of bufuralol is decreased in renal failure and that changes in systemic clearance are compensated in our patients by modifications of the volume of distribution, resulting in little net change in the halflife of elimination.

Four subjects received 5 mg 14C-glipizide orally, 3 subjects 1 mg intravenously and 2 subjects 5 mg 14C-glibenclamide orally. Plasma levels of radioactivity, and urinary and faecal excretion were measured. For both drugs the disappearance of radioactivity from plasma followed complex kinetics and the apparent half-lives increased steadily with time. The two sulfonylureas were extensively metabolized and were excreted in the urine as hydroxylated or conjugated metabolites. The effects of both drugs on blood glucose and immunoreactive insulin were comparable. The findings are compared with other published results.

Forty chronic venous leg ulcers were treated, before split skin grafting, with human amnion prepared in one of the four following ways: tissue-culture-maintained, frozen, fresh or lyophilised. Although there was no significant statistical difference in the results obtained with the different preparations of amnion, we found that lyophilised amnion was at least as good as the other preparations in promoting a good take of the skin grafts and was the simplest to store and use. It also produced the shortest healing times. Frozen and fresh amnion were easier to prepare than lyophilised amnion but gave a lower graft take and a longer healing time. Tissue-culture-maintained amnion was the most difficult to prepare and gave the poorest results. Its use was abandoned during the trial because of technical difficulties and a high infection rate.

Four subjects received 5 mg14C-glipizide orally and3 subjects1 mg intravenously. The average absorption of the oral dose was nearly 100% with peak plasma levels occurring between 90 and 360 min. The apparent half-life of plasma radioactivity was approximatively 3.7 h, the disappearance of radioactivity following complex kinetics due to metabolism of the drug. Extraction with CH2Cl2 and chromatography showed that in plasma 85% of the total radioactivity corresponded to unchanged glipizide, but in urine 98% to more polar and more readily excreted metabolites. The urinary excretion is 68% of the dose. The hypoglycaemic effect of glipizide is comparable to glibenclamide. The administration of14C-glipizide to two patients with renal insufficiency showed that the metabolism of the drug is independent of kidney function, that the rate of disappearance of the unchanged glipizide was approximately the same as in normals, but that the “halflife” of the metabolites was increased to 20 h and more.

Nephropathy associated with type 1 (insulin-dependent Juvenile onset) or type 2 (noninsulin-dependent, maturity onset) diabetes mellitus is histologically characterized by glomerulosclerosis, hyalinosis of afferent and efferent glomerular arterioles and sometimes pyelonephritis [1–5]. Because diabetic nephropathy with renal failure is considered the cause of death in 42% of the patients below age 20 at the onset of diabetes mellitus, 9% between ages 20 and 39 but only 2.5 or 0.8% between ages 40 and 59 or beyond age 60, respectively [2], it is not surprising that interest in the clinical manifestations and pathophysiology of this complication has centered almost exclusively on type 1, insulin-dependent, juvenile onset diabetes mellitus [6–8]. However, type 2 diabetes mellitus is the most prevalent form of the syndrome, occurring principally after age 40, noninsulin-dependent, without a tendency to ketoacidosis and frequently associated with obesity. Indeed 80% of all diabetic patients show their first symptoms after age 40. Accordingly, this study investigated the clinical manifestations of renal disease in a large number of patients with maturity onset diabetes mellitus. Emphasis in this study was placed on hypertension, frequently observed in these patients, and on quantitative as well as qualitative protein excretion, which provide a useful marker of glomerular or tubule dysfunction when analyzed according to the molecular weight of the various fractions excreted. In this way, the course of renal involvement in maturity onset diabetes mellitus has been assessed and quantified. The results revealed an evolution which is quite different from that seen in juvenile onset, insulin-dependent diabetes mellitus.