Effects of grapefruit juice on the pharmacokinetics of the enantiomers of methadone

BACKGROUND AND OBJECTIVES: Cytochrome P450 (CYP) 3A4 is the main CYP isozyme involved in methadone metabolism. We investigated the influence of grapefruit juice, which contains inhibitors of intestinal CYP3A, on the steady-state pharmacokinetics of methadone. METHODS: For 5 days, 8 patients undergoing methadone maintenance treatment received 200 mL water or grapefruit juice 30 minutes before and again together with their daily dose of methadone. Blood sampling for R-, S-, and R,S-methadone plasma determination was performed over a 24-hour period. CYP3A activity was determined by measuring the plasma 1'-hydroxymidazolam/midazolam ratio. RESULTS: A decrease in the midazolam ratio was measured in all patients after grapefruit juice (mean +/- SD before grapefruit juice, 9.3 +/- 5.9; mean +/- SD after grapefruit juice, 3.9 +/- 1.2; P <.05). Grapefruit juice led to a mean 17% increase in the area under the curve extrapolated to 24 hours for both enantiomers of methadone (range, 3% to 29% [P <.005]; range, -4% to 37% [P <.05]; and range, 1% to 32% [P <.01]; for R-, S-, and R,S-methadone, respectively). A similar increase in peak level and decrease in apparent clearance were measured with grapefruit juice, whereas time to peak level, terminal half-life, and apparent volume during the terminal phase of R-, S-, and R,S-methadone were not affected by grapefruit juice. No symptom of overmedication was either detected by the clinical staff or reported by the patients. CONCLUSIONS: Grapefruit juice administration is associated with a modest increase in methadone bioavailability, which is not expected to endanger patients. However, it cannot be excluded that a much stronger effect may occur in some patients, and thus grapefruit juice intake is not recommended during methadone maintenance treatment, in particular in patients initiating such a treatment.

Body mass index: comparing mean values and prevalence rates from telephone and examination surveys.

BACKGROUND: Cost effective means of assessing the levels of risk factors in the population have to be defined in order to monitor these factors over time and across populations. This study is aimed at analyzing the difference in population estimates of the mean levels of body mass index (BMI) and the prevalences of overweight, between health examination survey and telephone survey. METHODS: The study compares the results of two health surveys, one by telephone (N=820) and the other by physical examination (N=1318). The two surveys, based on independent random samples of the population, were carried out over the same period (1992-1993) in the same population (canton of Vaud, Switzerland). RESULTS: Overall participation rates were 67% and 53% for the health interview survey (HIS) and the health examination survey (HES) respectively. In the HIS, the reporting rate was over 98% for weight and height values. Self-reported weight was on average lower than measured weight, by 2.2 kg in men and 3.5 kg in women, while self-reported height was on average greater than measured height, by 1.2 cm in men and 1.9 cm in women. As a result, in comparison to HES, HIS led to substantially lower mean levels of BMI, and to a reduction of the prevalence rates of obesity (BMI>30 kg/m(2)) by more than a half. These differences are larger for women than for men. CONCLUSION: The two surveys were based on different sampling procedures. However, this difference in design is unlikely to explain the systematic bias observed between self-reported and measured values for height and weight. This bias entails the overall validity of BMI assessment from telephone surveys.

Reduced ejection fraction after myocardial infarction: is it sufficient to justify implantation of a defibrillator?

BACKGROUND: Improved survival after prophylactic implantation of a defibrillator in patients with reduced left ventricular ejection fraction (EF) after myocardial infarction (MI) has been demonstrated in patients who experienced remote MIs in the 1990s. The absolute survival benefit conferred by this recommended strategy must be related to the current risk of arrhythmic death, which is evolving. This study evaluates the mortality rate in survivors of MI with impaired left ventricular function and its relation to pre-hospital discharge baseline characteristics. METHODS: The clinical records of patients who had sustained an acute MI between 1999 and 2000 and had been discharged from the hospital with an EF of < or = 40% were included. Baseline characteristics, drug prescriptions, and invasive procedures were recorded. Bivariate and multivariate analyses were performed using a primary end point of total mortality. RESULTS: One hundred sixty-five patients were included. During a median follow-up period of 30 months (interquartile range, 22 to 36 months) 18 patients died. The 1-year and 2-year mortality rates were 6.7% and 8.6%, respectively. Variables reflecting coronary artery disease and its management (ie, prior MI, acute reperfusion, and complete revascularization) had a greater impact on mortality than variables reflecting mechanical dysfunction (ie, EF and Killip class). CONCLUSIONS: The mortality rate among survivors of MIs with reduced EF was substantially lower than that reported in the 1990s. The strong decrease in the arrhythmic risk implies a proportional increase in the number of patients needed to treat with a prophylactic defibrillator to prevent one adverse event. The risk of an event may even be sufficiently low to limit the detectable benefit of defibrillators in patients with the prognostic features identified in our study. This argues for additional risk stratification prior to the prophylactic implantation of a defibrillator.

Holy harlots : authority, gender, and the body in medieval English hagiography

This doctoral dissertation aims at describing the representation of holy harlots (Mary Magdalene, Mary of Egypt, Pelagia, Thai's, Afra of Augsburg) in medieval English hagiography. These saints are unique representatives that combine both extremes of the feminine in the medieval imaginaire: she is both, as a saint, the Virgin Mary, the pure and virtuous woman, and, in her past as a prostitute, Eve, the evil female tempter who led all mankind to destruction. The initial question of this thesis is how did hagiographers negotiate the representation of a formerly sinful, sexually active, long- living woman as an authoritative saint? This thesis aims at finding elements of answer to this question, investigating the intersections between gender and authority in the saints' lives of repentant prostitutes in all the vernaculars of medieval England: Old English, Anglo-Norman, and Middle English. It posits that the portrayal of holy harlots' authority and gender is dependent upon social, religious and literary shifts during the medieval period. My contention is that the harlot's gender portrayal changes over the course of the eleventh and twelfth centuries, due notably to the rise of affective piety and the important influence of the romance genre over hagiography. In Anglo-Saxon England, the harlot's gender changes with the saint's conversion: a woman beforehand, her gender is portrayed after her repentance as ambiguous in order for her to become a saint. Her authority derives from her own sanctity in this case. From the twelfth century onward, however, the harlot, now often turned into a beautiful and landed romance lady, is more and more represented as a woman throughout her life, and becomes after her conversion a Bride of Christ. In this way, the dangerously free woman who roamed the streets and prostituted her body becomes less threatening after her conversion, being (re-)inscribed within the male dominated institution of marriage. She now draws her authoritative stance from her gendered intimacy with Christ: although she submits to Christ as his bride, she also gains greater authority than before by way of her privileged relationship with the Savior.

Daily physical activity assessment: what is the importance of upper limb movements vs whole body movements?

OBJECTIVE: The movement of the upper limbs (eg fidgeting-like activities) is a meaningful component of nonexercise activity thermogenesis (NEAT). This study examined the relationship between upper limb movements and whole body trunk movements, by simultaneously measuring energy expenditure during the course of the day. DESIGN: A cross-sectional study consisting of 88 subjects with a wide range in body mass index (17.3-32.5 kg/m(2)). The energy expenditure over a 24-h period was measured in a large respiratory chamber. The body movements were assessed by two uniaxial-accelerometers during daytime, one on the waist and the other on the dominant arm. The accelerometry scores from level 0 (=immobile) up to level 9 (=maximal intensity) were recorded. The activities of subjects were classified into eight categories: walking at two speeds on a horizontal treadmill (A & B), ambling (C), self-care tasks (D), desk work (E), meals (F), reading (G), watching TV (H). RESULTS: There was a significant relationship between the accelerometry scores from the waist (ACwaist) and that from the wrist (ACwrist) over the daytime period (R(2)=0.64; P<0.001). The ACwrist was systematically higher than the ACwaist during sedentary activities, whereas it was the reverse for walking activities. ACwrist to ACwaist ratio of activities E-H were above 1.0 and for walking activities (A-C) were below 1.0. A multiple regression analysis for predicting daytime energy expenditure revealed that the explained variance improved by 2% only when the ACwrist was added as a second predictor in addition to the ACwaist. This indicates that the effect of the ACwrist for predicting energy expenditure was of limited importance in our conditions of measurement. CONCLUSIONS: The acceleration of the upper limbs which includes fidgeting is more elevated than that of the whole body for sitting/lying down activities. However, their contribution to energy expenditure is lower than whole body trunk movements, thus indicating that the weight-bearing locomotion activities may be a key component of NEAT. However, its contribution may depend on the total duration of the upper limb movements during the course of the day.

Experimental Uveitis can be Maintained in Rabbits for a Period of Six Weeks After a Safe Sensitization Method.

Abstract Purpose: New treatments against long-lasting uveitis need to be tested. Our aim was to develop a six-week model of uveitis in rabbits. Methods: Rabbits were presensitized with an s.c. injection of Mycobacterium tuberculosis H37RA emulsified with TiterMax® Gold adjuvant. Uveitis was induced at day 28 and 50, by intravitreal challenges of antigen suspension. Ocular inflammation was assessed till euthanasia at day 71 after s.c. injection of M. tuberculosis H37RA by: (a) the number of inflammatory cells in aqueous humor (AH); (b) the protein concentration in AH; (c) the clinical score (mean of conjunctival hyperaemia, conjunctival chemosis, oedema and secretion); (d) the microscopical score (mean presence of fibrin and synechiae, aqueous cell density and aqueous flare grade, as scored by slit lamp). Results: At the sites of presensitization injection, rabbits presented flat nodules which progressively vanished. The first challenge induced a significant increase in the four parameters (p < 0.05 the Wilcoxon/Kruskal-Wallis test). The AH contained 764 ± 82 cells/µl and 32 ± 0.77 mg protein/ml. During the following days, inflammatory parameters decreased slightly. The second intravitreal challenge increased inflammation (3564 ± 228 cells/µl AH and 31 ± 1 mg protein/ml), which remained at a high level for a longer period of time. Conclusion: We developed a model of long-term uveitis, which could be maintained in rabbits for at least six weeks. Such a model could be used to test the efficacy of either new drugs or various drug delivery systems intended to deliver active agents during a few months.

Economic growth and inequality: the role of fiscal policies

This paper analyses the impact of different instruments of fiscal policy on economic growth as well as on income inequality, using an unbalanced panel of 43 upper-middle and high income countries for the period 1972-2006. We consider and estimate two individual equations explaining growth and inequality in order to assess the incidence of different fiscal policies. Firstly, our approach considers imposing orthogonal assumptions between growth and inequality in both equations, and secondly, it allows growth to be included in the inequality equation, and inequality to be included in the growth equation. The empirical results suggest that an increase in the size of government measured through current expenditures and direct taxes diminishes economic growth while reducing inequality, being public investment the only fiscal policy that may break this trade-off between efficiency and equity, since increases in this item reduces inequality without harming output. Therefore, the results reflect that the trade-off between efficiency and equity that governments often confront when designing their fiscal policies may be avoided.

Subjective Memory Deficits in People with and without Dementia: Findings from the 10/66 Dementia Research Group Pilot Studies in Low- and Middle-Income Countries

OBJECTIVES To compare subjective memory deficit (SMD) in older adults with and without dementia or depression across multiple centers in low- and middle-income countries (LAMICs). DESIGN Secondary analysis of data from 23 case control studies. SETTING Twenty-three centers in India, Southeast Asia (including China), Latin America and the Caribbean, Nigeria, and Russia. PARTICIPANTS Two thousand six hundred ninety-two community-dwelling people aged 60 and older in one of three groups: people with dementia, people with depression, and controls free of dementia and depression. MEASUREMENTS SMD was derived from the Geriatric Mental State examination. RESULTS Median SMD frequency was lowest in participants without dementia (26.2%) and higher in those with depression (50.0%) and dementia (66.7%). Frequency of SMD varied between centers. Depression and dementia were consistently associated with SMD. Older age and hypochondriasis were associated with SMD only in subjects without dementia. In those with dementia, SMD was associated with better cognitive function, whereas the reverse was the case in controls. CONCLUSION Associations with SMD may differ between subjects with and without dementia living in LAMICs.

The Rise of The Swiss Tax Haven in the Interwar Period: An International Comparison

The history of tax havens during the decades before World War II is still little known. To date, the studies that have focused on the 1920s and 1930s have presented either a very general perspective on the development of tax havens or a narrow national point of view. Based on unpublished historical archives of five countries (Switzerland, Great Britain, Belgium, France, Germany), this paper offers therefore a new comparative appraisal of international tax competition during this period in order to answer the following question: What was the specificity of the Swiss case - already considered a quintessential tax haven at the time - in comparison to other banking centres? The findings of this research study are twofold. First, the 1920s and 1930s appear as something of a golden age of opportunity for avoiding taxation through the relocation of assets. Most of the financial centres granted consistent tax benefits for imported capital, while the limited degree of international cooperation and the usual guarantee of banking secrecy in European countries prevented the taxation of exported assets. Second, within this general environment, the fiscal strategies of a tax haven like Switzerland differed from those of a great financial power like Great Britain. Whereas the Swiss administration readily placed itself at the service of the banking community, British policy was more balanced between the contradictory interests of the Board of Inland Revenue, the Treasury, and the English business circles.

Humoral Immune Response to the Anti-malaria Vaccine SPf66 in the Colombian Atrato River Region

The immunogenicity of anti-malaria synthetic vaccine SPf66 was tested in a region of the Colombian middle Atrato river. The specific serum antibodies against SPf66 were quantified in vaccinees and placebo injected controls for a two-years period post-immunization. The frequency of individuals showing seroconversion of anti-SPf66 antibodies three months after completion of the immunization schedule was higher in vaccinees than in controls (52.7% and 25.5%, respectively, p<0.01). However, an over than four-fold increase of the specific anti-SPf66 antibody titers was observed only in 1.4% of vaccinees and 0.2% of the controls (p<0.01). The anti-SPf66 antibody titers augmented in vaccinees from first dose application to three months after the third dose, continuously decreasing thereafter to reach below baseline values two years after completion of the immunization schedule. The results show that SPf66 has very low immunogenicity and induces a short term humoral immune response (six months).

Prevalence of victims of violence admitted to an emergency department.

OBJECTIVE: To collect data on the consultation frequency and demographic profile of victims of violence attending an emergency department (ED) in Switzerland. METHODS: We undertook screening of all admitted adult patients (>16 years) in the ED of the CHUV, Lausanne, Switzerland, over a 1 month period, using a modified version of the Partner Violence Screen questionnaire. Exclusionary criteria were: life threatening injury (National Advisory Committee on Aeronautics score > or =4), or inability to understand or speak French, to give oral informed consent, or to be questioned without a family member or accompanying person being present. Data were collected on history of physical and/or psychological violence during the previous 12 months, the type of violence experienced by the patient, and if violence was the reason for the current consultation. Sociodemographic data were obtained from the registration documents. RESULTS: The final sample consisted of 1602 patients (participation rate of 77.2%), with a refusal rate of 1.1%. Violence during the past 12 months was reported by 11.4% of patients. Of the total sample, 25% stated that violence was the reason for the current consultation; of these, 95% of patients were confirmed as victims of violence by the ED physicians. Patients reporting violence were more likely to be young and separated from their partner. Men were more likely to be victims of public violence and women more commonly victims of domestic violence. CONCLUSIONS: Based on this monthly prevalence rate, we estimate that over 3000 adults affected by violence consult our ED per annum. This underlines the importance of the problem and the need to address it. Health services organisations should establish measures to improve quality of care for victims. Guidelines and educational programmes for nurses and physicians should be developed in order to enhance providers' skills and basic knowledge of all types of violence, how to recognise and interact appropriately with victims, and where to refer these patients for follow up care in their local networks.

Coronary MR angiography at 3T during diastole and systole

PURPOSE: To investigate the impact of end-systolic imaging on quality of right coronary magnetic resonance angiography (MRA) in comparison to diastolic and to study the effect of RR interval variability on image quality. MATERIALS AND METHODS: The right coronary artery (RCA) of 10 normal volunteers was imaged at 3T using parallel imaging (sensitivity encoding [SENSE]). Navigator-gated three-dimensional (3D) gradient echo was used three times: 1) end-systolic short acquisition (SS): 35-msec window; 2) diastolic short (DS): middiastolic acquisition using 35-msec window; and 3) diastolic long (DL): 75-msec diastolic acquisition window. Vectorcardiogram (VCG) data was used to analyze RR variability. Vessel sharpness, length, and diameter were compared to each other and correlated with RR variability. Blinded qualitative image scores of the images were compared. RESULTS: Quantitative and qualitative parameters were not significantly different and showed no significant correlation with RR variability. CONCLUSION: Imaging the RCA at 3T during the end-systolic rest period using SENSE is possible without significant detrimental effect on image quality. Breaking away from the standard of imaging only during diastole can potentially improve image quality in tachycardic patients or used for simultaneous imaging during both periods in a single scan.

Combination of transient lymphodepletion with busulfan and fludarabine and peptide vaccination in a phase I clinical trial for patients with advanced melanoma.

Taking advantage of homeostatic mechanisms to boost tumor-specific cellular immunity is raising increasing interest in the development of therapeutic strategies in the treatment of melanoma. Here, we have explored the potential of combining homeostatic proliferation, after transient immunosuppression, and antigenic stimulation of Melan-A/Mart-1 specific CD8 T-cells. In an effort to develop protocols that could be readily applicable to the clinic, we have designed a phase I clinical trial, involving lymphodepleting chemotherapy with Busulfan and Fludarabine, reinfusion of Melan-A specific CD8 T-cell containing peripheral blood mononuclear cells (exempt of growth factors), and Melan-A peptide vaccination. Six patients with advanced melanoma were enrolled in this outpatient regimen that demonstrated good feasibility combined with low toxicity. Consistent depletion of lymphocytes with persistent increased CD4/CD8 ratios was induced, although the proportion of circulating CD4 regulatory T-cells remained mostly unchanged. The study of the immune reconstitution period showed a steady recovery of whole T-cell numbers overtime. However, expansion of Melan-A specific CD8 T-cells, as measured in peripheral blood, was mostly inconsistent, accompanied with marginal phenotypic changes, despite vaccination with Melan-A/Mart-1 peptide. On the clinical level, 1 patient presented a partial but objective antitumor response following the beginning of the protocol, even though a direct effect of Busulfan/Fludarabine cannot be completely ruled out. Overall, these data provide further ground for the development of immunotherapeutic approaches to be both effective against melanoma and applicable in clinic.

Long-term stability of retinal function despite retained intraocular metallic foreign body.

BACKGROUND: Persisting metallic intraocular foreign bodies (IOFB) with a ferrous content have been associated with ocular siderosis and retinal degeneration. We describe two patients in whom a metallic IOFB containing iron was left embedded for many years in the choroid and sclera after having penetrated through the vitreous and the retina. HISTORY AND SIGNS: Two male patients, aged 41 and 48 years, presented with a metallic IOFB sustained during a work accident involving metal tools. THERAPY AND OUTCOME: For the first patient it was deemed unwise to operate, as the IOFB was also lodged very deeply in the choroid and sclera in the inferior temporal quadrant. The second patient underwent pars plana vitrectomy, but the IOFB could not be removed surgically as it was too deeply embedded in the sclera and choroid. After a period of 6 years (Case 1) and 4 years (Case 2) of follow-up, visual acuity remained at 1.0 and the IOFB was encased in a fibrotic capsule in both cases. Full-field and multifocal electroretinograms showed an inter-ocular asymmetry at baseline, which remained stable during the follow-up. CONCLUSIONS: Ocular siderosis may not develop in patients with a deeply embedded metallic IOFB. Regular monitoring of both visual function and the electroretinogram is mandatory when the IOFB is left inside the eye.