The length of consent documents in oncological trials is doubled in twenty years.

BACKGROUND: The aim of the study was to investigate whether the length of informed consent documents (ICDs) for oncological trials have increased from 1987 to 2007 and analyze the content of the ICDs. DESIGN: In total, 87 ICDs from oncological trials approved by the Regional Committee for Medical and Health Research Ethics (REC) in the central region of Norway from 1987 to 2007 were analyzed. A list of 17 basic (fundamental medical and ethical aspects) and 30 formal (juridical aspects, financing, insurance and storage of data) content components was constructed based upon international and REC guidelines for ICDs. The number of words and presence of components were registered for all ICDs. RESULTS: The mean length of the ICDs increased from 338 (range 276-464) words in 1987-1990 to 1087 words (range 399-2345) in 2005-2007. The number of components increased from nine to 25 during the same period. Basic components increased steadily from seven in 1987-1989 to 14 in 2005-2007 while the components concerning formalities increased substantially from two to 11. CONCLUSIONS: The increased length of the ICDs is explained by an increased complexity of the documents and especially more information about formalities. This development increasingly demands competent readers and might prohibit truly informed consents.

Modulation of P-glycoprotein activity by acridones and coumarins from Citrus sinensis.

Bioguided fractionation of the roots of Citrus sinensis (Rutaceae) led to the isolation and identification of five coumarins, namely, clausarin, suberosin, poncitrin, xanthyletin and thamnosmonin, seven acridones, namely, acrimarine B, 2-methoxycitpressine I, citpressine I, buntanine, acrimarine E, honyumine and acrimarine C, and one terpenoid, namely, limonin. Among these compounds, clausarin, 2-methoxycitpressine I and acrimarine E inhibited P-glycoprotein-mediated drug efflux in K562/R7 human leukemic cells over-expressing P-glycoprotein.

Focal neurological complications of handcuff application.

The application of handcuffs may result in compression neuropathies at the wrist. The frequency of these complications is unknown. Twelve of 190 (6.3%) consecutive subjects kept in police custody presented distal neurological symptoms possibly related to handcuff application. The duration of handcuffing was significantly longer in patients with neurological symptoms than in patients without neurological symptoms (mean +/- SD: 3.7+/-5.2 h vs. 1.8+/-2.6 h, P = 0.02). A long duration of handcuff application and, possibly, the existence of somnolence or acute alcohol intoxication could be predisposing factors to handcuff neuropathy. A prospective study of clinical and electrophysiological detection and follow up is needed.

HIV-1 penetrates coronary artery endothelial cells by transcytosis.

BACKGROUND: The pathogenesis of HIV-1-related cardiomyopathy is poorly understood, but HIV-1 has been detected in cardiomyocytes. Whether HIV-1 penetrates into the myocardium by infection of coronary artery endothelial cells (CAEC) or using transcellular or paracellular routes across CAEC has not been resolved. MATERIALS AND METHODS: A model of the CAEC barrier was constructed with primary CAEC (derived from human coronary vessels). Polymerase chain reaction (PCR) assay, infectious assay, and immunofluorescence were employed to show abortive nature of HIV-1 infection of CAEC. Tight junction (TJ) and cell adhesion proteins were visualized by immunofluorescence. The time course of HIV-1 invasion was measured by HIV-1 RNA assay. Inulin permeability assay determined paracellular leakage. Transmission electron microscopy demonstrated virus-induced endothelial vacuolization. RESULTS: Despite a strong display on CAEC of CXCR4 and a lesser expression of CCR3 and CCR5, HIV-1 did not productively replicate in CAEC, as shown by infectious assay, immunofluorescence, and electron microscopy. HIV-1 infection of CAEC was abortive with minimal reverse transcription of strong stop DNA and pol but not full-length or two LTR DNA circles. Upon infection of the model with 1 million RNA copies of HIV-1JR-FL, virus penetration 2 hr postinfection (PI) was negligible but increased by 1,750% 24 hr PI. The paracellular permeability increased during this period by only 25%. Neither AOP-RANTES nor v-MIPII significantly reduced HIV-1JR-FL invasion. Virus infection did not alter the integral TJ protein occludin and the TJ-associated protein ZO-1. HIV-1 exposed CAEC and brain microvascular endothelial cells (BMVEC) developed extensive cytoplasmic vacuolization with retroviral-like particles in the vacuoles. CONCLUSIONS: The endothelium is not an impenetrable barrier to HIV-1. The virus opens a transcellular route across coronary and brain endothelia in cytoplasmic vacuoles.

Contribution of residential exposures to asthma in us children and adolescents.

CONTEXT: Residential exposures are recognized risk factors for asthma, but the relative contribution of specific indoor allergens and their overall contribution to asthma among older children and adolescents in the United States are unknown. OBJECTIVE: To estimate the relative contributions, population-attributable risks, and costs of residential risk factors for doctor-diagnosed asthma. Design. Nationally representative, cross-sectional survey conducted from 1988 to 1994. SETTING AND PARTICIPANTS: A total of 5384 children who were 6 to 16 years old and participated in the National Health and Nutrition Examination Survey III, a survey of the health and nutritional status of children and adults in the United States. MAIN OUTCOME MEASURE: Doctor-diagnosed asthma, as reported by the parent. RESULTS: Five hundred three of 5384 children and adolescents (11.4%) had doctor-diagnosed asthma. After adjusting for age, gender, race, urban status, region of country, educational attainment of the head of household, and poverty, predictors of doctor-diagnosed asthma included a history of allergy to a pet (odds ratio [OR: 2.4; 95% confidence interval [CI]: 1.7, 3.3), presence of a pet in the household (OR: 1.5; 95% CI: 1.1, 2.1), and immediate hypersensitivity to dust mite (OR: 1.5; 95% CI: 1.05, 2.0), Alternaria (OR: 1.9; 95% CI: 1.3, 2.8), and cockroach allergens (OR: 1.4; CI: 1.04, 1.9). Family history of atopy (OR: 1.7; 95% CI: 1.1, 2.7) and diagnosis of allergic rhinitis (OR: 2.1; CI: 1.1, 3.7) were also predictors for asthma. The population-attributable risk of having 1 or more residential exposures associated with doctor-diagnosed asthma was 44.4% (95% CI: 29-60), or an estimated 2 million excess cases. The attributable cost of asthma resulting from residential exposures was $405 million (95% CI: $264-$547 million) annually. CONCLUSIONS: The elimination of identified residential exposures, if causally associated with asthma, would result in a 44% decline in doctor-diagnosed asthma among older children and adolescents in the United States.

Optic neuropathy in uremia: an interdisciplinary emergency.

Optic neuropathy in uremia is rare. Although the consequences of optic neuropathy-blindness or substantial loss of vision-are devastating, only a few cases have been reported by way of single case reports and case series studies. The reported patients are heterogeneous with regard to the cause of neuropathy. We report the case of a patient with uremic optic neuropathy and summarize the other cases reported in the literature so far. Based on the data available from these reports, we propose a classification system, which includes nonischemic neurotoxic uremic optic neuropathy; ischemic optic neuropathy, more specifically anterior ischemic optic neuropathy; and optic neuropathy as a result of drug side effects, benign intracranial hypertension, and optic neuritis. The immediate institution of dialysis and corticosteroid therapy and correction of anemia and relative hypotension can optimize the chances of visual recovery for these patients. Close collaboration among nephrologists, ophthalmologists, and neurologists is important in this interdisciplinary emergency.

Early exposure to lead and juvenile delinquency.

Cross-sectional studies have reported an association between lead (Pb) levels in bone and delinquent behavior in later childhood and adolescence. This is the first prospective longitudinal study of Pb and child development to address this question with comprehensive assessments of toxicant exposure and other developmental cofactors. A prospective longitudinal birth cohort of 195 urban, inner-city adolescents recruited between 1979 and 1985 was examined. Relationships between prenatal and postnatal exposure to Pb (serial blood Pb determinations) and antisocial and delinquent behaviors (self- and parental reports) were examined. Prenatal exposure to Pb was significantly associated with a covariate-adjusted increase in the frequency of parent-reported delinquent and antisocial behaviors, while prenatal and postnatal exposure to Pb was significantly associated with a covariate-adjusted increase in frequency of self-reported delinquent and antisocial behaviors, including marijuana use. Use of marijuana itself by Cincinnati Lead Study (CLS) teens was strongly associated with all measures of delinquent and antisocial behavior. This prospective longitudinal study confirmed earlier clinical observations and recent retrospective studies that have linked Pb exposure with antisocial behavior in children and adolescents. Both prenatal and postnatal exposure to Pb were associated with reported antisocial acts and may play a measurable role in the epigenesis of behavioral problems independent of the other social and biomedical cofactors assessed in this study.

Symptomatic lead poisoning in infancy: a prospective case analysis.

This report of a case of symptomatic lead poisoning in infancy reinforces the need for continued vigilance in screening and the application of effective therapies to prevent serious physiologic, neurocognitive, and behavioral sequelae. Furthermore, this case illustrates the efficacy of repeated courses of outpatient succimer therapy in limiting a rebound in blood lead concentrations.

No difference in iron status between children with low and moderate lead exposure.

We compared the iron status between children 11 to 33 months old with confirmed blood lead levels of 20 to 44 microg/dL and demographically similar children with blood lead levels of <10 microg/dL. There were no differences. Laboratory investigation or empirical treatment for iron deficiency is not justified on the basis of moderately elevated blood lead levels alone.

Cocaine enhances brain endothelial adhesion molecules and leukocyte migration.

Leukocyte infiltration of cerebral vessels in cocaine-associated vasculopathy suggests that cocaine may enhance leukocyte migration. We have investigated cocaine's effects on leukocyte adhesion in human brain microvascular endothelial cell (BMVEC) cultures and monocyte migration in an in vitro blood-brain barrier (BBB) model constructed with BMVEC and astrocytes. Cocaine (10(-5) to 10(-9) M) enhanced adhesion of monocytes and neutrophils to BMVEC. In the BBB model, cocaine (10(-4) to 10(-8) M) enhanced monocyte transmigration. Cocaine increased expression of endothelial adhesion molecules, intercellular adhesion molecule-1 (ICAM-1, CD54), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (ELAM-1) on BMVEC. The peak effect on ICAM-1 expression was between 6 and 18 h after treatment. ICAM-1 was increased by cocaine in BMVEC, but not in human umbilical vein endothelial cells, and the enhancement was greater in a coculture of BMVEC with monocytes. ICAM-1 expression was enhanced by a transcriptional mechanism. Polymyxin B inhibited up-regulation of adhesion molecules by LPS but not by cocaine. In LPS-activated BMVEC/monocyte coculture, cocaine increased secretion of tumor necrosis factor-alpha and interleukin-6. Taken together, these findings indicate that cocaine enhances leukocyte migration across the cerebral vessel wall, in particular under inflammatory conditions, but the effects are variable in different individuals. Cocaine's effects are exerted through a cascade of augmented expression of inflammatory cytokines and endothelial adhesion molecules. These could underlie the cerebrovascular complications of cocaine abuse.

[Jaundice with free bilirubin following preventive anti-retroviral therapy after sexual aggression]. / Ictère à bilirubine libre au cours d'un traitement prophylactique antirétroviral après agression sexuelle.

BACKGROUND: Interest has recently focused on anti-HIV prophylaxis in case of sexual exposure. A circular from the French Ministry of Health (DGS/DH n(o) 97/560, 12 August 1997) envisages such treatment in certain risk situations such as sexual aggression. The toxic risk of prescribing a tritherapy or a bitherapy, even for a short period of a few weeks must be considered. CASE REPORT: A 20-year-old rape victim with an uneventful medical history was given a prophylactic regimen including zidovudine, laminovudine and indinavir. Three months later, she developed free-bilirubin jaundice with biological signs of hemolysis. DISCUSSION: We draw attention to the risk of severe adverse effects of short-duration anti-HIV prophylaxis in apparently healthy subjects. The protocol must included careful patient information and rigorous surveillance.

[Evaluation of the efficacy of foraminal infusions of corticosteroids guided by computed tomography in the treatment of radicular pain by foraminal injection]. / Evaluation de l'efficacité des infiltrations foraminales de corticoïdes guidées sous tomodensitométrie, dans le traitement des radiculalgies par conflit foraminal.

PURPOSE: To evaluate the efficacy of foraminal steroid injections performed under CT guidance for the management of radicular pain. METHODS: Periganglionic infiltrations were performed in 160 patients with radicular pain refractory to medical treatment. Imaging showed either degenerative foraminal stenosis, herniated disk or postsurgical fibrosis. RESULTS: 102 patients (63.8%) had significant pain reduction. Pain relief was lasting in 68 (66.6%). CT showed the position of the needle tip, as well as the diffusion of the therapeutic compounds. CONCLUSION: We consider that CT-guided periganglionic steroid injections should be an integral part of the management strategy for radicular pain resistant to medical treatment.

CXC and CC chemokine receptors on coronary and brain endothelia.

BACKGROUND: Chemokine receptors on leukocytes play a key role in inflammation and HIV-1 infection. Chemokine receptors on endothelia may serve an important role in HIV-1 tissue invasion and angiogenesis. MATERIALS AND METHODS: The expression of chemokine receptors in human brain microvascular endothelial cells (BMVEC) and coronary artery endothelial cells (CAEC) in vitro and cryostat sections of the heart tissue was determined by light and confocal microscopy and flow cytometry with monoclonal antibodies. Chemotaxis of endothelia by CC chemokines was evaluated in a transmigration assay. RESULTS: In BMVEC, the chemokine receptors CCR3 and CXCR4 showed the strongest expression. CXCR4 was localized by confocal microscopy to both the cytoplasm and the plasma membrane of BMVEC. In CAEC, CXCR4 demonstrated a strong expression with predominantly periplasmic localization. CCR5 expression was detected both in BMVEC and CAEC but at a lower level. Human umbilical cord endothelial cells (HUVEC) expressed strongly CXCR4 but only weakly CCR3 and CCR5. Two additional CC chemokines, CCR2A and CCR4, were detected in BMVEC and CAEC by immunostaining. Immunocytochemistry of the heart tissues with monoclonal antibodies revealed a high expression of CXCR4 and CCR2A and a low expression of CCR3 and CCR5 on coronary vessel endothelia. Coronary endothelia showed in vitro a strong chemotactic response to the CC chemokines RANTES, MIP-1alpha, and MIP-1beta. CONCLUSIONS: The endothelia isolated from the brain display strongly both the CCR3 and CXCR4 HIV-1 coreceptors, whereas the coronary endothelia express strongly only the CXCR4 coreceptor. CCR5 is expressed at a lower level in both endothelia. The differential display of CCR3 on the brain and coronary endothelia could be significant with respect to the differential susceptibility of the heart and the brain to HIV-1 invasion. In addition, CCR2A is strongly expressed in the heart endothelium. All of the above chemokine receptors could play a role in endothelial migration and repair.

[Cerebral panthrombophlebitis in a paucisymptomatic patient]. / Panthrombophlébite cérébrale chez un patient paucisymptomatique.

In most cases, extensive cerebral venous thrombosis present themselves with a severe clinical outcome and poor prognosis. We present the case of a 59-years-old patient with a slight rather unrevealing symptoms but suffering from a cerebral thrombosis impacting on both superficial and deep venous system. The etiologic assessment revealed activated protein C resistance. Clinical evolution under systemic anticoagulation was prompt, with complete repermeabilization of the various venous structures.

Cocaine infusion increases interferon-gamma and decreases interleukin-10 in cocaine-dependent subjects.

The effects of cocaine infusion (40 mg) on interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) cytokine secretion were examined in 15 cocaine-dependent subjects. Pre- and postcocaine infusion peripheral blood mononuclear cells (PBMC), stimulated with phytohemagglutinin A, were cultured for 48 h and the cytokines in the supernatant measured by enzyme-linked immunosorbent assay. Cocaine infusion, but not saline infusion, increased IFN-gamma secretion and decreased IL-10 secretion, while, in PBMC collected simultaneously from control subjects, secretion of these cytokines was unaltered. Baseline IFN-gamma levels were lower and IL-10 levels higher in addicted subjects compared to those in control subjects. White blood cell and lymphocyte number and CD4(+) and CD8(+) counts were all increased following cocaine infusion. In vitro cocaine treatment of PBMC from addicted subjects suppressed both IL-10 and IFN-gamma secretion. These data suggest that acute cocaine administration, via both central and peripheral effects, may enhance Th1-type immune responses and inhibit Th2-type responses.

[Role of electrophysiology in diagnosis of polyneuropathies]. / Die Rolle der Elektrophysiologie bei der Diagnostik der Polyneuropathien.

Most for polyneuropathies present in a uniform, distally accentuated, rather symmetrical pattern, although asymmetric or multifocal distributions occur. The main feature of diagnosis is the history of development and the neurological clinical examination. Neurophysiologic studies, mainly nerve conduction studies (motor and sensory), reflex studies and electromyography are very accurate, but unspecific tools in order to establish the diagnosis of polyneuropathies, define special electrophysiologic features and can also reveal undetected (subclinical) lesions. For clinical purposes most neuropathies can be divided according the nerve conduction studies in axonal, demyelinating and mixed types. In recent years additional electrophysiological features as conduction block have appeared and are still under discussion. The etiology of polyneuropathy has to be determined in each patient with scrutinity. Additionally to general diseases (e.g. diabetes), common toxins (e.g. alcohol), concurrent medication (e.g. some cytostatic drugs) also immunologic (e.g. vasculitis) and hereditary factors have to be considered. A nerve biopsy is only indicated after a thorough consideration of electrophysiology and ancilliary findings. This applies in particular to hereditary neuropathies, where genetic testing has become a highly reliable test replacing biopsy.

Adhesion forces of lipids in a phospholipid membrane studied by molecular dynamics simulations.

Lipid adhesion forces can be measured using several experimental techniques, but none of these techniques provide insight on the atomic level. Therefore, we performed extensive nonequilibrium molecular dynamics simulations of a phospholipid membrane in the liquid-crystalline phase out of which individual lipid molecules were pulled. In our method, as an idealization of the experimental setups, we have simply attached a harmonic spring to one of the lipid headgroup atoms. Upon retraction of the spring, the force needed to drag the lipid out of the membrane is recorded. By simulating different retraction rates, we were able to investigate the high pull rate part of the dynamical spectrum of lipid adhesion forces. We find that the adhesion force increases along the unbinding path, until the point of rupture is reached. The maximum value of the adhesion force, the rupture force, decreases as the pull rate becomes slower, and eventually enters a friction-dominated regime. The computed bond lengths depend on the rate of rupture, and show some scatter due to the nonequilibrium nature of the experiment. On average, the bond length increases from approximately 1.7 nm to 2.3 nm as the rates go down. Conformational analyses elucidate the detailed mechanism of lipid-membrane bond rupture. We present results of over 15 ns of membrane simulations. Implications for the interpretation and understanding of experimental rupture data are discussed.

The effect of succimer therapy in lead intoxication using postural balance as a measure: a case study in a nine year old child.

Postural balance testing was used as a measure of the effect of therapy on a 9 year old boy with high lead levels. Following therapy with CaEDTA and succimer, the patient's postural sway responses were comparable to a low-lead (< 10 micrograms/dL) comparison group for 3 out of 4 tests which rely relatively less on the higher centers for balance. This improvement in postural balance may be attributable to the combined influence of pharmacologic and age associated maturational effects. This case study provides suggestive evidence that while chelation therapy can reduce PbB levels quickly, it can also modify gross neuromotor function manifested by postural balance characteristics.