Tobacco sales to underage buyers in France: findings from a mystery shopping study.

OBJECTIVES: In 2017, one in four French 17-year-olds was a daily smoker, even though France prohibited the sale of tobacco to under-18 minors in 2009. This research aims to evaluate the retail violation rate for sale to minors (RVRms) and the associated factors. STUDY DESIGN: The study design used is observational mystery shopping study. METHODS: We conducted a mystery shopping study enlisting 12-year-old and 17-year-old youths in a representative sample of 527 tobacco outlets during three weeks in spring 2019. Multinomial Logit and Probit regressions were estimated on the data collected. RESULTS: The law is not respected. Two of three sellers (65.2%) were willing to make an illegal sale to a 17-year-old minor, and almost one in 12 (8.1%) were willing to sell to a 12-year-old child attempting to buy tobacco. Illegal sales were more likely to be made by male sellers, retailing in big cities, when there were no in-shop queues, and to 17-year-old females. The absence of the mandatory enforcement poster flagging up the ban on the sale of tobacco to minors appears to be a strong factor associated with RVRm. CONCLUSIONS: These findings show that progress needs to be made to better enforce tobacco control legislation to help decrease underage smoking in France. Rate of compliance with the law could be improved by stronger enforcement measures and tougher sanctions, but also by training and the provision of age-verification tools for sellers, as demonstrated by experiments in other countries.

[Increased risk of stillbirth in older mothers--a rationale for induction of labour before term?]. / Erhöhtes Risiko für Totgeburt bei älteren Müttern - Rationale für Geburtseinleitung vor dem Termin?

The average age of childbearing has risen markedly in Germany and other high-income countries during the past 2 decades. Women aged 35 years or older have an increase in pregnancy complications and in preexisting medical conditions including obesity, diabetes and hypertension as well as a significant increase in the gestational age-related rate of stillbirth compared to younger mothers. Additional individual risk factors for stillbirth are primiparity, body mass index>30 and smoking. After exclusion of risk factors the absolute risk of stillbirth in women aged≥40 years old is 2-fold higher (1 in 503 maternities) at 39/40 weeks of gestation compared to women aged<35 years (1 in 1 020 maternities) at the same gestational age. Women aged 40 years or older have a similar stillbirth risk at 39 weeks of gestation to 25-29-year-olds at 41 weeks gestation. The underlying mechanism for the excess risk of stillbirth in women of advanced maternal age after exclusion of congenital anomalies is unknown. Independent of maternal age the cumulative probability of perinatal death increases from 1.8/1 000 deliveries at 38 weeks of gestation to 9.3/1 000 deliveries at 42 weeks of gestation. Whether on the basis of these data induction of labour at 39 weeks of gestation should be recommended in women of advanced maternal age has recently been discussed in a Scientific Impact Paper of the Royal College of Obstetricians and Gynaecologists. In this context it should be taken into account that the rate of Caesarean sections in women aged 40 years or over is 40%, and, in particular, older nulliparous may request elective Caesaran section rather than elective induction of labour. Recent metaanalyses have shown that elective induction of labour before or after term is not associated with an increase of the Caesarean section rate compared to expectant management. Up to now no randomised controlled trials exist and consequently no -recommendations from current guidelines regarding induction of labour in women of advanced maternal age can be given. In any case, a careful consultation and an individual risk-benefit analysis regarding the obstetric management is mandatory, and the final decision should be made in agreement between the pregnant women and the obstetrician. Currently a randomised controlled trial in the U.K. comparing induction of labour at 39 weeks of gestation with expectant management in nulliparous women aged over 35 years is recruiting, with the aim to determine intrapartum complications and perinatal morbidity and mortality in both managements.

[Contribution of clinical biology in the etiological exploration and follow-up of urolithiasis]. / Apport de la biologie clinique dans l'exploration étiologique et le suivi de l'urolithiase.

Urolithiasis is a frequent pathology with a constantly increasing prevalence in industrial countries. The relapse frequency is around 50 % with a risk of complications. The laboratory input is essential in the determination of the etiology and in the therapeutic monitoring. The morphoconstitutional analysis of the stone is the most important element. It comprises the examination of the stone with binocular loupes and the simultaneous analysis of its crystalline composition. This can be done by different techniques but infrared spectrophotometry is the most powerful. The chemical analysis should be definitely proscribed. The analysis of crystalluria includes the search, the identification and the counting of crystals in fresh morning urines. It is useful for the diagnosis and for the patient follow-up. Finally, the biochemical analyses in urine and serum, in first line or on the basis of the stone composition, are an important part of the etiological exploration and therapeutic monitoring.

Metapopulation dynamics on the brink of extinction.

We analyse metapopulation dynamics in terms of an individual-based, stochastic model of a finite metapopulation. We suggest a new approach, using the number of patches in the population as a large parameter. This approach does not require that the number of individuals per patch is large, neither is it necessary to assume a time-scale separation between local population dynamics and migration. Our approach makes it possible to accurately describe the dynamics of metapopulations consisting of many small patches. We focus on metapopulations on the brink of extinction. We estimate the time to extinction and describe the most likely path to extinction. We find that the logarithm of the time to extinction is proportional to the product of two vectors, a vector characterising the distribution of patch population sizes in the quasi-steady state, and a vector-related to Fisher's reproduction vector-that quantifies the sensitivity of the quasi-steady state distribution to demographic fluctuations. We compare our analytical results to stochastic simulations of the model, and discuss the range of validity of the analytical expressions. By identifying fast and slow degrees of freedom in the metapopulation dynamics, we show that the dynamics of large metapopulations close to extinction is approximately described by a deterministic equation originally proposed by Levins (1969). We were able to compute the rates in Levins' equation in terms of the parameters of our stochastic, individual-based model. It turns out, however, that the interpretation of the dynamical variable depends strongly on the intrinsic growth rate and carrying capacity of the patches. Only when the local growth rate and the carrying capacity are large does the slow variable correspond to the number of patches, as envisaged by Levins. Last but not least, we discuss how our findings relate to other, widely used metapopulation models.

[Do smokers and potential smokers have to be offended in order to be dissuaded from smoking? The effectiveness of anti-smoking pictograms]. / Faut-il choquer les fumeurs et les fumeurs potentiels pour dissuader les comportements tabagiques ? Efficacité des pictogrammes contre le tabagisme.

BACKGROUND: As recommended by WHO in the fight against smoking, the French authorities have decided to implement the display of 14 "shock pictures" on cigarette packages in 2011. This study examines the effectiveness of this policy. METHODS: The present study is based on a self-reported questionnaire administered to a sample of 418 first-year medical students from a private faculty in January 2010. We consider a set of 12 European visual warnings that address different smoking problems. Econometric modeling is used to study the determinants of answers. RESULTS: Our results were twofold. Firstly, the most effective symbols concern the smoker himself/herself, they are explicit and related to an advanced stage of disease. Secondly, the warnings seem to be more effective to confirm the non-smokers in their choice than to deter smokers to smoke. CONCLUSION: This tobacco control policy seems to be effective. Therefore, visual warnings have to be carefully chosen before implementation.

[From personnel administration to human resource management : demographic risk management in hospitals]. / Von der Personalverwaltung zur Personalentwicklung : "Demographic risk management" in Krankenhäusern.

BACKGROUND: The healthcare market is facing a serious shortage of qualified personnel in 2020. Aging of staff members is one important driver of this human resource deficit but current planning periods of 1-2 years cannot compensate the demographic effects on staff portfolio early enough. Therefore, prospective human resource planning is important to avoid loss of competence. METHODS: The long range development (10 years) of human resources in the hospitals of the City of Cologne was analyzed. The basis for the analysis was a simulation model that included fluctuation of staff, retirement, maternity leave, status of employee illness, partial retirement and fresh engagements per department and profession. The model was matched with the staff requirements for each department. The results showed a capacity analysis which was used to convey strategic measures for staff recruitment and retention. RESULTS: The greatest risk for shortage of qualified staff was found in the fluctuation of doctors and in the aging work force. Without strategic human resource management the hospitals would face a 50% reduction of the work force within 10 years and after 2 years there would be a 25% deficit of anesthesiologists with impact on the function of operation rooms (OR) and intensive care units. Qualification and continuous training of staff members as well as process optimization are the most important spheres of activity for human resource management in order to recruit and retain qualified staff members. CONCLUSION: Prospective human resource planning for the OR and intensive care units can help to detect shortage of staff and loss of competence early enough to apply effective personnel development measures. A growing number of companies have started to plan ahead of the current demand of human resources. Hospitals should follow this example because the competition for qualified staff members is increasing rapidly.

Simultaneous determination of 8 beta-lactams and linezolid by an ultra-performance liquid chromatography method with UV detection and cross-validation with a commercial immunoassay for the quantification of linezolid.

Linezolid and beta-lactams are anti-infective drugs frequently used in intensive care unit patients. Critical illness could induce alterations of pharmacokinetic parameters due to changes in the distribution, the metabolism and the elimination process. Therapeutic drug monitoring (TDM) is therefore recommended to prevent mainly under-dosing of beta-lactams or hematological and neurological toxicities of linezolid. In Multi-or Extensively-Drugs Resistant-Tuberculosis Bacteria, the regimen could include linezolid with meropenem and amoxicillin/clavulanate justifying the development of a method allowing their simultaneous quantification. The aim of this work was to develop an in-house ultra-performance liquid chromatography method with UV detection (UHPLC-PDA) allowing the simultaneous determination of 8 beta-lactams (amoxicillin, aztreonam, cefepime, ceftazidime, ceftriaxone, cefuroxime, meropenem and piperacillin) and linezolid and to cross-validate the linezolid quantification with a new commercial immunoassay (ARK kit) tested on a Cobas analyzer. The main advantages of the immunoassay are a 24/24 h random access assay which is fully automated and results provided within 2 h. The interference due to potential co-administrated drugs was evaluated on both methods. The preanalytical factors (type of matrix, stability) for linezolid were also investigated. The influence of hemolysis, icteria or lipemia on the spectroscopic detection of the immunoassay was assessed. The analytical performances were evaluated using the accuracy profiles approach with acceptance limits fixed at ±30%. Seventy patient samples were measured using both methods. No cross-reaction with the tested anti-infective drugs as well as no influence of hemolysis, lipemia, icteria were observed. The linezolid concentration could be measured on heparinized plasma or serum without a significant difference and remained stable for at least 72h at 4°C.The UHPLC-PDA method performed well in the analytical range investigated (0.25-50 mg/L for meropenem, 0.75-50 mg/L for linezolid and 1-200 mg/L for other beta-lactams) with an intermediate precision and a relative bias below 7.6 and 7.7%, respectively. The analytical range of the immunoassay was narrower, from 0.85 to 18.5 mg/L. The precision and relative bias were lower than 8.1% and 4.2%, respectively. Results obtained on clinical samples showed an acceptable difference between methods with a mean bias of -1.8% [95% confidence interval: -5.2% - 1.6%]. To conclude, both methods showed acceptable performance to perform TDM of linezolid considering the therapeutic through target of 2-8 mg/L. The choice of the method should be made according to the degree of emergency of the response required and the field of application justifying or not the simultaneous quantification of beta-lactams and linezolid.

Origin differences in self-reported health among older migrants living in France.

OBJECTIVES: Little is known about the health status of older migrants living in Europe. Using detailed data collected in 2003, this study investigated differences in health status by country of origin within the older immigrant population living in France using a self-rated health measure. STUDY DESIGN: The database used in this research was the Passage à la Retraite des Immigrés survey, conducted from November 2002 to February 2003 on a sample of 6211 migrants aged 45-70 years and living in France at the time of the survey. METHODS: A difficulty with a self-rated outcome is that it may not be comparable between different origin groups, particularly because of cultural and linguistic differences. Therefore, generalized ordered Probit models were estimated, and an indicator of health, net of cross-cultural effects was constructed for each respondent. RESULTS: This study found that male immigrants from southern Africa and Asia, and female immigrants from northern Europe, southern Africa and Asia are more likely to be in good health, while the health status is lower among immigrants from Eastern Europe living in France. CONCLUSION: The diversity in health status within the immigrant population is large in France. These results are helpful in order to target the more disadvantaged origin groups and to adjust the provision of health care.

Investigation of unbound colistin A and B in clinical samples using a mass spectrometry method.

Colistin, used as a last-resort drug, has a narrow therapeutic range that justifies therapeutic drug monitoring. Few data are available in the literature regarding the in vivo unbound fraction of colistin. The objectives of this study were to develop a method to isolate unbound colistin in clinical samples by ultrafiltration and to quantify it. The association between unbound colistin and biological parameters (total protein, albumin, alpha-1-acid glycoprotein and creatinine) was investigated. The measured ranges were 0.036-7.160 mg/L for colistin A and 0.064-9.630 mg/L for colistin B. The process of isolation and determination of unbound colistin was applied to clinical samples (n = 30) within 40 min and no non-specific binding was observed during the ultracentrifugation step. The median unbound fractions of colistin measured were 34.3% (12.8-51.0%) and 53.4% (27.0-77.8%) for colistin A and B, respectively. High interindividual biological variation of binding was observed for colistin A and B that was not explained by the biochemical parameters studied. The method developed could be useful to improve outcomes for patients.

Images from the surface of asteroid Ryugu show rocks similar to carbonaceous chondrite meteorites.

The near-Earth asteroid (162173) Ryugu is a 900-m-diameter dark object expected to contain primordial material from the solar nebula. The Mobile Asteroid Surface Scout (MASCOT) landed on Ryugu's surface on 3 October 2018. We present images from the MASCOT camera (MASCam) taken during the descent and while on the surface. The surface is covered by decimeter- to meter-sized rocks, with no deposits of fine-grained material. Rocks appear either bright, with smooth faces and sharp edges, or dark, with a cauliflower-like, crumbly surface. Close-up images of a rock of the latter type reveal a dark matrix with small, bright, spectrally different inclusions, implying that it did not experience extensive aqueous alteration. The inclusions appear similar to those in carbonaceous chondrite meteorites.

Comparative toxicity of arsenite metabolites in wild type CHO cells and in cells deficient in excision repair cross-complementing 1 and 2.

Arsenic (As) has been shown to alter one or more DNA repair processes. Excision repair cross-complementing 1 and 2 (ERCC1 and ERCC2) have shown to be associated with arsenic-induced toxicity and carcinogenicity. In this study, we investigated cytotoxic effects of various As metabolites in relation to two nucleotide excision repair genes: ERCC1 and ERCC2. Various arsenate (pentavalent) and arsenite (trivalent) metabolites were tested in ERCC1, ERCC2 deficient and wild type cells. Our results showed that in the selected concentration range pentavalent As metabolites; iAs(V), MMA(V) and DMA(V) were not cytotoxic, unlike the trivalent As metabolites; iAs(III), MMA(III) and DMA(III). The measured LC(50) demonstrated a significant difference (p<0.01) for iAs(III) between the three cell lines, while MMA(III) and DMA(III) are more cytotoxic to all three cell lines. UV5 (ERCC2 deficient) cells also showed a lower resistance to iAs(III) in comparison to AA8 (wild type) and UV20 (ERCC2 deficient) cells. This might be explained through the generation of hydrogen peroxide (H(2)O(2)), which is generated by increase of intracellular Ca(2+) level. Generation of H(2)O(2) in UV5 cells after incubation with iAs(III) is significantly higher than AA8 and UV20 cells (p<0.01). In conclusion, absence of ERCC2 leads to a increased generation of H(2)O(2) by iAs(III) in UV5 cells, which is in contrast to AA8 and UV20 cells.

Mechanism of arsenic-induced neurotoxicity may be explained through cleavage of p35 to p25 by calpain.

In recent studies we have demonstrated that arsenic (As) metabolites change the composition of neuronal cytoskeletal proteins in vivo and in vitro. To further examine the mechanism of arsenic-induced neurotoxicity with various arsenate metabolites (iAsV, MMAV and DMAV) and arsenite metabolites (iAsIII, MMAIII and DMAIII), we investigated the role of the proteolytic enzyme calpain and its involvement in the cleavage of p35 protein to p25, and also mRNA expression levels of calpain, cyclin-dependent kinase 5 (cdk5) and glycogen synthase kinase 3 beta (gsk3ss). A HeLa cell line transfected with a p35 construct (HeLa-p35) was used as a model, since all other proteins such as calpain, CDK5 and GSK3beta are already present in HeLa cells as they are in neuronal cells. HeLa-p35 cells were incubated with various As metabolites and concentrations of 0, 10 and 30 microM for duration of 4 h. Subsequently the cells were either lysed to study their relative quantification levels of these genes or to be examined on their p35-protein expression. P35-RNA expression levels were significantly (p<0.01) increased by arsenite metabolites, while p35 protein was cleaved to p25 (and p10) after incubation with these metabolites. The cleavage of p35 is caused by calcium (Ca2+) induced activation of calpain. Inhibition of calpain activity by calpeptin prevents cleavage of p35 to p25. These results suggest that cleavage of p35 to p25 by calpain, probably As-induced Ca2+-influx, may explain the mechanism by which arsenic induces its neurotoxic effects.

Arsenic metabolites affect expression of the neurofilament and tau genes: an in-vitro study into the mechanism of arsenic neurotoxicity.

Neurological studies indicate that the central (CNS) and peripheral nervous system (PNS) may be affected by arsenic (As). As-exposed patients show significantly lower nerve conduction velocities (NCVs) in their peripheral nerves in comparison to healthy subjects. As may play a role in the disruption of neuroskeletal integrity, but the mechanisms by which it exerts a toxic effect on the peripheral and central nervous system are still unclear. In the present study, we examined the neurotoxic effects of various arsenic metabolites (iAs(III), iAs(V), MMA(V) and DMA(V)) on two different cell lines derived from the peripheral (ST-8814) and central (SK-N-SH) nervous system. The effects of the arsenic metabolites were examined on the relative quantification levels of the cytoskeletal genes, neurofilament-light (NEFL), neurofilament-medium (NEF3), neurofilament-heavy (NEFH) and microtubule-associated protein-tau (MAPT), using real-time PCR. Our results show that iAs(III) and iAs(V) have no significant effects on either cell lines. On the other hand, MMA(V) and DMA(V) cause significant changes in expression levels of NEF3 and NEFL genes, while the expression level of the NEFH gene is significantly increased in both cell lines.

Arsenic neurotoxicity--a review.

Arsenic (As) is one of the oldest poisons known to men. Its applications throughout history are wide and varied: murder, make-up, paint and even as a pesticide. Chronic As toxicity is a global environmental health problem, affecting millions of people in the USA and Germany to Bangladesh and Taiwan. Worldwide, As is released into the environment by smelting of various metals, combustion of fossil fuels, as herbicides and fungicides in agricultural products. The drinking water in many countries, which is tapped from natural geological resources, is also contaminated as a result of the high level of As in groundwater. The environmental fate of As is contamination of surface and groundwater with a contaminant level higher than 10 particle per billion (ppb) as set by World Health Organization (WHO). Arsenic exists in both organic and inorganic species and either form can also exist in a trivalent or pentavalent oxidation state. Long-term health effects of exposure to these As metabolites are severe and highly variable: skin and lung cancer, neurological effects, hypertension and cardiovascular diseases. Neurological effects of As may develop within a few hours after ingestion, but usually are seen in 2-8 weeks after exposure. It is usually a symmetrical sensorimotor neuropathy, often resembling the Guillain-Barré syndrome. The predominant clinical features of neuropathy are paresthesias, numbness and pain, particularly in the soles of the feet. Electrophysiological studies performed on patients with As neuropathy have revealed a reduced nerve conduction velocity, typical of those seen in axonal degeneration. Most of the adverse effects of As, are caused by inactivated enzymes in the cellular energy pathway, whereby As reacts with the thiol groups of proteins and enzymes and inhibits their catalytic activity. Furthermore, As-induced neurotoxicity, like many other neurodegenerative diseases, causes changes in cytoskeletal protein composition and hyperphosphorylation. These changes may lead to disorganization of the cytoskeletal framework, which is a potential mechanism of As-induced neurotoxicity.

Arsenic-induced toxicity: effect on protein composition in sciatic nerve.

Exposure to arsenic compounds may lead to skin and lung cancer and various disorders such as vascular disease and peripheral neuropathy in humans. Peripheral arsenic neurotoxicity has been demonstrated clinically and in electrophysiological studies. Patients intoxicated with arsenic show neurological symptoms in their feet and hands. These patients show significantly lower nerve conduction velocities (NCVs) in their peripheral nerves in comparison with controls. The mechanism of arsenic peripheral nervous system (PNS) toxicity, however, has never been described before. This is the first study to investigate the toxicity of arsenic on the PNS. Male Wistar rats were exposed to arsenite given as a single dose i.v. After sacrifice, sciatic nerves were excised and the protein composition was analysed. Protein analysis of sciatic nerves showed disappearance of neurofilament and fibroblast proteins in rats treated with arsenite doses of 15 and 20 mg/kg in comparison with the control groups. Some fibroblast protein bands had disappeared in the 20-mg/kg dose group. The analysed neurofilament-M and -L proteins decreased dose dependency over time. arsenic affects the composition of proteins in the rat sciatic nerve, especially the neurofilaments. The reduction of signals in Western blot analysis reveals changes in cytoskeletal composition, which may well lead to neurotoxic effects in vivo.

Cortical serotonin transporter density and verbal memory in individuals who stopped using 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy"): preliminary findings.

BACKGROUND: Although the popular drug 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") has been shown to damage brain serotonin (5-HT) neurons in animals, the fate and functional consequences of 5-HT neurons after MDMA injury are not known in humans. We investigated the long-term effects of MDMA use on cortical 5-HT neurons in humans and memory function, because brain 5-HT has been implicated in memory function. METHODS: Twenty-two recent MDMA users, 16 ex-MDMA users who had stopped using MDMA for more than 1 year, and 13 control subjects. The effects of MDMA use on cortical 5-HT neurons was studied by means of single-photon emission computed tomography with iodine 123-labeled 2beta-carbomethoxy-3beta-(4-iodophenyl) tropane ([(123)I]beta-CIT) by quantification of brain 5-HT transporter densities. Verbal memory performance was assessed with the Rey Auditory Verbal Learning Test. RESULTS: Mean cortical [(123)I]beta-CIT-labeled 5-HT transporter density was significantly lower in recent MDMA users than in controls (1.17 vs. 1.28 [-9%]) but not in ex-MDMA users (1.24 vs. 1.28 [-3%]). Recent and ex-MDMA users recalled significantly fewer words than did controls on the immediate recall (47.0 and 48.0 vs 60.0, respectively; P =.001) as well as the delayed recall (9.8 and 10.1 vs. 13.1, respectively; P =.003). Greater use of MDMA was associated with greater impairment in immediate verbal memory. However, memory performance was not associated with [(123)I]beta-CIT binding to cortical 5-HT transporters or duration of abstinence from MDMA. CONCLUSION: The present study suggests that, while the neurotoxic effects of MDMA on 5-HT neurons in the human cortex may be reversible, the effects of MDMA on memory function may be long-lasting.

Elevated ß-lactam concentrations associated with neurological deterioration in ICU septic patients.

BACKGROUND: Although ß-lactams are considered to have a safe therapeutic profile, neurotoxicity has been reported. The aim of this study was to assess the association between ß-lactam concentrations and neurological alterations in septic ICU patients. METHODS: Retrospective study on all ICU patients who were treated with meropenem (MEM), piperacillin-tazobactam (TZP) or ceftazidime/cefepime (CEF) and in whom at least one ß-lactam trough concentration (C min) was determined. Drug levels were measured using high-performance liquid chromatography; C min was normalized to the clinical breakpoint of Pseudomonas aeruginosa (as determined by EUCAST) for each drug (C min/MIC). Changes in neurological status were evaluated using changes in the neurological sequential organ failure assessment score (ΔnSOFA) using the formula: ΔnSOFA = nSOFA(day of TDM) - nSOFA(ICU admission). Worsening neurological status (NWS) was defined as a ΔnSOFA ≥ 1 for an nSOFA on admission of 0-2. RESULTS: We collected 262 C min in 199 patients (130 MEM, 85 TZP, 47 CEF). Median APACHE II score and GCS on admission were 17 and 15, respectively. Overall ICU mortality was 27 %. There were no differences in the occurrence of NWS between antibiotics (39% for MEM, 32% for TZP and 35% for CEF). The occurrence of NWS increased with increasing C min/MIC ranges (P = 0.008); this correlation was found for TZP (P = 0.05) and MEM (P = 0.01), but not for CEF. C min/MIC was an independent predictive factor for NWS (OR 1.12 [1.04-1.20]). CONCLUSION: We found a correlation between high ß-lactam trough concentrations and increased occurrence of neurological deterioration in septic ICU patients. Although our data cannot determine causality, monitoring of ß-lactam levels should be considered when deterioration of neurological status occurs during critical illness.

Sensitivity to 2,5-hexanedione of neurofilaments in neuroblastoma cell line SK-N-SH increases during differentiation.

The effect of 2,5-hexanedione (2,5-HD) on the distribution of the neurofilamental (NF) proteins and vimentin was examined in human neuroblastoma cell line SK-N-SH with immunocytochemical methods. Retinoic acid (10 microM) induced differentiation into neuronal cells resulting in the outgrowth of processes and synthesis of NF proteins in the majority of the cells. A minority (4%) differentiated as large fibroblasts. Cells were exposed to 0-10 mM 2,5-HD for 3 days. In neuronal cells a concentration-dependent accumulation of NF proteins was detected as a spherical structure in the perikaryon. Neurofilaments in differentiated SK-N-SH cells were more susceptible to 2,5-HD than NF in undifferentiated cells, as the effects were observed at much lower 2,5-HD concentrations. In contrast, no accumulation of vimentin was detected in the fibroblastic cells.

Intraindividual and interindividual variability in 8-methoxypsoralen kinetics and effect in psoriatic patients.

Our purpose was to investigate the origin of intraindividual variation in comparison with interindividual variation of 8-methoxypsoralen (8-MOP) kinetics in different body fluids. The clinical test in therapy with psoralens and ultraviolet A (PUVA), expressed as the minimal phototoxic dose (MPD), was performed to establish a possible connection between biologic effect and kinetics of 8-MOP. The MPD and 8-MOP kinetics in serum and suction blister fluid (sbf) were determined in 18 psoriatic patients on PUVA therapy in 4 test days spread over a 7-mo period. Evidence showed that interindividual fluctuations are caused by differences in intrinsic clearance (Cl). Interindividual variations are large in comparison with intraindividual variations. A correlation was found among maximal serum concentrations, Cls, MPDs, and concentrations in sbf. In clinical practice the maximal serum concentration, determined in blood samples taken at 1, 2, and 3 hr after 8-MOP ingestion, is indicative of the rate of 8-MOP metabolism and thus of the biologic effect in the patient.

Inheritance of poor phenytoin parahydroxylation capacity in a Dutch family.

The mode of inheritance of insufficient phenytoin p-hydroxylation was studied in the family of a patient who had previously suffered from a phenytoin intoxication caused by insufficient metabolism of this drug. This family was compared with a control group. The rate of phenytoin metabolism was derived from the phenytoin/metabolite ratio in serum 6 hours after an oral test dose of 300 mg phenytoin. The propositus, a brother and a sister, were very slow metabolizers of phenytoin, with a metabolic ratio of approximately 20. In the other individuals, 22 family members of the second generation and 37 control subjects, a metabolic ratio of 4.7 +/- 2.2 (mean +/- SD; n = 59) was found. When comparing the members of the second generation (F2) with the control group, two statistically significantly different groups appear to exist: F2, with a metabolic ratio of 6.6 +/- 1.7 (mean +/- SD; n = 22), and the control group, with a metabolic ratio of 3.7 +/- 1.8 (mean +/- SD; n = 37) (p less than 0.001). Based on these results the mode of inheritance of this defect seems to be autosomal recessive.