Risk factors for head and neck cancer in young adults : a pooled analysis in the INHANCE consortium

BACKGROUND: Increasing incidence of head and neck cancer (HNC) in young adults has been reported. We aimed to compare the role of major risk factors and family history of cancer in HNC in young adults and older patients. METHODS: We pooled data from 25 case-control studies and conducted separate analyses for adults ≤45 years old ('young adults', 2010 cases and 4042 controls) and >45 years old ('older adults', 17 700 cases and 22 704 controls). Using logistic regression with studies treated as random effects, we estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The young group of cases had a higher proportion of oral tongue cancer (16.0% in women; 11.0% in men) and unspecified oral cavity / oropharynx cancer (16.2%; 11.1%) and a lower proportion of larynx cancer (12.1%; 16.6%) than older adult cases. The proportions of never smokers or never drinkers among female cases were higher than among male cases in both age groups. Positive associations with HNC and duration or pack-years of smoking and drinking were similar across age groups. However, the attributable fractions (AFs) for smoking and drinking were lower in young when compared with older adults (AFs for smoking in young women, older women, young men and older men, respectively, = 19.9% (95% CI = 9.8%, 27.9%), 48.9% (46.6%, 50.8%), 46.2% (38.5%, 52.5%), 64.3% (62.2%, 66.4%); AFs for drinking = 5.3% (-11.2%, 18.0%), 20.0% (14.5%, 25.0%), 21.5% (5.0%, 34.9%) and 50.4% (46.1%, 54.3%). A family history of early-onset cancer was associated with HNC risk in the young [OR = 2.27 (95% CI = 1.26, 4.10)], but not in the older adults [OR = 1.10 (0.91, 1.31)]. The attributable fraction for family history of early-onset cancer was 23.2% (8.60% to 31.4%) in young compared with 2.20% (-2.41%, 5.80%) in older adults. CONCLUSIONS: Differences in HNC aetiology according to age group may exist. The lower AF of cigarette smoking and alcohol drinking in young adults may be due to the reduced length of exposure due to the lower age. Other characteristics, such as those that are inherited, may play a more important role in HNC in young adults compared with older adults.

Isaac et Ismaël, concurrents ou cohéritiers de la promesse ? Une lecture de Genèse 16

La lecture chrétienne traditionnelle du cycle d'Abraham oublie souvent que le patriarche a deux fils : Ismaël et Isaac. A partir d'une enquête sur Gn 16, l'A. s'efforce de montrer que, pour les auteurs et rédacteurs de Gn 12-25, Ismaël et sa mère Hagar ne sont nullement une quantité négligeable. La version primitive de Gn 16 a été écrite par une représentante de l'aristocratie rurale en Juda au VII e S. av. J-C. Cet auteur s'oppose aux tendances nationalistes en montrant le lien profond entre Israël et ses voisins.

The Enigma of the Silent Closing of Acts (28,16-31)

(Résumé de l'ouvrage) In the first volume of this long-anticipated collection by Moessner and Tiede, seventeen leading scholars of antiquity present an amazing "sea change" of opinion that Luke is indeed the interpreter of Israel. The book represents an unprecedented international consensus that the Hellenistic author Luke composed a carefully crafted narrative in two parts to claim Jesus of Nazareth as Israel's true heritage and enduring legacy to the world. Part One explores the nature of Luke's prologues and his intention to write a narrative of "events brought to fruition," using the narrative conventions and audience expectations of the Greco-Roman milieu. Part Two illuminates the relation of Luke's second "volume" to the first by inquiring about the consistency and coherence of his narrative-thematic strategies in retelling the story of Israel's legacy of "the Christ." Whether Luke completed Acts, the larger role of Paul and, most significantly, the meaning of Israel by the end of Acts are approached from new perspectives and charged with provocative insights. In addition to the volume editors, the contributors include L. Alexander, D. Schmidt, V. Robbins, C. Thornton, R. Pervo, W. Kurz, C. Holladay, G. Sterling, D. Balch, E. Plmacher, Charles H. Talbert, J.H. Hayes, D. Marguerat, M. Wolter, R. Tannehill, and I. H. Marshall.

Clinical follow-up of women infected with human papillomavirus-16, either alone or with other human papillomavirus types: identification of different risk groups.

OBJECTIVES: Evaluation of the clinical impact of multiple infections of the cervix by human papillomavirus, including human papillomavirus-16, compared with single human papillomavirus-16 infection. STUDY DESIGN: One hundred sixty-nine women were classified in 3 categories depending on their human papillomavirus profile: human papillomavirus-16 only, human papillomavirus-16 and low-risk type(s), and human papillomavirus-16 and other high-risk type(s). Cervical brush samples were analyzed for human papillomavirus DNA by polymerase chain reaction and reverse line blot hybridization. All women were evaluated with colposcopy during 24 months or more. Management was according to the Bethesda recommendations. RESULTS: Women infected with human papillomavirus-16 and other high-risk human papillomavirus type(s) presented more progression or no change in the grade of dysplasia, compared with women of the other groups (relative risk [RR], 1.39; 95% confidence interval [CI], 1.07-1.82; P = .02 at 6 months; RR, 2.10; 95% CI, 1.46-3.02; P < .001 at 12 months; RR, 1.82; 95% CI, 1.21-2.72; P = .004 at 24 months). CONCLUSION: Coinfection of women with human papillomavirus-16 and other high-risk human papillomavirus type(s) increases the risk of unfavorable evolution.

Lentiviral gene transfer to the nonhuman primate brain.

Lentiviral vectors infect quiescent cells and allow for the delivery of genes to discrete brain regions. The present study assessed whether stable lentiviral gene transduction can be achieved in the monkey nigrostriatal system. Three young adult Rhesus monkeys received injections of a lentiviral vector encoding for the marker gene beta galatosidase (beta Gal). On one side of the brain, each monkey received multiple lentivirus injections into the caudate and putamen. On the opposite side, each animal received a single injection aimed at the substantia nigra. The first two monkeys were sacrificed 1 month postinjection, while the third monkey was sacrificed 3 months postinjection. Robust incorporation of the beta Gal gene was seen in the striatum of all three monkeys. Stereological counts revealed that 930,218; 1,192,359; and 1,501,217 cells in the striatum were beta Gal positive in monkeys 1 (n = 2) and 3 (n = 1) months later, respectively. Only the third monkey had an injection placed directly into the substantia nigra and 187,308 beta Gal-positive cells were identified in this animal. The injections induced only minor perivascular cuffing and there was no apparent inflammatory response resulting from the lentivirus injections. Double label experiments revealed that between 80 and 87% of the beta Gal-positive cells were neurons. These data indicate that robust transduction of striatal and nigral cells can occur in the nonhuman primate brain for up to 3 months. Studies are now ongoing testing the ability of lentivirus encoding for dopaminergic trophic factors to augment the nigrostriatal system in nonhuman primate models of Parkinson's disease.

Evaluation of oral versus intravenous dose of vinorelbine to achieve equivalent blood exposures in patients with solid tumours.

Patient's preference is for oral chemotherapy when both oral and i.v. are available, provided that efficacy is equivalent. Reliable switch from oral to i.v. is possible if correspondence between respective doses has been established. Vinorelbine oral was developed as a line extension of VRL i.v. on the basis that similar AUCs result in similar activities. From a first crossover study on 24 patients receiving VRL 25 mg/m2 i.v. and 80 mg/m2 oral data extrapolation concluded on AUCs bioequivalence between Vinorelbine 30 mg/m2 i.v. and 80 mg/m2 oral. A new trial was performed to support this calculation. In a crossover design study on patients (PS 0-1) with advanced solid tumours (44% breast carcinoma), VRL was administered (30 mg/m2 i.v., 80 mg/m2 oral) with a standard meal and 5-HT3 antagonists, at 2 weeks interval. Pharmacokinetics was performed over 168 h and VRL was measured by LC-MS/MS. Statistics included bioequivalence tests. Forty-eight patients were evaluable for PK: median age 58 years (25-71), PS0/PS1: 20/28, M/F: 11/37. Mean AUCs were 1,230 +/- 290 and 1,216 +/- 521 ng/ml for i.v. and oral, respectively. The confidence interval of the AUC ratio (0.83-1.03) was within the required regulatory range (0.8-1.25) and proved the bioequivalence between the two doses. The absolute bioavailability was 37.8 +/- 16.0%, and close to the value from the first study (40%). Patient tolerability was globally comparable between both forms with no significant difference on either haematological or non-haematological toxicities (grade 3-4). This new study, conducted on a larger population, confirmed the reliable dose correspondence previously established between vinorelbine 80 mg/m2 oral and 30 mg/m2 i.v.

Effect of school based physical activity programme (KISS) on fitness and adiposity in primary schoolchildren: cluster randomised controlled trial.

To assess the effectiveness of a school based physical activity programme during one school year on physical and psychological health in young schoolchildren. Cluster randomised controlled trial. 28 classes from 15 elementary schools in Switzerland randomly selected and assigned in a 4:3 ratio to an intervention (n=16) or control arm (n=12) after stratification for grade (first and fifth grade), from August 2005 to June 2006. 540 children, of whom 502 consented and presented at baseline. Children in the intervention arm (n=297) received a multi-component physical activity programme that included structuring the three existing physical education lessons each week and adding two additional lessons a week, daily short activity breaks, and physical activity homework. Children (n=205) and parents in the control group were not informed of an intervention group. For most outcome measures, the assessors were blinded. Primary outcome measures included body fat (sum of four skinfolds), aerobic fitness (shuttle run test), physical activity (accelerometry), and quality of life (questionnaires). Secondary outcome measures included body mass index and cardiovascular risk score (average z score of waist circumference, mean blood pressure, blood glucose, inverted high density lipoprotein cholesterol, and triglycerides). 498 children completed the baseline and follow-up assessments (mean age 6.9 (SD 0.3) years for first grade, 11.1 (0.5) years for fifth grade). After adjustment for grade, sex, baseline values, and clustering within classes, children in the intervention arm compared with controls showed more negative changes in the z score of the sum of four skinfolds (-0.12, 95 % confidence interval -0.21 to -0.03; P=0.009). Likewise, their z scores for aerobic fitness increased more favourably (0.17, 0.01 to 0.32; P=0.04), as did those for moderate-vigorous physical activity in school (1.19, 0.78 to 1.60; P<0.001), all day moderate-vigorous physical activity (0.44, 0.05 to 0.82; P=0.03), and total physical activity in school (0.92, 0.35 to 1.50; P=0.003). Z scores for overall daily physical activity (0.21, -0.21 to 0.63) and physical quality of life (0.42, -1.23 to 2.06) as well as psychological quality of life (0.59, -0.85 to 2.03) did not change significantly. A school based multi-component physical activity intervention including compulsory elements improved physical activity and fitness and reduced adiposity in children. Trial registration Current Controlled Trials ISRCTN15360785.

NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: A randomised phase III trial of a novel treatment modality.

PURPOSE: NovoTTF-100A is a portable device delivering low-intensity, intermediate frequency electric fields via non-invasive, transducer arrays. Tumour Treatment Fields (TTF), a completely new therapeutic modality in cancer treatment, physically interfere with cell division. METHODS: Phase III trial of chemotherapy-free treatment of NovoTTF (20-24h/day) versus active chemotherapy in the treatment of patients with recurrent glioblastoma. Primary end-point was improvement of overall survival. RESULTS: Patients (median age 54years (range 23-80), Karnofsky performance status 80% (range 50-100) were randomised to TTF alone (n=120) or active chemotherapy control (n=117). Number of prior treatments was two (range 1-6). Median survival was 6.6 versus 6.0months (hazard ratio 0.86 [95% CI 0.66-1.12]; p=0.27), 1-year survival rate was 20% and 20%, progression-free survival rate at 6months was 21.4% and 15.1% (p=0.13), respectively in TTF and active control patients. Responses were more common in the TTF arm (14% versus 9.6%, p=0.19). The TTF-related adverse events were mild (14%) to moderate (2%) skin rash beneath the transducer arrays. Severe adverse events occurred in 6% and 16% (p=0.022) of patients treated with TTF and chemotherapy, respectively. Quality of life analyses favoured TTF therapy in most domains. CONCLUSIONS: This is the first controlled trial evaluating an entirely novel cancer treatment modality delivering electric fields rather than chemotherapy. No improvement in overall survival was demonstrated, however efficacy and activity with this chemotherapy-free treatment device appears comparable to chemotherapy regimens that are commonly used for recurrent glioblastoma. Toxicity and quality of life clearly favoured TTF.

A stable and 40Ar/39Ar isotope study of a major thrust in the Helvetic nappes (Swiss Alps) - Evidence for fluid-flow and constraints on nappe kinematics

Stable isotope and Ar-40/Ar-39 measurements,were made on samples associated with a major tectonic discontinuity in the Helvetic Alps, the basal thrust of the Diablerets nappe (external zone of the Alpine Belt) in order to determine both the importance of fluids in this thrust zone and the timing of thrusting. A systematic decrease in the delta(18)O values (up to 6 parts per thousand) of calcite, quartz, and white mica exists within a 10- to 70-m-wide zone over a distance of 37 km along the thrust, and they become more pronounced toward the root of the nappe. A similar decrease in the delta(13)C values of calcite is observed only in the deepest sections (up to 3 parts per thousand). The delta D-SMOW (SMOW = standard mean ocean water) values of white mica are -54 parts per thousand +/- 8 parts per thousand (n = 22) and are independent of the distance from the thrust. These variations are interpreted to reflect syntectonic solution reprecipitation during fluid passage along the thrust. The calculated delta(18)O and delta D values (versus SMOW) for the fluid in equilibrium with the analyzed minerals is 12 parts per thousand to 16 parts per thousand and -30 parts per thousand to +5 parts per thousand, respectively, for assumed temperatures of 250 to 450 degrees C. The isotopic and structural data are consistent with fluids derived from the deep-seated roots of the Helvetic nappes where large volumes of Mesozoic sediments were metamorphosed to the amphibolite facies, It is suggested that connate and metamorphic waters, overpressured by rapid tectonic burial in a subductive system escaped by upward infiltration along moderately dipping pathways until they reached the main shear zone at the base of the moving pile, where they were channeled toward the surface, This model also explains the mechanism by which large amounts of fluid were removed from the Mesozoic sediments during Alpine metamorphism. White mica Ar-49/Ar-39 ages vary from 27 Ma far from the Diablerets thrust to 15 Ma along the thrust. An older component is observed in micas far from the thrust, interpreted as a detrital signature, and indicates that regional metamorphic temperatures were less than about 350 degrees C. The;plateau and near plateau ages nearest the thrust are consistent with either neocrystallization of white mica or argon loss by recrystallization during thrusting, which may have been enhanced in the zones of highest fluid flow. The 15 Ma Ar-40/Ar-39 age plateau measured on white mica sampled exactly on the thrust surface dates the end of both fluid flow and tectonic transport.

Caffeine intake and CYP1A2 variants associated with high caffeine intake protect non-smokers from hypertension.

The 15q24.1 locus, including CYP1A2, is associated with blood pressure (BP). The CYP1A2 rs762551 C allele is associated with lower CYP1A2 enzyme activity. CYP1A2 metabolizes caffeine and is induced by smoking. The association of caffeine consumption with hypertension remains controversial. We explored the effects of CYP1A2 variants and CYP1A2 enzyme activity on BP, focusing on caffeine as the potential mediator of CYP1A2 effects. Four observational (n = 16 719) and one quasi-experimental studies (n = 106) including European adults were conducted. Outcome measures were BP, caffeine intake, CYP1A2 activity and polymorphisms rs762551, rs1133323 and rs1378942. CYP1A2 variants were associated with hypertension in non-smokers, but not in smokers (CYP1A2-smoking interaction P = 0.01). Odds ratios (95% CIs) for hypertension for rs762551 CC, CA and AA genotypes were 1 (reference), 0.78 (0.59-1.02) and 0.66 (0.50-0.86), respectively, P = 0.004. Results were similar for the other variants. Higher CYP1A2 activity was linearly associated with lower BP after quitting smoking (P = 0.049 and P = 0.02 for systolic and diastolic BP, respectively), but not while smoking. In non-smokers, the CYP1A2 variants were associated with higher reported caffeine intake, which in turn was associated with lower odds of hypertension and lower BP (P = 0.01). In Mendelian randomization analyses using rs1133323 as instrument, each cup of caffeinated beverage was negatively associated with systolic BP [-9.57 (-16.22, -2.91) mmHg]. The associations of CYP1A2 variants with BP were modified by reported caffeine intake. These observational and quasi-experimental results strongly support a causal role of CYP1A2 in BP control via caffeine intake.

Mothers' and Fathers' Early Relationship With Their Infant: Similar Yet Temporally Discordant Themes [La relation initiale des parents avec leur nourrisson: Thèmes similaires quoique temporellement discordants]

Objective: To examine first-time mothers' and fathers' themes in their relationship with their infant, how these themes change during the first four months postpartum, and similarities and differences in mothers' and fathers' themes. Participants: Eighteen first-time mother-father couples were separately interviewed at one; six and 16 weeks postpartum. Data Analysis: Audio-taped, transcribed interviews were analysed using a Grounded Theory approach. Results: Our findings reveal a common set of themes for mothers and fathers in relation to the infant : 1: Discovery, 2: Physical Proximity, 3: Emotional Closeness, 4: Initiation of Complementary Interactions and 5: Commitment to Love and Care. However, there was a striking lack of concordance between mothers and fathers for these themes at each point in time. Conclusions: Mothers' and fathers' experience of the early relationship with their infant is unique. Focussing on maternal as well as paternal ways of experiencing the early relationship with their infant sets the way to understanding early developing relationships in the family context.

MRI following severe perinatal asphyxia: preliminary experience.

In 30 children suffering from severe perinatal asphyxia an attempt was made to determine the early prognostic signs of severe hypoxic-ischemic brain injury with magnetic resonance imaging (MRI). Ten early (1-4 days of age), 16 intermediate (2-4 weeks of age), and 38 late MRI (older than 1 month of age) procedures were performed on a 2.35 T MR-system. Severe cerebral necrosis was suspected by T2 hyperintensity of the white matter, with blurred limits to the cortex in early MRI, and was confirmed by T1 hyperintensity of the cortex in intermediate MRI. Severe cerebral necrosis was established at 3 months of age. Of the 11 children with this pattern (group A), 8 had severe and 3 had moderate cerebral palsy on subsequent examination. Thirteen children (group B) had normal late MRI scans; none developed severe cerebral palsy or marked mental retardation. Two children (group C) had focal ischemic lesions. Four children had intracranial hemorrhage (group D). Groups A and B did not differ in the severity of their perinatal histories and findings, suggesting that MRI during the first 3 months is of significant prognostic value.

A Randomized Trial for the Treatment of Refractory Status Epilepticus.

BACKGROUND: Refractory status epilepticus (RSE) has a mortality of 16-39%; coma induction is advocated for its management, but no comparative study has been performed. We aimed to assess the effectiveness (RSE control, adverse events) of the first course of propofol versus barbiturates in the treatment of RSE. METHODS: In this randomized, single blind, multi-center trial studying adults with RSE not due to cerebral anoxia, medications were titrated toward EEG burst-suppression for 36-48 h and then progressively weaned. The primary endpoint was the proportion of patients with RSE controlled after a first course of study medication; secondary endpoints included tolerability measures. RESULTS: The trial was terminated after 3 years, with only 24 patients recruited of the 150 needed; 14 subjects received propofol, 9 barbiturates. The primary endpoint was reached in 43% in the propofol versus 22% in the barbiturates arm (P = 0.40). Mortality (43 vs. 34%; P = 1.00) and return to baseline clinical conditions at 3 months (36 vs. 44%; P = 1.00) were similar. While infections and arterial hypotension did not differ between groups, barbiturate use was associated with a significantly longer mechanical ventilation (P = 0.03). A non-fatal propofol infusion syndrome was detected in one patient, while one subject died of bowel ischemia after barbiturates. DISCUSSION: Although undersampled, this trial shows significantly longer mechanical ventilation with barbiturates and the occurrence of severe treatment-related complications in both arms. We describe practical issues necessary for the success of future studies needed to improve the current unsatisfactory state of evidence.