Should Koos grade I vestibular schwannomas be treated early with gamma knife surgery? A subgroup analysis in a series of 190 consecutive patients.

INTRODUCTION: Gamma knife surgery (GKS) for vestibular schwannomas (VS) has a long-term clinical and scientific track record. After a period of de-escalation of dose prescription, results show a high rate of tumor control with improvement of clinical outcome (less than 1% facial palsy, 50-70% hearing preservation). Régis et al. (J Neurosurg 2013;119 Suppl.:105-11) suggested recently that proactive GKS management in intracanalicular tumors is better than a « wait and see » strategy when hearing is still useful at the time of diagnosis. MATERIALS AND METHODS: Based on these previous findings, we prospectively analyzed 190 vestibular schwannomas (VS), treated with GKS as first intention over a period of 4 years (2010-2014). We concentrated on patient, tumor and dosimetric characteristics. Special attention was given on the dose to the cochlea and its impact in maintaining serviceable hearing. RESULTS: The mean follow-up period was 1.3years (range 0.6-3.6). Preoperative serviceable hearing was present in 63.11% patients. The mean maximal diameter was 15.1mm (range 5-29.5). The size and volume of the tumor corresponded to Koos grade I, II, III and IV in 15.9%, 34.8%, 45.4% and 3.8% of the cases, respectively. The mean target volume was 1.24cm(3) (0.017-7.8). The mean prescription isodose volume was 1.6 cc (0.032-8.5). The mean marginal dose was 12Gy (11-12). The mean maximal dose received by the cochlea in patients with GR class 1 and 2 was 4.1Gy (1.5-7.6). Our preliminary neuroradiological follow-up shows 97% tumor control, with 45% shrinkage. Patients presenting with GR class 1 and class 2 at baseline retained serviceable hearing in 85% of cases. Among the patients with a follow-up of at least one year, those with Koos I tumors had the highest probability to maintain identical level of hearing after GKS. CONCLUSION: Our preliminary data suggest that Koos I patients should be treated early with GKS, before tumor growth and/or hearing deterioration, as they have the highest probability of hearing preservation.

Subgroup analyses in randomised controlled trials: cohort study on trial protocols and journal publications

OBJECTIVE: To investigate the planning of subgroup analyses in protocols of randomised controlled trials and the agreement with corresponding full journal publications. DESIGN: Cohort of protocols of randomised controlled trial and subsequent full journal publications. SETTING: Six research ethics committees in Switzerland, Germany, and Canada. DATA SOURCES: 894 protocols of randomised controlled trial involving patients approved by participating research ethics committees between 2000 and 2003 and 515 subsequent full journal publications. RESULTS: Of 894 protocols of randomised controlled trials, 252 (28.2%) included one or more planned subgroup analyses. Of those, 17 (6.7%) provided a clear hypothesis for at least one subgroup analysis, 10 (4.0%) anticipated the direction of a subgroup effect, and 87 (34.5%) planned a statistical test for interaction. Industry sponsored trials more often planned subgroup analyses compared with investigator sponsored trials (195/551 (35.4%) v 57/343 (16.6%), P<0.001). Of 515 identified journal publications, 246 (47.8%) reported at least one subgroup analysis. In 81 (32.9%) of the 246 publications reporting subgroup analyses, authors stated that subgroup analyses were prespecified, but this was not supported by 28 (34.6%) corresponding protocols. In 86 publications, authors claimed a subgroup effect, but only 36 (41.9%) corresponding protocols reported a planned subgroup analysis. CONCLUSIONS: Subgroup analyses are insufficiently described in the protocols of randomised controlled trials submitted to research ethics committees, and investigators rarely specify the anticipated direction of subgroup effects. More than one third of statements in publications of randomised controlled trials about subgroup prespecification had no documentation in the corresponding protocols. Definitive judgments regarding credibility of claimed subgroup effects are not possible without access to protocols and analysis plans of randomised controlled trials.

Periodontitis and gingivitis in inflammatory bowel disease: a case-control study.

BACKGROUND: The oral cavity is frequently affected in patients with inflammatory bowel disease (IBD), especially in patients with Crohn's disease (CD). Periodontitis is thought to influence systemic autoimmune or inflammatory diseases. We aimed to analyze the relationship of periodontitis and gingivitis markers with specific disease characteristics in patients with IBD and to compare these data with healthy controls. METHODS: In a prospective 8-month study, systematic oral examinations were performed in 113 patients with IBD, including 69 patients with CD and 44 patients with ulcerative colitis. For all patients, a structured personal history was taken. One hundred thirteen healthy volunteers served as a control group. Oral examination focussed on established oral health markers for periodontitis (bleeding on probing, loss of attachment, and periodontal pocket depth) and gingivitis (papilla bleeding index). Additionally, visible oral lesions were documented. RESULTS: Both gingivitis and periodontitis markers were higher in patients with IBD than in healthy control. In univariate analysis and logistic regression analysis, perianal disease was a risk factor for periodontitis. Nonsmoking decreased the risk of having periodontitis. No clear association was found between clinical activity and periodontitis in IBD. In only the CD subgroup, high clinical activity (Harvey-Bradshaw index > 10) was associated with 1 periodontitis marker, the loss of attachment at sites of maximal periodontal pocket depth. Oral lesions besides periodontitis and gingivitis were not common, but nevertheless observed in about 10% of patients with IBD. CONCLUSIONS: IBD, and especially perianal disease in CD, is associated with periodontitis. Optimal therapeutic strategies should probably focus on treating both local oral and systemic inflammation.

Which subgroup of patients with rheumatoid arthritis benefits from switching to rituximab versus alternative anti-tumour necrosis factor (TNF) agents after previous failure of an anti-TNF agent?

BACKGROUND: Patients with rheumatoid arthritis (RA) with an inadequate response to TNF antagonists (aTNFs) may switch to an alternative aTNF or start treatment from a different class of drugs, such as rituximab (RTX). It remains unclear in which clinical settings these therapeutic strategies offer most benefit. OBJECTIVE: To analyse the effectiveness of RTX versus alternative aTNFs on RA disease activity in different subgroups of patients. METHODS: A prospective cohort study of patients with RA who discontinued at least one aTNF and subsequently received either RTX or an alternative aTNF, nested within the Swiss RA registry (SCQM-RA) was carried out. The primary outcome, longitudinal improvement in 28-joint count Disease Activity Score (DAS28), was analysed using multivariate regression models for longitudinal data and adjusted for potential confounders. RESULTS: Of the 318 patients with RA included; 155 received RTX and 163 received an alternative aTNF. The relative benefit of RTX varied with the type of prior aTNF failure: when the motive for switching was ineffectiveness to previous aTNFs, the longitudinal improvement in DAS28 was significantly better with RTX than with an alternative aTNF (p = 0.03; at 6 months, -1.34 (95% CI -1.54 to -1.15) vs -0.93 (95% CI -1.28 to -0.59), respectively). When the motive for switching was other causes, the longitudinal improvement in DAS28 was similar for RTX and alternative aTNFs (p = 0.40). These results were not significantly modified by the number of previous aTNF failures, the type of aTNF switches, or the presence of co-treatment with a disease-modifying antirheumatic drug. CONCLUSION: This observational study suggests that in patients with RA who have stopped a previous aTNF treatment because of ineffectiveness changing to RTX is more effective than switching to an alternative aTNF.

Maximal Physiological Parameters during Partial Body-Weight Support Treadmill Testing.

PURPOSE: This study investigated maximal cardiometabolic response while running in a lower body positive pressure treadmill (antigravity treadmill (AG)), which reduces body weight (BW) and impact. The AG is used in rehabilitation of injuries but could have potential for high-speed running, if workload is maximally elevated. METHODS: Fourteen trained (nine male) runners (age 27 ± 5 yr; 10-km personal best, 38.1 ± 1.1 min) completed a treadmill incremental test (CON) to measure aerobic capacity and heart rate (V˙O2max and HRmax). They completed four identical tests (48 h apart, randomized order) on the AG at BW of 100%, 95%, 90%, and 85% (AG100 to AG85). Stride length and rate were measured at peak velocities (Vpeak). RESULTS: V˙O2max (mL·kg·min) was similar across all conditions (men: CON = 66.6 (3.0), AG100 = 65.6 (3.8), AG95 = 65.0 (5.4), AG90 = 65.6 (4.5), and AG85 = 65.0 (4.8); women: CON = 63.0 (4.6), AG100 = 61.4 (4.3), AG95 = 60.7 (4.8), AG90 = 61.4 (3.3), and AG85 = 62.8 (3.9)). Similar results were found for HRmax, except for AG85 in men and AG100 and AG90 in women, which were lower than CON. Vpeak (km·h) in men was 19.7 (0.9) in CON, which was lower than every other condition: AG100 = 21.0 (1.9) (P < 0.05), AG95 = 21.4 (1.8) (P < 0.01), AG90 = 22.3 (2.1) (P < 0.01), and AG85 = 22.6 (1.6) (P < 0.001). In women, Vpeak (km·h) was similar between CON (17.8 (1.1) ) and AG100 (19.3 (1.0)) but higher at AG95 = 19.5 (0.4) (P < 0.05), AG90 = 19.5 (0.8) (P < 0.05), and AG85 = 21.2 (0.9) (P < 0.01). CONCLUSIONS: The AG can be used at maximal exercise intensities at BW of 85% to 95%, reaching faster running speeds than normally feasible. The AG could be used for overspeed running programs at the highest metabolic response levels.

The effectiveness and safety of rescue treatments in 108 patients with steroid-refractory ulcerative colitis with sequential rescue therapies in a subgroup of patients.

BACKGROUND: Among patients with steroid-refractory ulcerative colitis (UC) in whom a first rescue therapy has failed, a second line salvage treatment can be considered to avoid colectomy. AIM: To evaluate the efficacy and safety of second or third line rescue therapy over a one-year period. METHODS: Response to single or sequential rescue treatments with infliximab (5mg/kg intravenously (iv) at week 0, 2, 6 and then every 8weeks), ciclosporin (iv 2mg/kg/daily and then oral 5mg/kg/daily) or tacrolimus (0.05mg/kg divided in 2 doses) in steroid-refractory moderate to severe UC patients from 7 Swiss and 1 Serbian tertiary IBD centers was retrospectively studied. The primary endpoint was the one year colectomy rate. RESULTS: 60% of patients responded to the first rescue therapy, 10% went to colectomy and 30% non-responders were switched to a 2(nd) line rescue treatment. 66% of patients responded to the 2(nd) line treatment whereas 34% failed, of which 15% went to colectomy and 19% received a 3(rd) line rescue treatment. Among those, 50% patients went to colectomy. Overall colectomy rate of the whole cohort was 18%. Steroid-free remission rate was 39%. The adverse event rates were 33%, 37.5% and 30% for the first, second and third line treatment respectively. CONCLUSION: Our data show that medical intervention even with 2(nd) and 3(rd) rescue treatments decreased colectomy frequency within one year of follow up. A longer follow-up will be necessary to investigate whether sequential therapy will only postpone colectomy and what percentage of patients will remain in long-term remission.

A vertebrate reproductive system involving three ploidy levels : hybrid origin of triploids in a contact zone of diploid and tetraploid green toads (Bufo viridis subgroup)

The rise and consequences of polyploidy in vertebrates, whose origin was associated with genome duplications, may be best studied in natural diploid and polyploid populations. In a diploid/tetraploid (2n/4n) geographic contact zone of Palearctic green toads in northern Kyrgyzstan, we examine 4ns and triploids (3n) of unknown genetic composition and origins. Using mitochondrial and nuclear sequence, and nuclear microsatellite markers in 84 individuals, we show that 4n (Bufo pewzowi) are allopolyploids, with a geographically proximate 2n species (B. turanensis) being their maternal ancestor and their paternal ancestor as yet unidentified. Local 3n forms arise through hybridization. Adult 3n mature males (B. turanensis mtDNA) have 2n mothers and 4n fathers, but seem distinguishable by nuclear profiles from partly aneuploid 3n tadpoles (with B. pewzowi mtDNA). These observations suggest multiple pathways to the formation of triploids in the contact zone, involving both reciprocal origins. To explain the phenomena in the system, we favor a hypothesis where 3n males (with B. turanensis mtDNA) backcross with 4n and 2n females. Together with previous studies of a separately evolved, sexually reproducing 3n lineage, these observations reveal complex reproductive interactions among toads of different ploidy levels and multiple pathways to the evolution of polyploid lineages.

Respiratory muscle training enhances maximal minute ventilation and forced vital capacity in adolescent athletes.

Introduction. Respiratory difficulties in athletes are common, especially in adolescents, even in the absence of exercise-induced bronchoconstriction. Immaturity of the respiratory muscles coupling at high respiratory rates could be a potential mechanism. Whether respiratory muscle training (RMT) can positively influence it is yet unknown. Goal. We investigate the effects of RMT on ventilation and performance parameters in adolescent athletes and hypothesize that RMT will enhance respiratory capacity. Methods. 12 healthy subjects (8 male, 4 female, 17±0.5 years) from a sports/study high school class, competitively involved in various sports (minimum of 10 hours per week) underwent respiratory function testing, maximal minute ventilation (MMV) measurements and a maximal treadmill incremental test with VO2max and ventilatory thresholds (VT1 and VT2) determination. They then underwent one month of RMT (4 times/week) using a eucapnic hyperventilation device, with an incremental training program. The same tests were repeated after RMT. Results. Subjects completed 14.8 sessions of RMT, with an increase in total ventilation per session of 211±29% during training. Borg scale evaluation of the RMT session was unchanged or reduced in all subjects, despite an increase in total respiratory work. No changes (p>0.05) were observed pre/post RMT in VO2max (53.4±7.5 vs 51.6±7.7 ml/kg/min), VT2 (14.4±1.4 vs 14.0±1.1 km/h) or Speed max at end of test (16.1±1.7 vs 15.8±1.7 km/h). MVV increased by 9.2% (176.7±36.9 vs 192.9±32.6 l/min, p<0.001) and FVC by 3.3% (6.70±0.75 vs 4.85±0.76 litres, p<0.05). Subjective evaluation of respiratory sensations during exercise and daily living were also improved. Conclusions. RMT improves MMV and FVC in adolescent athletes, along with important subjective respiratory benefits, although no changes are seen in treadmill maximal performance tests and VO2max measurements. RMT can be easily performed in adolescent without side effects, with a potential for improvement in training capacity and overall well-being.

Differences in whole-body fat oxidation kinetics between cycling and running.

This study aimed to quantitatively describe and compare whole-body fat oxidation kinetics in cycling and running using a sinusoidal mathematical model (SIN). Thirteen moderately trained individuals (7 men and 6 women) performed two graded exercise tests, with 3-min stages and 1 km h(-1) (or 20 W) increment, on a treadmill and on a cycle ergometer. Fat oxidation rates were determined using indirect calorimetry and plotted as a function of exercise intensity. The SIN model, which includes three independent variables (dilatation, symmetry and translation) that account for main quantitative characteristics of kinetics, provided a mathematical description of fat oxidation kinetics and allowed for determination of the intensity (Fat(max)) that elicits maximal fat oxidation (MFO). While the mean fat oxidation kinetics in cycling formed a symmetric parabolic curve, the mean kinetics during running was characterized by a greater dilatation (i.e., widening of the curve, P < 0.001) and a rightward asymmetry (i.e., shift of the peak of the curve to higher intensities, P = 0.01). Fat(max) was significantly higher in running compared with cycling (P < 0.001), whereas MFO was not significantly different between modes of exercise (P = 0.36). This study showed that the whole-body fat oxidation kinetics during running was characterized by a greater dilatation and a rightward asymmetry compared with cycling. The greater dilatation may be mainly related to the larger muscle mass involved in running while the rightward asymmetry may be induced by the specific type of muscle contraction.

Genome size rather than content might affect call properties in toads of three ploidy levels (Anura: Bufonidae: Bufo viridis subgroup).

In vertebrates, genome size has been shown to correlate with nuclear and cell sizes, and influences phenotypic features, such as brain complexity. In three different anuran families, advertisement calls of polyploids exhibit longer notes and intervals than diploids, and difference in cellular dimensions have been hypothesized to cause these modifications. We investigated this phenomenon in green toads (Bufo viridis subgroup) of three ploidy levels, in a different call type (release calls) that may evolve independently from advertisement calls, examining 1205 calls, from ten species, subspecies, and hybrid forms. Significant differences between pulse rates of six diploid and four polyploid (3n, 4n) green toad forms across a range of temperatures from 7 to 27 °C were found. Laboratory data supported differences in pulse rates of triploids vs. tetraploids, but failed to reach significance when including field recordings. This study supports the idea that genome size, irrespective of call type, phylogenetic context, and geographical background, might affect call properties in anurans and suggests a common principle governing this relationship. The nuclear-cell size ratio, affected by genome size, seems the most plausible explanation. However, we cannot rule out hypotheses under which call-influencing genes from an unexamined diploid ancestral species might also affect call properties in the hybrid-origin polyploids.

Hyperthermia and maximal oxygen uptake in men and women.

To compare the effect of hyperthermia on maximal oxygen uptake (VO2max) in men and women, VO2max was measured in 11 male and 11 female runners under seven conditions involving various ambient temperatures (Ta at 50% RH) and preheating designed to manipulate the esophageal (Tes) and mean skin (Tsk) temperatures at VO2max. The conditions were: 25 degrees C, no preheating (control); 25, 35, 40, and 45 degrees C, with exercise-induced preheating by a 20-min walk at approximately 33% of control VO2max; 45 degrees C, no preheating; and 45 degrees C, with passive preheating during which Tes and Tsk were increased to the same degree as at the end of the 20-min walk at 45 degrees C. Compared to VO2max (l x min(-1)) in the control condition (4.52+/-0.46 in men, 3.01+/-0.45 in women), VO2max in men and women was reduced with exercise-induced or passive preheating and increased Ta, approximately 4% at 35 degrees C, approximately 9% at 40 degrees C and approximately 18% at 45 degrees C. Percentage reductions (7-36%) in physical performance (treadmill test time to exhaustion) were strongly related to reductions in VO2max (r=0.82-0.84). The effects of hyperthermia on VO2max and physical performance in men and women were almost identical. We conclude that men and women do not differ in their thermal responses to maximal exercise, or in the relationship of hyperthermia to reductions in VO2max and physical performance at high temperature. Data are reported as mean (SD) unless otherwise stated.

Right-left digit ratio (2D:4D) and maximal oxygen uptake.

A low digit ratio (2D:4D) and low 2D:4D in the right compared with the left hand (right-left 2D:4D) are thought to be determined by high in utero concentrations of testosterone, and are related to "masculine" traits such as aggression and performance in sports like running and rugby. Low right-left 2D:4D is also related to sensitivity to testosterone as measured by the number of cytosine-adenine-guanine triplet repeats in exon 1 of the androgen receptor gene. Here we show that low right-left 2D:4D is associated with high maximal oxygen uptake (VO2(max)), high velocity at VO2(max), and high maximum lactate concentration in a sample of teenage boys. We suggest that low right-left 2D:4D is linked to performance in some sports because it is a proxy of high sensitivity to prenatal and maybe also circulating testosterone and high VO2(max).

Low rates of X-Y recombination, not turnovers, account for homomorphic sex chromosomes in several diploid species of Palearctic green toads (Bufo viridis subgroup).

Contrasting with birds and mammals, most ectothermic vertebrates present homomorphic sex chromosomes, which might be due either to a high turnover rate or to occasional X-Y recombination. We tested these two hypotheses in a group of Palearctic green toads that diverged some 3.3 million years ago. Using sibship analyses of sex-linked markers, we show that all four species investigated share the same pair of sex chromosomes and a pattern of male heterogamety with drastically reduced X-Y recombination in males. Phylogenetic analyses of sex-linked sequences show that X and Y alleles cluster by species, not by gametolog. We conclude that X-Y homomorphy and fine-scale sequence similarity in these species do not stem from recent sex-chromosome turnovers, but from occasional X-Y recombination.

Strong reproductive barriers in a narrow hybrid zone of West-Mediterranean green toads (Bufo viridis subgroup) with Plio-Pleistocene divergence

Background One key question in evolutionary biology deals with the mode and rate at which reproductive isolation accumulates during allopatric speciation. Little is known about secondary contacts of recently diverged anuran species. Here we conduct a multi-locus field study to investigate a contact zone between two lineages of green toads with an estimated divergence time of 2.7 My, and report results from preliminary experimental crosses. Results The Sicilian endemic Bufo siculus and the Italian mainland-origin B. balearicus form a narrow hybrid zone east of Mt. Etna. Despite bidirectional mtDNA introgression over a ca. 40 km North-South cline, no F1 hybrids could be found, and nuclear genomes display almost no admixture. Populations from each side of the contact zone showed depressed genetic diversity and very strong differentiation (FST = 0.52). Preliminary experimental crosses point to a slightly reduced fitness in F1 hybrids, a strong hybrid breakdown in backcrossed offspring (F1 x parental, with very few reaching metamorphosis) and a complete and early mortality in F2 (F1 x F1). Conclusion Genetic patterns at the contact zone are molded by drift and selection. Local effective sizes are reduced by the geography and history of the contact zone, B. balearicus populations being at the front wave of a recent expansion (late Pleistocene). Selection against hybrids likely results from intrinsic genomic causes (disruption of coadapted sets of genes in backcrosses and F2-hybrids), possibly reinforced by local adaptation (the ranges of the two taxa roughly coincide with the borders of semiarid and arid climates). The absence of F1 in the field might be due to premating isolation mechanisms. Our results, show that these lineages have evolved almost complete reproductive isolation after some 2.7 My of divergence, contrasting sharply with evidence from laboratory experiments that some anuran species may still produce viable F1 offspring after > 20 My of divergence.