Cosmological Models and Latest Observational Data

In this note, we consider the observational constraints on some cosmological models by using the 307 Union type Ia supernovae (SNIa), the 32 calibrated Gamma-Ray Bursts (GRBs) at $z>1.4$, the updated shift parameter $R$ from WMAP 5-year data (WMAP5), and the distance parameter $A$ of the measurement of the baryon acoustic oscillation (BAO) peak in the distribution of SDSS luminous red galaxies with the updated scalar spectral index $n_s$ from WMAP5. The tighter constraints obtained here update the ones obtained previously in the literature.Comment: 10 pages, 5 figures, 1 table, revtex4; v2: discussions added, accepted by Eur. Phys. J. C; v3: published versio

Constraints on coupling constant between dark energy and dark matter

We have investigated constraints on the coupling between dark matter and the interacting Chaplygin gas. Our results indicate that the coupling constant $c$ between these two entities can take arbitrary values, which can be either positive or negative, thus giving arbitrary freedom to the inter-conversion between Chaplygin gas and dark matter. Thus our results indicate that the restriction $0<c<1$ on the coupling constant occurs as a very special case. Our analysis also supports the existence of phantom energy under certain conditions on the coupling constant.Comment: 16 Pages, 3 figure

Intensive Teenage Activity Is Associated With Greater Muscle Hyperintensity on T1W Magnetic Resonance Imaging in Adults With Dysferlinopathy

Practice of sports during childhood or adolescence correlates with an earlier onset and more rapidly progressing phenotype in dysferlinopathies. To determine if this correlation relates to greater muscle pathology that persists into adulthood, we investigated the effect of exercise on the degree of muscle fatty replacement measured using muscle MRI. We reviewed pelvic, thigh and leg T1W MRI scans from 160 patients with genetically confirmed dysferlinopathy from the Jain Foundation International clinical outcomes study in dysferlinopathy. Two independent assessors used the Lamminen-Mercuri visual scale to score degree of fat replacement in each muscle. Exercise intensity for each individual was defined as no activity, minimal, moderate, or intensive activity by using metabolic equivalents and patient reported frequency of sports undertaken between the ages of 10 and 18. We used ANCOVA and linear modeling to compare the mean Lamminen-Mercuri score for the pelvis, thigh, and leg between exercise groups, controlling for age at assessment and symptom duration. Intensive exercisers showed greater fatty replacement in the muscles of the pelvis than moderate exercisers, but no significant differences of the thigh or leg. Within the pelvis, Psoas was the muscle most strongly associated with this exercise effect. In patients with a short symptom duration of <15 years there was a trend toward greater fatty replacement in the muscles of the thigh. These findings define key muscles involved in the exercise-phenotype effect that has previously been observed only clinically in dysferlinopathy and support recommendations that pre-symptomatic patients should avoid very intensive exercise

P.165 Clinical outcome study of dysferlinopathy: lower limb water T2 predicts functional decline in patients with dysferlinopathy

Water-T2 (T2H2O) mapping is used in muscular dystrophies to assess disease activity. It has been suggested as a surrogate outcome measure for clinical trials. However, the prognostic utility of T2H2O to identify changes in muscle function over time has not been described. A cohort of 18 patients (7 male) from two sites (Newcastle and Paris) with genetically confirmed dysferlinopathy were assessed as part of the Jain Foundation Clinical Outcomes Study of dysferlinopathy. Imaging used 3.0 T MRI clinical scanners with acquisition parameters standardised across sites. A multi-spin-echo sequence, with 17 equidistant echoes at 9.5ms spacing, was used for T2H2O mapping. T2H2O value was defined as higher or lower than the median in each muscle bilaterally. The degree of deterioration on four functional tests over three years was assessed in a linear model against covariates of high or low T2H2O at baseline, age, disease duration and baseline function. The T2H2O threshold which best predicted functional decline was determined. Higher T2H2O value correlated with greater functional decline in 21/35 muscles, and was never associated with slower decline (p0.6). Higher T2H2O values in adductor magnus, vastus intermedius, vastus lateralis and vastus medialis were the most sensitive, being associated with greater decline in timed tests. Patients with a higher than median T2H2O value (40.6 milliseconds (ms)) in these muscles deteriorated 11 points more on the North Star Ambulatory Assessment for Dysferlinopathy (NSAD) and lost an additional 86 metres on the six-minute walk than those with a lower T2H2O value (p<0.05). In dysferlinopathy, T2H2O did not correlate with current functional ability. However, T2H2O at baseline was higher in patients who worsened more rapidly on functional tests. With its capacity to predict progression, T2H2O mapping could be used to improve prognostication, patient selection and disease modelling for clinical trials

Rapamycin treatment for amyotrophic lateral sclerosis protocol for a phase II randomized, double-blind, placebo-controlled, multicenter, clinical trial (RAP-ALS trial)

Introduction: Misfolded aggregated proteins and neuroinflammation significantly contribute to amyotrophic lateral sclerosis (ALS) pathogenesis, hence representing therapeutic targets to modify disease expression. Rapamycin inhibits mechanistic target of Rapamycin (mTOR) pathway and enhances autophagy with demonstrated beneficial effects in neurodegeneration in cell line and animal models, improving phenotype in SQSTM1 zebrafish, in Drosophila model of ALS-TDP, and in the TDP43 mouse model, in which it reduced neuronal loss and TDP43 inclusions. Rapamycin also expands regulatory T lymphocytes (Treg) and increased Treg levels are associated with slow progression in ALS patients. Therefore, we planned a randomized clinical trial testing Rapamycin treatment in ALS patients. Methods: RAP-ALS is a phase II randomized, double-blind, placebo-controlled, multicenter (8 ALS centers in Italy), clinical trial. The primary aim is to assess whether Rapamycin administration increases Tregs number in treated patients compared with control arm. Secondary aims include the assessment of safety and tolerability of Rapamycin in patients with ALS; the minimum dosage to have Rapamycin in cerebrospinal fluid; changes in immunological (activation and homing of T, B, NK cell subpopulations) and inflammatory markers, and on mTOR downstream pathway (S6RP phosphorylation); clinical activity (ALS Functional Rating Scale-Revised, survival, forced vital capacity); and quality of life (ALSAQ40 scale). Discussion: Rapamycin potentially targets mechanisms at play in ALS (i.e., autophagy and neuroinflammation), with promising preclinical studies. It is an already approved drug, with known pharmacokinetics, already available and therefore with significant possibility of rapid translation to daily clinics. Findings will provide reliable data for further potential trials. Ethics and dissemination: The study protocol was approved by the Ethics Committee of Azienda Ospedaliero Universitaria of Modena and by the Ethics Committees of participating centers (Eudract n. 2016-002399-28) based on the Helsinki declaration

Combined treatment modality for intracranial germinomas: results of a multicentre SFOP experience

Conventional therapy for intracranial germinomas is craniospinal irradiation. In 1990, the Société Française d'Oncologie Pédiatrique initiated a study combining chemotherapy (alternating courses of etoposide–carboplatin and etoposide–ifosfamide for a recommended total of four courses) with 40 Gy local irradiation for patients with localized germinomas. Metastatic patients were allocated to receive low-dose craniospinal radiotherapy. Fifty-seven patients were enrolled between 1990 and 1996. Forty-seven had biopsy-proven germinoma. Biopsy was not performed in ten patients (four had diagnostic tumour markers and in six the neurosurgeon felt biopsy was contraindicated). Fifty-one patients had localized disease, and six leptomeningeal dissemination. Seven patients had bifocal tumour. All but one patient received at least four courses of chemotherapy. Toxicity was mainly haematological. Patients with diabetus insipidus (n = 25) commonly developed electrolyte disturbances during chemotherapy. No patient developed tumour progression during chemotherapy. Fifty patients received local radiotherapy with a median dose of 40 Gy to the initial tumour volume. Six metastatic patients, and one patient with localized disease who stopped chemotherapy due to severe toxicity, received craniospinal radiotherapy. The median follow-up for the group was 42 months. Four patients relapsed 9, 10, 38 and 57 months after diagnosis. Three achieved second complete remission following salvage treatment with chemotherapy alone or chemo-radiotherapy. The estimated 3-year survival probability is 98% (CI: 86.6–99.7%) and the estimated 3-year event-free survival is 96.4% (CI: 86.2–99.1%). This study shows that excellent survival rates can be achieved by combining chemotherapy and local radiotherapy in patients with non-metastatic intracranial germinomas. © 1999 Cancer Research Campaig