Background and purpose
Combining different therapies may improve disease control in patients with relapsing−remitting multiple sclerosis (RRMS). This study assessed the efficacy and safety of ...minocycline added to subcutaneous (sc) interferon (IFN) β‐1a therapy.
Methods
This was a double‐blind, randomized, placebo‐controlled multicentre study. Within 3 months (±1 month) of starting sc IFN β‐1a 44 μg three times weekly, patients with RRMS were randomized to minocycline 100 mg twice daily or placebo, added to sc IFN β‐1a, for 96 weeks. The primary efficacy endpoint was the time to first qualifying relapse. Secondary efficacy endpoints were the annualized relapse rate for qualifying relapses, the number of new/enlarging T2‐weighted lesions and change in brain volume magnetic resonance imaging (MRI) was performed only in a few selected centres. In addition, a number of tertiary efficacy endpoints were assessed.
Results
One hundred and forty‐nine patients received minocycline and 155 received placebo; MRI data were available for 23 and 27 patients, respectively. The time to first qualifying relapse did not differ significantly for minocycline versus placebo (hazard ratio 0.85; 95% confidence interval 0.53, 1.35; log‐rank = 0.50; P = 0.48). There were no statistically significant differences between the two groups on other efficacy endpoints, although some numerical trends in favour of minocycline were observed. No unexpected adverse events were reported, but more patients discontinued because of adverse events with minocycline versus placebo.
Conclusion
Minocycline showed no statistically significant beneficial effect when added to sc IFN β‐1a therapy.
In this review, we report on relevant current topics in allergen immunotherapy (AIT) which were broadly discussed during the first Aarhus Immunotherapy Symposium (Aarhus, Denmark) in December 2015 by ...leading clinicians, scientists and industry representatives in the field. The aim of this symposium was to highlight AIT‐related aspects of public health, clinical efficacy evaluation, mechanisms, development of new biomarkers and an overview of novel therapeutic approaches. Allergy is a public health issue of high socioeconomic relevance, and development of evidence‐based action plans to address allergy as a public health issue ought to be on national and regional agendas. The underlying mechanisms are in the focus of current research that lays the ground for innovative therapies. Standardization and harmonization of clinical endpoints in AIT trials as well as current knowledge about potential biomarkers have substantiated proof of effectiveness of this disease‐modifying therapeutic option. Novel treatments such as peptide immunotherapy, intralymphatic immunotherapy and use of recombinant allergens herald a new age in which AIT may address treatment of allergy as a public health issue by reaching a large fraction of patients.
Several gene expression signatures based on mRNAs and a few based on long non-coding RNAs (lncRNAs) have been developed to provide prognostic information beyond clinical evaluation in breast cancer ...(BC). However, the comparison of such signatures for predicting recurrence is very scarce. Therefore, we compared the prognostic utility of mRNAs and lncRNAs in low-risk BC patients using two different classification strategies. Frozen primary tumor samples from 160 lymph node negative and systemically untreated BC patients were included; 80 developed recurrence—i.e., regional or distant metastasis while 80 remained recurrence-free (mean follow-up of 20.9 years). Patients were pairwise matched for clinicopathological characteristics. Classification based on differential mRNA or lncRNA expression using seven individual machine learning methods and a voting scheme classified patients into risk-subgroups. Classification by the seven methods with a fixed sensitivity of ≥90% resulted in specificities ranging from 16–40% for mRNA and 38–58% for lncRNA, and after voting, specificities of 38% and 60% respectively. Classifier performance based on an alternative classification approach of balanced accuracy optimization also provided higher specificities for lncRNA than mRNA at comparable sensitivities. Thus, our results suggested that classification followed by voting improved prognostic power using lncRNAs compared to mRNAs regardless of classification strategy.
The aim of this study was to estimate genetic correlations (ra) between 2 lactation average somatic cell count (LASCC) traits and 6 different mastitis traits in 226,482 first-parity Danish Holstein ...cows that calved between 1998 and 2008. The LASCC traits were defined from 5 to either 170 d (LASCC_170) or 300 d (LASCC_300) after calving, and the mastitis traits were unspecific mastitis (all mastitis treatments, both clinical and subclinical, regardless of the causative pathogen) and mastitis caused by either Streptococcus dysgalactiae, Escherichia coli, coagulase-negative staphylococci (CNS), Staphylococcus aureus, or Streptococcus uberis. Variance components were estimated using bivariate threshold-Gaussian models via Gibbs sampling. The posterior means of ra between LASCC_170 and the mastitis traits were greatest for unspecific mastitis (ra=0.71), followed by CNS, Strep. dysgalactiae, Strep. uberis, and E. coli (ra=0.54 to 0.69) and were lowest for Staph. aureus mastitis (ra=0.44). The genetic correlation between LASCC_300 and the mastitis traits were generally smaller (ra=0.47 to 0.69). Caution should be taken when interpreting the results, however, because some posterior density intervals for ra were large (between 0.14 and 0.47 units). Phenotypically, Staph. aureus is known to be associated with high SCC and especially with subclinical mastitis through chronic infections, so the low ra between Staph. aureus mastitis and LASCC, compared with ra for the other pathogens, was not expected. Subclinical cases are usually submitted to dry cow therapy (not included in the present study), not treated at all, or wrongly recorded as clinical cases. Thus, the incidence of Staph. aureus mastitis is likely too low, and the genetic correlation between Staph. aureus mastitis and LASCC may therefore be underestimated in the present study. The results for the remaining pathogens were as expected, smallest for E. coli and larger but similar for Strep. dysgalactiae, Strep. uberis, and CNS. Selection for lower LASCC is expected to decrease the incidence of pathogen-specific mastitis, especially for Strep. uberis, Strep. dysgalactiae, and CNS and, to a lesser extent, for Staph. aureus and E. coli. Data recording should preferably be improved, and economic weights for the pathogen-specific mastitis traits should be estimated before implementing an udder health index that includes pathogen-specific mastitis traits.
Mastitis in dairy cows is an unavoidable problem and genetic variation in recovery from mastitis, in addition to susceptibility, is therefore of interest. Genetic parameters for susceptibility to and ...recovery from mastitis were estimated for Danish Holstein-Friesian cows using data from automatic milking systems equipped with online somatic cell count measuring units. The somatic cell count measurements were converted to elevated mastitis risk, a continuous variable on a (0–1) scale indicating the risk of mastitis. Risk values >0.6 were assumed to indicate that a cow had mastitis. For each cow and lactation, the sequence of health states (mastitic or healthy) was converted to a weekly transition: 0 if the cow stayed within the same state and 1 if the cow changed state. The result was 2 series of transitions: one for healthy to diseased (HD, to model mastitis susceptibility) and the other for diseased to healthy (DH, to model recovery ability). The 2 series of transitions were analyzed with bivariate threshold models, including several systematic effects and a function of time. The model included effects of herd, parity, herd-test-week, permanent environment (to account for the repetitive nature of transition records from a cow) plus two time-varying effects (lactation stage and time within episode). In early lactation, there was an increased risk of getting mastitis but the risk remained stable afterwards. Mean recovery rate was 45% per lactation. Heritabilities were 0.07 posterior mean of standard deviations (PSD) = 0.03 for HD and 0.08 (PSD = 0.03) for DH. The genetic correlation between HD and DH has a posterior mean of −0.83 (PSD = 0.13). Although susceptibility and recovery from mastitis are strongly negatively correlated, recovery can be considered as a new trait for selection.
Lipoprotein lipase (LPL) activity is considered the rate-limiting step of very-low-density-lipoprotein triglycerides (VLDL-TG) tissue storage, and has been suggested to relate to the development of ...obesity as well as insulin resistance and type 2 diabetes.
The objective of the study was to assess the relationship between the quantitative storage of VLDL-TG fatty acids and LPL activity and other storage factors in muscle and adipose tissue. In addition, we examine whether such relations were influenced by type 2 diabetes.
We recruited 23 men (12 with type 2 diabetes, 11 nondiabetic) matched for age and body mass index. Postabsorptive VLDL-TG muscle and subcutaneous adipose tissue (abdominal and leg) quantitative storage was measured using tissue biopsies in combination with a primed-constant infusion of ex vivo triolein labeled 1-14CVLDL-TG and a bolus infusion of ex vivo triolein labeled 9,10-3HVLDL-TG. Biopsies were analyzed for LPL activity and cellular storage factors.
VLDL-TG storage rate was significantly greater in men with type 2 diabetes compared with nondiabetic men in muscle tissue (P = 0.02). We found no significant relationship between VLDL-TG storage rate and LPL activity or other storage factors in muscle or adipose tissue. However, LPL activity correlated with fractional VLDL-TG storage in abdominal fat (P = 0.04).
Men with type 2 diabetes have increased VLDL-TG storage in muscle tissue, potentially contributing to increased intramyocellular triglyceride and ectopic lipid deposition. Neither muscle nor adipose tissue storage rates were related to LPL activity. This argues against LPL as a rate-limiting step in the postabsorptive quantitative storage of VLDL-TG.
To investigate whether the efficacy of interferon-beta (IFNbeta) treatment of relapsing-remitting MS (RR-MS) was influenced by type, dose, and frequency of administration.
From June 1996 through ...October 1997, the authors offered participation to all Danish RR-MS patients who met the following criteria: definite MS, at least two relapses within 2 years, age 18 to 55, and an Expanded Disability Status Scale (EDSS) score of < or = 5.5. The study was multicenter, controlled, open-label, randomized, head-to-head comparing IFNbeta-1a 22 microg once a week (n = 143) with IFNbeta-1b 250 microg every other day (n = 158), both subcutaneously, for 24 months. Patients who declined randomization were offered treatment with IFNbeta-1b 250 microg every other day (n = 120). The primary end-points were the annualized relapse rate, the time to first relapse, and neutralizing antibody formation. The secondary endpoint was time to sustained progression.
The annual relapse rates were virtually equal in the two arms of the randomized study (IFNbeta-1a: 0.70; IFNbeta-1b: 0.71); so were the time to first relapse and the time to sustained progression. In the nonrandomized patients (IFNbeta-1b), the annual relapse rate was not significantly different, but the time to progression was shorter.
In this study, 250 microg interferon-beta-1b administered every other day did not prove clinically superior to once-a-week administration of 22 microg interferon-beta-1a.
Abstract
The analytical point of departure in this paper is the ongoing debate, initiated by Ulrich Beck, on methodological nationalism within the social sciences. Based on a comprehensive study of ...research collaboration and mobility of researchers this paper discusses possible traces of methodological nationalism in comparative studies of research performance. These studies are often carried out as country comparisons with no or little focus on the growing transnationality of what is measured. However, research is a transnational activity and must be understood as such. Researchers increasingly collaborate with researchers in other countries. The national research institutions are increasingly transnationalised due to the growing mobility of researchers. Based on an examination of all the papers registered in the Thompson Reuter’s Web of Science database we follow the development in research collaboration in the period 1980–2014 for 17 leading research countries.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
To assess basal and insulin-mediated VLDL-triglyceride (TG) kinetics and the relationship between VLDL-TG secretion and hepatic insulin resistance assessed by endogenous glucose production (EGP) in ...obese and lean men.
A total of 12 normoglycemic, obese (waist-to-hip ratio >0.9, BMI >30 kg/m(2)) and 12 lean (BMI 20-25 kg/m(2)) age-matched men were included. Ex vivo-labeled 1-(14)CVLDL-TGs and 3-(3)Hglucose were infused postabsorptively and during a hyperinsulinemic-euglycemic clamp to determine VLDL-TG kinetics and EGP. Body composition was determined by dual X-ray absorptiometry and computed tomography scanning. Energy expenditure and substrate oxidation rates were measured by indirect calorimetry.
Basal VLDL-TG secretion rates were increased in obese compared with lean men (1.25 ± 0.34 vs. 0.86 ± 0.34 μmol/kg fat-free mass FFM/min; P = 0.011), whereas there was no difference in clearance rates (150 ± 56 vs. 162 ± 77 mL/min; P = NS), resulting in greater VLDL-TG concentrations (0.74 ± 0.40 vs. 0.38 ± 0.20 mmol/L; P = 0.011). The absolute insulin-mediated suppression of VLDL-TG secretion was similar in the groups. However, the percentage reduction (-36 ± 18 vs. -54 ± 10%; P = 0.008) and achieved VLDL-TG secretion rates (0.76 ± 0.20 vs. 0.41 ± 0.19 μmol/kg FFM/min; P < 0.001) were impaired in obese men. Furthermore, clearance rates decreased significantly in obese men, but there was no significant change in lean men (-17 ± 18 vs. 7 ± 20%; P = 0.007), resulting in less percentage reduction of VLDL-TG concentrations in obese men (-22 ± 20 vs. -56 ± 11%; P < 0.001). Insulin-suppressed EGP was similar (0.4 0.0-0.8 vs. 0.1 0.0-1.2 mg/kg FFM/min (median range); P = NS), and the percentage reduction was equivalent (-80% 57-98 vs. -98% 49-100, P = NS). Insulin-mediated glucose disposal was significantly reduced in obese men.
Basal VLDL-TG secretion rates are increased in normoglycemic but insulin-resistant, obese men, resulting in hypertriglyceridemia. Insulin-mediated suppression of EGP is preserved in obese men, whereas suppression of VLDL-TG secretion is less pronounced in obese men. Compared with EGP, the inability to achieve suppression of VLDL-TG secretions to a level similar to control subjects during hyperinsulinemia seems to be an early manifestation in male obesity.
PDF
