Who Is in Love with Multilateralism? Treaty Commitment in the Post-Cold War Era

Since the end of the Cold War, multilateral treaties have again become a central vehicle for international cooperation. In this article, we study states’ commitment to 76 multilateral treaties concluded between 1990 and 2005. The article offers a systematic account of present-day multilateral treaty-making efforts and asks what explains variation in states’ participation as witnessed in the act of treaty ratification.We test existing explanations and provide a novel argument that accounts for the strong participation of new European democracies in multilateral treaties. We find that regime type and being part of the European Union (EU) strongly affect treaty ratification. New EU democracies, in particular, are much more likely to ratify multilateral treaties than are other new democracies.

Stratification and compartmentalisation of immunoglobulin responses to commensal intestinal microbes

The gastrointestinal tract is heavily colonized with commensal microbes with the concentration of bacteria increasing longitudinally down the length of the intestine. Bacteria are also spatially distributed transversely from the epithelial surface to the intestinal lumen with the inner mucus layer normally void of bacteria. Maintenance of this equilibrium is extremely important for human health and, as the dominant immunoglobulin at mucosal sites, IgA influences mutualism between the host and its normal microbiota. In this review we focus on the links between immune and microbial geography of the mammalian intestinal tract.

Dehydrin expression as a potential diagnostic tool for cold stress in white clover

Cold acclimation is important for crop survival in environments undergoing seasonal low temperatures. It involves the induction of defensive mechanisms including the accumulation of different cryoprotective molecules among which are dehydrins (DHN). Recently several sequences coding for dehydrins were identified in white clover (Trifolium repens). This work aimed to select the most responsive to cold stress DHN analogues in search for cold stress diagnostic markers. The assessment of dehydrin transcript accumulation via RT-PCR and immunodetection performed with three antibodies against the conserved K-, Y-, and S-segment allowed to outline different dehydrin types presented in the tested samples. Both analyses confirmed that YnKn dehydrins were underrepresented in the controls but exposure to low temperature specifically induced their accumulation. Strong immunosignals corresponding to 37–40 kDa with antibodies against Y- and K-segment were revealed in cold-stressed leaves. Another ‘cold-specific’ band at position 52–55 kDa was documented on membranes probed with antibodies against K-segment. Real time RT-qPCR confirmed that low temperatures induced the accumulation of SKn and YnSKn transcripts in leaves and reduced their expression in roots. Results suggest that a YnKn dehydrin transcript with GenBank ID: KC247805 and the immunosignal at 37–40 kDa, obtained with antibodies against Y- and K-segment are reliable markers for cold stress in white clover. The assessment of SKn (GenBank ID: EU846208) and YnSKn (GenBank ID: KC247804) transcript levels in leaves could serve as additional diagnostic tools.

The MI SYNTAX score for risk stratification in patients undergoing primary percutaneous coronary intervention for treatment of acute myocardial infarction: A substudy of the COMFORTABLE AMI trial.

BACKGROUND To investigate the performance of the MI Sxscore in a multicentre randomised trial of patients undergoing primary percutaneous coronary intervention (PPCI). METHODS AND RESULTS The MI Sxscore was prospectively determined among 1132 STEMI patients enrolled into the COMFORTABLE AMI trial, which randomised patients to treatment with bare-metal (BMS) or biolimus-eluting (BES) stents. Patient- (death, myocardial infarction, any revascularisation) and device-oriented (cardiac death, target-vessel MI, target lesion revascularisation) major adverse cardiac events (MACEs) were compared across MI Sxscore tertiles and according to stent type. The median MI SXscore was 14 (IQR: 9-21). Patients were divided into tertiles of Sxscorelow (≤10), Sxscoreintermediate (11-18) and Sxscorehigh (≥19). At 1year, patient-oriented MACE occurred in 15% of the Sxscorehigh, 9% of the Sxscoreintermediate and 5% of the Sxscorelow tertiles (p<0.001), whereas device-oriented MACE occurred in 8% of the Sxscorehigh, 6% of the Sxscoreintermediate and 4% of the Sxscorelow tertiles (p=0.03). Addition of the MI Sxscore to the TIMI risk score improved prediction of patient- (c-statistic value increase from 0.63 to 0.69) and device-oriented MACEs (c-statistic value increase from 0.65 to 0.70). Differences in the risk for device-oriented MACE between BMS and BES were evident among Sxscorehigh (13% vs. 4% HR 0.33 (0.15-0.74), p=0.007 rather than those in Sxscorelow: 4% vs. 3% HR 0.68 (0.24-1.97), p=0.48) tertiles. CONCLUSIONS The MI Sxscore allows risk stratification of patient- and device-oriented MACEs among patients undergoing PPCI. The addition of the MI Sxscore to the TIMI risk score is of incremental prognostic value among patients undergoing PPCI for treatment of STEMI.

Cardiac biomarkers and clinical scores for risk stratification in elderly patients with non-high-risk pulmonary embolism.

OBJECTIVE To determine the prognostic accuracy of cardiac biomarkers alone and in combination with clinical scores in elderly patients with non-high-risk pulmonary embolism (PE). DESIGN Ancillary analysis of a Swiss multicentre prospective cohort study. SUBJECTS A total of 230 patients aged ≥65 years with non-high-risk PE. MAIN OUTCOME MEASURES The study end-point was a composite of PE-related complications, defined as PE-related death, recurrent venous thromboembolism or major bleeding during a follow-up of 30 days. The prognostic accuracy of the Pulmonary Embolism Severity Index (PESI), the Geneva Prognostic Score (GPS), the precursor of brain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) was determined using sensitivity, specificity, predictive values, receiver operating characteristic (ROC) curve analysis, logistic regression and reclassification statistics. RESULTS The overall complication rate during follow-up was 8.7%. hs-cTnT achieved the highest prognostic accuracy [area under the ROC curve: 0.75, 95% confidence interval (CI): 0.63-0.86, P < 0.001). At the predefined cut-off values, the negative predictive values of the biomarkers were above 95%. For levels above the cut-off, the risk of complications increased fivefold for hs-cTnT [odds ratio (OR): 5.22, 95% CI: 1.49-18.25] and 14-fold for NT-proBNP (OR: 14.21, 95% CI: 1.73-116.93) after adjustment for both clinical scores and renal function. Reclassification statistics indicated that adding hs-cTnT to the GPS or the PESI significantly improved the prognostic accuracy of both clinical scores. CONCLUSION In elderly patients with nonmassive PE, NT-proBNP or hs-cTnT could be an adequate alternative to clinical scores for identifying low-risk individuals suitable for outpatient management.

Stratification of high-risk prostate cancer into prognostic categories: a European multi-institutional study

BACKGROUND High-risk prostate cancer (PCa) is an extremely heterogeneous disease. A clear definition of prognostic subgroups is mandatory. OBJECTIVE To develop a pretreatment prognostic model for PCa-specific survival (PCSS) in high-risk PCa based on combinations of unfavorable risk factors. DESIGN, SETTING, AND PARTICIPANTS We conducted a retrospective multicenter cohort study including 1360 consecutive patients with high-risk PCa treated at eight European high-volume centers. INTERVENTION Retropubic radical prostatectomy with pelvic lymphadenectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Two Cox multivariable regression models were constructed to predict PCSS as a function of dichotomization of clinical stage (< cT3 vs cT3-4), Gleason score (GS) (2-7 vs 8-10), and prostate-specific antigen (PSA; ≤ 20 ng/ml vs > 20 ng/ml). The first "extended" model includes all seven possible combinations; the second "simplified" model includes three subgroups: a good prognosis subgroup (one single high-risk factor); an intermediate prognosis subgroup (PSA >20 ng/ml and stage cT3-4); and a poor prognosis subgroup (GS 8-10 in combination with at least one other high-risk factor). The predictive accuracy of the models was summarized and compared. Survival estimates and clinical and pathologic outcomes were compared between the three subgroups. RESULTS AND LIMITATIONS The simplified model yielded an R(2) of 33% with a 5-yr area under the curve (AUC) of 0.70 with no significant loss of predictive accuracy compared with the extended model (R(2): 34%; AUC: 0.71). The 5- and 10-yr PCSS rates were 98.7% and 95.4%, 96.5% and 88.3%, 88.8% and 79.7%, for the good, intermediate, and poor prognosis subgroups, respectively (p = 0.0003). Overall survival, clinical progression-free survival, and histopathologic outcomes significantly worsened in a stepwise fashion from the good to the poor prognosis subgroups. Limitations of the study are the retrospective design and the long study period. CONCLUSIONS This study presents an intuitive and easy-to-use stratification of high-risk PCa into three prognostic subgroups. The model is useful for counseling and decision making in the pretreatment setting.

p.L1612P, a Novel Voltage-gated Sodium Channel Nav1.7 Mutation Inducing a Cold Sensitive Paroxysmal Extreme Pain Disorder

BACKGROUND Mutations in the SCN9A gene cause chronic pain and pain insensitivity syndromes. We aimed to study clinical, genetic, and electrophysiological features of paroxysmal extreme pain disorder (PEPD) caused by a novel SCN9A mutation. METHODS Description of a 4-generation family suffering from PEPD with clinical, genetic and electrophysiological studies including patch clamp experiments assessing response to drug and temperature. RESULTS The family was clinically comparable to those reported previously with the exception of a favorable effect of cold exposure and a lack of drug efficacy including with carbamazepine, a proposed treatment for PEPD. A novel p.L1612P mutation in the Nav1.7 voltage-gated sodium channel was found in the four affected family members tested. Electrophysiologically the mutation substantially depolarized the steady-state inactivation curve (V1/2 from -61.8 ± 4.5 mV to -30.9 ± 2.2 mV, n = 4 and 7, P < 0.001), significantly increased ramp current (from 1.8% to 3.4%, n = 10 and 12) and shortened recovery from inactivation (from 7.2 ± 5.6 ms to 2.2 ± 1.5 ms, n = 11 and 10). However, there was no persistent current. Cold exposure reduced peak current and prolonged recovery from inactivation in wild-type and mutated channels. Amitriptyline only slightly corrected the steady-state inactivation shift of the mutated channel, which is consistent with the lack of clinical benefit. CONCLUSIONS The novel p.L1612P Nav1.7 mutation expands the PEPD spectrum with a unique combination of clinical symptoms and electrophysiological properties. Symptoms are partially responsive to temperature but not to drug therapy. In vitro trials of sodium channel blockers or temperature dependence might help predict treatment efficacy in PEPD.

The Efficacy of a Novel Microbial 6-Phytase Expressed in Aspergillus oryzae on the Performance and Phosphorus Utilization of Cold- and Warm-Water Fish: Rainbow Trout, Oncorhynchus mykiss , and Nile Tilapia, Oreochromis niloticus

The efficacy and tolerance of a novel microbial 6-phytase were investigated in rainbow trout, Oncorhynchus mykiss, and Nile tilapia, Oreochromis niloticus. Reference diets were sufficient in available phosphorus (P). The test diet limiting in available P was supplemented with phytase at 500, 1000, or 2000 phytase units/kg feed. The enzyme was effective in increasing total P apparent digestibility coefficient in relation to increasing the dose of phytase in rainbow trout and Nile tilapia. Zinc apparent digestibility improved in relation to phytase supplementation in rainbow trout. P release due to phytase supplementation ranged from 0.06 to 0.18% P/kg feed in rainbow trout and from 0.13 to 0.26% P/kg feed in Nile tilapia. A 58-d performance trial was conducted to evaluate tolerance of fish to phytase supplementation. Dietary treatments consisted of a basal diet without phytase or supplemented with 2000 and 200,000 phytase units/kg feed. Results indicate that this novel microbial 6-phytase is well tolerated by fish. Significant improvements for growth as well as feed conversion ratio were observed when the phytase was fed at 2000 phytase units/kg feed. This phytase is proven efficient in releasing P from phytate and could be added when plants are used for fish meal replacement in diets for salmonid and omnivorous fish.