The objective was to determine whether metabolic goals have been achieved with locally isolated and transported preparations over the first 3 years of the UK's nationally funded integrated islet ...transplant program. Twenty islet recipients with C‐peptide negative type 1 diabetes and recurrent severe hypoglycemia consented to the study, including standardized meal tolerance tests. Participants received a total of 35 infusions (seven recipients: single graft; 11 recipients: two grafts: two recipients: three grafts). Graft function was maintained in 80% at median (interquartile range) 24 (13.5–36) months postfirst transplant. Severe hypoglycemia was reduced from 20 (7–50) episodes/patient‐year pretransplant to 0.3 (0–1.6) episodes/patient‐year posttransplant (p < 0.001). Resolution of impaired hypoglycemia awareness was confirmed pretransplant: Gold score 6 (5–7); 24 (13.5–36) months: 3 (1.5–4.5); p < 0.03. Target HbA1c of <7.0% was attained/maintained in 70% of recipients pretransplant: 8.0 (7.0–9.6)%; 24 (13.5–36) months: 6.2 (5.7–8.4)%; p < 0.001, with 60% reduction in insulin dose pretransplant: 0.51 (0.41–0.62) units/kg; 24 (13.5–36) months: 0.20 (0–0.37) units/kg; p < 0.001. Metabolic outcomes were comparable 12 months posttransplant in those receiving transported versus only locally isolated islets 12 month stimulated C‐peptide: transported 788 (114–1764) pmol/L (n = 9); locally isolated 407 (126–830) pmol/L (n = 11); p = 0.32. Metabolic goals have been attained within the equitably available, fully integrated UK islet transplant program with both transported and locally isolated preparations.
In this report on a cohort of recipients within the UK government–funded fully integrated islet transplant program, the authors demonstrate attainment of metabolic goals with both locally isolated and transported islets with comparable graft survival up to 36 months posttransplant.
Elastic neutrino scattering on electrons is a precisely known purely leptonic process that provides a standard candle for measuring neutrino flux in conventional neutrino beams. Using a total sample ...of 810 neutrino-electron scatters after background subtraction, the measurement reduces the normalization uncertainty on the ν μ NuMI beam flux between 2 and 20 GeV from 7.6 to 3.9%. This is the most precise measurement of neutrino-electron scattering to date, will reduce uncertainties on MINER ν A's absolute cross section measurements, and demonstrates a technique that can be used in future neutrino beams such as long baseline neutrino facility.
Final-state kinematic imbalances are measured in mesonless production of νμ+A→μ-+p+X in the MINERvA tracker. Initial- and final-state nuclear effects are probed using the direction of the μ- - p ...transverse momentum imbalance and the initial-state momentum of the struck neutron. Differential cross sections are compared to predictions based on current approaches to medium modeling. These models underpredict the cross section at intermediate intranuclear momentum transfers that generally exceed the Fermi momenta. As neutrino interaction models need to correctly incorporate the effect of the nucleus in order to predict neutrino energy resolution in oscillation experiments, this result points to a region of phase space where additional cross section strength is needed in current models, and demonstrates a new technique that would be suitable for use in fine-grained liquid argon detectors where the effect of the nucleus may be even larger.
We present double-differential measurements of antineutrino charged-current quasielastic scattering in the MINERvA detector. This study improves on a previous single-differential measurement by using ...updated reconstruction algorithms and interaction models and provides a complete description of observed muon kinematics in the form of a double-differential cross section with respect to muon transverse and longitudinal momentum. We include in our signal definition zero-meson final states arising from multinucleon interactions and from resonant pion production followed by pion absorption in the primary nucleus. We find that model agreement is considerably improved by a model tuned to MINERvA inclusive neutrino scattering data that incorporates nuclear effects such as weak nuclear screening and two-particle, two-hole enhancements.
Zika virus (ZIKV) is a mosquito-borne flavivirus responsible for thousands of cases of severe fetal malformations and neurological disease since its introduction to Brazil in 2013. Antibodies to ...flaviviruses can be protective, resulting in lifelong immunity to reinfection by homologous virus. However, cross-reactive antibodies can complicate flavivirus diagnostics and promote more severe disease, as noted after serial dengue virus (DENV) infections. The endemic circulation of DENV in South America and elsewhere raises concerns that preexisting flavivirus immunity may modulate ZIKV disease and transmission potential. Here, we report on the ability of human monoclonal antibodies and immune sera derived from dengue patients to neutralize contemporary epidemic ZIKV strains. We demonstrate that a class of human monoclonal antibodies isolated from DENV patients neutralizes ZIKV in cell culture and is protective in a lethal murine model. We also tested a large panel of convalescent-phase immune sera from humans exposed to primary and repeat DENV infection. Although ZIKV is most closely related to DENV compared to other human-pathogenic flaviviruses, most DENV immune sera (73%) failed to neutralize ZIKV, while others had low (50% effective concentration EC50, <1:100 serum dilution; 18%) or moderate to high (EC50, >1:100 serum dilution; 9%) levels of cross-neutralizing antibodies. Our results establish that ZIKV and DENV share epitopes that are targeted by neutralizing, protective human antibodies. The availability of potently neutralizing human monoclonal antibodies provides an immunotherapeutic approach to control life-threatening ZIKV infection and also points to the possibility of repurposing DENV vaccines to induce cross-protective immunity to ZIKV.
ZIKV is an emerging arbovirus that has been associated with severe neurological birth defects and fetal loss in pregnant women and Guillain-Barré syndrome in adults. Currently, there is no vaccine or therapeutic for ZIKV. The identification of a class of antibodies (envelope dimer epitope 1 EDE1) that potently neutralizes ZIKV in addition to all four DENV serotypes points to a potential immunotherapeutic to combat ZIKV. This is especially salient given the precedent of antibody therapy to treat pregnant women infected with other viruses associated with microcephaly, such as cytomegalovirus and rubella virus. Furthermore, the identification of a functionally conserved epitope between ZIKV and DENV raises the possibility that a vaccine may be able to elicit neutralizing antibodies against both viruses.
Relaxin-3 (INSL-7) is a recently discovered member of the insulin superfamily. Relaxin-3 mRNA is expressed in the nucleus incertus of the brainstem, which has projections to the hypothalamus. ...Relaxin-3 binds with high affinity to the LGR7 receptor and to the previously orphan G protein-coupled receptor GPCR135. GPCR135 mRNA is expressed predominantly in the central nervous system, particularly in the paraventricular nucleus (PVN). The presence of relaxin-3 and these receptors in the PVN led us to investigate the effect of central administration of relaxin-3 on food intake in male Wistar rats. The receptor involved in mediating these effects was also investigated. Intracerebroventricular injections of human relaxin-3 (H3) to satiated rats significantly increased food intake 1 h post administration in the early light phase 0.96 ± 0.16 g (vehicle) vs. 1.81 ± 0.21 g (180 pmol H3), P < 0.05 and the early dark phase 2.95 ± 0.45 g (vehicle) vs. 4.39 ± 0.39 g (180 pmol H3), P < 0.05. Intra-PVN H3 administration significantly increased 1-h food intake in satiated rats in the early light phase 0.34 ± 0.16 g (vehicle) vs. 1.23 ± 0.30 g (18 pmol H3), P < 0.05 and the early dark phase 4.43 ± 0.32 g (vehicle) vs. 6.57 ± 0.42 g (18 pmol H3), P < 0.05. Feeding behavior increased after intra-PVN H3. Equimolar doses of human relaxin-2, which binds the LGR7 receptor but not GPCR135, did not increase feeding. Hypothalamic neuropeptide Y, proopiomelanocortin, or agouti-related peptide mRNA expression did not change after acute intracerebroventricular H3. These results suggest a novel role for relaxin-3 in appetite regulation.
Summary
Reasons for performing study: Hyperinsulinaemia is known to induce laminitis experimentally in healthy ponies with no history of the condition. Horses are more insulin sensitive than ponies ...and whether prolonged hyperinsulinaemia and euglycaemia would have a similar laminitogenic effect requires study.
Objectives: To determine if laminitis results when the prolonged euglycaemic hyperinsulinaemic clamp technique (p‐EHC) is applied to clinically normal Standardbred horses, and to monitor hoof wall temperature seeking an association between vascular activity and laminitis development.
Methods: Eight young, clinically normal Standardbred horses were assigned into 4 pairs and within each pair, one was assigned randomly to either treatment (n = 4) or control (n = 4) groups. Treated horses received continuous infusions of insulin and glucose until clinical signs of laminitis developed, at which point the horses were subjected to euthanasia. Control horses received an equivalent volume of a balanced electrolyte infusion for the same period. Hoof wall surface temperature (HWST) was monitored continuously throughout the experimental period.
Results: All horses in the treatment group were calculated to have normal insulin sensitivity. All treated horses, and none in the control group, developed laminitis (P = 0.01). Pronounced digital pulses were a feature of the treatment group, while insignificant digital pulses occurred in control horses. HWST was higher and less variable in treated horses once hyperinsulinaemia was established.
Conclusions: Healthy Standardbred horses subjected to prolonged hyperinsulinaemia develop laminitis within 48 h, demonstrating that laminitis in horses can be triggered by insulin.
Potential relevance: Insulin resistance and the associated hyperinsulinaemia place horses and ponies at risk of developing laminitis. This study demonstrates a need for prompt management of the persistent hyperinsulinaemia seen in some endocrinopathies.
Muon-neutrino elastic scattering on electrons is an observable neutrino process whose cross section is precisely known. Consequently a measurement of this process in an accelerator-based nu sub(mu) ...beam can improve the knowledge of the absolute neutrino flux impinging upon the detector; typically this knowledge is limited to ~10% due to uncertainties in hadron production and focusing. We have isolated a sample of 135+ or -17 neutrino-electron elastic scattering candidates in the segmented scintillator detector of MINERvA, after subtracting backgrounds and correcting for efficiency. We show how this sample can be used to reduce the total uncertainty on the NuMI flux nu sub(mu) from 9% to 6%. Our measurement provides a flux constraint that is useful to other experiments using the NuMI beam, and this technique is applicable to future neutrino beams operating at multi-GeV energies.
Knowledge of the neutrino flux produced by the Neutrinos at the Main Injector (NuMI) beamline is essential to the neutrino oscillation and neutrino interaction measurements of the MINERvA, MINOS+, ...NOvA and MicroBooNE experiments at Fermi National Accelerator Laboratory. We have produced a flux prediction which uses all available and relevant hadron production data, incorporating measurements of particle production off of thin targets as well as measurements of particle yields from a spare NuMI target exposed to a 120 GeV proton beam. The result is the most precise flux prediction achieved for a neutrino beam in the one to tens of GeV energy region. We have also compared the prediction to in situ measurements of the neutrino flux and find good agreement.
IMPORTANCE: Left ventricular assist device (LVAD) therapy improves myocardial function, but few patients recover sufficiently for explant, which has focused attention on stem cells to augment cardiac ...recovery. OBJECTIVE: To assess efficacy and adverse effects of intramyocardial injections of mesenchymal precursor cells (MPCs) during LVAD implant. DESIGN, SETTING, AND PARTICIPANTS: A randomized phase 2 clinical trial involving patients with advanced heart failure, undergoing LVAD implant, at 19 North American centers (July 2015-August 2017). The 1-year follow-up ended August 2018. INTERVENTIONS: Intramyocardial injections of 150 million allogeneic MPCs or cryoprotective medium as a sham treatment in a 2:1 ratio (n = 106 vs n = 53). MAIN OUTCOMES AND MEASURES: The primary efficacy end point was the proportion of successful temporary weans (of 3 planned assessments) from LVAD support within 6 months of randomization. This end point was assessed using a Bayesian analysis with a predefined threshold of a posterior probability of 80% to indicate success. The 1-year primary safety end point was the incidence of intervention-related adverse events (myocarditis, myocardial rupture, neoplasm, hypersensitivity reactions, and immune sensitization). Secondary end points included readmissions and adverse events at 6 months and 1-year survival. RESULTS: Of 159 patients (mean age, 56 years; 11.3% women), 155 (97.5%) completed 1-year of follow-up. The posterior probability that MPCs increased the likelihood of successful weaning was 69%; below the predefined threshold for success. The mean proportion of successful temporary weaning from LVAD support over 6 months was 61% in the MPC group and 58% in the control group (rate ratio RR, 1.08; 95% CI, 0.83-1.41; P = .55). No patient experienced a primary safety end point. Of 10 prespecified secondary end points reported, 9 did not reach statistical significance. One-year mortality was not significantly different between the MPC group and the control group (14.2% vs 15.1%; hazard ratio HR, 0.89; 95%, CI, 0.38-2.11; P = .80). The rate of serious adverse events was not significantly different between groups (70.9 vs 78.7 per 100 patient-months; difference, −7.89; 95% CI, −39.95 to 24.17; P = .63) nor was the rate of readmissions (0.68 vs 0.75 per 100 patient-days; difference, −0.07; 95% CI, −0.41 to 0.27; P = .68). CONCLUSIONS AND RELEVANCE: Among patients with advanced heart failure, intramyocardial injections of mesenchymal precursor cells, compared with injections of a cryoprotective medium as sham treatment, did not improve successful temporary weaning from left ventricular assist device support at 6 months. The findings do not support the use of intramyocardial mesenchymal stem cells to promote cardiac recovery as measured by temporary weaning from device support. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02362646
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