Amelioration of Proteolipid Protein 139–151-Induced Encephalomyelitis in SJL Mice by Modified Amino Acid Copolymers and Their Mechanisms

Copolymer 1 [Cop1, glatiramer acetate, Copaxone, poly(Y,E,A,K)n] is widely used in the treatment of relapsing/remitting multiple sclerosis in which it reduces the frequency of relapses by ≈30%. In the present study, copolymers with modified amino acid compositions (based on the binding motif of myelin basic protein 85–99 to HLA-DR2) have been developed with the aim of suppressing multiple sclerosis more effectively. The enhanced efficacy of these copolymers in experimental autoimmune encephalomyelitis (EAE) induced in SJL/J mice with proteolipid protein 139–151 was demonstrated by using three protocols: (i) simultaneous administration of autoantigen and copolymer (termed prevention), (ii) pretreatment with copolymers (vaccination), or (iii) administration of copolymers after disease onset (treatment). Strikingly, in the treatment protocol administration of soluble VWAK and FYAK after onset of disease led to stasis of its progression and suppression of histopathological evidence of EAE. The mechanisms by which these effects are achieved have been examined in several types of assays: binding of copolymers to I-As in competition with proteolipid protein 139–151 (blocking), cytokine production by T cells (T helper 2 polarization), and transfer of protection by CD3+ splenocytes or, notably, by copolymer-specific T cell lines (induction of regulatory T cells). The generation of these copolymerspecific regulatory T cells that secrete IL-4 and IL-10 and are independent of the immunizing autoantigen is very prominent among the multiple mechanisms that account for the observed suppressive effect of copolymers in EAE

FDG-PET as a predictive biomarker for therapy with everolimus in metastatic renal cell cancer

AbstractThe mTOR (mammalian target of rapamycin) inhibitor, everolimus, affects tumor growth by targeting cellular metabolic proliferation pathways and delays renal cell carcinoma (RCC) progression. Preclinical evidence suggests that baseline elevated tumor glucose metabolism as quantified by FDG-PET ([18F] fluorodeoxy-glucose positron emission tomography) may predict antitumor activity. Metastatic RCC (mRCC) patients refractory to vascular endothelial growth factor (VEGF) pathway inhibition were treated with standard dose everolimus. FDG-PET scans were obtained at baseline and 2weeks; serial computed tomography (CT) scans were obtained at baseline and every 8weeks. Maximum standardized uptake value (SUVmax) of the most FDG avid lesion, average SUVmax of all measured lesions and their corresponding 2-week relative changes were examined for association with 8-week change in tumor size. A total of 63 patients were enrolled; 50 were evaluable for the primary endpoint of which 48 had both PET scans. Patient characteristics included the following: 36 (72%) clear cell histology and median age 59 (range: 37–80). Median pre- and 2-week treatment average SUVmax were 6.6 (1–17.9) and 4.2 (1–13.9), respectively. Response evaluation criteria in solid tumors (RECIST)-based measurements demonstrated an average change in tumor burden of 0.2% (−32.7% to 35.9%) at 8weeks. Relative change in average SUVmax was the best predictor of change in tumor burden (all evaluable P=0.01; clear cell subtype P=0.02), with modest correlation. Baseline average SUVmax was correlated with overall survival and progression-free survival (PFS) (P=0.023; 0.020), but not with change in tumor burden. Everolimus therapy decreased SUVs on follow-up PET scans in mRCC patients, but changes were only modestly correlated with changes in tumor size. Thus, clinical use of FDG-PET-based biomarkers is challenged by high variability.In this phase II trial, FDG-PET was explored as a predictive biomarker for response to everolimus (mTOR inhibition) in metastatic renal cell carcinoma. Everolimus therapy decreased SUVs on follow-up FDG-PET scans in these patients. SUV changes were modestly correlated with changes in tumor size and baseline average SUVmax values were correlated with overall survival

The risk stratification of adverse neonatal outcomes in women with gestational diabetes (STRONG) study

Aims: To assess the risk of adverse neonatal outcomes in women with gestational diabetes (GDM) by identifying subgroups of women at higher risk to recognize the characteristics most associated with an excess of risk. Methods: Observational, retrospective, multicenter study involving consecutive women with GDM. To identify distinct and homogeneous subgroups of women at a higher risk, the RECursive Partitioning and AMalgamation (RECPAM) method was used. Overall, 2736 pregnancies complicated by GDM were analyzed. The main outcome measure was the occurrence of adverse neonatal outcomes in pregnancies complicated by GDM. Results: Among study participants (median age 36.8 years, pre-gestational BMI 24.8 kg/m2), six miscarriages, one neonatal death, but no maternal death was recorded. The occurrence of the cumulative adverse outcome (OR 2.48, 95% CI 1.59–3.87), large for gestational age (OR 3.99, 95% CI 2.40–6.63), fetal malformation (OR 2.66, 95% CI 1.00–7.18), and respiratory distress (OR 4.33, 95% CI 1.33–14.12) was associated with previous macrosomia. Large for gestational age was also associated with obesity (OR 1.46, 95% CI 1.00–2.15). Small for gestational age was associated with first trimester glucose levels (OR 1.96, 95% CI 1.04–3.69). Neonatal hypoglycemia was associated with overweight (OR 1.52, 95% CI 1.02–2.27) and obesity (OR 1.62, 95% CI 1.04–2.51). The RECPAM analysis identified high-risk subgroups mainly characterized by high pre-pregnancy BMI (OR 1.68, 95% CI 1.21–2.33 for obese; OR 1.38 95% CI 1.03–1.87 for overweight). Conclusions: A deep investigation on the factors associated with adverse neonatal outcomes requires a risk stratification. In particular, great attention must be paid to the prevention and treatment of obesity

Improved S factor of the 12C(p,γ)13N reaction at E=320–620 keV and the 422 keV resonance

The 12C(p,γ)13N reaction is the onset process of both the CNO and hot CNO cycles that drive massive star, red and asymptotic giant branch star, and novae nucleosynthesis. The 12C(p,γ)13N rate affects the final abundances of the stable 12,13C nuclides with ramifications for meteoritic carbon isotopic abundances and the s-process neutron source strength. Here, an underground measurement of the 12C(p,γ)13N cross section is reported. The present data, obtained at the Felsenkeller shallow-underground laboratory in Dresden (Germany), encompass the 320–620 keV center of mass energy range to include the wide and poorly constrained E=422 keV resonance that dominates the rate at high temperatures. This work's S-factor results, lower than literature by 25%, are included in a comprehensive R-matrix fit, and the energy of the 12+ first excited state of 13N is found to be 2369.6(4) keV with a radiative and proton width of 0.49(3) eV and 34.9(2) keV, respectively. A reaction rate, based on the present R-matrix fit and extrapolation, is suggested

Underground experimental study finds no evidence of low-energy resonance in the 6Li(p,γ)7Be reaction

The astrophysical Li6(p,\u3b3)Be7 reaction occurs during Big Bang nucleosynthesis and the pre-main sequence and main sequence phases of stellar evolution. The low-energy trend of its cross section remains uncertain, since different measurements have provided conflicting results. A recent experiment reported a resonancelike structure at center-of-mass energy 195 keV, associated to a positive-parity state of Be7. The existence of such resonance is still a matter of debate. We report a new measurement of the Li6(p,\u3b3)Be7 cross section performed at the Laboratory for Underground Nuclear Astrophysics, covering the center-of-mass energy range E=60-350 keV. Our results rule out the existence of low-energy resonances. The astrophysical S-factor varies smoothly with energy, in agreement with theoretical models

First direct limit on the 334 keV resonance strength in the 22^{22}Ne({\alpha},{\gamma})26^{26}Mg reaction

In stars, the fusion of $^{22}$Ne and $^4$He may produce either $^{25}$Mg, with the emission of a neutron, or $^{26}$Mg and a $\gamma$ ray. At high temperature, the ($\alpha,n$) channel dominates, while at low temperature, it is energetically hampered. The rate of its competitor, the $^{22}$Ne($\alpha$,$\gamma$)$^{26}$Mg reaction, and, hence, the minimum temperature for the ($\alpha,n$) dominance, are controlled by many nuclear resonances. The strengths of these resonances have hitherto been studied only indirectly. The present work aims to directly measure the total strength of the resonance at $E$_{r}$\,=\,$334$\,$keV (corresponding to $E$_{x}$\,=\,$10949$\,$keV in $^{26}$Mg). The data reported here have been obtained using high intensity $^4$He$^+$ beam from the INFN LUNA 400 kV underground accelerator, a windowless, recirculating, 99.9% isotopically enriched $^{22}$Ne gas target, and a 4$\pi$ bismuth germanate summing $\gamma$-ray detector. The ultra-low background rate of less than 0.5 counts/day was determined using 67 days of no-beam data and 7 days of $^4$He$^+$ beam on an inert argon target. The new high-sensitivity setup allowed to determine the first direct upper limit of 4.0$\,\times\,$10$^{-11}$ eV (at 90% confidence level) for the resonance strength. Finally, the sensitivity of this setup paves the way to study further $^{22}$Ne($\alpha$,$\gamma$)$^{26}$Mg resonances at higher energy.Comment: Submitted to Eur. Phys. J.

Characterization of the LUNA neutron detector array for the measurement of the 13C(α,n)16O reaction

We introduce the LUNA neutron detector array developed for the investigation of the 13C(\u3b1, n)16O reaction towards its astrophysical s-process Gamow peak in the low-background environment of the Laboratori Nazionali del Gran Sasso (LNGS). Eighteen 3He counters are arranged in two different configurations (in a vertical and a horizontal orientation) to optimize neutron detection efficiency, target handling and target cooling over the investigated energy range E\u3b1,lab=300 12400 keV (En=2.2 122.6MeV in emitted neutron energy). As a result of the deep underground location, the passive shielding of the setup and active background suppression using pulse shape discrimination, we reached a total background rate of 1.23\ub10.12 counts/hour. This resulted in an improvement of two orders of magnitude over the state of the art allowing a direct measurement of the 13C(\u3b1, n)16O cross-section down to E\u3b1,lab=300 keV. The absolute neutron detection efficiency of the setup was determined using the 51V(p,n)51Cr reaction and an AmBe radioactive source, and completed with a Geant4 simulation. We determined a (34 \ub1 3)% and (38 \ub1 3)% detection efficiency for the vertical and horizontal configurations, respectively, for En=2.4MeV neutrons

Undiagnosed comorbidities among individuals hospitalised with COVID-19 in South African public hospitals

Background. Previous studies have reported comorbid disease, including hypertension, diabetes mellitus, chronic cardiac and renal disease, malignancy, HIV, tuberculosis (TB) and obesity, to be associated with COVID‑19 mortality. National demographic surveys have reported a high proportion of undiagnosed and untreated comorbid disease in South Africa (SA). Objectives. To determine the number of individuals with previously undiagnosed HIV, TB and non-communicable diseases (NCDs) among patients hospitalised with COVID‑19, and the level of medical control of these chronic diseases. Methods. We conducted a sentinel surveillance study to collect enhanced data on HIV, TB and NCDs among individuals with COVID‑19 admitted to 16 secondary-level public hospitals in six of the nine provinces of SA. Trained surveillance officers approached all patients who met the surveillance case definition for inclusion in the study, and consenting patients were enrolled. The data collection instrument included questions on past medical history to determine the self-reported presence of comorbidities. The results of clinical and laboratory testing introduced as part of routine clinical care for hospitalised COVID‑19 patients were collected for the study, to objectively determine the presence of hypertension, diabetes, HIV and TB and the levels of control of diabetes and HIV. Results. On self-reported history, the most prevalent comorbidities were hypertension (n=1 658; 51.5%), diabetes (n=855; 26.6%) and HIV (n=603; 18.7%). The prevalence of self-reported active TB was 3.1%, and that of previous TB 5.5%. There were 1 254 patients admitted with COVID‑19 (39.0%) who met the body mass index criteria for obesity. On clinical and laboratory testing, 87 patients were newly diagnosed with HIV, 29 with TB, 215 with diabetes and 40 with hypertension during their COVID‑19 admission. There were 151/521 patients living with HIV (29.0%) with a viral load >1 000 copies/mL and 309/570 (54.2%) with a CD4 count <200 cells/μL. Among 901 patients classified as having diabetes, 777 (86.2%) had a glycated haemoglobin (HbA1c) level ≥6.5%. Conclusion. The study revealed a high prevalence of comorbid conditions among individuals with COVID‑19 admitted to public hospitals in SA. In addition, a significant number of patients had previously undiagnosed hypertension, diabetes, HIV and active TB, and many and poorly controlled chronic disease, as evidenced by high HbA1c levels in patients with diabetes, and high viral loads and low CD4 levels in patients with HIV. The findings highlight the importance of strengthening health systems and care cascades for chronic disease management, which include prevention, screening for and effectively treating comorbidities, and ensuring secure and innovative supplies of medicines in primary healthcare during the COVID‑19 pandemic