Chirped pulse Raman amplification in warm plasma: towards controlling saturation

Stimulated Raman backscattering in plasma is potentially an efficient method of amplifying laser pulses to reach exawatt powers because plasma is fully broken down and withstands extremely high electric fields. Plasma also has unique nonlinear optical properties that allow simultaneous compression of optical pulses to ultra-short durations. However, current measured efficiencies are limited to several percent. Here we investigate Raman amplification of short duration seed pulses with different chirp rates using a chirped pump pulse in a preformed plasma waveguide. We identify electron trapping and wavebreaking as the main saturation mechanisms, which lead to spectral broadening and gain saturation when the seed reaches several millijoules for durations of 10's - 100's fs for 250 ps, 800 nm chirped pump pulses. We show that this prevents access to the nonlinear regime and limits the efficiency, and interpret the experimental results using slowly-varying-amplitude, current-averaged particle-in-cell simulations. We also propose methods for achieving higher efficiencies.close0

Nivolumab combined with brentuximab vedotin for R/R primary mediastinal large B-cell lymphoma: a 3-year follow-up.

Patients with relapsed/refractory primary mediastinal large B-cell lymphoma (R/R PMBL) have poor responses to salvage therapy. Nivolumab and brentuximab vedotin (BV) showed promising early efficacy in patients with R/R PMBL in the phase 1/2 open-label, multicenter CheckMate 436 study; we report safety and efficacy findings from the 3-year follow-up. Patients who were eligible were aged ≥15 years with R/R PMBL previously treated with either high-dose chemotherapy plus autologous hematopoietic cell transplantation (HCT) or ≥2 prior multiagent chemotherapies, and had Eastern Cooperative Oncology Group performance status scores of 0 to 1 and CD30 expression of ≥1%. Patients were treated with nivolumab 240 mg and BV 1.8 mg/kg once every 3 weeks until disease progression or unacceptable toxicity. Primary end point was objective response rate (ORR); secondary end points included complete response rate, duration of response, progression-free survival (PFS), and overall survival (OS). Safety was monitored throughout. At final database lock (30 March 2022), 29 patients had received nivolumab plus BV; median follow-up was 39.6 months. Investigator-assessed ORR was 73.3%; median time to response was 1.3 months (range, 1.1-4.8). Median PFS was 26.0 months; median OS was not reached. PFS and OS rates at 24 months were 55.5% (95% confidence interval [CI], 32.0-73.8) and 75.5% (95% CI, 55.4-87.5), respectively. The most frequently occurring grade 3/4 treatment-related adverse event was neutropenia. Consolidative HCT was received by 12 patients, with a 100-day complete response rate of 100.0%. This 3-year follow-up showed long-term efficacy for nivolumab plus BV in R/R PMBL, with no new safety signals. This trial was registered at www.clinicaltrials.gov as #NCT02581631

Rhinocerebral mucormycosis treated with 32 gram liposomal amphotericin B and incomplete surgery: a case report

BACKGROUND: Mucormycosis (or zygomycosis) is the term for infection caused by fungi of the order Mucorales. Mucoraceae may produce severe disease in susceptible individuals, notably patients with diabetes and leukemia. Rhinocerebral mucormycosis most commonly manifests itself in the setting of poorly controlled diabetes, especially with ketoacidosis. CASE PRESENTATION: A 31-year-old diabetic man presented to the outpatient clinic with the following signs and symptoms: headache, periorbital pain, swelling and loss of vision in the right eye. On physical examination his right eye was red and swollen. There was periorbital cellulitis and the conjunctiva was edematous. KOH preparation of purulent discharge showed broad, ribbonlike, aseptate hyphae when examined under a fluorescence microscope. Cranial MRI showed involvement of the right orbit, thrombosis in cavernous sinus and infiltrates at ethmoid and maxillary sinuses. Mucormycosis was diagnosed based on these findings. Amphotericin B (AmBisome(®); 2 mg/kg.d) was initiated after the test doses. Right orbitectomy and right partial maxillectomy were performed; the lesions in ethmoid and maxillary sinuses were removed. The duration of the liposomal amphotericin B therapy was approximately 6 months and the total dose of liposomal amphotericin B used was 32 grams. Liposomal amphotericin B therapy was stopped six months later and oral fluconazole was started. CONCLUSIONS: Although a total surgical debridement of the lesions could not be performed, it is remarkable that regression of the disease could be achieved with medical therapy alone

Ears of the Armadillo: Global Health Research and Neglected Diseases in Texas

Neglected tropical diseases (NTDs) have\ud been recently identified as significant public\ud health problems in Texas and elsewhere in\ud the American South. A one-day forum on the\ud landscape of research and development and\ud the hidden burden of NTDs in Texas\ud explored the next steps to coordinate advocacy,\ud public health, and research into a\ud cogent health policy framework for the\ud American NTDs. It also highlighted how\ud U.S.-funded global health research can serve\ud to combat these health disparities in the\ud United States, in addition to benefiting\ud communities abroad

Inhibitory Control and Moral Emotions: Relations to Reparation in Early and Middle Childhood

This study examined links between inhibitory control, moral emotions (sympathy and guilt), and reparative behavior in an ethnically diverse sample of 4- and 8-year-olds (N = 162). Caregivers reported their children's reparative behavior, inhibitory control, and moral emotions through a questionnaire, and children reported their guilt feelings in response to a series of vignettes depicting moral transgressions. A hypothesized meditation model was tested with inhibitory control relating to reparative behavior through sympathy and guilt. In support of this model, results revealed that high levels of inhibitory control were associated with high levels of reparative behavior through high levels of sympathy and guilt. However, the mediation of inhibitory control to reparation through guilt was significant for 4-year-olds only. Results are discussed in relation to the temperamental, regulatory, and affective-moral precursors of reparative behavior in early and middle childhood

Selective sigma-2 ligands preferentially bind to pancreatic adenocarcinomas: applications in diagnostic imaging and therapy

<p>Abstract</p> <p>Background</p> <p>Resistance to modern adjuvant treatment is in part due to the failure of programmed cell death. Therefore the molecules that execute the apoptotic program are potential targets for the development of anti-cancer therapeutics. The sigma-2 receptor has been found to be over-expressed in some types of malignant tumors, and, recently, small molecule ligands to the sigma-2 receptor were found to induce cancer cell apoptosis.</p> <p>Results</p> <p>The sigma-2 receptor was expressed at high levels in both human and murine pancreas cancer cell lines, with minimal or limited expression in normal tissues, including: brain, kidney, liver, lung, pancreas and spleen. Micro-PET imaging was used to demonstrate that the sigma-2 receptor was preferentially expressed in tumor as opposed to normal tissues in pancreas tumor allograft-bearing mice. Two structurally distinct sigma-2 receptor ligands, SV119 and WC26, were found to induce apoptosis to mice and human pancreatic cancer cells <it>in vitro </it>and <it>in vivo</it>. Sigma-2 receptor ligands induced apoptosis in a dose dependent fashion in all pancreatic cell lines tested. At the highest dose tested (10 μM), all sigma-2 receptor ligands induced 10–20% apoptosis in all pancreatic cancer cell lines tested (p < 0.05). In pancreas tumor allograft-bearing mice, a single bolus dose of WC26 caused approximately 50% apoptosis in the tumor compared to no appreciable apoptosis in tumor-bearing, vehicle-injected control animals (p < 0.0001). WC26 significantly slowed tumor growth after a 5 day treatment compared to vehicle-injected control animals (p < 0.0001) and blood chemistry panels suggested that there is minimal peripheral toxicity.</p> <p>Conclusion</p> <p>We demonstrate a novel therapeutic strategy that induces a significant increase in pancreas cancer cell death. This strategy highlights a new potential target for the treatment of pancreas cancer, which has little in the way of effective treatments.</p

Modelling the associations between fat-free mass, resting metabolic rate and energy intake in the context of total energy balance

© 2016 Macmillan Publishers Limited.The relationship between body composition, energy expenditure and ad libitum energy intake (EI) has rarely been examined under conditions that allow any interplay between these variables to be disclosed.Objective:The present study examined the relationships between body composition, energy expenditure and EI under controlled laboratory conditions in which the energy density and macronutrient content of the diet varied freely as a function of food choice.Methods:Fifty-nine subjects (30 men: mean body mass index=26.7±4.0 kg m-2; 29 women: mean body mass index=25.4±3.5 kg m-2) completed a 14-day stay in a residential feeding behaviour suite. During days 1 and 2, subjects consumed a fixed diet designed to maintain energy balance. On days 3-14, food intake was covertly measured in subjects who had ad libitum access to a wide variety of foods typical of their normal diets. Resting metabolic rate (RMR; respiratory exchange), total daily energy expenditure (doubly labelled water) and body composition (total body water estimated from deuterium dilution) were measured on days 3-14.Results:Hierarchical multiple regression indicated that after controlling for age and sex, both fat-free mass (FFM; P<0.001) and RMR (P<0.001) predicted daily EI. However, a mediation model using path analysis indicated that the effect of FFM (and fat mass) on EI was fully mediated by RMR (P<0.001).Conclusions:These data indicate that RMR is a strong determinant of EI under controlled laboratory conditions where food choice is allowed to freely vary and subjects are close to energy balance. Therefore, the conventional adipocentric model of appetite control should be revised to reflect the influence of RMR

Compulsive Internet Use Among Adolescents: Bidirectional Parent–Child Relationships

Although parents experience growing concerns about their children’s excessive internet use, little is known about the role parents can play to prevent their children from developing Compulsive Internet Use (CIU). The present study addresses associations between internet-specific parenting practices and CIU among adolescents, as well as the bidirectionality of these associations. Two studies were conducted: a cross-sectional study using a representative sample of 4,483 Dutch students and a longitudinal study using a self-selected sample of 510 Dutch adolescents. Results suggest that qualitatively good communication regarding internet use is a promising tool for parents to prevent their teenage children from developing CIU. Besides, parental reactions to excessive internet use and parental rules regarding the content of internet use may help prevent CIU. Strict rules about time of internet use, however, may promote compulsive tendencies. Finally, one opposite link was found whereby CIU predicted a decrease in frequency of parental communication regarding internet use

Prolactin Receptor in Primary Hyperparathyroidism – Expression, Functionality and Clinical Correlations

<div><h3>Background</h3><p>Primary hyperparathyroidism (PHPT) is an endocrine disorder most commonly affecting women, suggesting a role for female hormones and/or their receptors in parathyroid adenomas. We here investigated the prolactin receptor (PRLr) which is associated with tumours of the breast and other organs.</p> <h3>Methodology/Principal Findings</h3><p>PRLr expression was investigated in a panel of 37 patients with sporadic parathyroid tumours and its functionality in cultured parathyroid tumour cells. In comparison with other tissues and breast cancer cells, high levels of prolactin receptor gene (<em>PRLR</em>) transcripts were demonstrated in parathyroid tissues. PRLr products of 60/70 kDa were highly expressed in all parathyroid tumours. In addition varying levels of the 80 kDa PRLr isoform, with known proliferative activity, were demonstrated. In parathyroid tumours, PRLr immunoreactivity was observed in the cytoplasm (in all cases, n = 36), cytoplasmic granulae (n = 16), the plasma membrane (n = 12) or enlarged lysosomes (n = 4). In normal parathyroid rim (n = 28), PRLr was uniformly expressed in the cytoplasm and granulae. In <em>in vitro</em> studies of short-term cultured human parathyroid tumour cells, prolactin stimulation was associated with significant transcriptional changes in JAK/STAT, RIG-I like receptor and type II interferon signalling pathways as documented by gene expression profiling. Moreover, <em>PRLR</em> gene expression in parathyroid tumours was inversely correlated with the patients’ plasma calcium levels.</p> <h3>Conclusions</h3><p>We demonstrate that the prolactin receptor is highly abundant in human parathyroid tissues and that PRLr isoforms expression and PRLr subcellular localisation are altered in parathyroid tumours. Responsiveness of PRLr to physiological levels of prolactin was observed in the form of increased PTH secretion and altered gene transcription with significant increase of RIG-I like receptor, JAK-STAT and Type II interferon signalling pathways. These data suggest a role of the prolactin receptor in parathyroid adenomas.</p> </div