Enhanced photocatalytic hydrogen production from aqueous-phase methanol reforming over cyano-carboxylic bifunctionally-modified carbon nitride.
Polymeric carbon nitride is a promising candidate for metal-free photocatalysis, but it is hampered by low activity due to poor carrier separation efficiency and lack of active sites. We have constructed a bifunctionally-modified structure, containing cyano groups internally and carboxyl groups on the surface, that was about 205 times more active than unmodified carbon nitride. The internal cyano groups enhanced the photoelectric performance of carbon nitride, while the surface carboxyl groups acted as active sites to promote hydrogen production. It is anticipated that this work will inform the rational design of polymeric carbon nitride and inspire similar attempts to modify polymers.


Chemistry with a thousand faces: new ways to play with clay.
Like a species that has moved into open niches, evolved, and diversified, chemistry can no longer be seen as a discrete scientific field. Its methods, concepts, and practitioners are penetrating virtually every nook and cranny of science and technology. That message came through clearly 2 weeks ago in New York City at the Fourth Chemical Congress of North America-a week-long conference organized by the American Chemical Society, the Chemical Institute of Canada, and the Chemical Society of Mexico and attended by some 10,000 scientists, engineers, and entrepreneurs. In roughly 4200 papers, participants explored such topics as borrowing from nature to improve industrial processes and electronic devices, and controlling the molecular architecture of clays and polymers.


Increased acid responsiveness in vagal sensory neurons in a guinea pig model of eosinophilic esophagitis.
Eosinophilic esophagitis (EoE) is characterized with eosinophils and mast cells predominated allergic inflammation in the esophagus and present with esophageal dysfunctions such as dysphagia, food impaction, and heartburn. However, the underlying mechanism of esophageal dysfunctions is unclear. This study aims to determine whether neurons in the vagal sensory ganglia are modulated in a guinea pig model of EoE. Animals were actively sensitized by ovalbumin (OVA) and then challenged with aerosol OVA inhalation for 2 wk. This results in a mild esophagitis with increases in mast cells and eosinophils in the esophageal wall. Vagal nodose and jugular neurons were disassociated, and their responses to acid, capsaicin, and transient receptor potential vanilloid type 1 (TRPV1) antagonist AMG-9810 were studied by calcium imaging and whole cell patch-clamp recording. Compared with naïve animals, antigen challenge significantly increased acid responsiveness in both nodose and jugular neurons. Their responses to capsaicin were also increased after antigen challenge. AMG-9810, at a concentration that blocked capsaicin-evoked calcium influx, abolished the increase in acid-induced activation in both nodose and jugular neurons. Vagotomy strongly attenuated those increased responses of nodose and jugular neurons to both acid and capsaicin induced by antigen challenge. These data for the first time demonstrated that prolonged antigen challenge significantly increases acid responsiveness in vagal nodose and jugular ganglia neurons. This sensitization effect is mediated largely through TRPV1 and initiated at sensory nerve endings in the peripheral tissues. Allergen-induced enhancement of responsiveness to noxious stimulation by acid in sensory nerve may contribute to the development of esophageal dysfunctions such as heartburn in EoE.


Swarm intelligence: when uncertainty meets conflict.
Good decision making is important for the survival and fitness of stakeholders, but decisions usually involve uncertainty and conflict. We know surprisingly little about profitable decision-making strategies in conflict situations. On the one hand, sharing decisions with others can pool information and decrease uncertainty (swarm intelligence). On the other hand, sharing decisions can hand influence to individuals whose goals conflict. Thus, when should an animal share decisions with others? Using a theoretical model, we show that, contrary to intuition, decision sharing by animals with conflicting goals often increases individual gains as well as decision accuracy. Thus, conflict-far from hampering effective decision making-can improve decision outcomes for all stakeholders, as long as they share large-scale goals. In contrast, decisions shared by animals without conflict were often surprisingly poor. The underlying mechanism is that animals with conflicting goals are less correlated in individual choice errors. These results provide a strong argument in the interest of all stakeholders for not excluding other (e.g., minority) factions from collective decisions. The observed benefits of including diverse factions among the decision makers could also be relevant to human collective decision making.


Is One Ear Good Enough? Unilateral Hearing Loss and Preschoolers' Comprehension of the English Plural.
Purpose The plural is one of the first grammatical morphemes acquired by English-speaking children with normal hearing (NH). Yet, those with hearing loss show delays in both plural comprehension and production. However, little is known about the effects of unilateral hearing loss (UHL) on children's acquisition of the plural, where children's ability to perceive fricatives (e.g., the /s/ in cats ) can be compromised. This study therefore tested whether children with UHL were able to identify the grammatical number of newly heard words, both singular and plural. Method Eleven 3- to 5-year-olds with UHL participated in a novel word two-alternative forced choice task presented on an iPad. Their results were compared to those of 129 NH 3- to 5-year-olds. During the task, children had to choose whether an auditorily presented novel word was singular (e.g., tep, koss) or plural (e.g., teps, kosses) by touching the appropriate novel picture. Results Like their NH peers, children with UHL demonstrated comprehension of novel singulars. However, they were significantly less accurate at identifying novel plurals, with performance at chance. However, there were signs that their ability to identify novel plurals may improve with age. Conclusion While comparable to their NH peers at identifying novel singulars, these results suggest that young children with UHL do not yet have a robust representation of plural morphology, particularly on words they have not encountered before.


Studies on the antigenicity of bone. II. Donor-specific anti-HLA antibodies in human recipients of freeze-dried allografts.
Freeze-dried bone allografts from donors of known tissue type evoked donor-specific anti-HLA antibodies in nine of forty-three patients (forty-four procedures). Eight of the nine sensitized patients were followed roentgenographically for an average of twenty-three months and were known to have had a satisfactory resolution of the benign process for which the graft was employed. The ninth patient was doing well when lost to follow-up four months after receiving a bone allograft. The questions of whether immune responses to bone allografts occur in humans and, if so, adversely influence the incorporation of the graft can be answered at this time only by demonstrating the presence and frequency of such responses and how they correlate with clinical events. A large variety of techniques can be used to demonstrate immune responses. The technique that we used revealed that a small group of patients became sensitized to HLA antigens that were known to be present in the allograft donor but none of the recipients had evidence of adverse effects caused by the graft, as judged non-invasively.


A novel lanreotide-encoded micelle system targets paclitaxel to the tumors with overexpression of somatostatin receptors.
Many tumor cells specifically overexpress somatostatin receptors, in particular, subtype 2 (SSTR2). Lanreotide, a somatostatin analogue with high affinity for SSTR2, can be exploited as a ligand for tumor targeted therapy. In this study, lanreotide was first conjugated to poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-b-PCL) copolymer, and the active targeting micelles with paclitaxel (lanreotide-PM-PTX) or fluorescent agent were constructed and characterized with various analytical methods. Lanreotide-PM-PTX micelles were spherical in shape with a hydrodynamic diameter of 43.2 ± 0.4 nm, high drug encapsulation (87.1 ± 2.8%) and slow drug release rate. Two cancer cell lines (human lung cancer H446 and human breast cancer MCF-7 cells) with different expression levels of SSTR2 were used in this study. As observed by flow cytometry, confocal microscopy and cytotoxicity studies, lanreotide-encoded PEG-b-PCL micelles demonstrated more specific cell uptake and cytotoxicity in SSTR2-positive tumor cells via a receptor-mediated mechanism over the passive targeting micelles. The active targeting micelles showed higher accumulation in tumor tissue and tumor cells in tumor-bearing mice in vivo by near-infrared fluorescence (NIRF) imaging, high-performance liquid chromatography and confocal microscopy, respectively. Furthermore, treatment with lanreotide-PM-PTX micelles resulted in stronger tumor inhibition, increased life span and enhanced tumor cell apoptosis in SSTR2-overexpressing tumor model in athymic nude mice. The in vivo efficacy test with both H446 and MCF-7 tumor models further demonstrated the involvement of receptor-mediated interaction. Finally, the active targeting micelles exhibited less body weight loss, lower hemolysis and lower myelosuppression, as compared with the control groups. In conclusion, lanreotide can serve as an effective homing peptide, and the lanreotide-modified PEG-b-PCL micelles hold considerable promise in the treatment of SSTR2-overexpressing solid tumors.


Expectations of trustworthiness in cross-status interactions.
Although the literature on trust is vast, little is known about the attributes that trigger or inhibit trusting others we do not know. Using a vignette version of the trust game, we addressed the role that social standing plays in estimating trustworthiness of strangers in cross-status interactions in Chile, a non-WEIRD context also characterized by high inequality and social segregation. While we found a positive relationship between social status and generalized trust, we found no relationship between the social status of trustors and trusting behavior in the game. Besides, trustees' income was the most important attribute for trustors to decide how much to trust. We also found that higher-income trustees are less trusted in general, particularly by lower-status trustors. Finally, the results revealed that the influence of income differences on trust was higher for lower-status participants: they are more trustful of others of similar status. We did not observe a similar effect of ingroup favoritism on trust among higher-status participants. Thus, higher levels of relational or particularized trust were found among participants of lower social status compared to those of higher social status.


Domestic violence against women from the perspective of the community health agent.
This study addresses violence against women from the perspective of Community Health Agents and related care practices developed at the basic care level. It aims to understand their opinions and care practices in daily care delivery in order to support training of workers on this theme. The theoretical-methodological reference was gender violence as a social construct and ideology as a social product and guider of health care practices. Data collection was carried out through a questionnaire with closed questions addressing these professionals' positions in relation to facts in the care delivery context. The results showed that positions and conceptions are mostly supported by common perceptions, that is, they do not differ from women victims of violence or lay people in general, which leads to the conclusion that it is necessary to broaden the discussion of this problem, introducing the gender perspective in the acknowledgement and care of women.


[Assessment and management of the risk for violence. An overview of the literature].
In general psychiatry the risk of violence has to be assessed regularly, for instance in cases where civil commitment is under consideration. This article gives an overview of the actuarial instruments for risk assessment, discusses a model for the clinical assessment of risks of violence and for the compulsory management of such risks. The relevant literature was located via cross-references from key publications and via bibliographic references in specialized journals. The key words used in the search were violence, violent behaviour, dangerousness, risk assessment, risk prediction and risk management. Standardised actuarial assessment of the risk of violence is only of limited value in general psychiatric practice. Among certain high-risk groups standardised instruments targeted at the specific type of risk (acute, long-term) and at the type of decision (relating to security, treatment) can have added value within a broader clinical assessment. In general psychiatric practice a potential risk of violence should be assessed systematically in a structured manner. If there are risks of violence these can best be studied and assessed in specialised clinics or by specialized teams. Dynamic risk factors and protective factors should be evaluated systematically in cooperation with the various organizations concerned.


Hippocampal volume reduction in first-episode and chronic schizophrenia: a review and meta-analysis.
Several magnetic resonance imaging studies have reported hippocampal volume reduction in patients with schizophrenia, but other studies have reported contrasting results. In this review and meta-analysis, the authors aim to clarify whether a reduction in hippocampal volume characterizes patients with schizophrenia by considering illness phase (chronic and first episode) and hippocampus side separately. They made a detailed literature search for studies reporting physical volumetric hippocampal measures of patients with schizophrenia and healthy control (HC) participants and found 44 studies that were eligible for meta-analysis. Individual meta-analyses were also performed on 13 studies of first-episode patients and on 22 studies of chronic patients. The authors also detected any different findings when only males or both males and females were considered. Finally, additional meta-analyses and analyses of variance investigated the role of the factors "illness phase" and "side" on hippocampal volume reduction. Overall, the patient group showed significant bilateral hippocampal volume reduction compared with HC. Interestingly, first-episode and chronic patients showed same-size hippocampal volume reduction. Moreover, the left hippocampus was smaller than the right hippocampus in patients and HC. This review and meta-analysis raises the question about whether hippocampal volume reduction in schizophrenia is of neurodevelopmental origin. Future studies should specifically investigate this issue.


Do we need another neural correlate of contour integration?
Gilad and colleagues use an elegant combination of voltage-sensitive dyes and high temporal and spatial resolution optical imaging to visualize a differential response to collinear contour elements in monkey V1. This result adds to the literature on the neural correlates of contour integration, but does not yet tackle (or seek to tackle) the question as to whether contour integration is mediated by lateral connections within an area (e.g., V1), through pooling of feedfoward connections, or feedback mechanisms. Moreover, while Gilad et al. find that their differential response is correlated with the behavioral performance of each monkey, there are reasons to suspect that the correlation they observe is a consequence of processing in higher regions, and that the differential V1 response may not play a critical role in integrating contour elements, or in generating the monkey's response. Moreover, this differential V1 response was not observed in a monkey who was not trained on the task, a result that can only be reconciled, if one assumes that the monkey could not see the contour prior to training. If valid, this could raise doubts as to whether the study of contour integration really provides insights into the processes by which normal visual perception is achieved.


Disruption of normal circadian clock function in a mouse model of tauopathy.
Disruption of normal circadian rhythm physiology is associated with neurodegenerative disease, which can lead to symptoms such as altered sleep cycles. In Alzheimer's disease (AD), circadian dysfunction has been attributed to β-amyloidosis. However, it is unclear whether tauopathy, another AD-associated neuropathology, can disrupt the circadian clock. We have evaluated the status of the circadian clock in a mouse model of tauopathy (Tg4510). Tg4510 mice display a long free-running period at an age when tauopathy is present, and show evidence of tauopathy in the suprachiasmatic nucleus (SCN) of the hypothalamus - the site of the master circadian clock. Additionally, cyclic expression of the core clock protein PER2 is disrupted in the hypothalamus of Tg4510 mice. Finally, disruption of the cyclic expression of PER2 and BMAL1, another core circadian clock protein, is evident in the Tg4510 hippocampus. These results demonstrate that tauopathy disrupts normal circadian clock function both at the behavioral and molecular levels, which may be attributed to the tauopathy-induced neuropathology in the SCN. Furthermore, these results establish the Tg4510 mouse line as a model to study how tauopathy disrupts normal circadian rhythm biology.


Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma.
Daratumumab, a monoclonal antibody targeting CD38, has been approved for use with standard myeloma regimens. An evaluation of subcutaneous daratumumab combined with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of transplantation-eligible patients with newly diagnosed multiple myeloma is needed. In this phase 3 trial, we randomly assigned 709 transplantation-eligible patients with newly diagnosed multiple myeloma to receive either subcutaneous daratumumab combined with VRd induction and consolidation therapy and with lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy and lenalidomide maintenance therapy alone (VRd group). The primary end point was progression-free survival. Key secondary end points were a complete response or better and minimal residual disease (MRD)-negative status. At a median follow-up of 47.5 months, the risk of disease progression or death in the D-VRd group was lower than the risk in the VRd group. The estimated percentage of patients with progression-free survival at 48 months was 84.3% in the D-VRd group and 67.7% in the VRd group (hazard ratio for disease progression or death, 0.42; 95% confidence interval, 0.30 to 0.59; P<0.001); the P value crossed the prespecified stopping boundary (P = 0.0126). The percentage of patients with a complete response or better was higher in the D-VRd group than in the VRd group (87.9% vs. 70.1%, P<0.001), as was the percentage of patients with MRD-negative status (75.2% vs. 47.5%, P<0.001). Death occurred in 34 patients in the D-VRd group and 44 patients in the VRd group. Grade 3 or 4 adverse events occurred in most patients in both groups; the most common were neutropenia (62.1% with D-VRd and 51.0% with VRd) and thrombocytopenia (29.1% and 17.3%, respectively). Serious adverse events occurred in 57.0% of the patients in the D-VRd group and 49.3% of those in the VRd group. The addition of subcutaneous daratumumab to VRd induction and consolidation therapy and to lenalidomide maintenance therapy conferred a significant benefit with respect to progression-free survival among transplantation-eligible patients with newly diagnosed multiple myeloma. (Funded by the European Myeloma Network in collaboration with Janssen Research and Development; PERSEUS ClinicalTrials.gov number, NCT03710603; EudraCT number, 2018-002992-16.).


Nutritional interventions for preventing and treating pressure ulcers.
Pressure ulcers affect approximately 10% of people in hospitals and older people are at highest risk. A correlation between inadequate nutritional intake and the development of pressure ulcers has been suggested by several studies, but the results have been inconsistent. To evaluate the effects of enteral and parenteral nutrition on the prevention and treatment of pressure ulcers. In March 2014, for this first update, we searched The Cochrane Wounds Group Specialised Trials Register, the Cochrane Central register of Controlled Trials (The Cochrane Library), the Database of Abstracts of Reviews of Effects (DARE) (The Cochrane Library), the Health Technology Assessment Database (HTA) (The Cochrane Library), the Cochrane Methodology Register (The Cochrane Library), NHS Economic Evaluation Database (The Cochrane Library), Ovid Medline, Ovid Embase and EBSCO CINAHL. No date, language or publication status limits were applied. Randomised controlled trials (RCTs) evaluating the effects of enteral or parenteral nutrition on the prevention and treatment of pressure ulcers, which measured the incidence of new ulcers, ulcer healing or changes in pressure ulcer severity. There were no restrictions on types of patient, setting, date, publication status or language. Two review authors independently screened for inclusion, and disagreement was resolved by discussion. Two review authors independently extracted data and assessed quality using the Cochrane Collaboration tool for assessing risk of bias. We included 23 RCTs, many were small (between 9 and 4023 participants, median 88) and at high risk of bias.Eleven trials compared a combination of nutritional supplements, consisting of a minimum of energy and protein in different dosages, for the prevention of pressure ulcers. A meta-analysis of eight trials (6062 participants) that compared the effects of mixed nutritional supplements with standard hospital diet found no clear evidence of an effect of supplementation on pressure ulcer development (pooled RR 0.86; 95% CI 0.73 to 1.00; P value 0.05; I(2) = 13%, random effects). This outcome is at unclear or high risk of bias.Fourteen trials evaluated the effects of nutritional supplements on the healing of existing pressure ulcers: seven trials examined mixed nutritional supplements, three the effects of proteins, two trials examined zinc, and two studies examined ascorbic acid. The included trials were heterogeneous with regard to participants, interventions, comparisons and outcomes and meta-analysis was not appropriate. There was no clear evidence of an improvement in pressure ulcer healing from the nutritional supplements evaluated in any of these individual studies. There is currently no clear evidence of a benefit associated with nutritional interventions for either the prevention or treatment of pressure ulcers. Further trials of high methodological quality are necessary.


Maternal and paternal diversity in Xinjiang Kazakh population from China.
The ancient silk road of China passed through Xinjiang and facilitated gene exchanges from the East and the West which impacted on the genetic variation and structure of the nomadic Kazakh population residing there. In order to understand the nature of this genetic variation; 151 Xinjiang Kazakh samples were obtained from four main Kazakh groups and were analyzed using mtDNA and Y-chromosome markers. The Xinjiang Kazakh population is heterogeneous, showing the coexistence of matrilineal lineages with different origins. No genetic differentiation of mtDNA is observed among the four different regional Xinjiang Kazakh populations in Xinjiang by AMOVA and Networks. The genetic diversity of Y-STR loci is higher in Xinjiang Kazakhs (0.968 ± 0.014) than the Kazakhs from Kazakhstan (0.629 ± 0.071) and Russia (0.835 ± 0.020). East Eurasians make a more than 50% contribution to the maternal and paternal lineages of Xinjiang Kazakhs. There is more gene flow from West Eurasian into the maternal lineages of Xinjiang Kazakh than to the Kazakhs from Russia and Kazakhstan. Moreover, mtDNA and Y-STR displayed high polymorphism in Xinjiang Kazakhs (the haplotype diversity and power of discrimination were 0.990 ± 0.003, 0.9137 for mtDNA HVS and 0.968 ± 0.014, 0.9489 for Y-STR system, respectively), suggesting they would be very useful and important markers for forensic analysis and population genetic studies.


Emotional processing in a ten-session general psychiatric treatment for borderline personality disorder: a case study.
This study examines the effects of a borderline-specific treatment, called general psychiatric management, on emotional change, outcome and therapeutic alliance of an outpatient presenting with borderline personality disorder. Based on the sequential model of emotional processing, emotional states were assessed in a 10-session setting. The case showed an increase in expressions of distress and no change in therapeutic alliance and tended towards general deterioration. Results suggest emotional processing may play a lesser role in general psychiatric management in early phase treatment than previously hypothezised.


Circ_0061140 promotes metastasis of bladder cancer through adsorbing microRNA-1236.
The purpose of this study was to investigate the expression characteristics of circular RNA circ_0061140 in bladder cancer (BCa), and to further explore its effects on invasiveness and migration capacity of BCa cells, as well as its possible potential mechanism. Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was performed to examine the expression level of circ_0061140 in tumor tissue samples and paracancerous ones collected from 42 patients with BCa, and the interplay between circ_0061140 level and the clinical indicators, as well as the prognosis of BCa patients were analyzed. Meanwhile, qRT-PCR was also used to verify circ_0061140 expression in BCa cell lines. In addition, a circ_0061140 knockdown model was constructed using Lentiviral in BCa cell lines, including T24 and 253j, and the effect of circ_0061140 on BCa cell functions and its underlying mechanisms were explored using Cell Counting Kit-8 (CCK-8), transwell, and cell wound healing assays. qPCR results showed that the expression level of circ_0061140 in tumor tissues of BCa patients was remarkably higher than that in adjacent tissues, and the difference was statistically significant. Compared with patients with low expression of circ_0061140, patients with high expression of circ_0061140 had worse prognosis and higher incidence of lymph node or distant metastasis. Compared with those in the negative control group, the proliferation and invasion, as well as the metastasis ability of BCa cells in the sh-circ_0061140 group, were remarkably attenuated. In addition, bioinformatics and Luciferase reporter gene assay demonstrated that circ_0061140 can specifically bind to microRNA-1236. At the same time, the results of qPCR revealed that the expression levels of circ_0061140 and microRNA-1236 were negatively correlated in the tumor tissues of BCa patients. Finally, cell recovery experiment indicated that silencing microRNA-1236 reversed the impact of the knockdown of circ_0061140 on the ability of BCa cells to proliferate and invade, suggesting that the two may regulate each other. Circ_0061140 level was found remarkably elevated in BCa tissues, as well as in cell lines, which was closely relevant to the incidence of lymph node or distant metastasis of BCa patients. In addition, circ_0061140 may enhance the proliferation rate and invasion ability of BCa cells through the modulation of microRNA-1236.


A robust protocol for regional evaluation of methacholine challenge in mouse models of allergic asthma using hyperpolarized 3He MRI.
Hyperpolarized (HP) (3)He magnetic resonance imaging has been recently used to produce high-resolution images of pulmonary ventilation after methacholine (MCh) challenge in mouse models of allergic inflammation. This capability presents an opportunity to gain new insights about these models and to more sensitively evaluate new drug treatments in the pre-clinical setting. In the current study, we present our initial experience using two-dimensional (2D), time-resolved (3)He MRI of MCh challenge-induced airways hyperreactivity (AHR) to compare ovalbumin-sensitized and challenged (N = 8) mice to controls (N = 8). Imaging demonstrated that ovalbumin-sensitized and challenged animals exhibited many large ventilation defects even prior to MCh challenge (four out of eight) compared to no defects in the control animals. Additionally, the ovalbumin-sensitized and challenged animals experienced a greater number of ventilation defects (4.5 +/- 0.4) following MCh infusion than did controls (3.3 +/- 0.6). However, due to variability in MCh delivery that was specific to the small animal MRI environment, the difference in mean defect number was not statistically significant. These findings are reviewed in detail and a comprehensive solution to the variability problem is presented that has greatly enhanced the magnitude and reproducibility of the MCh response. This has permitted us to develop a new imaging protocol consisting of a baseline 3D image, a time-resolved 2D series during MCh challenge, and a post-MCh 3D image that reveals persistent ventilation defects.


Release of endothelium-derived relaxing factor from pig cultured aortic endothelial cells, as assessed by changes in endothelial cell cyclic GMP content, is inhibited by a phorbol ester.
1. Cultured aortic endothelial cells of the pig respond to the endothelium-derived relaxing factor (EDRF) they release with an increase in cyclic GMP content. This response is inhibited by haemoglobin or by L-NG-monomethyl-arginine (L-NMMA), and has been used to investigate the effects of phorbol esters on EDRF release. 2. Pretreatment with phorbol-12,13-dibutyrate (PDB) but not the inactive 4 alpha-phorbol-12,13,-didecanoate (PDD), inhibited increases in cyclic GMP induced by substance P (10(-8) M) in a time and concentration-dependent manner. PDB did not affect basal cyclic GMP levels. 3. PDB (3 x 10(-7) M), but not PDD (3 x 10(-7) M), also inhibited ATP (10(-5) M)-induced increases in cyclic GMP, but did not affect those induced by bradykinin (10(-7) M). 4. Increases in cyclic GMP induced by low (10(-7) M) but not high (10(-6) M) concentrations of the calcium ionophore A23187 were inhibited by PDB (3 x 10(-7) M). This inhibitory effect was due to enhanced destruction of EDRF by superoxide anions rather than inhibition of EDRF release, as the inhibition was abolished in the presence of superoxide dismutase (SOD, 30 mu ml-1) and catalase (CAT, 100 mu ml-1). 5. SOD and CAT did not affect the inhibitory action of PDB on substance P or ATP-induced increases in cyclic GMP. 6. Increases in endothelial cell cyclic GMP content induced by sodium nitroprusside (10(-5) M) were unaffected by PDB pretreatment. 7. The inhibitory effects of PDB are probably a result of an action of protein kinase C on the steps between receptor occupation and phospholipase C activation.


Effect of short-term prednisone use on blood flow, muscle protein metabolism, and function.
Glucocorticoids can cause muscle atrophy, but the effect on muscle protein metabolism in humans has not been adequately studied to know whether protein synthesis, breakdown, or both are altered. We tested the effect of 6 d of oral prednisone (Pred, 0.5 mg/kg.d) on muscle protein metabolism and function. Six healthy subjects (three men/three women, 22-41 yr) completed two trials (randomized, double-blind, cross-over) with Pred and placebo. Fasting glucose, insulin, IGF-I, and glucagon were higher on Pred vs. placebo, whereas IGF-II and IGF binding protein-1 and -2 were lower. Whole-body amino acid fluxes, blood urea nitrogen, and urinary nitrogen loss were not statistically different between trials. Leg blood flow was 25% lower on Pred leading to 15-30% lower amino acid flux among the artery, vein, and muscle. However, amino acid net balance and rates of protein synthesis and breakdown were unchanged, as were synthesis rates of total mixed, mitochondrial, sarcoplasmic, and myosin heavy chain muscle proteins. Muscle mitochondrial function, muscle strength, and resting energy expenditure were also unchanged. These results demonstrate that a short-term moderate dose of prednisone affects glucose metabolism but has no effect on whole-body or leg muscle protein metabolism or muscle function.


Advances in the treatment of bronchial asthma.
Asthma is defined as a syndrome of variable and reversible airway obstruction. The successful treatment of the acute attack of asthma depends on prompt and appropriate intervention, while the aim of management following the acute attack should be that of optimal control of chronic symptoms and avoidance of recurrent attacks. A better recognition of triggers and improved medical management prompt optimism regarding the treatment of this potentially reversible process.


Methotrexate-induced acute toxic leukoencephalopathy.
Acute lymphoblastic leukemia (ALL) is one of the most common malignancies of childhood, which is treated with high doses of methotrexate (MTX), as it crosses the blood-brain barrier and can be administered intravenously and via intrathecal route to eradicate leukemic cells from central nervous system (CNS). Additionally, high doses of MTX not only prevent CNS recurrence but also hematologic relapses. Although, standard treatment protocol for ALL includes multimodality therapy, MTX is usually associated with neurotoxicity and affects periventricular deep white matter region. Methotrexate-induced 'acute toxic leukoencephalopathy' has varying clinical manifestations ranging from acute neurological deficit to seizures or encephalopathy. Diffusion weighted magnetic resonance imaging (DW-MRI) is widely available and routinely used in clinical practice to identify acute stroke and also to distinguish acute stroke from non-stroke like conditions. We report a local teenage Chinese girl who developed 2 discrete episodes of left upper and lower limb weakness with left facial nerve paresis after receiving the 2 nd and 3 rd cycle of high dose of intravenous and intrathecal methotrexate, without having cranial irradiation. After each episode of her neurological deficit, the DW-MRI scan showed focal restricted diffusion in right centrum semiovale. Her left sided focal neurological deficit and facial nerve paresis almost completely subsided on both these occasions within 3 days of symptom onset. Follow-up DW-MRI, after her neurological recovery, revealed almost complete resolution of previously noted restricted diffusion in right centrum semiovale, while the lesion was not evident on concurrent T2W (T2-weighted) and FLAIR (Fluid-Attenuated Inversion recovery) sequences, nor showed any post contrast enhancement on post gadolinium enhanced T1W (T1-weighted) sequences. No residual neurological deficit or intellectual impairment was identified on clinical follow up over a 2 year period.


Messenger RNA-based vaccines: progress, challenges, applications.
Twenty years after the demonstration that messenger RNA (mRNA) was expressed and immunogenic upon direct injection in mice, the first successful proof-of-concept of specific protection against viral infection in small and large animals was reported. These data indicate wider applicability to infectious disease and should encourage continued translation of mRNA-based prophylactic vaccines into human clinical trials. At the conceptual level, mRNA-based vaccines-more than other genetic vectors-combine the simplicity, safety, and focused immunogenicity of subunit vaccines with favorable immunological properties of live viral vaccines: (1) mRNA vaccines are molecularly defined and carry no excess information. In the environment and upon physical contact, RNA is rapidly degraded by ubiquitous RNases and cannot persist. These characteristics also guarantee tight control over their immunogenic profile (including avoidance of vector-specific immune responses that could interfere with repeated administration), pharmacokinetics, and dosing. (2) mRNA vaccines are synthetically produced by an enzymatic process, just requiring information about the nucleic acid sequence of the desired antigen. This greatly reduces general complications associated with biological vaccine production, such as handling of infectious agents, genetic variability, environmental risks, or restrictions to vaccine distribution. (3) RNA can be tailored to provide potent adjuvant stimuli to the innate immune system by direct activation of RNA-specific receptors; this may reduce the need for additional adjuvants. The formation of native antigen in situ affords great versatility, including intracellular localization, membrane association, posttranslational modification, supra-molecular assembly, or targeted structural optimization of delivered antigen. Messenger RNA vaccines induce balanced immune responses including B cells, helper T cells, and cytotoxic T lymphocytes, rendering them an extremely adaptable platform. This article surveys the design, mode of action, and capabilities of state-of-the-art mRNA vaccines, focusing on the paradigm of influenza prophylaxis.


Very Rapid Improvement in Extended Nitric Oxide Parameters Is Associated With Clinical and Functional Improvement in Patients With Chronic Rhinosinusitis With Nasal Polyps Treated With Dupilumab.
Dupilumab, an anti-IL-4 receptor a monoclonal antibody, was recently approved for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) and moderate-to-severe asthma. Onset of its clinical effects is rapid. CRSwNP is characterized by extended type 2 inflammatory involvement that can be assessed using extended nitric oxide analysis. We investigated whether dupilumab was associated with a rapid improvement in extended nitric oxide parameters, lung function, and clinical outcomes in patients with CRSwNP. Consecutive patients with CRSwNP and an indication for dupilumab were evaluated for extended nitric oxide analysis (exhaled, FeNO; bronchial, JawNO; alveolar, CalvNO; nasal, nNO) and lung function 15 and 30 days after initiation of treatment and for clinical outcomes (nasal polyps score [NPS], quality of life questionnaires, visual analog scale [VAS] for the main symptoms, and the Asthma Control Test [ACT]) 30 days after initiation of treatment. We enrolled 33 patients. All extended nitric oxide and lung function parameters improved significantly after 15 days of treatment, remaining stable at 30 days. Scores on the NPS, VAS for the main RSwNP symptoms, quality of life questionnaires, and the ACT improved significantly 30 days after initiation of treatment. Dupilumab is associated with very rapid improvement in type 2 inflammation in all airway areas. This is associated with improved lung function and clinical parameters in patients with CRSwNP.


Perioperative events in children with pulmonary hypertension undergoing non-cardiac procedures.
Prior limited research indicates that children with pulmonary hypertension (PH) have higher rates of adverse perioperative outcomes when undergoing non-cardiac procedures and cardiac catheterizations. We examined a single-center retrospective cohort of children with active or pharmacologically controlled PH who underwent cardiac catheterization or non-cardiac surgery during 2006-2014. Preoperative characteristics and perioperative courses were examined to determine relationships between the severity or etiology of PH, type of procedure, and occurrence of major and minor events. We identified 77 patients who underwent 148 procedures at a median age of six months. The most common PH etiologies were bronchopulmonary dysplasia (46.7%), congenital heart disease (29.9%), and congenital diaphragmatic hernia (14.3%). Cardiac catheterizations (39.2%), and abdominal (29.1%) and central venous access (8.9%) were the most common procedures. Major events included failed planned extubation (5.6%), postoperative cardiac arrest (4.7%), induction or intraoperative cardiac arrest (2%), and postoperative death (1.4%). Major events were more frequent in patients with severe baseline PH ( P = 0.006) and the incidence was associated with procedure type ( P = 0.05). Preoperative inhaled nitric oxide and prostacyclin analog therapies were associated with decreased incidence of minor events (odds ratio [OR] = 0.32, P = 0.046 and OR = 0.24, P = 0.008, respectively), but no change in the incidence of major events. PH etiology was not associated with events ( P = 0.24). Children with PH have increased risk of perioperative complications; cardiac arrest and death occur more frequently in patients with severe PH and those undergoing thoracic procedures. Risk may be modified by using preoperative pulmonary vasodilator therapy and lends itself to further prospective studies.


Biliary peritonitis due to gall bladder perforation after percutaneous nephrolithotomy.
A 19-year-old male patient underwent right percutaneous nephrolithotomy (PNL) for right renal 1.5 × 1.5 cm lower pole stone. The procedure was completed uneventfully with complete stone clearance. The patient developed peritonitis and shock 48 h after the procedure. Exploratory laparotomy revealed a large amount of bile in the abdomen along with three small perforations in the gall bladder (GB) and one perforation in the caudate lobe of the liver. Retrograde cholecystectomy was performed but the patient did not recover and expired post-operatively. This case exemplifies the high mortality of GB perforation after PNL and the lack of early clinical signs.


[Preferably a gastric sleeve operation].
One third of patients undergoing a gastric bypass operation will experience chronic abdominal symptoms. Diagnosis and treatment of this abdominal pain is a difficult task. The biggest problem is the ruling out of one of the possible causes of abdominal pain, such as internal herniation. Current diagnostic methods have generally not been successful in diagnosing internal herniation, and - more importantly - have not been able to rule out this diagnosis either. This leads to a high number of visits by these patients to the emergency department and outpatient clinic. Patients with pre-existing abdominal pain, or those who use analgesia preoperatively should preferably be treated by means of a gastric sleeve operation, instead of an operation involving anastomosis, such as a gastric bypass procedure.


Gastroesophageal reflux and diaphragmatic motility after repair of congenital diaphragmatic hernia.
At the Department of Pediatric Surgery in Graz, 31 boys and 23 girls were operated on for congenital diaphragmatic hernia (CDH) from 1978 to 1994. In 49 patients the defect was on the left, in five on the right side. In 46 cases, the hernia was diagnosed within the first week of life; in eight children at a later date. 19 children (35%) died. 25 of the 35 survivors (71%) came to a follow-up examination on average 9.4 (1-17) years after the operation. 24 h pH-monitoring or manometry and Upper G.I. series revealed pathological gastroesophageal reflux (GER) in 16 patients. Nine children were treated conservatively; in seven patients an antireflux procedure was performed. A thoracic position of the stomach or left liver lobe, presence of a hernial sac, gestational age, prenatal diagnosis, use of a patch or severity of lung hypoplasia did not significantly influence the incidence of GER. In three patients, a hiatal hernia was found. The motility of the diaphragm was documented with M-mode sonography (n = 18); a restricted motility could be demonstrated in five patients. GER is very common in patients after repair of CDH. We recommend long-term follow-up with special interest in respect of GER.


Multiple tumoricidal effector mechanisms induced by adriamycin.
The antitumor cytotoxic mechanisms of Adriamycin-elicited peritoneal exudate cells were investigated. Peritoneal exudate cells from mice collected 1 day after an i.p. injection of Adriamycin (10 mg/kg) displayed enhanced cytotoxicity against P815 (natural killer-insensitive, macrophage-sensitive) but not YAC-1 (natural killer-sensitive) tumor cell lines. These cells contained a sufficient concentration of the drug to be cytotoxic for P815 tumor cells in 18-hr chromium release assays. Freeze-thaw lysates of these peritoneal exudate cells were found to be as cytotoxic to P815 as their corresponding whole cells. The lytic activity of these lysates was removed by centrifugation at 100,000 X g, indicating the insolubility of the effector moiety. These cells were also shown to produce significant amounts of superoxide anion and H2O2 in response to phorbol myristate acetate. A catalase-inhibitable augmentation of the cytotoxicity of these cells against P815 was observed when phorbol myristate acetate was added to the assay. Neutrophils and not macrophages were likely responsible for this effect. Peritoneal lymphocytes from mice given injections of Adriamycin 5 to 7 days previously were cytotoxic to YAC-1 tumor cells in 4-hr assays. Finally, peritoneal macrophages harvested 5 to 7 days after Adriamycin administration were cytotoxic to P815 in the absence of detectable Adriamycin. The addition of phorbol myristate acetate inhibited the lysis of P815 by these cells.


[Wernicke-Korsakoff syndrome: diagnostic contribution of magnetic resonance imaging].
Data regarding the magnetic resonance imaging (MRI) features in Wernicke-Korsakoff syndrome (WKS) are scarce. WKS usually combines a cerebellar syndrome, oculomotor disorder and confusion. The aim of this study was to determine more precisely the clinical presentation of WKS and the frequency and topography of MRI abnormalities. Furthermore, we try to assess the prognostic value of both clinical signs and MRI abnormalities. We retrospectively studied 25 patients with WKS in which an MRI was available. We assessed the initial clinical presentation and the outcome. We also analyzed the frequency and the location of MRI lesions. We then correlated clinical and MRI data with the clinical outcome. Eleven patients (44 p. 100) had the full WKS. Fourteen of the 25 patients (56 p. 100) had a poor evolution. The occurrence of full WKS was correlated with a poor outcome (p < 0.02). Signal abnormalities on T2-weighted images were found in the periacqueducal region, in the thalami or in the mamillar bodies in 16 cases (64 p. 100). There was a correlation between an hypersignal in at least one region and a poor clinical outcome (p < 0.02). Our study demonstrates the high frequency of brain MRI lesions in WKS and the correlation of both initial clinical signs and MRI abnormalities with a poor clinical outcome.


Multifunctional polymeric nanoplexes for anticancer co-delivery of p53 and mitoxantrone.
Co-delivery of the anticancer drug, mitoxantrone (MTO) and the gene encoding tumor suppressor protein p53 was evaluated towards anticancer combinatorial therapy. The nanoplatforms developed herein are assembled by coupling β-cyclodextrin and the cationic polymer, polyethyleneimine to a hydrophilic polymer, pullulan (PPEICD). The β-cyclodextrin serves as a nanocontainer for the drug MTO, while the cationic moiety can condense pDNA. Acid base titrations provided insight into the buffering capacity of the PPEICD conjugate. Cytotoxicity studies by MTT assay in HepG2 and C6 cell lines and hemocompatibility studies confirmed the conjugate to be nontoxic and hemocompatible. In vitro release studies of MTO in phosphate buffered saline pH 7.4 showed an initial burst effect followed by a slow drug release. The released data fitted with the Korsmeyer-Peppas model and their diffusional exponents suggest that the drug release from the polymeric system followed diffusion and non-Fickian transport. Combined drug and gene loaded nanoplexes have a more apoptotic effect than either the drug or gene individually as confirmed by MTT assay and live dead assay. This indicated the significance of the combined drug and gene delivery system and the ability of the nanoplatform to overcome the multidrug resistance (MDR) of MTO. Moreover, preference of asialoglycoprotein receptor (ASGPR) mediated internalization for nanoparticle cellular uptake in HepG2 cell lines was identified by treating with the inhibitor asialofetuin. Cell studies in both HepG2 and C6 cell lines demonstrated that the nanoplatform PPEICD can efficiently and selectively deliver both p53 and MTO to cancer cells inducing high cell death.


Omega-3 and its domain-specific effects on cognitive test performance in youths: A meta-analysis.
Omega-3 fatty acids are vital for brain development. The aim of this meta-analysis was to broaden current knowledge of the effects of omega-3 supplementation on cognitive test performance in youths. Randomized controlled trials (RCTs) meeting selection criteria were identified through two independent literature searches on PubMed, Cochrane Library, PsycARTICLES and PsycINFO (last search June 2019). Twenty-nine out of 1126 studies assessing 4247 participants met all selection criteria. A meta-analysis using random-effects model was performed for eight different cognitive domains. This first analysis revealed no main effect of omega-3 fatty acid supplementation on domain-specific cognitive test performance in youths. Subgroup analyses identified beneficial effects of eicosapentaenoic acid (EPA)-rich but not docosahexaenoic acid (DHA)-rich formulations in the domains of long-term memory, working memory and problem solving and a tendency towards beneficial effects in clinical rather than non-clinical populations. Future research should investigate differential effects of EPA and DHA and consider their baseline levels, other nutritional components and interactions with gene variations as potential predictors of response.


Multiple neuropeptide Y receptors regulate K+ and Ca2+ channels in acutely isolated neurons from the rat arcuate nucleus.
We examined the effects of neuropeptide Y (NPY) and related peptides on Ca2+ and K+ currents in acutely isolated neurons from the arcuate nucleus of the rat. NPY analogues that activated all of the known NPY receptors (Y1-Y5), produced voltage-dependent inhibition of Ca2+ currents and activation of inwardly rectifying K+ currents in arcuate neurons. Both of these effects could occur simultaneously in the same cells. In some cells, activation of Y4 NPY receptors also caused oscillations in [Ca2+]i. NPY hyperpolarized arcuate neurons through the activation of a K+ conductance and increased the spike threshold. Molecular biological studies indicated that arcuate neurons possessed all of the previously cloned NPY receptor types (Y1, Y2, Y4, and Y5). Thus activation of multiple types NPY receptors on arcuate neurons can regulate both Ca2+ and K+ conductances leading to a reduction in neuronal excitability and a suppression of neurotransmitter release.


Characterization of the extra-large G protein alpha-subunit XLalphas. I. Tissue distribution and subcellular localization.
Our group previously described a new type of G protein, the 78-kDa XLalphas (extra large alphas) (Kehlenbach, R. H., Matthey, J., and Huttner, W. B. (1994) Nature 372, 804-809 and (1995) Nature 375, 253). Upon subcellular fractionation, XLalphas labeled by ADP-ribosylation with cholera toxin was previously mainly detected in the bottom fractions of a velocity sucrose gradient that contained trans-Golgi network and was differentially distributed to Galphas, which also peaked in the top fractions containing plasma membrane. Here, we investigate, using a new antibody specific for the XL domain, the tissue distribution and subcellular localization of XLalphas and novel splice variants referred to as XLN1. Upon immunoblotting and immunofluorescence analysis of various adult rat tissues, XLalphas and XLN1 were found to be enriched in neuroendocrine tissues, with a particularly high level of expression in the pituitary. By both immunofluorescence and immunogold electron microscopy, endogenous as well as transfected XLalphas and XLN1 were found to be predominantly associated with the plasma membrane, with only little immunoreactivity on internal, perinuclear membranes. Upon subcellular fractionation, immunoreactive XLalphas behaved similarly to Galphas but was differentially distributed to ADP-ribosylated XLalphas. Moreover, the bottom fractions of the velocity sucrose gradient were found to contain not only trans-Golgi network membranes but also certain subdomains of the plasma membrane, which reconciles the present with the previous observations. To further investigate the molecular basis of the association of XLalphas with the plasma membrane, chimeric proteins consisting of the XL domain or portions thereof fused to green fluorescent protein were analyzed by fluorescence and subcellular fractionation. In both neuroendocrine and non-neuroendocrine cells, a fusion protein containing the entire XL domain, in contrast to one containing only the proline-rich and cysteine-rich regions, was exclusively localized at the plasma membrane. We conclude that the physiological role of XLalphas is at the plasma membrane, where it presumably is involved in signal transduction processes characteristic of neuroendocrine cells.


Transdiaphragmatic lymphatic transport of intraperitoneally administered marker in hamsters.
To determine whether transdiaphragmatic transport in hamsters is similar to that described in other animals by examining transport of an intraperitoneally administered marker. Monastral blue B suspension was administered intraperitoneally to 28 male Syrian hamsters (Mesocricetus auratus). Four hamsters each were euthanized 7, 15, and 30 min, and 1, 2, 3, and 24 h later. Specimens were examined microscopically for presence of marker. Marker was present in intrathoracic lymphatic vessels and cranial and caudal mediastinal lymph nodes by 7 min after its administration. The amount of marker in lymph nodes increased with time. The subcapsular distribution of marker was consistent with lymphatic transport. By 1 h after its administration, marker was present in the liver, spleen, bone marrow, and mesenteric and mandibular lymph nodes. Patterns of marker distribution in these tissues were consistent with hematogenous transport, but the amount of marker was considerably less than that in the intrathoracic lymph nodes at corresponding times. Particulates were most likely translocated from the hamster peritoneal cavity to intrathoracic lymph nodes via transdiaphragmatic lymphatic vessels. A portion of the translocated particulates entered the blood, where they were distributed to a variety of tissues within a short time.


A comprehensive peptidome profiling technology for the identification of early detection biomarkers for lung adenocarcinoma.
The mass spectrometry-based peptidomics approaches have proven its usefulness in several areas such as the discovery of physiologically active peptides or biomarker candidates derived from various biological fluids including blood and cerebrospinal fluid. However, to identify biomarkers that are reproducible and clinically applicable, development of a novel technology, which enables rapid, sensitive, and quantitative analysis using hundreds of clinical specimens, has been eagerly awaited. Here we report an integrative peptidomic approach for identification of lung cancer-specific serum peptide biomarkers. It is based on the one-step effective enrichment of peptidome fractions (molecular weight of 1,000-5,000) with size exclusion chromatography in combination with the precise label-free quantification analysis of nano-LC/MS/MS data set using Expressionist proteome server platform. We applied this method to 92 serum samples well-managed with our SOP (standard operating procedure) (30 healthy controls and 62 lung adenocarcinoma patients), and quantitatively assessed the detected 3,537 peptide signals. Among them, 118 peptides showed significantly altered serum levels between the control and lung cancer groups (p<0.01 and fold change >5.0). Subsequently we identified peptide sequences by MS/MS analysis and further assessed the reproducibility of Expressionist-based quantification results and their diagnostic powers by MRM-based relative-quantification analysis for 96 independently prepared serum samples and found that APOA4 273-283, FIBA 5-16, and LBN 306-313 should be clinically useful biomarkers for both early detection and tumor staging of lung cancer. Our peptidome profiling technology can provide simple, high-throughput, and reliable quantification of a large number of clinical samples, which is applicable for diverse peptidome-targeting biomarker discoveries using any types of biological specimens.


Relationship between in vitro sperm functional tests and in vivo fertility of rams following cervical artificial insemination of ewes with frozen-thawed semen.
Several procedures have been proposed to assess structural and functional characteristics of cryopreserved ram semen but none so far have yielded consistent relationships with in vivo fertility. The objectives of this study were to evaluate several sperm function tests as potential markers of in vivo ram fertility (determined by pregnancy rate in ewes) using frozen-thawed semen. In experiment 1, frozen-thawed straws (n=3 per ram) of semen from three high and three low fertility rams were assessed using fluorescent microscopy for (1) progressive motility, (2) viability and, (3) acrosomal status. In experiment 2, frozen-thawed straws (n=3 per ram) of semen from 18 rams of known fertility were analysed using either computer-assisted sperm analysis (CASA) for eight motion characteristics or flow cytometric staining for: (1) viability and acrosomal status, (2) plasma membrane status and capacitation-like changes, and (3) live cells following an osmotic resistance test (ORT). In experiment 3, platelet-activating factor (PAF) was isolated from straws (n=2 per ram) of semen using high-pressure liquid chromatography (HPLC) and quantified using HPLC-tandem mass spectrometry for 18 rams. In experiment 1, no association was found between motility, viability (% live) or acrosomal status (% damaged, % intact and % reacted) and in vivo fertility. In experiment 2, no correlation was found between motility (CASA), viability (% live), acrosomal status (% live, % live intact and % reacted), capacitation status (% capacitated, % non-capacitated), plasma membrane stability (% dead) and % live cells following ORT and ram in vivo fertility. In experiment 3, there was no relationship between PAF content in spermatozoa and ram fertility. In conclusion, we were unable to relate the in vivo fertility of rams with in vitro functional tests of their frozen-thawed semen and suggest that the fertility of a given semen sample cannot easily be quantified using available in vitro tests.


Truncating mutation of the DFNB59 gene causes cochlear hearing impairment and central vestibular dysfunction.
We have identified a consanguineous family from Morocco segregating autosomal recessive congenital progressive hearing loss (ARNSHL) and retinal degeneration. Detailed clinical investigation of the six siblings revealed combined severe cone-rod dystrophy (CORD) and severe/profound hearing impairment in two of them, while there is isolated CORD in three and nonsyndromic profound hearing loss in one. We therefore assumed a partial overlap of two nonsyndromic autosomal recessive conditions instead of a monogenic syndrome and performed genomewide linkage analysis. The disease loci were mapped to chromosome 2q31.1-2q32.1 for ARNSHL and to 2q13-2q14.1 for CORD, respectively. The retinal phenotype was shown to be due to homozygosity for a novel splice site mutation, c.2189+1G>T, in the retinitis pigmentosa gene MERTK. The ARNSHL interval comprised the DFNB59 locus. The DFNB59 gene has been identified recently, and two missense mutations (p.R183W and p.T54I) have been shown to cause auditory neuropathy in both humans and transgenic mice. Mutation screening in the DFNB59 gene in our family revealed homozygosity for a 1-bp insertion in exon 2 (c.113_114insT), predicting a truncated protein of 47 amino acids, in all three hearing impaired subjects. This is the first description of biallelic putative loss-of-function of the DFNB59 gene. Detailed audiological investigation clearly indicated hair cell dysfunction and, in contrast to cases reported previously, excluded auditory neuropathy. We show that besides otoferlin (OTOF), DFNB59 is the second known gene in which mutations can result in these two distinct forms of hearing impairment. Moreover, all patients in our family with homozygosity for the DFNB59 mutation display central vestibular dysfunction.


Getting pre-exposure prophylaxis (PrEP) to the people: opportunities, challenges and emerging models of PrEP implementation.
Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) is now accepted as an efficacious approach to preventing HIV acquisition among people at high risk of HIV infection but, in most places, PrEP uptake to date has not been sufficient to have a large effect on HIV incidence. In this paper we consider several key elements of the effort to expand PrEP uptake for at-risk populations who would benefit most, such as increasing access to PrEP, integrating PrEP programs with other services, promoting PrEP persistence and developing systems for monitoring PrEP use. We used a PrEP Continuum framework to describe barriers to equitable uptake of PrEP, and to illustrate possible solutions to barriers. Access to PrEP includes regulatory issues and geographic proximity to PrEP providers. Integrating PrEP programs with other comprehensive sexual health services, through clinic-based programs or technology-based approaches, offers opportunities to identify PrEP candidates and improve linkages to PrEP care. Once at-risk people are prescribed PrEP, lowering barriers to persistence on PrEP is critical to realising the most population benefits. To understand progress and identify underserved groups and communities, systems to monitor the uptake of PrEP are needed. Making the most of a new biomedical intervention tool requires ongoing research about implementation, scale-up through multiple channels, including community-based organisations, and high-quality monitoring of uptake. We must turn to questions of PrEP implementation and continue to seek innovative approaches to reduce barriers to PrEP uptake and persistence on PrEP.


Immunity to gastrointestinal nematodes: a story of immune modulation.
Infections with gastrointestinal nematodes are some of the most prevalent infections in the world today. Despite the fact that antihelminthic drugs are generally regarded as safe, efficient and are widely available, the level of infection remains as high or, in some cases, even higher than 50 years ago. It is clear that immune-mediated resistance to infection in mouse models is mediated by a T-helper 2-type immune response. Gastrointestinal nematodes are powerful modulators of the immune response, and as such, they may have the potential to affect the outcome of concurrent infections with other parasites, bacteria or viruses. Importantly, they also appear to have the ability to influence the development of allergic reactions and modulate the effects of vaccination.


A defect in nurturing in mice lacking the immediate early gene fosB.
Although expression of the Fos family of transcription factors is induced by environmental stimuli that trigger adaptive neuronal response, evidence that Fos family members mediate these responses is lacking. To address this issue, mice were generated with an inactivating mutation in the fosB gene. fosB mutant mice are profoundly deficient in their ability to nurture young animals but are normal with respect to other cognitive and sensory functions. The nurturing defect is likely due to the absence of FosB in the preoptic area, a region of the hypothalamus that is critical for nurturing. These observations suggest that a transcription factor controls a complex behavior by regulating a specific neuronal circuit and indicate that nurturing in mammals has a genetic component.


Structural analysis of the human U3 ribonucleoprotein particle reveal a conserved sequence available for base pairing with pre-rRNA.
The human U3 ribonucleoprotein (RNP) has been analyzed to determine its protein constituents, sites of protein-RNA interaction, and RNA secondary structure. By using anti-U3 RNP antibodies and extracts prepared from HeLa cells labeled in vivo, the RNP was found to contain four nonphosphorylated proteins of 36, 30, 13, and 12.5 kilodaltons and two phosphorylated proteins of 74 and 59 kilodaltons. U3 nucleotides 72-90, 106-121, 154-166, and 190-217 must contain sites that interact with proteins since these regions are immunoprecipitated after treatment of the RNP with RNase A or T1. The secondary structure was probed with specific nucleases and by chemical modification with single-strand-specific reagents that block subsequent reverse transcription. Regions that are single stranded (and therefore potentially able to interact with a substrate RNA) include an evolutionarily conserved sequence at nucleotides 104-112 and nonconserved sequences at nucleotides 65-74, 80-84, and 88-93. Nucleotides 159-168 do not appear to be highly accessible, thus making it unlikely that this U3 sequence base pairs with sequences near the 5.8S rRNA-internal transcribed spacer II junction, as previously proposed. Alternative functions of the U3 RNP are discussed, including the possibility that U3 may participate in a processing event near the 3' end of 28S rRNA.


Intraretinal signaling by ganglion cell photoreceptors to dopaminergic amacrine neurons.
Retinal dopaminergic amacrine neurons (DA neurons) play a central role in reconfiguring retinal function according to prevailing illumination conditions, yet the mechanisms by which light regulates their activity are poorly understood. We investigated the means by which sustained light responses are evoked in DA neurons. Sustained light responses were driven by cationic currents and persisted in vitro and in vivo in the presence of L-AP4, a blocker of retinal ON-bipolar cells. Several characteristics of these L-AP4-resistant light responses suggested that they were driven by melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs), including long latencies, marked poststimulus persistence, and a peak spectral sensitivity of 478 nm. Furthermore, sustained DA neuron light responses, but not transient DA neuron responses, persisted in rod/cone degenerate retinas, in which ipRGCs account for virtually all remaining retinal phototransduction. Thus, ganglion-cell photoreceptors provide excitatory drive to DA neurons, most likely by way of the coramification of their dendrites and the processes of DA neurons in the inner plexiform layer. This unprecedented centrifugal outflow of ganglion-cell signals within the retina provides a novel basis for the restructuring of retinal circuits by light.


Tofacitinib for the Treatment of Ulcerative Colitis: Analysis of Infection Rates from the Ulcerative Colitis Clinical Programme.
Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis. We report integrated analyses of infections in the Phase [P]2 and P3 OCTAVE programmes. Three cohorts were analysed: Induction [P2/3 induction studies]; Maintenance [P3 maintenance study]; and Overall [all tofacitinib-treated patients in induction, maintenance, or ongoing, open-label, long-term extension studies; as of May 2019]. Proportions and incidence rates [IRs; unique patients with events/100 patient-years] of serious infections [SIs], herpes zoster [HZ] [non-serious and serious], and opportunistic infections [OIs] are reported [censored at time of event]. In the Induction Cohort [N = 1220], no patients receiving placebo and eight [0.9%] receiving tofacitinib 10 mg twice daily [BID] developed SIs. Maintenance Cohort [N = 592] SI IRs (95% confidence interval [CI]) were 1.94 [0.23-7.00] for placebo and 1.35 [0.16-4.87] and 0.64 [0.02-3.54] for tofacitinib 5 and 10 mg BID, respectively; HZ IRs were 0.97 [0.02-5.42], 2.05 [0.42-6.00], and 6.64 [3.19-12.22], respectively. In the Overall Cohort [N = 1157; 82.9% predominantly received tofacitinib 10 mg BID], SI, HZ, and non-HZ OI IRs were 1.70 [1.24-2.27], 3.48 [2.79-4.30], and 0.15 [0.04-0.38], respectively. No SIs resulted in death. During induction, SIs were more frequent with tofacitinib versus placebo. SIs were generally infrequent in the Maintenance and Overall Cohorts, with rates comparable between treatment groups. Maintenance Cohort HZ IR was numerically higher with tofacitinib 10 mg BID versus 5 mg BID. Overall Cohort HZ IRs remained stable over time. Non-HZ OIs and viral infections were rare.


Measurement of vessel diameter during angioplasty: are we accurately performing this task?
Vessel diameter is objectively measured by a lead ruler positioned in the fluoroscopic field and software calibration during angioplasty. We conducted a prospective study to evaluate the accuracy of lead ruler determination of vessel diameter. Chronic hemodialysis patients undergoing an angioplasty procedure were included in this study (n = 37). Vessel diameter was determined by calibrating the fluoroscopy machine to a ruler with lead markers placed in the fluoroscopic field. The same calibration was used to measure the fully effaced angioplasty balloon in its intravascular location. We compared the measured balloon diameter with the actual (manufacturer's) diameter. The approximate depth of the ruler from the measured vessel was also determined. Angioplasty balloons appeared 13.75-40.83% (mean 25.8% ± 7.015) smaller than the actual size of the balloon (p < 0.0001) when measured using a calibrated fluoroscopic machine. There was a tendency toward the fact that the bigger the distance between the ruler and the vessel (that contained the angioplasty balloon), the more likely the technique underestimated the size of the angioplasty balloon. Lead ruler method underestimates the diameter of the vessel. Recognizing such a discrepancy is important when determining the size of an angioplasty balloon or endovascular stent.


Previously unreported high-grade complications of adrenalectomy.
Serious complications of adrenalectomy are rare but the incidence may be underestimated if they occur outside major referral centers. We report five cases of high-grade complications after adrenalectomy that have not been previously described. The records of five cases of adrenalectomy performed at outside hospitals were reviewed. Four cases were referred for management of complications and one for medical-legal review. The nature of the adrenal lesion, operative approach, complication(s), and subsequent clinical course and complication management were assessed. Both open adrenalectomy (OA) and laparoscopic adrenalectomy (LA) cases were included. Operative indications were pheochromocytoma (N = 3), aldosteronoma (N = 1), and a nonfunctioning 6-cm hypervascular mass (N = 1). Complications of adrenalectomy included: case 1--complete transection of the porta hepatitis during right LA resulting in hepatic failure requiring emergent liver transplantation; case 2--ligation of the hepatic artery during right OA resulting in recurrent cholangitis and bile duct sclerosis requiring liver transplantation; case 3--ligation of the left ureter during LA resulting in postoperative hydronephrosis and loss of renal function; case 4--loss of left kidney function after OA, likely secondary to renal artery ligation ultimately requiring laparoscopic nephrectomy; case 5--LA of a normal adrenal gland for a 6-cm hypervascular mass thought to be arising from the adrenal gland. Three-month postoperative imaging demonstrated a persistent mass and the patient underwent hand-assisted laparoscopic nephrectomy for a left upper pole renal cell carcinoma that was missed at the time of LA. Despite the generally low morbidity of adrenalectomy, serious and potentially life-threatening complications can occur. Surgeon inexperience may be a factor in the occurrence of some of these complications which have not been previously described.


Insulin sensitivity across the lifespan from obese adolescents to obese adults with impaired glucose tolerance: Who is worse off?
Youth type 2 diabetes mellitus (T2DM) occurs decades earlier than adult T2DM and is characterized by high therapeutic failure rates and decreased response to insulin sensitizers suggesting a more severe disease process than in adults. To explain these observations, we hypothesized that insulin resistance is worse in obese youth than adults with impaired glucose tolerance (IGT), a state of high-risk for T2DM. As proof-of-concept, we compared insulin sensitivity between BMI-, sex-, and race-matched obese youth vs adults with IGT. This retrospective analysis of IGT youth and adults included 34 obese adolescents matched (2:1) for BMI, sex, and race to 17 adults. Hepatic and peripheral insulin sensitivity were measured by [6,6-2 H2 ]glucose and hyperinsulinemic-euglycemic clamp. Body composition (DEXA) and serum lipid profile were examined. Despite similar percent body fat, obese adolescents had 2-fold higher fasting insulin concentration, lower hepatic (~53%) and peripheral (~42%) insulin sensitivity and lower HDL compared with adults (all P < .01). Surrogate estimate of insulin sensitivity, 1/fasting insulin was lower and HOMA-IR was higher in adolescents vs adults. Adults had a more atherogenic lipid profile with higher total-, LDL-, and non-HDL cholesterol. Obese youth and adults with IGT differ in that youth are more insulin resistant than adults in spite of similar adiposity. This could potentially explain the earlier onset of T2DM in youth through an early and amplified burden on a β-cell destined to decompensate, and explicate their lower therapeutic response to insulin sensitizers.


Preoperative anemia in colon cancer: assessment of risk factors.
Anemia is common in cancer patients and is associated with reduced survival. Recent studies document that treatment of anemia with blood transfusion in cancer patients is associated with increased infection risk, tumor recurrence, and mortality. We therefore investigated the incidence of preoperative anemia in colorectal cancer and assessed risk factors for anemia. Prospective data were collected on 311 patients diagnosed with colorectal cancer over a 6-year period from 1994 through 1999. Patients were stratified by age, gender, presenting complaint, preoperative hematocrit, American Joint Committee on Cancer (AJCC) stage, and TNM classification. Discrete variables were compared using Pearson's Chi-square analysis. Continuous variables were compared using Student's t test. Differences were considered significant when P < 0.05. The mean age of the study cohort was 67 +/- 9.2 with 98 per cent of the study population being male. The mean AJCC stage was 2.2 +/- 1.2 and the mean preoperative hematocrit was 35 +/- 7.9 with an incidence of 46.1 per cent. The most common presenting complaints were hematochezia (n = 59), anemia (n = 51), heme-occult-positive stool (n = 33), bowel obstruction (n = 26), abdominal pain (n = 21), and palpable mass (n = 13). Preoperative anemia was most common in patients with right colon cancer with an incidence of 57.6 per cent followed by left colon cancer (42.2%) and rectal cancer (29.8%). Patients with right colon cancer had significantly lower preoperative hematocrits compared with left colon cancer (33 +/- 8.5 vs 36 +/- 7.4; P < 0.01) and rectal cancer (33 +/- 8.5 vs 38 +/- 6.0; P < 0.0001). Patients with right colon cancer also had significantly increased stage at presentation compared with left colon cancer (2.3 +/- 1.3 vs 2.1 +/- 1.2; P < 0.02). Age was not a significant risk factor for preoperative anemia in colorectal cancer. We conclude that there is a high incidence of anemia in patients with colon cancer. Patients with right colon cancer had significantly lower preoperative hematocrits and higher stage of cancer at diagnosis. Complete colon evaluation with colonoscopy is warranted in patients with anemia to improve earlier diagnosis of right colon cancer. A clinical trial of preoperative treatment of anemic colorectal cancer patients with recombinant human erythropoietin is warranted.


Treatment of patients with small renal masses: a survey of the American Urological Association.
We surveyed American Urological Association members to determine factors that influence the treatment of patients with small renal masses. In June 2009 American Urological Association members were solicited to complete an online survey. Respondents were asked their preferred treatment for 8 cases and 3 index patients. In each case computerized tomographic axial and schematic coronal images were provided. A total of 759 active urologists with varied training backgrounds and clinical practice settings completed the survey. Tumor size (OR 8.4, 95% CI 7.1-10.1), tumor depth (OR 19.2, 95% CI 14.8-25.0) and tumor location (OR 24.0, 95% CI 18.1-31.8) were markedly associated with preference for radical nephrectomy instead of partial nephrectomy. Fellowship trained urologists (OR 0.4, 95% CI 0.2-0.6) and urologists at academic hospitals (OR 0.6, 95% CI 0.4-0.9) were less likely to choose radical nephrectomy. Respondents were more likely to choose active surveillance in an older patient (OR 2.7, 95% CI 2.1-3.6) or in a patient with comorbidities (OR 10.0, 95% CI 8.0-12.4). Urologists were less likely to choose active surveillance for a 4 vs 2 cm tumor (OR 0.18, 95% CI 0.15-0.21). Active surveillance was chosen more often if the tumor was perihilar vs mid kidney (OR 2.0, 95% CI 1.8-2.3) or polar (OR 2.1, 95% CI 1.9-2.5). There is considerable heterogeneity in the treatment of patients with clinical T1a tumors. Several factors explain these differences as selected treatments are independently associated with tumor, patient and urologist factors.


Functional bowel complaints and quality of life after surgery for colon cancer: prevalence and predictive factors.
Low anterior resection syndrome (LARS) severely affects the quality of life (QoL) of patients after surgery for rectal cancer. There are very few studies that have investigated LARS-like symptoms and their effect on QoL after colon cancer surgery. The aim of this study was to investigate the prevalence of functional abdominal complaints and related QoL after colon cancer surgery compared with patients with similar complaints after rectal cancer surgery. All patients who underwent colorectal cancer resections between January 2008 and December 2015, and who were free of colostomy for at least 1 year, were eligible (n = 2136). Bowel function was assessed by the LARS score, QoL by the EORTC QLQ-C30 and QLQ-CR29 questionnaires. QoL was compared between the LARS score categories and tumour height categories. A total of 1495 patients (70.0%) were included in the analyses, of whom 1145 had a colonic and 350 a rectal tumour. Symptoms of LARS were observed in 55% after rectal cancer resection compared with 21% after colon cancer resection. Female gender (OR 1.88, CI 1.392-2.528) and a previous diverting stoma (OR 1.84, CI 1.14-2.97) were independently associated with a higher prevalence of LARS after colon cancer surgery. Patients with LARS after colon cancer surgery performed significantly worse in most QoL domains. The results of this study highlight the presence of LARS-like symptoms after surgery for colonic cancer. Patients suffering from major LARS-like symptoms after colon resection reported the same debilitating effect on their QoL as patients with major LARS after rectal resection. This should be addressed by colorectal cancer specialists in order to adequately inform patients.


ERRATUM.
Ovarian cancer is highly malignant with a gradually increasing incidence and a high mortality rate. Immunosuppression is induced in ovarian cancer, although the mechanism detail is not clear. It has been indicated that HVEM (herpesvirus entry mediator) B- and T-lymphocyte attenuator (BTLA) negatively regulates the immune responses of T lymphocytes. Here, HVEM mRNA was found to be elevated in ovarian cancer tissue samples and primary ovarian cancer cells in comparison with benign tissue samples. We then knocked down HVEM expression in an ovarian cancer cell line, OVCAR3, by lentivirus-based small hairpin RNA (shRNA). Cell Counting Kit-8 (CCK-8) assay and flow cytometry analysis showed that HVEM-shRNA had no effect on the proliferation, early apoptosis, or cell cycle distribution of OVCAR3. We then isolated activated T cells and performed coculture experiments in Transwell. Remarkably, HVEM-silenced ovarian cancer cells (primary ovarian cancer cells and OVCAR3) increased the number of T cells and the secretion of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), while activated T cells promoted the apoptosis of HVEM-silenced ovarian cancer cells. The current study partially explains the immune escape mechanism of ovarian cancer cells and provides a possible target for immunotherapy.


Laser-induced damage studies in silicon and silicon-based photodetectors.
Laser-induced damage studies have been carried out on single-crystal silicon and silicon-based photodetectors, FND 100 P-I-N photodiodes, and C30954E avalanche photodiodes as a function of repetition frequency for a 1064-nm wavelength. It has been observed that the damage threshold decreases significantly when the samples are irradiated with a large number of pulses. However, this effect is evident only when the repetition frequency is greater than 1 Hz. The results are discussed in light of various existing theories.


University students with attention deficit hyperactivity disorder (ADHD): a literature review.
To review existing literature about university students with Attention Deficit Hyperactivity Disorder (ADHD). A framework for scoping studies and content analysis were used to source and review selected publications from PubMed, ScienceDirect, Google Scholar and relevant bibliographies. Seventy-four publications were reviewed and key findings were categorised under six core themes that represent the issues germane to university students with ADHD. These themes are: academic, social and psychological functioning, giftedness, new media technologies, treatment, substance misuse and the non-medical use of prescription stimulants, and malingering. In Ireland and the United Kingdom (UK) young people with ADHD are unlikely to enrol into further education, and of those who do go to university, few will graduate at the same time as their non-ADHD peers. ADHD is associated with poor educational outcomes and it may be a hidden disability within institutions of higher education (e.g. universities). Surprisingly, in this topic area, there is a paucity of research in Ireland and the UK. Most studies originate from North America were research activity in the field has been ongoing since the 1990s. These studies however, tend to use relatively small samples of college (university) students recruited at a single institution. It is difficult to generalise the findings of these studies to student populations in North America, let alone in Ireland and the UK. At the very least, these North American studies provide insights into key areas of concern. This topic area straddles education and psychiatry. This means an inter-disciplinary approach is required to examine, better understand and address the impact of ADHD on the educational outcomes of university students. The philosophies of difference, equity and self-realisation can offer a conceptual framework for conducting further research and/or developing services to deliver more personalised learning support for university students with ADHD.


Grass-fed vs. grain-fed beef systems: performance, economic, and environmental trade-offs.
Between increasing public concerns over climate change and heightened interest of niche market beef on social media, the demand for grass-fed beef has increased considerably. However, the demand increase for grass-fed beef has raised many producers' and consumers' concerns regarding product quality, economic viability, and environmental impacts that have thus far gone unanswered. Therefore, using a holistic approach, we investigated the performance, carcass quality, financial outcomes, and environmental impacts of four grass-fed and grain-fed beef systems currently being performed by ranchers in California. The treatments included 1) steers stocked on pasture and feedyard finished for 128 d (CON); 2) steers grass-fed for 20 mo (GF20); 3) steers grass-fed for 20 mo with a 45-d grain finish (GR45); and 4) steers grass-fed for 25 mo (GF25). The data were analyzed using a mixed model procedure in R with differences between treatments determined by Tukey HSD. Using carcass and performance data from these systems, a weaning-to-harvest life cycle assessment was developed in the Scalable, Process-based, Agronomically Responsive Cropping Systems model framework, to determine global warming potential (GWP), consumable water use, energy, smog, and land occupation footprints. Final body weight varied significantly between treatments (P < 0.001) with the CON cattle finishing at 632 kg, followed by GF25 at 570 kg, GR45 at 551 kg, and GF20 478 kg. Dressing percentage differed significantly between all treatments (P < 0.001). The DP was 61.8% for CON followed by GR45 at 57.5%, GF25 at 53.4%, and GF20 had the lowest DP of 50.3%. Marbling scores were significantly greater for CON compared to all other treatments (P < 0.001) with CON marbling score averaging 421 (low-choice ≥ 400). Breakeven costs with harvesting and marketing for the CON, GF20, GR45, and GF25 were $6.01, $8.98, $8.02, and $8.33 per kg hot carcass weight (HCW), respectively. The GWP for the CON, GF20, GR45, and GF25 were 4.79, 6.74, 6.65, and 8.31 CO2e/kg HCW, respectively. Water consumptive use for CON, GF20, GR45, and GF25 were 933, 465, 678, and 1,250 L/kg HCW, respectively. Energy use for CON, GF20, GR45, and GF25 were 18.7, 7.65, 13.8, and 8.85 MJ/kg HCW, respectively. Our results indicated that grass-fed beef systems differ in both animal performance and carcass quality resulting in environmental and economic sustainability trade-offs with no system having absolute superiority.


Current Awareness and Use of the Strain Echocardiography in Routine Clinical Practices: Result of a Nationwide Survey in Korea.
Because conventional echocardiographic parameters have several limitations, strain echocardiography has often been introduced in clinical practice. However, there are also obstacles in using it in clinical practice. Therefore, we wanted to find the current status of awareness on using strain echocardiography in Korea. We conducted a nationwide survey to evaluate current use and awareness of strain echocardiography from the members of the Korean Society of Echocardiography. We gathered total 321 questionnaires from 25 cardiology centers in Korea. All participants were able to perform or interpret echocardiographic examinations. All participating institutions performed strain echocardiography. Most of our study participants (97%) were aware of speckle tracking echocardiography and 185 (58%) performed it for clinical and research purposes. Two-dimensional strain echocardiography was the most commonly used modality and left ventricle (LV) was the most commonly used cardiac chamber (99%) for clinical purposes. Most of the participants (89%) did not think LV strain can replace LV ejection fraction (LVEF) in their clinical practice. The common reasons for not performing routine use of strain echocardiography was diversity of strain measurements and lack of normal reference value. Many participants had a favorable view of the future of strain echocardiography. Most of our study participants were aware of strain echocardiography, and all institutions performed strain echocardiography for clinical and research purposes. However, they did not think the LV strain values could replace LVEF. The diversity of strain measurements and lack of normal reference values were common reasons for not using strain echocardiography in clinical practice.


Hemagglutinin Sequence Conservation Guided Stem Immunogen Design from Influenza A H3 Subtype.
Seasonal epidemics caused by influenza A (H1 and H3 subtypes) and B viruses are a major global health threat. The traditional, trivalent influenza vaccines have limited efficacy because of rapid antigenic evolution of the circulating viruses. This antigenic variability mediates viral escape from the host immune responses, necessitating annual vaccine updates. Influenza vaccines elicit a protective antibody response, primarily targeting the viral surface glycoprotein hemagglutinin (HA). However, the predominant humoral response is against the hypervariable head domain of HA, thereby restricting the breadth of protection. In contrast, the conserved, subdominant stem domain of HA is a potential "universal" vaccine candidate. We designed an HA stem-fragment immunogen from the 1968 pandemic H3N2 strain (A/Hong Kong/1/68) guided by a comprehensive H3 HA sequence conservation analysis. The biophysical properties of the designed immunogen were further improved by C-terminal fusion of a trimerization motif, "isoleucine-zipper", or "foldon". These immunogens elicited cross-reactive, antiviral antibodies and conferred partial protection against a lethal, homologous HK68 virus challenge in vivo. Furthermore, bacterial expression of these immunogens is economical and facilitates rapid scale-up.


Primary exposure to Zika virus increases risk of symptomatic dengue virus infection with serotypes 2, 3, and 4 but not serotype 1.
Infection with any of the four dengue virus serotypes (DENV1-4) can protect against or enhance subsequent dengue depending on pre-existing antibodies and the subsequent infecting serotype. Additionally, primary infection with the related flavivirus Zika virus (ZIKV) has been shown to increase DENV2 disease. Here, we measured how prior DENV and ZIKV immunity influenced risk of disease caused by all four serotypes in a pediatric Nicaraguan cohort. Of 3,412 participants in 2022, 10.6% experienced symptomatic DENV infections caused by DENV1 (n=139), DENV4 (n=133), DENV3 (n=54), DENV2 (n=9), or an undetermined serotype (n=39). Longitudinal clinical and serological data were used to define infection histories, and generalized linear and additive models adjusted for age, sex, time since the last infection, cohort year, and repeat measurements were used to predict disease risk. Compared to flavivirus-naïve participants, primary ZIKV infection increased disease risk of DENV4 (relative risk = 2.62, 95% confidence interval: 1.48-4.63) and DENV3 (2.90, 1.34-6.27) but not DENV1 (1.20, 0.72-1.99). Primary DENV infection or a DENV followed by ZIKV infection also increased DENV4 risk. We re-analyzed 19 years of cohort data and demonstrated that prior flavivirus-immunity and pre- existing antibody titer differentially affected disease risk for incoming serotypes, increasing risk of DENV2 and DENV4, protecting against DENV1, and protecting at high titers but enhancing at low titers against DENV3. We thus find that prior ZIKV infection, like prior DENV infection, increases risk of certain DENV serotypes. Cross-reactivity among flaviviruses should be carefully considered when assessing vaccine safety and efficacy. Dengue disease risk is differentially modulated depending on pre- existing immunity to dengue and Zika virus infections and the secondary infecting serotype.


Repression of the eIF2α kinase PERK alleviates mGluR-LTD impairments in a mouse model of Alzheimer's disease.
Mounting evidence indicates that impairments of synaptic efficacy and/or plasticity may be a key step in the development of Alzheimer's disease (AD) pathophysiology. Among the 2 major forms of synaptic plasticity, long-term potentiation and long-term depression (LTD), much less is known about how LTD is regulated in AD and its molecular mechanisms. Recent studies indicate that metabotropic glutamate receptor 5 (mGluR5) may function as a receptor and/or co-receptor for amyloid beta. Herein, we examined mGluR-LTD in hippocampal slices from aged APP/PS1 mutant mice that model AD. Our findings demonstrate that mGluR-LTD is blocked in APP/PS1 mice, and that the mGluR-LTD failure is reversed by either genetically or pharmacologically suppressing the activity of PERK, a kinase for the mRNA translation factor eIF2α. These data are congruent with recent evidence that inhibition of eIF2α phosphorylation via PERK suppression and reversal of de novo protein synthesis deficits can mitigate cognitive deficits in neurodegenerative diseases. Together with reports indicating that mGluR5 may mediate amyloid beta synaptotoxicity, our findings offer insights into novel therapeutic targets for AD and other cognitive syndromes.


Full optimization of Jastrow-Slater wave functions with application to the first-row atoms and homonuclear diatomic molecules.
We pursue the development and application of the recently introduced linear optimization method for determining the optimal linear and nonlinear parameters of Jastrow-Slater wave functions in a variational Monte Carlo framework. In this approach, the optimal parameters are found iteratively by diagonalizing the Hamiltonian matrix in the space spanned by the wave function and its first-order derivatives, making use of a strong zero-variance principle. We extend the method to optimize the exponents of the basis functions, simultaneously with all the other parameters, namely, the Jastrow, configuration state function, and orbital parameters. We show that the linear optimization method can be thought of as a so-called augmented Hessian approach, which helps explain the robustness of the method and permits us to extend it to minimize a linear combination of the energy and the energy variance. We apply the linear optimization method to obtain the complete ground-state potential energy curve of the C(2) molecule up to the dissociation limit and discuss size consistency and broken spin-symmetry issues in quantum Monte Carlo calculations. We perform calculations for the first-row atoms and homonuclear diatomic molecules with fully optimized Jastrow-Slater wave functions, and we demonstrate that molecular well depths can be obtained with near chemical accuracy quite systematically at the diffusion Monte Carlo level for these systems.


Seroprevalence of herpes simplex virus types 1 and 2, Epstein-Barr virus, and cytomegalovirus in children with acute lymphoblastic leukemia in Egypt.
Viral infection, especially caused by herpes viruses, is now recognized as an important cause of morbidity and mortality in immunocompromised cancer patients. This study aimed at studying seroprevalence of 3 herpes viruses Herpes simplex virus types 1 and 2 (HSV 1 and 2), Epstein-Barr virus (EBV), and cytomegalovirus (CMV) in children with acute lymphoblastic leukemia (ALL). We conducted this study on 68 newly diagnosed pediatric patients with ALL presented to the Pediatric Oncology Service of National Cancer Institute, Cairo University, Egypt from November 2001 to June 2003. We used enzyme-linked immunosorbent assay in detecting HSV 1 and 2, CMV, EBV antibodies of both types immunoglobulin (Ig) M and IgG detection of DNA for both CMV and EBV by polymerase chain reaction was carried out. High seroprevalence of HSV-1 and 2, CMV and EBV IgG antibodies in both leukemic children and their control was observed (69%, 100%, 83%) and (80%, 100%, 95%). Significantly higher percentage of HSV-1 and 2 IgM or reactivated infection was found among leukemic children 17/68 (25%) compared with normal control 0%. Analysis showed that prevalence of HSV 1 and 2 IgG increased from 18/33 (54%) in children <5 years to 11/13 (77%) in children >10 years, and reactivation of HSV-1 and 2 increased with increasing age from 1/33 (3%) in children <5 years to 4/13 (30%) in children >10 year. This was in contrast to seroprevalence of CMV and EBV IgG which were 100% and 83% in children <5 years. No difference in seroprevalence was found among both gender, and no difference was found in leukemic patients with granulocytopenia. The data show a higher exposure to HSV-1 and 2 both primary infections and reactivation among ALL children. Therefore, acyclovir prophylaxis could be highly effective for seropositive leukemic patients who are undergoing induction chemotherapy.


Suppressor of Cytokine Signaling-2 (SOCS2) Regulates the Microglial Response and Improves Functional Outcome after Traumatic Brain Injury in Mice.
Traumatic brain injury (TBI) is frequently characterized by neuronal, axonal and myelin loss, reactive gliosis and neuroinflammation, often associated with functional deficits. Endogenous repair mechanisms include production of new neurons from precursor cells, but usually the new neurons fail to integrate and survive more than a few weeks. This is in part mediated by the toxic and inflammatory environment present in the injured brain which activates precursor cells to proliferate and differentiate but limits survival of the newborn progeny. Therefore, an understanding of mechanisms that regulate production and survival of newborn neurons and the neuroinflammatory response after brain injury may lead to therapeutic options to improve outcomes. Suppressor of Cytokine Signaling 2 (SOCS2) promotes hippocampal neurogenesis and survival of newborn neurons in the adult brain and regulates anti-inflammatory responses in the periphery, suggesting it may be a useful candidate to improve outcomes of TBI. In this study the functional and cellular responses of SOCS2 over-expressing transgenic (SOCS2Tg) mice were compared to wildtype littermates following mild or moderately severe TBI. Unlike wildtype controls, SOCS2Tg mice showed functional improvement on a ladder test, with a smaller lesion volume at 7d post injury and increased numbers of proliferative CD11b+ microglia/macrophages at 35d post-injury in the mild injury paradigm. At 7d post-moderately severe injury there was an increase in the area covered by cells expressing an anti-inflammatory M2 phenotype marker (CD206+) but no difference in cells with a pro-inflammatory M1 phenotype marker (CD16/32+). No effect of SOCS2 overexpression was observed in production or survival of newborn neurons, even in the presence of the neuroprotective agent erythropoietin (EPO). Therefore, SOCS2 may improve outcome of TBI in mice by regulating aspects of the neuroinflammatory response, promoting a more anti-inflammatory environment, although this was not sufficient to enhance survival of newborn cortical neurons.