Cloning and characterization of DNA complementary to human UDP-GalNAc: Fuc alpha 1----2Gal alpha 1----3GalNAc transferase (histo-blood group A transferase) mRNA.
Based on the partial amino acid sequence, the cDNA encoding UDP-GalNAc:Fuc alpha 1----2Gal alpha 1----3GalNAc transferase, the specific primary gene product of histo-blood group A gene (A transferase), was cloned and sequenced. Poly(A)+ RNA from human stomach cancer cell line MKN45, expressing high levels of A antigen, was used for construction of a lambda gt10 cDNA library. Degenerate synthetic oligodeoxynucleotides were used for polymerase chain reactions to detect the presence of the sequence of interest in cDNA (presence test) and to identify the correct clones (identification test) after screening the library with a radiolabeled polymerase chain reaction amplified fragment. Nucleotide sequence analysis revealed a coding region of 1062 base pairs encoding a protein of 41 kDa. Hydrophobicity plot analysis shows the existence of three domains: N-terminal short stretch, transmembranous hydrophobic region, and a long C-terminal domain (a feature common to all glycosyltransferases cloned so far). Southern hybridization analysis has shown that this DNA does not represent a multigene family. No restriction fragment length polymorphism was found to correlate with ABO blood group type. Bands were detected in Northern hybridization of mRNAs from cell lines expressing A, B, AB, or H antigens. These results suggest that sequences of ABO genes are essentially very similar (with minimal differences), and the inability of the O gene to encode A or B transferases is probably due to structural differences rather than A or B transferase expression failure.


Quality of Life in Patients With Chronic Rhinosinusitis and Sleep Dysfunction Undergoing Endoscopic Sinus Surgery: A Pilot Investigation of Comorbid Obstructive Sleep Apnea.
Patients with chronic rhinosinusitis (CRS) have reduced sleep quality linked to their overall well-being and disease-specific quality of life (QOL). Other primary sleep disorders also affect QOL. To determine the impact of comorbid obstructive sleep apnea (OSA) on CRS disease-specific QOL and sleep dysfunction in patients with CRS following functional endoscopic sinus surgery. Prospective multisite cohort study conducted between October 2011 and November 2014 at academic, tertiary referral centers with a population-based sample of 405 adults. Functional endoscopic sinus surgery for medically refractory symptoms of CRS. Primary outcome measures consisted of preoperative and postoperative scores operationalized by the Rhinosinusitis Disability Index (RSDI) survey, the 22-item Sinonasal Outcome Test (SNOT-22), and the Pittsburgh Sleep Quality Index (PSQI). Obstructive sleep apnea was the primary, independent risk factor. Of 405 participants, 60 (15%) had comorbid OSA. A total of 285 (70%) participants provided preoperative and postoperative survey responses, with a mean (SD) of 13.7 (5.3) months of follow-up. Significant postoperative improvement (P < .05) was reported across all mean disease-specific QOL measures for both participants with and without comorbid OSA. Participants without OSA reported significant greater improvement in unadjusted mean (SD) RSDI global scores (−25.0 [23.3] vs. −16.5 [22.1]; P = .03), RSDI physical (−10.7 [9.2] vs. −7.3 [9.1]; P = .03) and functional (−8.4 [8.7] vs. −5.1 [7.5]; P = .03) subdomain scores, and SNOT-22 rhinologic symptom domain scores (−9.1 [7.7] vs. −5.7 [6.9]; P = .008). Participants without OSA also reported greater improvements on mean (SD) PSQI global (−1.9 [4.0] vs. −0.5 [3.7]; P = .03), sleep quality (−0.4 [0.8] vs. −0.03 [0.7]; P = .02), and sleep disturbance (−0.4 [0.7] vs. −0.1 [0.7]; P = .03) scores. The majority of these associations were found to be durable after adjustment for alternate independent cofactors using stepwise linear regression modeling. Patients with CRS and comorbid OSA have poor QOL with substantial disease-specific QOL improvements following surgery. Patients who present with CRS should be assessed for primary sleep disorders and, if identified, should be treated concurrently for both CRS and OSA to improve sleep dysfunction to optimize surgical outcomes. clinicaltrials.gov Identifier: NCT01332136.


Pathologic node-negative lung cancer: Adequacy of lymph node yield and a tool to assess the risk of occult nodal disease.
Accurate lymph node (LN) staging is crucial for prognostication in NSCLC. Diagnosis of pN0 disease is based on the absence of positive LNs, irrespective of the number of LNs excised, and is thus susceptible to sampling error. Tumors that are assumed to be pN0 may in fact be understaged. We developed a tool to quantify the risk of occult nodal disease (OND) among patients with pN0 NSCLC in terms of the number of LNs examined. Patients treated surgically for stage I-III primary NSCLC between 2004 and 2014 (n = 49,356) were extracted from the Surveillance, Epidemiology, and End Results database. The probability of missing a positive node in terms of the number of LNs examined was modeled using a beta-binomial model. A mathematical tool was then used to calculate the negative predictive value (NPV) corresponding to the number of LNs examined. Ranging from 0 to 100%, higher NPV reflects greater confidence in the pN0 diagnosis and a lower probability of OND. The median number of LNs examined was 7 for N0, 10 for N1/N2, and 8 for N3 disease. The probability of missing a positive node decreased as LNs examined increased. Additionally, higher T stage required more LNs to confirm an N0 diagnosis. After accounting for false-negative diagnoses, the prevalence of node-positive disease was readjusted from 16% to 22% among patients with T1 disease. According to our tool, with 10 LNs examined, the NPV was 85% (15% probability of OND) for a patient with T3 disease, compared with 95% (5% probability of OND) for a patient with T1 disease. Accurate pN0 diagnosis depends on the number of LNs examined. The proposed tool offers the ability to quantify, in a patient-specific manner, the confidence in a diagnosis of node-negative disease on the basis of the number of LNs examined.


Routine hypercapnic challenge after cervical spinal hemisection affects the size of phrenic motoneurons.
After an individual experiences a cervical cord injury, the cell body's adaptation to the smaller size of phrenic motoneurons occurs within several weeks. It is not known whether a routine hypercapnic load can alter this adaptation of phrenic motoneurons. We investigated this question by using rats with high cervical cord hemisection. The rats were divided into four groups: control, hypercapnia, sham, and sham hypercapnia. Within 72 h post-hemisection, the hypercapnia groups began a hypercapnic challenge (20 min/day, 4 times/week for 3 weeks) with 7% CO2 under awake conditions. After the 3-week challenge, the phrenic motoneurons in all of the rats were retrogradely labeled with horseradish peroxidase, and the motoneuron sizes in each group were compared. The average diameter, cross-sectional area, and somal surface area of stained phrenic motoneurons as analyzed by software were significantly smaller in only the control group compared to the other groups. The histogram distribution was unimodal, with larger between-group size differences for motoneurons in the horizontal plane than in the transverse plane. Our findings indicate that a routine hypercapnic challenge may increase the input to phrenic motoneurons and alter the propensity for motoneuron adaptations.


Clinical introduction of a linac head-mounted 2D detector array based quality assurance system in head and neck IMRT.
IMRT QA is commonly performed in a phantom geometry but the clinical interpretation of the results in a 2D phantom plane is difficult. The main objective of our work is to move from film measurement based QA to 3D dose reconstruction in a patient CT scan. In principle, this could be achieved using a dose reconstruction method from 2D detector array measurements as available in the COMPASS system (IBA Dosimetry). The first step in the clinical introduction of this system instead of the currently used film QA procedures is to test the reliability of the dose reconstruction. In this paper we investigated the validation of the method in a homogeneous phantom with the film QA procedure as a reference. We tested whether COMPASS QA results correctly identified treatment plans that did or did not fulfil QA requirements in head and neck (H&N) IMRT. A total number of 24 treatments were selected from an existing database with more than 100 film based H&N IMRT QA results. The QA results were classified as either good, just acceptable or clinically rejected (mean gamma index <0.4, 0.4-0.5 or >0.5, respectively with 3%/3mm criteria). Film QA was repeated and compared to COMPASS QA with a MatriXX detector measurement performed on the same day. Good agreement was found between COMPASS reconstructed dose and film measured dose in a phantom (mean gamma 0.83±0.09, 1SD with 1%/1mm criteria, 0.33±0.04 with 3%/3mm criteria). COMPASS QA results correlated well with film QA, identifying the same patients with less good QA results. Repeated measurements with film and COMPASS showed changes in delivery after a modified MLC calibration, also visible in a standard MLC check in COMPASS. The time required for QA reduced by half by using COMPASS instead of film. Agreement of COMPASS QA results with film based QA supports its clinical introduction for a phantom geometry. A standard MLC calibration check is sensitive to <1mm changes that could be significant in H&N IMRT. These findings offer opportunities to further investigate the method based on a 2D detector array to 3D dose reconstruction in a patient anatomy.


Long-term recurrence risk after a first venous thromboembolism in men and women under 50 years old: A French prospective cohort.
Data on long-term venous thromboembolism (VTE) recurrence risk according to gender are conflicting. To evaluate long-term VTE recurrence risk after a first VTE in men and women under 50 years old. Since May 2000, 875 consecutive patients (315 men, 560 women) with a first symptomatic VTE under 50 years old were enrolled in a French prospective multicentre cohort study and were followed up as long as possible. The primary outcome was symptomatic recurrent VTE during follow-up. At baseline, men were older and had more comorbidities than women. First VTE was mainly unprovoked in men (80.6%) and hormone-related in women (84.3%). During a median follow-up of 7.0 years (inter-quartile range, 5.0-11.0), recurrent VTE occurred in 97 men (30.8%) and in 72 women (12.9%) (annual incidence rates of recurrent VTE of 4.8% versus 1.8%-person-years, P<0.001). However, there was no difference according to gender in subgroups of patients with a first unprovoked VTE (5.8% versus 3.8%-person-years, P = 0.09). In women, duration of hormonal treatment before first VTE did not influence recurrence risk. In multivariable analysis, unprovoked VTE and family history of VTE were independently associated with recurrence (hazard ratio of 2.50 (95% confidence interval, 1.61 to 3.85) and 1.52 (1.11 to 2.09) respectively). Number of women with unprovoked VTE was low. In patients with a first VTE under 50 years old, a first unprovoked episode and a family history of VTE, but not gender, were associated with a high risk of long-term recurrence.


Qualities of care managers in chronic disease management: patients and providers' expectations.
The collaborative care model has been shown in studies to be effective in achieving sustained treatment outcomes in chronic disease management. Its success is highly dependent on active patient engagement, provider endorsement and effective care management. This study sought to ask patients and providers what qualities they look for in a care manager. A questionnaire with 3 open ended questions was mailed out randomly to 1000 patients residing in Olmsted County, MN identified through the registry to have type 2 diabetes mellitus. Forty-two primary care providers received similar questionnaire with 2 open ended questions. Answers were qualitatively analyzed using coding and identification of major themes. One hundred seventy-five patients and 22 providers responded. Both groups listed being knowledgeable, having good communication skills and certain personality traits as common themes on what are desirable qualities in a care manager. Patients felt that a care manager would be most helpful by being accessible. Providers listed undesirable qualities to include not being a team player and not knowing practice limitations. Both patients and providers have clear expectations of a care manager which carry significant implications in recruiting and training care managers for chronic disease management.


GRETTA: an R package for mapping in silico genetic interaction and essentiality networks.
Mapping genetic interactions and essentiality networks in human cell lines has been used to identify vulnerabilities of cells carrying specific genetic alterations and to associate novel functions to genes, respectively. In vitro and in vivo genetic screens to decipher these networks are resource-intensive, limiting the throughput of samples that can be analyzed. In this application note, we provide an R package we call Genetic inteRaction and EssenTiality neTwork mApper (GRETTA). GRETTA is an accessible tool for in silico genetic interaction screens and essentiality network analyses using publicly available data, requiring only basic R programming knowledge. The R package, GRETTA, is licensed under GNU General Public License v3.0 and freely available at https://github.com/ytakemon/GRETTA and https://doi.org/10.5281/zenodo.6940757, with documentation and tutorial. A Singularity container is also available at https://cloud.sylabs.io/library/ytakemon/gretta/gretta.


Granular cell tumor of the glans penis in a 9-year-old boy.
Granular cell tumor of the penis is a rare lesion, especially in the pediatric population. We present a case of a 9-year-old white boy with a granular cell tumor of the glans penis, as well as a review of literature. We also discuss clinical management and subsequent implications pertinent to lesion location.


HPV vaccination among adolescent males: results from the National Immunization Survey-Teen.
US guidelines provided a permissive recommendation for HPV vaccine for males in 2009, with an updated recommendation for routine vaccination in 2011. Data on vaccine uptake among males, however, remain sparse. We analyzed 2010-2011 data (collected mostly prior to the recommendation for routine vaccination) from the National Immunization Survey-Teen for a nationally representative sample of adolescent males ages 13-17 (n=22,365). We examined HPV vaccine initiation (receipt of at least one dose based on healthcare provider records) as the primary outcome. Analyses used weighted logistic regression. HPV vaccine initiation increased from 1.4% in 2010 to 8.3% in 2011. Parents who reported receiving a healthcare provider recommendation to get their sons HPV vaccine were much more likely to have vaccinated sons (OR=19.02, 95% CI: 14.36-25.19). Initiation was also higher among sons who were Hispanic (OR=1.83, 95% CI: 1.24-2.71) or who were eligible for the Vaccines for Children program (OR=1.53, 95% CI: 1.01-2.31). Only 31.0% of parents with unvaccinated sons indicated their sons were "somewhat likely" or "very likely" to receive HPV vaccine in the next year. The most common main reasons for parents not intending to vaccinate were believing vaccination is not needed or not necessary (24.5%), not having received a provider recommendation (22.1%), and lack of knowledge (15.9%). HPV vaccination is low among adolescent males in the US, and provider recommendation for vaccination is likely key to improving vaccine uptake. Given the updated recommendation for routine vaccination and the changes in health insurance coverage that are likely to follow, continued efforts are needed to monitor HPV vaccination among males.


Phylogeny of the families Zoothamniidae and Epistylididae (Protozoa: Ciliophora: Peritrichia) based on analyses of three rRNA-coding regions.
Peritrichs are a major group of ciliates with worldwide distribution, and they play important roles in many habitats. Intrafamilial phylogeny of some peritrichs was investigated using information from three genes, which provided more robust interpretations than single-gene analyses. Sixty-seven new sequences including SSU rDNA, ITS1-5.8S-ITS2 and LSU rDNA were aligned with available sequences in GenBank to infer phylogenetic relationships within the families Zoothamniidae and Epistylididae. Results reveal the following relationships: (1) Epistylididae is polyphyletic, consisting of two clades that nest within the Zoothamniidae as part of the crown clade of peritrichs (order Vorticellida) and a third one that is part of the basal clade of peritrichs (order Opercularida); (2) Epistylis elongata falls within one of the clades of Zoothamnium rather than with congeners; (3) Zoothamnium is probably paraphyletic, consisting of three divergent clades, with the genera Myoschiston and Zoothamnopsis intermingled with species of Zoothamnium. The following evolutionary hypotheses can be inferred from these results: (1) the contractile stalk of Zoothamnium is plesiomorphic. (2) Myoschiston, Zoothamnopsis and clade II of Epistylididae are derived from the Zoothamnium morphotype by partial or incomplete development of the spasmoneme that forms the contractile center of the stalk around which the rigid cortex is secreted. (3) Clade I of the Epistylididae, which are primarily colonial forms that appear never to have evolved a spasmoneme of any sort, may represent the ancestral morphotype of peritrichs.


Adjuvant chemotherapy after curative resection for gastric cancer: a meta-analysis.
The aim of this article is to review up-to-date clinical data published in the literature in regard to adjuvant chemotherapy in patients with gastric cancer after radical surgical resection. Medline, Embase, PubMed, the Cochrane Library and CBMDisc were searched to identify data published regarding this issue from 1966 to 2013. All the calculations and statistical tests were done using RevMan5.2 software. A total of 29 trials with 8580 patients met all inclusion criteria. Among them, 27 studies reported survival rates at the end of follow-ups, 64.2% alive among 3981 patients in the adjuvant chemotherapy arm and 57.3% alive among 4027 patients in the observation arm. Statistical results showed that the observation arm had a shorter disease-free survival (RR: 1.11, 95% CI: 1.07-1.15), and the treatment arm had a lower recurrence rate (RR: 0.79, 95% CI: 0.74-0.84). Leucopenia, anemia, nausea and vomiting, diarrhea, alopecia and infection occurred more frequently in the treatment arm. Adjuvant chemotherapy decreased the occurrence of peritoneum relapse [RR = 0.77, 95% CI (0.66-0.90)], lymphoid nodes relapse [RR = 0.58, 95% CI (0.45-0.75)] and local relapse [RR = 0.57, 95% CI (0.41-0.80)]. Adjuvant chemotherapy can improve the survival rate and disease-free survival rate and reduce the relapse rate after curative resection. Adjuvant chemotherapy cannot induce thrombocytopenia and mucositis or affect liver function. The tumor in situ recurrence and peritoneum, lymph nodes relapse decrease after chemotherapy, and patients benefit from adjuvant chemotherapy regardless of the numbers of positive lymph node, depth of local invasion, Asian or non-Asian, the length of follow-up, and numbers of cycles.


Persistent but reversible coma in encephalitis.
Nontraumatic coma in adults has a poor prognosis, and late recovery of consciousness is unlikely. Functional recovery is usually extremely poor. However, a few nontraumatic comatose patients have shown late recovery of both awareness and function. A retrospective survey was conducted by reviewing the medical records of all inpatients to our department during the 1990s. Patients with persistent but reversible nontraumatic coma were identified according to the following criteria: (a) deep coma with a Glasgow Coma Scale (GCS) score of 7 or less on admission; (b) nontraumatic cause; (c) persistence of unconsciousness for longer than 1 month; and (d) subsequent recovery of GCS (total) to normal. The clinical spectrum of patients meeting these criteria was evaluated. Six patients (ages 16-75 years) met the criteria. Viral encephalitis was diagnosed in five (two with herpes simplex virus, two with cytomegalovirus, and one with Epstein-Barr virus or cytomegalovirus). Two young female patients with encephalitis manifested extremely protracted coma persisting for 3 and 18 months, respectively. Complications included nonconvulsive status epilepticus in two patients and relative overdose of clonazepam in one patient. Recognition of the clinical spectrum of persistent but reversible nontraumatic coma is important.


"A source of empowerment and well-being": Experiences of a dance and yoga intervention for young girls with functional abdominal pain disorders.
Functional abdominal pain disorders are common among children and adolescents worldwide and effective treatments are needed to alleviate suffering for these children and their families. This study aimed to explore the experience of participating in a combined dance and yoga intervention from the perspectives of girls aged 9-13 years with functional abdominal pain disorders. A randomized controlled trial called Just in TIME (Try, Identify, Move and Enjoy) recruited 121 girls aged 9-13 years with functional abdominal pain disorders. The eight-month intervention combined dance and yoga twice a week, focusing on enjoyment, socialization and playful creativity in an undemanding and non-judgemental environment. The intervention group comprised 64 girls, of whom 25 were purposefully selected for this qualitative interview study. Semi-structured interviews were conducted and analysed using qualitative content analysis with an inductive approach. The girls' experiences of the Just in TIME intervention can be described as "A source of empowerment and well-being which facilitated personal growth and new ways of engaging in life". The main category was derived from six generic categories: "A sense of belonging", "Joy and emotional expression through movement", "Relief from pain", "More self-confident", "More active in daily life" and "A sense of calm." Regular participation in an eight-month intervention with combined dance and yoga in a supportive and non-judgemental atmosphere can ease pain and strengthen inner resources, resulting in empowerment, well-being and a more active life for girls with functional abdominal pain disorders. The Just in TIME study is available online at clinicaltrials.gov, ID: NCT02920268.


Type 2 inositol trisphosphate receptor gene expression in hepatocytes is regulated by cyclic AMP.
The type 2 inositol 1,4,5-trisphosphate receptor (IP3R2) is the principal intracellular Ca2+ release channel in hepatocytes, and so is important for bile secretion and other functions. IP3R2 activity is regulated in part by post-translational modifications but little is known about transcriptional regulation of its expression. We found that both IP3R2 mRNA and protein levels in liver were increased during fasting. Treatment of hepatocytes with forskolin or 8-CPT-cAMP also increased IP3R2, and this was reduced by actinomycin D. Analysis of the IP3R2 promoter revealed five CREs, and CREB potently increased promoter activity. Mutation of CRE4 or CRE5 decreased induction by CREB, and ChIP assay showed recruitment of CREB to these sites. Adenylyl cyclase (AC) 6 and 9 were the principal AC isoforms detected in rat hepatocytes, and silencing either one decreased organic anion secretion, which depends on IP3R2. Secretion furthermore was increased by overnight but not acute treatment with forskolin or 8-CPT-cAMP. These findings provide evidence that IP3R2 expression is transcriptionally regulated by cAMP via CREB binding to CRE elements in its promoter. The findings furthermore suggest that this mechanism is relevant for hormonal regulation of bile secretion.


Beta-arrestins specifically constrain beta2-adrenergic receptor signaling and function in airway smooth muscle.
Chronic use of inhaled beta-agonists by asthmatics is associated with a loss of bronchoprotective effect and deterioration of asthma control. Beta-agonist-promoted desensitization of airway smooth muscle beta-2-adrenergic receptors, mediated by G protein-coupled receptor kinases and arrestins, is presumed to underlie these effects, but such a mechanism has never been demonstrated. Using in vitro, ex vivo, and in vivo murine models, we demonstrate that beta-arrestin-2 gene ablation augments beta-agonist-mediated airway smooth muscle relaxation, while augmenting beta-agonist-stimulated cyclic adenosine monophosphate production. In cultures of human airway smooth muscle, small interfering RNA-mediated knockdown of arrestins also augments beta-agonist-stimulated cyclic adenosine monophosphate production. Interestingly, signaling and function mediated by m2/m3 muscarinic acetylcholine receptors or prostaglandin E(2) receptors were not affected by either beta-arrestin-2 knockout or arrestin knockdown. Thus, arrestins are selective regulators of beta-2-adrenergic receptor signaling and function in airway smooth muscle. These results and our previous findings, which demonstrate a role for arrestins in the development of allergic inflammation in the lung, identify arrestins as potentially important therapeutic targets for obstructive airway diseases.


Provider Practice and Perceptions of Pediatric Obesity in Appalachian Kentucky.
This study assessed providers' present practices and perceived needs in Appalachian Kentucky to identify the standard of care and implementation of expert recommendations for managing pediatric obesity. Questionnaire data were gathered from 28 providers at a pediatric obesity continuing medical education workshop in eastern Kentucky. We assessed current practices, perceived barriers to treatment, and needed resources for managing pediatric obesity. Respondents reported mixed adherence to expert recommendations, with providers less frequently addressing family-reported barriers to change and assessing a family's readiness to change behaviors related to pediatric obesity. Respondents also reported service barriers related to patient motivation, lack of time with patients, and a lack of referral options. Finally, providers reported needing multiple community resources to better address pediatric obesity, including improved physical education programs, access to community recreation centers, additional referral resources for multidisciplinary care, and additional training in motivational techniques. There remains a significant need for education and guidance regarding the implementation of expert recommendations for addressing pediatric obesity in Appalachian Kentucky. Providers reported needing multiple community resources, including improved physical education programs, access to community recreation centers, additional referral resources for multidisciplinary care, and additional training in motivational techniques. We discuss the implications for disseminating and implementing expert recommendations in rural eastern Kentucky, with an emphasis on the roles of behavioral health experts.


Porcine Intestinal Apical-Out Organoid Model for Gut Function Study.
Pig models provide valuable research information on farm animals, veterinary, and biomedical sciences. Experimental pig gut models are used in studies on physiology, nutrition, and diseases. Intestinal organoids are powerful tools for investigating intestinal functions such as nutrient uptake and gut barrier function. However, organoids have a basal-out structure and need to grow in the extracellular matrix, which causes difficulties in research on the intestinal apical membrane. We established porcine intestinal organoids from jejunum tissues and developed basal-out and apical-out organoids using different sub-culture methods. Staining and quantitative real-time PCR showed the difference in axis change of the membrane and gene expression of epithelial cell marker genes. To consider the possibility of using apical-out organoids for intestinal function, studies involving fatty acid uptake and disruption of the epithelial barrier were undertaken. Fluorescence fatty acid was more readily absorbed in apical-out organoids than in basal-out organoids within the same time. To determine whether apical-out organoids form a functional barrier, a fluorescent dextran diffusion assay was performed. Hence, we successfully developed porcine intestinal organoid culture systems and showed that the porcine apical-out organoid model is ideal for the investigation of the intestinal environment. It can be used in future studies related to the intestine across various research fields.


Play-Based Strategies for Speech Therapy and Vocal Health Face-to-Face and Distance Learning Actions for Children Distance Learning Actions for Children: An Integrative Literature Review.
Diversifying voice therapy strategies is critical to get children and adolescents to adhere to the therapeutic process. To investigate the face-to-face and distance playful strategies have been used for vocal health education and voice therapy in children and adolescents. An integrative literature review was carried out based on the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA). A search for full texts was conducted on the Virtual Health Library, Scientific Electronic Library Online (SCIELO) and PuBMed databases using the following descriptors, and their corresponding Medical Subject Headings (MeSH): voice (voz); voice quality (qualidade da voz); dysphonia (disfonia); voice disorders (distúrbios da fala); voice training (treinamento da voz); telemedicine (telemedicina); therapeutics (terapêutica); health promotion (promoção da saúde); group practice (prática de grupo); recreation therapy (terapia recreacional); child (criança); preschool (pré-escolar) and adolescent (adolescente). After full reading of the studies, 15 articles were included and categorized into the following topics: face-to-face and distance playful strategies for voice therapy in children; playful strategies with gamification for education and for voice therapy in children; and vocal health educational actions in children. The study found a higher number of studies that carried out educational actions and playful strategies, while fewer studies were related to the production of materials, gamification and online services for voice therapy in children. Given the proven benefits of this strategy for children, further studies focusing on the development and application of playful strategies, such as the use of gamification, should be conducted in order to stimulate the skills and adherence of this population to therapy.


A literature review of professionalism in surgical education: suggested components for development of a curriculum.
While it is evident that a surgeon must master medical knowledge and technical skill, there are other "soft skills" that are essential to a successful surgeon. One of these skills is professionalism. The challenge in surgical education lies in developing an effective professionalism curriculum and a related method of evaluation. Our review updates the literature and provides recommendations for improving instruction and evaluation of professionalism. A literature review was conducted using PubMed, Google Scholar, and Web of Knowledge. We restricted our search to documents published from 2009 to 2012 that address methods of teaching and tools for assessing professionalism in surgical education. Sixty-three documents were reviewed, with 14 fitting our search criteria for professionalism in surgical education completely. Other articles focused on the topics of professionalism in surgery, medical professionalism, and professionalism education in medical specialties other than surgery. Development of a professionalism curriculum for surgical residents might begin with defining professionalism in terms of tangible behaviors. The program might also include a precurriculum preparatory course and simulation-based training. Residency programs must also maintain professionalism among its faculty. Assessment in the form of multisource feedback that is consistent with observable behavioral definitions of professionalism should also be considered in evaluating resident professionalism.


Regulation of anti-apoptotic BCL2-proteins by non-canonical interactions: the next step forward or two steps back?
All aspects of cellular biology affect the process of regulated cell death, or apoptosis, and disruption of this process is a causative event in many diseases. Therefore, a comprehensive understanding of all pathways that regulate apoptosis would increase our knowledge of basic cellular functions, as well as the etiologies of many diseases. In turn, we may be able to use this knowledge to better treat patients with diseases, including cancer. Although the basic signaling pathway that regulates apoptosis has been known for over 10 years, we still have much to learn about the upstream signaling components that can directly regulate the core apoptosis machinery. The focus of this review will be to direct attention to non-canonical regulators of the BCL2-family of proteins, especially our void of understanding of such interactions, and the controversy that surrounds some such interactions.


Ethanol flush for the prevention of catheter occlusion.
Catheter occlusion by lipid material has been associated with the use of compounded nutrient solutions containing lipid. We have studied the incidence of catheter occlusion when either a saline or an ethanol flush has been used prior to the application of a heparin lock following an overnight infusion of such nutrients. Lipid occlusion occured in 13 of 23 catheters when a saline flush preceeded the application of a heparin lock, whereas the use of a 20% ethanol solution before the application of the heparin lock resulted in only 2 occlusoins in 28 catheters (p < 0.001). In addition there was significantly longer catheter survival in the ethanol group (p < 0.01). It is concluded that an ethanol flush may significantly reduce the incidence of catheter occlusion during the use of lipid mixes.


Abdominal peritoneum as a defense organ: analysis of ICAM-1 expression in the LPS-stimulated rat.
To investigate the immune environment of the peritoneal cavity, ICAM-1 (intercellular adhesion molecule) expression on the apical surface of the hepatic peritoneum of LPS (lipopolysaccharide) stimulated rats was analyzed ultrastructurally and chronologically with immunoTEM&SEM. ICAM-1 expression was restricted to the side of microvilli of the mesothelial cells. Microvilli demonstrated bulbous tips and included fuzzy coats and strands. Bulbous tips sometimes expressed the antigen, but fuzzy coats and strands did not. Intervillar cell surfaces lacked its expression. Although ICAM-1 expression increased eightfold 24 hr after stimulation, the selective expression remained unchanged. These results suggest that microvilli are closely associated with cell migration in the peritoneal cavity through adhesion molecules that establish a road for migration.


The in vitro behavior of as-prepared and pre-immersed RF-sputtered calcium phosphate thin films in a rat bone marrow cell model.
In this paper we focus on the behavior of radio frequency (RF)-sputtered calcium phosphate (CaP) thin films in a rat bone marrow (RBM) cell model. Two issues are addressed. Firstly, we benchmarked the in vitro cell behavior of these CaP coatings by comparing their proliferation, differentiation and mineralization behavior and the structure of the formed interface to similar coatings of alumina and titania. We found that the CaP coatings showed reduced proliferation, enhanced early differentiation and enhanced activity of mature osteoblasts compared to the alumina coatings. Enhanced production of mineralized extracellular matrix (ECM) was seen for both CaP and titania. Two types of CaP precipitates could be observed, one directly bonded CaP layer at the coating interface and one of globular accretions associated with the ECM. The directly bonded layer was not observed on the alumina coatings. Further, no thin film effects were found. Secondly, the effect of pre-immersion of the CaP coatings in SBF2 was explored. We found that the early formation of a directly bonded CaP layer is obstructed by the absence of CaP nuclei. After approximately 8 days, cell activity induces the nucleation of CaP crystals on both the surface and the ECM, and growth is enhanced. By initially providing these coatings with CaP crystals, growth of the directly bonded CaP layer is immediate. Hence, the formation of the interfacial CaP layer and the matrix-associated CaP accretions can effectively be decoupled.


Deamidation and isoaspartate formation during in vitro aging of recombinant tissue plasminogen activator.
When incubated at pH 7.3, 37 degrees C, human recombinant tissue plasminogen activator accumulated 0.77 mol of isoaspartate per mol of plasminogen activator over a 14-day period. Isoaspartate was detected by enzymatic transfer of 3H-labeled methyl groups from S-adenosyl-L-methionine in a reaction catalyzed by protein L-isoaspartyl methyltransferase. Analysis of tryptic peptides derived from aged plasminogen activator revealed that the two major sites of isoaspartate accumulation resulted from deamidation of Asn58 in the sequence -FNGG- and Asn177 in the sequence -GNSD-. Significant levels of isoaspartate also accumulated via deamidation of Asn37 in the sequence -CNSG-. All three sites occur in sequences predicted from studies with synthetic peptide to be unstable. All three sites appear to be on the surface of the protein, and all three occur in regions of the protein predicted to have higher than average chain mobility. These findings add support to the idea that sequence and flexibility play major roles in determining susceptibility to deamidation and peptide bond isomerization at Asn and Asp sites under mild conditions. These studies also illustrate the utility of enzymatic methylation for characterizing sites of deamidation in a large protein that contains numerous disulfide bonds and several sites of glycosylation.


APLNR marks a cardiac progenitor derived with human induced pluripotent stem cells.
Cardiomyocytes can be readily derived from human induced pluripotent stem cell (hiPSC) lines, yet its efficacy varies across different batches of the same and different hiPSC lines. To unravel the inconsistencies of in vitro cardiac differentiation, we utilized single cell transcriptomics on hiPSCs undergoing cardiac differentiation and identified cardiac and extra-cardiac lineages throughout differentiation. We further identified APLNR as a surface marker for in vitro cardiac progenitors and immunomagnetically isolated them. Differentiation of isolated in vitro APLNR+ cardiac progenitors derived from multiple hiPSC lines resulted in predominantly cardiomyocytes accompanied with cardiac mesenchyme. Transcriptomic analysis of differentiating in vitro APLNR+ cardiac progenitors revealed transient expression of cardiac progenitor markers before further commitment into cardiomyocyte and cardiac mesenchyme. Analysis of in vivo human and mouse embryo single cell transcriptomic datasets have identified APLNR expression in early cardiac progenitors of multiple lineages. This platform enables generation of in vitro cardiac progenitors from multiple hiPSC lines without genetic manipulation, which has potential applications in studying cardiac development, disease modelling and cardiac regeneration.


Relationship between sarcopenia and cachexia with prognostic markers of middle-aged and older inpatients with COVID-19: a case-control study.
SARS-CoV-2 infection can lead to various manifestations beyond an inflammatory response, such as anorexia, hyposmia, and other symptoms that may increase the risk of nutritional disorders. Sarcopenia and cachexia are conditions that appear to influence COVID-19 evolution. Thus, this study aimed to evaluate sarcopenia and cachexia in hospitalized patients with COVID-19, verifying their clinical impacts and relationship with prognostic markers. This is a case-control study involving inpatients with and without a COVID-19 diagnosis. The occurrence of sarcopenia was evaluated according to European Working Group on Sarcopenia 2 criteria. Cachexia was evaluated according to (Evans et al. in Clin Nutr 27:793-799, 2008) criteria. Inflammatory markers and the 4C Mortality Score were evaluated. Our study included 96 individuals, divided into two groups: COVID-19 (n = 32) and control (n = 64). The mean age of the COVID-19 group was 63.3 ± 11.8 years, and the control group had a mean age of 64.3 ± 5.5 years. No significant differences in mean age were found between the groups. The prevalence of sarcopenia and cachexia in patients with COVID-19 was 21.9% and 28.1%, respectively, while in the control group, it was 29.7% and 26.6%, respectively. Sarcopenic patients with COVID-19 had a higher risk of death (4C Mortality Score) (p = 0.038). The occurrence of sarcopenia or cachexia within the COVID-19 group was not associated with inflammatory biomarkers or a higher number of COVID-19 symptoms (p > 0.05). The presence of sarcopenia among COVID-19 patients increased the risk of mortality.


Traditional methods and biosensors for detecting disinfection by-products in water: A review.
In recent years, pollution caused by disinfection by-products (DBPs) has become a global concern. Initially, there were fewer contaminants, and the mechanism of their generation was unclear; however, the number of contaminants has increased exponentially as a result of rapid industrialization and numerous economic activities (e.q., during the outbreak of COVID-19 a surge in the use of chlorinated disinfectants was observed). DBP toxicity results in various adverse health effects and organ failure in humans. In addition, it profoundly affects other forms of life, including animals, plants, and microorganisms. This review comprehensively discusses the pre-treatment methods of traditional and emerging DBPs and the technologies applied for their detection. Additionally, this paper provides a detailed discussion of the principles, applicability, and characteristics of traditional large-scale instrumentation methods (such as gas/liquid/ion chromatography coupled with mass spectrometry) for detecting DBPs based on their respective detection techniques. At the same time, the design, functionality, classification, and characteristics of rapid detection technologies (such as biosensors) are also detailed and analyzed.


Characterization of nuclear factor of activated T-cells-c3 (NFATc3) and gene expression of upstream-downstream signaling molecules in response to immunostimulants in Pacific red snapper cells.
The nuclear factor of activated T cells (NFAT) proteins have crucial roles in the development and function of the immune system since they not only regulate activation of T cells but are also involved in the control of thymocyte development and T-cell differentiation. In this study, NFATc3 was characterized from the Pacific red snapper, Lutjanus peru. LpNFAtc3, which contains an open reading of 3300 bp frame coding for a protein of 1100 aa with a predicted molecular weight of 118.52 kDa. The predicted protein showed a conserved NFAT family structure with signature motifs and domains, sharing high identity (up to 76%) compared to other fish sequences. NFATc3 gene expression was analyzed by real time-PCR in head-kidney cells (leukocytes and lymphocytes) following yeast, zymosan and Vibrio parahaemolyticus stimulation along with the expression of upstream (ILF2, ILF3 and CaN) and downstream (CD3, TCRβ, IL-6 and IL-12) molecules. This study revealed a broad expression of NFATc3 with a relative strong expression in intestine and lymphocytes. The expression of NFATc3 was differentially up-regulated after stimulation with yeast in head-kidney leukocytes and after bacterial infection in lymphocytes at 24 h. Interestingly, the yeast and zymosan were able to activate ILF2, ILF3 and CaN mRNA gene expression in both kinds of cells. On the other hand, NFAT downstream genes such as CD3, TCRβ, IL-6 and IL-12 were significantly up-regulated in leukocytes stimulated with yeast or zymosan at 12 h; however in lymphocytes, this up-regulation was detected when cells reacted to V. parahaemolyticus stimuli at 24 h. Stimulating Pacific red snapper leukocytes with immunostimulants as yeast significantly up-regulated the expression of NFATc3, and up- and down-stream molecular genes and NFATc3 lymphocytes expression were potentially involved in responses to invasion of bacterial pathogens in an early immune response.


Bactericidal activity of catechin-copper (II) complexes on Escherichia coli ATCC11775 in the absence of hydrogen peroxide.
Washed Escherichia coli ATCC11775 cells were killed by (-)-epigallocatechin (EGC) in the presence of a non-lethal concentration of Cu2+ (1 mumol l-1) without additional H2O2, but not by (-)-epicatechin (EC). EGC alone (< 0.1 mmol l-1) did not reduce the viability of the cells. The survival curve obtained in the presence of EGC and Cu2+ was similar to that obtained in the presence of (-)-adrenaline (EN) and Cu2+.


The elusive task of biomarkers of renal injury.
Neutrophil gelatinase-associated lipocalin (NGAL) is one of the most promising candidate biomarkers of renal injury, with expression in renal tissue increasing dramatically after ischemia-reperfusion injury but not in the case of pure pre-renal failure. In a recent issue of Critical Care, Di Somma and colleagues reported that NGAL could improve the classification of acute kidney injury compared with clinical assessment and showed that NGAL was associated with poor prognosis. NGAL may therefore carry different information than biomarkers of renal function. This study finally provides additional evidence for the highly complex relationship between renal function and renal injury.


S-2-amino-5-azolylpentanoic acids related to L-ornithine as inhibitors of the isoforms of nitric oxide synthase (NOS).
S-2-Amino-5-(2-aminoimidazol-1-yl)pentanoic acid and S-2-amino-5-(2-nitroimidazol-1-yl)pentanoic acid have been used as weakly inhibitory lead compounds in the design of 2-amino-5-azolylpentanoic acids which are more potent in their inhibition of nitric oxide synthases. Treatment of 2-(Boc-amino)-5-bromopentanoic acid t-butyl ester with appropriate imidazoles and 1,2,4-triazoles and with tetrazole under basic conditions, followed by acidolytic deprotection, gave many of the required 2-amino-5-azolylpentanoic acids. Tetrazole was alkylated at 1-N and at 2-N in approximately equal amounts whereas the 1,2,4-triazoles reacted principally at 1-N. A nitrile was introduced at the 2-position of the imidazole by reaction of the 2-unsubstituted precursor with 1-cyano-4-dimethylaminopyridine. Of this series of compounds, 2-amino-5-(imidazol-1-yl)pentanoic acid was identified as the most potent member against rat iNOS, rat nNOS and a human-derived cNOS. Examination of the structure-activity relationships for the identity and substitution of the azoles has led to the proposal of a model for the binding of the inhibitors to the binding site for the natural substrate.


Human-Human Handover Tasks and How Distance and Object Mass Matter.
We investigated the coordination between two individuals during object handovers. Ten participants (eight males, two females; 26.0 ± 5.0 years, 72.7 ± 13.5 kg, 1.73 ± 0.8 m) arranged in pairs (a giver and a receiver), passed an object from the giver to the receiver at a self-selected speed. A motion capture system quantified the giver and the receiver's motion simultaneously. Three interpersonal distances and three object masses were chosen to study the handover. We hypothesized that (a) the handover occurs at half of the interpersonal distance between the giver and receiver and (b) the handover height depends on the objects' mass. Taken together, our results show that the handover strongly depends on the interpersonal distance between the giver and receiver, while object mass related only to handover duration.


Cometabolic degradation mechanism and microbial network response of methanotrophic consortia to chlorinated hydrocarbon solvents.
The cometabolism mechanism of chlorinated hydrocarbon solvents (CHSs) in mixed consortia remains largely unknown. CHS biodegradation characteristics and microbial networks in methanotrophic consortia were studied for the first time. The results showed that all CHSs can efficiently be degraded via cometabolism with a maximum degradation rate of 4.8 mg/(h·gcell). Chloroalkane and chloroethylene were more easily degraded than chlorobenzenes by methanotrophic consortia, especially nonfully chlorinated aliphatic hydrocarbons, which were converted to Cl- with a production rate of 0.29-0.36 mg/(h·gcell). In addition, the microecological response results indicated that Methylocystaceae (49.0%), Methylomonas (65.3%) and Methylosarcina (41.9%) may be the major functional degraders in methanotrophic consortia. Furthermore, the results of the microbial correlation network suggested that interactive relationships constructed by type I methanotrophs and heterotrophs determined biodegradability. Additionally, PICRUSt analysis showed that CHSs could increase the relative abundance of CHS degradation genes and reduce the relative abundance of methane oxidation genes, which was in good agreement with the experimental results.


[Autotransfusion of UV-irradiated blood in the treatment of suppurative peritonitis in children].
The inclusion of autotransfusions of the UV-irradiated blood in the complex of therapeutic measures for the treatment of children with peritonitis resulted in substantial shortening of the time of treatment and in a less volume of the infusion therapy. The autotransfusion of the UV-irradiated blood brings about positive dynamics of the ABC of blood, the content of immunoglobulins in plasma becomes normal within 5-6 days. The non-specific resistance factors were found to be activated.


Plasma HIV-1 RNA detection below 50 copies/ml and risk of virologic rebound in patients receiving highly active antiretroviral therapy.
Plasma human immunodeficiency virus type 1 (HIV-1) RNA suppression <50 copies/mL is regarded as the optimal outcome of highly active antiretroviral therapy (HAART). Current viral load (VL) assays show increased sensitivity, but the significance of RNA detection <50 copies/mL is unclear. This study investigated the virologic outcomes of 1247 patients with VL <50 copies/mL at an arbitrary time point during HAART (= T0), according to whether the actual, unreported (T0)VL was 40-49 copies/mL, RNA detected <40 copies/mL (RNA(+)), or RNA not detected (RNA(-)), as measured by the Abbott Real Time assay. Predictors of rebound >50 and >400 copies/mL over 12 months following T0 were analyzed with Cox proportional hazards models incorporating the (T0)VL and demographic and clinical data. Rebound rates >50 copies/mL were 34.2% for (T0)VL 40-49 copies/mL, 11.3% for RNA(+), and 4.0% for RNA(-); rebound rates >400 copies/mL were 13.0%, 3.8%, and 1.2%, respectively. The adjusted hazard ratios for rebound >50 copies/mL were 4.67 (95% confidence interval, 2.91-7.47; P < .0001) and 1.97 (1.25-3.11; P < .0001) with (T0)VL 40-49 copies/mL and RNA(+), respectively, relative to RNA(-), and 6.91 (2.90-16.47; P < .0001) and 2.88 (1.24-6.69; P < .0001), respectively, for rebound >400 copies/mL. The association was independent of adherence levels. In treated patients monitored by RealTime, a VL of 40-49 copies/mL and, to a lesser extent, RNA detection <40 copies/mL predict rebound >50 and >400 copies/mL independently of other recognized determinants. The goal of HAART may need to be revised to a lower cutoff than 50 copies/mL.


Cholelithiasis in the cottonrat, Sigmodon hispidus, from the high plains of Texas.
A high prevalence (71%) of gallstones was noted in free-ranging cottonrats, Sigmodon hispidus, collected from one site in Lubbock County, Texas. The gallbladder of affected animals was distended and filled with white, soft, friable, cholesterol gallstones of variable sizes. Focal hyperplasia of the epithelium and connective tissue layer of the gallbladder was evident in affected cottonrats. As the forage available to affected animals was different from that available to gallstone-free animals collected from other areas, this may be the cause of the higher prevalence of cholelithiasis in this population. The significance of this disease and possible use of the cottonrat as an experimental model are discussed.


LDR brachytherapy offers superior tumor control to single-fraction HDR prostate brachytherapy: A prospective study.
To compare the clinical outcomes of single-fraction high-dose-rate (HDR) brachytherapy and single-fraction low-dose-rate (LDR) brachytherapy as the sole treatment for primary prostate cancer. A quasi-randomized study that allocated, from March 2008 to February 2012, 129 low and intermediate risk prostate cancer patients to one single-fraction HDR of 19 Gy (61 patients) or to a 145 Gy 125 I LDR permanent implant (68 patients. Biochemical relapse-free survival (bRFS) and overall survival (OS) were compared using the Kaplan-Meier method and Cox regression analysis. After a median follow-up of 72 months in the HDR group, 26 patients relapsed, and after a median follow-up of 84 months in the LDR group, 7 patients relapsed (p < 0.0001). The 5-year bRFS was significantly better for the LDR group than for the HDR group (93.7% and 61.1%, respectively) (p < 0.0001). The 5-year OS also was significantly better in the LDR group (95.5% vs. 89.9%) (p = 0.0436). Permanent LDR prostate implant brachytherapy offers better clinical outcomes than single-fraction HDR for prostate cancer.


Cervical foraminal stenosis causing unilateral diaphragmatic paralysis without neurologic manifestation: A case report and review of the literature.
Unilateral diaphragmatic paralysis due to cervical spondylosis has rarely been reported. We present the first case of unilateral diaphragmatic paralysis without radicular pain or motor weakness due to cervical foraminal stenosis and a review of the related literature. A 59-year-old man presented with dyspnea and fever. His chest radiograph revealed right hemidiaphragmatic paralysis. The differential diagnosis of phrenic nerve palsy excluded mediastinal and neurodegenerative diseases. Imaging studies showed right foraminal stenosis caused by cervical spondylosis at C3-4 and C4-5. The patient underwent foraminotomy at C3-4 and C4-5 on the right side. The operative findings revealed a severe compression of the C4 root. At 3 months postoperatively, the unilateral diaphragmatic paralysis and dyspnea were recovered. Hemidiaphragmatic paralysis deserves careful evaluation for the presence of cervical spondylosis, even without concomitant neurologic manifestations.


A lipoxygenase inhibitor from Aspergillus niger.
A lipoxygenase-1 (LOX-1) inhibitor was isolated from the fermented broth of Aspergillus niger CFTRI 1105. It was purified, using column and preparative thin layer chromatography. 1H NMR and GC-MS examination revealed the structure of the inhibitor to be 2-(2'-methyl, 4'-hydroxyphenyl), 2-(4"hydroxyphenyl)-propane with a molecular weight of 242 and the molecular formula C,6H18O2. This bisphenol-derivative inhibitor shows 50% inhibition of soybean LOX-I at 0.98 mM concentration. The activity of this inhibitor was compared with commercial bisphenol A and its structural analogues, butylhydroxyanisole and butylhydroxytoluene in an attempt to understand the role of functional groups affecting lipoxygenase activity.


Phenotypic and functional characterization of human T cell clones indirectly activated against adult pig islet cells.
Xenotransplanted patients produce xenospecific IgG1 antibodies directed against epitopes other than Galalpha1,3Gal. IgG1 antibody production is believed to be dependent upon T cell help. Therefore, as a natural continuation of our work aimed at characterizing the xenoimmune antibody response against pig islet cells, we have also examined the T cell response. T cell reactivity against islet cells is believed to result from indirect antigen presentation, and our in vitro study was designed to mimic the response in vivo. The main purpose of this study was to characterize the phenotype, the immunological specificity and the functional capacity of indirectly activated T cell clones, reactive against pig islet cell antigens. Human T cell clones, activated against pig islet cells in the presence of autologous antigen-presenting cells, were produced from limiting dilutions of bulk cultures. Clonality was investigated by T cell receptor Vbeta (TcRVbeta) expression analysis. Clonal specificity was studied in proliferation assays using different pig cells as stimulators. ELISpot experiments were performed to detect cytokine production patterns. The cytotoxic capacity of the clones was assessed using standard cell-mediated lysis tests and different porcine and human target cells. Several long-term bulk cultures of human lymphocytes, indirectly activated against pig islet cells, maintained for up to 60 days, were used as a control for possible bias in the selection of the clones. Nineteen CD4+ TcRValphabeta+ T cell clones were recovered. No activation of natural killer T cells or gammadelta-T cells was recorded. There was no bias in the TcRVbeta-usage. The immunological specificity differed between clones; some were specifically reactive against pig islet cell antigens, while others were reactive with antigens present on a variety of pig cells. All clones produced a broad spectrum of cytokines, e.g. interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)5, IL10 and IL13, with no evidence of bias for a particular phenotype. None of the T cell clones were cytotoxic against pig islet cells, but two clones were cytotoxic against pig phytohemagglutinin (PHA)-blasts. The analysis of several, indirectly activated, human CD4+ T cell clones shows that the response against pig islet cells is heterogeneous both with regard to immunological specificity and functional characteristics. This heterogeneity was further confirmed by analysis of the long-term bulk cultures of human lymphocytes, indirectly activated against pig islet cells.


Hyperalgesia and myoclonus in terminal cancer patients treated with continuous intravenous morphine.
Eight cancer patients in the terminal stages of the disease treated with high doses of intravenous morphine developed hyperalgesia. All cases were retrospectively sampled from three different hospitals in Copenhagen. Five patients developed universal hyperalgesia and hyperesthesia which in 2 cases were accompanied by myoclonus. In 3 patients a pre-existing neuralgia increased to excruciating intensity and in 2 of these cases myoclonus occurred simultaneously. Although only few clinical descriptions of the relationship between hyperalgesia/myoclonus and high doses of morphine are available, experimental support from animal studies indicates that morphine, or its metabolites, plays a causative role for the observed behavioural syndrome. The possible mechanisms are discussed and treatment proposals given suggesting the use of more efficacious opioids with less excitatory potency in these situations.


Liangxue Jiedu formula improves imiquimod-induced psoriasiform dermatitis with circadian desynchrony by regulating Th17 cell differentiation based on network pharmacological analysis.
Liangxue Jiedu formula (LXJDF) is an effective traditional Chinese medicine (TCM) formula for treating psoriasis of blood-heat syndrome and has been used in clinics for decades. This study aimed to discover the mechanism of LXJDF in psoriasis and the circadian clock by network pharmacology and experimental studies. The compounds of LXJDF were obtained from the TCMSP and BATMAN-TCM databases. The genes related to psoriasis and circadian rhythm/clock were identified by the OMIM and GeneCards databases. Then, target genes were integrated by Venn and analyzed by the String, CytoNCA, DAVID (GO and KEGG) databases, and the network was constructed using Cytoscape. Mice were raised under light disturbance for fourteen days. On the eighth day, mouse dorsal skin was shaved and smeared with 62.5 mg 5% imiquimod at 8:00 (ZT0) for six successive days. Mice were randomly divided into the model, LXJDF-H (49.2 g/kg·bw), LXJDF-L (24.6 g/kg·bw), and positive drug (dexamethasone) groups. Other mice were smeared with Vaseline under the normal light cycle as the control. The drug of each group was administered at 10:00 (ZT2) and 22:00 (ZT14). The skin lesions were observed, and PASI was scored daily. HE and immunofluorescence were used to measure pathological morphology. Th17 cytokines in serum and skin were measured by flow cytometry and qPCR. Circadian clock gene and protein expression levels were determined by qPCR and Western blotting. We found 34 potential targets of LXJDF in the treatment of psoriasis and circadian rhythm and confirmed their importance by topology analysis. KEGG pathway analysis revealed that the two major pathways were Th17 cell differentiation and the HIF-1 signaling pathway. At ZT2 and ZT14, LXJDF improved IMQ-induced light disturbance mouse skin lesions, including alleviating scales, erythema, and infiltration, reducing PASI, and inhibiting keratinocyte hyperproliferation and parakeratosis. LXJDF reduced IL-17A, IL-17F, TNF-α, and IL-6 in serum at ZT2 and increased IL-10 at ZT2 and ZT14. LXJDF downregulated the expression of IL-17A and IL-17F in skin. At ZT2, LXJDF significantly upregulated CLOCK and REV-ERBα expression and downregulated HIF-1α expression. At ZT14, LXJDF decreased HIF-1α and RORγt expression and significantly increased REV-ERBα expression. LXJDF improves psoriasis dermatitis with circadian rhythm disorders by regulating Th17 cell differentiation.


Mortality in Emergency Department Sepsis score as a prognostic indicator in patients with pyogenic liver abscess.
The purpose of this study was to explore the predictor index of mortality in patients with pyogenic liver abscess (PLA). We performed a retrospective review that enrolled 431 patients 18 years and older hospitalized due to PLA between January 2005 and December 2010. Clinical characteristics, laboratory results, treatments, and outcomes retrieved from medical records were analyzed. Multiple logistic regression and receiver operating characteristic curve analyses were performed. The mean age of the 431 patients identified with PLA was 56.9 ± 15.0 years. The mean Mortality in Emergency Department Sepsis (MEDS) score on admission was 4.8 ± 4.1 (range, 0-17). During hospitalization, 94 patients (22%) required intensive care. Of the 431 patients, 63 died, yielding a 15% case fatality rate. Multivariate analysis revealed that higher MEDS scores on admission (P < .0001) and the presence of underlying malignancy (P = .006), multiple abscesses (P = .001), anaerobic infections (P < .0001), hyperbilirubinemia (P < .0001), and higher serum creatinine levels (P < .0001) were significantly associated with PLA mortality. The estimated area under the receiver operating characteristic curve for MEDS in predicting PLA mortality was 0.829 (95% confidence interval, 0.791-0.864; P < .0001). The optimal cutoff MEDS value of 7 or higher had a sensitivity of 76% sensitivity and a specificity of 81%, with a 10.7-fold PLA mortality risk (P < .0001) and a 26.2-fold intensive care unit admission risk (P < .0001). The MEDS scores on admission represent a significant prognostic indicator for patients with PLA.


Symposium: Imaging modalities for drug-related osteonecrosis of the jaw (6), assessment of mandibular metabolism due to long-term administration of an anti-resorptive agent by bone scintigraphy (secondary publication).
It is not yet known why anti-resorptive agent-related osteonecrosis specifically affects the jaw. Here we assessed changes in the bone metabolism of the mandible in response to long-term bisphosphonate (BP) therapy, and we compared the bone metabolism changes of the mandible with those of other bone sites using a quantitative analysis by bone scintigraphy. The region of interest was selected by identifying without an abnormal accumulation of the mandible, humerus, second and fourth lumbar vertebrae, iliac crest, intertrochanteric femur and diaphysis. Bone scintigraphy images were quantified using a value we termed the 'bone uptake value (BUV)'. In the low-dose bisphosphonate (LBP) group (n = 21), the patients were undergoing osteoporosis treatment with low-dose BP. The high-dose BP (HBP) group consisted of 12 bone metastasis patients undergoing high-dose BP treatment. The Control group was 47 subjects with oral disease who had never been treated with an anti-resorptive agent. Our analyses demonstrated that with long-term BP administration, the bone metabolism of the iliac crest and intertrochanteric femur was suppressed but that of the mandible was enhanced. There was no significant difference in bone metabolism with either the low-dose BP or high-dose BP treatment. The effects of the long-term administration of BP were site-specific.


Optical coherence tomography before and after vitrectomy with internal limiting membrane removal in a child with optic disc pit maculopathy.
The pathogenesis of optic disc pit maculopathy is still unknown, although recent optical coherence tomographic (OCT) analyses have made a great contribution to clarifying its morphological appearance. The best treatment for this disease is also controversial. We report on a 7-year-old girl with optic disc pit maculopathy associated with a separation of the internal limiting membrane (ILM) near the optic disc. The OCT images before treatment showed a conduit from the perineural space to the schisislike separation of the sensory retina with a dome-shaped separation of the ILM. A serous detachment (SD) in the macula, centered on the fovea, was also present. In OCT images after laser photocoagulation, the conduit appeared to be closed, but the SD was still present. Vitrectomy with ILM removal and gas tamponade resulted in a marked reduction of the SD in the macular area. Focal macular electroretinograms and visual acuity demonstrated a recovery of macular function. The dome-shaped separation of the ILM suggested that the vitreous might be exerting a tractional force on the optic disc pit, and vitrectomy with ILM peeling released the traction on the optic disc pit.


Trophic specialisations in alternative heterochronic morphs.
Polymorphisms are suspected of reducing competition among conspecifics in heterogeneous environments by allowing differential resource use. However the adaptive significance of alternative morphs has been poorly documented. The aim of this study is to determine food partitioning of two heterochronic morphs of the Alpine newt, Triturus alpestris, in mountain lakes. The morphs differ in the functional morphology of their feeding apparatus. Only paedomorphs are able to expel water during prey suction behind the mouth through gill slits. We observed a substantial trophic differentiation between morphs in all lakes. Paedomorphs preyed mainly on plankton, whereas metamorphs foraged on terrestrial invertebrates that fell upon the water surface. This resource partitioning may facilitate the coexistence of the alternative morphs in lakes devoid of vertebrate competitors. Food diversity may thus favour the evolutionary maintenance of facultative polymorphism in natural populations.


Semen collection and evaluation in the ram. The effect of method of stimulation on response to electroejaculation.
Nine different methods of electrical stimulation with a bi-polar rectal probe, were used on 5 rams. The quantity and quality of semen collected, the time taken to produce ejaculation and the maximum voltage required were compared. Semen of good quality was collected by applying a stimulus every 7 seconds for a period of 3 seconds commencing at 1 volt and increasing by 1 volt at a time. A mean maximum voltage of 5.1 volts produced ejaculation. Electrical stimulation, using a voltage rise of 2 volts applied at 5 sec intervals frequently produced smaller volumes of semen, a greater number of collection failures, and severe physical stress to the rams.


A comprehensive quality assurance program for four-dimensional computed tomography in radiotherapy.
This study aimed to develop and validate a comprehensive, reproducible and automatic 4DCT Quality Assurance (QA) workflow (QAMotion) that evaluates image accuracy across various regular and irregular breathing patterns. Volume and amplitude deviations, CT number accuracy, and spatial integrity were used as evaluation metrics. For repeatability tests, tolerances were respected with a mean CT number deviation < 10 HU, volume deviation < 2% and diameter and amplitude deviation < 2 mm except for irregular amplitude curves for which an amplitude deviation up to 6 mm was measured. QAMotion was able to flag image artefacts for our clinical 4DCT system.


Identification of Q-Markers from Hedan Tablet by employing "spider-web" mode and taking compounds' hepatotoxicity into account.
Due to the complicated compounds and the synergistic effect of multi-compounds, the quality control and assessment of Chinese materia medica (CMM) encounters a great challenge about how to identify the key compounds, which are directly correlated with its efficacy and safety. On the guidance of study on quality marker (Q-Marker), identification of Q-Markers was performed from Hedan Tablet (HDT) by the aid of the "spider-web" mode and hepatotoxicity evaluation derived from our previous researches and literatures. By the established ultra performance liquid chromatography with photodiode array detector (UPLC-PDA) method, online UPLC-DPPH· and offline antioxidant assay, 21 candidate compounds of HDT were systematically investigated and comprehensively evaluated by the "spider-web" mode for them properties of Q-Marker based on "content-stability-activity". In addition, the Q-Markers related with hepatotoxicity based on our previous researches and literatures were identified. Salvianolic acid B (SaB), quercetin-3-O-glucuronide (Qug), isoquercitrin (IQ) and hyperoside (Hyp) were adopted as the preferable Q-Markers of HDT according to the shaded area (A) of tested compounds in "spider-web" mode. Psoralen (Ps), isopsoralen (IP), psoralenoside (PO) and isopsoralenoside (IPO) were also strongly recommended as Q-Markers closely related with safety by considering hepatotoxicity of the accumulated Ps and IP and conversion between glycoside (PO and IPO) and aglycone (Ps and IP). This study provided scientific evidence for quality control and assessment of HDT, and also provided a meaningful reference for application of Q-Markers in CMM.


Angioscintigraphic assessment of arterial and portal liver blood flow: comparison with splanchnic angiography.
In order to validate an angioscintigraphic method for the evaluation of the components of hepatic blood flow, the results of angioscintigraphy were compared with splanchnic angiography in 25 cirrhotics. Two indices of hepatic portal perfusion and a splenohepatic arterial index were calculated. These were correlated with portal diameter and hepatic artery diameter, respectively. No correlation was found between grades of portal perfusion according Nordlinger's criteria and these indices. The method is very simple and could be applied to evaluate the changes of liver hemodynamics induced by drugs or shunt surgery.


Current and future trends in colorectal cancer screening.
Current modalities for colorectal cancer screening include fecal occult-blood testing, flexible sigmoidoscopy, colonoscopy, and double-contrast barium enema. Among these, colonoscopy is becoming the dominant modality, in light of its efficacy and continuing technical refinements. Emerging technologies, such as stool DNA tests and virtual colonoscopy, hold promise for the future but cannot be recommended for screening at present.


Association between TGFB1 genetic polymorphisms and chronic allograft dysfunction: a systematic review and meta-analysis.
Epidemiological studies have investigated the role of transforming growth factor-β1 (TGF-β1) in chronic allograft dysfunction (CAD) following kidney transplantation. TGFB1 gene polymorphisms (SNP rs1800470 and rs1800471) may be associated with the risk of CAD. In this meta-analysis, the relationship between these two variations and the risk of CAD was explored. MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, the Chinese CNKI and WANFANG databases were searched. Data were extracted and pooled results were estimated from odds ratios (ORs) with 95% confidential intervals (95% CIs). Quality assessments were performed, and publication bias of all eligible studies examined. Eight studies with 1038 subjects were included in our analysis. According to the effects on TGF-β1 secretion, haplotypes were categorized as "HIGH", "INTERMEDIATE" and "LOW". The combined results showed a statistically significant difference of TGFB1 haplotypes between the CAD recipients and control subjects when "HIGH" with "INTERMEDIATE" and "LOW" ("HIGH" vs. "INTERMEDIATE" + "LOW": OR: 3.56, 95% CIs: 2.20, 5.78, P < 0.001) were compared. No significant association was found between the TGFB1 codon 10 or codon 25 and the CAD risk in all five genetic models. Our meta-analysis has found the haplotype of TGFB1 codon 10/25 T/T G/G and T/C G/G genotypes, associated with increased production of TGF-β1, was linked with CAD risk following kidney transplantation. Moreover, no significant difference was found between TGFB1 codon 10 or codon 25 and the development of CAD.


Sjögren syndrome: a review for the maxillofacial surgeon.
Sjögren syndrome is a multisystemic condition that predominantly involves the salivary and lacrimal glands. Also known as sicca complex, the disease often is underdiagnosed and poorly understood. This article provides a comprehensive review on Sjögren syndrome, with an emphasis on diagnosis and treatment modalities.


5-(3,4-Dimeth-oxy-benzyl-idene)-1,3-dimethyl-1,3-diazinane-2,4,6-trione.
In the title compound, C(15)H(16)N(2)O(5), the dihedral angle between 1,3-diazinane and benzene rings is only 4.27 (1)°. The essentially planar mol-ecular structure is characterized by a short intra-molecular C-H⋯O separation and by an exceptionally large bond angle of 138.25 (14)° at the bridging methine C atom. The meth-oxy groups deviate somewhat from the plane of the benzene ring, with C-C-O-C torsion angles of -15.6 (1) and 9.17 (6)°. In the crystal, mol-ecules form centrosymmetric dimers via donor-acceptor π-π inter-actions, with a centroid-centroid distance of 3.401 (1) Å.


Full flexion of the hips and knees in the supine position to treat an episode of acute hypotension and pulseless electrical activity in a patient with severe aortic stenosis.
This is a case report of a 77-year-old man with severe symptomatic aortic stenosis who underwent removal of an impacted ureteral stone under general anesthesia. During emergence from general anesthesia, his legs were lowered from lithotomy position, resulting in sudden hypotension with progression to pulseless electrical activity. The legs were raised and placed into full flexion of the hips and knees. This maneuver was temporally related to a return of spontaneous circulation and full recovery. Possible mechanisms for this effect are discussed.


Parents' views and experiences of the autism spectrum disorder diagnosis of their young child: a longitudinal interview study.
Parents are valuable stakeholders in research, clinical practice and policy development concerning autism spectrum disorder (ASD). Little is known, however, about how parents view and experience an ASD diagnosis. We investigated the evolution of parents' views and experiences of the ASD diagnosis before, right after and 12 months after their child was diagnosed. Seventeen Flemish parents waiting for their young child's diagnostic ASD assessment participated in a longitudinal study consisting of three in-depth interviews. They described their views and experiences concerning their child's ASD diagnosis at three separate moments: (T1) prior to a diagnostic ASD assessment; (T2) immediately after their final feedback session at the end of the assessment; and (T3) 12 months later. Interviews were digitally recorded, transcribed and analysed in Nvivo 11 according to the procedures of interpretative phenomenological analysis. We extracted three themes from the interview material throughout the parental journey: (T1) expecting certainty and exculpation; (T2) vulnerabilisation of the child; and (T3) pragmatic attitude and some disappointment. At T3, the parents overall had come to value the diagnosis because of two reasons: they were satisfied with their child's entitlement to ASD-related support at school, and with the diagnosis' impact on the child's relationships with parents and teachers. Many parents experienced their child with an ASD diagnosis as vulnerable, and themselves as acutely responsible for his development and future. Our findings may lead to a higher satisfaction with the clinical trajectory in both clinician and parents by inspiring a conversation between them about parents' evolving views, hopes and concerns related to their child's ASD diagnosis.


Factor XI contributes to thrombus propagation on injured neointima of the rabbit iliac artery.
Thrombus formation through the activation of tissue factor (TF) and factor (F) XI is a critical event in the onset of cardiovascular disease. TF expressed in atherosclerotic plaques and circulating blood is an important determinant of thrombogenicity that contributes to fibrin-rich thrombus formation after plaque disruption. However, the contribution of FXI to thrombus formation on disrupted plaques remains unclear. A mouse monoclonal antibody against FXI and activated FXI (FXIa) (XI-5108) was generated by immunization with activated human FXI. Prothrombin time (PT), activated partial thromboplastin time (APTT), bleeding time, and ex vivo platelet aggregation in rabbits were measured before and after an intravenous bolus injection of XI-5108. We investigated the role of FXI upon arterial thrombus growth in the rabbit iliac artery in the presence of repeated balloon injury. The XI-5108 antibody reacted to the light chain of human and rabbit FXI/FXIa, and inhibited FXIa-initiated FXa and FXIa generation. Fibrin-rich thrombi developed on the injured neointima that was obviously immunopositive for glycoprotein IIb-IIIa, fibrin, TF, and FXI. Intravenous administration of XI-5108 (3.0 mg kg(-1)) remarkably reduced thrombus growth, and the APTT was significantly prolonged. However, PT, bleeding time and platelet aggregation were not affected. These results indicate that plasma FXI plays a potent role in thrombus growth on the injured neointima. Inhibition of plasma FXI activity might help to reduce thrombus growth on ruptured plaques without prolonging bleeding time.


Successful surgical correction of a cataract in a chimpanzee (Pan troglodytes) via field setting at a zoological facility.
A 41-year-old male vasectomized, zoo-housed chimpanzee (Pan troglodytes) presented with progressive visual deficits due to bilateral cataract formation. Phacoemulsification and lenticular implant were performed by a veterinary and human board-certified ophthalmologist team in a field setting. Post-operative healing occurred without complication, and the patient returned to the troop with improved vision.


Investigation of plant latices of Asteraceae and Campanulaceae regarding proteolytic activity.
Occurrence of plant latices is widespread, there are more than 40 families of plants characterized to establish lactiferous structures. The appearance of hydrolytic active proteins, incorporated in latices is already characterized, and hydrolytic active proteins are considerable, and for several plant families, the occurrence of hydrolytic active proteins is already specified e.g. Apocynaceae Juss., Caricaceae Dumort, Euphorbiaceae Juss., Moraceae Gaudich and Papaveraceae Juss. In our investigation, focused on latex bearing plants of order Asterales, Asteraceae and Campanulaceae in particular. The present outcomes represent a comprehensive study, relating to the occurrence of proteolytic active enzymes of order Asterales for the first time. 131 different species of Asteraceae and Campanulaceae were tested, and the appearance of plant latex proteases were determined in different quantities. Proteolytic activity was investigated by inhibitory studies and determination of residual activity in the following, enable us to characterize the proteases. Most of the considered species exhibit a serine protease activity and a multiplicity of species exhibited two or more subclasses of proteases.


Effect of intranasal fluticasone on cellular infiltration, endothelial adhesion molecule expression, and proinflammatory cytokine mRNA in nasal polyp disease.
Nasal polyp (NP) disease demonstrates a gradual response to treatment with intranasal steroids. We hypothesized that various inflammatory features that promote NP eosinophilia would show a differential sensitivity to treatment with intranasal fluticasone. We conducted a double-blind, placebo-controlled trial of 4 weeks of intranasal fluticasone propionate or matching placebo to assess their effectiveness in reducing NP inflammatory cells, expression of endothelial vascular cell adhesion molecule (VCAM)-1 and P-selectin, and expression of cytokines involved in induction of a group of adhesion molecules (ie, IL-4, IL-13, TNF-alpha, and IL-1beta). Twenty subjects (9 women and 11 men) with severe chronic sinusitis and NP were studied. Systemic and intranasal steroids were withheld for a minimum of 1 month and 2 weeks, respectively, before the study. Biopsy specimens of NPs were obtained 1 week before and 4 weeks after treatment with intranasal fluticasone 100 microg or placebo per nostril administered twice daily. Biopsy specimens were snap frozen for immunostaining or fixed in paraformaldehyde for in situ hybridization. Pretreatment to posttreatment results were analyzed with Wilcoxon's signed-rank test. Fluticasone treatment significantly reduced NP eosinophilia (P =.02) and CD4(+) T lymphocytes (P =.02). Eosinophils expressing the marker EG2 were more significantly reduced (P =.007). Fluticasone also reduced the expression of P-selectin (P =.005) and the number of IL-4 and IL-13 mRNA+ cells (P =.02 and.05, respectively). In contrast, fluticasone did not significantly reduce expression of endothelial VCAM-1 or the number of TNF-alpha or IL-1beta mRNA+ cells in the polyps. We conclude that intranasal fluticasone reduced NP inflammation but that expression of proinflammatory cytokines and endothelial VCAM-1 were relatively unaffected by fluticasone treatment. These latter inflammatory features may contribute to the persistence of NP disease despite intranasal steroid treatment.


[The pacemaker and the practitioner (author's transl)].
Considering the increasing importance of cardiac pacing (800-1000 pacemaker patients per million population according to most recent evaluations), the Authors made an investigation on a sample of 100 general practitioners, to evaluate their knowledge on pacemakers. These physicians have been questioned following a form, which resumed the most important problems that can arise in patients with cardiac pacemakers. The conclusion is that the practitioner has little knowledge on cardiac pacing and that he is not able to handle this sort of patient.


Evaluation of Metarhizium anisopliae (Metsch) Sorok. to target larvae and adults of Capnodis tenebrionis (L.) (Coleoptera: Buprestidae) in soil and fiber band applications.
The aim of this work has been to evaluate in the laboratory the potential of entomopathogenic fungi against adults and larvae of Capnodis tenebrionis (L.) (Coleoptera: Buprestidae) through fiber band application and a potted plant bioassay with soil application, respectively. Our previous findings revealed that Metarhizium anisopliae EAMa 01/58-Su isolate was the most virulent against neonate larvae of the buprestid. In the present work, M. anisopliae EAMa 01/58-Su isolate has been also shown to be highly virulent against adult beetles by immersion in a conidial suspension; thus it was selected to accomplish our objectives. When adult beetles were stimulated to climb 100 x 200 mm non-woven commercial fiber bands impregnated with conidia of M. anisopliae EAMa 01/58-Su isolate, total mortality rates varied from 85.7% to 100.0%; whereas no significant correlation was detected between the time needed to cross the band (mean value 648.7+/-22.4s) and the time of death, with mean average survival time ranging between 10.3 and 16.0 days, compared to 28 days of the controls. Potted seedlings (5-6 months old) of cherry plum (Prunus myrobalana Lois.), a commonly used apricot rootstock, were used to study the efficacy of soil treatment with M. anisopliae EAMa 01/58-Su isolate against neonate C. tenebrionis larvae. The soil inoculation with M. anisopliae EAMa 01/58-Su isolate had a significant effect on the mean number of dead larvae recovered from the roots, with mean mortality ranging from 83.3% to 91.6%; whereas no significant differences were detected between the three fungal doses. In all cases, dead larvae found within roots exhibited external signs of fungal growth. Hence, it may be possible to use M. anisopliae EAMa 01/58-Su isolate in a biocontrol strategy targeting both adults and larvae of C. tenebrionis.


Porosity as a Design Element for Developing Catalytic Molecular Materials for Electrochemical and Photochemical Carbon Dioxide Reduction.
The catalytic reduction of carbon dioxide (CO2 ) using sustainable energy inputs is a promising strategy for upcycling of atmospheric carbon into value-added chemical products. This goal has inspired the development of catalysts for selective and efficient CO2 conversion using electrochemical and photochemical methods. Among the diverse array of catalyst systems designed for this purpose, 2D and 3D platforms that feature porosity offer the potential to combine carbon capture and conversion. Included are covalent organic frameworks (COFs), metal-organic frameworks (MOFs), porous molecular cages, and other hybrid molecular materials developed to increase active site exposure, stability, and water compatibility while maintaining precise molecular tunability. This mini-review showcases catalysts for the CO2 reduction reaction (CO2 RR) that incorporate well-defined molecular elements integrated into porous materials structures. Selected examples provide insights into how different approaches to this overall design strategy can augment their electrocatalytic and/or photocatalytic CO2 reduction activity.


Cervical muscle response to trunk flexion in whiplash-type lateral impacts.
The purpose of this study was to determine the response of the cervical muscles to increasing low-velocity, whiplash-type lateral impacts when the occupant is seated out of the recommended driving position (neutral posture). Twenty healthy volunteers were subjected to left lateral impacts of 4.1, 7.7, 10.5, and 13.7 m/s(2) acceleration, with their trunk flexed by 45 degrees and laterally flexed to the right and left also by 45 degrees at the time of impact. Bilateral electromyograms of the sternocleidomastoids, trapezii, and splenii capitis were recorded. Under these conditions of trunk-flexed postures, in a left lateral impact, muscle responses were of generally low magnitude with the trunk flexed to either the left or right. Even at the highest acceleration of 13.7 m/s(2), all muscles generated less than 37% of their known maximal voluntary contraction electromyogram. Also, in these left lateral impacts, the right splenius capitis showed a greater EMG response than the left splenius capitis regardless of whether the subject was flexed to the right or left at the time of impact. The right splenius capitis (the one contralateral to the left lateral impact direction) was more active than its counterpart. Compared to what is known for EMG responses with an occupant in the neutral posture, the right sternocleidomastoid (usually the most active muscle in a left lateral collision) was significantly less-active with trunk flexion than with neutral posture conditions (P<0.01). In the absence of bodily impact, the flexed trunk posture does not produce a biomechanical response that would increase the likelihood of cervical muscle injury in low velocity lateral impacts, and may lessen the risk of injury for some muscles.


Mitochondrial ROS accumulation inhibiting JAK2/STAT3 pathway is a critical modulator of CYT997-induced autophagy and apoptosis in gastric cancer.
Gastric cancer (GC) is a common form of malignant cancer in worldwide which has a poor prognosis. Despite recent improvements in the treatment of GC, the prognosis is not yet satisfactory for GC patients. CYT997, a novel microtubule-targeting agent, recently has been identified to be a promising anticancer candidate for the treatment of cancers; however, the effects of CYT997 in GC remain largely unknown. Cell proliferation and apoptosis were detected by CCK8 assay and flow cytometry. The mitochondrial ROS were detected by confocal microscope and flow cytometry. Gastric cancer patient-derived xenograft (PDX) model was used to evaluate its antitumor activity of CYT997 in vivo. CYT997 inhibited gastric cancer cell proliferation and induced cell apoptosis and triggered autophagy. CYT997 induced apoptosis through triggering intracellular mitochondrial ROS generation in GC cells. ROS scavengers N-acetylcysteine (NAC) and Mitoquinone (MitoQ) distinctly weakened CYT997-induced cell cycle G2/M arrest and apoptosis in GC cells. Pretreatment with autophagy inhibitor 3-MA promoted the effect of CYT997 on cells apoptosis. Mechanistically, CYT997 performed its function through regulation of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in GC cells. In addition, CYT997 inhibited growth of gastric cancer patient-derived xenograft (PDX) tumors. CYT997 induces autophagy and apoptosis in gastric cancer by triggering mitochondrial ROS accumulation to silence JAK2/STAT3 pathway. CYT997 might be a potential antitumor drug candidate to treat GC.


The contribution of ecdysis to the fate of copper, zinc and cadmium in grass shrimp, Palaemonetes pugio Holthius.
Depuration through ecdysis by grass shrimp, Palaemonetes pugio, was examined by exposure to a sublethal mixture of copper, zinc and cadmium for 72 h, followed by placement in uncontaminated water to molt. Percent eliminated with the exuviae varied for each metal; of the total intermolt body burden, 11% Cu, 18% Zn and 26% Cd was associated with the exuviae. Cu concentrations of intermolt exoskeletons were significantly higher than of the exuviae of post-ecdysis shrimp suggesting that Cu contained in the exoskeleton was reabsorbed before molting. Exuvial Cd concentration was not significantly different than the concentration of the intermolt exoskeleton, suggesting that most Cd in the exoskeleton was depurated with the exuviae. Although Zn whole-body burdens were lower after a molt, Zn losses were most likely due to excretion because exuvial concentrations were significantly lower than in the intermolt exoskeleton. Cu, Cd and Zn concentrations in exuviae shed in metal-enriched water were significantly higher due to adsorption than exuviae produced in uncontaminated water.


Time to -30°C as a predictor of acute success during cryoablation in patients with atrial fibrillation.
Freezing rate of second-generation cryoballoon (CB) is a biophysical parameter that could assist pulmonary vein isolation. The aim of this study is to assess freezing rate (time to reach -30°C ([TT-30C]) as an early predictor of acute pulmonary vein isolation using the CB. Biophysical data from CB freeze applications within a multicenter, nation-wide CB ablation registry were gathered. Successful application (SA), was defined as achieving durable intraprocedural vein isolation. And SA with time to isolation under 60 s (SA-TTI<60) as achieving durable vein isolation in under 60 s. Logistic regressions were performed and predictive models were built for the data set. 12,488 CB applications from 1,733 atrial fibrillation (AF) ablation procedures were included within 27 centers from a Spanish CB AF ablation registry. SA was achieved in 6,349 of 9,178 (69.2%) total freeze applications, and SA-TTI<60 was obtained in 2,673 of 4,784 (55.9%) freezes where electrogram monitoring was present. TT-30C was shorter in the SA group (33.4 ± 9.2 vs 39.3 ± 12.1 s; p < 0.001) and SA-TTI<60 group (31.8 ± 7.6 vs. 38.5 ± 11.5 s; p < 0.001). Also, a 10 s increase in TT-30C was associated with a 41% reduction in the odds for an SA (odds ratio [OR] 0.59; 95% confidence interval [CI] 0.56-0.63) and a 57% reduction in the odds for achieving SA-TTI<60 (OR 0.43; 95% CI 0.39-0.49), when corrected for electrogram visualization, vein position, and application order. Time to reach -30°C is an early predictor of the quality of a CB application and can be used to guide the ablation procedure even in the absence of electrogram monitoring.


Pharmacokinetic/pharmaco-dynamic modelling and simulation of the effects of different cannabinoid receptor type 1 antagonists on Δ(9)-tetrahydrocannabinol challenge tests.
The severe psychiatric side effects of cannabinoid receptor type 1 (CB1 ) antagonists hampered their wide development but this might be overcome by careful management of drug development with pharmacokinetic/pharmacodynamic (PK/PD) analyses. PK/PD models suitable for direct comparison of different CB1 antagonists in Δ(9) -tetrahydrocannabinol (THC) challenge tests in healthy volunteer were constructed. The pharmacokinetic models of THC and four CB1 antagonists were built separately. THC-induced effects on heart rate and the visual analogue scale of feeling high in healthy volunteers and inhibitive effects of CB1 antagonists on THC-induced effects were modelled in PD models linked to the PK models. Simulations were then applied to evaluate the reduction rate of each antagonist on the reversal of the THC-induced effect in a unified simulation scenario. The final PK model of THC and antagonists was a two compartment model. An Emax model and logistic regression model were used for effect measures and the antagonist effect was added in these models in a competitive binding manner. t1/2ke0 ranged from 0.00462 to 63.7 h for heart rate and from 0.964 to 150 h for VAS. IC50 ranged from 6.42 to 202 ng ml(-1) for heart rate and from 12.1 to 376 ng ml(-1) for VAS. Benchmark simulation showed different dose-efficacy profiles of two efficacy measures for each CB1 antagonist. PK/PD modelling and simulation approach was suitable for describing and predicting heart rate and feeling high for CB1 antagonists in THC challenge tests. Direct comparison of four antagonists based on simulated efficacy profiles might be of benefit to guide future studies.


Fluorescence-detected circular dichroism studies of serum albumins.
Multidimensional fluorescence-detected circular dichroism (FDCD) is used to investigate the binding of bilirubin to four mammalian serum albumins. It is shown that the complexes formed with the albumins have distinctly different FDCD spectra. The effect of the pH-dependent transition from basic to acidic conditions on the complexes is examined. The binding of warfarin to albumin is also presented to demonstrate the general analytical utility of the multidimensional FDCD measurement for biochemical analysis.


'Project launch': from research finding to therapeutic product.
Only 0.1-0.5% of new therapy candidates gains marketing approval; just 10-20% of the approved ones ultimately recoup the ~0.6-0.9$USbn invested into their R&D until marketing authorisation. One reason is the high inherent risk of new therapeutic products development. Further reasons are suboptimal decisions during R&D and, too often, lack of adequate experience. To bridge the latter gap, this article succinctly reviews identification of new product opportunities and their patent protection, the resulting commercial opportunity and portfolio valuation, planning and conduct of the ensuing preclinical and clinical tests, as well as therapeutic product registration and price reimbursement, covering risk management as an aside. The article also clarifies the key terms, identifies the main pit falls, highlights the essential requirements for and the goals of different product development steps, to facilitate communication between researchers and developers. By combining public information with personal experience and recommendations the article aims at informing more broadly those who are familiar mainly with some of the (strictly regulated) activities involved in design, development and launch of new therapeutic products, be it that they are medicinal products or medical devices. Taken together, this should support initiation and evolution of new therapeutic products and assist researchers in finding-and better and more smoothly co-operating with-consultants or partners in development and marketing.


Prefrontal modulation of tactile responses in the ventrobasal thalamus of rats.
Prefrontal cortex (PFC) has been implicated in modulation of sensory information processing in somatosensory cortex. However, it remains unclear whether or not PFC regulates sensory information in thalamus. In the present study, the effect of PFC stimulation on tactile responses of neurons in the ventrobasal thalamus (VB) of the rat was investigated by single-unit recording. PFC stimulation significantly enhanced the signal-noise ratio (tactile responses/background activities) in 16 out of 66 VB neurons (24.2%) that had receptive fields in fore or hind limbs. Such changes can be classified into three different categories: (1) PFC stimulation not only increased the tactile responses, but also suppressed the background activities of neurons (six neurons, 9.1%); (2) PFC stimulation only increased the tactile responses of neurons (five neurons, 7.6%); (3) PFC stimulation only suppressed the background activities of neurons (five neurons, 7.6%). Our results suggest that PFC also modulates somatosensory information at the thalamic level.