Interinstitutional comparison of frozen section consultations. A college of American Pathologists Q-Probes study of 90,538 cases in 461 institutions.
To assess concordant, discordant, and deferred diagnosis rates from frozen sections; to determine reasons for discordance; to identify pathologic processes associated with discordant diagnoses; to determine false-positive or false-negative rates for neoplasms; and to identify anatomic sites associated with discordant frozen section diagnoses. Q-Probes study of the College of American Pathologists. Four hundred sixty-one institutions participating in the Q-Probes program from November 1, 1990, through March 31, 1991. Concordant and discordant diagnosis rates. The frozen section concordance rate for diagnoses from the aggregate group was 98.58% and the discordance rate was 1.42%, when uncorrected for deferred diagnoses. During the study period, participating institutions accessioned 1,693,331 surgical pathology cases; 90,538 of these cases were evaluated by frozen section consultation, resulting in the examination of 121,668 specimens and 148,506 frozen section blocks. The majority of the frozen section discordances occurred because of misinterpretation of the original frozen section (31.8%), presence of diagnostic tissue in permanent sections of the frozen block when the frozen section was negative (30.0%), and presence of diagnostic tissue in the portion of the specimen not sampled by the frozen section (31.4%). Of the discordant diagnoses, 67.8% had false-negative diagnoses for neoplasm. The pathology processes and anatomic sites represented in discordant diagnoses are also evaluated. High diagnostic accuracy of frozen section consultations was demonstrated. Frozen sections are used to evaluate a variety of pathologic processes and anatomic sites.


Dreams and age.
This work evaluated the association of age and dream reports. The verbal reports of 148 dreams of elderly people (M age=75.8 yr.) were compared with 151 dreams of a group of young people (M age=22.0). The dreams were analyzed according to the Jungian vision (which looks at the dream as a text produced by the dreamer's unconscious while sleeping), using processing techniques derived from textual analysis. Significant differences were found between the number of words denoting emotion, with the young people reporting more explicit statements regarding emotional states. Significant differences were found also in use of verb tenses. When older people explicitly expressed an emotional state in a dream text, they shifted between present and past tense more frequently than young people. A significant prevalence in the semantic field of visual sense was evident as younger subjects used more sentences referring to sight than the elderly participants.


Novel Pyridinium Cross-Link Structures Derived from Glycolaldehyde and Glyoxal.
Short-chained α-hydroxycarbonyl compounds such as glycolaldehyde (GA) and its oxidized counterpart glyoxal (GX) are known as potent glycating agents. Here, a novel fluorescent lysine-lysine cross-link 1-(5-amino-5-carboxypentyl)-3-(5-amino-5-carboxy-pentylamino)pyridinium salt (meta-DLP) was synthesized and its structure unequivocally proven by 1H NMR, 13C-NMR attached proton test, and 2D NMR. Further characterization of chemical properties and mechanistic background was obtained in comparison to the known monovalent protein modification 2-ammonio-6-(3-oxidopyridinium-1-yl)hexanoate (OP-lysine). Identification and quantitation in various sugar incubations with N2-t-Boc-lysine revealed a novel alternative formation pathway for both advanced glycation end products (AGEs) by the interplay of both carbonyl compounds, GA and GX, which was confirmed by isotope labeling experiments. The concentration of pyridinium AGEs was about 1000-fold lower compared to the well-established N6-carboxymethyl lysine. However, pyridinium AGEs were shown to lead to the photosensitized generation of singlet oxygen in irradiation experiments, which was verified by the detection of 3,3'-(naphthalene-1,4-diyl)-dipropionate endoperoxide. Furthermore, meta-DLP was identified in hydrolyzed potato chip proteins by collision-induced dissociation mass spectrometry after HPLC enrichment.


Benzodiazepine use among mothers of small children: a register-based cohort study.
To compare benzodiazepine (BZD) purchases in different groups of mothers of small children. Prospective population-based cohort study based on the Finnish social and health care registers. Finnish women of child-bearing age. All women who gave birth in 2002 in Finland (n = 54 519). Latent class analysis (LCA) was used to create a typology of mothers according to their substance abuse status, psychiatric disorders and socio-demographic characteristics. The mothers were followed-up yearly for purchases of benzodiazepines, starting 4 years before the child's birth and continuing up to the child's 7th birthday. BZD purchases in different mother groups were compared using negative binomial hurdle models. The five mother types identified by LCA were mothers with substance abuse (1%), mothers with psychiatric disorders (1%), mothers with a risk of social marginalization (11%), mothers with minor social problems (18%) and mothers with no identified problems (69%; the comparison group). Mothers with substance abuse problems had the highest odds of purchasing BZDs [odds ratio OR = 27.5, 95%CI = 22.9-33.0; RR = 20.2, 95%CI = 14.9-27.3. The change in time was similar in all groups: the probability of purchasing and the number of purchases were lowest during pregnancy and the year of the child's birth. In Finland, among mothers of young children, prevalence of benzodiazepine use is reduced during pregnancy and the child's first year, and then increases as the child grows older. Mothers with substance abuse and psychiatric disorders are at particularly high risk of benzodiazepine use.


FGFR/Heartless and Smog interact synergistically to negatively regulate Fog mediated G-protein coupled receptor signaling in the Drosophila nervous system.
Folded gastrulation (Fog) is a secreted ligand that signals through the G-protein-coupled receptors Mist and Smog and the G-protein Concertina to activate downstream effectors to elicit cell-shape change during gastrulation. In the embryonic central nervous system (CNS), Fog has roles in axon guidance and glial morphogenesis. However, the elements of the pathway as well as mechanisms required for transducing the signal in this context have not been determined. We find that while Concertina is essential for Fog signaling, Mist is dispensable and Smog, surprisingly, functions as a negative regulator of the pathway in the CNS. Interestingly Heartless, a fibroblast growth factor receptor, also functions as a negative regulator. Furthermore, both Heartless and Smog interact in a synergistic manner to regulate Fog signaling. Our results thus identify Heartless and Smog as part of a common regulatory pathway that functions to restrict Fog signaling in the embryonic CNS and highlights the context-specific role for Fog receptors during development.


Review of the risk factors for SARS-CoV-2 transmission.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, which has lasted for nearly a year, has made people deeply aware of the strong transmissibility and pathogenicity of SARS-CoV-2 since its outbreak in December 2019. By December 2020, SARS-CoV-2 had infected over 65 million people globally, resulting in more than 1 million deaths. At present, the exact animal origin of SARS-CoV-2 remains unclear and antiviral vaccines are now undergoing clinical trials. Although the social order of human life is gradually returning to normal, new confirmed cases continue to appear worldwide, and the majority of cases are sporadic due to environmental factors and lax self-protective consciousness. This article provides the latest understanding of the epidemiology and risk factors of nosocomial and community transmission of SARS-CoV-2, as well as strategies to diminish the risk of transmission. We believe that our review will help the public correctly understand and cope with SARS-CoV-2.


Studies on cellular immunity against bile proteins in primary biliary cirrhosis by the leukocyte migration inhibition test (microdroplet method).
Cellular immunity against human bile proteins was investigated by the leukocyte migration inhibition test (LMIT) with 13 primary biliary cirrhosis (PBC) patients, 10 chronic aggressive hepatitis (CAH) patients and 21 healthy adults. Hepatic bile taken from patients operated on for lithiasis of the biliary tract was fractionated into five fractions with Sepharose 6B gel. A subtoxic dose of each fraction was determined in the healthy adults, and used as the antigen for LMIT. Out of the 5 fractions, only the third fraction led to an LMIT positive response in 8 out of 11 (73%) PBC patients and in 1 out of 10 (10%) CAH patients. The difference between PBC and CAH was significant (p less than 0.005). The remaining 3 PBC patients with LMIT negative responses were all under D-penicillamine treatment. Antibody to each fraction was prepared in rabbits. Using the antibodies after absorption with human serum, the localization of the antigens which were present in each fraction was investigated immunohistochemically using human liver sections. The antigen to the anti-first fraction antibody was detected specifically in the epithelial cells of the bile ducts and the ductules, and the antigen to the anti-third fraction antibody was detected specifically on the membrane of the bile canalicules. The third fraction was fractionated into three fractions by Sephadex G-200 gel. Only the first of the 3 fractions showed an LMIT positive response in 3 PBC patients, and its molecular weight was determined to be about 500,000. It is concluded that PBC patients develop cellular immunity against canalicular-antigen-containing fractions but not ductal-antigen-containing ones.


Antifibrotic effects of gallic acid on hepatic stellate cells: In vitro and in vivo mechanistic study.
Few studies reported the antifibrotic effects of gallic acid (GA) despite its known hepatoprotective and antioxidant activities. Accordingly, this study investigated the antifibrotic effects of GA through clarifying its mechanisms on hepatic stellate cells' (HSCs) activation, proliferation and/or apoptosis. In vitro effects of GA on HSC-T6 activation/proliferation, morphology and safety on hepatocytes were assessed. In vivo, hepatic fibrosis was induced via chronic thioacetamide (TAA)-intoxication. TAA-intoxicated rats were treated with silyamrin or GA. At end of experiment, liver functions, hepatic MDA, GSH, PDGF-BB, TGF-β1, TIMP-1 and hydroxyproline were determined. Histological analysis and Sirius red staining of hepatic sections, expressions of alpha-smooth muscle actin (α-SMA), proliferating cellular nuclear antigen (PCNA) and caspase-3 were examined. In vitro, GA resulted in a concentration and time-dependent inhibition in HSCs activation, proliferation (IC50= 45 and 19 μg/mL at 24 and 48 h respectively); restored the quiescent morphology of some activated HSCs plus its safety on hepatocytes. In vivo, GA reduced ALT, AST, MDA, PDGF-BB levels, collagen deposition and fibrosis score (S1 vs S4); increased caspase-3 expression and restored GSH stores, TGF-β1 level, α-SMA and PCNA expressions. In conclusion, GA counteracted the progression of hepatic fibrosis through reduction of HSCs proliferation/activation mutually with their apoptosis induction.


Design and Dynamic Locomotion Control of Quadruped Robot with Perception-Less Terrain Adaptation.
In this paper, a parallel quadrupedal robot was designed that is capable of versatile dynamic locomotion and perception-less terrain adaptation. Firstly, a quadrupedal robot with a symmetric legs and a powerful actuator was implemented for highly dynamic movement. Then, a fast and reliable method based on generalized least square was proposed for estimating the terrain parameters by fusing the body, leg, and contact information. On the basis of virtual model control (VMC) with the quadratic program (QP) method, the optimal foot force for terrain adaptation was achieved. Finally, the results obtained by simulation and indoor and outdoor experiments demonstrate that the robot can achieve a robust and versatile dynamic locomotion on uneven terrain, and the rejection of disturbances is reliable, which proves the effectiveness and robustness of this proposed method.


The intention-behaviour gap in physical activity: a systematic review and meta-analysis of the action control framework.
Intention is the proximal antecedent of physical activity in many popular psychological models. Despite the utility of these models, the discrepancy between intention and actual behaviour, known as the intention-behaviour gap, is a central topic of current basic and applied research. The purpose of this meta-analysis was to quantify intention-behaviour profiles and the intention-behaviour gap. Systematic review and meta-analysis. Literature search was conducted in June 2022 and updated in February 2023 in five databases. Eligible studies included a measure of physical activity, an assessment of physical activity intention and the employment of the intention-behaviour relationship into profile quadrants. Only papers published in the English language and in peer-reviewed journals were considered. Screening was assisted by the artificial intelligence tool ASReview. Twenty-five independent samples were selected from 22 articles including a total of N=29 600. Random-effects meta-analysis revealed that 26.0% of all participants were non-intenders not exceeding their intentions, 4.2% were non-intenders who exceeded their intentions, 33.0% were unsuccessful intenders and 38.7% were successful intenders. Based on the proportion of unsuccessful intenders to all intenders, the overall intention-behaviour gap was 47.6%. The findings underscore that intention is a necessary, yet insufficient antecedent of physical activity for many. Successful translation of a positive intention into behaviour is nearly at chance. Incorporating mechanisms to overcome the intention-behaviour gap are recommended for clinical practice.


Canakinumab in pediatric rheumatic diseases.
Hitherto, some of the most severe forms of arthritis with onset in the neonatal period and early childhood have been resistant to conventional and anti-tumour necrosis factor agents. Recent results from drug trials of novel monoclonal antibodies will significantly alter the treatment of two of these diseases. This review is for canakinumab, a new monoclonal antibody to interleukin 1β that has been shown to be specifically efficacious in two groups of arthritis with systemic features. The clinical features and treatment to-date in the autoinflammatory disease, cryopyrin associated periodic fever syndrome and systemic juvenile idiopathic arthritis are briefly reviewed. An overview of current IL-1 inhibitors is provided. Clinical trials of Canakinumab in the treatment of these two diseases are evaluated. The last decade has seen a major advance in treatment leading to remission while on therapy for many children with CAPS and sJIA. The outcomes of the anti-IL-1β and the anti-IL-6 trials for sJIA are quite similar and do not enable preferential use of either biological in a given patient.


Melatonin exhibits antioxidant properties in a mouse brain slice model of excitotoxicity.
Stroke is a major cause of brain injury in Alaska. Since antioxidant levels are decreased in aged brain, the greater predisposition to neuronal death in stroke leading to subsequent neurodegeneration in aged individuals may be related to changes in oxidant balance. We studied the effect of the endogenous antioxidant melatonin on excitotoxic injury resulting from N-methyl-D-aspartate (NMDA)-induced damage by developing an organotypic mouse brain slice model. Our objective was to inhibit the effects of oxidative stress induced by NMDA in mouse brain slices, using melatonin. An organotypic mouse brain slice culture was established at PO2 levels maintained between 80 - 100 mm Hg. NMDA, melatonin or both were added to the slices and antioxidant function was determined using the redox active iron assay as well as 8-OHG and HO-1 immunoassays. This slice system allows for better regulation of both NMDA and melatonin concentrations than can be achieved by in vivo studies. Supporting an antioxidant function, melatonin (100 microM) significantly decreased redox active iron, heme-oxygenase (HO-1) induction and 8-hydroxyguanosine (8-OHG) following NMDA (50-100 microM) insult. However, somewhat surprisingly, high concentrations of melatonin alone (1 mM), increased redox active iron levels and HO-1 induction. These results support the hypothesis that melatonin is a neuroprotective antioxidant. Our data also suggest that 1 mM melatonin may have detrimental effects.


Superior Vena Cava Syndrome from Pacemaker Leads in an Elderly Woman.
Superior vena cava (SVC) syndrome is a constellation of clinical signs and symptoms secondary to obstruction of the SVC. The most common etiology is malignancy. However, the incidence of device-related SVC syndrome is increasing. The current management for device-related SVC syndrome includes open surgical intervention, endovascular repair, or systemic anticoagulation. We present a case of a 95-year-old female who developed SVC syndrome due to thrombosis secondary to pacemaker leads. She was treated conservatively due to her frailty and comorbid conditions. We discuss the evolving etiology of SVC syndrome, the most common presenting signs and symptoms, and a variety of potential treatments for non-malignant SVC syndrome. We also provide an example of when conservative management for chronic device-related SVC syndrome is appropriate.


Immunity to cytomegalovirus in women with unexplained recurrent spontaneous abortion.
Humoral and cellular immunity to cytomegalovirus (CMV) has been assessed in women suffering unexplained recurrent spontaneous abortions (RSA). A significantly lower prevalence of serum anti-CMV antibodies was observed for RSA women compared with either their male partners or age-matched female controls, unlike for serum antibodies to Herpes simplex virus. In addition, there was a markedly impaired lymphocyte proliferative response to CMV for CMV-sero-positive RSA women compared with CMV-seropositive controls. These results indicate that women with unexplained RSA have difficulty in responding to CMV, and are of significance when considering leukocyte transfusion immunotherapy.


The effects of the thiolation with thioglycolic acid and l-cysteine on the mucoadhesion properties of the starch-graft-poly(acrylic acid).
The aim of this study is to investigate the effects of the thiolation on the mucoadhesion characteristics of the gelatinized and crosslinked wheat starch-graft-poly(acrylic acid) [(WS-g-PAA)gc] for potential use in drug delivery via vaginal route. Thiolation of (WS-g-PAA)gc was first time realized using l-cysteine hydrochloride monohydrate (CyS) and thioglycolic acid (TGA). These conjugates [(WS-g-PAA)gcth] were characterized using FTIR. The free SH group, mucoadhesion, cytotoxicity characteristics and the mechanism of the thiolation were also evaluated. To obtain fundamental data for possible application such as drug carrier, in vitro and in vivo progesterone release profiles from the mucoadhesive tablet formulations were also determined. The results showed that, vaginal tablet containing (WS-g-PAA)gc-TGA, which has not contain free SH groups in its structure, displays higher mucoadhesion than (WS-g-PAA)gc and (WS-g-PAA)gc-CyS. This tablet formulation can also be used as a drug carrier in vaginal applications.


[The history of the drop. Prolapse of the umbilical cord].
Prolapse of the umbilical cord which is still, nowadays, a very dangerous ailment for the fetus, is the type of obstetrical emergency where a quick therapeutic decision may save the child. Its current management is perfectly organized and the authors thought it would be interesting to retrace the history of ideas and techniques leading to the current concepts.


The Pennsylvania Infant and Family Development Project, I: Stability and change in mother-infant and father-infant interaction in a family setting at one, three, and nine months.
In order to further understanding of the development of the father-infant relationship, patterns of mothering and fathering in 72 families were observed longitudinally (at 1, 3, and 9 months) and from the perspective of the family system. Analyses of variance revealed comparable developmental change in maternal and paternal behaviors, but striking differences between parents, with mothers engaging in far more interaction at all ages studied. Analyses of individual differences in maternal and paternal behavior revealed consistent stability over time, especially from 3 to 9 months, thereby highlighting points of similarity in mothering and fathering. Within-age correlational analyses revealed consistent positive associations between measures of father-infant and husband-wife interaction, yet little relationship between measures of mother-infant and spousal interaction. These findings and others are discussed in terms of similarities and differences in mothering and fathering.


Fish-oil-containing diet and platelet aggregation.
Current research suggests that a diet high in fish oil may be useful for immunomodulation in hospitalized patients. However, one of the side effects of fish oil is a prolongation of the bleeding time, specifically by reducing platelet aggregability. Although this effect might be beneficial for patients with cardiovascular disease, it would be a potential concern in certain critically ill patients. To address this concern, we conducted a prospective study of platelet aggregation in 16 surgical patients who were randomly assigned to receive either a diet containing 16.5 g of fish oil in 1500 ml (Impact) or usual care (standard enteral formulas devoid of fish oil). Feeding was successfully accomplished in the patient group receiving a diet that provided approximately 14.2 g of fish oil/day for 1 wk without significantly affecting platelet aggregability. Thus, it appears that, over the short term, this dose of fish oil does not alter platelet function in hospitalized surgical patients.


Accumulation of overproduced ferritin in the chloroplast provides protection against photoinhibition induced by low temperature in tobacco plants.
Wild-type tobacco plants (Nicotiana tabacum L. cv. Petit Havanna line SR1) and plants transformed with full-length alfalfa ferritin cDNA with the chloroplast transit peptide under the control of a Rubisco small subunit gene promoter (C3 and C8) were cold-treated at 0 degrees C with continuous light (250 micromol m(-2)s(-1)). These transgenic plants had higher chlorophyll content and higher F(v)/F(m) chlorophyll-a fluorescence induction parameters than wild-type plants after 2 or 3d of cold treatment in C3 and C8 transgenic plants, respectively. Thermoluminescence studies on the high-temperature bands suggest that these plants suffered less oxidative damage in comparison to the wild-type genotype. The present experiments provide evidence that transgenic tobacco lines overexpressing alfalfa ferritin, which is accumulated in the chloroplasts, may show higher tolerance to various stress factors, generating ROS including low temperature-induced photoinhibition.


Comparison of hyperelastic models for granular materials.
Three recently proposed hyperelastic models for granular materials are compared with experiment data. Though all three are formulated to give elastic moduli that are power law functions of the mean stress, they have rather different dependencies on individual stresses, and generally differ from well established experimental forms. Predicted static stress distributions are in qualitative agreement with experiments, but do not differ greatly from isotropic linear elasticity, and similarly fail to account for variability in experiment data that presumably occurs due to a preparation dependence of granular materials.


Disability in everyday life.
The authors explored how persons with disabilities perceived the experience of disability in their everyday lives. The findings suggest that the current models in the literature do not address disability adequately. Instead, disability was described as a multifaceted, complex experience that is integrated into the lives of persons with disabilities. The degree to which integration was possible was influenced by three disability-related factors: (a) the fundamental effects of the disabling condition, (b) others' perceptions of disability, and (c) the need for and use of resources. Important contextual conditions included the environment, time, and experience. Ultimately, it was the match between how these persons perceived themselves and what was important in their lives, and the influence of the three factors that determined how well they were able to integrate disability into their lives. The findings suggest the need for a conceptual model that reflects the personal experience of disability.


Analysis of adjunctive serological detection to nucleic acid test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection diagnosis.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused coronavirus disease 2019 (COVID-19) epidemic in China, December 2019. The clinical features and treatment of COVID-19 patients remain largely elusive. However, accurate detection is required for SARS-CoV-2 infection diagnosis. We aimed to evaluate the antibodies-based test and nucleic acid-based test for SARS-CoV-2-infected patients. We retrospectively studied 133 patients diagnosed with SARS-CoV-2 and admitted to Renmin Hospital of Wuhan University, China, from January 23 to March 1, 2020. Demographic data, clinical records, laboratory tests, and outcomes were collected. Data were accessed by SARS-CoV-2 IgM-IgG antibody test and real-time reverse transcriptase PCR (RT-PCR) detection for SARS-CoV-2 nucleic acid in COVID-19 patients. Of 133 COVID-19 patients, there were 44 moderate cases, 52 severe cases, and 37 critical cases with no differences in gender and age among three subgroups. In RT-PCR detection, the positive rate was 65.9%, 71.2%, and 67.6% in moderate, severe, and critical cases, respectively. Whereas the positive rate of IgM/IgG antibody detection in patients was 79.5%/93.2%, 82.7%/100%, and 73.0%/97.3% in moderate, severe, and critical cases, respectively. Moreover, the IgM and IgG antibodies concentrations were also examined with no differences among three subgroups. The IgM-IgG antibody test exhibited a useful adjunct to RT-PCR detection, and improved the accuracy in COVID-19 diagnosis regardless of the severity of illness, which provides an effective complement to the false-negative results from a nucleic acid test for SARS-CoV-2 infection diagnosis after onsets.


Burnout in Orthopaedic Surgeons: A Challenge for Leaders, Learners, and Colleagues: AOA Critical Issues.
Burnout, depression, suicidal ideation, and dissatisfaction with work-life balance have been reported in all medical specialties and at all stages of medical education and practice experience. Burnout consists of progressive emotional, attitudinal, and physical exhaustion. Physicians with burnout may treat patients as objects and feel emotionally depleted. Burnout is characterized by a loss of enthusiasm for work (emotional exhaustion), feelings of cynicism (depersonalization), and a low sense of personal accomplishment. The most complete study of emotional burnout among different medical specialties demonstrated that orthopaedic surgery is one of the specialties with the highest burnout rate. Qualitative descriptive studies are available. There was a 45.8% burnout rate among physicians in the U.S. in 2012, and a 2014 update suggested even higher rates. Burnout has a correlation with medical education. Burnout rates are similar to those in the general population when medical students enter school, and increase steadily through medical education prior to residency. Burnout rates in residents are high, reported to be between 41% and 74% across multiple specialties. This impacts our young physician workforce in orthopaedics. The purpose of this review is to provide the available information that characterizes burnout and addresses the issues inherent to preventing burnout, and to build awareness in orthopaedic surgeons. Wellness "goes beyond merely the absence of distress and includes being challenged, thriving, and achieving success in various aspects of personal and professional life." The challenge for the orthopaedic community is to develop interventions and strategies that are personalized to the individuals in this specialty.


Acute cardiac manifestations under immune checkpoint inhibitors-beware of the obvious: a case report.
Immune checkpoint inhibitors (ICI) have revolutionized the management of many cancer types by drastically improving the median survival rate of patients. However, this efficiency comes at the cost of a high rate of immune-related adverse events, including lethal cardiac manifestations. Rapidly fatal cases of ICI-induced myocarditis have been reported and drawn considerable attention over the past years. However, it is essential to bear in mind that not all cardiac events occurring under ICI therapy are necessarily myocarditis. A 61-year-old female treated with pembrolizumab for a stage IV melanoma was admitted for chest pain leading to the diagnosis of ICI-related myocarditis based on the description of a discrete left ventricular subepicardial late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging. ICI were suspended and intravenous methylprednisolone initiated. A second line anti-MEK therapy was initiated. After a month of treatment, similar chest pain occurred. CMR revealed a midventricular stress cardiomyopathy and no LGE was detected. A posteriori interrogation revealed emotional stressors preceding both episodes. Review of the first CMR, performed 2 weeks after symptom onset, indicated a pattern compatible with the recovery phase of a stress cardiomyopathy and the presence of LGE was questioned. ICI were reintroduced without recurrence of cardiac events. Not all cardiac manifestations occurring under ICI therapy are drug-related adverse events, therefore differential diagnoses must systematically be considered as the contraindication of ICI may have a major impact on patient prognosis. Cardiac imaging should be performed early and plays a key role in the management strategy.


Determination of inosine triphosphate pyrophosphatase phenotype in human red blood cells using HPLC.
Thiopurine drugs, widely used in cancer chemotherapy, inflammatory bowel disease, and autoimmune hepatitis, are responsible for common adverse events. Only some of these may be explained by genetic polymorphism of thiopurine S-methyltransferase. Recent articles have reported that inosine triphosphate pyrophosphatase (ITPase) deficiency was associated with adverse drug reactions toward thiopurine drug therapy. Here, we report a weak anion exchange high-performance liquid chromatography method to determine ITPase activity in red blood cells and to investigate the relationship with the occurrence of adverse events during azathioprine therapy. ITPase activity was assessed by the enzymatic conversion of inosine triphosphate (ITP) to inosine monophosphate (IMP). The reaction was stopped by heating for 3 minutes at 120°C. IMP, inosine diphosphate, and ITP were analyzed on a Hypersil APS-2 column, a weak anion exchange phase that exhibits both ionic and hydrophobic properties. The chromatographic method reported allows the analysis of IMP, inosine diphosphate, and ITP in a single run in <12.5 minutes. The method was linear in the range 5-1500 μmole/L of IMP. Intraassay and interassay precisions were <5% for red blood cell lysates supplemented with 50, 500, and 1000 μmole/L IMP. Km and Vmax evaluated by Lineweaver-Burk plot were 677.4 μmole/L and 19.6 μmole·L·min, respectively. The frequency distribution of ITPase from 73 patients was investigated. The method described is useful to determine the ITPase phenotype from patients on thiopurine therapy and to investigate the potential relation between ITPase deficiency and the occurrence of adverse events.


Demographic and medication characteristics of traditional Chinese medicine users among dementia patients in Taiwan: a nationwide database study.
Few studies have reported on the utilization of traditional Chinese medicine (TCM) among dementia patients. The aim of the present study is to analyze factors associated with TCM users in the dementia populations and to investigate the medical conditions related to TCM visits. A total of 18,141 dementia patients were screened from the one million sample of the National Health Insurance Research Database. The dementia patients were then divided into TCM users and non-TCM users according to their medical records between 1997 and 2008. Demographic characteristics included gender, age, insured amount, and geographic location and medical conditions including comorbidity diseases, behavioral and psychological symptoms, and anti-dementia medication were also investigated. Their tendency of TCM usage was investigated using a multivariate logistic regression. In Taiwan, 43.3% dementia patients had sought TCM treatments. The inclination of TCM usage was inversely proportional to age; the younger and early-onset dementia (age less than 55 years) patients constituted the high usage group. Female, living in central Taiwan, and higher insured amount were also associated with higher tendency of TCM use. Multilevel Poisson regression analysis showed that the Adjust odds ratios (OR) of TCM use were 1.80 (95% CI=1.68-1.94), 2.52 (95% CI=2.30-2.76), and 3.41 (95% CI=3.01-3.86) for those with one, two, three or more behavioral and psychological symptoms of dementia (BPSD), respectively compared with dementia sufferers without BPSD. In addition, polypharmacy led to higher utilization of TCM (one type: Adjust OR=1.41, 95% CI=1.28-1.56, two types: Adjust OR=1.97, 95% CI=1.63-2.00; three or more types: Adjust OR=2.95, 95% CI=2.27-2.78). More than 70% TCM visits were treated with Chinese herbal remedies, while others used acupuncture and manipulative therapies. Qi-Ju-Di-Huang-Wan (9.7%) was the most frequently prescribed formula, followed by Jia-Wei-Xiao-Yao-San and Ban-Xia-Bai-Zhu-Tian-Ma-Tang. More than 40% of the dementia patients in Taiwan used TCM. Young-onset dementia, higher number of BPSD, multiple chronic diseases, and polypharmacy were independent predictors for dementia patients seeking TCM medical advice. On the basis of the current findings, additional clinical or epidemiologic study on the prescription patterns of TCM in dementia treatment, or the herb-drug interaction and safety issue can be conducted.


The Role of Aeromonas-Goblet Cell Interactions in Melatonin-Mediated Improvements in Sleep Deprivation-Induced Colitis.
Our previous studies demonstrated that melatonin could effectively ameliorate sleep deprivation- (SD-) caused oxidative stress-mediated gut microbiota disorder and colitis. The research further clarified the mechanism of melatonin in improving colitis from the perspective of the interaction between Aeromonas and goblet cells. A seventy-two hours SD mouse model with or without melatonin intervention and fecal microbiota transplantation (FMT) to explore the vital position of Aeromonas-goblet cell interactions in melatonin improving SD-induced colitis. Moreover, Aeromonas or LPS-supplied mice were assessed, and the influence of melatonin on Aeromonas-goblet cell interactions-mediated oxidative stress caused colitis. Furthermore, in vitro experiment investigated the regulation mechanism of melatonin. Our study showed that SD induced colitis, with upregulation of Aeromonas and LPS levels and reductions in goblet cells number and MUC2 protein. Similarly, FMT from SD mice, Aeromonas veronii colonization, and LPS treatment restored the SD-like goblet cells number and MUC2 protein decrease and colitis. Moreover, LPS treatment downregulated the colonic antioxidant capacity. Yet, melatonin intervention reversed all consequence in SD, A.veronii colonization, and LPS-treated mice. In vitro, melatonin reversed A. veronii- or LPS-induced MUC2 depletion in mucus-secreting human HT-29 cells via increasing the expression level of Villin, Tff3, p-GSK-3β, β-catenin, and melatonin receptor 2 (MT2) and decreasing the level of p-IκB, p-P65, ROS, TLR4, and MyD88 proteins, while the improvement effect was blocked with pretreatment with a MT2 antagonist but were mimicked by TLR4 and GSK-3β antagonists and ROS scavengers. Our results demonstrated that melatonin-mediated MT2 inhibits Aeromonas-goblet cell interactions to restore the level of MUC2 production via LPS/TLR4/MyD88/GSK-3β/ROS/NF-κB loop, further improving colitis in SD mice.


Biomaterial strategies to reduce implant-associated infections.
Although the prophylaxis in controlling sterility within the operating room environment has been greatly improved, implant-associated infection is still one of the most serious complications in implant surgeries due to the existence of immune depression in the peri-implant area. The antibacterial ability of materials themselves logically becomes an important factor in preventing implant-associated infections. With the understanding of the pathogenesis of implant-associated infections, many approaches have been developed through providing an anti-adhesive surface, delivering antibacterial agents to disrupt cell-cell communication and preventing bacteria aggregation or biofilm formation, or killing bacteria directly (lysing the cell membrane). In this article, we review the current strategies in improving the antibacterial ability of materials to prevent implant infection and further present promising tactics in materials design and applications.


Variability of chlorophyll-a concentration in the Gulf of Guinea and its relation to physical oceanographic variables.
The Gulf of Guinea represents a wide tract of the African coast with complex and rich coastal ecosystems undergoing various pressures. The seasonal variations of chlorophyll-a concentration (Chla) along the Gulf of Guinea (GoG) and their relations with physical oceanographic variables were analyzed using satellite observations covering the period 2002-2012. The effects of sea surface temperature (SST), sea level anomalies (SLA), winds, geostrophic currents, eddy kinetic energy (EKE), mesoscale eddies and fronts were considered on a monthly time scale. The analysis for each unit area was carried out on a chlorophyll index (IChla) computed as the product of the mean distance from the coast to the eutrophic threshold (1 mg m-3 isoline) and the average Chla in the eutrophic area. The study, based on satellite-derived Chla, was allowed by the unprecedented coverage given by the products distributed by the ESA Ocean Colour Climate Change Initiative (OC_CCI) resulting from the merging of data from several satellite missions. The physical variables served as potential predictors in a statistical Boosted Regression Tree (BRT) model. To account for the heterogeneous nature of the GoG, the analysis was conducted on eight systems that made up a partition of the whole region defined on the basis of the BRT model results and climatological properties. The western-most domain, from Guinea-Bissau to Sierra Leone, was associated with upwelling properties in boreal winter and appeared to share some characteristics with the overall Northwest African upwelling system. The region of Ivory Coast and Ghana also had upwelling properties but the main upwelling season was in boreal summer. In general upwelling conditions with cold SST, negative SLA, fairly strong frontal activity, and moderate winds, appeared as the environmental window most favorable to high IChla values. For these systems, the BRT model fitted the IChla data well with a percentage of explained total deviance [Formula: see text] between 70% and 91% when using only physical oceanographic variables. Finally, the systems associated with the coasts of Nigeria to Gabon showed some mixed properties, with [Formula: see text] values of 54-60%. Among these systems, a common feature seemed to be the importance of river discharge to explain IChla variations. Where possible (for the Niger River in the Nigeria system), the addition of river data as predictor in the BRT model resulted in a significant increase of [Formula: see text] to 75%. Further progress is needed to understand the observed relationships and to predict how they can evolve in the face of climate change.


Relationship between cerebral oxygenation and phosphorylation potential during secondary energy failure in hypoxic-ischemic newborn piglets.
The aim of this study was to evaluate the hypothesis that cerebral hemoglobin (Hb) oxygenation is related to phosphorylation potential during primary and secondary cerebral energy failure in newborn infants who have experienced birth asphyxia. We subjected newborn piglets to severe transient cerebral hypoxic-ischemia followed by resuscitation and examined cerebral energy metabolism by 31P-magnetic resonance spectroscopy and evaluated changes in cerebral Hb oxygen saturation (ScO2) using full-spectrum near-infrared spectroscopy before, during, and up to 54 h after the hypoxic-ischemic insult. ScO2 was significantly decreased during the hypoxic-ischemic insult compared with baseline values. During secondary energy failure, piglets were separated based on the relationship between the ratio of phosphocreatine to inorganic phosphate and ScO2; those with a negative correlation were less injured than those with a positive correlation. These results indicate that changes in ScO2 as measured by near-infrared spectroscopy are related to phosphorylation potential during secondary energy failure in asphyxiated infants.


Quantum-confined Stark effect and mechanisms of its screening in InGaN/GaN light-emitting diodes with a tunnel junction.
Nitride-based light-emitting diodes (LEDs) are well known to suffer from a high built-in electric field in the quantum wells (QWs). In this paper we determined to what extent the electric field is screened by injected current. In our approach we used high pressure to study this evolution. In LEDs with a narrow QW (2.6 nm) we found that even at a high injection current a large portion of built-in field remains. In LEDs with very wide QWs (15 and 25 nm) the electric field is fully screened even at the lowest currents. Furthermore, we examined LEDs with a tunnel junction in two locations - above and below the active region. This allowed us to study the cases of parallel and antiparallel fields in the well and in the barriers.


Superiority of ProMACE-CytaBOM over ProMACE-MOPP in the treatment of advanced diffuse aggressive lymphoma: results of a prospective randomized trial.
One hundred ninety-three patients with stage II, III, or IV follicular large-cell, diffuse large-cell, diffuse mixed, immunoblastic, or diffuse small noncleaved-cell (non-Burkitt's) lymphoma were randomized to receive either cyclophosphamide 650 mg/m2 intravenously (IV), doxorubicin 25 mg/m2 IV, etoposide 120 mg/m2 IV on day 1, mechlorethamine 6 mg/m2 IV, vincristine 1.4 mg/m2 (no cap at 2 mg total dose) IV on day 8, prednisone 60 mg/m2 orally daily days 1 through 14, procarbazine 100 mg/m2 orally daily days 8 through 14, and methotrexate 500 mg/m2 IV on day 15 with leucovorin 50 mg/m2 orally every 6 hours for four doses beginning 24 hours after methotrexate with cycles repeated every 28 days (ProMACE-MOPP) or same day-1 treatment as ProMACE-MOPP plus cytarabine 300 mg/m2 IV, bleomycin 5 U/m2 IV, vincristine 1.4 mg/m2 (no cap at 2 mg total dose) IV, and methotrexate 120 mg/m2 IV on day 8, leucovorin 25 mg/m2 orally every 6 hours for four doses beginning 24 hours after methotrexate, and prednisone 60 mg/m2 orally daily days 1 through 14 with cycles repeated every 21 days (ProMACE-CytaBOM). Co-trimoxazole two double-strength tablets orally twice daily throughout the period of treatment was added to the ProMACE-CytaBOM regimen when an increased risk of Pneumocystis carinii pneumonia was found in the first 35 patients receiving this combination. Median follow-up is 5 years. Among the 99 patients treated with ProMACE-MOPP, 73 achieved a complete remission (CR) (74%), 30 complete responders have relapsed (41%), and 45 patients have died (45%), including two (2%) of treatment-related causes. Among the 94 patients treated with ProMACE-CytaBOM, 81 achieved a CR (86%), 22 complete responders have relapsed (27%), and 31 patients have died (33%). The complete response rate (P2 = .048) and survival (P2 = .046) were significantly higher for patients treated with ProMACE-CytaBOM. The mortality of ProMACE-CytaBOM treatment overall was six of 94 patients (6.4%). There was no treatment-related mortality among patients treated with prophylactic co-trimoxazole (n = 59). ProMACE-CytaBOM combination chemotherapy with co-trimoxazole prophylaxis is a safe and effective treatment for patients with aggressive histology malignant lymphoma and is superior to ProMACE-MOPP.


Electrocatalytic Reduction of N2 Using Metal-Doped Borophene.
Ammonia synthesis is an essential process in chemistry and industry. However, it is limited by the lack of efficient catalysts and high energy costs. Developing highly efficient systems for ammonia synthesis is an important and long-standing challenge. In this paper, a large class of metal atoms (including 3d/4d transition metals and main group metals) anchored onto borophene have been studied as single atom catalysts for ammonia synthesis. After comprehensive computational screening and systematic evaluation, four candidates stand out. We predict that Mo, Mn, Tc, and Cr@BM-β12 will have superior performance for catalytic reduction of N2 to NH3 with low limiting potentials of -0.26, -0.32, -0.38, and -0.48 V, respectively. Furthermore, we studied the activity of the competitive HER on M@BM-β12. The results implied that the two materials Mo@BM-β12 and Mn@BM-β12 showed HER suppression. These properties exceed most currently reported nitrogen reduction reaction electrocatalysts. Our results suggest the possibility of efficient electrochemical reduction of N2 to NH3 in a lower energy process.


Blood pressure is a risk factor for progression of diabetic retinopathy in normotensive patients with type 2 diabetes: correlation with carotid intima-media thickness.
Carotid atherosclerotic lesions have been described more frequently in patients with diabetes and microvascular disease than in those with uncomplicated diabetes. In this study, we investigated the role of blood pressure as a risk factor of diabetic retinopathy in normotensive patients with type 2 diabetes. We also assessed the correlation of carotid intima-media thickness with both blood pressure and diabetic retinopathy. The study group consisted of 140 normotensive patients (68 males and 72 females) with type 2 diabetes and diabetic retinopathy. Carotid intima-media thickness was evaluated using high-resolution B-mode ultrasonography. Diabetic retinopathy was assessed and graded, using colored fundus photography and fundus fluorescein angiography, as either non-proliferative or proliferative. Patients with proliferative diabetic retinopathy showed a higher systolic and diastolic blood pressure (p<0.01). Carotid intima-media thickness was higher in patients with proliferative than non-proliferative diabetic retinopathy ones (1.094 ± 0.142 vs. 0.842 ± 0.134 mm, respectively; p<0.001) Carotid intima-media thickness showed positive correlation with both systolic (p<0.001) and diastolic blood pressures (p<0.01). No significant differences were found between males and females in any of the studied parameters. Our study proves that both systolic and diastolic blood pressures are important risk factors for the progression of retinopathy in normotensive patients with type 2 diabetes. We also demonstrate that carotid intima-media thickness, as a marker of atherosclerosis, is strongly correlated with both blood pressure and diabetic retinopathy in those patients.


Effective Antitumor of Orally Intestinal Targeting Penetrating Peptide-Loaded Tyroserleutide/PLGA Nanoparticles in Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC) is a common malignant tumor that seriously threatens human life and health. Currently, the majority of antitumor drugs are administered in an injectable manner, which can cause pain and side effects to patients. Objective of this study is to establish an effective oral drug delivery system for anti hepatoma drugs. In this study, intestinal targeting cell penetrating peptide (R6LRVG) was obtained by binding cell penetrating peptide (R6) with the polypeptide of LRVG (targeting intestinal epithelial cells). Next, R6LRVG-modified tyroserleutide-poly(lactic-co-glycolic acid) (PLGA) nanoparticles (YSL-PLGA/R6LRVG NPs) were prepared. After that, the nanoparticles were characterized and their stability was evaluated. The cellular uptake, in vitro bioactivity and in vivo antitumor activity of the nanoparticles were investigated. In addition, the mechanism, including the endocytic pathway and respiratory rate detection of mitochondria, was further investigated. YSL-PLGA/R6LRVG NPs were successfully prepared. Characterization revealed YSL-PLGA/R6LRVG NPs to be globular particles with smooth surfaces and an average diameter of 222.6 nm. The entrapment efficiency and drug loading of tyroserleutide were 70.27% and 19.69%, respectively. Furthermore, the YSL-PLGA/R6LRVG NPs group exhibited the largest amount of YSL uptake. We also found that cell uptake of YSL-PLGA/R6LRVG NPs could be related to the endocytosis pathways mediated by reticulin and caveolae/lipid rafts. Additionally, the YSL-PLGA/R6LRVG NPs could interfere with mitochondrial function. In vivo experiments revealed that orally administered YSL-PLGA/R6LRVG NPs exerted excellent anticancer effects in tumor-bearing mice. Hematoxylin-eosin staining did not show any histological changes in the major organs. To summarize, YSL-PLGA/R6LRVG NPs could be a useful oral delivery system of YSL and may provide a new platform for the oral delivery of anticancer drugs.


Ordered Topographically Patterned Silicon by Insect-Inspired Capillary Submicron Stamping.
Insect-inspired capillary submicron stamping and subsequent surface-limited metal-assisted chemical etching (MACE) with ammonium bifluoride as a HF source are employed for the high-throughput production of ordered topographically patterned silicon (tpSi). Insect feet often possess hairy contact elements through which adhesive secretion is deployed. Thus, arrays of adhesive secretion drops remain as footprints on contact surfaces. Stamps for insect-inspired capillary submicron stamping having surfaces topographically patterned with contact elements mimic the functional principles of such insect feet. They contain spongy continuous nanopore networks penetrating the entire stamps. Any ink (organic or aqueous) may be supplied from the backside of the nanoporous stamps to the contact elements. We generated ordered arrays of submicron AgNO3 dots extending square millimeters on Si by manual stamping with cycle times of a few seconds under ambient conditions; at higher load, ordered holey AgNO3 films were obtained. Surface-limited MACE correspondingly yielded either macroporous tpSi or Si pillar arrays. Inkjet printing of polymer solutions onto the tpSi yielded patterns of polymer blots conformally covering the tpSi. Such blot patterns could potentially represent a starting point for the development of persistent and scratch-resistant identity labels or quick response codes on silicon surfaces.


Activation of volume-sensitive outwardly rectifying chloride channel by ROS contributes to ER stress and cardiac contractile dysfunction: involvement of CHOP through Wnt.
Endoplasmic reticulum (ER) stress occurring in stringent conditions is critically involved in cardiomyocytes apoptosis and cardiac contractile dysfunction (CCD). However, the molecular machinery that mediates cardiac ER stress and subsequent cell death remains to be fully deciphered, which will hopefully provide novel therapeutic targets for these disorders. Here, we establish tunicamycin-induced model of cardiomyocyte ER stress, which effectively mimicks pathological stimuli to trigger CCD. Tunicamycin activates volume-sensitive outward rectifying Cl(-) currents. Blockade of the volume-sensitive outwardly rectifying (VSOR) Cl(-) channel by 4,4'-diisothiocya-natostilbene-2,2'-disulfonic acid (DIDS), a non-selective Cl(-) channel blocker, and 4-(2-butyl-6,7-dichlor-2-cyclopentyl-indan-1-on-5-yl) oxybutyric acid (DCPIB), a selective VSOR Cl(-) channel blocker, improves cardiac contractility, which correlates with suppressed ER stress through inhibiting the canonical GRP78/eIF2α/ATF4 and XBP1 pathways, and promotes survival of cardiomyocytes by inverting tunicamycin-induced decrease of Wnt through the CHOP pathway. VSOR activation of tunicamycin-treated cardiomyocytes is attributed to increased intracellular levels of reactive oxygen species (ROS). Our study demonstrates a pivotal role of ROS/VSOR in mediating ER stress and functional impairment of cardiomyocytes via the CHOP-Wnt pathway, and suggests the therapeutic values of VSOR Cl(-) channel blockers against ER stress-associated cardiac anomalies.


Metabolic responses to protein restriction during pregnancy in rat and translation initiation factors in the mother and fetus.
A low-protein diet during pregnancy in the rat results in intrauterine growth restricted (IUGR) fetuses. The adaptive responses of the mother to low-protein diet and the mechanisms of IUGR in this model are not understood. In the present study, we report the maternal metabolic responses to protein restriction and their impact on growth, carcass composition, and translation initiation in the fetus. Pregnant Sprague-Dawley rats were pair-fed either a 6% protein (LP, n = 7) or a 24% protein (NP, n = 7) diet from conception until delivery. Plasma amino acids and urea levels and rate of oxygen consumption were measured sequentially through pregnancy. Translation initiation factors eIF2alpha, Ser51 phosphorylated eIF2alpha, eIF4E, phosphorylated eIF4E, and 4E-BP1 were quantified in the maternal and fetal muscle and liver. Protein restriction resulted in higher rate of oxygen consumption (p < 0.01), lower plasma branched chain amino acid (p < 0.05) in the mother, and lower plasma histidine levels (p < 0.05) in the fetus. Plasma urea nitrogen was lower in the LP group throughout gestation. The phosphorylated 4E-BP1 (gamma form) in the maternal liver was 4-fold higher in the LP group. The phosphorylated eIF2alpha was higher in the livers of IUGR fetuses. We speculate that the lower plasma branched chain amino acids in the mother during early pregnancy may be due to a lower rate of protein turnover in the LP group. The mechanism of increased energy consumption due to protein restriction remains unclear. The data on translation initiation factors suggest a higher rate of protein synthesis in the maternal liver and a lower rate in the fetal liver in response to protein restriction.


Cypris morphology in the barnacles Ibla and Paralepas (Crustacea: Cirripedia Thoracica) implications for cirripede evolution.
We used scanning electron microscopy (SEM) to describe cypris morphology in species of the barnacles Ibla and Paralepas, both of which are pivotal in understanding cirripede evolution. In Ibla, we also studied late naupliar stages with video and SEM. Special emphasis was put on the lattice organs, the antennules and the thorax and telson. In Paralepas we had settled specimens only and could therefore only investigate the carapace with the lattice organs. Cyprids of Ibla quadrivalvis and Paralepas dannevigi have five sets of lattice organs, grouped as two anterior and three posterior pairs. The organs are of the pore-field type and the terminal pore is situated anteriorly in the first pair, just as in the Rhizocephala and the Thoracica. In Ibla the armament of antennular sensilla resembles that found in the Thoracica but differs from the Rhizocephala. The absence of setules on the A and B setae sited terminally on the fourth antennular segment is a similarity with the Acrothoracica. The attachment disc is angled rather than facing distally and is encircled by a low cuticular velum. The thoracopods have two-segmented endopods and exopods as in the Thoracica, but the number, shape, and position of thoracopodal setae differ somewhat from other species of that superorder. Both Ibla and Paralepas cyprids have a deeply cleaved telson, but no independent abdominal part. In cypris morphology, Ibla and Paralepas show several synapomorphies with the clade comprising Rhizocephala and Thoracica and there are no specific apomorphies with either the Acrothoracica, the Rhizocephala or any particular subgroup within the Thoracica. This is in agreement with recent molecular evidence that Ibla (Ibliformes) is the sister taxon to all other Thoracica and the ibliforms therefore become the outgroup of choice for studying character evolution within the superorder. Paralepas, and other pedunculated barnacles without shell plates, are apparently not primitive but are secondarily evolved and nested within the Thoracica.


GNG4, as a potential predictor of prognosis, is correlated with immune infiltrates in colon adenocarcinoma.
The tumour microenvironment (TME) and immunosuppression play an important role in colon cancer (CC) metastasis, which seriously affects the prognosis of CC. G protein subunit gamma 4 (GNG4) has been shown to participate in tumour progression and the tumour mutation burden (TMB) in colorectal cancer. However, the effect of GNG4 on the CC TME and immunology remains elusive. Weighted gene coexpression network analysis (WGCNA) was employed for screening aberrantly expressed genes associated with the immune score, and GNG4 was then selected through prognostic and immune correlation analysis. Based on RNA sequencing data obtained from the TCGA and GEO databases, the expression pattern and immune characteristics of GNG4 were comprehensively examined using a pan-cancer analysis. Upregulation of GNG4 was linked to an adverse prognosis and immune inhibitory phenotype in CC. Pan-cancer analysis demonstrated higher GNG4 expression in tumours than in paired normal tissue in human cancers. GNG4 expression was closely related to prognosis, TMB, immune checkpoints (ICPs), microsatellite instability (MSI) and neoantigens. GNG4 promoted CC cell proliferation, migration and invasion and participated in immune regulation in the TME. Significantly, GNG4 expression was found to negatively correlate with tumour-infiltrating immune cells, ICP, TMB and MSI in CC. GNG4 expression predicted the immunotherapy response in the IMvigor210 cohort, suggesting that GNG4 could be used as a potential biomarker in CC for prognostication and immunology. Moreover, the expression of GNG4 predicted the immunotherapy response of ICB in CC.


Designer Drugs and the Impact on the Adolescent User.
There are serious concerns regarding adolescent use of designer drugs. Designer drug usage is often undetected and can result in life-threatening physical and psychiatric reactions. This article explores the history of designer drugs, identifies some of the more recent designer drugs available, distinguishes the symptoms of designer drugs usage, and identifies reasons the designer drugs are popular with our young population. Lastly, this paper addresses what nurses can do to facilitate early and proper treatment to reduce serious physiological damage and death that can result from not detecting the use of designer drugs.


Continuous synthesis of artificial speech sounds from human cortical surface recordings during silent speech production.
Objective. Brain-computer interfaces can restore various forms of communication in paralyzed patients who have lost their ability to articulate intelligible speech. This study aimed to demonstrate the feasibility of closed-loop synthesis of artificial speech sounds from human cortical surface recordings during silent speech production.Approach. Ten participants with intractable epilepsy were temporarily implanted with intracranial electrode arrays over cortical surfaces. A decoding model that predicted audible outputs directly from patient-specific neural feature inputs was trained during overt word reading and immediately tested with overt, mimed and imagined word reading. Predicted outputs were later assessed objectively against corresponding voice recordings and subjectively through human perceptual judgments.Main results. Artificial speech sounds were successfully synthesized during overt and mimed utterances by two participants with some coverage of the precentral gyrus. About a third of these sounds were correctly identified by naïve listeners in two-alternative forced-choice tasks. A similar outcome could not be achieved during imagined utterances by any of the participants. However, neural feature contribution analyses suggested the presence of exploitable activation patterns during imagined speech in the postcentral gyrus and the superior temporal gyrus. In future work, a more comprehensive coverage of cortical surfaces, including posterior parts of the middle frontal gyrus and the inferior frontal gyrus, could improve synthesis performance during imagined speech.Significance.As the field of speech neuroprostheses is rapidly moving toward clinical trials, this study addressed important considerations about task instructions and brain coverage when conducting research on silent speech with non-target participants.


Insight into structural phase transitions from the decoupled anharmonic mode approximation.
We develop a formalism (decoupled anharmonic mode approximation, DAMA) that allows calculation of the vibrational free energy using density functional theory even for materials which exhibit negative curvature of the potential energy surface with respect to atomic displacements. We investigate vibrational modes beyond the harmonic approximation and approximate the potential energy surface with the superposition of the accurate potential along each normal mode. We show that the free energy can stabilize crystal structures at finite temperatures which appear dynamically unstable at T = 0. The DAMA formalism is computationally fast because it avoids statistical sampling through molecular dynamics calculations, and is in principle completely ab initio. It is free of statistical uncertainties and independent of model parameters, but can give insight into the mechanism of a structural phase transition. We apply the formalism to the perovskite cryolite, and investigate the temperature-driven phase transition from the P21/n to the Immm space group. We calculate a phase transition temperature between 710 and 950 K, in fair agreement with the experimental value of 885 K. This can be related to the underestimation of the interaction of the vibrational states. We also calculate the main axes of the thermal ellipsoid and can explain the experimentally observed increase of its volume for the fluorine by 200-300% throughout the phase transition. Our calculations suggest the appearance of tunneling states in the high temperature phase. The convergence of the vibrational DOS and of the critical temperature with respect of reciprocal space sampling is investigated using the polarizable-ion model.


Anti-discoloration system: a new chlorhexidine mouthwash.
Chlorhexidine is defined as biocompatible, which is why it is used as a mouthrinse for the patient before starting dental procedures (2). It has the ability to bind well to teeth and mucous membranes and is released for twelve hours, which is why it is used as a treatment for gingivitis and also in post-operative wound healing. The long-term side effects of chlorhexidine are pigmentations. To remedy this, various types of antidiscoloration have been tried out over time. Nowadays there are other types of anti-discoloration systems such as, for example, in our study we used a test group containing an anti-discoloration system called SPPD. A single-center, prospective, double-blind randomized clinical trial on 84 patients. The investigated treatments consisted of 4 mouthwashes (CHX 0.12% SPDD alcohol free; CHX 0.20% SPDD alcohol free; CHX 0.12% alcohol free with ADS; CHX 0.20% alcohol free with ADS). Despite the limitations of the study, all the mouthwashes tested showed good efficacy in reducing the amount of plaque. Comparing the two experimental concentrations (0.12% and 0.20%) tested here demonstrates that the 0.20% chlorhexidine concentration slightly surpasses its 0.12% equivalent with regard to the PI and BI parameters. The SPDD is an innovative anti-discoloration system and gives the mouthwash a great taste.


Age-Dependent Regulation of the Blood-Brain Barrier Influx/Efflux Equilibrium of Amyloid-β Peptide in a Mouse Model of Alzheimer's Disease (3xTg-AD).
The involvement of transporters located at the blood-brain barrier (BBB) has been suggested in the control of cerebral Aβ levels, and thereby in Alzheimer's disease (AD). However, little is known about the regulation of these transporters at the BBB in animal models of AD. In this study, we investigated the BBB expression of Aβ influx (Rage) and efflux (Abcb1-Abcg2-Abcg4-Lrp-1) transporters and cholesterol transporter (Abca1) in 3-18-month-old 3xTg-AD and control mice. The age-dependent effect of BBB transporters regulation on the brain uptake clearance (Clup) of [3H]cholesterol and [3H]Aβ1 - 40 was then evaluated in these mice, using the in situ brain perfusion technique. Our data suggest that transgenes expression led to the BBB increase in Aβ influx receptor (Rage) and decrease in efflux receptor (Lrp-1). Our data also indicate that mice have mechanisms counteracting this increased net influx. Indeed, Abcg4 and Abca1 are up regulated in 3- and 3/6-month-old 3xTg-AD mice, respectively. Our data show that the balance between the BBB influx and efflux of Aβ is maintained in 3 and 6-month-old 3xTg-AD mice, suggesting that Abcg4 and Abca1 control the efflux of Aβ through the BBB by a direct (Abcg4) or indirect (Abca1) mechanism. At 18 months, the BBB Aβ efflux is significantly increased in 3xTg-AD mice compared to controls. This could result from the significant up-regulation of both Abcg2 and Abcb1 in 3xTg-AD mice compared to control mice. Thus, age-dependent regulation of several Aβ and cholesterol transporters at the BBB could ultimately limit the brain accumulation of Aβ.


Discovery of the First Non-cGMP Mimetic Small Molecule Activators of cGMP-Dependent Protein Kinase 1 α (PKG1α).
PKG1α is a central node in cGMP signaling. Current therapeutics that look to activate this pathway rely on elevation of cGMP levels and subsequent activation of PKG1α. Direct activation of PKG1α could potentially drive additional efficacy without associated side effects of blanket cGMP elevation. We undertook a high-throughput screen to identify novel activators. After triaging through numerous false positive hits, attributed to compound mediated oxidation and activation of PKG1α, a piperidine series of compounds was validated. The hit 1 was a weak activator with EC50 = 47 μM. The activity could be improved to single digit micromolar, as seen in compounds 21 and 25 (7.0 and 3.7 μM, respectively). Several compounds were tested in a pVASP cell-based assay, and for compounds with moderate permeability, good agreement was observed between the biochemical and functional assays. These compounds will function as efficient tools to further interrogate PKG1α biology.


Estrogen enhances gonadotropin-releasing hormone-stimulated transcription of the luteinizing hormone subunit promoters via altered expression of stimulatory and suppressive transcription factors.
Transcription of the LH subunit genes is stimulated by GnRH and may be modulated physiologically by steroids such as 17beta-estradiol (E). We found that E treatment amplified GnRH stimulation of the rat LHbeta and alpha-subunit promoters, and expression of the endogenous mRNA, in LbetaT2 gonadotrope cells 2- to 5-fold above GnRH alone. We examined gene expression in LbetaT2 cells after E and/or GnRH treatment, and found that E suppressed expression of transcription factor Zfhx1a, and enhanced GnRH stimulation of Egr-1 mRNA and protein. E effects were abolished in the presence of antiestrogen. Egr-1 is critical for LHbeta expression; however, the role of Zfhx1a, which binds to E-box sequences, was untested. We found E-box motifs in both the rat LHbeta (-381, -182, and -15 bp) and alpha-subunit (-292, -64, -58 bp) promoters. Zfhx1a overexpression suppressed basal and GnRH-stimulated activity of both promoters. Mutation of the alpha-subunit promoter E boxes at either -64 or -58 bp eliminated Zfhx1a suppression, whereas mutation of the -292 bp E box had no effect. Gel shift assays demonstrated that Zfhx1a bound to the -64 and -58, but not -292, bp E-box DNA. Similarly, mutation of LHbeta promoter E boxes at either -381 or -182, but not -15, bp reduced Zfhx1a suppression, correlating with binding of Zfhx1a. The -381 bp LHbeta E box overlaps with an Sp1 binding site in the distal GnRH-stimulatory region, and increased Sp1 expression overcame Zfhx1a suppression. Thus, one mechanism by which E may enhance GnRH-stimulated LH subunit promoter activity is through regulation of both activators and suppressors of transcription.


Resonant reflection spectroscopy of biomolecular arrays in muscle.
Sarcomeres, the functional units of contraction in striated muscle, are composed of an array of interdigitating protein filaments. Direct interaction between overlapping filaments generates muscular force, which produces animal movement. When filament length is known, sarcomere length successfully predicts potential force, even in whole muscles that contain billions of sarcomere units. Inability to perform in vivo sarcomere measurements with submicrometer resolution is a long-standing challenge in the muscle physiology field and has hampered studies of normal muscle function, adaptation, injury, aging, and disease, particularly in humans. Here, we develop theory and demonstrate the feasibility of to our knowledge a new technique that measures sarcomere length with submicrometer resolution. In this believed novel approach, we examine sarcomere structure by measuring the multiple resonant reflections that are uniquely defined by Fourier decomposition of the sarcomere protein spatial framework. Using a new supercontinuum spectroscopic system, we show close agreement between sarcomere lengths measured by resonant reflection spectroscopy and laser diffraction in an ensemble of 10 distinct muscles.


Impact of surface ozone interactions on indoor air chemistry: A modeling study.
An INdoor air Detailed Chemical Model was developed to investigate the impact of ozone reactions with indoor surfaces (including occupants), on indoor air chemistry in simulated apartments subject to ambient air pollution. The results are consistent with experimental studies showing that approximately 80% of ozone indoors is lost through deposition to surfaces. The human body removes ozone most effectively from indoor air per square meter of surface, but the most significant surfaces for C6 -C10 aldehyde formation are soft furniture and painted walls owing to their large internal surfaces. Mixing ratios of between 8 and 11 ppb of C6 -C10 aldehydes are predicted to form in apartments in various locations in summer, the highest values are when ozone concentrations are enhanced outdoors. The most important aldehyde formed indoors is predicted to be nonanal (5-7 ppb), driven by oxidation-derived emissions from painted walls. In addition, ozone-derived emissions from human skin were estimated for a small bedroom at nighttime with concentrations of nonanal, decanal, and 4-oxopentanal predicted to be 0.5, 0.7, and 0.7 ppb, respectively. A detailed chemical analysis shows that ozone-derived surface aldehyde emissions from materials and people change chemical processing indoors, through enhanced formation of nitrated organic compounds and decreased levels of oxidants.


Microbiota composition, gene pool and its expression in Gir cattle (Bos indicus) rumen under different forage diets using metagenomic and metatranscriptomic approaches.
Zebu (Bos indicus) is a domestic cattle species originating from the Indian subcontinent and now widely domesticated on several continents. In this study, we were particularly interested in understanding the functionally active rumen microbiota of an important Zebu breed, the Gir, under different dietary regimes. Metagenomic and metatranscriptomic data were compared at various taxonomic levels to elucidate the differential microbial population and its functional dynamics in Gir cattle rumen under different roughage dietary regimes. Different proportions of roughage rather than the type of roughage (dry or green) modulated microbiome composition and the expression of its gene pool. Fibre degrading bacteria (i.e. Clostridium, Ruminococcus, Eubacterium, Butyrivibrio, Bacillus and Roseburia) were higher in the solid fraction of rumen (P<0.01) compared to the liquid fraction, whereas bacteria considered to be utilizers of the degraded product (i.e. Prevotella, Bacteroides, Parabacteroides, Paludibacter and Victivallis) were dominant in the liquid fraction (P<0.05). Likewise, expression of fibre degrading enzymes and related carbohydrate binding modules (CBMs) occurred in the solid fraction. When metagenomic and metatranscriptomic data were compared, it was found that some genera and species were transcriptionally more active, although they were in low abundance, making an important contribution to fibre degradation and its further metabolism in the rumen. This study also identified some of the transcriptionally active genera, such as Caldicellulosiruptor and Paludibacter, whose potential has been less-explored in rumen. Overall, the comparison of metagenomic shotgun and metatranscriptomic sequencing appeared to be a much richer source of information compared to conventional metagenomic analysis.


Uptake of [18F]fluorodeoxyglucose in initial positron-emission tomography predicts survival in MALT lymphoma.
The role of [18F]fluorodeoxyglucose (FDG) positron-emission tomography (PET) in mucosa-associated lymphoid tissue (MALT) of marginal zone lymphoma remains poorly defined. We correlated initial PET with pathology, clinical factors, and outcome. From January 2001 to July 2012, 173 MALT lymphoma patients with a biopsied lesion identified on PET within 90 days of tissue biopsy were analyzed. PET positivity and intensity of FDG uptake were correlated with clinical factors and patient outcome. Among 173 accrued cases, biopsied site was PET avid in 123 patients (71%); median standardized uptake value (SUV) was 6.0 (range: 0.7-28.0), and SUV >10.0 in 20 patients (16%). PET avidity varied by organ sites. PET positivity correlated with higher International Prognostic Index, but not with 5-year overall survival (OS; 96% vs 88%, PET negative vs positive, P = .229) or 5-year progression-free survival (67% vs 56%, P = .493). SUV was an independent prognostic factor of OS, and an increased SUV was associated with a decreasing 5-year OS. Patients who presented with SUV ≥10 had a higher rate of subsequent large cell transformation (20% vs 5%, P = .035) and inferior OS (78% vs 92%, P = .008). The exact role of FDG PET in the management of MALT lymphoma, beyond initial staging, remains to be defined.


Examining Factors Influencing Protective Actions Among Persons with Disabilities During the December 10-11, 2021, Tornado Outbreak in the United States.
This study examined various factors influencing protective actions among persons with disabilities exposed to the December 10-11, 2021, tornado outbreak in the US Midwest and Southeastern regions. Survey administration occurred 5 months following the tornado outbreak and included a total of 209 persons with disabilities who lived in one of the counties impacted by tornado warnings. Structural equation modeling was used to examine the direct and indirect effects of hypothesized predictors impacting protective behavioral actions. Results found that persons with disabilities who had access to more tornado warning sources increased their protective actions, and tornado risk perception further mediated the relationship between warning information sources and protective actions. In addition, results found that persons with disabilities who encountered more situational barriers in their physical and social environment were found to have a decrease in protective action, and having more situational resources was found to contribute to the ability to take protective action. The current study's results highlight the need for policies and practices that provide additional physical and social resources for persons with disabilities to seek protection during tornado threats.


Transport Spectroscopy of Sublattice-Resolved Resonant Scattering in Hydrogen-Doped Bilayer Graphene.
We report the experimental observation of sublattice-resolved resonant scattering in bilayer graphene by performing simultaneous cryogenic atomic hydrogen doping and electron transport measurements in an ultrahigh vacuum. This allows us to monitor the hydrogen adsorption on the different sublattices of bilayer graphene without atomic-scale microscopy. Specifically, we detect two distinct resonant scattering peaks in the gate-dependent resistance, which evolve as a function of the atomic hydrogen dosage. Theoretical calculations show that one of the peaks originates from resonant scattering by hydrogen adatoms on the α sublattice (dimer site) while the other originates from hydrogen adatoms on the β sublattice (nondimer site), thereby enabling a method for characterizing the relative sublattice occupancy via transport measurements. Utilizing this new capability, we investigate the adsorption and thermal desorption of hydrogen adatoms via controlled annealing and conclude that hydrogen adsorption on the β sublattice is energetically favored. Through site-selective desorption from the α sublattice, we realize hydrogen doping with adatoms primarily on a single sublattice, which is highly desired for generating ferromagnetism.


Molecular and genetic characteristics of small ruminant lentiviruses in Slovenia.
Small ruminant lentiviruses (SRLV) are spread throughout the world, including Slovenia, where the first evidence of caprine arthritis encephalitis virus (CAEV) infection was found in 1996. This study was conducted to investigate the molecular and genetic characteristics of SRLV infection in Slovenia in order to classify our strains in relation to other known SRLV strains worldwide as well as to establish molecular techniques in concordance with serology. In this study, 340 goats and sheep were tested. Serological examination revealed that 57% of the goats and only 14% of the sheep were seropositive. The results of this study also show that the polymerase chain reaction (PCR) used in this study is less reliable than ELISA, with only 60.6% of the seropositive animals being PCR positive. Thirty-eight nucleotide sequences of the gag region encoding the matrix protein were determined and compared to sequences derived from the GenBank, revealing that Slovenian SRLV strains belong to sequence groups A and B, being maedivisna virus (MVV) and CAEV-like, respectively. In one goat herd, the presence of more than one genotype was confirmed and the majority of goat SRLV sequences were more closely related to MVV than to CAEV prototype strains.


Core clock gene BMAL1 and RNA-binding protein MEX3A collaboratively regulate Lgr5 expression in intestinal crypt cells.
The intestinal epithelium is highly regenerative. Rapidly proliferating LGR5+ crypt base columnar (CBC) cells are responsible for epithelial turnover needed to maintain intestinal homeostasis. Upon tissue damage, loss of LGR5+ CBCs can be compensated by activation of quiescent +4 intestinal stem cells (ISCs) or early progenitor cells to restore intestinal regeneration. LGR5+ CBC self-renewal and ISC conversion to LGR5+ cells are regulated by external signals originating from the ISC niche. In contrast, little is known about intrinsic regulatory mechanisms critical for maintenance of LGR5+ CBC homeostasis. We found that LGR5 expression in intestinal crypt cells is controlled by the circadian core clock gene BMAL1 and the BMAL1-regulated RNA-binding protein MEX3A. BMAL1 directly activated transcription of Mex3a. MEX3A in turn bound to and stabilized Lgr5 mRNA. Bmal1 depletion reduced Mex3a and Lgr5 expression and led to increased ferroptosis, which consequently decreased LGR5+ CBC numbers and increased the number of crypt cells expressing +4 ISC marker BMI1. Together, these findings reveal a BMAL1-centered intrinsic regulatory pathway that maintains LGR5 expression in the crypt cells and suggest a potential mechanism contributing to ISC homeostasis.


Inhibition of in vitro granulopoiesis by autologous allogeneic human NK cells.
This study demonstrates the ability of human NK cells to inhibit in vitro granulopoiesis of autologous and allogeneic BM cells. NK lytic activity and GM-CFC inhibition was present among nonstimulated lymphocytes from healthy donors and could be increased by treatment of PBL with IFN. Both the cytotoxic NK cells and the GM-CFC inhibitory cells could be enriched for among nonadherent, low-density cells. High-density cells were not cytotoxic, only inhibitory to a small extent, and could become neither cytotoxic nor more inhibitory after IFN treatment. In contrast, low-density cells showed an increased cytotoxic and GM-CFC inhibitory capacity after IFN treatment. The NK mediated GM-CFC inhibition was dependent on cell contact with BM cells, increased with longer preincubation times, and was most efficient against 7-day GM-CFC as compared with 14 day GM-CFC progenitors. In conclusion, these data provide new information about the human NK cell as a potent inhibitor of in vitro granulopoiesis and also as a possible regulator of hematopoiesis in vivo.


Establishment and evaluation of an experimental rat model for high-altitude intestinal barrier injury.
In the present study an experimental high-altitude intestinal barrier injury rat model was established by simulating an acute hypoxia environment, to provide an experimental basis to assess the pathogenesis, prevention and treatment of altitude sickness. A total of 70 healthy male Sprague-Dawley rats were divided into two groups: Control group (group C) and a high-altitude hypoxia group (group H). Following 2 days adaptation, the rats in group H were exposed to a simulated 4,000-m, high-altitude hypoxia environment for 3 days to establish the experimental model. To evaluate the model, bacterial translocation, serum lipopolysaccharide level, pathomorphology, ultrastructure and protein expression in rats were assessed. The results indicate that, compared with group C, the rate of bacterial translocation and the apoptotic index of intestinal epithelial cells were significantly higher in group H (P<0.01). Using a light microscope it was determined that the intestinal mucosa was thinner in group H, there were fewer epithelial cells present and the morphology was irregular. Observations with an electron microscope indicated that the intestinal epithelial cells in group H were injured, the spaces among intestinal villi were wider, the tight junctions among cells were open and lanthanum nitrate granules (from the fixing solution) had diffused into the intestinal mesenchyme. The expression of the tight junction protein occludin was also decreased in group H. Therefore, the methods applied in the present study enabled the establishment of a stable, high-altitude intestinal barrier injury model in rats.


Nephropathia epidemica (hemorrhagic fever with renal syndrome) in Scandinavia.
Nephropathia epidemica (NE) in Scandinavia is a zoonosis caused by Puumala virus. The main animal reservoir is the bank vole. NE predominantly affects men. Its annual incidence varies in a cyclic fashion, with peaks occurring every third to fourth year. The clinical picture of NE in Scandinavia is similar to that of hemorrhagic fever with renal syndrome in other parts of the world, although NE generally has a milder course. The case-fatality rate is approximately 0.2%. The most common clinical findings in NE are an acute onset of symptoms, fever (greater than or equal to 38 degrees C), oliguria, headache, back pain, and polyuria. Hemorrhagic manifestations are seen in about one-third of cases, and up to 5% of patients have gastrointestinal bleeding or disseminated intravascular coagulation. Thrombocytopenia occurs in a majority of patients. In the acute phase, the glomerular filtration rate is markedly decreased and tubular dysfunction is evident. Most patients with NE recover within 6 months.


(2E)-3-(4-Chloro-phen-yl)-1-(2,4-dimethyl-quinolin-3-yl)prop-2-en-1-one.
Two independent mol-ecules comprise the asymmetric unit of the title compound, C(20)H(16)ClNO, which differ in the orientation of the chalcone residue with respect to the quinoline ring [the C-C-C(=O)-C torsion angles are 69.5 (2) and 86.0 (2)°]. The configuration about each of the ethyl-ene bonds [1.342 (2) and 1.338 (2) Å] is E. The three-dimensional crystal structure is stabilized by a combination of C-H⋯O, C-H⋯N, C-H⋯π inter-actions and π-π contacts between the independent mol-ecules [Cg(C(6) of quinoline)⋯Cg(C(6) of quinoline) = 3.6719 (11) Å].


TPA induction leads to a Th17-like response in transgenic K14/VEGF mice: a novel in vivo screening model of psoriasis.
Psoriasis is a common chronic inflammatory skin disease, characterized by epidermal hyperplasia, immune cell infiltration, increased dermal angiogenesis and local up-regulation of a variety of inflammatory mediators. Psoriasis is thought to be driven primarily by CD4(+) T cells with a T(h)1 and/or T(h)17 phenotype. Transgenic keratin 14 (K14)/vascular endothelial growth factor (VEGF) mice have previously been reported to develop a psoriasis-like phenotype. The aim of this study was to further characterize the model for validation as an in vivo screening model of psoriasis. Inflammation was induced in the ear skin with five topical applications of 12-O-tetradecanoyl phorbol-13-acetate (TPA) and a significantly increased inflammation was found in TPA-induced K14/VEGF transgenic animals compared with wild-type mice. The amount of VEGF in the ear tissue was significantly elevated resulting in increased dermal angiogenesis. Furthermore, intense epidermal hyperplasia, CD3(+) infiltration and significantly increased amounts of (TNF) tumor necrosis factor alpha, IL-1 beta, IL-6, IL-12/23p40, IL-12p70, IL-22 and IL-17 were detected in the inflamed ear skin. This cytokine profile strongly suggests a T(h)17-mediated inflammation. All findings were a result of induced over-expression of VEGF. Topical treatment with betamethasone-17-valerate (BMS) significantly reduced ear skin inflammation and epidermal hyperplasia and also decreased the CD3(+) infiltration. In conclusion, the TPA-induced phenotype in K14/VEGF animals displayed several features of psoriasis, including a T(h)17 cytokine profile and a chronic-like progression, and can be used as an in vivo screening model of psoriasis.


A high-throughput imaging system to quantitatively analyze the growth dynamics of plant seedlings.
Most current methods for analyzing the growth rate of plant seedlings are limited to low-throughput experimental configurations. We have developed an automatic system to investigate the dynamics of the growth of hypocotyls using Arabidopsis as model. This system is able to capture time-lapse infrared images of 24 seedlings automatically, with a spatial resolution of 2 μm per pixel and temporal interval of 5 min. Seedling length is rapidly calculated using automated geometric image-processing algorithms. With this high-throughput platform, we have investigated the genotype dependent difference of growth patterns, as well as the response to plant hormone - ethylene. Our analyses suggest that cytoskeleton function is not required in ethylene-induced hypocotyl inhibition. This novel integrative method can be applied to large-scale dynamic screening of plants, as well as any other image-based biological studies related to dynamic growth.


Effects of the juçara fruit supplementation on metabolic parameters in individuals with obesity: a double-blind randomized controlled trial.
Adipose tissue inflammation has been proposed as a central mechanism connecting obesity with its metabolic and vascular complications due to the imbalance in the expression of several hormones and adipokines. Berries rich in polyphenols and unsaturated fatty acids have been able to prevent both obesity and adipose tissue inflammation, improving metabolic functions in human subjects and animal models of obesity. Juçara has been considered a super fruit owing to its nutritional composition and relevant biological activities with an interesting response in animals. Thus, we aimed to verify the potential antiobesogenic effect of juçara supplementation in humans. We conducted a double-blind, placebo-controlled, randomized trial with 35 adults with obesity of both sexes. They were assessed for resting metabolic rate, anthropometry and body composition, blood pressure, metabolic parameters and adipokines. Subsequently, they were randomized into two groups to use or not (placebo) 5 g lyophilized juçara for 6 weeks. Supplementation with juçara was significantly effective in reducing body fat, increasing high-density lipoprotein cholesterol and doubling serum adiponectin. Besides, juçara supplementation, high-density lipoprotein cholesterol and neck circumference were predictors to explain the enhancement in adiponectin. Juçara supplementation was determinant to improve adiponectin levels, and it may be considered a novel strategy for the treatment of obesity-related metabolic diseases.


The staining of the synaptonemal complex for light microscopic study in the mouse.
Demonstration of the synaptonemal complex for light microscopy has until now been based on staining with silver. After fixation at pH 9-10 it is also possible to visualize synaptonemal complexes with several nonspecific protein stains such as Coomassie brilliant blue, Giemsa, fast green, light green and Stains All. Although staining with silver gives the best contrast between synaptonemal complexes and the background, the other dyes have a number of advantages, such as more even staining, easy extractability, and lower cost than silver.


Initial Preoperative Management of Geriatric Hip Fractures.
Hip fractures are a common emergency among the geriatric population and often requires immediate hospitalization for proper assessment. More than 90% of the time, hip fractures are suffered by individuals older than 65 and are usually precipitated predominantly by falls. Current studies show that the average individual over 65 years falls at least once a year, and roughly 1 out of every 4 of these individuals succumb to their injuries just 12 months following surgical treatment. Moreover, timely treatment and management of these hip fractures have shown to decrease mortality by reducing cardiopulmonary and venous thromboembolic complications that often accompany hip surgeries. As a result, an emphasis on initial preoperative assessment is important to help identify the presence of ancillary factors such as preexisting comorbidities, which can impact the course of treatment. Delaying surgical management of hip fractures has been linked to decreased functional outcomes and increased mortality rates. Time, rather than technique, appears to be a recurring factor that can impact the long-term survival of these patients. The initial preoperative assessment, therefore, presents a window of opportunity where possible interventions can be made in an effort to reduce the delay of surgery, minimize postsurgical complications, and ultimately improve mortality rate among patients with hip fracture.


MRI for development of disease-modifying osteoarthritis drugs.
MRI has advantages as an imaging modality for drug development through its potential to provide information regarding localized morphological parameters, in addition to metrics of the structural and molecular state of cartilage. These metrics have the potential to provide earlier indications of pathology and may progress more rapidly than radiographic measures. These combined scans of localized morphology and matrix parameters will most likely provide a fuller assessment of cartilage state and will improve the cost and practicality of an overall evaluation of cartilage status by MRI. In the first part of this review, the relevant parameters are presented in terms of the information content they might provide in the drug development process. In the second part, applications of the MRI parameters in preclinical and clinical drug development are presented.


Psychoacoustic modelling of rotor noise.
The aviation sector is rapidly evolving with more electric propulsion systems and a variety of new technologies of vertical take-off and landing manned and unmanned aerial vehicles. Community noise impact is one of the main barriers for the wider adoption of these new vehicles. Within the framework of a perception-driven engineering approach, this paper investigates the relationship between sound quality and first order physical parameters in rotor systems to aid design. Three case studies are considered: (i) contra-rotating versus single rotor systems, (ii) varying blade diameter and thrust in both contra-rotating and single rotor systems, and (iii) varying rotor-rotor axial spacing in contra-rotating systems. The outcomes of a listening experiment, where participants assessed a series of sound stimuli with varying design parameters, allow a better understanding of the annoyance induced by rotor noise. Further to this, a psychoacoustic annoyance model optimised for rotor noise has been formulated. The model includes a novel psychoacoustic function to account for the perceptual effect of impulsiveness. The significance of the proposed model lies in the quantification of the effects of psychoacoustic factors, such as loudness as the dominant factor, and also tonality, high frequency content, temporal fluctuations, and impulsiveness on rotor noise annoyance.


When visibility matters: short-term versus long-term costs and benefits of visible and invisible support.
Sixty-one couples engaged in two video-recorded discussions in which one partner (the support recipient) discussed a personal goal with the other partner (the support provider). The support provider's visible and invisible support behaviors were coded by independent raters. Measures of perceived support, discussion success, and support recipients' distress during the discussion were gathered. Recipients also reported their goal achievement at 3-month intervals over the following year. Greater visible emotional support was associated with greater perceived support and discussion success for highly distressed recipients, but it was costly for nondistressed recipients who reported lower discussion success. In contrast, greater invisible emotional support was not associated with perceived support or discussion success, but it predicted greater goal achievement across time. These results advance our current understanding of support processes by indicating that the costs and benefits of visible support hinge on recipients' needs, whereas invisible support shapes recipients' long-term goal achievement.


An Integrative Review of the Use of the Individual and Family Self-Management Theory in Research.
The extent of the application of the Individual and Family Self-Management Theory (IFSMT) in research has yet to be determined. The purpose of this analysis was to review the use of the IFSMT in published research and evaluate posited constructs and relationships. Dimensions and categories of the IFSMT and the interrelationships were generally supported in the 77 articles reviewed. A majority focused on self-management of chronic conditions in the adult population. More research on the strength, direction, and interaction of relationships is needed. Defining and exploring social constructs, including race, ethnicity, and gender, should be prioritized in future IFSMT research.


Validity of in vitro tests on aqueous spray pumps as surrogates for nasal deposition, absorption, and biologic response.
This research investigated the impact of the full range of in vitro spray characterization tests described in the FDA Draft Bioequivalence Guidance on nasal deposition pattern, pharmacokinetics, and biological response to nicotine administered by two aqueous nasal spray pumps in human volunteers. Nicotine was selected as a model drug (even though it is not locally acting) based on its ability to alter cardiac function and available plasma assay. Significant differences in pump performance-including mean volume diameters, spray angle, spray width, and ovality ratios-were observed between the two pumps. There were no significant differences in deposition pattern, or pharmacokinetic or pharmacodynamic response to the nasally administered nicotine. Although there were statistical differences in the in vitro tests between the two pumps, these differences did not result in significant alterations in the site of droplet deposition within the nose, the rate and extent of nicotine absorption, or the physiologic response it induced. These results suggest that current measures of in vitro performance, particularly spray angle and spray pattern (ovality), may not be clinically relevant. Additional research is needed to define what spray pump characteristics are likely to produce differences in deposition pattern and drug response.