Surface expression and limited proteolysis of ADAM10 are increased by a dominant negative inhibitor of dynamin.
The amyloid precursor protein (APP) is cleaved by β- and γ-secretases to generate toxic amyloid β (Aβ) peptides. Alternatively, α-secretases cleave APP within the Aβ domain, precluding Aβ formation and releasing the soluble ectodomain, sAPPα. We previously showed that inhibition of the GTPase dynamin reduced APP internalization and increased release of sAPPα, apparently by prolonging the interaction between APP and α-secretases at the plasma membrane. This was accompanied by a reduction in Aβ generation. In the present study, we investigated whether surface expression of the α-secretase ADAM (a disintegrin and metalloprotease)10 is also regulated by dynamin-dependent endocytosis. Transfection of human embryonic kidney (HEK) cells stably expressing M3 muscarinic receptors with a dominant negative dynamin I mutant (dyn I K44A), increased surface expression of both immature, and mature, catalytically active forms of co-expressed ADAM10. Surface levels of ADAM10 were unaffected by activation of protein kinase C (PKC) or M3 receptors, indicating that receptor-coupled shedding of the ADAM substrate APP is unlikely to be mediated by inhibition of ADAM10 endocytosis in this cell line. Dyn I K44A strongly increased the formation of a C-terminal fragment of ADAM10, consistent with earlier reports that the ADAM10 ectodomain is itself a target for sheddases. The abundance of this fragment was increased in the presence of a γ-secretase inhibitor, but was not affected by M3 receptor activation. The dynamin mutant did not affect the distribution of ADAM10 and its C-terminal fragment between raft and non-raft membrane compartments. Surface expression and limited proteolysis of ADAM10 are regulated by dynamin-dependent endocytosis, but are unaffected by activation of signaling pathways that upregulate shedding of ADAM substrates such as APP. Modulation of ADAM10 internalization could affect cellular behavior in two ways: by altering the putative signaling activity of the ADAM10 C-terminal fragment, and by regulating the biological function of ADAM10 substrates such as APP and N-cadherin.


Association between 6-thioguanine nucleotides levels and clinical remission in inflammatory disease: a meta-analysis.
A previous meta-analysis suggested that 6-thioguanine nucleotides levels are associated with clinical remission in inflammatory bowel disease. It was criticized because of the relatively small number of patients included in this meta-analysis and heterogeneity between studies. Recent studies provided conflicting results, and the source of those discrepancies has yet to be explored. A comprehensive, computerized literature search was conducted in Medline, ISI Web of Science, and EMBASE until December 31, 2012. A combined odd ratio with its 95% confidence interval was calculated using a fixed effects model based on the Mantel-Haenszel method. Between-study heterogeneity was assessed using Cochran's Q statistic. Seventeen studies enrolling 2049 patients with inflammatory bowel disease were analyzed. A significant heterogeneity was found in the overall analysis (P = 0.005). As heterogeneity among studies could be explained by differences in metabolite assay methods, an analysis including only studies using the reference method by Lennard et al (N = 10) was performed, and the pooled odds ratio for clinical remission among patients with 6-thioguanine nucleotides levels over a cut-off value between 230 and 260 pmol/8.10^8 RBC was 3.15 (95% confidence interval, 2.41-4.11). This meta-analysis clearly establishes an association between 6-thioguanine nucleotides levels and clinical remission rates in patients with inflammatory bowel disease and explains the heterogeneity of results among selected studies. The lack of standardization in 6-thioguanine nucleotides assays is responsible for recent contradictory results. Whether therapeutic drug monitoring of thiopurines should be systematically used in clinical practice in inflammatory bowel disease to improve disease outcomes will require further investigation.


Interaction of the tumor metastasis suppressor nonmetastatic protein 23 homologue H1 and estrogen receptor alpha alters estrogen-responsive gene expression.
Metastasis of cancer cells from the primary tumor is associated with poor prognosis and decreased overall survival. One protein implicated in inhibiting metastasis is the tumor metastasis suppressor nonmetastatic protein 23 homologue 1 (NM23-H1). NM23-H1 is a multifunctional protein, which, in addition to limiting metastasis, has DNase and histidine protein kinase activities. We have identified new functions for NM23-H1 in influencing estrogen receptor alpha (ER alpha)-mediated gene expression. Using a battery of molecular and biochemical techniques, we show that NM23-H1 interacts with ER alpha and increases the ER alpha-estrogen response element (ERE) interaction. When NM23-H1 expression is increased in U2 osteosarcoma and MDA-MB-231 breast cancer cells, transcription of a transiently transfected, estrogen-responsive reporter plasmid is decreased. More importantly, when endogenous NM23-H1 expression is knocked down in MCF-7 human breast cancer cells using small interfering RNA, estrogen responsiveness of the progesterone receptor (PR), Bcl-2, cathepsin D, and cyclin D1 genes, but not the pS2 gene, is enhanced. Furthermore, NM23-H1 associates with the region of the PR gene containing the +90 activator protein 1 site, but not with the ERE-containing region of the pS2 gene, indicating that NM23-H1 mediates gene-specific effects by association with endogenous chromatin. Our studies suggest that the capacity of NM23-H1 to limit the expression of estrogen-responsive genes such as cathepsin D and Bcl-2, which are involved in cell migration, apoptosis, and angiogenesis, may help to explain the metastasis-suppressive effects of this protein. The complementary abilities of ER alpha and NM23-H1 together to influence gene expression, cell migration, and apoptosis could be key factors in helping to determine tumor cell fate.


The contribution of asymptomatic SARS-CoV-2 infections to transmission on the Diamond Princess cruise ship.
A key unknown for SARS-CoV-2 is how asymptomatic infections contribute to transmission. We used a transmission model with asymptomatic and presymptomatic states, calibrated to data on disease onset and test frequency from the Diamond Princess cruise ship outbreak, to quantify the contribution of asymptomatic infections to transmission. The model estimated that 74% (70-78%, 95% posterior interval) of infections proceeded asymptomatically. Despite intense testing, 53% (51-56%) of infections remained undetected, most of them asymptomatic. Asymptomatic individuals were the source for 69% (20-85%) of all infections. The data did not allow identification of the infectiousness of asymptomatic infections, however low ranges (0-25%) required a net reproduction number for individuals progressing through presymptomatic and symptomatic stages of at least 15. Asymptomatic SARS-CoV-2 infections may contribute substantially to transmission. Control measures, and models projecting their potential impact, need to look beyond the symptomatic cases if they are to understand and address ongoing transmission.


Salmonella expressing detoxified lipopolysaccharide is immunogenic and protective both as an attenuated vaccine and for delivery of foreign antigens.
The construction of safe and protective vaccines, derived from human pathogens that have been genetically modified to remove pathogenicity, is often easier to accomplish on paper than it is in the laboratory. Kong and colleagues have pursued a clever strategy to reduce the reactogenicity of attenuated Salmonella oral vaccines by genetically modifying the surface lipopolysaccharide to lower endotoxic activity. The resulting candidate vaccine strains were highly reduced in virulence yet were able to confer protection in a mouse model against challenge with virulent Salmonella. Remarkably, these strains could also be further modified to present foreign antigens from unrelated human pathogens and again confer protection against heterologous challenge. This work brings important new tools to bear on solving the problem of creating efficacious attenuated bacterial vaccines that maximize both safety and immunogenicity in clinical trials.


Exploring the benefits of group psychotherapy in reducing alexithymia in coronary heart disease patients: a preliminary study.
Although there is preliminary evidence that alexithymia may influence the course of coronary heart disease (CHD), there are no studies exploring attempts to modify alexithymic characteristics in cardiac patients. Twenty post-myocardial infarction (MI) patients (19 men and 1 woman) were placed in a treatment group, which received weekly group psychotherapy for 4 months. Seventeen post-MI patients (16 men and 1 woman) were placed in a comparison group which received two educational sessions over a period of 1 month. All subjects completed the Toronto Alexithymia Scale (TAS) before the start of group therapy, at the end of the 4-month period, and in follow-up assessment after 6-month, 1-year, and 2-year intervals. In the psychotherapy treatment group, there was a significant reduction in the mean TAS score following group therapy, which was maintained over the 2-year follow-up period. In the educational group, there were no significant changes in mean TAS scores between the initial testing and any of the follow-up intervals. On an individual basis, a decrease to a lower level of TAS scores occurred in a higher percentage of patients in the treatment group than in the educational group. Over the 2-year follow-up period, patients with decreased alexithymia following group therapy experienced fewer cardiac events (reinfarction, sudden cardiac death, or rehospitalization for rhythm disorder or severe angina) than patients whose alexithymia remained unchanged. The results indicate that group psychotherapy is able to decrease alexithymia and that for many patients this change can be maintained for at least 2 years. A reduction in the degree of alexithymia seems to influence favorably the clinical course of CHD.


Protease activated-receptor 4 activation as a model of persistent bladder pain: Essential role of macrophage migration inhibitory factor and high mobility group box 1.
To develop a rodent model of persistent non-inflammatory bladder pain and to test macrophage migration inhibitory factor and high mobility box group 1 as mediators of bladder pain. Female C57BL/6 mice received intravesical instillations of protease activated receptor 4 (100 μmol/L, for 1 h) three times every other day and abdominal mechanical hypersensitivity (50% mechanical threshold) was tested on day 0 (baseline), and at days 1, 2, 3, 4, 7 and 9 after the first protease-activated receptor 4 injection. At the end of the experiment, micturition changes were measured and bladders were examined for histological changes. Macrophage migration inhibitory factor antagonist (MIF098; 40 mg/kg i.p. b.i.d.) or high mobility group box 1 inhibitor (glycyrrhizin; 50 mg/kg i.p. daily) was administered from day 2 until day 8. There was a significant and persistent decrease in abdominal mechanical threshold starting from day 3 in the protease-activated receptor 4-treated group that persisted until day 9 (5 days post-last instillation), but not in the control group. Glycyrrhizin fully reversed while MIF098 partially reversed abdominal mechanical hypersensitivity in protease-activated receptor 4-treated mice. The changes started on day 3 after the first protease-activated receptor 4 instillation, and analgesic effects lasted throughout the rest of the testing period. None of the groups had significant micturition changes or overt bladder histological changes. Repeated intravesical protease activated receptor 4 instillations produce persistent bladder pain without inflammation. Macrophage migration inhibitory factor and high mobility group box 1 are possible effective target molecules for bladder pain alleviation.


Osteocyte mechanobiology and pericellular mechanics.
An impressive range of tissues and cells are regulated by mechanical loading, and this regulation is central to disease processes such as osteoporosis, atherosclerosis, and osteoarthritis. However, other than a small number of specialized excitable cells involved in hearing and touch, cellular mechanosensing mechanisms are generally quite poorly understood. A lack of mechanistic understanding of these processes is one of the primary foci of the nascent field of mechanobiology, which, as a consequence, enjoys enormous potential to make critical new insights into both physiological function and etiology of disease. In this review we outline the process in bone by tracing mechanical effects from the organ level to the cellular and molecular levels and by integrating the biological response from molecule to organ. A case is made that a fundamental roadblock to advances in mechanobiology is the dearth of information in the area of pericellular mechanics.


Factors affecting behavior toward people with disabilities.
Two field experiments were designed to explore ambivalence-induced behavior toward people with disabilities in low-cost helping situations. In Experiment 1, confederates, who either rode in a wheelchair or walked, asked shoppers for a small sum of money and either provided a reason (positive presentation) or did not provide a reason (negative presentation) for the request. Contrary to prediction, more people with a physical disability than without a physical disability were helped, regardless of their presentation. In Experiment 2, the presence of confederates in wheelchairs resulted in significantly fewer violations of parking spaces reserved for people with handicaps.


[Combined alcohol dependence and personality disorder and its legal consequences with respect to commitment].
People frequently consuming an excessive amount of alcohol often show symptoms of personality disorder. Personality disorder and alcohol dependence are frequently connected with each other. However, there are only very few conditions enhancing concomitant dependence and personality disorder to the rank of a mental disease according to German guardianship legislation. If the patient's condition meets the criteria of a psychic disease and endangers his own health and public safety, commitment to a mental hospital or guardianship are justified. The purpose of this clinical analysis was to compare the medical proposal for treatment with legal prerequisites which are indispensable for involuntary admission to a mental hospital. Whereas the Psychiatric Disorders Act intends to avert danger to the public, guardianship legislation aims at individual help. We present a patient who suffered from alcoholism and simultaneously met criteria of a serious personality disorder, which was classified according to ICD-10 (F 60.31). As the aggravation of the symptoms was most likely to entail serious danger to his health the judge ordered immediate involuntary admission. Two other patients had similar comorbidity but had to be released from hospital because of finalisation of detoxification. Neither dependence nor personality disorder were pronounced enough to restrict the rights of the individual. Our analysis shows that the psychiatrist must present with an expert medical report that quantifies the extent of alcoholism and personality disorder and characterises them as psychic disease. Consequently, for the purpose of quantifying the extent of dependence, we recommend to apply the European Addiction Severity Index whose suitability should be assessed.


Reducing pain and distress related to needle procedures in children with cancer: A clinical practice guideline.
Children with cancer often undergo long treatment trajectories involving repeated needle procedures that potentially cause pain and distress. As part of a comprehensive effort to develop clinical practice guidelines (CPGs) to address pain prevention and management in children with cancer, we aimed to provide recommendations on the pharmacological and psychological management of procedure-related pain and distress. Of the international inter-disciplinary CPG development panel (44 individuals), two working groups including 13 healthcare professionals focused on procedural pain and distress. Grading of Recommendations Assessment, Development and Evaluation methodology was used, including the use of systematic literature reviews to inform recommendations and the use of evidence to decision frameworks. At an in-person meeting in February 2018, the guideline panel discussed these frameworks and formulated recommendations which were then discussed with a patient-parent panel consisting of 4 survivors and 5 parents. The systematic reviews led to the inclusion of 48 randomised controlled trials (total number of participants = 2271). Quality of evidence supporting the recommendations ranged from very low to moderate. Strong recommendations were made for the use of topical anesthetics in all needle procedures, for offering deep sedation (DS)/general anesthesia (GA) to all children undergoing lumbar puncture, for the use of DS/ GA in major procedures in children of all ages, for the use of hypnosis in all needle procedures and for the use of active distraction in all needle procedures. In this CPG, an evidence-based approach to manage procedure-related pain and distress in children with cancer is presented. As children with cancer often undergo repeated needle procedures during treatment, prevention and alleviation of procedure-related pain and distress is of the utmost importance to increase quality of life in these children and their families.


A method for the automated, reliable retrieval of publication-citation records.
Publication records and citation indices often are used to evaluate academic performance. For this reason, obtaining or computing them accurately is important. This can be difficult, largely due to a lack of complete knowledge of an individual's publication list and/or lack of time available to manually obtain or construct the publication-citation record. While online publication search engines have somewhat addressed these problems, using raw search results can yield inaccurate estimates of publication-citation records and citation indices. In this paper, we present a new, automated method that produces estimates of an individual's publication-citation record from an individual's name and a set of domain-specific vocabulary that may occur in the individual's publication titles. Because this vocabulary can be harvested directly from a research web page or online (partial) publication list, our method delivers an easy way to obtain estimates of a publication-citation record and the relevant citation indices. Our method works by applying a series of stringent name and content filters to the raw publication search results returned by an online publication search engine. In this paper, our method is run using Google Scholar, but the underlying filters can be easily applied to any existing publication search engine. When compared against a manually constructed data set of individuals and their publication-citation records, our method provides significant improvements over raw search results. The estimated publication-citation records returned by our method have an average sensitivity of 98% and specificity of 72% (in contrast to raw search result specificity of less than 10%). When citation indices are computed using these records, the estimated indices are within of the true value 10%, compared to raw search results which have overestimates of, on average, 75%. These results confirm that our method provides significantly improved estimates over raw search results, and these can either be used directly for large-scale (departmental or university) analysis or further refined manually to quickly give accurate publication-citation records.


Femtosecond laser-induced apodized Bragg grating waveguides.
We report on the inscription of apodized Bragg grating waveguides (BGWs) in fused silica using a modulated high repetition rate fs laser system. Tailoring of the grating's coupling strength is facilitated by appropriately substructuring the modulation of the inscribing laser radiation. The proposed alteration delivers an unchanged constant mean refractive index entailing homogeneous guiding properties along the entire waveguide. The BGWs fabricated using a Gaussian apodized modulation profile exhibit a 10 dB improvement in sideband suppression compared to waveguide gratings written with a uniform modulation profile.


Glomangioma of the ankle simulating injury to the flexor hallucis longus: a case report.
The glomangioma is one of a group of benign tumors of glomus body origin. Commonly found in the distal extremities, they may present with pain, tenderness to palpation, and sensitivity to temperature. Histologically, varying proportions of glomus cells, as well as vascular and smooth muscle elements, are found. Complete surgical excision is usually curative. We report on a glomangioma of the ankle in a 12-year-old male patient that simulated injury to the flexor hallucis longus tendon.


Anticancer Applications and Pharmacological Properties of Piperidine and Piperine: A Comprehensive Review on Molecular Mechanisms and Therapeutic Perspectives.
Piperine and piperidine are the two major alkaloids extracted from black pepper (Piper nigrum); piperidine is a heterocyclic moiety that has the molecular formula (CH2)5NH. Over the years, many therapeutic properties including anticancer potential of these two compounds have been observed. Piperine has therapeutic potential against cancers such as breast cancer, ovarian cancer, gastric cancer, gliomal cancer, lung cancer, oral squamous, chronic pancreatitis, prostate cancer, rectal cancer, cervical cancer, and leukemia. Whereas, piperidine acts as a potential clinical agent against cancers, such as breast cancer, prostate cancer, colon cancer, lung cancer, and ovarian cancer, when treated alone or in combination with some novel drugs. Several crucial signalling pathways essential for the establishment of cancers such as STAT-3, NF-κB, PI3k/Aκt, JNK/p38-MAPK, TGF-ß/SMAD, Smac/DIABLO, p-IκB etc., are regulated by these two phytochemicals. Both of these phytochemicals lead to inhibition of cell migration and help in cell cycle arrest to inhibit survivability of cancer cells. The current review highlights the pharmaceutical relevance of both piperine and piperidine against different types of cancers.


Coping with the challenges of living in an Indonesian residential institution.
The aim of this study was to describe challenges and strategies for coping with these challenges among individuals living in an institutional setting. This study used a qualitative approach to analyze the interviews of fourteen participants (11 males and 3 females) ages 10-24 residing in an Indonesian residential institution (orphanage and Muslim boarding school). Insufficient access to educational resources and basic necessities were major concerns of the participants, as was the residential institution's unresponsiveness and the lack of connection experienced by residents. Individuals coped with these challenges by turning to others for social support and by trying to change the focus of their thoughts, such as to more pleasant thoughts or simply to mentally disengage. Some youths and young adults residing in institutions such as a residential institution demonstrate resilience at the individual level by utilizing coping strategies to address problems in obtaining adequate educational, material and psychological support. However, because inadequacies in these kinds of support ultimately impede psychosocial development, it is imperative to develop solutions for addressing these problems at the institutional and societal level rather than at the level of individual youths and young adults.


Rendezvous ductoplasty for biliary anastomotic stricture after living-donor liver transplantation.
Biliary anastomotic stricture (BAS) after living-donor liver transplantation (LDLT) is difficult to manage. We used rendezvous ductoplasty (RD) to treat BAS after LDLT. We retrospectively analyzed 53 patients with BAS after adult-to-adult LDLT with duct-to-duct biliary reconstruction. BAS was classified according to endoscopic retrograde cholangiography findings after normal-pressure contrast injection: type I (n=32) in which the stricture was visualized; type II (n=13) in which the common hepatic duct and graft intrahepatic ducts were visualized, but the stricture was not visualized; or type III (n=8) in which the stricture and graft intrahepatic ducts were not visualized. In right lobe grafts, types II and III occurred more frequently than type I (P=0.0023). Type I had significantly shorter cold ischemic time (76±11 vs. 118±12 min; P=0.0155) and warm ischemic time (38±2 vs. 49±3 min; P=0.0069) than types II and III. The number of attempts to pass the guidewire through the stricture was significantly lower in type I (1.2±0.2 attempts) than type II (2.2±0.2 attempts; P=0.0018) or type III (2.8±0.3 attempts; P<0.0001). The treatment success rate was 78.1% for type I, 38.5% for type II, and 50.0% for type III (P=0.0282). RD was the first successful treatment in a higher proportion of types II and III patients than type I patients (66.7% vs. 6.3%; P<0.0001). Cumulative treatment success rates were not significantly different between the RD and the non-RD groups (P=0.0920). RD was a useful treatment for difficult cases of BAS after LDLT and achieved successful outcomes.


[Medical illustrations and technique; 19th-century graphic procedures and their suitability fo scientific illustrations].
For a publisher of a scientific journal around 1850 there were various possibilities with regard to illustration technique. The ultimate choice was determined by considerations of necessity, clarity but particularly also, price. In the Nederlandsch Tijdschrift voor Geneeskunde the last-mentioned aspect appears to have been very weighty, especially in the beginning. Newly introduced techniques permitting better detail were often applied relatively late and infrequently. Photography proved to be an important aid in illustrating, although the printed reproduction was initially primitive and of poor quality. Improvement of the financial situation of the Journal was immediately reflected in an increase of the number of illustrations.


Deregulation of DNA polymerase beta by sense and antisense RNA expression in mouse 3T3 cells alters cell growth.
DNA polymerase beta (beta-pol) and its mRNA are maintained at constitutive levels during the cell cycle and during stages of cell growth in culture. To study biological consequences of variations in the level of this DNA repair enzyme and/or its mRNA, we prepared expression vectors in which cDNA for human beta-pol is inserted under the control of a metallothionein promoter (pMT) in the sense and antisense orientation, respectively, and these vectors then were used for stable transformation of mouse 3T3 cells. Vectors also contained the mouse DHFR gene, such that culture of transformants in medium with increasing concentrations of methotrexate resulted in amplification of inserted DNA. The levels of sense and antisense transcripts are strongly increased by culture of transformants in medium with 65 microM Zn2+, although some expression is detected even without Zn2+ induction. After five days of induction, the beta-pol level was about threefold higher in sense cells and about 10-fold lower in antisense cells than in parallel cultures without induction. The antisense line has a threefold increased cell doubling time in the presence of 65 microM Zn2+ compared with the absence of Zn2+. Zn2+ (65 microM) induction for the sense line results in normal growth for the first three days and, thereafter, a complete cessation of growth. Yet, these blocked cells remain fully viable. The results indicate that sudden deregulation of beta-pol expression alters cell growth in mouse 3T3 cells.


Retroperitoneal bronchogenic cyst resembling an adrenal tumor with high levels of serum carbohydrate antigen 19-9: A case report.
Retroperitoneal bronchogenic cysts without specific clinical manifestations are extremely rare and difficult to diagnose preoperatively and are easily misdiagnosed as left adrenal or pancreatic tumors. A 48-year-old woman with the chief complaint of obscure epigastric pain for 1 month and with no other gastrointestinal symptoms and no significant medical history. The patient had signed informed consent for publication of this case report. The serum level of carbohydrate antigen 19-9 (CA 19-9) in the patient was >1200 U/mL, which far exceeded the normal level of <37 U/mL. Computed tomography (CT) initially suggested the presence of an adrenal tumor. However, endoscopic ultrasound (EUS) showed that the adrenal gland had an intact capsule and that the mass originated in the retroperitoneal space and did not involve the paranephros. Surgical resection was performed on the patient. Histopathological examination demonstrated that the mass was a retroperitoneal bronchogenic cyst. At the 2-month postoperative follow-up, the level of CA 19-9 had returned to normal. EUS appears to be superior to CT because it clearly delineated the mass from the surrounding structures of the retroperitoneal region. EUS-fine needle aspiration can be used for diagnosis or determining whether the mass is malignant or benign. To the best of our knowledge, retroperitoneal bronchogenic cysts with significantly elevated serum CA 19-9 have not been reported. Measurement of serum CA 19-9 may be helpful in the diagnosis of retroperitoneal bronchogenic cysts. However, this was a rare case, and the mechanism behind CA 19-9 elevation is not clear and needs further investigation.


Rapid and reactive nitric oxide production by astrocytes in mouse neocortical slices.
Nitric oxide (NO), a cellular signaling molecule, is produced in the brain by both neurons and astrocytes. While neurons are capable of rapid release of small amounts of NO serving as neurotransmitter, astrocytic NO production has been demonstrated mainly as a slow reaction to various stress stimuli. Little is known about the role of astrocyte-produced NO. Using the NO indicator 4,5-diaminofluorescein-2 diacetate (DAF-2DA) and acute slices from mouse brain, we distinguished neurons from astrocytes based on their different fluorescence kinetics and pattern, cellular morphology, electrophysiology, and responses to selective nitric oxide synthase (NOS) inhibitors. Typically, astrocytic fluorescence followed neuronal fluorescence with a delay of 1-2 min and was dependent on the inducible NOS isoform (iNOS) activity. Western blot analysis established the presence of functional iNOS in the neocortex. An assay for cell death revealed that most DAF-2DA-positive neurons, but not astrocytes, were damaged. Whole cell recordings from astrocytes confirmed that these cells maintained their membrane potential and passive properties during illumination and afterward. Induction of excitotoxicity by brief application of glutamate triggered an immediate and intense astrocytic response, while high-frequency electrical stimulation failed to do so. The present study demonstrates, for the first time, rapid and massive iNOS-dependent NO production by astrocytes in situ, which appears to be triggered by acute neuronal death. These data may bear important implications for our theoretical understanding and practical management of acute brain insults.


Making ICU alarms meaningful: a comparison of traditional vs. trend-based algorithms.
Much of the work in the ICU revolves around information that is recorded by electronic devices. Such devices typically incorporate simple alarm functions that trigger when a value exceeds predefined limits. Depending on the parameter followed, these "boundary based" alarms tend to produce vast numbers of false alarms. Some are the result of false reading and some the result of true but clinically insignificant readings. We present a computerized module that analyzes real-time data from multiple monitoring devices using a customizable logic engine. The module was tested on 6 intensive care unit patients over 5 days, running alarm algorithms for heart rate, systolic and diastolic blood pressure as well as arterial oxygen saturation. Results show a ten-fold increase in positive predictive value of alarms from 3% using monitor alarms to 32% using the module. The module's overall sensitivity was 82%, failing to detect 18% of significant alarms as defined by the ICU staff. The results suggests that implementation of such methodology may assist in filtering false and insignificant alarms in the ICU setting.


Sensitivity and Specificity of the ImPACT Neurocognitive Test in Collegiate Athletes and US Military Service Academy Cadets with ADHD and/or LD: Findings from the NCAA-DoD CARE Consortium.
Computer-based neurocognitive tests are widely used in sport-related concussion management, but the performance of these tests is not well understood in the participant population with attention-deficit/hyperactivity disorder (ADHD) and/or learning disorder (LD). This research estimates the sensitivity and specificity performance of the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) computer-based neurocognitive test in identifying concussion in this population. Study participants consisted of collegiate university athletes and military service academy cadets from the National Collegiate Athletic Association-Department of Defense CARE Consortium who completed the ImPACT test between 2014 and 2021. Participants who self-identified as belonging to one of the subgroups of interest (ADHD with or without LD [ADHD:LD+/-], LD with or without ADHD [LD:ADHD+/-], ADHD and/or LD [ADHD a/o LD]) and completed a baseline (1874 ADHD:LD+/-, 779 LD:ADHD+/-, 2338 ADHD a/o LD) or 24-48 h post-concussion (175 ADHD:LD+/-, 77 LD:ADHD+/-, 216 ADHD a/o LD) ImPACT assessment were included. Sensitivity and specificity were calculated using a normative data method and three machine learning classification methods: logistic regression, classification and regression tree, and random forest. Using the four methods, participants with ADHD:LD+/- had sensitivities that ranged from 0.474 to 0.697, and specificities that ranged from 0.538 to 0.686. Participants with LD:ADHD+/- had sensitivities that ranged from 0.455 to 0.688, and specificities that ranged from 0.456 to 0.588. For participants with ADHD a/o LD, sensitivities ranged from 0.542 to 0.755, and specificities ranged from 0.451 to 0.724. For all subgroups and analytical methods, the results illustrate sensitivity and specificity values below typically accepted levels indicative of clinical utility. These findings support that using ImPACT alone may be insufficient to inform concussion diagnoses and encourages the use of a multi-dimensional concussion assessment.


Don't stand so close to me: Microbiota-facilitated enemy release dynamics in introduced Onthophagus taurus dung beetles.
Microbial symbionts can influence their hosts in stunningly diverse ways. Emerging research suggests that an underappreciated facet of these relationships is the influence microbes can have on their host's responses to novel, or stressful, environmental conditions. We sought to address these and related questions in populations resulting from the recent introduction and subsequent rapid range expansion of Onthophagus taurus dung beetles. Specifically, we manipulated both microbial communities and rearing temperature to detect signatures of developmental and life history differentiation in response to the local thermal conditions in two populations derived from the southern most (Florida) and northern most (Michigan) extremes of the exotic Eastern U.S. range of O. taurus. We then sought to determine the contributions, if any, of host-associated microbiota to this differentiation. We found that when reared under common garden conditions individuals from Florida and Michigan populations differed significantly in developmental performance measures and life history traits, consistent with population divergence. At the same time, and contrary to our predictions, we failed to find support for the hypothesis that animals perform better if reared at temperatures that match their location of origin and that performance differences may be mediated by host-associated microbiota. Instead, we found that microbiome swapping across host populations improved developmental performance in both populations, consistent with enemy release dynamics. We discuss the implications of our results for our understanding of the rapid spread of exotic O. taurus through the Eastern United States and the significance of symbiosis in host responses to novel environmental conditions more broadly.


Ethical Responsibility for the Social Production of Tuberculosis.
Approximately one in two hundred persons in the Marshall Islands have active tuberculosis (TB). We examine the historical antecedents of this situation in order to assign ethical responsibility for the present situation. Examining the antecedents in terms of Galtung's dialectic of personal versus structural violence, we can identify instances in the history of the Marshall Islands when individual subjects made decisions (personal violence) with large-scale ecologic, social, and health consequences. The roles of medical experimenters, military commanders, captains of the weapons industry in particular, and industrial capitalism in general (as the cause of global warming) are examined. In that, together with Lewontin, we also identify industrial capitalism as the cause of tuberculosis, we note that the distinction between personal versus structural violence is difficult to maintain. By identifying the cause of the tuberculosis in the Marshall Islands, we also identify what needs be done to treat and prevent it.


The methodology for developing a prospective meta-analysis in the family planning community.
Prospective meta-analysis (PMA) is a collaborative research design in which individual sites perform randomized controlled trials (RCTs) and pool the data for meta-analysis. Members of the PMA collaboration agree upon specific research interventions and outcome measures, ideally before initiation but at least prior to any individual trial publishing results. This allows for uniform reporting of primary and secondary outcomes. With this approach, heterogeneity among trials contributing data for the final meta-analysis is minimized while each site maintains the freedom to design a specific trial. This paper describes the process of creating a PMA collaboration to evaluate the impact of misoprostol on ease of intrauterine device (IUD) insertion in nulliparous women. After the principal investigator developed a preliminary PMA protocol, he identified potential collaborating investigators at other sites. One site already had a trial underway and another site was in the planning stages of a trial meeting PMA requirements. Investigators at six sites joined the PMA collaborative. Each site committed to enroll subjects to meet a pre-determined total sample size. A final common research plan and site responsibilities were developed and agreed upon through email and face-to-face meetings. Each site committed to contribute individual patient data to the PMA collaboration, and these data will be analyzed and prepared as a multi-site publication. Individual sites retain the ability to analyze and publish their site's independent findings. All six sites have obtained Institutional Review Board approval and each has obtained individual funding to meet the needs of that site's study. Sites have shared resources including study protocols and consents to decrease costs and improve study flow. This PMA protocol is registered with the Cochrane Collaboration and data will be analyzed according to Cochrane standards for meta-analysis. PMA is a novel research method that improves meta-analysis by including several study sites, establishing uniform reporting of specific outcomes, and yet allowing some independence on the part of individual sites with respect to the conduct of research. The inclusion of several sites increases statistical power to address important clinical questions. Compared to multi-center trials, PMA methodology encourages collaboration, aids in the development of new investigators, decreases study costs, and decreases time to publication. ClinicalTrials.gov: NCT00613366, NCT00886834, NCT01001897, NCT01147497 and NCT01307111.


Mesenchymal stem cells from preterm to term newborns undergo a significant switch from anaerobic glycolysis to the oxidative phosphorylation.
We evaluated the energy metabolism of human mesenchymal stem cells (MSC) isolated from umbilical cord (UC) of preterm (< 37 weeks of gestational age) and term (≥ 37 weeks of gestational age) newborns, using MSC from adult bone marrow as control. A metabolic switch has been observed around the 34th week of gestational age from a prevalently anaerobic glycolysis to the oxidative phosphorylation. This metabolic change is associated with the organization of mitochondria reticulum: preterm MSCs presented a scarcely organized mitochondrial reticulum and low expression of proteins involved in the mitochondrial fission/fusion, compared to term MSCs. These changes seem governed by the expression of CLUH, a cytosolic messenger RNA-binding protein involved in the mitochondria biogenesis and distribution inside the cell; in fact, CLUH silencing in term MSC determined a metabolic fingerprint similar to that of preterm MSC. Our study discloses novel information on the production of energy and mitochondrial organization and function, during the passage from fetal to adult life, providing useful information for the management of preterm birth.


Cortical activity during motor execution, motor imagery, and imagery-based online feedback.
Imagery of motor movement plays an important role in learning of complex motor skills, from learning to serve in tennis to perfecting a pirouette in ballet. What and where are the neural substrates that underlie motor imagery-based learning? We measured electrocorticographic cortical surface potentials in eight human subjects during overt action and kinesthetic imagery of the same movement, focusing on power in "high frequency" (76-100 Hz) and "low frequency" (8-32 Hz) ranges. We quantitatively establish that the spatial distribution of local neuronal population activity during motor imagery mimics the spatial distribution of activity during actual motor movement. By comparing responses to electrocortical stimulation with imagery-induced cortical surface activity, we demonstrate the role of primary motor areas in movement imagery. The magnitude of imagery-induced cortical activity change was approximately 25% of that associated with actual movement. However, when subjects learned to use this imagery to control a computer cursor in a simple feedback task, the imagery-induced activity change was significantly augmented, even exceeding that of overt movement.


Environmental exposure to air pollution and allergens and peak flow changes.
Laboratory-based studies have shown that ozone and nitrogen dioxide can potentiate the effect of allergen in sensitized asthmatic subjects, but it is not known whether this interaction is important under natural exposure conditions. Thirty-five subjects with clinical diagnoses of asthma or chronic obstructive pulmonary disease and with a provocative dose causing a 20% fall in forced expiratory volume in one second methacholine <12.25 micromol (using the Yan method) kept peak expiratory flow (PEF) records for a 4-week period during late summer, with concurrent measurement of spore and pollen counts and pollution levels. Multiple regression analysis was then used to determine the effect on PEF of aeroallergen, and of the interaction between aeroallergen and pollutant levels. A statistically significant interaction was demonstrated between total spore count and ozone, but not nitrogen dioxide. Mean PEF fell in association with increasing spore count (same-day and 24-h lag level) and PEF variability increased with increasing spore count (24-h lag level only); both changes were greater the higher the prior ozone level. These results suggest that ozone can potentiate the effect of aeroallergens in subjects with bronchial hyperreactivity under natural exposure conditions. However, the effect was small, and the clinical significance of the interaction requires further study.


Defining Competence in Nursing and Its Relevance to Quality Care.
A consistent definition of competence in nursing is needed considering the significance to nursing professional development. The author bridges the gap between previous concept analyses of competence by creating an overarching model, while discussing the relationship to quality of nursing care. Significance of competence and quality care to nursing professional development is explored. The author concludes with implications for nursing professional development practice and research, while highlighting the relevance to professional nursing.


Intrauterine growth restriction alters nutrient metabolism in the intestine of porcine offspring.
Intrauterine growth restriction (IUGR) has negative impacts on the postnatal survival, growth and development of humans and animals, with not only on newborns but also adulthood. However, the characteristics for nutrient digestion and absorption in IUGR offspring are still largely unknown. Therefore, the normal birth weight (NBW) and IUGR growing pigs were used in this study to investigate their differences in nutrient utilization, with an expectition for further nutritional optimization of the IUGR offspring during their later life. Twelve IUGR and 12 NBW growing pigs were fitted with catheters in their portal vein to measure blood flow rate as well as nutrients and metabolites in plasma. The digestibilities of nutrients in different intestinal segments, and bacterial fermentation in the large intestine were examined to reveal the characteristics of nutrients utilization in IUGR versus NBW pigs. The rate of portal venous blood flow did not differ beween IUGR and NBW pigs. Plasma concentrations of total cholesterol, triglycerides and glucose were much lower but those of urea were higher in the portal vein of IUGR pigs, compared with the NBW pigs. The ileal digestibility of dry matter, gross energy and starch were lower in IUGR pigs than in NBW pigs. IUGR increased hindgut microbial diversity and bacterial fermentation activity in the caecum. In vitro cross-fermentation of ileal digesta by caecal microbes of NBW and IUGR pigs showed that gas production was much higher for IUGR ileal digesta regardless of the source of caecal inocula. IUGR impairs the nutrient digestion and absorption in small intestine, reduces caecal microbial diversity and promotes bacterial fermentation in the large intestine during the growing phase. These findings aid in our understanding of nutrient metabolism in IUGR pigs and provide the basis for future nutritional interventions.


Intraoperative ultrasonographically guided excisional biopsy or vacuum-assisted core needle biopsy for nonpalpable breast lesions.
To compare duration and rates of underestimation and complete excision for nonpalpable breast lesions using either intraoperative ultrasonographically guided excisioned biopsy (IUGE) or directional vacuum-assisted biopsy (DVAB). Percutaneous ultrasonography-guided core needle biopsy is preferable to stereotactic biopsy for treatment of nonpalpable breast lesions; however, underestimation and false-negative results can occur, and rebiopsy may be required. To date, however, there has been no comparison of these two procedures in terms of diagnostic accuracy and duration. For 4 consecutive years, IUGE was performed for 104 nonpalpable breast lesions and DVAB for 128 lesions at Chang Gung Memorial Hospital. Of the DVAB cases, the handheld mammotome was used for 53 procedures, with all lesions removed as completely as possible. The duration of the two procedures was calculated from initial skin incision until completion of wound closure. Most of the patients with benign pathology underwent ultrasonographic examination at 3 months after surgery, with a follow-up examination at 1 year. Surgery was performed subsequently for all of the malignancy cases. The average ages and mean tumor sizes for patients undergoing IUGE or DVAB were 46 and 47 years and 1.1 and 1.0 cm, respectively. The average IUGE and DVAB surgery durations for 88 benign tumors and 117 benign lesions were 44.3 and 21.5 minutes, respectively (P < 0.001), and 43.5 and 20.6 minutes for the malignant tumors (n = 16 and n = 11), respectively (P = 0.036). The IUGE and DVAB surgery durations for tumors <1 cm in diameter were 43.5 and 20.6 minutes, respectively, and 44.2 and 23.6 minutes for tumors over that size (P < 0.001). An older-model mammotome was used for 75 patients, with an average duration of 24 minutes in comparison to 18 minutes for the handheld variant (P < 0.001). No false-negative results were noted and, except in the case of the malignant tumors, there was no need for reexcisional biopsy. Further, there were no underestimates of the disease for the 4 cases of atypical ductal hyperplasia and the 12 of noninvasive carcinoma. No further ultrasonographic evidence of tumors was noted for 95% of the benign pathologies, with no residual abnormality detected for 13 of the 27 malignant tumors after IUGE or DVAB. For treatment of nonpalpable breast lesions, both IUGE and DVAB eliminate false-negative results, underestimates, and the requirement for reexcisional biopsies. In comparison to IUGE, DVAB is more convenient and time efficient for excisional biopsy of nonpalpable breast lesions.


Sphincter behaviour in myelomeningocele.
Four hundred and two videourodynamic studies were performed on 207 children with neuropathic vesicourethral dysfunction due to myelomeningocele. The children were divided into three groups (contractile, intermediate and acontractile) according to the urodynamic behaviour of their bladders, and the behaviour of the bladder neck and distal sphincter mechanism was assessed in each group. The bladder neck may be competent or incompetent in children with contractile bladders but is never obstructive, and is always incompetent in children with either intermediate or acontractile bladders at their usual bladder volumes. The distal sphincter mechanism is nearly always dynamically obstructive (detrusor-sphincter dyssynergia) in children with contractile bladders but is rarely if ever incompetent, whereas in children with intermediate or acontractile bladders, both (static) distal sphincter obstruction and sphincter weakness incontinence exist to some degree, although the predominance of one of these may mask the existence of the other unless it is specifically looked for or some therapeutic manoeuvre unmasks it. The main conclusion from this study is that, with the possible exception of those few children with more minor partial cord lesions, dysfunction of one or both sphincter mechanisms is the rule in congenital cord lesions.


Helicenic N-heterocyclic carbene copper(I) complex displaying circularly polarized blue fluorescence.
Enantiopure copper(I) chloride complexes bearing a monodentate N-(carbo[6]helicenyl)-NHC ligand have been prepared and characterized experimentally and computationally. Their high stability enables the stereochemistry to be probed by X-ray crystallography and NMR spectroscopy. The resolved enantiomeric complexes emit circularly polarized blue fluorescence with glum ∼1.3 × 10-3 in solution. The photophysical and chiroptical properties of these systems, with their helicene-centred origin, are similar to those of the organic helicene-benzimidazole precursor proligand, although the reverse axial chirality configuration is preferentially observed for the complex compared to the ligand.


The pupil collaboration: A multi-lab, multi-method analysis of goal attribution in infants.
The rise of pupillometry in infant research over the last decade is associated with a variety of methods for data preprocessing and analysis. Although pupil diameter is increasingly recognized as an alternative measure of the popular cumulative looking time approach used in many studies (Jackson & Sirois, 2022), an open question is whether the many approaches used to analyse this variable converge. To this end, we proposed a crowdsourced approach to pupillometry analysis. A dataset from 30 9-month-old infants (15 girls; Mage = 282.9 days, SD = 8.10) was provided to 7 distinct teams for analysis. The data were obtained from infants watching video sequences showing a hand, initially resting between two toys, grabbing one of them (after Woodward, 1998). After habituation, infants were shown (in random order) a sequence of four test events that varied target position and target toy. Results show that looking times reflect primarily the familiar path of the hand, regardless of target toy. Gaze data similarly show this familiarity effect of path. The pupil dilation analyses show that features of pupil baseline measures (duration and temporal location) as well as data retention variation (trial and/or participant) due to different inclusion criteria from the various analysis methods are linked to divergences in findings. Two of the seven teams found no significant findings, whereas the remaining five teams differ in the pattern of findings for main and interaction effects. The discussion proposes guidelines for best practice in the analysis of pupillometry data.


Medically Refractory Multiple Sclerosis Is Successfully Treated with Plasmapheresis in a Super Morbidly Obese Pregnant Patient.
Multiple sclerosis (MS) is a relapse remitting immune-mediated demyelinating neurological disorder that primarily affects women of childbearing age. In most patients, the hormonal changes during pregnancy are protective against MS relapses. When relapses do occur, treatment options are limited to use of intravenous steroids and plasmapheresis rescue therapy. We present a case of steroid refractory MS-transverse myelitis with quadriplegia in a 25-year-old pregnant super morbidly obese woman. Our clinical case is unique because the severity of her relapse early in pregnancy, which was intractable and resistant to steroids. This may have been a rebound demyelination due to the discontinuation of fingolimod; a newly recognized entity by the FDA. Our case report therefore seeks to raise awareness about a potential complication of discontinuing MS disease modifying therapies, highlighting that these rebound relapses can be steroid resistant and occur despite the usual protective hormonal influence of early pregnancy and that plasma exchange is a valid treatment option. Finally, we discuss the challenges of determining exchange volumes for plasmapheresis in the super morbid obese population to secure good maternal and fetal outcomes.


Blood pressure and waist circumference: an empirical study of the effects of waist circumference on blood pressure among Bengalee male jute mill workers of Belur, West Bengal, India.
An investigation of 150 adult Bengalee Hindu male jute mill workers in Belur, a suburb of Kolkata, West Bengal, India, was conducted to study the relationship between central obesity and blood pressure. In accordance with their waist circumference measurement, the subjects were divided into two categories: centrally non-obese (CNO) and centrally obese (CO). The participants were classified as the CO group if they had a WC of 80 cm or more. Results showed that none of the CNO subjects was mild hypertensive (SBP>/=140 mmHg and/or DBP>/=90 mmHg) while 85 of the CO subjects (82.5%) were mild hypertensives, the difference being statistically significant (chi-square=9.33; p<0.0025). Moreover, the data also revealed that the CO subjects had much (p<0.001) greater mean weight, body mass index (BMI), systolic (SBP), diastolic (DBP) and mean arterial (MAP) blood pressure than the CNO group members. The significant difference in blood pressure was found even after correcting the confounding effects of age and BMI variables. The results of this study showed that, the Bengalee male jute mill workers in the CO group had significantly higher blood pressure irrespective of age and overall adiposity (BMI). Therefore, the presence of central obesity is deemed a risk factor, for hypertension regardless of age and BMI. Thus, a WC cut-off point of 80 cm could be employed for health promotion among Bengalee men so as to prevent and manage hypertension effectively.


Cognitive behavioural therapy monotherapy for insomnia: A meta-analysis of randomized controlled trials.
This was a meta-analysis of randomized controlled trials (RCTs) comparing the effects of cognitive behavioural therapy for insomnia (CBTI) as a monotherapy and active control treatments in persons with insomnia who have no major medical conditions or psychiatric comorbidities. PubMed, PsycINFO, EMBASE, Cochrane Library databases, WanFang and CNKI were systematically and independently searched. Standardized mean differences (SMDs) and risk ratio (RR) with their 95% confidence intervals (CIs) were calculated. Nine RCTs with 12 treatment arms comparing CBTI (n = 479) and active control (n = 510) groups were analyzed. Compared to the active control group, the CBTI group showed significantly less improvement in insomnia at post-CBTI assessment in terms of sleep efficiency (SMD: 0.32, 95% CI: 0.00 to 0.63), sleep latency (SMD: -0.33, 95% CI: -0.56 to -0.09), wake after sleep onset (SMD: -0.27, 95% CI: -0.52 to -0.01), the total scores of Pittsburgh Sleep Quality Index (SMD: -0.52, 95% CI: -0.86 to -0.19), the Insomnia Symptom Index (SMD: -0.68, 95% CI: -1.01 to -0.36), the Dysfunctional Attitudes and Beliefs About Sleep Scale (SMD: -0.76, 95% CI: -1.25 to -0.27), and the Athens Insomnia Scale (SMD: -0.66, 95% CI: -1.07 to -0.24). In this meta-analysis, CBTI monotherapy showed no advantage in improving insomnia compared with other standard treatments.


Innocent blood: a history of hemorrhagic disease of the newborn.
Hemorrhages occurring in the newborn without trauma have been observed by obstetricians since the 17th century, but have been considered different diseases depending on their location. Umbilical hemorrhage associated with obstructed bile canals was described by Cheyne in 1802. Grandidier in 1871 and Townsend in 1894 grouped together various forms of neonatal bleeds and associated them with disturbed coagulation. When the clotting system became better understood in the last decade of the 19th century, effective symptomatic treatment was developed: gelatin, serum injection, and the transfusion of fresh blood. In 1935, Dam detected the function of vitamin K in the coagulation system and 4 years later, Waddell introduced vitamin K administration into therapy and prevention of neonatal hemorrhagic disease. Kernicterus occurred when high doses of synthetic water-soluble vitamin K analogues were given to preterm infants, reminding physicians that progress in neonatal therapy rests on the cornerstones of controlled trials and follow-up.


Symboldrama, a psychotherapeutic method for adolescents with dissociative and PTSD symptoms: a pilot study.
A total of 15 clinically referred adolescents who had been sexually or physically abused participated in this pilot study of the use of symboldrama psychotherapy. Symboldrama is a psychotherapeutic method that uses imagery as the major psychotherapeutic tool. All adolescents reported to be suffering from a high level of dissociative symptoms and other symptoms such as anxiety, depression, posttraumatic stress, and anger after their traumas. The objective of the study was to test the hypothesis that symboldrama psychotherapy in addition to psycho-education of the non-offending parent would significantly reduce the reported symptoms. Before treatment, the participants answered three questionnaires: (a) the Life Incidence of Traumatic Events Scale, (b) the Trauma Symptom Checklist for Children, and (c) the Dissociation Questionnaire-Swedish version. After treatment, the participants once again filled out the Trauma Symptom Checklist for Children and the Dissociation Questionnaire-Swedish version. The scores from before and after treatment were compared, and the results showed that the symptoms had been statistically significantly reduced.


The innervated gracilis muscle for microsurgical functional lip reconstruction: review of the literature.
Reconstruction of the lower and upper lip should meet both aesthetic and functional requirements, whenever possible. Achievement of these goals presents a major challenge particularly in extensive lip defects requiring microsurgical reconstruction. Successful reconstructive outcomes have been reported using free fasciocutaneous flaps such as composite radial forearm flap or anterolateral thigh flap in conjunction with static tendon slings. In recent years, neurovascular gracilis muscle transfer has been introduced in hopes to overcome noncontractile properties of these flaps and to restore oral competence by muscle contractility. This article reviews the available data on the innervated gracilis muscle transfer for functional lip reconstruction. Tips and techniques gleaned from all of the current literature are discussed.


Wheezing in infants: frequency, clinical characteristics and treatment.
To estimate the frequency and describe the clinical characteristics and respective treatments of previous history of wheezing. Infants aged 6-23 months with upper respiratory tract complaints and reporting previous wheezing were followed-up retrospectively. Data were registered on a validated standardized form. Out of 451 infants, 164 (36.4%; 95%CI:31.9-41.0) had a report of prior history of wheezing, 148 (32.8%; 95%CI:28.5-37.4) during the first year of life. The mean age at the first episode of wheezing was 5.3±3.9 months. Among those who had had their first episode before 12 months of age, 38.5% reported 3 to 6 episodes and 14.2% > 6 episodes. Mean age at first episode was lower for those with ≥ 3 episodes in comparison with those with ≤ 2 episodes (3.2±2.7 vs. 5.7±2.5 months, p < 0.001). One third of the infants reported wheezing during the first year of life. The earlier the first episode occurs, the more frequently wheezing recurs.


Future of adenoviruses in the gene therapy of arthritis.
Recombinant adenoviruses are straightforward to produce at high titres, have a promiscuous host-range, and, because of their ability to infect nondividing cells, lend themselves to in vivo gene delivery. Such advantages have led to their widespread and successful use in preclinical studies of arthritis gene therapy. While adenoviral vectors are well suited to 'proof of principle' experiments in laboratory animals, there are several barriers to their use in human studies at this time. Transient transgene expression limits their application to strategies, such as synovial ablation, which do not require extended periods of gene expression. Moreover, there are strong immunological barriers to repeat dosing. In addition, safety concerns predicate local, rather than systemic, delivery of the virus. Continued engineering of the adenoviral genome is producing vectors with improved properties, which may eventually overcome these issues. Promising avenues include the development of 'gutted' vectors encoding no endogenous viral genes and of adenovirus-AAV chimeras. Whether these will offer advantages over existing vectors, which may already provide safe, long-term gene expression following in vivo delivery, remains to be seen.


A Residual Based Attention Model for EEG Based Sleep Staging.
Sleep staging is to score the sleep state of a subject into different sleep stages such as Wake and Rapid Eye Movement (REM). It plays an indispensable role in the diagnosis and treatment of sleep disorders. As manual sleep staging through well-trained sleep experts is time consuming, tedious, and subjective, many automatic methods have been developed for accurate, efficient, and objective sleep staging. Recently, deep learning based methods have been successfully proposed for electroencephalogram (EEG) based sleep staging with promising results. However, most of these methods directly take EEG raw signals as input of convolutional neural networks (CNNs) without considering the domain knowledge of EEG staging. Apart from that, to capture temporal information, most of the existing methods utilize recurrent neural networks such as LSTM (Long Short Term Memory) which are not effective for modelling global temporal context and difficult to train. Therefore, inspired by the clinical guidelines of sleep staging such as AASM (American Academy of Sleep Medicine) rules where different stages are generally characterized by EEG waveforms of various frequencies, we propose a multi-scale deep architecture by decomposing an EEG signal into different frequency bands as input to CNNs. To model global temporal context, we utilize the multi-head self-attention module of the transformer model to not only improve performance, but also shorten the training time. In addition, we choose residual based architecture which makes training end-to-end. Experimental results on two widely used sleep staging datasets, Montreal Archive of Sleep Studies (MASS) and sleep-EDF datasets, demonstrate the effectiveness and significant efficiency (up to 12 times less training time) of our proposed method over the state-of-the-art.


A nutrient mediates intraspecific competition between rodent malaria parasites in vivo.
Hosts are often infected with multiple strains of a single parasite species. Within-host competition between parasite strains can be intense and has implications for the evolution of traits that impact patient health, such as drug resistance and virulence. Yet the mechanistic basis of within-host competition is poorly understood. Here, we demonstrate that a parasite nutrient, para-aminobenzoic acid (pABA), mediates competition between a drug resistant and drug susceptible strain of the malaria parasite, Plasmodium chabaudi We further show that increasing pABA supply to hosts infected with the resistant strain worsens disease and changes the relationship between parasite burden and pathology. Our experiments demonstrate that, even when there is profound top-down regulation (immunity), bottom-up regulation of pathogen populations can occur and that its importance may vary during an infection. The identification of resources that can be experimentally controlled opens up the opportunity to manipulate competitive interactions between parasites and hence their evolution.


Hospital costs and length of stay related to robot-assisted versus open radical and partial nephrectomy for kidney cancer in the USA.
There are scant national outcomes data for robot-assisted laparoscopic surgery. We assessed costs and length of stay (LOS) related to robot-assisted radical and partial nephrectomy in a nationally representative population database. We performed a cohort analysis of the US Nationwide Inpatient Sample database. Using ICD-9 procedure codes, we identified patients who underwent radical or partial nephrectomy for kidney cancer from October 2008 to December 2008. We excluded patients with non-robot-assisted laparoscopic procedures and those under age 18 years. We performed multivariate analyses of LOS and total hospital charges, adjusting for age, race, gender, Charlson comorbidity index, and teaching hospital status. Records of 2,242 patients were analyzed. On adjusted multivariate analysis, robot-assisted partial nephrectomy was associated with shorter LOS compared with open surgery (-2.0 days, P = 0.032). Robot-assisted radical nephrectomy was associated with shorter LOS compared with open surgery (-1.8 days, P = 0.077). There were no significant differences in total charges for robot-assisted compared with open surgery for either radical (P = 0.631) or partial (P = 0.713) nephrectomy. In this large, population-based analysis, robot-assisted radical and partial nephrectomy were associated with shorter LOS and equivalent hospital charges compared with their open surgery counterparts. These data suggest that, for renal surgery, diminished LOS offsets other hospital costs associated with robot-assisted procedures.


The lethal effects of pharmacological cyclin-dependent kinase inhibitors in human leukemia cells proceed through a phosphatidylinositol 3-kinase/Akt-dependent process.
The impact of disruption of the PI3K (phosphatidylinositol 3-kinase) pathway on the response of human leukemia cells to pharmacological cyclin-dependent kinase (CDK) inhibitors has been examined. Exposure of U937 monocytic leukemia cells to minimally toxic concentrations of flavopiridol (FP), roscovitine, or CGP74514A for 3 h in conjunction with the PI3K inhibitor LY294002 (abbreviated LY in the article) resulted in a marked decrease in Akt phosphorylation. Coexposure of cells to LY and CDK inhibitors also resulted in an early (i.e., within 3 h) and striking increase in mitochondrial damage [e.g., cytochrome c, second mitochondria-derived activator of caspases/direct inhibitor of apoptosis (IAP)-binding protein with low isoelectric point (Smac/DIABLO), and apoptosis-initiating factor (AIF) release], caspase activation, and apoptosis. Similar interactions were observed in a variety of other leukemia cell types (e.g., HL-60, Jurkat, Raji, and NB4). Apoptosis, induced by FP/LY, was substantially blocked by ectopic expression of Bcl-2, but to a considerably lesser extent by dominant-negative caspase-8. FP-induced apoptosis was not enhanced by agents that inhibited protein kinase (PK) A (H89), PKC (GFX), mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK1/2; U0126), p38 MAP kinase (MAPK; SB202190), m-target of rapamycin (TOR; rapamycin), or ataxia-telangiectasia mutation (ATM; caffeine), whereas the PI3K inhibitor wortmannin exerted effects similar to those of LY. The dramatic potentiation of CDK inhibitor-induced apoptosis by LY was accompanied by diminished Bad phosphorylation, induction of Bcl-2 cleavage, and down-regulation of X-linked IAP (XIAP) and Mcl-1. Cells exposed to CDK inhibitors + LY also exhibited reduced phosphorylation of glycogen synthase kinase (GSK)-3, forkhead transcription factor (FKHR), p70(S6K), and ERK, but increased activation of p34(cdc2) and p38 MAPK. LY/CDK inhibitor-treated cells also displayed diminished pRb dephosphorylation on CDK2- and CDK4-specific sites, retinoblastoma protein cleavage, and down-regulation of cyclin D(1). Inducible expression of constitutively active (myristolated) Akt significantly, albeit partially, attenuated apoptosis in Jurkat leukemia cells treated with either FP alone or the combination of FP and LY. Finally, cotreatment with LY and FP resulted in a dramatic increase in apoptosis in primary leukemic blasts obtained from a patient with acute myeloblastic leukemia. Together, these findings suggest that the PI3K/Akt pathway plays a major role in regulating the apoptotic response of human leukemia cells to pharmacological CDK inhibitors and raise the possibility that combined interruption of CDK- and PI3K-related pathways may represent a novel therapeutic strategy in hematological malignancies.


Medium-Term Outcomes of the Arthroscopic Brostrom Procedure: A Retrospective Analysis of 66 Patients.
The arthroscopic Brostrom procedure is a minimally invasive technique that is a viable option surgeons have to treat patients with chronic lateral ankle instability (CAI). Our hypothesis was that there will be a statistically significant difference in pre- and postoperative scores and that patient satisfaction scores remained consistent at a minimum of 5 years postoperatively. Preoperative American Orthopedic Foot and Ankle (AOFAS) hindfoot scores, visual analog scale (VAS), foot function index (FFI) were compared with postoperative scores. Karlsson-Peterson (KP) scores were assessed at the final follow-up. Unpaired t tests were performed to determine if there was a statistically significant difference in AOFAS, VAS and FFI scores. Mean preoperative scores were (AOFAS) 51.8, (VAS) 7.36, and (FFI) 83.5, respectively. At the 5-year mark, the postoperative scores were 88.9, 2.24, 18.4 respectively and 83.6, for the KP scores. Furthermore, we compared those patients with a BMI <30 kg/m2 to those with a BMI ≥30 kg/m2. This comparison showed no statistically significant postoperative difference between groups at 5 years. The aim of the study was to determine the longevity of the procedure based on 5-year outcomes scores comparing preoperative and 5+-year AOFAS, VAS, and FFI scores. We found that there was a significant difference in all scores which suggests that this repair provides adequate relief of pain and improved outcomes at 5 years.


A theoretical comparison of energy sources--microwave, ultrasound and laser--for interstitial thermal therapy.
A number of heating sources are available for minimally invasive thermal therapy of tumours. The purpose of this work was to compare, theoretically, the heating characteristics of interstitial microwave, laser and ultrasound sources in three tissue sites: breast, brain and liver. Using a numerical method, the heating patterns, temperature profiles and expected volumes of thermal damage were calculated during standard treatment times with the condition that tissue temperatures were not permitted to rise above 100 degrees C (to ensure tissue vaporization did not occur). Ideal spherical and cylindrical applicators (200 microm and 800 microm radii respectively) were modelled for each energy source to demonstrate the relative importance of geometry and energy attenuation in determining heating and thermal damage profiles. The theoretical model included the effects of the collapse of perfusion due to heating. Heating patterns were less dependent on the energy source when small spherical applicators were modelled than for larger cylindrical applicators due to the very rapid geometrical decrease in energy with distance for the spherical applicators. For larger cylindrical applicators, the energy source was of greater importance. In this case, the energy source with the lowest attenuation coefficient was predicted to produce the largest volume of thermally coagulated tissue, in each tissue site.


[Photodynamic therapy of urinary bladder cancer using a chlorin based photosensitizer].
Photodynamic therapy (PDT) is a modem, low-invasive method of urinary bladder (UB) cancer treatment. PDT can induce complete or partial destruction of the tumor, reduce recurrence rate, provide assistance to elderly patients with compromised somatic status who are not radically operable. A combined technique improves the results of photodynamic therapy in patients with surface and invasive UB cancer of stage T2 because photodynamic impact affects not only the tumor but also all UB mucosa by light fiber with cylindric diffusor introduced in a silicon balloon with water. This leads to tumor destruction and a recurrence rate decrease.


Molecular mechanisms of tumor invasion and metastasis: an integrated view.
As tumors progress to increased malignancy, cells within them develop the ability to invade into surrounding normal tissues and through tissue boundaries to form new growths (metastases) at sites distinct from the primary tumor. The molecular mechanisms involved in this process are incompletely understood but those associated with cell-cell and cell-matrix adhesion, with the degradation of extracellular matrix, and with the initiation and maintenance of early growth at the new site are generally accepted to be critical. This article discusses current knowledge of molecular events involved in these various processes. The potential role of adhesion molecules (eg. integrins and cadherins) has undergone a major transition over the last ten years, as it has become apparent that such molecules play a major role in signaling from outside to inside a cell, thereby controlling how a cell is able (or not) to sense and interact with its local environment. Similarly the roles of proteolytic enzymes and their inhibitors (eg. matrix metalloproteinases and TIMPs) have also expanded as it has become apparent that they not only have the abilities to break down the components of the extracellular matrix but also are involved in the release of factors which can affect the growth of the tumor cells positively or negatively. Recent work has highlighted the importance of the later, post-extravasational stages of metastasis, where adhesion and proteolysis are now known to play a role along with other processes such as apoptosis, dormancy, growth factor-receptor interactions and signal transduction. Recent work has also demonstrated that not only the immediate cellular microenvironment, in terms of specific cell-cell and cell-matrix interactions, but also the extended cellular microenvironment, in terms of vascular insufficiency and hypoxia in the primary tumor, can modify cellular gene expression and enhance metastasis. Mechanisms of metastasis appear to involve a complex array of genetic and epigenetic changes many of which appear to be specific both for different types of tumors and for different sites of metastasis. Our improved understanding of the expanded roles of the individual molecules involved has resulted in a mechanistic blurring of the previously described discrete stages of the metastatic process.


Evaluating processing temperature and feeding value of extruded-expelled soybean meal on nursery and finishing pig growth performance.
We conducted two experiments comparing the use of extruded-expelled soybean meal (EESoy) to solvent-extracted soybean meal (SBM) in swine diets. In Exp. 1, the objective was to determine the optimal processing temperature of EESoy for nursery pig growth performance. Pigs (n = 330, 13.2 +/- 2.3 kg of BW) were fed a control diet containing SBM with added fat or one of five diets containing EESoy extruded at 143.3, 148.9, 154.4, 160.0, or 165.6 degrees C. All diets were formulated on an equal apparent digestible lysine:ME ratio. From d 0 to 20, no differences were observed (P > 0.32) in ADG or ADFI (average of 544 and 924 g/d, respectively). However, gain:feed ratio (G/F) improved (quadratic, P < 0.01, range of 0.56 to 0.60) with increasing processing temperature, with the greatest improvement at 148.9 degrees C. In Exp. 2, the objective was to determine the feeding value of EESoy relative to SBM with or without added fat for growing-finishing pigs in a commercial production facility. A total of 1,200 gilts (initially 24.5 +/- 5.1 kg of BW) was used, with 25 pigs per pen and eight replications per treatment. Dietary treatments were arranged in a 2 x 3 factorial, with two sources of soybean meal (SBM or EESoy) and three levels of added fat. Pigs were phase-fed four diets over the experimental period and added fat (choice white grease) levels were 0, 3.4, and 7% initially, with the added fat levels decreasing in the next three dietary phases. Energy levels were based such that the higher energy in EESoy (with or without added fat) was calculated to be equal to that provided by SBM with added fat. From 24.5 to 61.2 kg, pigs fed EESoy had greater (P < 0.07) G/F than those fed SBM. Increasing added fat in either EESoy- or SBM-based diets increased G/F (linear, P < 0.0003). From 61.2 to 122.5 kg, ADG and G/F were unaffected in pigs fed EESoy and/or increasing added fat (P > 0.10). For the overall growing-finishing period, ADG was unaffected (P > 0.61) by increasing energy density of the diet; however, ADFI decreased (P < 0.05) and G/F increased (P < 0.02, range of 0.37 to 0.40) as energy density increased with either EESoy or added fat. Carcass leanness was not affected by dietary treatment. These results indicate that EESoy should be extruded at 148.9 to 154.4 degrees C, and that increasing dietary energy density by using EESoy and/or added fat improves feed efficiency in finishing pigs reared in a commercial environment.


Mental disorder among refugees and the impact of persecution and exile: some findings from an out-patient population.
Refugees have long been considered at risk for mental disorder. We sought to characterise this risk in an out-patient refugee sample by analysing the relationship between psychiatric symptoms and dysfunction, and between symptoms and the socio-demographic background and stressors specific to this refugee sample. A consecutive sample of 231 refugee patients referred to the psychiatric out-patient unit at the Psychosocial Centre for Refugees, University of Oslo, was examined with a semi-structured interview guide, Brief Psychiatric Rating Scale (BPRS), Hopkins Symptom Check-List (HSCL-25) and a check-list for post-traumatic symptoms (PTSS-10). Global Assessment of Function (GAF) scores were obtained; and the data were analysed using nine predictor variables. It was found that 46.6% of the patients had a post-traumatic stress disorder according to the criteria for DSM-III-R as the main diagnosis, while the mean GAF score for the patients was 57.3. Analysis of the GAF and BPRS data did not reveal any predictor of psychotic behaviour. However, torture emerged as an important predictor of emotional withdrawal/retardation. Also, age, gender and no employment or education predicted for anxiety/depression, while refugee status and no employment or school predicted for hostility/aggression. The results confirm earlier findings that refugees constitute a population at risk for mental disorder. Past traumatic stressors and current existence in exile constitute independent risk factors. However, stressors other than those discussed here appear to be important also, particularly with regard to psychotic symptoms.


Unrecognized myocardial infarction: the association with cardiopulmonary symptoms and mortality is mediated via echocardiographic abnormalities of global dysfunction instead of regional dysfunction: the Olmsted County Heart Function Study.
There are very few data describing the association of electrocardiogram-based unrecognized myocardial infarction (ECG-UMI) with nonanginal cardiopulmonary symptoms, echocardiographic abnormalities, and mortality in the community. We studied 2042 Olmsted County residents, who were randomly selected and aged > or = 45 years, by a survey questionnaire for symptoms, echocardiogram for structural abnormalities, and a 5-year follow-up for all-cause mortality. Unrecognized myocardial infarctions (n = 81) were diagnosed if ECG-based myocardial infarction (MI) criteria were met without the history of a documented recognized MI. In UMI versus no MI controls, the prevalence (%) of dyspnea on exertion (49 vs 29), orthopnea (6 vs 4), palpitations (20 vs 15), and history of fluid overload (6 vs 1) was significantly higher (P < .05). The associations of exertional dyspnea and history of fluid overload with UMI were independent of age, sex, and pulmonary disease but had a significant reduction in their magnitude after adjusting for global dysfunction (diastolic or systolic dysfunction). All the 4 symptoms were associated with increased risk of mortality (hazard ratios ranging from 2.3 to 9.1, P < .0001), which was meaningfully attenuated by adjusting for ECG-UMI status. Global ventricular dysfunction had a more significant impact on this association than regional ventricular dysfunction (wall motion abnormalities). The increased risk of mortality associated with symptoms is at least in part mediated via ECG-UMI. Structural abnormalities of global dysfunction play a greater role in mediating this risk than regional dysfunction, challenging the current clinical practice of calling an ECG-based MI false positive in symptomatic adults in the absence of wall motion abnormalities.


HIF-1α Dependent Wound Healing Angiogenesis In Vivo Can Be Controlled by Site-Specific Lentiviral Magnetic Targeting of SHP-2.
Hypoxia promotes vascularization by stabilization and activation of the hypoxia inducible factor 1α (HIF-1α), which constitutes a target for angiogenic gene therapy. However, gene therapy is hampered by low gene delivery efficiency and non-specific side effects. Here, we developed a gene transfer technique based on magnetic targeting of magnetic nanoparticle-lentivirus (MNP-LV) complexes allowing site-directed gene delivery to individual wounds in the dorsal skin of mice. Using this technique, we were able to control HIF-1α dependent wound healing angiogenesis in vivo via site-specific modulation of the tyrosine phosphatase activity of SHP-2. We thus uncover a novel physiological role of SHP-2 in protecting HIF-1α from proteasomal degradation via a Src kinase dependent mechanism, resulting in HIF-1α DNA-binding and transcriptional activity in vitro and in vivo. Excitingly, using targeting of MNP-LV complexes, we achieved simultaneous expression of constitutively active as well as inactive SHP-2 mutant proteins in separate wounds in vivo and hereby specifically and locally controlled HIF-1α activity as well as the angiogenic wound healing response in vivo. Therefore, magnetically targeted lentiviral induced modulation of SHP-2 activity may be an attractive approach for controlling patho-physiological conditions relying on hypoxic vessel growth at specific sites.


How Thermophilic Gram-Positive Organisms Perform Extracellular Electron Transfer: Characterization of the Cell Surface Terminal Reductase OcwA.
Extracellular electron transfer is the key process underpinning the development of bioelectrochemical systems for the production of energy or added-value compounds. Thermincola potens JR is a promising Gram-positive bacterium to be used in these systems because it is thermophilic. In this paper, we describe the structural and functional properties of the nonaheme cytochrome OcwA, which is the terminal reductase of this organism. The structure of OcwA, determined at 2.2-Å resolution, shows that the overall fold and organization of the hemes are not related to other metal reductases and instead are similar to those of multiheme cytochromes involved in the biogeochemical cycles of nitrogen and sulfur. We show that, in addition to solid electron acceptors, OcwA can also reduce soluble electron shuttles and oxyanions. These data reveal that OcwA can work as a multipurpose respiratory enzyme allowing this organism to grow in environments with rapidly changing availability of terminal electron acceptors without the need for transcriptional regulation and protein synthesis.IMPORTANCE Thermophilic Gram-positive organisms were recently shown to be a promising class of organisms to be used in bioelectrochemical systems for the production of electrical energy. These organisms present a thick peptidoglycan layer that was thought to preclude them to perform extracellular electron transfer (i.e., exchange catabolic electrons with solid electron acceptors outside the cell). In this paper, we describe the structure and functional mechanisms of the multiheme cytochrome OcwA, the terminal reductase of the Gram-positive bacterium Thermincola potens JR found at the cell surface of this organism. The results presented here show that this protein can take the role of a respiratory "Swiss Army knife," allowing this organism to grow in environments with soluble and insoluble substrates. Moreover, it is shown that it is unrelated to terminal reductases found at the cell surface of other electroactive organisms. Instead, OcwA is similar to terminal reductases of soluble electron acceptors. Our data reveal that terminal oxidoreductases of soluble and insoluble substrates are evolutionarily related, providing novel insights into the evolutionary pathway of multiheme cytochromes.


Contralateral coordination and retargeting of limb movements during scratching in the locust
Locusts, Schistocerca gregaria, in common with many limbed vertebrates, can make directed scratching movements in response to tactile stimulation. For instance, stimulation of different sites on a wing elicits different movements that are accurately targeted so that the hindleg tarsus passes across the stimulus site. I have analysed these limb movements to define the ability of a locust to target stimulus sites correctly under a range of experimental conditions. In particular, I describe aspects of the behaviour that reveal possible neuronal pathways underlying the responses. These neuronal pathways will be the subject of further physiological analyses. Limb targeting during scratching is continuously graded in form; different patterns of movement are not separated by sharp transitions. The computation of limb trajectory takes into account the starting posture of the hindleg, so that different trajectories can be used to reach a common stimulus site from different starting postures. Moreover, the trajectories of the two hindlegs moving simultaneously from different starting postures in response to a single stimulus can be different, so that their tarsi converge onto the common stimulus site. Different trajectories can be used to reach a common stimulus site from the same start posture. Targeting information from a forewing is passed not only down the nerve cord to the ipsilateral hindleg but also across the nerve cord, so that the contralateral hindleg can also make directed movements. This contralateral transmission does not rely on peripheral sensory feedback. When the stimulus site moves during a rhythmical scratch, the targeting of subsequent cycles reflects this change. Both ipsilateral and contralateral hindlegs can retarget their movements. The trajectory of a single cycle of scratching directed towards a particular stimulus site can be modified after it has begun, so that the tarsus is redirected towards a new stimulus site.


The survey of the patient received the epiduroscopic laser neural decompression.
Neuroplasty using a Racz catheter or epiduroscope and percutaneous endoscopic laser discectomy are performed as treatment for chronic refractory low back and/or lower extremity pain, but they are limited in that they cannot completely remove the causing pathology. Lately, epiduroscopic laser neural decompression (ELND) has been receiving attention as an alternative treatment, but there are insufficient reports of results. Hence we aimed to investigate and report the data in our hospital. Seventy-seven patients were selected who had received ELND via the anterior and posterior epidural approach through the pain clinic in our hospital from March 2011 to July 2012. Their medical records including age, diagnosis, epiduroscopic findings and degree of symptom relief were investigated. The degree of symptom relief following the procedure was categorized into 5 stages of very good (5), good (4), no change (3), bad (2), and very bad (1) at 2 weeks and 1 month after the procedure. The subjects were 30 males and 47 females. Mean age was 54.6 for males and 59.6 for females, so the overall mean age was 58.1 years old, with the youngest being 23 and the oldest 88 years old. In epiduroscopic images of all patients, more than one situation of herniated disc, fibrous tissue and adhesion, or inflammation was observed. Sixty-seven patients (87.0%) showed symptom relief 2 weeks after the procedure and 63 patients (81.8%) showed relief after 1 month. ELND is considered to be an effective treatment alternative for chronic refractory low back and/or lower extremity pain, including lumbar disc herniation, lumbar spinal stenosis, and failed back surgery syndrome which cannot be alleviated with existing non-invasive conservative treatment.


Nonverbal learning disability: adult outcomes.
There are few empirical studies of the adult outcomes of nonverbal learning disability (NLD). An overwhelming majority of NLD studies has been devoted to the nature of academic difficulties of school children, whereas the few follow-up studies have tended to be limited to college-age young adults. Herein, it is argued that the problems of adults with NLD do not fall solely in academic areas, and that early academic remediation programs might do well to include intervention in emotional and social skills enhancement.


Decreased mononuclear cell NR3C1 SKA2 and FKPB5 expression levels among adult survivors of suicide bombing terror attacks in childhood are associated with the development of PTSD.
Life threatening trauma and the development of PTSD during childhood, may each associate with transcriptional perturbation of immune cell glucocorticoid reactivity, yet their separable longer term contributions are less clear. The current study compared resting mononuclear cell gene expression levels of the nuclear receptor, subfamily 3, member 1 (NR3C1) coding the glucocorticoid receptor, its trans-activator spindle and kinetochore-associated protein 2 (SKA2), and its co-chaperon FKBP prolyl isomerase 5 (FKBP5), between a cohort of young adults first seen at the Hadassah Emergency Department (ED) after surviving a suicide bombing terror attack during childhood, and followed longitudinally over the years, and matched healthy controls not exposed to life threatening trauma. While significant reductions in mononuclear cell gene expression levels were observed among young adults for all three transcripts following early trauma exposure, the development of subsequent PTSD beyond trauma exposure, accounted for a small but significant portion of the variance in each of the three transcripts. Long-term perturbation in the expression of immune cell glucocorticoid response transcripts persists among young adults who develop PTSD following life threatening trauma exposure in childhood, denoting chronic dysregulation of immune stress reactivity.


An unusual p53 mutation detected in Burkitt's lymphoma: 30 bp duplication.
Burkitt's lymphomas (BL) are aggressive rapidly growing tumors typified by a high c-myc expression resulting from t(8;14)(q24;q32), t(2;8)(p12;q24) or t(8;22)(q24;q11) translocations. Alterations of the p53 tumor suppressor are also relatively frequent in BL. Several approaches have been adopted for detection of the p53 aberrations such as immunohistochemical analyses, immunoblotting, DNA sequencing, fluorescence in situ hybridization (FISH), and functional assays. We used these methods to characterize the p53 mutation in tumor cells of a 53-year-old male suffering from Burkitt's lymphoma. By immunohistochemical analyses, we detected high levels of the p53 protein in the tumor tissue. Immunoblotting showed a higher molecular weight of the p53 protein overexpressed in the tumor tissues than that of the standard p53 protein. Similarly, the molecular weight of the PCR product prepared by amplification of the tumor p53 cDNA was higher than that of the standard p53 cDNA. Functional analyses of separated alleles in yeast evidently revealed that the tumor p53 protein was transcriptionally non-functional. The yeast colonies expressing this p53 variant possessed a unique phenotype in that they were red with many white spots on their surface. Sequencing of the tumor cDNA revealed a duplication of the 30 bp region of the p53 gene (g.12155_12184dup30) leading to a repeat of 10 amino acids (Pro-77 to Ala-86) in the p53 protein. Further analyses showed that the mutation was unstable in yeast cells. The FISH analyses did not confer loss of the p53-specific locus 17p13.


Incidence Rates of Psoriasis in Children With Inflammatory Bowel Disease and Juvenile Arthritis Treated With Tumor Necrosis Factor Inhibitors and Disease-Modifying Antirheumatic Drugs.
To estimate the differential effect of tumor necrosis factor inhibitor (TNFi) therapies and presence or absence of conventional synthetic disease-modifying antirheumatic drugs (DMARDs) on the incidence of psoriasis (PsO) in children with inflammatory bowel disease (IBD), juvenile idiopathic arthritis (JIA), and chronic nonbacterial osteomyelitis (CNO). This was a retrospective cohort study from 2008 to 2020. TNFi and DMARD exposures were dichotomized as ever/never. The primary outcome was incident PsO. Incidence rates (IRs) of PsO were stratified by underlying diagnosis, TNFi agent, and DMARD use. Poisson regression was used to assess the IR ratios (IRRs) between exposure groups. There were 5088 children who met the inclusion criteria: 3794 (75%) had IBD, 1189 (23%) had JIA, and 105 (2%) had CNO. Of the 2023 children with TNFi exposure, 613 (30%) and 1410 (70%) were with or without a DMARD, respectively. When controlling for DMARD, sex, and family history of PsO, the IRR of developing PsO in patients exposed to adalimumab (ADA) was 2.70 times higher (95% CI 1.53-4.75; P < 0.001) than those who did not receive any TNFi treatment. IRR was lower, but not significantly different, for patients exposed to infliximab (IFX; IRR 2.34, 95% CI 1.56-3.51; P < 0.001) and etanercept (ETN; IRR 2.21; 95% CI 1.17-4.21; P = 0.006) compared to TNFi-unexposed patients. IRR of TNFi exposure was lower by 0.25 (P < 0.001) in DMARD-exposed patients compared to non-DMARD-exposed patients. IRR of TNFi-induced PsO was not significantly different among ADA, IFX, and ETN. However, for patients with exposure to any of the TNFi evaluated, the IRR was significantly lower in those also exposed to a DMARD.