Vitamin A active metabolite, all-trans retinoic acid, induces spinal cord sensitization. II. Effects after intrathecal administration.
In our previous study (see accompanying paper) we observed that all-trans retinoic acid (ATRA) p.o. induces changes in spinal cord neuronal responses similar to those observed in inflammation-induced sensitization. In the present study we assessed the it. effects of ATRA, and its mechanisms of action. The effects of all drugs were studied after it. administration in nociceptive withdrawal reflexes using behavioural tests in awake male Wistar rats. The administration of ATRA in normal rats induced a dose-dependent enhancement of nociceptive responses to noxious mechanical and thermal stimulation, as well as responses to innocuous stimulation. The intensity of the responses was similar to that observed in non-treated animals after carrageenan-induced inflammation. The effect induced by ATRA was fully prevented by the previous administration of the retinoic acid receptor (RAR) pan-antagonist LE540 but not by the retinoid X receptor (RXR) pan-antagonist HX531, suggesting a selective action on spinal cord RARs. The COX inhibitor dexketoprofen and the interleukin-1 receptor antagonist IL-1ra inhibited ATRA effect. The results indicate that COX and interleukin-1 are involved in the effects of ATRA in the spinal cord, similar to that seen in inflammation. In conclusion, ATRA induces changes in the spinal cord similar to those observed in inflammation. The sensitization-like effect induced by ATRA was mediated by RARs and associated with a modulation of COX-2 and interleukin-1 activities. ATRA might be involved in the mechanisms underlying the initiation and/or maintenance of sensitization in the spinal cord.


Prevalence and correlates of abuse screening items among community-dwelling Hong Kong Chinese older adults.
The present study aims to describe the prevalence of potential elder abuse, and to examine correlates of abuse screening items among Chinese community-dwelling older adults. We analyzed the data of 3435 older persons aged ≥60 years who had first applied for the long-term care services in Hong Kong and completed the screening tool (Minimum Data Set-Home Care) in 2006. For each of the five abuse screening items ("fearful of a family member/caregiver," "unexplained injuries/broken bones/burns," "physically restrained," "unusually poor hygiene" and "neglected/abused/mistreated"), we examined its relationship with four types of factors: older person, perpetrator, relationship and environment. The rates of individual abuse screening items ranged from 3.9% for physically restrained to 0.03% for unexplained injures/broken bones/burns. Physically restrained was positively associated with activities of daily living impairments, instrumental activities of daily living impairments, perceived poor health, physically abusive behavior and caregiver mental health. Unusually poor hygiene was positively associated with socially inappropriate behavior and actively resisted care. "Fearful of a family member/caregiver" was positively associated with perceived poor health, conflicting relationship and mental health, and negatively with care activities. Neglected/abused/mistreated was positively associated with age and informal care, and negatively with care activities. We identified a number of associated factors of different abuse screening items among older adults. Our findings could inform healthcare practitioners in identifying those older persons who might be at higher risk of abuse, and provide a knowledge base on which to develop effective preventive measures in the Chinese population. Geriatr Gerontol Int 2017; 17: 150-160.


Mechanism of action of icaritin on uterine corpus endometrial carcinoma based on network pharmacology and experimental evaluation.
Uterine corpus endometrial carcinoma (UCEC) belongs to a group of epithelial malignant tumors. Icaritin is the main active compound of Epimedii Folium. Icaritin has been utilized to induce UCEC cells to death. We wished to identify potential targets for icaritin in the treatment of UCEC, as well as to provide a groundwork for future studies into its pharmacologic mechanism of action. Network pharmacology was employed to conduct investigations on icaritin. Target proteins were chosen from the components of icaritin for UCEC treatment. A protein-protein interaction (PPI) network was established using overlapping genes. Analyses of enrichment of function and signaling pathways were undertaken using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, respectively, to select "hub genes". Finally, experiments were carried out to ascertain the effect of icaritin on endometrial cancer (HEC-1-A) cells. We demonstrated that icaritin has bioactive components and putative targets that are therapeutically important. Icaritin treatment induced sustained activation of the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt pathway) and inhibited growth of HEC-1-A cells. Our data provide a rationale for preclinical and clinical evaluations of icaritin for UCEC therapy.


Multiomics and Machine Learning Accurately Predict Clinical Response to Adalimumab and Etanercept Therapy in Patients With Rheumatoid Arthritis.
To predict response to anti-tumor necrosis factor (anti-TNF) prior to treatment in patients with rheumatoid arthritis (RA), and to comprehensively understand the mechanism of how different RA patients respond differently to anti-TNF treatment. Gene expression and/or DNA methylation profiling on peripheral blood mononuclear cells (PBMCs), monocytes, and CD4+ T cells obtained from 80 RA patients before they began either adalimumab (ADA) or etanercept (ETN) therapy was studied. After 6 months, treatment response was evaluated according to the European League Against Rheumatism criteria for disease response. Differential expression and methylation analyses were performed to identify the response-associated transcription and epigenetic signatures. Using these signatures, machine learning models were built by random forest algorithm to predict response prior to anti-TNF treatment, and were further validated by a follow-up study. Transcription signatures in ADA and ETN responders were divergent in PBMCs, and this phenomenon was reproduced in monocytes and CD4+ T cells. The genes up-regulated in CD4+ T cells from ADA responders were enriched in the TNF signaling pathway, while very few pathways were differential in monocytes. Differentially methylated positions (DMPs) were strongly hypermethylated in responders to ETN but not to ADA. The machine learning models for the prediction of response to ADA and ETN using differential genes reached an overall accuracy of 85.9% and 79%, respectively. The models using DMPs reached an overall accuracy of 84.7% and 88% for ADA and ETN, respectively. A follow-up study validated the high performance of these models. Our findings indicate that machine learning models based on molecular signatures accurately predict response before ADA and ETN treatment, paving the path toward personalized anti-TNF treatment.


Assessing quality of life in young adult cancer survivors: development of the Survivorship-Related Quality of Life scale.
Scientific advances in treatments and outcomes for those diagnosed with cancer in late adolescence and early adulthood depend, in part, on the availability of adequate assessment tools to measure health-related quality of life (HRQOL) for survivors in this age group. Domains especially relevant to late adolescence and young adulthood (LAYA; e.g., education and career, committed romantic relationships, worldview formation) are typically overlooked in studies assessing the impact of cancer, usually more appropriate for middle-aged or older survivors. Current HRQOL measures also tend to assess issues that are salient during or shortly after treatment rather than reflecting life years after treatment. To develop a new measure to better capture the experience of LAYA cancer survivors in longer-term survivorship (the LAYA Survivorship-Related Quality of Life measure, LAYA-SRQL), we completed an extensive measure development process. After a literature review and focus groups with LAYA cancer survivors, we generated items and ran confirmatory factor and reliability analyses using a sample of 292 LAYA cancer survivors. We then examined validity using existing measures of physical and mental health, quality of life, and impact of cancer. The final model consisted of two domains (satisfaction and impact), each consisting of ten factors: existential/spirituality, coping, relationship, dependence, vitality, health care, education/career, fertility, intimacy/sexuality, and cognition/memory. Confirmatory factor analysis and validity analyses indicated that the LAYA-SRQL is a psychometrically sound instrument with good validity. The LAYA-SRQL fills an important need in survivorship research, providing a way to assess HRQOL in LAYAs in a developmentally informed way.


Mitral valve replacement with the Carpentier-Edwards standard bioprosthesis: performance into the second decade.
From March 1978, 196 Carpentier-Edwards standard bioprostheses (stCE) were implanted in 194 patients. There were 154 isolated mitral valve replacements (MVR) and 42 aortic plus mitral valve replacements (AVR/MVR) with a mean follow-up of 7.05 (range 0-15.2) years and 7.15 (range 0-13.8) years, respectively. Freedom from structural valve failure at 10 years was 70.8% +/- 4.9% (MVR) and 59.6% +/- 11.1% (AVR/MVR). The incidence of structural valve failure increased sharply after 7 years. Freedom from thromboembolism was 83.0% +/- 3.8% (MVR) and 89.0 +/- 6.0% (AVR/MVR). Thromboembolic events were related to the presence of atrial fibrillation in patients not receiving anticoagulation. Anticoagulant-related haemorrhage was rare. Freedom from mitral valve prosthetic endocarditis at 10 years was 90.9% +/- 3.1% (MVR) and 86.1% +/- 8.4% (AVR/MVR). Prosthetic valve endocarditis was associated with more than 60% mortality. The probability of event-free survival at 10 years follow-up was 43.6% +/- 4.6% (MVR) and 33.3% +/- 8.6% (AVR/MVR). The performance of the stCE in the mitral position shows a low rate of thromboembolic events and anticoagulant-related haemorrhage, but the long-term performance of the prosthesis is unsatisfactory due to a high rate of structural valve failure. This confirms earlier reports.


Atypical teratoid/rhabdoid tumour: 7-year event-free survival with gross total resection and radiotherapy in a 7-year-old boy.
We report the case of a 7-year-old boy who presented in 1998 a tumour of the left frontal lobe. Initially diagnosed as anaplastic ependymoma, the boy was treated by gross total resection followed by radiotherapy at the operated site. In July 2005, an orbital tumour was discovered and resected. The tumour was composed of sheets of rhabdoid cells which diffusely expressed vimentin and focally epithelial membrane antigen (EMA) and alpha-smooth actin by immunohistochemistry. The first tumour was re-examined. Small foci of rhabdoid cells were found. Immunohistochemistry anti-INI1 performed on both tumours was negative. Molecular techniques performed on frozen specimen of the orbital tumour confirmed the diagnosis of atypical teratoid/rhabdoid tumour (ATRT). We discuss the pathological criteria for diagnosis of ATRT and the usefulness of early radiotherapy in the light of the recent literature.


Peritoneal fluid flow influences anatomical distribution of endometriotic lesions: why Sampson seems to be right.
Endometriosis is a frequent pathology for which the dominant signs and symptoms are pelvic pain and infertility. The physiopathology remains the subject of controversy. Four physiopathological hypotheses have been put forward: regurgitation, metaplasia, induction and (vascular and lymphatic) embolization. The anatomical distribution of endometriotic lesions would appear to be fundamental for a better understanding of Sampson's menstrual regurgitation theory of endometriosis. Analysis of the results in the literature and comparison with our experience clearly shows that the distribution of endometriotic lesions is asymmetrical in several respects. Abdominopelvic anatomy and peritoneal fluid flow can explain this asymmetrical distribution of endometriotic lesions in the great majority of cases. These observations are a very strong argument in favour of the crucial role played by tubal regurgitation and the peritoneal fluid in the physiopathology of endometriosis. The similarity in anatomical distribution of endometriomas, superficial and deeply invasive endometriotic lesions would tend to indicate a common origin for these different types of lesions.


Multicentre cross over study of aminoglutethimide and trilostane in advanced postmenopausal breast cancer.
Trilostane and Aminoglutethimide, each given with a physiological replacement dose of hydrocortisone, were randomly allocated to 72 eligible postmenopausal advanced breast cancer patients; following treatment failure on either drug the patient continued with the other drug, if in a suitable clinical condition. Thirty-eight patients initially received Trilostane of whom 19 subsequently received Aminoglutethimide; 34 patients initially had Aminoglutethimide and seven of these then received Trilostane. Both groups of patients were comparable in all respects. There was no difference in the objective response rate to either drug, Trilostane 11/38 = 29%, Aminoglutethimide 12/34 = 35%, nor in the average time to disease progression for the two drugs, Trilostane 64 weeks, Aminoglutethimide 68 weeks. Of the 26 patients who received both drugs, four showed a response to both suggesting no cross resistance. Side effects were seen to both drugs in approximately half of the patients, but were mainly gastro-intestinal with Trilostane and rash and drowsiness with Aminoglutethimide. There was no evidence of cross over patient susceptibility to side effects.


Alpha-fetoprotein: cellular origin of a biological marker in rat liver under various experimental conditions.
Alpha1-fetoprotein (AFP) was detected by serological, light and electron microscopic methods in various experimental models. These included (a) liver regeneration after partial hepatectomy or CCl4 intoxication (mouse and rat); (b) liver intoxication by high doses of N-nitrosomorpholine (NNM) and chemical induction of hepatomas (rat). AFP levels varied greatly according to the animal species and strains used. Low and high AFP-producing species and strains were distinguished. In liver regeneration after hepatectomy or CCl4 intoxication, cellular AFP was found in the cytoplasm of hepatocytes. In NNM-intoxicated livers, elevated AFP levels were associated with proliferation of canalicular epithelial cells in which AFP was localized. In early stages of hepatocarcinogenesis, significant AFP increase occurred after high-dose carcinogen feeding and AFP was also localized in proliferating canalicular epithelial cells. On low-dose NNM feeding, no cellular AFP was detected unless hepatomas had developed. At the stage of malignant conversion, distinct AFP staining and non-AFP staining hepatocellular carcinomas appeared in livers.


Global research trends in the medical therapy of pulmonary arterial hypertension 2000-2014.
Pulmonary arterial hypertension is a progressive disease of the pulmonary vasculature that affects more than 200.000 patients worldwide. Without medical treatment it leads to right heart failure and death. Extensive fundamental and clinical research has been performed throughout the globe to modify the disease and improve survival. We performed a bibliometric study on medical treatment for pulmonary arterial hypertension to identify study characteristics, impact factors and the countries of origin of basic and clinical studies that were published between 2000 and 2014. For visualization of the obtained data density equalizing maps were prepared. A total of 681 studies were eligible, of these 56% were clinical studies that have included a total of 30960 patients. Most studies were performed on endothelin receptor antagonists, followed by prostacyclins and phosphodiesterase type 5 inhibitors. Impact factors did not differ between clinical and basic science studies. The United States for clinical studies, and China for basic science studies were identified as main contributors to the global scientific output. This first bibliometric study in the field of pulmonary arterial hypertension shows that a significant amount of scientific research was performed within the last 14 years mainly in North America, Asia and Europe. As current trends in this field of research we identified combination therapies and Asian countries being a new hatchery for emerging experimental and clinical studies.


Chemiluminescence Detection of Serine, Proline, Glycine, Asparagine, Leucine, and Histidine by Using Corresponding Aminoacyl-tRNA Synthetases as Recognition Elements.
Analysis of the concentration of free amino acids in biological samples is useful in clinical diagnostics. However, currently available methods are time consuming, potentially delaying diagnosis. Therefore, the development of more rapid analytical tools is needed. In this study, a chemiluminescence detection method for amino acids was developed, and the conditions for the enzyme reaction and assay were examined. For the recognition of each amino acid (here, serine, proline, glycine, asparagine, leucine, and histidine), the corresponding aminoacyl-tRNA synthetase (aaRS) was employed, and multiple enzymatic reactions were combined with a luminol chemiluminescence reaction. This method provided selective quantification from 1 to 20 μM for serine, proline, glycine, and leucine; 1 to 60 μM for asparagine; and 1 to 150 μM for histidine. This assay, which utilized aaRSs for the detection of amino acids, could be useful for simple and rapid analysis of amino acids in clinical diagnostics.


Sequence of chicken ovalbumin mRNA.
The complete sequence of chicken ovalbumin mRNA is presented; it is 1,859 residues long, excluding its terminal 'cap' and poly(A). The region coding for ovalbumin lies close to the 'cap' but is separated from the poly(A) by an extensive 3' noncoding region of 637 nucleotides which may have no function that is precisely dependent on its sequence.


Complement therapeutics; history and current progress.
Complement (C) performs vital roles in immune surveillance, from killing of bacteria to generation of an optimal antibody response. However, the mediators responsible for this protective role can inappropriately target self tissues and cause pathology in many inflammatory diseases, in ischaemia-reperfusion injuries and also as a result of therapeutic intervention, such as in cardiopulmonary bypass. Here we review the history of anti-complement therapeutics and describe the plethora of reagents that have evolved to treat complement-mediated pathologies. These agents range from small compounds, including natural products isolated from plants and synthetic peptides designed to target and inhibit the complement cascade, to large, intricately engineered biological reagents. Recombinant, humanised antibody fragments which inhibit at specific points in the complement cascade have been generated and used successfully in man. Other reagents, mimicking the action of the natural complement regulatory proteins present on the surface of self cells, have also been developed and extensively tested. We discuss the pros and cons of these different reagents and describe recent advances in the field, such as specific targeting of drugs to sites of inflammation, which have opened the door to the use of anti-complement therapy in both acute and chronic inflammatory conditions.


New tricks for old NODs.
Recent work has identified the human NOD-like receptor NLRX1 as a negative regulator of intracellular signaling leading to type I interferon production. Here we discuss these findings and the questions and implications they raise regarding the function of NOD-like receptors in the antiviral response.


The response of the neuronal activity in the somatosensory cortex after high-intensity intermediate-frequency magnetic field exposure to the spinal cord in rats under anesthesia and waking states.
Novel technologies using the intermediate-frequency magnetic field (IF-MF) in living environments are becoming popular with the advance in electricity utilization. However, the biological effects induced by the high-intensity and burst-type IF-MF exposure used in the wireless power transfer technologies for electric vehicles or medical devices, such as the magnetic stimulation techniques, are not well understood. Here, we developed an experimental platform using rats, that combined an 18 kHz, high-intensity (Max. 88 mT), Gaussian-shaped burst IF-MF exposure system with an in vivo extracellular recording system. In this paper, we aimed to report the qualitative differences in stimulus responses in the regions of the somatosensory cortex and peripheral nerve fibers that were induced by the IF-MF exposure to the rat spinal cord. We also report the modulation of the stimulus responses in the somatosensory cortex under anesthesia or waking states. Using this experimental platform, we succeeded in the detection of the motor evoked potentials or the neuronal activity in the somatosensory cortex that was induced by the IF-MF exposure to the spinal cord in rats. Compared to the state of anesthesia, the neuronal activities in the somatosensory cortex was enhanced during the waking state. On the other hand, these neuronal responses could not be confirmed by the IF-MF exposure-related coil sound only. Our experimental results indicated the basic knowledge of the biological responses and excitation mechanisms of the spinal cord stimulation by the IF-MF exposure.


Evolving Role of Novel Quantitative PET Techniques to Detect Radiation-Induced Complications.
Radiation-induced normal tissue toxicities vary in terms of pathophysiologic determinants and timing of disease development, and they are influenced by the dose and radiation volume the critical organs receive, and the radiosensitivity of normal tissues and their baseline rate of cell turnover. Radiation-induced lung injury is dose limiting for the treatment of lung and thoracic cancers and can lead to fibrosis and potentially fatal pneumonitis. This article focuses on pulmonary and cardiovascular complications of radiation therapy and discusses how PET-based novel quantitative techniques can be used to detect these events earlier than current imaging modalities or clinical presentation allow.


Detection of Surgical Site Infection Utilizing Automated Feature Generation in Clinical Notes.
Postsurgical complications (PSCs) are known as a deviation from the normal postsurgical course and categorized by severity and treatment requirements. Surgical site infection (SSI) is one of major PSCs and the most common healthcare-associated infection, resulting in increased length of hospital stay and cost. In this work, we proposed an automated way to generate keyword features using sublanguage analysis with heuristics to detect SSI from cohort in clinical notes and evaluated these keywords with medical experts. To further valid our approach, we also applied different machine learning algorithms on cohort using automatically generated keywords. The results showed that our approach was able to identify SSI keywords from clinical narratives and can be used as a foundation to develop an information extraction system or support search-based natural language processing (NLP) approaches by augmenting search queries.


A novel inducible formaldehyde dehyrogenase of Pseudomonas sp. (RJ1).
A novel, pyridine-nucleotide-independent, inducible formaldehyde dehydrogenase acitivity was detected in cells of Pseudomonas sp. (RJ1) propagated on methylamine and oxalated. The pH optimum of the dehydrogenase was 7.0. Dichlorophenol-indophenol or potassium ferricyanide served as an electron acceptor. The rate of reduction of these electron acceptors was shown to be stimulated by phenazine methosulfate. The dehydrogenase was inhibited by parahydroxymercuric benzoate and iodoacetamide. This inhibition suggests that the enzyme contains sulfhydryl groups. The stoichiometry of the reaction in terms of oxygen uptake to formate formation was 0.5, which agrees with the theoretical value.


Respiratory Effects of Traffic-Related Air Pollution: A Randomized, Crossover Analysis of Lung Function, Airway Metabolome, and Biomarkers of Airway Injury.
Exposure to traffic-related air pollution (TRAP) has been associated with increased risks of respiratory diseases, but the biological mechanisms are not yet fully elucidated. Our aim was to evaluate the respiratory responses and explore potential biological mechanisms of TRAP exposure in a randomized crossover trial. We conducted a randomized crossover trial in 56 healthy adults. Each participant was exposed to high- and low-TRAP exposure sessions by walking in a park and down a road with high traffic volume for 4 h in random order. Respiratory symptoms and lung function, including forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), the ratio of FEV1 to FVC, and maximal mid-expiratory flow (MMEF), were measured before and after each exposure session. Markers of 8-isoprostane, tumor necrosis factor-α (TNF-α), and ezrin in exhaled breath condensate (EBC), and surfactant proteins D (SP-D) in serum were also measured. We used linear mixed-effects models to estimate the associations, adjusted for age, sex, body mass index, meteorological condition, and batch (only for biomarkers). Liquid chromatography-mass spectrometry was used to profile the EBC metabolome. Untargeted metabolome-wide association study (MWAS) analysis and pathway enrichment analysis using mummichog were performed to identify critical metabolomic features and pathways associated with TRAP exposure. Participants had two to three times higher exposure to traffic-related air pollutants except for fine particulate matter while walking along the road compared with in the park. Compared with the low-TRAP exposure at the park, high-TRAP exposure at the road was associated with a higher score of respiratory symptoms [2.615 (95% CI: 0.605, 4.626), p=1.2×10-2] and relatively lower lung function indicators [-0.075L (95% CI: -0.138, -0.012), p=2.1×10-2] for FEV1 and -0.190L/s (95% CI: -0.351, -0.029; p=2.4×10-2) for MMEF]. Exposure to TRAP was significantly associated with changes in some, but not all, biomarkers, particularly with a 0.494-ng/mL (95% CI: 0.297, 0.691; p=9.5×10-6) increase for serum SP-D and a 0.123-ng/mL (95% CI: -0.208, -0.037; p=7.2×10-3) decrease for EBC ezrin. Untargeted MWAS analysis revealed that elevated TRAP exposure was significantly associated with perturbations in 23 and 32 metabolic pathways under positive- and negative-ion modes, respectively. These pathways were most related to inflammatory response, oxidative stress, and energy use metabolism. This study suggests that TRAP exposure might lead to lung function impairment and respiratory symptoms. Possible underlying mechanisms include lung epithelial injury, inflammation, oxidative stress, and energy metabolism disorders. https://doi.org/10.1289/EHP11139.


Differential mesocorticolimbic responses to palatable food in binge eating prone and binge eating resistant female rats.
Binge eating is a key symptom of many eating disorders (e.g. binge eating disorder, bulimia nervosa, anorexia nervosa binge/purge type), yet the neurobiological underpinnings of binge eating are poorly understood. The mesocorticolimbic reward circuit, including the nucleus accumbens and the medial prefrontal cortex, is likely involved because this circuit mediates the hedonic value and incentive salience of palatable foods (PF). Here we tested the hypothesis that higher propensity for binge eating is associated with a heightened response (i.e., Fos induction) of the nucleus accumbens and medial prefrontal cortex to PF, using an animal model that identifies binge eating prone (BEP) and binge eating resistant (BER) rats. Forty adult female Sprague-Dawley rats were given intermittent access to PF (high fat pellets) 3×/week for 3 weeks. Based on a pattern of either consistently high or consistently low PF consumption across these feeding tests, 8 rats met criteria for categorization as BEP, and 11 rats met criteria for categorization as BER. One week after the final feeding test, BEP and BER rats were either exposed to PF in their home cages or were given no PF in their home cages for 1h prior to perfusion, leading to three experimental groups for the Fos analysis: BEPs given PF, BERs given PF, and a No PF control group. The total number of Fos-immunoreactive (Fos-ir) cells in the nucleus accumbens core and shell, and the cingulate, prelimbic, and infralimbic regions of the medial prefrontal cortex was estimated by stereological analysis. PF induced higher Fos expression in the nucleus accumbens shell and core and in the prelimbic and infralimbic cortex of BEP rats compared to No PF controls. Throughout the nucleus accumbens and medial prefrontal cortex, PF induced higher Fos expression in BEP than in BER rats, even after adjusting for differences in PF intake. Differences in the neural activation pattern between BEP and BER rats were more robust in prefrontal cortex than in nucleus accumbens. These data confirm that PF activates brain regions responsible for encoding the incentive salience and hedonic properties of PF, and suggest that binge eating proneness is associated with enhanced responses to PF in brain regions that exert executive control over food reward.


Synthesis of 5,6-dihydro-11H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidine-N-cyanoguanidine derivatives as inhibitors of ras farnesyl protein transferase.
A series of novel N-cyanoguanidine tricyclic farnesyl protein transferase (FPT) inhibitors was prepared. Replacement of a piperidine amide-group with a N-cyanoguanidine functionality increased FPT activity. X-ray crystal structure determination of 42 complexed with FPT revealed differences in the interactions of the amide and N-cyanoguanidine groups with the protein.


Quantitative comparison of excitation modes of tuning forks for shear force in probe microscopy.
This article provides a careful comparison between the electric and mechanical excitation of a tuning fork for shear force feedback in scanning probe microscopy, an analysis not found in present literature. A setup is designed and demonstrated for robust signal and noise measurements at comparable levels of physical movement of the probe. Two different signal amplification methods, combined with two excitation ways provide three possible configurations. For each method a quantitative analysis, supported by analytical elaboration and numerical simulations, is provided. Finally, it is shown that in practical circumstances electric excitation followed by detection with a transimpedance amplifier provides the best result.


Feasibility and application of machine learning enabled fast screening of poly-beta-amino-esters for cartilage therapies.
Despite the large prevalence of diseases affecting cartilage (e.g. knee osteoarthritis affecting 16% of population globally), no curative treatments are available because of the limited capacity of drugs to localise in such tissue caused by low vascularisation and electrostatic repulsion. While an effective delivery system is sought, the only option is using high drug doses that can lead to systemic side effects. We introduced poly-beta-amino-esters (PBAEs) to effectively deliver drugs into cartilage tissues. PBAEs are copolymer of amines and di-acrylates further end-capped with other amine; therefore encompassing a very large research space for the identification of optimal candidates. In order to accelerate the screening of all possible PBAEs, the results of a small pool of polymers (n = 90) were used to train a variety of machine learning (ML) methods using only polymers properties available in public libraries or estimated from the chemical structure. Bagged multivariate adaptive regression splines (MARS) returned the best predictive performance and was used on the remaining (n = 3915) possible PBAEs resulting in the recognition of pivotal features; a further round of screening was carried out on PBAEs (n = 150) with small variations of structure of the main candidates from the first round. The refinements of such characteristics enabled the identification of a leading candidate predicted to improve drug uptake > 20 folds over conventional clinical treatment; this uptake improvement was also experimentally confirmed. This work highlights the potential of ML to accelerate biomaterials development by efficiently extracting information from a limited experimental dataset thus allowing patients to benefit earlier from a new technology and at a lower price. Such roadmap could also be applied for other drug/materials development where optimisation would normally be approached through combinatorial chemistry.


Non-invasive measurement of azygos venous blood flow using magnetic resonance.
Monitoring treatment efficacy in patients with portal venous hypertension has been limited by the difficulty of direct or indirect assessment of portal vein pressure. The majority of currently available haemodynamic tests, such as hepatic vein wedge pressure or azygos vein flow measurement by thermodilution catheter, are invasive which has restricted their application. We describe a non-invasive cine phase contrast magnetic resonance technique for quantitative measurements of bulk volume flow and for demonstrating flow changes during the cardiac cycle in the azygos vein. The technique was used to analyse the azygos vein flow in seven adult volunteers and five patients with biopsy-confirmed chronic liver disease, portal hypertension and endoscopically proven oesophageal varices. In the volunteers the mean volume flow rates varied between 81 and 241 ml/min with a mean for the group of 171 ml/min. The patients had a significantly higher mean volume flow rate of 628 ml/min (p < 0.01), with a range of 339 to 945 ml/min. These preliminary results suggest that cine phase contrast magnetic resonance angiography is a practical non-invasive method for measuring absolute azygos vein flow, and may provide a non-invasive method of monitoring portal hypertension.


Auditory sensitivity, equal loudness, temporal resolving power, and vocalizations in the house finch (Carpodacus mexicanus).
Absolute thresholds for pure tones were measured in four house finches by use of avoidance conditioning and a modified method of limits. Response reaction time to each tone presentation served as a data base for generating a family of "equal loudness" contours. Temporal resolving power was measured in two additional birds and compared with similar measures in man. The results are discussed in relation to previous studies of vocalizations in the house finch, and the average power spectra of selected individual vocalizations are presented.


Alternative medicine remedies might stimulate viability of leukemic cells.
Ex vivo activity of three products of alternative therapy against leukemic and normal cells was analyzed. Extracts of Viscum album, Uncaria tomentosa, and Croton lechleri were used for the study. Leukemic cells of 53 children with acute leukemias and four cell lines, Jurkat, CCRF-CEM, HL-60, and K-562 were tested for sensitivity to alternative medicine remedies by the MTT assay, cell-cycle analysis and annexin-V binding assay. Leukemic cells showed high resistance to tested three compounds of alternative medicine in all performed assays. Additionally, tested remedies stimulated survival of leukemic cells in 45%, 96%, and 83% cases, respectively; while no effect was observed in normal lymphocytes. In combination studies, Viscum album extract did not increase prednisolone and cytarabine cytotoxicity in leukemic cells. We conclude that some alternative medicine remedies might stimulate the viability of childhood leukemic cells.


Optimization of physical schemes in WRF model on cyclone simulations over Bay of Bengal using one-way ANOVA and Tukey's test.
Evaluation of appropriate physics parameterization schemes for the Weather Research and Forecasting (WRF) model is vital for accurately forecasting tropical cyclones. Three cyclones Nargis, Titli and Fani have been chosen to investigate the combination of five cloud microphysics (MP), three cumulus convection (CC), and two planetary boundary layer (PBL) schemes of the WRF model (ver. 4.0) with ARW core with respect to track and intensity to determine an optimal combination of these physical schemes. The initial and boundary conditions for sensitivity experiments are drawn from the National Centers for Environmental Prediction (NCEP) global forecasting system (GFS) data. Simulated track and intensity of three cyclonic cases are compared with the India Meteorological Department (IMD) observations. One-way analysis of variance (ANOVA) is applied to check the significance of the data obtained from the model. Further, Tukey's test is applied for post-hoc analysis in order to identify the cluster of treatments close to IMD observations for all three cyclones. Results are obtained through the statistical analysis; average root means square error (RMSE) of intensity throughout the cyclone period and time error at landfall with the step-by-step elimination method. Through the elimination method, the optimal scheme combination is obtained. The YSU planetary boundary layer with Kain-Fritsch cumulus convection and Ferrier microphysics scheme combination is identified as an optimal combination in this study for the forecasting of tropical cyclones over the Bay of Bengal.


Development of white spot lesions during orthodontic treatment: perceptions of patients, parents, orthodontists, and general dentists.
Despite the many advances to improve the practice of orthodontics, white spot lesions, or decalcifications, remain a common complication in patients with poor oral hygiene. The purpose of this study was to assess the perceptions and level of awareness of patients, parents, orthodontists, and general dentists toward the development of white spot lesions during orthodontic treatment. This was a prospective epidemiologic survey of the perceptions of orthodontic patients (n = 315), parents (n = 279), orthodontists (n = 305), and general dentists (n = 191) regarding the significance, prevention, and treatment of white spot lesions. All surveyed groups indicated that white spot lesions detracted from the overall appearance of straight teeth, attributed primary responsibility for the prevention of white spot lesions to the patients themselves, and thought that the general dentist should be responsible for treating white spot lesions. Patients regarded themselves as ultimately responsible for the prevention of white spot lesions (P <0.05). The patients, parents, orthodontists, and general dentists had similar perceptions regarding the significance, prevention, and treatment of white spot lesions. All groups indicated that patients were the most responsible for the prevention of white spot lesions. Communication among patients, parents, orthodontists, and general dentists needs to improve to decrease the incidence of white spot lesions in the orthodontic population.


Management of esophageal perforations in infants by endoscopic vacuum therapy: a single center case series.
Endoscopic vacuum therapy (EVT) has become a standard treatment method for esophageal perforations in adults. However, experience with EVT in infants is scarce. In this retrospective case series, we report on four very young infants who were successfully treated with EVT for esophageal perforations of different etiology. Four infants were diagnosed with esophageal perforations on day 7, 32, 35 and 159 of life, respectively. The youngest one was prematurely born in the 31st week of pregnancy weighing 980 g only. Three infants had perforations due to foreign body insertion (nasogastric tube or pulling through of percutaneous endoscopic gastrostomy (PEG) tube through the esophagus). One child had an anastomotic dehiscence after Foker's surgery for atresia. In three children EVT was applied as first-line therapy for perforation, in one child EVT was a rescue therapy due to persisting leakage after surgical closure involving thoracotomy. Depending on the esophageal diameter, either an open-pore drainage film or polyurethane sponge was attached to a single-lumen 8 Fr suction catheter, endoscopically (or fluoroscopically by wire-guidance) placed into the esophagus (intraluminal EVT) and supplied with continuous negative pressure (ranging between 75 and 150 mmHg). The EVT system was exchanged twice per week. Complete closure of the perforation/leakage could be achieved in all four infants (100%) after 22 days of continuous EVT (median value; range 7-39) and 4.5 EVT exchanges (median value; range 1-12). No serious adverse events occurred. EVT is an effective and safe addition to our therapeutic armamentarium in the management of esophageal perforations irrespective of its etiology. Here we prove the feasibility of EVT even in very young infants. The use of an extra thin vacuum open-pore drainage film is helpful to cope with the small esophageal diameter. EVT settings and exchange rates similar to those known from adult treatment were used.


Fractures of the femoral head: a long-term follow-up study.
The femoral head fracture has become an increasingly frequent injury, usually sustained by individuals during high-energy trauma. Regardless of the type of treatment, long-term consequences, as avascular necrosis, post-traumatic arthritis, and heterotopic ossification, may complicate the clinical outcome leading to variable degree of disability. The aim of this study was to review the clinical and radiological long-term follow-up of patients with a fracture of the femoral head. Between January 1985 and January 2002, twenty-one patients with mean age 42.0 ± 15.9 years (range, 21-70 years) with a fracture of the femoral head were evaluated retrospectively. According to Pipkin's classification, there were four type I, nine type II, and eight type IV fractures. Functional outcomes were measured using the Merle d'Aubigné-Postel and Thompson-Epstein scoring scale. Heterotopic calcifications was graded according to the Brooker classification. All patients were followed up from 12 to 210 months, with an average of 81.19 ± 37.4 months. The average Merle d'Aubigné-Postel score was 12.9 ± 4.5. According to the Thompson-Epstein criteria, eight patients had excellent results, eight patients good, two patients fair, and three patients poor results. Overall, almost all (95. 2%) patients were determined to have radiographic criteria of post-traumatic arthritis (PA). Ten patients (47.6%) had a mild PA, seven patients (33.3%) had a moderate PA, and three patients (14.2%) had a severe PA. Open reduction and internal fixation of the fragments provided better results in comparison to excision. Although degenerative changes of the hip were observed in almost all patients, most severe case occurred in the excision group.


[Assessment of superficial contamination of bovine and ovine carcasses from the municipal slaughterhouse of Constantine in Algeria].
The neck, shoulder, flank, and thigh of 36 bovine and 30 ovine carcasses were swabbed for bacteriological analyses. The greatest microbial load was found on the neck. The site averages for the flora analyzed indicated that the levels of contamination were greater than those in similar studies in France, Morocco, and Tunisia.


Sleep-wake characterization of double MT₁/MT₂ receptor knockout mice and comparison with MT₁ and MT₂ receptor knockout mice.
The neurohormone melatonin activates two G-protein coupled receptors, MT1 and MT2. Melatonin is implicated in circadian rhythms and sleep regulation, but the role of its receptors remains to be defined. We have therefore characterized the spontaneous vigilance states in wild-type (WT) mice and in three different types of transgenic mice: mice with genetic inactivation of MT1 (MT1(-/-)), MT2 (MT2(-/-)) and both MT1/MT2 (MT1(-/-)/MT2(-/-)) receptors. Electroencephalographic (EEG) and electromyographic sleep-wake patterns were recorded across the 24-h light-dark cycle. MT1(-/-)mice displayed a decrease (-37.3%) of the 24-h rapid eye movement sleep (REMS) time whereas MT2(-/-)mice showed a decrease (-17.3%) of the 24-h non rapid eye movement sleep (NREMS) time and an increase in wakefulness time (14.8%). These differences were the result of changes occurring in particular during the light/inactive phase. Surprisingly, MT1(-/-)/MT2(-/-) mice showed only an increase (8.9%) of the time spent awake during the 24-h. These changes were correlated to a decrease of the REMS EEG theta power in MT1(-/-)mice, of the NREMS EEG delta power in MT2(-/-)mice, and an increase of the REMS and wakefulness EEG theta power in MT1(-/-)/MT2(-/-) mice. Our results show that the genetic inactivation of both MT1 and MT2 receptors produces an increase of wakefulness, likely as a result of reduced NREMS due to the lack of MT2 receptors, and reduced REMS induced by the lack of MT1 receptors. Therefore, each melatonin receptor subtype differently regulates the vigilance states: MT2 receptors mainly NREMS, whereas MT1 receptors REMS.


γδ T cells in cancer.
With the promise of T cell-based therapy for cancer finally becoming reality, this Review focuses on the less-studied γδ T cell lineage and its diverse responses to tumours. γδ T cells have well-established protective roles in cancer, largely on the basis of their potent cytotoxicity and interferon-γ production. Besides this, recent studies have revealed a series of tumour-promoting functions that are linked to interleukin-17-producing γδ T cells. Here, we integrate the current knowledge from both human and mouse studies to highlight the potential of γδ T cell modulation to improve cancer immunotherapy.


PP-O and PP-V, Monascus pigment homologues, production, and phylogenetic analysis in Penicillium purpurogenum.
The production of pigments as secondary metabolites by microbes is known to vary by species and by physiological conditions within a single strain. The fungus strain Penicillium purpurogenum IAM15392 has been found to produce violet pigment (PP-V) and orange pigment (PP-O),Monascus azaphilone pigment homologues, when grown under specific culture conditions. In this study, we analysed PP-V and PP-O production capability in seven strains of P. purpurogenum in addition to strain IAM15392 under specific culture conditions. The pigment production pattern of five strains cultivated in PP-V production medium was similar to that of strain IAM15392, and all violet pigments produced by these five strains were confirmed to be PP-V. Strains that did not produce pigment were also identified. In addition, two strains cultivated in PP-O production medium produced a violet pigment identified as PP-V. The ribosomal DNA (rDNA) internal transcribed spacer (ITS) region sequences from the eight P. purpurogenum strains were sequenced and used to construct a neighbor-joining phylogenetic tree. PP-O and PP-V production of P. purpurogenum was shown to be related to phylogenetic placement based on rDNA ITS sequence. Based on these results, two hypotheses for the alteration of pigment production of P. purpurogenum in evolution were proposed.


Gender Differences in the Link Between Marital Quality and Cognitive Decline Among Older Adults in Korea.
This study aimed to investigate the association between positive marital quality and cognitive health over time and to examine gender differences in this association. Drawing on 2006-2018 Korean Longitudinal Study of Aging data (n=7,427 respondents, 35,066 person-year observations), a series of hybrid mixed-effects models were used to estimate the effects of time-invariant (gender) and time-variant (marital quality) variables on within-person changes and on between-person differences in cognitive decline over the observation period. The results showed that individuals' likelihood of having higher cognitive health grew when their spousal relationship became more positive and that, compared with those with lower levels of marital quality, people with higher levels of marital quality were more likely to have higher cognitive health. Interestingly, improvements in marital quality were more beneficial for men than for women, whereas level of marital quality had similar effects on men's and women's cognitive health. Couple-based intervention programs aiming to improve marital quality should be encouraged, especially among older adults.


Relationship between the evaporation rate and vapor pressure of moderately and highly volatile chemicals.
Volatilization of chemicals can be an important form of dissipation in the environment. Rates of evaporative losses from plant and soil surfaces are useful for estimating the potential for food-related dietary residues and operator and bystander exposure, and can be used as source functions for screening models that predict off-site movement of volatile materials. A regression of evaporation on vapor pressure from three datasets containing 82 pesticidal active ingredients and co-formulants, ranging in vapor pressure from 0.0001 to >30,000 Pa was developed for this purpose with a regression correlation coefficient of 0.98.


Typing of SHV extended-spectrum beta-lactamases by pyrosequencing in Klebsiella pneumoniae strains with chromosomal SHV beta-lactamase.
In Klebsiella pneumoniae, the cooccurrence of chromosomal and plasmid-mediated beta-lactamases can hinder their accurate molecular detection. We developed a fast and reliable method that allows the typing of isolates carrying more than one SHV gene. The method is based on pyrosequencing the DNA sequence corresponding to amino acid positions 35, 238, and 240.


Internal neurolysis or ligament division only in carpal tunnel syndrome. II. A 3 year follow-up with an evaluation of various neurophysiological parameters for diagnosis.
48 patients with clinical and neurophysiological signs of carpal tunnel syndrome were randomized to any of two operative methods: Internal neurolysis of the median nerve with a microsurgical technique, or simple division of the carpal ligament (flexor retinaculum). After a minimum follow-up period of 3 years 81% of the patients did not report any complaints at all, and all patients considered themselves improved after operation. There was no difference between the operation groups. Therefore there seems to be no justification to perform the more difficult procedure of internal microsurgical neurolysis for treatment of the carpal tunnel syndrome. A study of the neurophysiological parameters before and after restitution showed the highest sensitivity (91%) for the sensory conduction velocity, and the highest specificity for motor distal latency and sensory distal latency (83 and 75% resp.).


Field response of Mediterranean fruit fly (Diptera: Tephritidae) to ceralure B1: evaluations of enantiomeric B1 ratios on fly captures.
(-)-Ceralure B1 (ethyl-cis-5-iodo-trans-2-methylcyclohexane-1-carboxylate), a male attractant for the Mediterranean fruit fly, Ceratitis capitata (Wiedemann), is significantly more attractive than trimedlure (tert-butyl esters of 4(5)-chloro-2-methylcyclohexane-1-carboxylate), the current standard male attractant used in detection programs. This article reports studies that compare the effectiveness of racemic ceralure B1, mixtures of racemic ceralure B1 and pure (-)-ceralure B1, and trimedlure in field tests conducted in Hawaii, Africa, and Spain with wild Mediterranean fruit flies and in Florida with sterile released Mediterranean fruit fly. Trapping results showed that doses of (-)-ceralure B1 of 87.5 and 75% are just as effective as the 98% (-)-ceralure B1 and the racemic form to be almost as attractive. In nearly all studies, the racemic ceralure B1 was significantly better than trimedlure. These studies suggest that the racemic ceralure B1 could be a viable replacement for trimedlure in areawide detection programs for Mediterranean fruit fly. Synthesizing racemic ceralure B1 instead of a specific stereoselective enantiomer of ceralure B1 would likely be more cost-effective to produce and also might be useful in control as well as detection of this pest.


Endothelial cells promote metastasis of prostate cancer by enhancing autophagy.
Prostate cancer is one of the most common malignancies. Increasing evidence suggested that endothelial cells may contribute to prostate cancer progression and metastasis. Most recently, autophagy has been proposed to plays a significant role in tumorigenesis and metastasis. Also, it is reported that downregulation of androgen receptor (AR) induces autophagy in prostate cancer cells. However, the underlying mechanisms remain unclear. Here, we aim to explore the role and mechanisms of endothelial cell in prostate cancer progression. The coculture system was established to test the effect of endothelial cells on prostate cancer cells. We performed antibody array and ELISA were used to profile the cytokine expression pattern of endothelial cells in supernatant. Western blot and RT-PCR were used to determine the mechanism by endothelial cells to promote invasion ability of prostate cancer cells. Maraviroc and chloroquine were used to block the CCL5/CCR5 and autophagy pathway respectively. Orthotopic xenograft mouse models and drug treatment study were conducted to determine the role of endothelial cells in promoting metastatic potential in vivo. We use CPRC prostate cancer model and demonstrate that endothelial cells secrete large amount of CCL5 and induces autophagy by suppressing AR expression in prostate cancer cell lines. Consequently, elevated autophagy accelerates focal adhesions proteins disassembly and promoted prostate cancer invasion. Inhibition of both CCL5/CCR5 signaling and autophagy significantly reduces metastasis in vivo. Together, our data establish the function for endothelial cells in tumor metastasis and propose new drug target for mCRPC.


[Endovascular aneurysm therapy--long-term treatment outcomes after 7 years].
Stentgrafts for endovascular treatment of abdominal aortic aneurysms (AAA) have been commercially available since 1994, with now large numbers of implantations all over the world. From 1994-2001, 115 patients were treated with Stentor, Vanguard and Talent stentgrafts in our institution. Late complications of the first- and second-generation stentgrafts as radiologic or surgical interventions to maintain complete exclusion of the aneurysm amounted to 30% with an additional 22% for observed endoleaks and configuration changes of the stentgraft. Third-generation stentgrafts had a lower complication rate of 12.2% for interventions and 18.3% for late endoleaks and graft changes. High costs of the devices, a pretty high late complication rate, and the uncertain maintenance of stentgraft function to prevent aneurysm rupture currently limit the widespread application of this new technology, leaving conventional aneurysmectomy the standard for aneurysm treatment and reserving the endovascular method for selected patients.


Potential use of chitosan nanoparticles for oral delivery of DNA vaccine in Asian sea bass (Lates calcarifer) to protect from Vibrio (Listonella) anguillarum.
In recent years, attention has been focused on the possibility of utilizing DNA vaccines in fish aquaculture. A successful regime for intramuscular injection of naked DNA into fish has been developed and novel methods to deliver this DNA to fish are under investigation. The potential of chitosan as a polycationic gene carrier for oral administration has been explored since 1990s. The present study examines the potential efficacy of DNA vaccine against Vibrio anguillarum through oral route using chitosan nanoparticles encapsulation. The porin gene of V. anguillarum was used to construct DNA vaccine using pcDNA 3.1, a eukaryotic expression vector and the construct was named as pVAOMP38. The chitosan nanoparticles were used to deliver the constructed plasmid. In vitro and in vivo expression of porin gene was observed in sea bass kidney cell line (SISK) and in fish, respectively by fluorescent microscopy. The cytotoxicity of chitosan encapsulated DNA vaccine construct was analyzed by MTT assay and it was found that the cytotoxicity of pVAOMP38/chitosan was quite low. Distribution of gene in different tissues was studied in fish fed with the DNA (pVAOMP38) encapsulated in chitosan by using immunohistochemistry. The results indicate that DNA vaccine can be easily delivered into fish by feeding with chitosan nanoparticles. After oral vaccination Asian sea bass were challenged with Vibrio anguillarum by intramuscular injection. A relative percent survival (RPS) rate of 46% was recorded. The results indicate that Sea bass (Lates calcarifer) orally vaccinated with chitosan-DNA (pVAOMP38) complex showed moderate protection against experimental V. anguillarum infection.


Clinical diagnosis of carpal tunnel syndrome: old tests-new concepts.
The diagnosis of carpal tunnel syndrome (CTS) continues to be neurophysiologically and clinically controversial. Earlier data concluding that the higher prevalence of persons with symptoms suggestive of CTS but without evidence of median mononeuropathy highlights the need for a better understanding of the underlying pathophysiology and natural history of CTS to provide a less empirical foundation for diagnosis and clinical management. To examine the relationship between the clinical manifestations of CTS with the outcome of the diagnostic tools (nerve conduction tests and ultrasonography), and its implication for clinical practice. Two-hundred and thirty-two patients (69 male and 163 female, ages ranging between 20 and 91 years) with CTS manifestations and 182 controls were included in this study. Diagnosis of CTS was based on the American Academy of Neurology clinical diagnostic criteria. All patients and controls completed a patient oriented questionnaire, were subjected to clinical testing for provocative tests for carpal tunnel syndrome (Tinel's, Phalen's, Reverse Phalen's and carpal tunnel compression tests), blood check for secondary causes of carpal tunnel syndrome, nerve conduction testing as well ultrasonographic assessment of the carpal tunnel and median nerve. One-hundred and seventy-seven out of 232 (76.3%) had abnormal nerve conduction studies. Forearm symptoms and tenosynovitis confirmed by US examination were found in 51.3% of cases. No significant difference was found on comparing anthropometric measures in the affected hands to the control group hands. A higher prevalence of positive Phalen's and CT compression were found in patients suffering from tenosynovitis regardless of their nerve conduction study results. Sensitivity of Tinel's, Phalen's, Reverse Phalen's and carpal tunnel compression tests was higher for the diagnosis of tenosynovitis than for the diagnosis of CTS (Tinel, 46% vs. 30%; Phalen's, 92% vs. 47%; Reverse Phalen's, 75% vs. 42%; carpal tunnel compression test, 95% vs. 46%). Similarly, higher specificity of these tests was found with tenosynovitis than CTS. The results of this study revealed that Tinel's, Phalen's, Reverse Phalen's and carpal tunnel compression tests are more sensitive, as well as being specific tests for the diagnosis of tenosynovitis of the flexor muscles of the hand, rather than being specific tests for carpal tunnel syndrome and can be used as an indicator for medical management of the condition.


Uridine kinase activity in human tumors.
The activity of uridine kinase, a key enzyme in the salvage pathway for pyrimidine bases and nucleosides and for the activation of the corresponding chemotherapeutic analogs, varied 10-fold in a series of human colon adenosarcomas; similar variations were observed with other tumor types. In contrast to the leukemias where only the adult isozyme appears to be present, both the adult and embryonic forms were present in the solid tumors examined. The qualitative and quantitative differences may account, in part, for differences in the innate (initial) sensitivity of the tumors to pyrimidine base and nucleoside analogs.


Adjunctive use of ezogabine/retigabine with either traditional sodium channel blocking antiepileptic drugs (AEDs) or AEDs with other mechanisms of action: Evaluation of efficacy and tolerability.
Integrated data from three double-blind, randomized, placebo-controlled trials were analyzed to evaluate the efficacy and tolerability of ezogabine (EZG; US adopted name)/retigabine (RTG; international non-proprietary name) when used in combination with ≥1 sodium channel blocking antiepileptic drug (AED), ≥1 non-sodium channel blocking AED, or ≥1 AED from both the sodium channel and non-sodium channel mechanistic groups. Efficacy and tolerability appeared to be similar across all three groups of patients.


The origin of genetic information: viruses as models.
A living entity can be described as a complex adaptive system which differs from any, however complex, chemical structure by its capability of functional self-organization based on the processing of information. If one asks, where does this information come from and what is its primary semantics, the answer is: information generates itself in feedback loops via replication and selection, the objective being 'to be or not to be'. This paper describes the theoretical framework of information-generating systems and provides experimental clues for some basic forms of genetic organization, such as molecular quasi-species, hypercyclic and compartmentalized RNA-protein assemblies. The results are primarily obtained with RNA viruses and virus-like systems. The experiments are carried out with the help of automated, computer-controlled bioreactors, called 'evolution machines', that may form the basis of a new 'evolutionary biotechnology'.


Lethal intoxication with diphenhydramine. Report of a case with analytical follow-up.
A fatal monointoxication with diphenhydramine in a male 28 year old is reported. The patient went into hyperpyrexia and tachycardia and died from sudden cardiac arrest. Hemorrhagic pulmonary edema and renal shock were the most prominent pathomorphological findings. At the time of death, the concentration of diphenhydramine was 5 mg/l plasma and was particularly high in the lungs (55 mg/kg) and kidneys (50 mg/kg).


Colony stimulating factors (CSF) biosimilars. Progress?
Biosimilars are equivalent drugs for other biotechnological drugs for which patent has expired. These biopharmaceuticals are often looked upon as simple copies of parent drugs whose goal is solely to potentially generate costs savings. The expansion of available drugs is a subject of attention, criticism and quarrels, often related to a lack of product knowledge. These drugs are copies but need scientific development that must meet many strict rules. Many questions arise in connection with the marketing of several biosimilar drugs in the field of hematopoietic growth factors of white and red cells. Many of them should be discussed.


Urine myo-inositol as a novel prognostic biomarker for diabetic kidney disease: a targeted metabolomics study using nuclear magnetic resonance.
As a leading cause of chronic kidney disease, clinical demand for noninvasive biomarkers of diabetic kidney disease (DKD) beyond proteinuria is increasing. Metabolomics is a popular method to identify mechanisms and biomarkers. We investigated urinary targeted metabolomics in DKD patients. We conducted a targeted metabolomics study of 26 urinary metabolites in consecutive patients with DKD stage 1 to 5 (n = 208) and healthy controls (n = 26). The relationships between estimated glomerular filtration rate (eGFR) or urine protein-creatinine ratio (UPCR) and metabolites were evaluated. Multivariate Cox analysis was used to estimate relationships between urinary metabolites and the target outcome, end-stage renal disease (ESRD). C statistics and time-dependent receiver operating characteristics (ROC) were used to assess diagnostic validity. During a median 4.5 years of follow-up, 103 patients (44.0%) progressed to ESRD and 65 (27.8%) died. The median fold changes of nine metabolites belonged to monosaccharide and tricarboxylic acid (TCA) cycle metabolites tended to increase with DKD stage. Myo-inositol, choline, and citrates were correlated with eGFR and choline, while mannose and myo-inositol were correlated with UPCR. Elevated urinary monosaccharide and TCA cycle metabolites showed associations with increased morality and ESRD progression. The predictive power of ESRD progression was high, in the order of choline, myo-inositol, and citrate. Although urinary metabolites alone were less predictive than serum creatinine or UPCR, myo-inositol had additive effect with serum creatinine and UPCR. In time-dependent ROC, myo-inositol was more predictive than UPCR of 1-year ESRD progression prediction. Myo-inositol can be used as an additive biomarker of ESRD progression in DKD.


Development and application of an online learning platform for nursing ethics: A teaching practice research.
It is crucial to diversify the methods for clinical nurses to continue learning nursing ethics in that ethical decision-making ability in nursing is regarded as one of the core competencies in nursing practice. In response to nurses' learning needs for nursing ethics, this study built an online learning platform for the pertinent topic, and tested its effect on improving nurses' ethical decision-making ability and critical thinking ability. A qualitative method was adopted to develop interventions, which were designed as a teaching practice research consisting of a study group and a control group. A total of 93 nurses, including 20 interviewees and 30 in the study group and 43 in the control group. Qualitative methods were employed to understand the learning needs of nurses. The judgment about nursing decisions and the critical thinking disposition inventory, learning effectiveness questionnaire and learning software quality evaluation scale were used as research tools in this teaching practice research. The SPSS 25.0 was adopted to analyze data by paired sample t-test and independent sample t-test. In the measurement of the judgment about nursing decisions scale, the study group scored higher than the control group. The critical thinking disposition inventory scale identified a similar result in the total score incorporating the four dimensions, including analyticity, systematicity, critical thinking self-confidence, inquisitiveness. There is a correlation between learning software quality and learning effect, with a correlation coefficient of 0.640. The online learning platform of nursing ethics built in this study has positive learning effects, and it demonstrates effectiveness to improve nurses' abilities in nursing ethics, decision-making and critical thinking. It is expected to be a viable way to improve the continuity of nurses' study of ethics.


S-type mammalian lectins in allergic inflammation.
Our understanding of the mechanisms of allergic disease is continuously influenced by new developments in the bio-medical sciences. The studies of glycoconjugates and animal lectins have emerged as an exciting new frontier. One family of animal lectins, soluble lactose-binding lectins, has been studied extensively by a number of laboratories. Evidence is mounting that members of this family of lectins exist in the extracellular space and may be capable of affecting functions of various cells. In this article Fu-Tong Liu presents a revised view of allergic inflammation with emphasis on the modulatory effect of soluble lectins on mast-cell function.


Treatment for Vitamin D Deficiency Prior to Bariatric Surgery: a Prospective Cohort Study.
Since obesity increases vitamin D deficiency (VDD) risk, bariatric surgery candidates are high-risk. Previously, we documented 71.4% VDD at our center. To investigate diagnosis and treatment for VDD in our bariatric candidates. 25(OH)D, if pending, and supplementation (form, dosing, frequency) were prospectively documented in 265 candidates. Candidates were 83.0% female, 48.9% white, age 43 ± 13 years and BMI 46.3 ± 10.5 kg/m(2). 25(OH)D was available for 18.5%: 35.7% VDD 39.3% insufficiency. VDD history did not differ by demographics or procedure, as with those tested versus not. VDD testing was lower than clinically-indicated. Of those tested, 35.7% were deficient and 39.3% insufficient. We previously reported higher rates: 71.4% deficiency, 92.9% insufficiency. Thus, many candidates are untested but high-risk.


Raloxifene prevents stress granule dissolution, impairs translational control and promotes cell death during hypoxia in glioblastoma cells.
Glioblastoma (GBM) is the most common primary malignant brain tumor, and it has a uniformly poor prognosis. Hypoxia is a feature of the GBM microenvironment, and previous work has shown that cancer cells residing in hypoxic regions resist treatment. Hypoxia can trigger the formation of stress granules (SGs), sites of mRNA triage that promote cell survival. A screen of 1120 FDA-approved drugs identified 129 candidates that delayed the dissolution of hypoxia-induced SGs following a return to normoxia. Amongst these candidates, the selective estrogen receptor modulator (SERM) raloxifene delayed SG dissolution in a dose-dependent manner. SG dissolution typically occurs by 15 min post-hypoxia, however pre-treatment of immortalized U251 and U3024 primary GBM cells with raloxifene prevented SG dissolution for up to 2 h. During this raloxifene-induced delay in SG dissolution, translational silencing was sustained, eIF2α remained phosphorylated and mTOR remained inactive. Despite its well-described role as a SERM, raloxifene-mediated delay in SG dissolution was unaffected by co-administration of β-estradiol, nor did β-estradiol alone have any effect on SGs. Importantly, the combination of raloxifene and hypoxia resulted in increased numbers of late apoptotic/necrotic cells. Raloxifene and hypoxia also demonstrated a block in late autophagy similar to the known autophagy inhibitor chloroquine (CQ). Genetic disruption of the SG-nucleating proteins G3BP1 and G3BP2 revealed that G3BP1 is required to sustain the raloxifene-mediated delay in SG dissolution. Together, these findings indicate that modulating the stress response can be used to exploit the hypoxic niche of GBM tumors, causing cell death by disrupting pro-survival stress responses and control of protein synthesis.


Apoptosis and keratin intermediate filaments.
Intermediate filament (IF) proteins utilize central alpha-helical domains to generate polymeric fibers intermediate in size between actin microfilaments and microtubules. The regions flanking the central structural domains have diverged greatly to permit IF proteins to adopt specialized functions. Keratins represent the largest two groups of IF proteins. Most keratins serve structural functions in hair or epidermis. Intracellular epidermal keratins also provide strength to epithelial sheets. The intracellular type I keratins and other IF proteins are cleaved by caspases during apoptosis to ensure the disposal of the relatively insoluble cellular components. However, recent studies have also revealed an unexpected protective role for keratin 8 during TNF and Fas mediated apoptosis. Evidence for possible functions of keratins both upstream and downstream of apoptotic signaling are considered.


Cysteine conjugate beta-lyase of rat kidney cytosol: characterization, immunocytochemical localization, and correlation with hexachlorobutadiene nephrotoxicity.
Cysteine conjugate beta-lyase (beta-lyase) was purified to electrophoretic homogeneity from the kidney cytosol of male Wistar rats. The highly purified enzyme exhibited a monomeric molecular weight of 50,000 Da and was active in the alpha-beta elimination of cysteine conjugates including S-(1,2-dichlorovinyl)-L-cysteine (DCVC), S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC), and S-(2-benzothiazolyl)-L-cysteine, particularly toward DCVC and TFEC. The purified enzyme also exhibited glutamine transaminase K activity with phenylalanine and alpha-keto-gamma-methiolbutyrate as substrates. An antibody was raised to the purified rat protein in sheep and the crude immune serum affinity purified, yielding a specific antibody that recognized only the beta-lyase protein in whole kidney homogenates. Immunocytochemical studies on rat kidney sections stained with the purified antibody revealed that the cytosolic beta-lyase enzyme was mainly localized in the pars recta of the proximal tubule in untreated rats. This localization is coincident with the site-specific kidney necrosis produced by hexachloro-1,3-butadiene (HCBD). These results indicate that the tissue localization of beta-lyase in the proximal tubule plays an important role in determining the specific nephrotoxicity produced by halogenated alkenes such as HCBD.


Cyclic tensile force stimulates BMP9 synthesis and in vitro mineralization by human periodontal ligament cells.
Periodontal ligament (PDL) cells are mechanosensitive and have the potential to differentiate into osteoblast-like cells under the influence of cyclic tensile force (CTF). CTF modulates the expression of regulatory proteins including bone morphogenetic proteins (BMPs), which are essential for the homeostasis of the periodontium. Among the BMPs, BMP9 is one of the most potent osteogenic BMPs. It is yet unknown whether CTF affects the expression of BMP9 and mineralization. Here, we demonstrated that continuously applied CTF for only the first 6 hr stimulated the synthesis of BMP9 and induced mineral deposition within 14 days by human PDL cells. Stimulation of BMP9 expression depended on ATP and P2Y 1 receptors. Apyrase, an ecto-ATPase, inhibited CTF-mediated ATP-induced BMP9 expression. The addition of ATP increased the expression of BMP9. Loss of function experiments using suramin (a broad-spectrum P2Y antagonist), MRS2179 (a specific P2Y 1 receptor antagonist), MRS 2365 (a specific P2Y 1 agonist), U-73122 (a phospholipase C [PLC] inhibitor), and thapsigargin (enhancer of intracytosolic calcium) revealed the participation of P2Y 1 in regulating the expression of BMP9. This was mediated by an increased level of intracellular Ca 2+ through the PLC pathway. A neutralizing anti-BMP9 antibody decreased mineral deposition, which was stimulated by CTF for almost 45% indicating a role of BMP9 in an in vitro mineralization. Collectively, our findings suggest an essential modulatory role of CTF in the homeostasis and regeneration of the periodontium.


Vitronectin mitigates stroke-increased neurogenesis only in female mice and through FAK-regulated IL-6.
Vitronectin (VTN) is a blood protein produced mainly by the liver. We show that VTN leaks from the bloodstream into the injury site and neighboring subventricular zone (SVZ) following ischemic stroke (middle cerebral artery occlusion, MCAO) in adult mice. MCAO is known to increase neurogenesis after stroke. VTN inhibits this response in females, but not in males, as shown by ~70% more stroke-induced SVZ neurogenesis in female VTN-/- mice at 14 d. In female VTN-/- mice, stroke-induced expression of interleukin-6 (IL-6) at 24 h was reduced in the SVZ. The closely related leukemia inhibitory factor (LIF) or pro-neurogenic ciliary neurotrophic factor (CNTF) were not affected. The female-specific effect of VTN on IL-6 expression was not due to sex hormones, as shown by ovariectomy and castration. IL-6 injection next to the SVZ reversed the MCAO-induced increase in neurogenesis seen in VTN-/- mice. Our in vitro and vivo data suggest that plasma VTN activates focal adhesion kinase (FAK) in the SVZ following MCAO, which reduces IL-6 expression in astrocytes but increases it in other cells such as microglia/macrophages. Inducible conditional astrocytic FAK deletion increased MCAO-induced IL-6 expression in females at 24 h and blocked MCAO-induced neurogenesis at 14 d, confirming a key detrimental role of IL-6. Collectively, these data suggest that leakage of VTN into the SVZ reduces the neurogenic response to stroke in female mice by promoting IL-6 expression. Reducing VTN or VTN signaling may be an approach to promote neurogenesis for neuroprotection and cell replacement after stroke in females.


Synchronous triple primary cancers of the pharynx and esophagus.
A 72-year-old male with nausea and heartburn was found to have early pharyngeal squamous cell carcinoma, superficial and advanced esophageal squamous cell carcinoma and early esophageal adenocarcinoma by esophagogastroduodenoscopy. Computerized tomography demonstrated left cardiac lymph node swellings. We prioritized the treatment for esophageal squamous cell carcinoma, as this was the most advanced cancer among the triple primaries. The patient underwent neoadjuvant chemotherapy for esophageal squamous cell carcinoma followed by esophagectomy. Four months after esophagectomy, endoscopic submucosal dissection for pharyngeal squamous cell carcinoma was performed. This is a first report of pharyngeal squamous cell carcinoma, esophageal squamous cell carcinoma and esophageal adenocarcinoma occurring as triple primary cancers in a single patient. Smoking-induced tumor formation through DNA methylation is a common risk factor for patients with triple primary malignancies, being an example of epigenetic field cancerization induced by exposure to carcinogenic factors.


Maximizing Impact: Can Interventions to Prevent Clinical Malaria Reduce Parasite Transmission?
Malaria interventions may reduce the burden of clinical malaria disease, the transmission of malaria parasites, or both. As malaria interventions are developed and evaluated, including those interventions primarily targeted at reducing disease, they may also impact parasite transmission. Achieving global malaria eradication will require optimizing the transmission-reducing potential of all available interventions. Herein, we discuss the relationship between malaria parasite transmission and disease, including mechanisms by which disease-targeting interventions might also impact parasite transmission. We then focus on three malaria interventions with strong evidence for reducing the burden of clinical malaria disease and examine their potential for also reducing malaria parasite transmission.


Feasibility of closed-chest left ventricular bypass using unilateral retrograde transpulmonary flow.
A method for closed-chest left heart bypass using retrograde unilateral transpulmonry blood flow originating from the left atrium and retrieved by a cuffed cannula wedged in a pulmonary artery branch is described. Technical feasibility and physiological implications were tested in 12 anesthetized sheep and 4 awake calves. Retrograde transpulmonary flow showed a curvilinear relationship to the left atrial pressure, with the highest rate of rise occurring when left atrial pressure approached levels of pulmonary edema (25 to 35 mm Hg); at this point retrograde transpulmonary flow became equal to control cardiac output. The intervention and the bypass were well tolerated for short periods by these healthy animals. The possible advantages of the method are discussed, with emphasis on self-regulation of bypass flow by the filling resistance of the left ventricle.


The Cost-Effectiveness of the BEAT-TB Regimen for Pre-Extensively Drug-Resistant TB.
To measure the economic impacts of the longer pre-XDR-TB treatment regimen and the shorter BEAT-TB India regimen. In the current study, the economic impacts of the current 18-month pre-XDR-TB treatment regimen and the 6-9 month BEAT-TB regimen were evaluated using an economic model via a decision tree analysis from a societal perspective. The incremental costs and quality-adjusted life years (QALYs) gained from the introduction of the BEAT-TB regimen for pre-XDR-TB patients were estimated. For a cohort of 1000 pre-XDR-TB patients, we found that the BEAT-TB India regimen yielded higher undiscounted life years (40,548 vs. 21,009) and more QALYs gained (27,633 vs. 15,812) than the 18-month regimen. The BEAT-TB India regimen was found to be cost-saving, with an incremental cost of USD -128,651 when compared to the 18-month regimen. The current analysis did not consider the possibility of reduced TB recurrence after use of the BEAT-TB regimen, so it might have under-estimated the benefits. As a lower-cost intervention with improved health outcomes, the BEAT-TB India regimen is dominant when compared to the 18-month regimen.


Current and Future Treatment Options for Narcolepsy: A Review.
Narcolepsy is a chronic neurological sleep disorder with potentially disabling symptoms ranging from occupational concerns to mental health difficulties. Recent advances related to the neurobiological basis of narcolepsy have led to newer pharmacological treatment options and adjunctive behavioral techniques that support symptom management. This article outlines evidence-based pharmacologic therapies, behavioral techniques, and psychosocial costs related to narcolepsy. Psychosocial factors, although frequently acknowledged, deserve further attention and awareness from researchers and providers. The American Academy of Sleep Medicine's (AASM) Quality Measure Drivers and potential future treatment options are also discussed.


Work-family spillover stress predicts health outcomes across two decades.
Work is a common source of stress for many adults, arising from situations that occur at work (e.g., job demands) as well as the worries and responsibilities that people take home with them (negative work-family spillover). Over time, work-related stress may impact physical health. The current study prospectively examined the effects of job demands and negative work-family spillover (NWFS) on three self-reported physical health measures. Participants in the Midlife in the United States (MIDUS) survey (N = 4200) reported their job demands and negative work-family spillover at wave 1. They also reported on their health across three waves of data collection. Higher levels of NWFS at baseline were related to a higher number of self-reported chronic illnesses, greater functional limitation, and poorer self-rated health approximately 10 and 20 years later. In contrast, job demands were unrelated to any health indices at baseline or at the approximately 10- and 20-year follow-ups. Findings suggest that NWFS is a unique form of stress with long-lasting and detrimental effects on physical health.


[Investigations on the penetration of cefamandole into spinal fluid (author's transl)].
In 20 test persons spinal fluid was taken at intervals of 15, 30, 60 and 90 minutes after a single injection of 40 mg cefamandole/kg body weight in order to determine the levels of the active substance. Whereas in serum an average peak value of 248 mcg/ml was determined after ten minutes, there was no trace at all of cefamandole in the spinal fluid.


IgG synthesis rate in evaluation of multiple sclerosis in a community hospital.
We obtained CSF and serum from 21 patients with definite MS in a community hospital. Ninety percent of patients had an elevated IgG synthesis rate, comparable with the sensitivity of oligoclonal bands (0.95) or the IgG index (0.90) and better than the IgG% (0.47) in definite MS. We found that no area hospital routinely employs the IgG synthesis rate. The low-sensitivity IgG% and the dimensionless IgG index can be abandoned. The linear IgG synthesis rate and oligoclonal band scanning should be the CSF tests of choice.


[The incidence of antibodies to hepatitis A virus in people from Vienna and certain Austrian provinces (author's transl)].
The prevalence of antibodies to hepatitis A virus was measured by solid-phase radioimmunoassay in sera of 651 persons from Vienna, Lower Austria, Upper Austria, Carinthia and Burgenland. On subdivision of the subjects according to age groups, a curve resulted which showed a steep rise in persons between 20 and 40 years. In the age groups over 40 more than 80% of the test-persons possessed the specific antibody. In all age groups the population of Vienna showed a higher incidence of hepatitis A antibody than the people from rural areas.


Induction of multiple myeloma-reactive T cells during post-transplantation immunotherapy with donor lymphocytes and recipient DCs.
Recently, we demonstrated that reduced intensity conditioning (RIC) followed by partial T-cell-depleted SCT creates a platform for inducing the graft-versus-myeloma effect by adjuvant immunotherapy. Here, we evaluated mHA-specific T-cell responses in a multiple myeloma (MM) patient who was treated with RIC-SCT followed by donor lymphocyte infusion (DLI) and subsequent recipient DC vaccination. We isolated a mHA-specific CTL clone with the capacity to target MM tumor cells from this patient experiencing long-term CR. This CTL clone recognizes an HLA-A3-restricted mHA and mediates killing of both primary MM cells and the MM-cell line U266, while BM-derived fibroblasts are not recognized. CTL-specific T-cell receptor (TCR) transcripts could be detected by quantitative PCR analysis in both peripheral blood and BM during tumor remission. Interestingly, a strong increase of CTL-specific TCR transcripts at the BM tumor site was observed following DLI and recipient DC vaccination, while the TCR signal in peripheral blood decreased. These findings illustrate that the approach of partial T-cell-depleted RIC-SCT followed by post-transplantation immunotherapy induces mHA-specific T-cell responses targeting MM tumor cells.


Development and psychometric evaluation of Sexual and Reproductive Health Assessment Scale for women with educable intellectual disability (SRH-WIDS): a sequential exploratory mixed-method study.
Women with Intellectual disability have many problems in their sexual and reproductive health due to their special mental and physical conditions caused by disability. This study aimed to develop and evaluate the psychometric properties of Sexual and Reproductive Health Scale for Women with Educable Intellectual disability. This sequential exploratory mixed-method study was conducted at two qualitative and quantitative stages in Tehran, from 2018 to 2020. At the qualitative stage, in-depth and semi-structured interviews were conducted with 21 parents and caregivers of women with intellectual disability to explain the concepts and to generate items. Thereafter, the item pool was formed based on the concepts and themes extracted from the qualitative phase as well as the review of literature. At the second stage, psychometric properties of the scale were assessed. Finally, responsiveness, interpretability, and feasibility of the scale were determined. An item pool containing 95 items was produced at the first stage. At the second stage, the final version of scale was developed. The psychometric properties of this final version were then assessed and the results showed that the instrument has good validity and reliability. The results of exploratory factory analysis showed that the instrument contains seven factors. Accordingly, these factors explained 53% of the total variance of the instrument variables. The results show that the SRH-WIDS with 25 items has sufficient validity and reliability, so it could be easily used by caregivers to assess the sexual and reproductive health of Women with Educable Intellectual disability. Ethical code: IRI.TUMS.VCR.REC 1397.340.


The fate of inhaled azodicarbonamide in rats.
Azodicarbonamide (ADA) is widely used as a blowing agent in the manufacture of expanded foam plastics, as an aging and bleaching agent in flour, and as a bread dough conditioner. Human exposures have been reported during manufacture as well as during use. Groups of male F344/N rats were administered ADA by gavage, by intratracheal instillation, and by inhalation exposure to determine the disposition and modes of excretion of ADA and its metabolites. At 72 hr following gavage, 30% of the administered ADA was absorbed whereas following intratracheal instillation, absorption was 90%. Comparison between groups of rats exposed by inhalation to ADA to achieve body burdens of 24 or 1230 micrograms showed no significant differences in modes or rates of excretion of [14C]ADA equivalents. ADA was readily converted to biurea under physiological conditions and biurea was the only 14C-labeled compound present in excreta. [14C]ADA equivalents were present in all examined tissues immediately after inhalation exposure, and clearance half-times on the order of 1 day were evident for all tissues investigated. Storage depots for [14C]ADA equivalents were not observed. The rate of buildup of [14C]ADA equivalents in blood was linearly related to the lung content as measured from rats withdrawn at selected times during a 6-hr inhalation exposure at an aerosol concentration of 25 micrograms ADA/liter. In a study extending 102 days after exposure, retention of [14C]ADA equivalents in tissues was described by a two-component negative exponential function. The results from this study indicate that upon inhalation, ADA is rapidly converted to biurea and that biurea is then eliminated rapidly from all tissues with the majority of the elimination via the urine.


Preventive strategies for dealing with violence among blacks.
In regular medicine if a patient goes to a doctor to be treated for a rat bite, the physician cleans the bite, dresses it, gives antibiotics, and gives a tetanus shot. The physician practicing social medicine would give our imaginary patient the same treatment but would go a step further; he would arrange for someone to go into the patient's community and set rat traps. A similar distinction is made between general psychiatry and community psychiatry, and this distinction highlights one of the main principles of the community psychiatrist's mission, community development. Community development being the art of helping a community achieve a social and interpersonal milieu that promotes an optimum level of mental health (Freed, 1972; Freed, 1972). This aspect of community psychiatry takes on an even greater significance when the community being served is a lower socioeconomic, minority community because of the conditions found in such communities that can impair the overall mental health of the community's individuals, families, and groups. This article will illustrate the principle of community development, the role of one psychiatrist in community development, and its importance to deprived minority communities by describing a community psychiatry approach to the problem of black-on-black homicide.


1-year survival rate of SARS-CoV-2 infected patients with acute respiratory distress syndrome based on ventilator types: a multi-center study.
The aim of this study was to evaluate the association between types of ventilator and the one-year survival rate of patients with acute respiratory distress syndrome (ARDS) due to SARS‑CoV-2 infection. This multi-center, retrospective observational study was conducted on 1078 adult patients admitted to five university-affiliated hospitals in Iran who underwent mechanical ventilator (MV) due to ARDS. Of the 1078 patients, 781 (72.4%) were managed with ICU ventilators and 297 (27.6%) with transport ventilators. Overall mortality was significantly higher in patients supported with transport ventilator compared to patients supported with ICU ventilator (16.5% vs. 9.3% P = 0.001). Regression analysis revealed that the expected hazard overall increased with age (HR: 1.525, 95% CI 1.112-1.938, P = 0.001), opacity score (HR: 1.448, 95% CI 1.122-2.074, P = 0.001) and transport ventilator versus ICU ventilator (HR: 1.511, 95% CI 1.143-2.187, P = 0.029). The Kaplan-Meier curves of survival analysis showed that patients supported with ICU ventilator had a significantly higher 1-year survival rate (P = 0.001). In MV patients with ARDS due to COVID-19, management with non-ICU sophisticated ventilators was associated with a higher mortality rate compared to standard ICU ventilators. However, more studies are needed to determine the exact effect of ventilator types on the outcome of critically ill patients.


An evaluation of the acceptability as forage of some nutritive and antinutritive components and of the dry matter degradation profiles of five species of Ficus.
The suitability of five species of Ficus, F. mucoso, F. thonningii, F. polita, F. religiosa and F. benjamina, for feeding ruminant livestock was studied. The nutritive and antinutritive components were determined and the acceptability of the forages to livestock was assessed using a cafeteria method in 8 adult small ruminants. Also, the degradation potential of the dry matter of the five Ficus species was investigated using 3 fistulated sheep. The crude protein (CP) content of the Ficus species varied significantly (p < 0.05), ranging from 130 to 180 g/kg DM. The content of neutral detergent fibre (NDF) also varied significantly (p < 0.05), ranging from 650 to 710 g/kg DM. The organic matter (OM) contents did not differ significantly (p > 0.05), having a mean value of 916 g/kg DM. The concentrations of tannin, saponin, phytic acid and oxalic acid were low. The acceptability of the forage was similar for four of the species but poor for F. polita. The extent of DM degradation varied significant among the Ficus species, the ranking order being F. benjamina > F. thonningii > F. mucoso > F. religiosa > F. polita.


Prevalence of Self-Reported Voice Concerns and Associated Risk Markers in a Nonclinical Sample of Military Service Members.
Difficult communication environments are common in military settings, and effective voice use can be critical to mission success. This study aimed to estimate the prevalence of self-reported voice disorders among U.S. military service members and to identify factors that contribute to their voice concerns. A nonclinical sample of 4,123 active-duty service members was recruited across Department of Defense hearing conservation clinics. During their required annual hearing evaluation, volunteers provided responses to voice-related questions including a slightly adapted version of the Voice Handicap Index-10 (VHI-10) as part of a larger survey about communication issues. Changepoint detection was applied to age and years of service to explore cohort effects in the reporting of voice concerns. Logistic regression analyses examined multiple available factors related to communication to identify factors associated with abnormal results on the VHI-10. Among the respondents, 41% reported experiencing vocal hoarseness or fatigue at least several times per year, and 8.2% (n = 336) scored above the recommended abnormal cut-point value of 11 on the VHI-10. Factors independently associated with the greatest risk for self-reported voice concerns were sex (female), cadmium exposure, vocal demands (the need for a strong, clear voice), and auditory health measures (frequency of experiencing temporary threshold shifts; self-reported hearing difficulties). Based on self-reported voice concerns and false negative rates reported in the literature, the prevalence of dysphonia in a large sample of active-duty service members is estimated to be 11.7%, which is higher than that in the general population. Certain predictors for voice concerns were expected based on previous literature, like female sex and voice use, but frequency of temporary threshold shifts and exposure to cadmium were surprising. The strong link between voice and auditory problems has particular implications regarding the need for effective communication in high-noise military and other occupational environments.


Effector functions of circumsporozoite peptide-primed CD4+ T cell clones against Plasmodium yoelii liver stages.
Previously, CD4+ T cell lines and clones were isolated after immunization of BALB/c and C57BL/6 mice with the Py1 peptide, a 21-mer synthetic peptide corresponding to a N-terminal segment of the circumsporozoite protein of Plasmodium yoelii. The clones were separated into the Th1 and Th2 subsets on the basis of lymphokine production. It was observed that immunization with the Py1 peptide induced preferentially Th1 cells in BALB/c and Th2 cells in C57BL/6 mice. These clones were then tested for their cytolytic ability in vitro. Some of the clones from BALB/c and C57BL/6 mice eliminated liver stage parasites from cultured hepatocytes in a MHC restricted manner. Nevertheless, none of these clones was able to lyse Py1 peptide-pulsed target cells. It was also found that two clones could protect BALB/c mice against a sporozoite challenge. These results provide evidence that CD4+ T cells, induced after priming with a defined peptide, could participate in the effector mechanisms against malaria liver stages.


Somatic Hypermutation Defects in Common Variable Immune Deficiency.
Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by impaired antibody production and recurrent infections. In the last 20 years, several groups have reported that B cells from CVID patients have an impaired somatic hypermutation (SHM). The reported frequency of this defect among CVID patient cohorts is highly variable and so is the methodology used to evaluate this process. Interestingly, the low level of SHM on B cells from CVID patients has been correlated with the presence of infectious and non-infectious complications. In this review, an overview of the studies regarding SHM in CVID patients is presented. We highlight the importance of SHM studies in CVID patients as a clinical tool due to the reported association with clinical complications by several groups. We also considered SHM measurement useful to guide future investigations in order to identify genetic defects involved in the development of the disease.


Sodium alginate-polyethylene glycol diacrylate based double network fiber: Rheological properties of fiber forming solution with semi-interpenetrating network structure.
In order to prepare the high mechanical properties fiber with double network, sodium alginate (SA)/polyethylene glycol diacrylate (PEGDA) gel solution with semi-interpenetrating network structure was prepared by using "one-pot" method. Rheological properties of SA/PEGDA gel solution were studied at steady state mode and dynamic mode respectively. The results showed that the SA/PEGDA solution's apparent viscosity was 0.67 Pa·s at PEGDA of 20 wt%, smaller 92.8% than that of the pure SA solution. When PEGDA content was 20 wt%, the consistency coefficient (k) of the solution reached the minimum (0.57). It meant the flow properties of the solution were the optimal at PEGDA of 20 wt%. Moreover, changes in the storage modulus (G') and the loss modulus (G″) were found to be dependent on PEGDA content and temperature. The tanδ was greater higher than 1, which meant the spinning solution exhibited viscoelastic behavior of liquid-like properties.