Cost-effectiveness of transdiagnostic group cognitive behavioural therapy versus group relaxation therapy for emotional disorders in primary care (PsicAP-Costs2): Protocol for a multicentre randomised controlled trial.
Several randomised controlled trials (RCT) have demonstrated the superiority of transdiagnostic group cognitive-behavioural therapy (TD-CBT) to treatment as usual (TAU) for emotional disorders in primary care. To date, however, no RCTs have been conducted to compare TD-CBT to another active intervention in this setting. Our aim is to conduct a single-blind RCT to compare group TD-CBT plus TAU to progressive muscle relaxation (PMR) plus TAU in adults (age 18 to 65 years) with a suspected emotional disorder. We expect that TD-CBT + TAU will be more cost-effective than TAU + PMR, and that these gains will be maintained at the 12-month follow-up. Seven therapy sessions (1.5 hours each) will be offered over a 24-week period. The study will be carried out at four primary care centres in Cantabria, Spain. The study will take a societal perspective. Psychological assessments will be made at three time points: baseline, post-treatment, and at 12-months. The following variables will be evaluated: clinical symptoms (anxiety, depression, and/or somatic); functioning; quality of life (QoL); cognitive-emotional factors (rumination, worry, attentional and interpretative biases, emotion regulation and meta-cognitive beliefs); and satisfaction with treatment. Data on health service use, medications, and sick days will be obtained from electronic medical records. Primary outcome measures will include: incremental cost-effectiveness ratios (ICER) and incremental cost-utility ratios (ICURs). Secondary outcome measures will include: clinical symptoms, QoL, functioning, and treatment satisfaction. Bootstrap sampling will be used to assess uncertainty of the results. Secondary moderation and mediation analyses will be conducted. Two questionnaires will be administered at sessions 1, 4, and 7 to assess therapeutic alliance and group satisfaction. If this trial is successful, widespread application of this cost-effective treatment could greatly improve access to psychological treatment for emotional disorders in the context of increasing demand for mental healthcare in primary care. Trial registration: ClinicalTrials.gov: Cost-effectiveness of a Transdiagnostic Psychological Treatment for Emotional Disorders in Primary Care (PsicAP). NCT05314920.


Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway.
Diabetic cardiomyopathy is related directly to hyperglycemia. Cell death such as apoptosis plays a critical role in cardiac pathogenesis. Whether hyperglycemia induces myocardial apoptosis, leading to diabetic cardiomyopathy, remains unclear. We tested the hypothesis that apoptotic cell death occurs in the diabetic myocardium through mitochondrial cytochrome c-mediated caspase-3 activation pathway. Diabetic mice produced by streptozotocin and H9c2 cardiac myoblast cells exposed to high levels of glucose were used. In the hearts of diabetic mice, apoptotic cell death occurred as detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Correspondingly, caspase-3 activation as determined by enzymatic assay and mitochondrial cytochrome c release detected by Western blotting analysis were observed. Supplementation of insulin inhibited diabetes-induced myocardial apoptosis as well as suppressed hyperglycemia. To explore whether apoptosis in diabetic hearts is related directly to hyperglycemia, we exposed cardiac myoblast H9c2 cells to high levels of glucose (22 and 33 mmol/l) in cultures. Apoptotic cell death was detected by TUNEL assay and DAPI nuclear staining. Caspase-3 activation with a concomitant mitochondrial cytochrome c release was also observed. Apoptosis or activation of caspase-3 was not observed in the cultures exposed to the same concentrations of mannitol. Inhibition of caspase-3 with a specific inhibitor, Ac-DEVD-cmk, suppressed apoptosis induced by high levels of glucose. In addition, reactive oxygen species (ROS) generation was detected in the cells exposed to high levels of glucose. These results suggest that hyperglycemia directly induces apoptotic cell death in the myocardium in vivo. Hyperglycemia-induced myocardial apoptosis is mediated, at least in part, by activation of the cytochrome c-activated caspase-3 pathway, which may be triggered by ROS derived from high levels of glucose.


Autophagy in the placenta.
Autophagy is an evolutionarily conserved catalytic process by which cytoplasmic components including damaged macromolecules and organelles are degraded. The role of autophagy includes adaptive responses to nutrition deprivation or intracellular stimuli. Although autophagosomes were first observed in early 1960s, it was 1990s that autophagy-related genes in yeast were identified and studied. Nowadays, the molecular machinery of autophagy and signaling pathway to various stimuli are almost outlined. Dysregulation of autophagic activity has been implicated in many human diseases including neurodegenerative diseases, infection and inflammation, and malignancies. However, since current understanding of autophagy in placenta is just at the beginning, this paper aims to provide general information on autophagy (part I) and to summarize articles on autophagy in human placenta (part II). This review article will serve as a basis for further researches on autophagy in relation to human pregnancy and its complications.


Systematic review of systematic reviews of non-pharmacological interventions to treat behavioural disturbances in older patients with dementia. The SENATOR-OnTop series.
To provide an overview of non-pharmacological interventions for behavioural and psychological symptoms in dementia (BPSD). Systematic overview of reviews. PubMed, EMBASE, Cochrane Database of Systematic Reviews, CINAHL and PsycINFO (2009-March 2015). Systematic reviews (SRs) that included at least one comparative study evaluating any non-pharmacological intervention, to treat BPSD. Eligible studies were selected and data extracted independently by 2 reviewers.The AMSTAR checklist was used to assess the quality of the SRs. Extracted data were synthesised using a narrative approach. 38 SRs and 129 primary studies were identified, comprising the following categories of non-pharmacological interventions: (1) sensory stimulation interventions (25 SRs, 66 primary studies) that encompassed: shiatsu and acupressure, aromatherapy, massage/touch therapy, light therapy, sensory garden and horticultural activities, music/dance therapy, dance therapy, snoezelen multisensory stimulation therapy, transcutaneous electrical nerve stimulation; (2) cognitive/emotion-oriented interventions (13 SRs; 26 primary studies) that included cognitive stimulation, reminiscence therapy, validation therapy, simulated presence therapy; (3) behaviour management techniques (6 SRs; 22 primary studies); (4) Multicomponent interventions (3 SR; four primary studies); (5) other therapies (5 SRs, 15 primary studies) comprising exercise therapy, animal-assisted therapy, special care unit and dining room environment-based interventions. A large number of non-pharmacological interventions for BPSD were identified. The majority of the studies had great variation in how the same type of intervention was defined and applied, the follow-up duration, the type of outcome measured, usually with modest sample size. Overall, music therapy and behavioural management techniques were effective for reducing BPSD.


Getting organized in your job.
The benefits of being organized when starting one's career are countless and worth the time and effort in developing an effective and efficient practice. Established protocols, good habits, and methodical communication that include all members of the team will help create a system that keeps all components of one's practice organized. Adhering to these strategies requires self-discipline. Applying these concepts to patient care, education, research, and administrative responsibilities is the key to a successful and sustainable career.


Impulsivity traits and suicide related outcomes: A systematic review and meta-analysis using the UPPS model.
The affective, cognitive, and behavioral aspects of impulsivity involved in suicide-related outcomes can be investigated through the UPPS model, which conceptualizes these facets in multidimensional terms related to negative and positive urgency, lack of premeditation and perseverance, and sensation seeking. This systematic review and meta-analysis provided a comprehensive understanding of the role of all facets of impulsivity in the development of suicidal ideation and behaviors. We conducted a systematic search on six databases (PsycINFO, PsycARTICLES, PubMed, MEDLINE, Scopus, and Web of Science) until May 5,2023. Overall, 49 studies met the criteria for systematic review, of which 37 were included in a meta-analysis of data from 17.898 individuals. Additional moderation analyses included age, gender, sample status, country of study conduct, assessment instruments, type of suicide-related outcome, study quality, and research design. We found significant relationships between aspects of impulsivity and suicide-related outcomes. Specially, affective facets related to impulsivity showed a stronger association with suicidal ideations and attempts than cognitive and behavioral dimensions, recommending the main involvement of emotional aspects-positive and negative-in suicide-related dimensions. The limited number of studies may have negatively impacted the power of moderation analyses. In addition, for most dimensions of impulsivity, the limited number of longitudinal studies did not allow to test the moderating role of research design. This study supports the role of impulsivity in suicidal ideation and behavior, identifying the affective component of impulsivity as the most involved, providing a significant contribution from a clinical and diagnostic point of view.


Two sisters with Reed's syndrome: treatment with pregabalin.
Cutaneous leiomyomas, which originate in the arrector pili muscles of the skin are rarely seen benign cutaneous tumors. Sometimes familial cutaneous and uterine leiomyomatosis can occur together, an autosomal dominant genetic condition called Reed syndrome or familial leiomyomatosis cutis et uteri. This disorder can be accompanied by malignancies, particularly by renal carcinoma. In this paper, two sisters with Reed syndrome are presented in view of the rarity of the disorder and good response to pregabalin therapy.


Ten yr of pediatric heart transplantation: a report from the Pediatric Heart Transplant Study.
The PHTS was founded in 1991 as a not-for-profit organization dedicated to the advancement of the science and treatment of children during listing for and following heart transplantation. Now, 21 yr later, the PHTS has contributed significantly to the field, most notably in the form of outcomes analyses and risk factor assessment, in addition to amassing the most detailed dataset on pediatric heart transplant recipients worldwide. The purpose of this report is to review the last decade of pediatric patients listed for heart transplantation (January 1, 2000-December 31, 2009) and summarize the changes, trends, outcomes, and lessons learned.


A kiloelectron-volt ultrafast electron micro-diffraction apparatus using low emittance semiconductor photocathodes.
We report the design and performance of a time-resolved electron diffraction apparatus capable of producing intense bunches with simultaneously single digit micrometer probe size, long coherence length, and 200 fs rms time resolution. We measure the 5d (peak) beam brightness at the sample location in micro-diffraction mode to be 7 × 10 13 A / m 2 rad 2 . To generate high brightness electron bunches, the system employs high efficiency, low emittance semiconductor photocathodes driven with a wavelength near the photoemission threshold at a repetition rate up to 250 kHz. We characterize spatial, temporal, and reciprocal space resolution of the apparatus. We perform proof-of-principle measurements of ultrafast heating in single crystal Au samples and compare experimental results with simulations that account for the effects of multiple scattering.


[Adhesive sealing of fissures and pits for the prevention of caries. Review].
Conformably to the order received, the present contribution aims, as desired by the editor, at meeting the information requirements of the practitioner as completely as possible. For that reason, the cruical points are stressed. This complex of questions is also analysed from the aspect of the author's opinion. This analysis is intended for aiding the reader in processing source material and in forming his own opinion. Starting from the epidemiological foundation of the necessity of caries prevention, the author integrates the method of adhesive sealing and describes the necessary materials and the various steps of the procedure. The article centers in a critical interpretation of its preventive efficiency in clinic and experiment and ends in an outlook.


[Conditions for the self-organization of submicroscopic structures from mycelial extracts of the "fructose" variant of Actinomyces roseflavus var. roseofungini].
Self-organization of various submicroscopic formations, such as "tubes", "ribbons", etc. differing in ultrastructure and containing a polyenic antibiotic was observed in acetone extracts of the mycelium of the "fructose" variant of Actinomyces roseoflavus var. roseofungini. Conditions for separate isolation of the above structures are described. Concentration of the extract and the ratio of the volumes of water added to the extract are determinant for the process of self-organization. A possibility of reorganization of the tubular structures into the ribbon-like ones and vice versa is shown.


Determination of Ligand-Binding Affinity (Kd) Using Transverse Relaxation Rate (R2) in the Ligand-Observed 1H NMR Experiment and Applications to Fragment-Based Drug Discovery.
High hit rates from initial ligand-observed NMR screening can make it challenging to prioritize which hits to follow up, especially in cases where there are no available crystal structures of these hits bound to the target proteins or other strategies to provide affinity ranking. Here, we report a reproducible, accurate, and versatile quantitative ligand-observed NMR assay, which can determine Kd values of fragments in the affinity range of low μM to low mM using transverse relaxation rate R2 as the observable parameter. In this study, we examined the theory and proposed a mathematical formulation to obtain Kd values using non-linear regression analysis. We designed an assay format with automated sample preparation and simplified data analysis. Using tool compounds, we explored the assay reproducibility, accuracy, and detection limits. Finally, we used this assay to triage fragment hits, yielded from fragment screening against the CRBN/DDB1 complex.


Clinical characteristics associated with occurrence and poor prognosis of interstitial lung disease in rheumatoid arthritis.
To analyze clinical characteristics of interstitial lung disease (ILD) associated with rheumatoid arthritis (RA), especially in patients with poor prognosis. Seventy-seven RA patients with ILD and 231 age, sex, and disease duration-matched RA patients without ILD were enrolled in this retrospective study. Epidemiologic, clinical, and laboratory information were obtained through a medical chart review. Logistic regression analysis was used to estimate the risk of mortality in RA patients with ILD. Compared to the RA without ILD group, the RA with ILD group had significantly higher titers of rheumatoid factor and the anti-cyclic citrullinated peptide (p = 0.001 for both), higher levels of C-reactive protein (CRP) at the time of RA diagnosis (p = 0.014), and a higher erythrocyte sedimentation rate (p = 0.022) and CRP levels (p < 0.001) throughout the 10-year follow-up period. These patients also received a higher mean daily dose of corticosteroids (p < 0.001). In the subgroup analysis of RA patients with ILD, 28 patients (36.4%) died during follow-up. Multivariate analysis revealed that older age at the time of ILD diagnosis was significantly associated with mortality. Usual interstitial pneumonia (UIP) subtype on high-resolution computed tomography (HRCT) was also suggested as a poor prognostic factor. The survival of RA patients with ILD is adversely affected by age at the time of ILD diagnosis. RA-ILD patients diagnosed after age 65 or with a UIP subtype on HRCT may have a poor prognosis.


[Comparison and application of two risk assessment methods for occupational lead exposure risk classification in a lead-acid battery enterprise].
Objective: To apply and compare two risk assessment methods for occupational lead exposure risk classification in a lead-acid battery enterprise. Methods: In April 2013, an occupational health survey was carried out in a lead-acid battery enterprise. Lead smoke and lead dust were tested in the workplace. The risk assessment index system for occupational chemical hazards that was established and optimized by the research group (referred to as "optimized index system" ) , as well as the Singapore semi-quantitative risk assessment model, was used for occupational lead exposure risk classification in the lead-acid battery enterprise. The two risk classification results were analyzed and compared. Results: In the lead smoke risk classification results, the optimized index system classified the raw material group and foundry group workshops as Class I hazardous and the assembling group workshop as Class II hazardous. The Singapore semi-quantitative risk assessment model classified the raw material group workshop as high risk and foundry group and assembling group workshops as extremely high risk. In the lead dust risk classification results, the optimized index system classified the raw material group workshop as Class I hazardous, while the plate painting group, plate cutting group, and assembling group workshops were classified as Class II hazardous. The Singapore semi-quantitative risk assessment model classified the raw material group workshop as medium risk, the plate painting group and plate cutting group workshops as high risk, and the assembling group workshop as extremely high risk. Conclusion: There are some differences in risk assessment of occupational lead exposure between the two risk assessment methods. The optimized index system is comparably more reasonable and feasible, and is highly operable.


High Reactivity of α-Boryl Radical of Potassium Alkyltrifluoroborate in Atom-Transfer Radical Addition.
We found that the α-boryl radical of potassium alkyltrifluoroborate shows higher reactivity compared to the α-boryl radicals of alkylboronic acid pinacol ester and alkyl N-methyl imidodiacetic acid (MIDA) boronate in the halogen atom abstraction step of atom-transfer radical addition (ATRA) between alkyl bromide and vinylborons. In this research, an ATRA of alkyl halides with potassium vinyltrifluoroborate furnished unique alkylborons, which are difficult to synthesize by other methods.


Evaluation of a Set of miRNAs in 26 Cases of Fatal Traumatic Brain Injuries.
In forensic medicine, identifying novel biomarkers for use as diagnostic tools to ascertain causes of death is challenging because of sample degradation. To that aim, a cohort (n = 26) of fatal traumatic brain injuries (TBIs) were tested for three candidate miRNAs (namely, miR-124-3p, miR-138-5p, and miR144-3p). For each case, three FFPE specimens (coup area (CA), contrecoup area (CCA), and the corpus callosum (CC)) were investigated, whereas the FFPE brain tissues of 45 subjects (deceased due to acute cardiovascular events) were used as controls. Relative quantification via the ∆∆Ct method returned significantly higher expression levels of the three candidate miRNAs (p < 0.01) in the TBI cases. No difference was detected in the expression levels of any miRNA investigated in the study among the CA, CCA, and CC. Furthermore, the analyzed miRNAs were unrelated to the TBI samples' post-mortem intervals (PMIs). On the contrary, has-miR-124-3p ahashsa-miR-144-3p were significantly correlated (p < 0.01) with the agonal time in TBI deaths. Since the RNA was highly degraded in autoptic FFPE tissues, it was impossible to analyze the mRNA targets of the miRNAs investigated in the present study, highlighting the necessity of standardizing pre-analytical processes even for autopsy tissues.


[Intratympanic Steroid Treatment for Severe Idiopathic Sudden Sensorineural Hearing Loss].
Systemic steroid therapy is the only standard drug therapy for severe idiopathic sudden sensorineural hearing loss (ISSHL). We have treated severe ISSHL patients with double combined therapy, intravenous steroids (IVS) and hyperbaric oxygen (HBO). In this study, we retrospectively examined the effects of intratympanic steroids (ITS) by adding it to the double combined therapy. The study subjects were 172 patients with severe ISSHL. Eighty patients (38 men and 42 women) were treated with the double combined IVS and HBO therapy between April, 2007 and July, 2010 (A group: Historical control arm). Ninety-two patients (51 men and 41 women) were treated with triple therapy, combined therapy with IVS and HBO plus ITS, between August, 2010 and October, 2013 (B group: Current protocol arm). Each group was divided into two subgroups; one with a pure-tone average (PTA) between 60 and 89 dB (A1 and B1) and the other with a PTA ≥ 90 dB. A 1, A2, B1, and B2 sub-groups had 56 (29 men, 27 women), 24 (9 men, 15 women), 64 (36 men, 28 women), and 28 (15 men, 13 women) patients, respectively. All patients were treated within 30 days from the onset. There was a statistically significant difference in hearing improvement between the A2 and B2 groups, whereas no significant difference was observed between the A1 and B1 groups. Furthermore, a significant difference was observed in all frequencies but 2 kHz between at the A2 group and B2 group, but not between the A1 and B1 groups. Multivariate logistic analysis revealed that the treatment method (double vs.. triple combined therapies) had the strongest impact on hearing improvement in the ISSHL patients with a PTA ≥ 90 dB. These results indicated that the B2 group demonstrated better hearing improvement than the A2 group and suggested that the addition of the ITS could be effective for profound ISSHL patients with a PTA ≥ 90 dB.


Homologous recognition promoted by RecA protein via non-Watson-Crick bonds between identical DNA strands.
The RecA protein of Escherichia coli forms a nucleoprotein filament that promotes homologous recognition and subsequent strand exchange between a single strand and duplex DNA via a three-stranded intermediate. Recognition of homology within three-stranded nucleoprotein complexes, which is probably central to genetic recombination, is not well understood as compared with the mutual recognition of complementary single strands by Watson-Crick base pairing. Using oligonucleotides, we examined the determinants of homologous recognition within RecA nucleoprotein filaments. Filaments that contained a single strand of DNA recognized homology not only in a complementary oligonucleotide but also in an identical oligonucleotide, whether their respective sugar-phosphate backbones were antiparallel or parallel, and a filament that contained duplex DNA showed the same polymorphic versatility in the recognition of homology. Recognition of self by a filament that contains a single strand reveals that RecA filaments can recognize homology via non-Watson-Crick hydrogen bonds. Recognition of multiple forms of the same sequence by duplex DNA in the filament shows that it primarily senses base-sequence homology, and suggests that recognition can be accomplished prior to the establishment of new Watson-Crick base pairs in heteroduplex products. However, unlike the initial recognition of homology, strand exchange is stereospecific, requiring the proper antiparallel orientation of complementary strands.


Autoantibodies in COVID-19 correlate with antiviral humoral responses and distinct immune signatures.
Several autoimmune features occur during coronavirus disease 2019 (COVID-19), with possible implications for disease course, immunity, and autoimmune pathology. In this study, we longitudinally screened for clinically relevant systemic autoantibodies to assess their prevalence, temporal trajectory, and association with immunity, comorbidities, and severity of COVID-19. We performed highly sensitive indirect immunofluorescence assays to detect antinuclear antibodies (ANA) and antineutrophil cytoplasmic antibodies (ANCA), along with serum proteomics and virome-wide serological profiling in a multicentric cohort of 175 COVID-19 patients followed up to 1 year after infection, eleven vaccinated individuals, and 41 unexposed controls. Compared with healthy controls, similar prevalence and patterns of ANA were present in patients during acute COVID-19 and recovery. However, the paired analysis revealed a subgroup of patients with transient presence of certain ANA patterns during acute COVID-19. Furthermore, patients with severe COVID-19 exhibited a high prevalence of ANCA during acute disease. These autoantibodies were quantitatively associated with higher SARS-CoV-2-specific antibody titers in COVID-19 patients and in vaccinated individuals, thus linking autoantibody production to increased antigen-specific humoral responses. Notably, the qualitative breadth of antibodies cross-reactive with other coronaviruses was comparable in ANA-positive and ANA-negative individuals during acute COVID-19. In autoantibody-positive patients, multiparametric characterization demonstrated an inflammatory signature during acute COVID-19 and alterations of the B-cell compartment after recovery. Highly sensitive indirect immunofluorescence assays revealed transient autoantibody production during acute SARS-CoV-2 infection, while the presence of autoantibodies in COVID-19 patients correlated with increased antiviral humoral immune responses and inflammatory immune signatures.


The influence of dietary restriction on vitamin B-6 vitamer distribution and on vitamin B-6 metabolizing enzymes in rats.
The purpose of this study was to assess the effect of dietary restriction on tissue distribution of vitamin B-6 vitamers and activities of vitamin B-6 metabolizing enzymes in rats. Male rats were subjected to a 40% dietary restriction for 10, 20 or 40 weeks. The tissue vitamin B-6 vitamer concentrations and activities of the vitamin B-6 metabolizing enzymes of the animals were determined. The plasma pyridoxal 5'-phosphate (PLP) concentrations of the diet-restricted (DR) rats were comparable to those of the control group at week ten but were significantly lower at weeks 20 and 40. These significantly lower levels of plasma PLP in DR rats might in part be related to lower hepatic pyridoxal kinase and pyridoxamine (pyridoxine) 5'-phosphate oxidase activities. The urinary 4-pyridoxic acid excretion of the DR groups responded to the reduced food intake and were lower at weeks 10 and 20. Tissue levels of PLP were not affected by dietary restriction. In contrast, greater levels of pyridoxamine 5'-phosphate were found in liver, kidney and heart of the DR animals. The duration of dietary restriction influenced the distribution of vitamin B-6 vitamers. When plasma PLP is used to evaluate vitamin B-6 status, the length of dietary restriction should be considered.


[Clinical study of penile cancer].
Recent progress in molecular biology suggests a certain relationship between penile cancer and human papilloma virus infection. However, the treatment for penile cancer has not been established since each institute has experienced only a small number of patients. We analyzed the result of our treatment for 14 penile cancer patients during past twenty years. Ten of the 14 patients were initially treated for the primary lesion with a combination of peplomycin (PEP) or bleomycin (BLM) and radiation therapy. Of these, 9 were found not to have residual viable cancer cells in their primary lesions. No local recurrence was found in all 7 patients in whom the penis was preserved. This result suggests that combination of PEP (BLM) and radiation preserves the penis without increasing the risk of local recurrence. Penile cancer-related death did not occur in patients without lymph node metastasis. However, this cancer death did occur in 4 out of 7 patients with lymph node metastasis, suggesting that metastasis is one of the important prognostic factors. PEP (BLM) and radiation therapy with or without regional lymph node dissection did not improve the prognosis of patients with advanced penile carcinoma, such as with pN2, pN3 or distant metastasis. More effective management may be necessary for these patients.


A Combination of Radiomic Features, Imaging Characteristics, and Serum Tumor Biomarkers to Predict the Possibility of the High-Grade Subtypes of Lung Adenocarcinoma.
Lung adenocarcinomas (LADC) containing high-grade subtypes have a poorer prognosis. And some studies have shown that high-grade subtypes have been identified as an independent predictor of local recurrence in patients treated with limited resection. The aim of this study was to construct a combined model based on radiomic features, imaging characteristics and serum tumor biomarkers to predict the possibility of preoperative high-grade subtypes. 156 patients with LADC were retrospectively recruited in this study. These patients were randomly divided into training and validation cohorts. Radiomics features and imaging characteristics were extracted from plain CT images. A nomogram was developed in a training cohort by univariate and multivariate logistic analysis, and its performance was evaluated by receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA) in the training and validation cohorts. A total of 1316 radiomic features were extracted from the lesions in plain chest CT images. After applying the mRMR algorithm and the LASSO regression, 4 features were retained. Based on these radiomic features, Radiomic score (Radscore) was calculated for each patient. Spiculation, air bronchogram sign, CYFRA 21-1 and Radscore had been used in the construction of the combined model. The AUC of the combined model was respectively 0.88 (95% CI, 0.82-0.95) and 0.94 (95% CI, 0.86-1.00) in the training and validation cohorts. The combined model based on CT images and serum tumor biomarkers, can predict the high-grade subtypes of LADC in a non-invasive manner, which may influence individual treatment planning, such as the choice of surgical approach and postoperative adjuvant therapy.


Aristolochic acid induced suicidal erythrocyte death.
Aristolochic Acid, a component of Aristolochia plants, has been shown to cause acute kidney injury, renal aristolochic acid nephropathy, Balkan endemic nephropathy, and urothelial carcinoma. Aristolochic acid nephropathy may be associated with severe anemia. The anemia could theoretically be due to stimulation of eryptosis, the suicidal death of erythrocytes characterized by cell shrinkage and cell membrane scrambling with translocation of phosphatidylserine to the erythrocyte cell membrane surface. Signalling involved in the stimulation of eryptosis include increase of cytosolic Ca(2+)-activity ([Ca(2+)]i) and formation of ceramide. Cell volume was estimated from forward scatter, phosphatidylserine-exposure from annexin V binding, [Ca(2+)]i from Fluo3 fluorescence, and ceramide abundance from binding of fluorescent antibodies in flow cytometry. A 48 hours exposure to Aristolochic Acid (≥ 75 µg/ml) was followed by a significant decrease of forward scatter and increase of annexin-V-binding. The effects were paralleled by a significant increase of [Ca(2+)]i and significantly blunted, but not abrogated by removal of extracellular Ca(2+). Aristolochic Acid further significantly increased ceramide abundance. Aristolochic Acid triggers eryptosis, an effect at least in part due to entry of extracellular Ca(2+) and ceramide formation.


Unveiling the Significance and Challenges of Integrating Prevention Levels in Healthcare Practice.
In recent years, there has been a global increase in human life expectancy, but preventable morbidity and mortality remain significant concerns. To address these issues, preventive healthcare practice has gained importance in various healthcare disciplines. Its goal is to maintain and promote health, reduce risk factors, diagnose illnesses early, and prevent complications. This approach encompasses different stages of disease progression, including primordial prevention, primary prevention, secondary prevention, tertiary prevention, and quaternary prevention. Primordial prevention focuses on addressing root causes and social determinants of diseases to prevent the emergence and development of risk factors. Primary prevention aims to prevent diseases before they occur by implementing interventions such as vaccinations and health education. Secondary prevention focuses on early detection and prompt intervention to prevent the progression of diseases. Tertiary prevention manages the consequences of diseases by restoring health and providing rehabilitation. Lastly, quaternary prevention aims to protect patients from unnecessary medical interventions and harm caused by excessive medicalization. Despite the recognition of the cost-effectiveness of preventive measures, a significant portion of healthcare resources and attention is still allocated to disease management, and only a small percentage of individuals receive all recommended preventive services. Healthcare providers need to prioritize the implementation of preventive care services, even when clinical interventions are necessary, and overcome barriers to preventive care. By investing in preventive care and implementing these strategies, healthcare practitioners can play a crucial role in disease prevention and contribute to the well-being of individuals, families, communities, and countries.


Sensitivity calibration of an imaging extreme ultraviolet spectrometer-detector system for determining the efficiency of broadband extreme ultraviolet sources.
We report on the absolute sensitivity calibration of an extreme ultraviolet (XUV) spectrometer system that is frequently employed to study emission from short-pulse laser experiments. The XUV spectrometer, consisting of a toroidal mirror and a transmission grating, was characterized at a synchrotron source in respect of the ratio of the detected to the incident photon flux at photon energies ranging from 15.5 eV to 99 eV. The absolute calibration allows the determination of the XUV photon number emitted by laser-based XUV sources, e.g., high-harmonic generation from plasma surfaces or in gaseous media. We have demonstrated high-harmonic generation in gases and plasma surfaces providing 2.3 μW and μJ per harmonic using the respective generation mechanisms.


Application and prospect of ROS-related nanomaterials for orthopaedic related diseases treatment.
The importance of reactive oxygen species (ROS) in the occurrence and development of orthopaedic related diseases is becoming increasingly prominent. ROS regulation has become a new method to treat orthopaedic related diseases. In recent years, the application of nanomaterials has become a new hope for precision and efficient treatment. However, there is a lack of reviews on ROS-regulated nanomaterials for orthopaedic related diseases. Based on the key significance of nanomaterials for the treatment of orthopaedic related diseases, we searched the latest related studies and reviewed the nanomaterials that regulate ROS in the treatment of orthopaedic related diseases. According to the function of nanomaterials, we describe the scavenging of ROS related nanomaterials and the generation of ROS related nanomaterials. In this review, we closely integrated nanomaterials with the treatment of orthopaedic related diseases such as arthritis, osteoporosis, wound infection and osteosarcoma, etc., and highlighted the advantages and disadvantages of existing nanomaterials. We also looked forward to the design of ROS-regulated nanomaterials for the treatment of orthopaedic related diseases in the future.


Characterization of the Phenanthrene-Degrading Sphingobium yanoikuyae SJTF8 in Heavy Metal Co-Existing Liquid Medium and Analysis of Its Metabolic Pathway.
Polycyclic aromatic hydrocarbons (PAHs) are common organic pollutants with great carcinogenic threaten, and metal/PAH-contaminated environments represent one of the most difficult remedial challenges. In this work, Sphingobium yanoikuyae SJTF8 was isolated and identified with great and stable PAH-degrading efficiency even under stress conditions. It could utilize typical PAHs (naphthalene, phenanthrene, and anthracene) and heterocyclic and halogenated aromatic compounds (dibenzothiophene and 9-bromophenanthrene) as the sole carbon source. It could degrade over 98% of 500 mg/L phenanthrene in 4 days, and the cis-3,4-dihydrophenanthrene-3,4-diol was the first-step intermediate. Notably, strain SJTF8 showed great tolerance to heavy metals and acidic pH. Supplements of 0.30 mM of Cu2+, 1.15 mM of Zn2+, and 0.01 mM of Cd2+ had little effect on its cell growth and phenanthrene degradation; phenanthrene of 250 mg/L could still be degraded completely in 48 h. Further, the whole genome sequence of S. yanoikuyae SJTF8 was obtained, and three plasmids were found. The potential genes participating in stress-tolerance and PAH-degradation were annotated and were found mostly distributed in plasmids 1 and 2. Elimination of plasmid 2 resulted in the loss of the PAH-degradation ability. On the basis of genome mining results, the possible degrading pathway and the metabolites of S. yanoikuyae SJTF8 to phenanthrene were predicted.


Expression patterns of novel genes encoding homeodomain leucine-zipper proteins in Arabidopsis thaliana.
A recently discovered class of genes in Arabidopsis thaliana encode putative transcription factors which contain a homeodomain closely linked to a leucine zipper motif. We have previously reported on the cloning and cDNA sequence of one gene of this class, Athb-3. In this article we show this gene to be expressed predominantly in the cortex of the root and the stem. Using the Athb-3 clone as a probe we have isolated cDNA clones corresponding to three novel homeodomain-leucine zipper proteins. These clones, Athb-5, Athb-6 and Athb-7, hybridized to transcripts that were relatively abundant in the leaf, but also present in other vegetative organs, as well as in the flower. Only weak hybridization was observed to seed pod samples. These observations indicate that these Athb genes have major functions in the mature plant, and therefore, in contrast to homeobox genes in other eukaryotes and to the kn-1 gene in maize, are unlikely to function in the primary control of developmental processes during embryogenesis or organogenesis. The deduced amino acid sequences of Athb-5, Athb-6 and Athb-7 are highly similar to the previously isolated Athb-1, Athb-2 and Athb-3 in the homeodomain and leucine-zipper parts of the proteins, whereas the similarities to homeodomain proteins from other eukaryotes are limited. The Athb proteins thus constitute a new and well defined class of homeodomain proteins, apparently unique to plants.


Effectiveness of a professional identity promotion strategy for nursing students during the COVID-19 pandemic: A quasi-experimental study.
To evaluate the effectiveness of a professional identity promotion strategy (PIPS) on nursing students' professional identity and resilience. This study was a quasi-experimental study with a random cluster sample of 103 sophomore undergraduate nursing students. One hundred students answered the questionnaires at both baseline and follow-up (51 of 53 in the intervention group and 49 of 50 in the control group). Intervention and control groups underwent 5 months PIPS and standard professional education from May 2 to September 27, respectively. Participants completed the professional identity questionnaire for nursing students (PIQNS) and Connor-Davidson resilience scale (CD-RISC). Data were collected at baseline (T0), after the intervention (T1) and 3 months after the intervention (T2), and analyzed using the Chi-squared test, Fisher's exact test, and repeated-measures analysis of variance. There were no significant differences between the two groups (p > .05) regarding demographic questions, professional identity, or resilience at baseline (p > .05). Significant differences were found in professional identity between groups (p < .001), measurement times (p = .026), and in the interaction between groups and measurement times (p = .018) from T0 to T2. Significant differences were found in resilience between groups (p < .001), measurement times (p = .007), and in the interaction between groups and measurement times (p = .035) from T0 to T2. The PIPS program improved nursing students' professional identity and resilience. Further long-term effectiveness of the program needs to be tested with implementation through various forms of mobile technology.


Redox sensitive PEG controlled octaarginine and targeting peptide co-modified nanostructured lipid carriers for enhanced tumour penetrating and targeting in vitro and in vivo.
To strengthen the anti-tumour efficacy and weaken the side effects, a nano targeted drug delivery system was constructed. The nanostructured lipid carriers (NLCs) were prepared by the melt-emulsification method. Modified with the octaarginine, thiolytic cleavable polyethylene glycol (PEG) and targeting peptide simultaneously on the surface, this multifunctional NLC could not only actively target to tumour tissues, but also control the cell penetration effect of the octaarginine easily by a safe reducing agent l-cysteine (l-Cys). In the present study, the pharmaceutical characteristics, the cytotoxicity and cellular uptake on NCI-H1299 cells in vitro, the biodistribution and targeting effect and anti-tumour ability in vivo were employed to evaluate the formulations. As the results revealed, various NLCs had a mean particle size of about 40 nm and a positive zeta potential of about 10 mV. The optimum density of cleavable PEG was confirmed as 10% and the best concentration of l-cysteine was determined as 20 mM via the qualitative and quantitative cellular uptake study. Based on these outcomes, the multiply decorated NLC manifested a great cell growth inhibition with the increased concentration of paclitaxel (PTX). Moreover, it preferred to accumulate at tumours, but not normal organs in vivo. Compared with Taxol®, this preparation demonstrated stronger anti-tumour efficacy and better security. Therefore, the multifunctional NLC can be considered as a promising drug delivery system targeting to tumours.


Effect of topical 0.1% indomethacin solution versus 0.1% fluorometholon acetate on ocular surface and pain control following laser subepithelial keratomileusis (LASEK).
To compare the effect of topical 0.1% indomethacin solution versus 0.1% fluorometholon acetate in the early postoperative period after LASEK treatment. One hundred thirty-five patients undergoing LASEK, having been randomized in a double-masked manner into 2 groups (1 receiving indomethacin and 1 fluorometholon), were evaluated 2-4 days before and 4 days after treatment. We examined corneal fluorescein staining and corneal esthesiometry; the level of pain experienced was reported by the patient on a visual pain scale. In addition, haze was evaluated at 14 +/- 1 weeks after surgery. The pain level and corneal fluorescein staining were significantly less in the indomethacin group. Corneal esthesiometry was reduced to the same extent in the 2 groups. There were no statistically significant differences in haze presentation between the 2 groups. Our study highlights the efficacy of indomethacin solution compared with fluorometholon as a pain reducer after LASEK treatment and suggests that indomethacin is associated with a faster epithelial healing process.


Neutrophil function and bactericidal activity against Staphylococcus aureus after cardiac surgery with cardiopulmonary bypass.
Staphylococcus aureus is the main bacterial pathogen encountered in mediastinitis after cardiac surgical procedures; it remains a devastating complication with a high mortality rate. As neutrophils have a primordial role in the defense against staphylococcus infection and cardiopulmonary bypass (CPB) is known to induce immunosuppression, the aim of this study was to investigate CPB impact on neutrophil functions. Patients without known immunosuppression scheduled for cardiac surgery with CPB were included. Bone marrow and blood samples were harvested before, during, and after surgery. Neutrophil phenotypic maturation and functions (migration, adhesion, neutrophil extracellular trap [NET] release, reactive oxygen species (ROS) production, phagocytosis, and bacteria killing) were investigated. Two types of Staphylococcus aureus strains (one from asymptomatic nasal carriage and another from mediastinitis infected tissues) were used to assess in vitro bacterial direct impact on neutrophils. We found that CPB induced a systemic inflammation with an increase in circulating mature neutrophils after surgery. Bone marrow sample analysis did not reveal any modification of neutrophil maturation during CPB. Neutrophil lifespan was significantly increased and functions such as NET release and ROS production were enhanced after CPB whereas bacteria killing and phagocytosis were not impacted. Results were similar with the two different isolates of Staphylococcus aureus. These data suggest that CPB induces a recruitment of mature neutrophils via a demargination process rather than impacting their maturation in the bone marrow. In addition, neutrophils are fully efficient after CPB and do not contribute to postoperative immunosuppression.


Continuous Glucose Monitoring in Newly Diagnosed Type 2 Diabetes Patients Reveals a Potential Risk of Hypoglycemia in Older Men.
Objectives. We performed continuous glucose monitoring (CGM) to define the features of patients with newly diagnosed type 2 diabetes (T2D) before and after Continuous Subcutaneous Insulin Infusion (CSII) therapy. Methods. This was a retrospective analysis. Newly diagnosed T2D patients (106) were admitted from eight centers in China. They were divided into a younger patient group (<60 years) and an older patient group (≥60 years). Each group was further divided into male and female patients. CSII therapy was maintained for 3 weeks after the glycemic target was reached. CGM was performed 2 times before and after completion of insulin treatment. Results. CGM data showed the expected significant improvement of mean amplitude glycemic excursion (MAGE) with CSII therapy. The older patients had lower hourly glucose concentrations from 0200 to 0700 o'clock compared to the younger patients at baseline. Surprisingly, in the older patient group, the male patients had a potential risk of hypoglycemia after CSII therapy, especially during periods from 2300 to 2400 and 0400 to 0600. Conclusions. Our data suggested that older male patients with newly diagnosed T2D may have lower nocturnal glucose concentrations. This may potentially increase the risk of nocturnal hypoglycemia during CSII therapy. This study was registered with Chinese Clinical Trial Registry, number CliCTR-TRC-11001218.


Hyperbilirubinemia Induces Pro-Apoptotic Effects and Aggravates Renal Ischemia Reperfusion Injury.
Hyperbilirubinemia is associated with postoperative acute kidney injury in patients undergoing cardiac surgeries. A high concentration of bilirubin could induce oxidative stress and cell apoptosis. The aim of this study was to investigate whether hyperbilirubinemia aggravated the renal tubule cells injury and the pro-apoptotic potential of bilirubin on renal ischemia reperfusion injury (RIRI). The human proximal tubular epithelial cell line HK-2 cells were challenged with a gradient concentration of bilirubin for 24 h. Cell injury was assessed by flow cytometry and MTT assay. Bilirubin was injected intraperitoneally into male Sprague-Dawley rats once every 12 h (100 mg/kg), 3 times in total. The same solvent volume without bilirubin powder was used as vehicle in non-bilirubin injection groups. The RIRI surgical procedure was a bilateral renal pedicles clamping (45 min) followed by 30 h reperfusion. The rats were divided into 4 groups: negative control (NC), similar surgical procedures without clamping; Bil, bilirubin injection for 36 h, then rats were sacrificed; RIRI, RIRI surgical procedures; Bil + RIRI, RIRI applied 6 h later than the first bilirubin injection, rats were sacrificed after another 30 h. In vitro, bilirubin induced cell apoptosis and significantly decreased the cell viability of HK-2 cells. Bilirubin induced the active caspase 3 and phosphorylation of p38 in HK-2 cells. In vivo, serum creatinine was higher in Bil + RIRI compared with RIRI (p < 0.01). The tubular injury scores of hematoxylin and eosin and tubular necrosis scores of periodic acid-Schiff were higher in Bil + RIRI than these in RIRI (All p < 0.05). The number of Tunel-positive nuclei was higher in Bil + RIRI compared to RIRI (p < 0.001). The active caspase 3 and phosphorylation of p38 were higher and the Bcl2 was lower in Bil + RIRI compared to RIRI. Moreover, the apoptosis level was higher in Bil compared to NC. Our results reveal that the hyperbilirubinemia induces pro-apoptotic effects and aggravates RIRI.


[Effects of extracts from different parts of Folium perillae (L.) Britt. on Hemorrheological parameters in rats].
In order to provide experimental data for the development and application of drug in clinic, we determined the effects of extracts from different parts of folium perillae (L. ) Britt. on hemorheological parameters, extracted from leaves (folium perillae), seeds (fructus perillae) and peduncles (caulis perillae). The results showed that all extracts from different parts of folium perillae (L. ) Britt. can significantly reduce the whole blood viscosity at low shear rate (10 s(-1)), erythrocyte aggregation index, erythrocyte electrophoresis index (P<0.05), and the whole blood reductive viscosity at low shear rate (10 s(-1)) (P<0.01). Extracts from folium perillae and caulis perillae can significantly decrease erythrocyte deformation index (P<0.05), whereas extracts from fructus perillae can not. Extracts from fructus perillae and caulis perillae can significantly decrease plasma viscosity at low shear rate(10 s(-1)), but extracts of folium perillae can not. Aspirin can only decrease the whole blood reductive viscosity at low shear rate and plasma viscosity (P<0.05). All extracts from different parts of folium perillae (L. ) Britt. had no significant effects on hematocrit, erythrocyte rigidity index, fibrinogen concentration , the whole blood viscosity and the whole blood reductive viscosity at middle and high shear rate (60 s(-1),120 s(-1)).


Advances in sampling and screening for chlamydia.
Chlamydia is the most commonly diagnosed bacterial sexually transmitted infection in the developed world, with diagnosis rates continuing to increase each year. As chlamydia is largely asymptomatic, screening and treatment is the main way to detect cases and reduce transmission. Recent advances in self-collected specimens and laboratory tests has made chlamydia screening easier to implement as well as possible in nonclinical settings. This review will discuss new approaches to specimen collection and how these have expanded opportunities for reaching target populations for chlamydia screening. Furthermore, it will discuss how advanced molecular microbiological methods can be used with self-collected specimens to further our knowledge of the epidemiology of chlamydia and the dynamics of transmission.


High-Throughput Bioanalysis of Bevacizumab in Human Plasma Based on Enzyme-Linked Aptamer Assay Using Anti-Idiotype DNA Aptamer.
We propose a highly selective, sensitive, accurate, and high-throughput bioanalysis method for bevacizumab utilizing an anti-idiotype DNA aptamer. With this method, bevacizumab in a plasma sample was reacted in a 96-well plate immobilized with the aptamer and further reacted with a protein A-HRP conjugate. The resulting HRP activity was colorimetrically detected using a microplate reader. The calibration curve of bevacizumab ranged from 0.05 to 5.0 μg/mL, and showed a good correlation coefficient ( r2 = 1.000). The limit of detection was 2.09 ng/mL. We also demonstrated both the possibility of highly sensitive detection using luminol chemiluminescence and the repeated use of affinity plates. The proposed method is applicable for planning optimal therapeutic programs and for an evaluation of the biological equivalencies in the development of biosimilars.


What do we owe the elderly? Allocating social and health care resources.
The purpose of this report is to present the reflections of an international research group that focused its attention on the moral problems of care for the elderly in the years ahead, and in particular on the problem of an equitable and reasonable allocation of resources. By stressing the "moral" problems, we mean to call attention to an often neglected dimension of the public and professional discussion: that of the obligations owed to the elderly by individuals and society, the reciprocal obligations on the part of the elderly, and the ethical dilemmas that sensitive care for them cannot avoid. Most generally, we want to call attention to the often hidden value issues and considerations of a discussion that, in most countries, is restricted to economic and institutional arrangements only.


Challenges to building and maintaining partnership in the prevention and treatment of pressure injuries in spinal cord injury: a qualitative study of health professionals' views.
The effective management of spinal cord injury (SCI) requires partnership between people with SCI and health professionals (HPs). This paper identifies HPs' perceived challenges in building and maintaining this partnership, with a specific focus on how people with SCI and HPs collaborate in the prevention and treatment of pressure injuries (PIs) in SCI. This study has a qualitative and explorative design. Data were collected through semi-structured interviews and analysed following the principles of thematic analysis. The study population consisted of a purposive sample of HPs (n = 26) working in inpatient and outpatient care in Switzerland with experience in the care of people with SCI. The analysis identified three main challenges: defining responsibilities and expectations, negotiating priorities and establishing and strengthening trust and respect. The HPs argue that the prevention of PIs and self-management are mainly the responsibility of the person with SCI. The HPs have, however, the responsibility to empower, guide, and support persons with SCI in self-management by educating and motivating them. Building and maintaining a partnership with individuals with SCI to prevent and treat PIs is crucial, but it is not an easy task for HPs. Specific communication skills can help HPs and patients find personalised solutions that take into account the patients' expertise and preferences. Additionally, the healthcare system must develop solutions that go beyond personal partnership to better integrate the prevention and treatment of PIs into the lifelong self-management of SCI. Assistive technologies, such as mobile technology, might help in this endeavour.


Rheological and clotting changes in the immediate post-myocardial infarction period.
Several coagulative, fibrinolytic, and rheologic indices were studied in a large group of patients with acute myocardial infarction. The results were compared with those obtained in a normal control group. Changes of blood and plasma viscosity, fibrinogen, and fibrinolytic activity, compatible with a hypercoagulable state, were found in the immediate post-infarction period. However, elevated AT III levels as compared to control group were observed. This could be interpreted as a reactive response to the hypercoagulable state. Significant correlations could be observed between blood viscosity and Ht, plasma viscosity and fibrinogen, fibrinogen and fibrinolytic levels and between fibrinogen and ESR.


[Molecular Biology of the Treatment of Amblyopia with Acupuncture: a Review of Recent Research].
Acupuncture has been found effective for the treatment of amblyopia, and its mechanism has been investigated. A review of recently published research results indicated that when used to treat amblyopia, acupuncture induced changes in the action of neurotransmitters in the visual system, promoted the secretion and synthesis of brain-derived neurotrophic factor, and stimulated the expression of genes related to visual plasticity.


[DNA damages in patients having occupational allergic dermatoses].
Studies of DNA damage processes identified high percentage of antibodies to single- and double-stranded DNA in patients having occupational allergic dermatoses,demonstrated successive increase of antibodies to single- and double-stranded DNA and to nucleosoma with longer length of service.


Discriminating Between Compressive Optic Neuropathy With Glaucoma-Like Cupping and Glaucomatous Optic Neuropathy Using OCT and OCTA.
To discriminate between compressive optic neuropathy with glaucoma-like cupping (GL-CON) and glaucomatous optic neuropathy (GON) by comparing the peripapillary retinal nerve fiber layer (pRNFL) thickness and retinal microvasculature using optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA). In this retrospective cross-sectional study, OCT scans were performed on 28 eyes of GL-CON, 34 eyes of GON, and 41control eyes to determine the pRNFL thickness, ganglion cell complex thickness, and cup/disc ratio. OCTA scans were conducted for 12 eyes of GL-CON, 15 eyes of GON, and 15 control eyes to measure the vessel density of the peripapillary and macular areas. Analysis of covariance was used to perform the comparisons, and the area under the curve was calculated. The GON eyes had a significantly thinner pRNFL in the inferior quadrant and greater vertical cup/disc ratio than the GL-CON eyes. In the radial peripapillary capillary segment, the vessel density of the GON in the inferior sectors was significantly lower than in the GL-CON. The superficial macular vessel density in the whole-image, peritemporal, perinasal, and peri-inferior sectors was significantly smaller in the GON group than in the GL-CON group. The best parameter for discriminating between GL-CON and GON was the superficial macular vessel density in the peritemporal sector. GL-CON eyes showed a characteristic pattern of pRNFL and retinal microvascular changes. GL-CON can be effectively distinguished from GON by detecting the alterations in the pRNFL and retinal microvasculature using OCT and OCTA.


The regulation of gene expression involved in TGF-β signaling by ZNF804A, a risk gene for schizophrenia.
ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. However, the biological functions of ZNF804A are not entirely understood. To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). Furthermore, we confirmed that the expression of ANKRD1, PIK3AP1, INHBE and DDIT3 at the protein level was significantly increased by ZNF804A-overexpression. This is the first report to identify genes whose protein expressions are regulated by ZNF804A. ANKRD1, PIK3AP1, INHBE and DDIT3 are related to transforming growth factor-β (TGF-β) signaling, which plays a crucial role in cell growth and differentiation. On the other hand, recent studies have reported that TGF-β signaling is associated with schizophrenia. These results provide basis for a more progressive investigation of ZNF804A contributions to the susceptibility or pathophysiology of schizophrenia.


Assessment of long term status of sputum positive pulmonary TB patients successfully treated with short course chemotherapy.
Long term status of pulmonary tuberculosis (PTB) patients treated with short course chemotherapy (SCC) regimens remains unknown. To assess the clinical, bacteriological, radiological status and health related quality of life (HRQoL) of PTB patients 14-18 years after successful treatment with SCC. In a cross-sectional study, cured PTB patients treated during 1986-1990 at the Tuberculosis Research Centre (TRC) were investigated for their current health status including pulmonary function tests (PFT). The St Georges respiratory questionnaire (SGRQ) was used to assess the HRQoL. The mean period after treatment completion for the 363 eligible participants was 16.5 yrs (range 14-18 yrs., 84% coverage); 25 (7%) had been re-treated and 52 (14%) died. Among the investigated, 58 (29%) had persistent respiratory symptoms; 170 (86%) had radiological sequelae but none had active disease. Abnormal PFT was observed in 96 (65%) with predominantly restrictive type of disease in 66 (45%). The SGRQ scores for activity and impact were high implying impairment in HRQoL. Assessment of long term status of cured PTB patients showed an impairment of lung functions and HRQoL highlighting the need to address these issues in the management of TB that may provide added value to patient care.


Rituximab Treatment for Idiopathic Hypertrophic Pachymeningitis.
Hypertrophic pachymeningitis (HP) is a rare disease caused by autoimmunity in the meninx that causes various neurologic symptoms, including headache, seizures, weakness, paresthesia, and cranial nerve palsies. Although the first-line therapy for HP is steroids, many HP cases are refractory to steroids or recur when the steroids are tapered. Here we report three HP cases that were successfully treated with rituximab (RTX). From an institutional cohort recruited from April 2012 to July 2016, three HP cases that were identified to be steroid-refractory were treated with RTX (four weekly doses of 375 mg/m²). Clinical improvement was assessed by the number of relapses of any neurologic symptom and the largest dural thickness in MRI. All three patients were recurrence-free of neurologic symptoms and exhibited prominent decreases in the dural thickness after RTX treatment. No adverse events were observed in the patients. We suggest RTX as a second-line therapy for steroid-refractory HP. Further studies are warranted to confirm this observation in a larger population and to consider RTX as a first-line therapy.


CC chemokine receptor 4-positive diffuse large B-cell lymphoma involving the skin: a case report.
Leukocyte trafficking is critically regulated by chemokines and their receptors. The involvement of the skin in certain subsets of T-cell malignancies has been explained by the discovery of an interaction between the thymus and activation-regulated chemokine (TARC), which is abundant in the skin, and its receptor, CC chemokine receptor 4 (CCR4), which is expressed in the tumor cells. We describe a diffuse large B-cell lymphoma (DLBCL) that showed CCR4 expression with involvement of the skin. A 55-year-old man presented with a giant skin ulcer of the right axilla, and his disease was diagnosed as DLBCL. Further clinical examination revealed an ulcerated gastric lymphoma lesion. Immunohistochemical and real-time reverse transcriptase-polymerase chain reaction analyses showed that the tumor cells were positive for CCR4, and TARC was expressed at extremely high levels in the lymphoma-affected skin. These observations suggest that the interaction between CCR4 and TARC played a significant role in the involvement of the skin in this case, similar to what has been observed in certain subsets of T-cell malignancies. To the best of our knowledge, this report is the first of a CCR4-positive B-cell lymphoma. The present case provides new insights into the pathogenesis of skin involvement in B-cell lymphomas.


[History of pre-existing angina and post-infarct myocardial ischemia (symptomatic and asymptomatic)].
353 patients enrolled in a cardiac rehabilitation program underwent a bicycle-ergometric test 28-60 days after an acute myocardial infarction. Twenty-nine patients (8.2%) had a previous history of chronic angina pectoris (more than 6 months before an acute myocardial infarction): 3 of these subjects did not develop myocardial ischemia after infarction; 26 (89.6%) (Group A) had an ischemic response on effort with horizontal or downsloping S-T segment depression of 2 mV. Ninety-four of 324 Patients without history of chronic angina pectoris had an ischemic response at exercise test (Group B) (p less than 0.001). In Group A the association of ischemic electrocardiographic changes and pain during the test was more frequent than in Group B (42.3% vs. 16%) p less than 0.01). During rehabilitation and follow up period (27.2 +/- 14 months) we observed that only 11.5% of Group A Patients remained symptomatic compared to 69.1% Group B Patients (p less than 0.001). In conclusion, a history of chronic pre-infarction angina pectoris appears to be a predictor of symptomatic ischemia after myocardial infarction.


Forecasting peaks of seasonal influenza epidemics.
We present a framework for near real-time forecast of influenza epidemics using a simulation optimization approach. The method combines an individual-based model and a simple root finding optimization method for parameter estimation and forecasting. In this study, retrospective forecasts were generated for seasonal influenza epidemics using web-based estimates of influenza activity from Google Flu Trends for 2004-2005, 2007-2008 and 2012-2013 flu seasons. In some cases, the peak could be forecasted 5-6 weeks ahead. This study adds to existing resources for influenza forecasting and the proposed method can be used in conjunction with other approaches in an ensemble framework.


Self-selection of Asylum Seekers: Evidence From Germany.
I examine the pattern of selection on education of asylum seekers recently arrived in Germany from five key source countries: Afghanistan, Albania, Iraq, Serbia, and Syria. The analysis relies on original individual-level data collected in Germany combined with surveys conducted at origin. The results reveal a positive pattern of selection on education for asylum seekers who were able to flee Iraq and Syria, and the selection is neutral for individuals seeking asylum from Afghanistan and negative for asylum seekers from Albania and Serbia. I provide an interpretation of these patterns based on differences in the expected length of stay at destination, the migration costs faced by asylum seekers to reach Germany, and the size of migration networks at destination.


A CASE OF ACCIDENTAL OCULAR INJURY FROM COSMETIC LASER BURN.
To report the clinical course of a patient sustaining a ocular laser injury from 1,064-nm Nd:YAG cosmetic laser machine. A 31-year-old beauty parlor aesthetician was operating an Nd:YAG cosmetic laser machine of 1,064 nm wavelength. However, the probe was held in the opposite direction, and on firing, the laser shot fired into her left eye. The patient heard a "pop" sound followed by immediate floaters and blurring of vision. Her clinical course was followed for 6 weeks, with investigations including optical coherence tomography, fluorescein angiogram, and Humphrey's visual field examination performed. Optical coherence tomography taken over the injured area showed thickened retina and preretinal hyperreflectivities. Fluorescein angiogram showed hypofluorescence superonasal to the disk with late staining of vessels. Humphrey's visual field showed a dense scotoma emanating from the blind spot. The lesion eventually scarred down, and the patient's vision recovered. The eye is the most susceptible body part to laser light injury. A review of reported laser accidents revealed the majority to be ocular injuries. The retina is particularly vulnerable, as laser light with wavelength between 400 nm and 1,400 nm is focused by the cornea and lens onto the retina, increasing the retinal irradiance as a result. Most injuries were parafoveal, suggesting that most injuries occurred during laser beam alignment. The prognosis is generally favorable. As laser use becomes more widespread and its application increasingly heterogeneous, regulation of laser use and monitoring of laser safety are crucial but at the same time challenging.


Comparative analysis of the canAV-1 and canAV-2 genomes.
The molecular weights of canine adenovirus type 1 (canAV-1, strain Utrecht) and type 2 (canAV-2, strain Toronto A26/61) DNAs were determined by contour length measurements and restriction endonuclease analysis. In each case, an average molecular weight value of 20 (+/- 0.5) X 10(6) daltons was obtained with both methods. Similar in size, the canAV-1 and canAV-2 DNA molecules were, however, cleaved at very distinct positions by a variety of restriction endonucleases. The observed lack of DNA sequence homology confirms the existence of at least two different canine adenovirus species [Intervirology 23: 23-28 (1985)].


Analyses of Respiratory Depression Associated with Opioids in Cancer Patients Based on the Japanese Adverse Drug Event Report Database.
Opioid-induced respiratory depression is a potentially life-threatening adverse drug event. The purpose of this study was to evaluate the incidence of respiratory depression using the Japanese Adverse Drug Event Report (JADER) Database to obtain data to promote proper use of opioids. The JADER database from April 2004 to March 2017 was obtained from the Pharmaceuticals and Medical Devices Agency. We calculated the reporting odds ratios (RORs) of suspected opioids (morphine, fentanyl, oxycodone, tapentadol, methadone, tramadol, pentazocine, buprenorphine, and codeine phosphate hydrate), analyzed the daily dose at first appearance and the time-to-onset profile, and assessed the hazard type using the Weibull shape parameter. ROR analysis detected adverse event signals for all opioids. Morphine showed a large ROR value with statistical significance in elderly (≥70 years old) patients. The median daily doses of oral morphine and oxycodone for inducing respiratory depression were comparably low (30 mg/d as oral morphine equivalent dose), while that of transdermal fentanyl was 120 mg/d (oral morphine equivalent dose). On time-to-onset analysis using the Weibull distribution, those opioids were classified as the early failure type. The median time-to-onset of oral morphine, oral oxycodone and transdermal fentanyl was 5.5, 11 and 12.5 d, respectively, and almost 50% of cases were reported within 30 d. Taken together, our results suggest that it is important to monitor patients carefully for at least the first one week to one month, even if opioids are administered at a relatively low dose, especially in elderly patients administered morphine.


Association of changes in delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) with changes in cartilage thickness in the medial tibiofemoral compartment of the knee: a 2 year follow-up study using 3.0 T MRI.
To determine the association between changes in the delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) index over 2 years as a measure of cartilage proteoglycan concentration, with changes in cartilage thickness in the medial tibiofemoral compartment of knees in middle-aged women. One hundred and forty-eight women (one knee for each subject) aged ≥40 years were included. 3.0 T MR images of the knee were acquired at baseline, 1 year and 2 years. Three-dimensional (3D) spoiled gradient recalled echo (SPGR) sequences (for cartilage thickness) and 3D inversion recovery-prepared SPGR sequences after dGEMRIC were acquired. Segmentation was performed in the medial central (weight-bearing) femur and tibia to determine cartilage proteoglycan concentration and thickness. The association of change in the dGEMRIC indices between baseline and 1-year follow-up with (a) concomitant changes in cartilage thickness and (b) change in cartilage thickness between 1 and 2 years was assessed using linear regression. In the whole-sample model, a decrease in dGEMRIC indices over time at the central medial femur significantly predicted an increase in cartilage thickness at both the central medial femur (p=0.008) and the medial tibia (p=0.04). A decrease in dGEMRIC indices was associated with an increase in cartilage thickness in the medial compartment. Our results suggest that an increase in cartilage thickness may also be related to a decrease in proteoglycan concentration, which may represent swelling of cartilage in early stages of degeneration.


Navigating the transition of care in patients with inborn errors of immunity: a single-center's descriptive experience.
The transition from pediatric to adult care is a critical milestone in managing children, especially in those with complex chronic conditions. It involves ensuring the patient and family adapt correctly to the new phase, maintaining continuity of ongoing treatments, and establishing an appropriate follow-up plan with specialists. Patients with Inborn error of immunity (IEI), formerly known as Primary Immune Disorders (PID) are part of a group of disorders characterized by alterations in the proper functioning of the immune system; as the diagnostic and treatment tools for these entities progress, life expectancy increases, and new needs emerge. These children have special needs during the transition. Particularly important in the group of children with PID and syndromic features, who often present multiple chronic medical conditions. In these cases, transition planning is a significant challenge, involving not only the patients and their families but also a wide range of specialists. To achieve this, a multidisciplinary transition team should be established between the pediatric specialists and the adult consultants, designing a circuit in which communication is essential. As few transition care guidelines in the field of PID are available, and to our knowledge, there is no specific information available regarding patients with PID associated with syndromic features, we share our experience in this issue as a Primary Immunodeficiencies Unit that is a National Reference Center for PID, and propose a guide to achieve an adequate and successful transition to adulthood in these patients, especially in those with associated syndromic features.


The gene transfection properties of a lipophosphoramidate derivative with two phytanyl chains.
Development of efficient and non-toxic gene delivery systems is among the most challenging requirements for successful gene therapy. Cationic lipophosphoramidates constitute a class of cationic lipids we have already shown to be efficient for in vivo gene transfer. Herein, we report the synthesis of a cationic lipophosphoramidate bearing two phytanyl chains (BSV18) as hydrophobic domain, and studied its gene transfection properties. In vitro, BSV18 exhibited a high transfection efficacy associated with a low cytotoxicity. (31)P NMR studies of various cationic lipophosphoramidates in water solution suggested that the phytanyl chains may favor the formation of an inverted hexagonal phase, a supramolecular arrangement which is presumed to enhance the endosomal escape and consequently increase the transfection efficiency. In vivo, systemic delivery of BSV18-based lipoplexes allowed a high efficiency of gene transfection into the mouse lung. With a view to clinical application, we evaluated not only the efficiency of lung transfection but also the eventual in vivo side-effects. Thus, in addition to monitoring the in vivo transfection efficiency by bioluminescent imaging and identifying by immunohistochemistry the cell types transfected, we also assessed in living animals the potential liver reaction as well as the inflammatory and immune responses induced by BSV18-mediated transfection. All those adverse effects were actually highly transient. Thus, taken together, these results indicate that lipophosphoramidates equipped with two phytanyl chains may have great potential for lung gene therapy, in particular for Cystic Fibrosis.


Efficacy of Liposomal Bupivacaine versus Ropivacaine in Adductor Canal Block for Total Knee Arthroplasty.
Adductor canal block (ACB) is advantageous for postoperative analgesia in total knee arthroplasty (TKA) because it results in minimal motor block. Liposomal bupivacaine (LB) is Food and Drug Administration-approved extended-release formulation of bupivacaine for interscalene peripheral nerve blocks. Its use is increasing in the TKA setting, mainly as a local infiltration agent. We compared the efficacy of ACB using LB versus ropivacaine in TKA. Two cohorts of patients were retrospectively analyzed at a single institution receiving ropivacaine and LB ACB for TKA. Duration of LB ACB, time to first opioid use postrecovery room, amount of opioid use postrecovery room, length of stay (LOS), and average and highest pain scores were collected. A total of 91 and 142 TKA patients received ropivacaine and LB for ACB, respectively. At 8 hours postrecovery room, more patients in the LB group required no opioids compared with the ropivacaine group (p = 0.026). Mean opioid consumption was lower in the LB group than in the ropivacaine group at 8 and 24 hours postrecovery room, although statistical significance was only observed at 8 hours (p = 0.022). The highest pain score for patients in the two groups was not statistically different. The average pain score for patients with a 2-day LOS was higher in the LB group, but average pain scores were similar for patients with 1- and 3-day LOS. Median LOS for the LB and ropivacaine groups was 1 and 2 days, respectively (p < 0.0001). Significantly lower opioid use at 8 hours postrecovery room was seen in the LB group compared with the ropivacaine group. There was no difference in opioid use at 24 and 48 hours. There was also no advantage with LB ACB in decreasing pain scores. However, the LB ACB group demonstrated a significantly shorter LOS compared with the ropivacaine ACB group.


Activin A decreases glucagon and arx gene expression in alpha-cell lines.
Activin A is a potent growth and differentiation factor involved in development, differentiation, and physiological functions of the endocrine pancreas; it increases insulin and pax4 gene expression in beta-cells and can induce transdifferentiation of the exocrine acinar cell line AR42J into insulin-producing cells. We show here that Activin A decreases glucagon gene expression in the alpha-cell lines InR1G9 and alphaTC1 in a dose- and time-dependent manner and that the effect is blocked by Follistatin. This effect is also observed in adult human islets. Glucagon gene expression is inhibited at the transcriptional level by the Smad signaling pathway through the G3 DNA control element. Furthermore, Activin A decreases cell proliferation of InR1G9 and alphaTC1 cells as well as cyclin D2 and arx gene expression, whose protein product Arx has been shown to be critical for alpha-cell differentiation. Overexpression of Arx in Activin A-treated InR1G9 cells does not prevent the decrease in glucagon gene expression but corrects the inhibition of cell proliferation, indicating that Arx mediates the Activin A effects on the cell cycle. We conclude that Activin A has opposite effects on alpha-cells compared with beta-cells, a finding that may have relevance during pancreatic endocrine lineage specification and physiological function of the adult islets.


Multidrug resistance related molecules in human and murine lung.
Transporter proteins known to mediate multidrug resistance (MDR) in tumour cells--MDR1 P-glycoprotein (P-gp) and multidrug resistance related protein 1 (MRP1)--are thought to be involved in protecting the lungs against inhaled toxic pollutants. Recently, several new transporter family members have been identified--for example, MRP2, MRP3, and breast cancer resistance protein (BCRP). To study the possible contribution of these proteins and the earlier defined MDR1 and MDR3 P-gp molecules, MRP1, and the major vault protein (MVP) to lung functioning, their expression was analysed in normal lung tissue of humans and several animal species. Frozen sections of normal lung tissues were examined for the expression of the multidrug resistance associated proteins, using an extended panel of monoclonal antibodies that specifically detect these proteins in immunohistochemical techniques. In line with earlier reports, the expression of MDR1 P-gp and MRP1 was readily detected in the apical and basolateral membranes, respectively, of the epithelial cell layers of the lungs. In addition, prominent cytoplasmic MVP staining was detected in these layers. In contrast, the recently discovered transporters were either undetectable or they were present at very low values in lung tissue. Immunohistochemical staining in tissues from mice, rats, and guinea pigs points to a strong evolutionary conservation for these transporter proteins. These results show that the "classic" MDR related molecules, MDR1 P-gp, MRP1, and MVP, should be considered the most important transporters in normal lung physiology. It will be of great interest to investigate differences in expression of both classic and newly defined transporters between normal individuals and-for example, patients with various bronchopulmonary pathological conditions.


Clinical experience with the new long-acting injectable testosterone undecanoate. Report on the educational symposium on the occasion of the 5th World Congress on the Aging Male, 9-12 February 2006, Salzburg, Austria.
This symposium report summarizes first extensive clinical findings with injectable testosterone undecanoate (Nebido) in hypogonadal patients showing clinical symptoms of androgen deficiency with or without erectile dysfunction (ED). This new testosterone formulation (1000 mg testosterone undecanoate in 4 ml castor oil) possesses nearly ideal long-term kinetics, i.e. sustained close mimicking of eugonadal testosterone serum levels without supra- or sub-physiological serum concentrations. The generally accepted administration scheme recommends the second injection 6 weeks after the first one followed by further injections every 12 weeks. Applying this regimen, administration intervals are drastically reduced in comparison to conventional i.m. testosterone preparations (e.g. about 16 injections of testosterone enanthate vs. 4-5 injections of testosterone undecanoate per year). Depending on the testosterone serum levels, individualized therapy is possible by shortening (every 10 weeks) or prolonging (every 14 weeks) the injection intervals. In hypogonadal patients with ED 58% respond to testosterone undecanoate alone. Best results are seen in diabetic hypogonadal patients. The regimen of injectable testosterone undecanoate administration ideally fits recommendations regarding pharmacokinetics, efficacy and safety monitoring.


Cyclooxygenase inhibitors for treating preterm labour: What is the molecular evidence? 1.
Preterm birth (<37 weeks of gestation) significantly increases the risk of neonatal mortality and morbidity. As many as half of all preterm births occur following spontaneous preterm labour. Since in such cases there are no known reasons for the initiation of labour, treatment of preterm labour (tocolysis) has sought to stop labour contractions and delay delivery. Despite some success, the use of cyclooxygenase (COX) inhibitors is associated with maternal/fetal side effects, and possibly increased risk of preterm birth. Clinical use of these drugs predates the collection of molecular and biochemical evidence in vitro, examining the expression and activity of COX enzymes in pregnant uterine tissues with and without labour. Such evidence is important to the rationale that COX enzymes are, or are not, appropriate targets for the tocolysis. The current study systematically searched existing scientific evidence to address the hypothesis that COX expression/activity is increased with the onset of human labour, in an effort to determine whether there is a rationale for the use of COX inhibitors as tocolytics. Our review identified 44 studies, but determined that there is insufficient evidence to support or refute a role of COX-1/-2 in the onset of preterm labour that supports COX-targeted tocolysis.


Hierarchical Surface Structures and Large-Area Nanoscale Gratings in As2S3 and As2Se3 Films Irradiated with Femtosecond Laser Pulses.
Chalcogenide vitreous semiconductors (ChVSs) find application in rewritable optical memory storage and optically switchable infrared photonic devices due to the possibility of fast and reversible phase transitions, as well as high refractive index and transmission in the near- and mid-infrared spectral range. Formed on such materials, laser-induced periodic surface structures (LIPSSs), open wide prospects for increasing information storage capacity and create polarization-sensitive optical elements of infrared photonics. In the present work, a possibility to produce LIPSSs under femtosecond laser irradiation (pulse duration 300 fs, wavelength 515 nm, repetition rate up to 2 kHz, pulse energy ranged 0.03 to 0.5 μJ) is demonstrated on a large (up to 5 × 5 mm2) area of arsenic sulfide (As2S3) and arsenic selenide (As2Se3) ChVS films. Scanning electron and atomic force microscopy revealed that LIPSSs with various periods (170-490 nm) and orientations can coexist within the same irradiated region as a hierarchical structure, resulting from the interference of various plasmon polariton modes generated under intense photoexcitation of nonequilibrium carriers within the film. The depth of the structures varied from 30 to 100 nm. The periods and orientations of the formed LIPSSs were numerically simulated using the Sipe-Drude approach. A good agreement of the calculations with the experimental data was achieved.


Synchronous contralateral axillary lymph node metastasis in a recurrent breast cancer following previous axillary clearance.
Ipsilateral axillary lymph node metastasis is common, while contralateral axillary lymph node metastasis (CAM) is uncommon. This report is of a patient that presented with a recurrence of left breast cancer and synchronous CAM, with a distant history of left breast conserving surgery and axillary dissection for invasive carcinoma. The CAM was confirmed following a non-routine lymphoscintigraphy and sentinel lymph node biopsy. This highlights the possibility of CAM representing as locoregional disease rather than advanced stage IV disease.


Voronoi neighbor statistics of hard-disks and hard-spheres.
The neighbor distribution in hard-sphere and hard-disk fluids is analyzed using Voronoi tessellation. The statistical measures analyzed are the nth neighbor coordination number (Cn), the nth neighbor distance distribution [fn(r)], and the distribution of the number of Voronoi faces (Pn). These statistics are sensitive indicators of microstructure, and they distinguish thermodynamic and annealed structures. A sharp rise in the hexagon population marks the onset of hard-disk freezing transition, and Cn decreases sharply to the hexagonal lattice values. In hard-disk random structures the pentagon and heptagon populations remain significant even at high volume fraction. In dense hard-sphere (three-dimensional) structures at the freezing transition, C1 is close to 14, instead of the value of 12 expected for a face-centered-cubic lattice. This is found to be because of a topological instability, where a slight perturbation of the positions in the centers of a pair of particles transforms a vertex in the Voronoi polyhedron into a Voronoi surface. We demonstrate that the pair distribution function and the equation-of-state obtained from Voronoi tessellation are equal to those obtained from thermodynamic calculations. In hard-sphere random structures, the dodecahedron population decreases with increasing density. To demonstrate the utility of the neighbor analysis, we estimate the effective hard-sphere diameter of the Lennard-Jones fluid by identifying the diameter of the spheres in the hard-sphere fluid which has C1 equal to that for the Lennard-Jones fluid. The estimates are within 2% deviation from the theoretical results of Barker-Henderson and Weeks-Chandler-Andersen.


Combining open and endovascular approaches to complex aneurysms.
Patients with aortic aneurysms commonly present with anatomic issues that preclude them from receiving purely endovascular repairs. In these situations, open surgical procedures can be used to manage anatomic problems and facilitate endovascular aneurysm repair. This report focuses on combined approaches that enable repair of abdominal or thoracoabdominal aortic aneurysms that involve the mesenteric and/or renal circulation. Current experience with combined open/endovascular repairs is essentially anecdotal. The common feature among the open procedures is establishment of extra-anatomic perfusion of the visceral arteries to enable ligation and subsequent coverage of their ostia during endograft placement. The existing reports are notable for the marked variability in many factors including extent of aneurysm repair, surgical approach, mode of visceral revascularization, conduit for bypass, and type of endovascular device used. Overall, current reports demonstrate that patients with limited physiologic reserve and complex aortic anatomy can be treated successfully by combining open and endovascular repairs. As endograft design and endovascular techniques continue to improve, combined approaches are likely to play an increasingly important role in the treatment of extensive aortic disease.


Isolation of plasmid deoxyribonucleic acid from two strains of Bacteroides.
Two clinical isolates of Bacteroides contained covalently closed circular deoxyribonucleic acid (DNA) as shown by sedimentation in an alkaline sucrose gradient, CsCl ethidium bromide equilibrium centrifugation, and electron microscopy. Bacteriodes fragilis N1175 contained a homogeneous species of plasmid DNA with a molecular weight of 25 x 10(6). Bacteroides ochraceus 2228 contained two distinct, covalently closed circular DNA elements. The larger cosedimented with the covalently closed circular DNA form of the R plasmid, R100, corresponding to a molecular weight of 70 x 10(6); the smaller sedimented as a 58S molecule with a calculated molecular weight of 25 x 10(6). The roles of these plasmids are unknown. Neither strain transferred antibiotic resistance to plasmid-negative Bacteroides or Escherichia coli, and neither produced bacteriocins active against other Bacteroides or sensitive indicator strains of E. coli.


Association of Polymorphism in SCN5A, GJA5, and KCNN3 Gene with Sudden Cardiac Death.
We studied association of single-nucleotide SCN5A (rs1805124), GJA5 (rs35594137), and KCNN3 (rs13376333) polymorphisms and sudden cardiac death. Humans died suddenly from cardiac causes (N=379) and unrelated sex- and age-matched control subjects were genotyped. No significant intergroup differences were found in the frequency of rs1805124 and rs13376333 genotypes and alleles. In women under 50 years, enhanced risk of sudden cardiac death was associated with rs35594137 GG genotype (OR=3.6; 95%CI=1.2-10.4; p=0.022), while in older women it was associated with rs35594137 AA genotype (OR=3.0; 95%CI=2.3-3.9; p=0.041). In women under 50 years, GA rs35594137 genotype was associated with a protective effect against sudden cardiac death (OR=0.3; 95%CI=0.1-0.8; p=0.036). Thus, GJA5 gene rs35594137 polymorphism is significantly associated with sudden cardiac death in the examined group.


The different facets of organelle interplay-an overview of organelle interactions.
Membrane-bound organelles such as mitochondria, peroxisomes, or the endoplasmic reticulum (ER) create distinct environments to promote specific cellular tasks such as ATP production, lipid breakdown, or protein export. During recent years, it has become evident that organelles are integrated into cellular networks regulating metabolism, intracellular signaling, cellular maintenance, cell fate decision, and pathogen defence. In order to facilitate such signaling events, specialized membrane regions between apposing organelles bear distinct sets of proteins to enable tethering and exchange of metabolites and signaling molecules. Such membrane associations between the mitochondria and a specialized site of the ER, the mitochondria associated-membrane (MAM), as well as between the ER and the plasma membrane (PAM) have been partially characterized at the molecular level. However, historical and recent observations imply that other organelles like peroxisomes, lysosomes, and lipid droplets might also be involved in the formation of such apposing membrane contact sites. Alternatively, reports on so-called mitochondria derived-vesicles (MDV) suggest alternative mechanisms of organelle interaction. Moreover, maintenance of cellular homeostasis requires the precise removal of aged organelles by autophagy-a process which involves the detection of ubiquitinated organelle proteins by the autophagosome membrane, representing another site of membrane associated-signaling. This review will summarize the available data on the existence and composition of organelle contact sites and the molecular specializations each site uses in order to provide a timely overview on the potential functions of organelle interaction.


Acute and long-term effects of once-daily oral bromocriptine and a new long-acting non-ergot dopamine agonist, quinagolide, in the treatment of hyperprolactinemia: a double-blind study.
Quinagolide (CV 205-502, Sandoz), an octahydrobenzo (g) quinoline, is a new non-ergot dopamine agonist which has specific D2 receptor activity and a long half-life, making it suitable for once-daily treatment. Recent uncontrolled reports have suggested that quinagolide may be successfully used for the clinical management of hyperprolactinemia with fewer adverse reactions than bromocriptine. This study is the first to compare quinagolide in a double-blind manner with bromocriptine, given only once-daily instead of the usual multidose regimen. In the first phase we compared, in 7 hyperprolactinemic patients, the effects over 24 h of a single oral dose of 0.05 mg quinagolide with 2.5 mg bromocriptine. Compared with placebo, both bromocriptine and quinagolide showed potent PRL-inhibiting and GH-releasing effects, with comparable effects at 24 h; no significant changes were observed in TSH, LH, FSH or cortisol. Twelve hyperprolactinemic patients were then randomized to receive either once-daily bromocriptine or quinagolide in incremental doses for a period of six months. Both drugs were found to be equally effective, and no differences were seen either in adverse reactions or PRL levels during repeated diurnal sampling. We therefore conclude that quinagolide and bromocriptine are therapeutically equivalent in long-term use, and both are equally effective when given once a day. However, some patients intolerant of bromocriptine may respond better to quinagolide, and vice versa.


Complete Bilateral Agenesis of the Diaphragm.
Bilateral agenesis of the diaphragm is a very rare congenital diaphragmatic defect. Bilateral congenital diaphragmatic hernia (CDH) is much more frequently associated with other anomalies compared with unilateral CDH (70% vs 30%-40%). These include cardiovascular, respiratory (other than lung hypoplasia), gastrointestinal, renal, and genital malformations. We report a case of complete bilateral agenesis of the diaphragm associated with a horseshoe kidney and an imperforate anus. These additional malformations have not previously been reported in association with complete bilateral agenesis of the diaphragm. We also present a review of previous cases of total diaphragm agenesis published in the English language and provide some insights about pathogenesis.


FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation.
Cytosolic sensing of pathogens and damage by myeloid and barrier epithelial cells assembles large complexes called inflammasomes, which activate inflammatory caspases to process cytokines (IL-1β) and gasdermin D (GSDMD). Cleaved GSDMD forms membrane pores, leading to cytokine release and inflammatory cell death (pyroptosis). Inhibiting GSDMD is an attractive strategy to curb inflammation. Here we identify disulfiram, a drug for treating alcohol addiction, as an inhibitor of pore formation by GSDMD but not other members of the GSDM family. Disulfiram blocks pyroptosis and cytokine release in cells and lipopolysaccharide-induced septic death in mice. At nanomolar concentration, disulfiram covalently modifies human/mouse Cys191/Cys192 in GSDMD to block pore formation. Disulfiram still allows IL-1β and GSDMD processing, but abrogates pore formation, thereby preventing IL-1β release and pyroptosis. The role of disulfiram in inhibiting GSDMD provides new therapeutic indications for repurposing this safe drug to counteract inflammation, which contributes to many human diseases.