The experiences and attitudes of general practitioners and hospital staff towards prehospital thrombolysis in a rural community.
In rural areas it is impossible for eligible patients presenting with acute myocardial infarction (AMI) to receive thrombolysis within the recommended 90 minutes unless administered in the community by the general practitioner. The aim of this study was to describe the attitudes of hospital staff and general practitioners towards pre-hospital administration of thrombolysis. General practitioners, consultant physicians and nursing staff participated in the survey. General practitioners were convinced of the added benefits of administration of thrombolysis in the community and believed the hospital had a role to play. Likewise the hospital staff agreed with the benefits of pre-hospital thrombolysis. However, they felt that the decision to thrombolyse patients should be made in consultation with the hospital. Pre-hospital thrombolysis programmes must be continuously monitored and evaluated to identify important factors that may prevent wider use of thrombolytic treatment.


Quality of life measurement in hidradenitis suppurativa: position statement of the European Academy of Dermatology and Venereology task forces on Quality of Life and Patient-Oriented Outcomes and Acne, Rosacea and Hidradenitis Suppurativa.
This paper is organized jointly by the European Academy of Dermatology and Venereology (EADV) Task Force (TF) on Quality of Life (QoL) and Patient-Oriented Outcomes and the EADV TF on acne, rosacea and hidradenitis suppurativa (ARHS). The purpose of this paper was to present current knowledge about QoL assessment in HS, including data on HS-specific health-related (HR) QoL instruments and HRQoL changes in clinical trials, and to make practical recommendations concerning the assessment of QoL in people with HS. HS results in significant quimp that is higher than in most other chronic skin diseases. HS impact in published studies was assessed predominantly (84% of studies) by the Dermatology Life Quality Index (DLQI). There is a lack of high-quality clinical trials in HS patients where HRQoL instruments have been used as outcome measures. One double-blind randomized placebo-controlled trial on infliximab with low number of participants reported significantly better HRQoL improvement in the treatment group than in the placebo group. Well-designed clinical studies in HS patients to compare different treatment methods, including surgical methods and assessing long-term effects, are needed. Because of lack of sufficient validation, the Task Forces are not at present able to recommend existing HS-specific HRQoL instruments for use in clinical studies. The EADV TFs recommend the dermatology-specific DLQI questionnaire for use in HS patients. The EADV TFs encourage the further development, validation and use of other HS-specific, dermatology-specific and generic instruments but such use should be based on the principles presented in the previous publications of the EADV TF on QoL and Patient-Oriented Outcomes.


Impact of Carbon Nano-Onions on Hydra vulgaris as a Model Organism for Nanoecotoxicology.
The toxicological effects of pristine and chemically modified carbon nano-onions (CNOs) on the development of the freshwater polyp Hydra vulgaris were investigated in order to elucidate the ecotoxicological effects of CNOs. Chemical modifications of the CNOs were accomplished by surface functionalization with benzoic acid, pyridine and pyridinium moieties. thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FT-IR) and Raman spectroscopy confirmed the covalent surface functionalization of CNOs. Hydra specimens were exposed to the carbon nanomaterials by prolonged incubation within their medium. Uptake was monitored by optical microscopy, and the toxicological effects of the CNOs on Hydra behavior, morphology, as well as the long-term effects on the development and reproductive capability were examined. The obtained data revealed the absence of adverse effects of CNOs (in the range 0.05-0.1 mg/L) in vivo at the whole animal level. Together with previously performed in vitro toxicological analyses, our findings indicate the biosafety of CNOs and the feasibility of employing them as materials for biomedical applications.


Enhanced production and activation of progelatinase A mediated by membrane-type 1 matrix metalloproteinase in human oral squamous cell carcinomas: implications for lymph node metastasis.
We measured the production levels of seven different matrix metalloproteinases (MMP-1, 2, 3, 7, 8, 9 and 13) and two tissue inhibitors of metalloproteinases (TIMP-1 and 2) in the homogenates of human oral squamous cell carcinomas and control normal squamous epithelia by the corresponding sandwich enzyme immunoassay systems. The levels of MMP-1, 2, 3, 8, 9, 13 and TIMP-1 were significantly higher in the carcinoma samples than in the control. Among them, only the production level of MMP-2 was significantly higher in the carcinomas with cervical lymph node metastasis than in those without metastasis (P < 0.05). Gelatin zymography demonstrated that activation ratio of the zymogen of MMP-2 (proMMP-2) is significantly higher in the carcinomas with lymph node metastasis than in those without metastasis (P < 0.05) or normal control (P < 0.01). Quantitative RT-PCR for membrane-types 1, 2 and 3 MMPs (MT1, 2 and 3-MMPs), which activate proMMP-2 in vitro, demonstrated that MT1-MMP is predominantly expressed in the carcinoma tissues, and the expression level is significantly higher in the carcinomas with lymph node metastasis than in those without metastasis (P < 0.05) or the control samples (P < 0.05). Although MT2-MMP and MT3-MMP were detected in approximately 30% of the carcinoma cases, their expression levels were extremely lower compared with that of MT1-MMP. There was a direct correlation between the MT1-MMP expression level and proMMP-2 activation ratio (r = 0.62, P < 0.01). In situ hybridization and immunohistochemistry indicated that carcinoma cells and stromal cells adjacent to carcinoma cell nests express MT1-MMP transcripts and protein. MMP-2 and TIMP-2 were also immunolocalized to the carcinoma cells in the carcinoma samples. By in situ zymography, gelatinolytic activity was demonstrated in the carcinoma cell nests and abolished by the treatment with an MMP inhibitor, BB94. These results suggest that among seven different MMPs, the production of proMMP-2 and its activation mediated by MT1-MMP play an important role in the cervical lymph node metastasis of the human oral squamous cell carcinomas.


Bacterial adhesion inhibitor prevents infection in a rodent surgical incision model.
Surgical site infection risk continues to increase due to lack of efficacy in current standard of care drugs. New methods to treat or prevent antibiotic-resistant bacterial infections are needed. Multivalent Adhesion Molecules (MAM) are bacterial adhesins required for virulence. We developed a bacterial adhesion inhibitor using recombinant MAM fragment bound to polymer scaffold, mimicking MAM7 display on the bacterial surface. Here, we test MAM7 inhibitor efficacy to prevent Gram-positive and Gram-negative infections. Using a rodent model of surgical infection, incision sites were infected with antibiotic-resistant bioluminescent strains of Staphylococcus aureus or Pseudomonas aeruginosa. Infections were treated with MAM7 inhibitor or control suspension. Bacterial abundance was quantified for nine days post infection. Inflammatory responses and histology were characterized using fixed tissue sections. MAM7 inhibitor treatment decreased burden of S. aureus and P. aeruginosa below detection threshold. Bacterial load of groups treated with control were significantly higher than MAM7 inhibitor-treated groups. Treatment with inhibitor reduced colonization of clinically-relevant pathogens in an in vivo model of surgical infection. Use of MAM7 inhibitor to block initial adhesion of bacteria to tissue in surgical incisions may reduce infection rates, presenting a strategy to mitigate overuse of antibiotics to prevent surgical site infections.


Elevated in vivo levels of a single transcription factor directly convert satellite glia into oligodendrocyte-like cells.
Oligodendrocytes are the myelinating glia of the central nervous system and ensure rapid saltatory conduction. Shortage or loss of these cells leads to severe malfunctions as observed in human leukodystrophies and multiple sclerosis, and their replenishment by reprogramming or cell conversion strategies is an important research aim. Using a transgenic approach we increased levels of the transcription factor Sox10 throughout the mouse embryo and thereby prompted Fabp7-positive glial cells in dorsal root ganglia of the peripheral nervous system to convert into cells with oligodendrocyte characteristics including myelin gene expression. These rarely studied and poorly characterized satellite glia did not go through a classic oligodendrocyte precursor cell stage. Instead, Sox10 directly induced key elements of the regulatory network of differentiating oligodendrocytes, including Olig2, Olig1, Nkx2.2 and Myrf. An upstream enhancer mediated the direct induction of the Olig2 gene. Unlike Sox10, Olig2 was not capable of generating oligodendrocyte-like cells in dorsal root ganglia. Our findings provide proof-of-concept that Sox10 can convert conducive cells into oligodendrocyte-like cells in vivo and delineates options for future therapeutic strategies.


Consistent production of kojic acid from Aspergillus sojae SSC-3 isolated from rice husk.
A consistent kojic acid producing fungal strain has been isolated from rice husk using glucose-peptone medium. The isolate was identified as Aspergillus sojae SSC-3 on 18S rDNA analysis. A. sojae was capable of producing substantially good amount of kojic acid, however the production was varying from batch to batch. In order to obtain consistent, repeated and high levels of kojic acid, monospore isolation procedures was adopted. The highest production of kojic acid obtained was 12 ± 2 g/L in 120 h with sucrose (10%) and yeast extract (0.5%) as carbon and nitrogen source respectively. The process was scale up to 10 L fermenter size which repeatedly resulted in the production of 18 ± 2 g/L of kojic acid in 96 h. Kojic acid was recovered (> 82%) from the fermentation broth with > 99% purity. Best to our knowledge this is the first report were kojic acid production is reported from Aspergillus sojae strain.


Patterns of papillary thyroid carcinoma cells analyzed in fine-needle aspiration smears may reveal changes in tumor cell behavior.
Fine-needle aspiration (FNA) cytology is widely used to examine thyroid lesions. However, its diagnostic accuracy is limited by the narrow choice of cytopathologic markers indicative of invasive/metastatic powers of a tumor. The aim of this study was to identify features that may serve as such indicators. We have examined FNA smears of 50 histologically proven papillary thyroid carcinoma (PTC) cases applying computer-assisted morphometry to assess patterns formed by PTC cells. Cytokeratine (CK) 8 immunocytochemistry was used to verify the epithelial origin of cells under study. All analyzed smears contained blood, histiocyte-like cells and CK8-positive follicular cells occurring both as single cells and in monolayer cell sheets. In 60% of cases we revealed cell sheets displaying two distinct cell patterns. The first one (pattern R) consisted of moderately pleomorphic, rather regularly arranged cells having an amphophilic cytoplasm. The second one (pattern I) was formed by highly pleomorphic cells with a basophilic cytoplasm. Patterns R and I were clearly different in cell size and shape as well as in nuclear size and shape. These patterns were never observed within the same cell sheet indicating that they may be formed by different subclones of tumor cells. Thus, it can be concluded that PTC frequently displays two definitely different cell patterns. We think that these patterns have a potential to serve as indicators for early events of an invasive/metastatic process. It remains to be seen whether the simultaneous occurrence of these patterns is a PTC-specific feature.


Switching Antipsychotic Medications in People with Schizophrenia: A 4-Year Naturalistic Study.
Although generally effective in ameliorating the core manifestations of schizophrenia, antipsychotics (APs) may lead to only suboptimal responses or may be associated with a variety of treatment-related adverse events which require additional treatment strategies. Under such clinical circumstances, switching APs represents a rational treatment option. The present study aimed to identify the variables that predict AP switch and to quantify the frequency of this phenomenon in people with schizophrenia in real-life. A secondary analysis was conducted on the data collected at baseline and at a 4-year follow-up from a large sample of community-dwelling Italian people with schizophrenia. Demographic and clinical variables as well as information about AP treatment were recorded at two time points. Over the 4-year period, 34.9% of the 571 participants switched the AP; in particular, 8.4% of participants switched from first-generation APs (FGAs) to second-generation APs or vice versa, while 8.2% of them switched to clozapine. Logistic regression models showed that combination of APs at baseline was negatively associated with AP switch, while treatment with FGAs and the presence of extrapyramidal symptoms at baseline were associated with AP class switch. Although the aim of the present study was not to assess predictors of clinical relapse in people with schizophrenia, we might speculate that switching APs represents a surrogate indicator of treatment failure in some patients and could lead into relapse, which is a costly aspect of schizophrenia management in both economic and human terms. The sooner such a negative outcome can be predicted and managed, the sooner the treatment can be optimized to avoid it.


Artefacts in MR images of electrical current distribution.
Artefacts in images of electrical current distribution measured by magnetic resonance imaging (MRI) are presented. These artefacts, caused by the effects of the connecting cables used to apply the electrical current to the object during the MRI scan, can lead to an underestimation of the magnitude of the electrical current measured in the experiment. The size of this underestimate depends upon the experimental geometry, but in the experiments and simulations described here, performed with a cylindrical phantom approximately 8 cm long and 8 cm in diameter, the difference can be 27%. These artefacts are reduced if the connecting cables are rigidly fixed to the object so that the induced magnetic field is correctly measured during the MRI experiment.


Prospective investigation of positron emission tomography in lung nodules.
Solitary pulmonary nodules (SPNs) are commonly identified by chest radiographs and computed tomography (CT). Biopsies are often performed to evaluate the nodules further. An accurate, noninvasive diagnostic test could avoid the morbidity and costs of invasive tissue sampling. We evaluated the ability of fluorine-18 deoxyglucose positron emission tomography (FDG-PET) to discriminate between benign and malignant pulmonary nodules in a prospective, multicenter trial. Eighty-nine patients who had newly identified indeterminate SPNs on chest radiographs and CT were evaluated with FDG-PET. PET data were analyzed semiquantitatively by calculating standardized uptake values (SUVs) as an index of FDG accumulation and also by a visual scoring method. PET results were compared with pathology results. Sixty SPNs were malignant and 29 were benign. Using SUV data, PET had an overall sensitivity and specificity for detection of malignant nodules of 92% and 90%. Visual analysis provided a slightly higher, but not statistically significant, sensitivity of 98% and lower specificity of 69%. For SPNs < or = 1.5 cm (34 of 89), the sensitivity and specificity of SUV and visual analysis were 80% and 95% and 100% and 74%, respectively. FDG-PET can accurately characterize indeterminate SPNs. PET imaging provides a noninvasive method to evaluate indeterminate SPNs, which can reduce the need for invasive tissue biopsy.


Effect of limb muscle fatigue on perception of respiratory effort in healthy subjects.
The role of nonrespiratory peripheral afferents in dyspnea perception has not been fully elucidated yet. Our hypothesis is that fatigue-induced activation of limb muscle metaboreceptors served by group IV fine afferent fibers may impact on respiratory effort perception. We studied 12 healthy subjects breathing against progressive inspiratory resistive loads (10, 18, 30, 40, and 90 cmH(2)O x l(-1) x s) before and after inducing low-frequency fatigue of quadriceps muscle by repeating sustained contractions at > or = 80% of maximal voluntary contraction. Subjects also underwent a sham protocol while performing two loaded breathing runs without muscle fatigue in between. During the loaded breathing, while subjects mimicked the quiet breathing pattern using a visual feedback, ventilation, tidal volume, respiratory frequency, pleural pressure swings, arterial oxygen saturation, end-tidal partial pressure of CO(2), and dyspnea by a Borg scale were recorded. Compared with prefatigue, limb muscle fatigue resulted in a higher increase in respiratory effort perception for any given ventilation, tidal volume, respiratory frequency, pleural pressure swings, end-tidal partial pressure of CO(2), and arterial oxygen saturation. No difference between the two runs was observed with the sham protocol. The present data support the hypothesis that fatigue of limb muscles increases respiratory effort perception associated with loaded breathing, likely by the activation of limb muscle metaboreceptors.


Bacteraemia following dental implants' placement.
To investigate the prevalence, duration and aetiology of bacteraemias following the placement of implants as well as the prophylactic efficacy of a chlorhexidine digluconate (CHX) mouthrinse. Fifty patients undergoing implant placement were randomly distributed into two groups: 30 patients with no prophylactic intervention before surgery. CHX group: 20 patients who performed a 0.2% CHX mouthrinse before surgery. Blood samples were collected at baseline, at 30 s after the insertion of implants and at 15 min after completion of the suturing of the mucoperiosteal flap. Samples were processed in the Bactec 9240, and the subculture and further identification of the isolates were performed using conventional microbiological techniques. The prevalence of bacteraemias was 2% at baseline. In the control group, the prevalence of bacteraemias was 6.7% at 30 s and 3.3% at 15 min, but no statistically significant differences were achieved compared with the baseline percentage. In the CHX group, there were no positive cultures from blood samples obtained at 30 s or at 15 min. Implant placement via a mucoperiosteal flap does not carry a significant risk of developing bacteraemias. The use of antibiotic prophylaxis for the prevention of focal infections such as bacterial endocarditis in "at-risk" patients undergoing dental implants is therefore questionable. Although its efficacy has not been confirmed statistically, we recommend a 0.2% CHX mouthrinse before treatment as proposed previously by the British Society for Antimicrobial Chemotherapy.


The Skin and Natural Cannabinoids-Topical and Transdermal Applications.
The chemical constituents of the Cannabis plant known as cannabinoids have been extensively researched for their potential therapeutic benefits. The use of cannabinoids applied to the skin as a potential method for both skin-related benefits and systemic administration has attracted increasing interest in recent years. This review aims to present an overview of the most recent scientific research on cannabinoids used topically, including their potential advantages for treating a number of skin conditions like psoriasis, atopic dermatitis, and acne. Additionally, with a focus on the pharmacokinetics and security of this route of administration, we investigate the potential of the transdermal delivery of cannabinoids as a method of systemic administration. The review also discusses the restrictions and difficulties related to the application of cannabinoids on the skin, emphasizing the potential of topical cannabinoids as a promising route for both localized and systemic administration. More studies are required to fully comprehend the efficacy and safety of cannabinoids in various settings.


[Significance of nonspecific histopathologic changes in the myocardium in sudden coronary death].
Informative value of non-specific histopathological myocardial changes was determined on the material of 31 autopsy cases of a sudden coronary death (SCD) and comparison of two groups: 18 observations of violent death and 17 observations of an acute alcoholic intoxication. Informative value was assessed using Kullback's criterion. Large- and small-focal cardiosclerosis and cardiomyocyte hyperthrophy were of a high informative value for SCD. Sclerosis of the intramural arteries, congestion on venas and capillaries, muscle fiber fragmentation had an informative value for SCD versus a violent death, and haemorrhages for SCD versus an alcoholic group. Cardiomyocyte vacuolisation and wavelike deformation of muscle fibers were of a low informative value. Cardiomyocyte atrophy and lymphohistiocytic infiltration were informative for SCD when compared to a violent death and for an alcoholic group when compared to SCD. Endothelial proliferation of the microcirculation vessels, myolysis, sludge-phenomenon, lypofuscinosis, stromal lipomatosis were of informative value for the alcoholic group and not for SCD.


Quantifying the loss of information from binning list-mode data.
List-mode data are increasingly being used in single photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging, among other imaging modalities. However, there are still many imaging designs that effectively bin list-mode data before image reconstruction or other estimation tasks are performed. Intuitively, the binning operation should result in a loss of information. In this work, we show that this is true for Fisher information and provide a computational method for quantifying the information loss. In the end, we find that the information loss depends on three factors. The first factor is related to the smoothness of the mean data function for the list-mode data. The second factor is the actual object being imaged. Finally, the third factor is the binning scheme in relation to the other two factors.


Shared carbohydrate epitopes on distinct surface and secreted antigens of the parasitic nematode Toxocara canis.
The nematode parasite Toxocara canis is found in all dog populations and poses a poorly defined health hazard to humans. We have studied excretory-secretory antigen (ES) and surface antigens of the infective larval stage which is tissue-invasive in mammalian hosts. Antigens were probed with a panel of eight monoclonal antibodies raised in mice to whole ES. Six of eight antibodies reacted with periodate-sensitive carbohydrate epitopes on ES molecules, and the remaining two (Tcn-3 and Tcn-6) recognized either peptide or periodate-resistant sugar determinants. By immunoprecipitation and immunoblotting, the anti-carbohydrate monoclonals each reacted with several distinct ES molecules, known from previously published work to possess contrasting biochemical properties. Tcn-3 and -6 were directed predominantly against 32,000 and 120,000 m.w. molecules, respectively. Iodinated surface antigens of similar m.w. were precipitated by each antibody after detergent solubilization, but only two clones (Tcn-2 and -8) were able to bind exposed sites on the epicuticle of intact Toxocara larvae. Significantly, these antibodies do not bind to newly hatched larvae, and their target antigens are poorly expressed until the second day of in vitro cultivation. The specificities of the monoclonals were further studied by cold antibody inhibition of radiolabeled monoclonal binding, and by a matrix of two-site binding assays. These data show that Tcn-2, -4, -5, and -8 recognize a related group of repetitive carbohydrate epitopes, whereas Tcn-1, -6, and -7 bind discrete determinants on the same molecules. These studies are being continued to define further the structure of antigenic Toxocara carbohydrates and to compare the diagnostic utility of carbohydrate and peptide antigens.


MicroRNA expression signatures during malignant progression from Barrett's esophagus to esophageal adenocarcinoma.
Barrett's esophagus is the precursor lesion of esophageal adenocarcinoma, whose progression follows sequential stages. However, the low progression rate and the inadequacy and subjective interpretation of histologic grading in predicting Barrett's esophagus progression call for more objective biomarkers that can improve risk prediction. We conducted a genome-wide profiling of 754 human microRNAs (miRNA) in 35 normal epithelium, 34 Barrett's esophagus, and 36 esophageal adenocarcinoma tissues using TaqMan real-time PCR-based profiling. Unsupervised hierarchical clustering using 294 modestly to highly expressed miRNAs showed clear clustering of two groups: normal epithelium versus Barrett's esophagus/esophageal adenocarcinoma tissues. Moreover, there was an excellent clustering of Barrett's metaplasia (without dysplasia) tissues from normal epithelium tissues. However, Barrett's esophagus tissues of different stages and esophageal adenocarcinoma tissues were interspersed. There were differentially expressed miRNAs at different stages. The majority of miRNA aberrations involved upregulation of expression in Barrett's esophagus and esophageal adenocarcinoma tissues, with the most dramatic alterations occurring at the Barrett's metaplasia stage. Known oncomiRs, such as miR-21, miR-25, and miR-223, and tumor suppressor miRNAs, including miR-205, miR-203, let-7c, and miR-133a, showed progressively altered expression from Barrett's esophagus to esophageal adenocarcinoma. We also identified a number of novel miRNAs that showed progressively altered expression, including miR-301b, miR-618, and miR-23b. The significant miRNA alterations that were exclusive to esophageal adenocarcinoma but not Barrett's esophagus included miR-375 downregulation and upregulation of five members of the miR-17-92 and its homologue clusters, which may become promising biomarkers for esophageal adenocarcinoma development.


Prevention of allergic eye disease by treatment with IL-1 receptor antagonist.
To determine the impact of interleukin-1 (IL-1) inhibition using IL-1 receptor antagonist (IL-1Ra) in a mouse model of allergic eye disease. A/J mice sensitized and challenged with cat dander in the eye were treated with topical IL-1Ra or vehicle alone. Control mice were treated with IL-1Ra or vehicle but sensitized and challenged with phosphate-buffered saline alone. Immediately after the final allergen challenge, the mice were observed for behavioral changes and assessed for lid injection and chemosis. The animals were then killed, eyes and attached lids were removed for either RNA extraction or histology, and draining lymph nodes were removed for either RNA extraction or in vitro stimulation assays. Differences in chemokine message between experimental and control groups-were determined by RNase protection assays. Treatment with IL-1Ra in allergen-challenged animals significantly reduced allergen-induced changes in photosensitivity (60%, P = 0.0002), chemosis (50%, P = 0.0151), and injection (86.7%, P = 0.0068) compared with vehicle-treated controls. Interleukin-1Ra reduced the number of degranulated mast cells and caused a significant reduction in the number of eosinophils infiltrating the conjunctival matrix (P<0.001) after allergen challenge. Examination of chemokine mRNA taken from the conjunctiva and draining lymph nodes by RNase protection assay showed a profound decrease in the production of a number of C-C chemokines. These findings suggest that IL-1Ra is suppressing allergic eye disease by a down-modulation of the recruitment of eosinophils and other inflammatory cells essential for the immunopathogenesis of ocular atopy.


Evolution and the molecular basis of somatic hypermutation of antigen receptor genes.
Somatic hypermutation of immunoglobulin genes occurs in many vertebrates including sharks, frogs, camels, humans and mice. Similarities among species reveal a common mechanism and these include the AGC/T sequence hot spot, preponderance of base substitutions, a bias towards transitions and strand bias. There are some differences among species, however, that may unveil layers of the mechanism. These include a G:C bias in frog and shark IgM but not in nurse shark antigen receptor (NAR), a high frequency of doublets in NAR hypermutation, and the co-occurrence of somatic hypermutation with gene conversion in some species. Here we argue that some of the similarities and differences among species are best explained by error-prone DNA synthesis by the translesion synthesis DNA polymerase zeta (Pol zeta) and, as suggested by others, induction of DNA synthesis by DNA breaks in antigen receptor variable genes. Finally, targeting of the variable genes is probably obtained via transcription-related elements, and it is the targeting phase of somatic hypermutation that is the most likely to reveal molecules unique to adaptive immunity.


Expression of the Ets-1 transcription factor in human astrocytomas is associated with Fms-like tyrosine kinase-1 (Flt-1)/vascular endothelial growth factor receptor-1 synthesis and neoangiogenesis.
Marked neovascularization and vascular endothelial proliferation are characteristic features of malignant gliomas. Vascular endothelial growth factor (VEGF), an angiogenic protein secreted by glioma cells, appears to play a crucial role for induction of neoangiogenesis. The VEGF receptors fms-like tyrosine kinase-1 (Flt-1)/VEGFR-1 and kinase insert domain-containing receptor (KDR)/ VEGFR-2 are up-regulated on the surface of endothelial cells (ECs) in gliomas. Both receptor genes contain an Ets-responsible element in their promoters. The proto-oncogene ets-1 encodes a transcription factor that has been associated with blood vessel formation in vivo under physiological and pathophysiological conditions including tumor neovascularization. Ets-1 is induced by VEGF in cultured ECs. In vitro data also point to a role of Ets-1 as a transcriptional activator of Flt-1. These properties prompted us to investigate Ets-1 expression in 32 human astroglial tumors of WHO grades I-IV and to correlate the data with the expression pattern of VEGF, Flt-1, and KDR. By in situ hybridization, high ets-1 mRNA levels were found in the glioma microvasculature with particularly prominent signals in glomeruloid vascular endothelial proliferations of glioblastomas (WHO grade IV). Semiquantitative reverse transcription-PCR identified the full-length ets-1 transcript but none of three known splice variants encoding isoforms with different functional domains. Immunohistochemical staining demonstrated Ets-1 protein preferentially in the nucleus of those ECs with an epithelioid morphology consistent with an activated state, whereas quiescent flat-shaped ECs predominantly displayed cytosolic immunoreactivity. This observation proposes nuclear translocation of Ets-1 during neoangiogenesis. VEGF synthesis by glioma cells was accompanied by Ets-1 expression in adjacent microvascular ECs. Furthermore, a highly significant correlation was observed between Ets-1 and Flt-1 (but not KDR) expression in ECs of the glioma microvasculature. Our data suggest that VEGF secreted by glioma cells induces Ets-1 in adjacent microvascular ECs, which subsequently transactivates the VEGF receptor Flt-1. This cascade may crucially promote neoangiogenesis in human gliomas.


Differences in first dose response to angiotensin converting enzyme inhibition in congestive heart failure: a placebo controlled study.
To compare the first dose responses to low dose angiotensin converting enzyme inhibitors (captopril, enalapril, and perindopril) in elderly patients with stable chronic heart failure. Double blind, randomised, placebo controlled, parallel, group prospective study of elderly patients with stable chronic heart failure. General hospital in-patient admissions for supervised diuretic withdrawal (24-48 hours) and the introduction of angiotensin converting enzyme inhibitor therapy. 48 unselected elderly (58-85 years) patients with symptomatic but stable chronic heart failure (New York Heart Association grades II-IV) confirmed by clinical history, examination, and cardiological investigations. Patients gave their written and informed consent to receive their initial treatment under double blind conditions; blood pressure was monitored and blood samples taken to measure the pharmacokinetic and neurohormonal responses. Patients were randomised to receive a daily oral dose of placebo, captopril (6.25 mg), enalapril (2.5 mg), or perindopril (2 mg). Blood pressure and heart rate responses, drug concentration, and plasma renin and ACE activities. Differences between treatment groups were analysed by analysis of variance. The four randomised groups of patients had similar age, severity of heart failure (NYHA class), pretreatment diuretic dosage, plasma renin activity, and serum electrolyte state. Placebo treatment caused a modest but significant diurnal fall in blood pressure. Captopril produced a significant early (1.5 hours) and brief fall in blood pressure. The blood pressure fall with enalapril was later (4-10 hours), longer lasting, and was associated with significant slowing of supine heart rate. Though perindopril produced a similar plasma ACE inhibition to that produced by enalapril, it only caused changes in blood pressure that were similar to those caused by placebo. This controlled study is the first to indicate a qualitative difference in the acute response to angiotensin converting enzyme inhibitors with similar structure and metabolism (that is, enalapril and perindopril). Low dose perindopril seems to be less likely to cause hypotension in patients with heart failure. The explanation for the differences is unclear but may reflect differential effects on local tissue angiotensin generation.


Investigation of the stabilisation of freeze-dried lysozyme and the physical properties of the formulations.
The long-term stability of a protein formulation requires that the glass transition temperature (Tg) of the formulation should be maximised and the perturbation of the protein native structure in the dried form after processing minimised. In the present study, the stabilisation of lysozyme structure conferred by excipients was monitored using second derivative Fourier transform infrared spectroscopy and the physical properties of protein formulations were investigated using differential scanning calorimetry. The results showed that the preservation of protein native structure during freeze-drying and the Tg of freeze-dried formulations were excipient- and excipient to enzyme mass ratio-dependent. The freeze-dried lysozyme appeared to be less effectively stabilised compared with the spray-dried enzyme when the excipients and the excipient to enzyme mass ratios were the same. In terms of the preservation of the secondary structure of lysozyme, glycerol and sucrose seemed to be more efficient than trehalose, although the Tg of trehalose-containing formulations were found to be higher than the Tg of the equivalent sucrose-based ones. With adding either trehalose or dextran to sucrose-containing formulations, the stabilisation of lysozyme native structure could be as effective as with sucrose alone, whilst the Tg could be enhanced. The results in this study suggested that lysozyme, processed by freeze-drying, is stabilised primarily by the water substitution mechanism.


Selection versus socialization effects of peer norms on adolescent cigarette use.
Adolescent smokers tend to have friends who also smoke. This association has been attributed to peer socialization and peer selection effects. However, evidence regarding timing and relative magnitude of these effects is mixed. Using a random-intercept cross-lagged panel model, we examined the reciprocal relations between adolescent cigarette use and perceptions of friends' cigarette use in a sample of 387 adolescents, assessed annually for 4 years. Adolescent cigarette use predicted increases in perceived friend use before the reverse effect emerged. Further, some of the effect of early adolescent cigarette use on subsequent use was mediated by changes in perceived friend use. The results support a greater role for friend selection than socialization in predicting early adolescent cigarette use.


Does the Use of a "Walking Bleaching" Technique Increase Bone Resorption Markers?
This randomized clinical trial evaluated the effect of 35% hydrogen peroxide in comparison with 37% carbamide peroxide in a nonvital bleaching technique of "walking bleaching" (four sessions of treatment) on periodontal markers: nuclear factor kappa B-ligand (RANK-L-process of root resorption marker) and interleukin 1β (IL-1β-inflammatory response marker). Fifty volunteers presenting with discoloration of nonvital teeth and endodontic treatment in good condition participated. Fifty teeth were randomly divided into two study groups according to bleaching gel: HP = 35% hydrogen peroxide (n=25) and 37% carbamide peroxide (n=25). Nonvital bleaching was performed with a walking bleaching technique consisting of four sessions of bleach application. Gingival crevicular fluid samples were taken in order to quantify the RANK-L and IL-1β levels by enzyme-linked immunosorbent assay. Samples were obtained from six periodontal sites for each bleached tooth: three vestibular and three palatine (mesial, middle, and distal) at seven time periods: baseline, after each of the four sessions of nonvital bleaching, at one week, and at one month after nonvital bleaching. Tooth color variations were analyzed in each session by VITA Bleachedguide 3D-MASTER (ΔSGU). Significant increments in the RANK-L and IL-1β levels were detected in each evaluated time compared with baseline ( p<0.05); however, no differences were detected between hydrogen peroxide and carbamide peroxide on increments of the biomarkers studied. The change of color was effective for both nonvital bleaching therapies ( p<0.05). Nonvital bleaching induced a significant increment in the RANK-L and IL-1β levels in periodontal tissues around bleached, nonvital teeth.


Lipophilicity Examination of Some ACE inhibitors andHydrochlorothiazide on Cellulose in RP Thin-Layer Chromatography.
In this assay, the evaluation of lipophilicity of four ACE-inhibitors and hydrochlorothiazide (HCTZ) with RP-TLC on cellulose layers was described using three binary solvent systems. The selected ACE inhibitors had sufficiently different structures which can indicate the method suitability for their lipophilicity evaluation as the model substances in comparison with HCTZ. In addition, the linear relationship between the RM-values and composition of mobile phases was established in the current study. From the regression data of the plots, the hydrophobicity parameters, R(0) M and m, were determined and C0 parameter was calculated. The correlations between the experimentally obtained hydrophobicity parameters and calculated log p values were studied. Furthermore, the obtained results were compared with those previously obtained on RP-18 modified silica gel. Very good correlation (r = 0.91; water-ethanol solvent system) between the chromatographically obtained hydrophobicity parameters and calculated log p values confirmed the selection of ACE inhibitors since lisinopril and quinapril were on the opposite sites of linear relationship. The results indicate that cellulose as an easily available sorbent can be successfully used for the lipophilicity investigation of examined substances with RP-TLC.


A tutorial on dealing with time-varying eligibility for treatment: Comparing the risk of major bleeding with direct-acting oral anticoagulants vs warfarin.
In this tutorial, we focus on the problem of how to define and estimate treatment effects when some patients develop a contraindication and are thus ineligible to receive a treatment of interest during follow-up. We first describe the concept of positivity, which is the requirement that all subjects in an analysis be eligible for all treatments of interest conditional on their baseline covariates, and the extension of this concept in the longitudinal treatment setting. We demonstrate using simulated datasets and regression analysis that under violations of longitudinal positivity, typical associational estimates between treatment over time and the outcome of interest may be misleading depending on the data-generating structure. Finally, we explain how one may define "treatment strategies," such as "treat with medication unless contraindicated," to overcome the problems linked to time-varying eligibility. Finally, we show how contrasts between the expected potential outcomes under these strategies may be consistently estimated with inverse probability weighting methods. We provide R code for all the analyses described.


Peptide and protein pheromones in amphibians.
Purification, characterization and biological activity of urodele and anuran sex-pheromones were reviewed. Female-attracting pheromones obtained from the abdominal gland of Cynops pyrrhogaster and C. ensicauda males are peptides consisting of 10 amino acid residues being designated sodefrin and silefrin, respectively. Each pheromone attracted only conspecific females. Molecular cloning of cDNAs encoding sodefrin and silefrin revealed that both are generated from precursor proteins. Synthesis of these pheromones is regulated by prolactin (PRL) and androgen. Responsiveness of the female vomeronasal epithelium to sodefrin is enhanced by PRL and estrogen. The submandibular gland of the male terrestrial salamander, Plethodon jardani secretes a 22-kD proteinaceous pheromone that enhances female receptivity. It was revealed that every salamander synthesizes multiple isoforms of this pheromone, Plethodontid receptivity factor. The magnificent tree frog, Litoria splendida breed in an aquatic environment. The skin glands of the male secrete a female-attracting peptide pheromone, splendipherin, comprising 25 amino acid residues. The significance of the structure of the amphibian sex-pheromone as peptide and protein is discussed in terms of their species specificity.


Second- and third-order nonlinear wavelength conversion in an all-optically poled Si3N4 waveguide.
Silicon nitride (Si3N4) is commonly employed to integrate third-order nonlinear optical processes on a chip. Its amorphous state, however, inhibits significant second-order nonlinear response. Recently, second-harmonic generation enhancement has been observed in Si3N4 waveguides after an all-optical poling (AOP) method. Here we demonstrate that, after AOP of a Si3N4 waveguide, for up to 2 W of coupled pump power, the same telecom-band signal undergoes larger interband wavelength conversion efficiency, based on sum-frequency generation (SFG), than intraband wavelength conversion, based on four-wave mixing. We also confirm the appearance of a phase-matching condition after AOP by measuring the conversion bandwidth and efficiency of SFG at different pump wavelengths.


The neoaortic root in children with transposition of the great arteries after an arterial switch operation.
Neoaortic root changes in children with transposition of the great arteries (TGA) are reportedly risk factors for the development of neoaortic regurgitation (NeoAR). The aims of this study were to assess the neoaortic root diameter and relative proportion in children with TGA after surgical correction and to identify possible correlations with the development of neoaortic insufficiency. Of the 611 children who had the arterial switch operation performed in the Cardiology Department of the Polish Mother's Memorial Hospital, 172 consecutive patients were qualified for this study. The inclusion criteria were: anatomical correction performed during the neonatal period, more than 10 years of postoperative observation and at least two full echocardiographic examinations. NeoAR increased during postoperative follow-up and at the end of the observation period, 76% of the patients had NeoAR (27%-trace, 42%-mild, 7%-moderate and 0.6%-severe). Among the analysed risk factors for NeoAR development, the significant ones were arterial valve discrepancy (OR = 2.05; 95% CI: 1.04-4.02; P = 0.031) and the non-facing commissures (OR = 4.05; 95% CI: 1.34-11.9; P = 0.01). The neoaortic root diameter was not statistically significantly correlated with the presence of NeoAR or with the heart defects associated with transposition. The neoaortic root was initially, on average, 37% (z-score = 1.58) bigger than the aortic root in healthy children. This disproportion increased during the follow-up evaluations to 57% (z-score = 2.09). The neoaortic root in children after the arterial switch procedure develops differently from that in healthy children, but this is not evidently related to NeoAR development or associated heart defects.


[Partial bilateral rupture of the Achilles tendon associated to levofloxacin].
Fluoroquinolones-associated tendonitis and tendon rupture are well described in the literature but these are not frequently observed and related to the new agents of this group, as levofloxacin. This is probably due to the recent introduction and expansion. Although epidemiological studies are needed to know the frequency of that levofloxacin-induced tendinopathies, case-report could alert to the physicians about this possible severe adverse reaction. We present a case of bilateral Achilles tendonitis with partial spontaneous rupture probably associated to levofloxacin.


[Complex diagnosis of bone lesions in lymphogranulomatosis].
A total of 401 patients: 148 men, 134 women and 119 children with Hodgkin's disease were examined to determine the diagnostic value of the radioisotope and x-ray methods in the early detection of metastatic involvement of the skeletal bones. Specific skeletal bone lesions were revealed in 72 patients. Metastatic lesions of the skeletal bones develop more frequently in adults than in children. No significant differences in the site of metastases were noted. Radioisotope examination is an earlier diagnostic method in the early detection of metastatic involvement of the skeletal bones in Hodgkin's disease and more informative in the diagnosis of costal and cranial bone lesions.


Inoculation with plant growth-promoting rhizobacteria improves seagrass Thalassia hemprichii photosynthesis performance and shifts rhizosphere microbiome.
Plant growth-promoting rhizobacteria (PGPR) inoculation is a crucial strategy for maintaining the sustainability of agriculture and presents a promising solution for seagrass ecological restoration in the face of disturbances. However, the possible roles and functions of PGPRs in the seagrass rhizosphere remain unclear. Here, we isolated rhizosphere bacterial strains from both reef and coastal regions and screened two PGPR isolates regarding their in vivo functional traits. Subsequently, we conducted microcosm experiments to elucidate how PGPR inoculation affected seagrass photosynthesis and shape within each rhizosphere microbiome. Both screened PGPR strains, Raoultella terrigena NXT28 and Bacillus aryabhattai XT37, excelled at expressing a specific subset of plant-beneficial functions and increased the photosynthetic rates of the seagrass host. PGPR inoculation not only decreased the abundance of sulfur-cycling bacteria, it also improved the abundance of putative iron-cycling bacteria in the seagrass rhizosphere. Strain XT37 successfully colonized the seagrass rhizosphere and displayed a leading role in microbial network structure. As a nitrogen-fixing bacteria, NXT28 showed potential to change the microbial nitrogen cycle with denitrification in the rhizosphere and alter dissimilatory and assimilatory nitrate reduction in bulk sediment. These findings have implications for the development of eco-friendly strategies aimed at exploiting microbial communities to confer sulfide tolerance in coastal seagrass ecosystem.


Are radiopharmaceuticals self-sterilizing? Radiation effect of gallium-68 and lutetium-177 on bacillus pumilus and staphylococcus succinus.
For radiopharmaceuticals, aseptic preparation in combination with filtration is the most commonly used sterilizing method. In general, the production of radiopharmaceuticals needs to fulfil the requirements of good manufacturing practice. In the scope of this work, we focused on the positron emitter gallium-68 and on the therapeutically used beta- and gamma-emitter lutetium-177, as they are routinely used for in-house synthesis of radiopharmaceuticals in nuclear medicine departments. Our hypothesis is, that radiopharmaceuticals might be self-sterilizing due to a high radioactivity concentration and high-energy radionuclides in the preparation for intravenous injections. Incubation with gallium-68 and lutetium-177 for both 30 minutes and 5 hours post-dispensing did not cause any significant effect on bacteria growth. As the theoretical dose is only 0.1-0.6 % of the Ph. Eur. recommended dose of 25 kGy, we conclude that the beta and positron energy of lutetium-177 and gallium-68 as used for standard radiopharmaceutical in-house production is not sufficient to decrease the number of colony forming units compared to the control values. Based on these findings, gallium-68 and lutetium-177 labeled radiopharmaceuticals are not self-sterilizing under the tested conditions with respect to bacillus pumilus and staphylococcus succinus. Consequently, strict aseptic preparation conditions in addition to end-sterilization of the radiopharmaceutical e.g. through membrane filtration are strongly advised for in-house productions.


Adiposity and Fat-Free Mass of Children Born with Very Low Birth Weight Do Not Differ in Children Fed Supplemental Donor Milk Compared with Those Fed Preterm Formula.
Many mothers of very-low-birth-weight (VLBW) infants (<1500 g) are unable to provide sufficient breast milk, and supplemental pasteurized donor human milk (donor milk) or preterm formula is required. The composition of donor milk differs from that of mother's milk and infants fed with donor milk often exhibit slower growth during hospitalization. The long-term impact of nutrient-enriched donor milk on growth, body composition, or blood pressure is unknown. We aimed to determine the effects of nutrient-enriched donor milk compared with preterm formula on growth, body composition, and blood pressure of children born preterm and with VLBW. Associations with in-hospital mother's milk intake were explored. This study was a follow-up of children at 5.5-y of age who participated in a randomized controlled trial evaluating the effect of nutrient-enriched donor milk (commencing at ≥120 mL·kg-1·d-1) or preterm formula fed as a supplement when mother's milk was unavailable. The trial intervention lasted 90 d or until hospital discharge, whichever occurred first. In this follow-up investigation, differences in total body fat percentage determined by using air displacement plethysmography (primary outcome), fat-free mass, skinfold thickness, waist circumference, BMI z scores, and blood pressure] were evaluated using linear regressions. Of 316 surviving infants from the earlier trial, 158 (50%) participated in the current study (53% male). Mean ± SD birth weight and gestational age were 1013 ± 264 g and 27.9 ± 2.5 wk. The median (IQR) intervention period was 67.5 d (52.0-91.0 d). Mean ± SD age and BMI z score at follow-up were 5.7 ± 0.2 y and -0.3 ± 1.2. Supplemental nutrient-enriched donor milk, compared to preterm formula, was not associated with growth, body composition, or blood pressure. In-hospital mother's milk intake was positively associated with height z score at 5.5 y (β: 0.07; 95% CI: 0.004, 0.1; P = 0.04). Supplemental nutrient-enriched donor milk and preterm formula during initial hospitalization results in comparable long-term growth and body composition in young children born VLBW. This trial was registered at clinicaltrials.gov as NCT02759809 and at isrctn.com as ISRCTN35317141.


Percutaneous removal of upper urinary tract calculi: experience with ultrasonic lithotripsy.
From October 1983 to March 1985, the authors removed upper urinary tract calculi percutaneously in 102 patients. In 89 patients, stones required disruption with an ultrasonic lithotriptor before removal. Fifty-two patients had a stone in the renal pelvis and 20 had calyceal stones only; 21 had stones at both sites and 9 had a stone in the upper ureter. Complete removal of all stone material was achieved in 67 of 68 patients with a solitary calculus, in 13 of 26 with multiple calculi and in 6 of 8 with ureteric calculi. Complications were minimal; three patients had pulmonary edema postoperatively as a result of excessive absorption of irrigating fluid, and one patient sustained a perforation of the descending colon. The mean postoperative hospital stay was 6.8 days and patients were able to return to work a few days after their discharge from hospital. Percutaneous stone removal is a safe and effective procedure and is the surgical procedure of choice for the removal of upper urinary tract calculi.


Desmosine and isodesmosine contents and elastase activity in normal and cirrhotic rat liver.
The contents of desmosine and isodesmosine, the cross-linking amino acids of elastin, were increased 4-fold in rat liver with carbon tetrachloride-induced cirrhosis, which suggests that insoluble elastin accumulates in cirrhosis. Elastase activity in the cirrhotic liver, as determined with 3-carboxypropionyl-L-alanyl-L-alanyl-L-alanine p-nitroanilide, was 17% less than in the normal liver; no change was found when Congo Red-elastin was used as a substrate.


Direct fluorescent antibody assay and polymerase chain reaction for the detection of Chlamydia trachomatis in patients with vernal keratoconjunctivitis.
To identify Chlamydia trachomatis via polymerase chain reaction and a direct fluorescent antibody assay in patients with vernal keratoconjunctivitis while comparing the efficacies of both tests for detecting Chlamydia trachomatis in these conditions. Conjunctival scraping samples were obtained from 177 patients who were divided into two groups: a vernal keratoconjunctivitis group (group A) and a control group (group B). The polymerase chain reaction and a direct fluorescent antibody assay were performed. Sensitivity, specificity, receiver operating characteristic curves, and areas under the curve were calculated for both tests in groups A and B. Receiver operating characteristic curves were plotted using a categorical variable with only two possible outcomes (positive and negative). Statistical analysis revealed a significant association between vernal keratoconjunctivitis and Chlamydia trachomatis infection detected by a direct fluorescent antibody assay with high sensitivity and specificity. All patients in group A with positive polymerase chain reactions also presented with positive direct fluorescent antibody assays. The association between vernal keratoconjunctivitis and Chlamydia trachomatis infection was confirmed by positive direct fluorescent antibody assays in 49.4% of vernal keratoconjunctivitis patients and by positive polymerase chain reactions in 20% of these patients. The direct fluorescent antibody assay detected Chlamydia trachomatis in a higher number of patients than did the polymerase chain reaction. Although the diagnosis of trachoma is essentially clinical, the disease may not be detected in vernal keratoconjunctivitis patients. Due to the high frequency of chlamydial infection detected in patients with vernal keratoconjunctivitis, we suggest considering routine laboratory tests to detect Chlamydia trachomatis in patients with severe and refractory allergic disease.


Cell type-specific DNA methylation in neonatal cord tissue and cord blood: a 850K-reference panel and comparison of cell types.
Accounting for cellular heterogeneity is essential in neonatal epigenome-wide association studies (EWAS) performed on heterogeneous tissues, such as umbilical cord tissue (CT) or cord blood (CB). Using a reference-panel-based statistical approach, the cell type composition of heterogeneous tissues can be estimated by comparison of whole tissue DNA methylation profiles with cell type-specific DNA methylation signatures. Currently, there is no adequate DNA methylation reference panel for CT, and existing CB panels have been generated on lower coverage Infinium HumanMethylation450 arrays. In this study, we generate a reference panel for CT and improve available CB panels by using the higher coverage Infinium MethylationEPIC arrays. We performed DNA methylation profiling of 9 cell types isolated from CT and CB samples from 14 neonates. In addition to these cell types, we profiled DNA methylation of unfractionated CT and CB. Cell type composition of these unfractionated tissue samples, as estimated by our reference panels, was in agreement with that obtained by flow cytometry. Expectedly, DNA methylation profiles from CT and CB were distinct, reflecting their mesenchymal and hematopoietic stem cell origins. Variable CpGs from both unfractionated CT and its isolated cell types were more likely to be located in open seas and intronic regions than those in CB. Cell type specific CpGs in CT were enriched in intercellular matrix pathways, while those from CB were enriched in immune-related pathways. This study provides an open source reference panel for estimation and adjustment of cellular heterogeneity in CT and CB, and broadens the scope of tissue utilization assessed in future neonatal EWAS studies.


New technics in the operative treatment of scoliosis.
Preoperative correction of scoliotic curves by traction and casting improves the results achieved by operation. Use of the halo-hoop apparatus allows controlled correction when combined with spinal osteotomies. The anterior approach to the spine allows better correction and fusion of the more difficult curves of congenital scoliosis and those associated with neurofibromatosis and myelomeningocele.


[Role of intraspecific phenotypic diversity in the ecology of escherichia coli and staphylococcus aureus].
Investigating a complex of biological characteristics, including the inactivating ability of some antiinfectious resistance agents (lysozyme, complement, immunoglobulins, the bactericide component of interferon) in 229 and 257 E. coli and S. aureus strains, respectively, isolated from various sources has revealed the phenotypical polymorphism in the populations of these microorganisms, whose degree and specific features may be characterized by the indices of biological diversity and by the spectra of dominant biological profiles. Interpopulational variability in the bacteria was found to be determined by the specific features of their colonized ecotopes and to reflect the level of their adaptation to their inhabitance. There is a view of the organizational structure of the bacterial species as a whole complex of discrete populations of microorganisms, which include representatives of phenotypically different clone lines that occupy the optimum and some marginal econiches whose relation is supported by migration processes.


Comparative analysis of monkeypox virus infection of cynomolgus macaques by the intravenous or intrabronchial inoculation route.
Monkeypox virus (MPXV) infection has recently expanded in geographic distribution and can be fatal in up to 10% of cases. The intravenous (i.v.) inoculation of nonhuman primates (NHPs) results in an accelerated fulminant disease course compared to that of naturally occurring MPXV infection in humans. Alternative routes of inoculation are being investigated to define an NHP model of infection that more closely resembles natural disease progression. Our goal was to determine if the intrabronchial (i.b.) exposure of NHPs to MPXV results in a systemic disease that better resembles the progression of human MPXV infection. Here, we compared the disease course following an i.v. or i.b. inoculation of NHPs with 10-fold serial doses of MPXV Zaire. Classical pox-like disease was observed in NHPs administered a high virus dose by either route. Several key events were delayed in the highest doses tested of the i.b. model compared to the timing of the i.v. model, including the onset of fever, lesion appearance, peak viremia, viral shedding in nasal and oral swabs, peak cytokine levels, and time to reach endpoint criteria. Virus distribution across 19 tissues was largely unaffected by the inoculation route at the highest doses tested. The NHPs inoculated by the i.b. route developed a viral pneumonia that likely exacerbated disease progression. Based on the observations of the delayed onset of clinical and virological parameters and endpoint criteria that may more closely resemble those of human MPXV infection, the i.b. MPXV model should be considered for the further investigation of viral pathogenesis and countermeasures.


Development of a high-density nonwoven structure to improve the stab resistance of protective clothing material.
The purpose of this research was to enhance the stab resistance of protective clothing material by developing a new high-density nonwoven structure. Ice picks often injure Japanese police officers due to the strict regulation of swords in the country. Consequently, this study was designed to improve stab resistance against ice picks. Most existing anti-stab protective clothing research has focused on various fabrics impregnated with resin, an approach that brings with it problems of high cost and complicated processing. Seldom has research addressed the potential for improving stab resistance by using nonwoven structures, which exhibit better stab resistance than fabric. In this research, we prepared a series of nonwoven structures with densities ranging from about 0.14 g/cm3 to 0.46 g/cm3 by varying the number of stacked layers of Kevlar/polyester nonwoven under a hot press. We then proposed two methods for producing such hot-press nonwovens: the multilayer hot-press method and the monolayer hot-press method. Stab resistance was evaluated according to NIJ Standard-0115.00. We also investigated the relationship among nonwoven density, stab resistance, and flexural rigidity, and here we discuss the respective properties of the two proposed methods. Our results show that stab resistance and flexural rigidity increase with nonwoven density, but flexural rigidity of nonwovens prepared using the monolayer hot-press method only shows a slight change as nonwoven density increases. Though the two methods exhibit little difference in maximum load, the flexural rigidity of nonwovens prepared using the monolayer hot-press method is much lower, which contributes to superior wear comfort. Finally, we investigated the mechanism behind the stabbing process. Stabbing with an ice pick is a complicated process that involves many factors. Our findings indicate that nonwovens stop penetration primarily in two ways: nonwoven deformation and fiber fractures.


Gap junctions: their presence and necessity in myometrium during parturition.
Thin sections of longitudinal and circular muscle of myometrium obtained from rats during pregnancy, at term, during delivery, and postpartum were quantitatively examined in the electron microscope. Gap junctions (low resistance pathways) were only present during or immediately prior to delivery and immediately postpartum. The absence of gap junctions during gestation may be necessary for maintenance of pregnancy, while their occurrence during parturition may lead to effective termination of pregnancy.


Biocuration with insufficient resources and fixed timelines.
Biological curation, or biocuration, is often studied from the perspective of creating and maintaining databases that have the goal of mapping and tracking certain areas of biology. However, much biocuration is, in fact, dedicated to finite and time-limited projects in which insufficient resources demand trade-offs. This typically more ephemeral type of curation is nonetheless of importance in biomedical research. Here, I propose a framework to understand such restricted curation projects from the point of view of return on curation (ROC), value, efficiency and productivity. Moreover, I suggest general strategies to optimize these curation efforts, such as the 'multiple strategies' approach, as well as a metric called overhead that can be used in the context of managing curation resources.


Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly.
CDP-choline (cytidine 5'-diphosphocholine) is a precursor essential for the synthesis of phosphatidylcholine, one of the cell membrane components that is degraded during cerebral ischaemia to free fatty acids and free radicals. Animal studies suggest that CDP-choline may protect cell membranes by accelerating resynthesis of phospholipids. CDP-choline may also attenuate the progression of ischaemic cell damage by suppressing the release of free fatty acids. CDP-choline is the endogenous compound normally produced by the organism. When the same substance is introduced as a drug it can be called citicoline.CDP-choline is mainly used in the treatment of disorders of a cerebrovascular nature. The many years of its presence in the clinical field have caused an evolution in dosage, method of administration, and selection criteria of patients to whom the treatments were given. Modalities of the clinical studies, including length of observation, severity of disturbance, and methodology of evaluation of the results were also heterogeneous. In spite of uncertainties about its efficacy due to these complexities, CDP-choline is a frequently prescribed drug for cognitive impairment in several European countries, especially when the clinical picture is predominantly one of cerebrovascular disease, hence the need for this review. Due to its effects on the adrenergic and dopaminergic activity of the CNS, CDP-choline has also been used as an adjuvant in the treatment of Parkinson's disease. To assess the efficacy of CDP-choline (cytidinediphosphocholine) in the treatment of cognitive, emotional, and behavioural deficits associated with chronic cerebral disorders in the elderly. The trials were identified from a last updated search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 22 April 2004 using the terms CDP-choline, CDP, citicoline, cytidine diphosphate choline or diphosphocholine. The Register contains records from all major health-care databases and many ongoing trials databases and is updated regularly. All relevant unconfounded, double-blind, placebo-controlled, randomized trials of CDP-choline for cognitive impairment due to chronic cerebral disorders were considered for inclusion in the review. Two reviewers independently reviewed the included studies, extracted the data, and pooled it when appropriate and possible. The pooled odd ratios (95% Confidence Interval (CI)) or the average differences (95% CI) were estimated. No intention-to-treat data were available from the studies included. Fourteen studies were included in this review. Some of the included studies did not present numerical data suitable for analysis. Description of participants varied over the years and by type of disorders and severity, and ranged from aged individuals with subjective memory disorders to patients with Vascular Cognitive Impairment (mild to moderate), Vascular Dementia or Senile Dementia (mild to moderate). Seven of the included studies observed the subjects for a period between 20 to 30 days, one study was of 6 weeks duration, four studies used periods extending over 2 and 3 months, one study observed continuous administration over 3 months and one study was prolonged, with 12 months of observation. The studies were heterogeneous in dose, modalities of administration, inclusion criteria for subjects, and outcome measures. Results were reported for the domains of attention, memory testing, behavioural rating scales, global clinical impression and tolerability. There was no evidence of a beneficial effect of CDP-choline on attention. There was evidence of benefit of CDP-choline on memory function and behaviour. The drug was well tolerated. There was some evidence that CDP-choline has a positive effect on memory and behaviour in at least the short to medium term. The evidence of benefit from global impression was stronger, but is still limited by the duration of the studies. Further research with CDP-choline should focus on longer term studies in subjects who have been diagnosed with currently accepted standardised criteria, especially Vascular Mild Cognitive Impairment (VaMCI) or vascular dementia.


A protocol for a pooled analysis of cohort studies: The association between depression and anxiety in epileptic disorders.
Depressive and anxiety disorders constitute major mental health challenges affecting adults of all ages globally. It has been reported that individuals with depressive or anxiety disorders face an elevated risk of developing neurological conditions, including seizures and epilepsy. Additionally, people with these disorders tend to exhibit distinct clinical outcomes compared to the general population. However, the associations between depressive or anxiety disorders and epilepsy remain contentious. Thus, this study aims to elucidate the associations between these neuropsychiatric disorders, including depressive and anxiety disorders, and epilepsy or seizures. We will systematically search three electronic databases-PubMed, EMBASE, and the Cochrane Library-from inception through March 2023 to identify relevant cohort studies investigating the associations between depressive or anxiety disorders and epilepsy or seizures. Two independent reviewers will extract data from eligible studies using pre-designed standardized data extraction forms, and cross-check results. A third author will resolve any discrepancies. Quality assessment will be performed using the Newcastle-Ottawa Quality Assessment Scale (NOS). Pooled risk estimates (Relative risks or hazard ratios with their 95% CI) will be calculated using the DerSimonian-Laird random-effects model. If between-study heterogeneity is identified, we will conduct subgroup analyses or meta-regressions to explore the possible sources of heterogeneity (participants, exposure, outcome, and study design) stratified by various study characteristics. Potential publication bias will be detected through the inspection of funnel plot asymmetry, complemented by the Egger linear regression approach (Egger's test) and the Begg rank correlation test (Begg's test). This pooled analysis will evaluate the association between depressive or anxiety disorders and epilepsy or seizures, providing high-level evidence to inform early identification and prevention strategies for epilepsy or seizures. Given that the data utilized for analysis in this pooled analysis does not involve human subjects or medical records, no ethical approval is required for this study. We intend to present the results of this study at national or international conferences or submit the findings to a peer-reviewed journal. DOI 10.17605/OSF.IO/WM2X8.


The importance of dehydration in determining ion transport in narrow pores.
The transport of hydrated ions through narrow pores is important for a number of processes such as the desalination and filtration of water and the conductance of ions through biological channels. Here, molecular dynamics simulations are used to systematically examine the transport of anionic drinking water contaminants (fluoride, chloride, nitrate, and nitrite) through pores ranging in effective radius from 2.8 to 6.5 Å to elucidate the role of hydration in excluding these species during nanofiltration. Bulk hydration properties (hydrated size and coordination number) are determined for comparison with the situations inside the pores. Free energy profiles for ion transport through the pores show energy barriers depend on pore size, ion type, and membrane surface charge and that the selectivity sequence can change depending on the pore size. Ion coordination numbers along the trajectory showed that partial dehydration of the transported ion is the main contribution to the energy barriers. Ion transport is greatly hindered when the effective pore radius is smaller than the hydrated radius, as the ion has to lose some associated water molecules to enter the pore. Small energy barriers are still observed when pore sizes are larger than the hydrated radius due to re-orientation of the hydration shell or the loss of more distant water. These results demonstrate the importance of ion dehydration in transport through narrow pores, which increases the current level of mechanistic understanding of membrane-based desalination and transport in biological channels.


Mutational loss of a K+ and NH4+ transporter affects the growth and endospore formation of alkaliphilic Bacillus pseudofirmus OF4.
A putative transport protein (Orf9) of alkaliphilic Bacillus pseudofirmus OF4 belongs to a transporter family (CPA-2) of diverse K+ efflux proteins and cation antiporters. Orf9 greatly increased the concentration of K+ required for growth of a K+ uptake mutant of Escherichia coli. The cytoplasmic K+ content of the cells was reduced, consistent with an efflux mechanism. Orf9-dependent translocation of K+ in E. coli is apparently bidirectional, since ammonium-sensitive uptake of K+ could be shown in K+ -depleted cells. The upstream gene product Orf8 has sequence similarity to a subdomain of KTN proteins that are associated with potassium-translocating channels and transporters; Orf8 modulated the transport capacities of Orf9. No Orf9-dependent K+(Na+)/H+ antiport activity was found in membrane vesicles. Nonpolar deletion mutants in the orf9 locus of the alkaliphile chromosome exhibited no K+ -related phenotype but showed profound phenotypes in medium containing high levels of amine-nitrogen. Their patterns of growth and ammonium content suggested a physiological role for the orf9 locus in bidirectional ammonium transport. Orf9-dependent ammonium uptake was observed in right-side-out membrane vesicles of the alkaliphile wild type and the mutant with an orf8 deletion. Uptake was proton motive force dependent and was inhibited by K+. Orf9 is proposed to be designated AmhT (ammonium homeostasis). Ammonium homeostasis is important in high-amine-nitrogen settings and is particularly crucial at high pH since cytosolic ammonium accumulation interferes with cytoplasmic pH regulation. Endospore formation in amino-acid-rich medium was significantly defective and germination was modestly defective in the orf9 and orf7-orf10 deletion mutants.


Limulus amebocyte lysate reactivity, complement activation, and patients' symptoms. Comparison of dialyzer membranes.
This study was undertaken to clarify the role of Limulus amebocyte lysate reactive material (LAL-RM) in the activation of complement in patients during hemodialysis with cuprophan membranes. The authors measured LAL-RM and complement C3a levels predialysis and at 15 and 60 minutes of dialysis in 16 patients dialyzed for 8 weeks on cuprophan membranes and then for a succeeding 8 weeks on cellulose acetate membranes. Patients' symptoms on dialysis with each membrane were assessed. The LAL-RM levels of these patients were compared to those of six patients dialyzed on cellulose acetate membranes only. The LAL-RM and C3a levels rose significantly in the 16 patients while on dialysis with cuprophan membranes, but there was no correlation between the LAL-RM and C3a levels. C3a levels rose significantly in the 16 patients while on dialysis with cellulose acetate membranes, but there was no rise in LAL-RM levels. C3a levels were significantly lower while the patients were on dialysis with the cellulose acetate membranes. The six patients on dialysis with the cellulose acetate membranes only had no detectable LAL-RM in their blood. Patients' symptoms were less while on dialysis with the cellulose acetate membrane, but the difference did not achieve statistical significance. We conclude that LAL-RM plays a very minor role, if any, in the complement activation caused by cuprophan membranes and that cellulose acetate membranes do not release LAL-RM.


First report on establishment and characterization of the extrahepatic cholangiocarcinoma sarcoma cell line CBC2T-2.
Extrahepatic cholangiocarcinoma sarcoma is extremely rare in clinical practice. These cells consist of both epithelial and mesenchymal cells. Patient-derived cell lines that maintain tumor characteristics are valuable tools for studying the molecular mechanisms associated with carcinosarcoma. However, cholangiocarcinoma sarcoma cell lines are not available in cell banks. To establish and characterize a new extrahepatic cholangiocarcinoma sarcoma cell line, namely CBC2T-2. We conducted a short tandem repeat (STR) test to confirm the identity of the CBC2T-2 cell line. Furthermore, we assessed the migratory and invasive properties of the cells and performed clonogenicity assay to evaluate the ability of individual cells to form colonies. The tumorigenic potential of CBC2T-2 cells was tested in vivo using non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice. The cells were injected subcutaneously and tumor formation was observed. In addition, immunohistochemical analysis was carried out to examine the expression of epithelial marker CK19 and mesenchymal marker vimentin in both CBC2T-2 cells and xenografts. The CBC2T-2 cell line was used to screen the potential therapeutic effects of various clinical agents in patients with cholangiocarcinoma sarcoma. Lastly, whole-exome sequencing was performed to identify genetic alterations and screen for somatic mutations in the CBC2T-2 cell line. The STR test showed that there was no cross-contamination and the results were identical to those of the original tissue. The cells showed round or oval-shaped epithelioid cells and mesenchymal cells with spindle-shaped or elongated morphology. The cells exhibited a high proliferation ratio with a doubling time of 47.11 h. This cell line has migratory, invasive, and clonogenic abilities. The chromosomes in the CBC2T-2 cells were polyploidy, with numbers ranging from 69 to 79. The subcutaneous tumorigenic assay confirmed the in vivo tumorigenic ability of CBC2T-2 cells in NOD/SCID mice. CBC2T-2 cells and xenografts were positive for both the epithelial marker, CK19, and the mesenchymal marker, vimentin. These results suggest that CBC2T-2 cells may have both epithelial and mesenchymal characteristics. The cells were also used to screen clinical agents in patients with cholangiocarcinoma sarcoma, and a combination of paclitaxel and gemcitabine was found to be the most effective treatment option. We established the first human cholangiocarcinoma sarcoma cell line, CBC2T-2, with stable biogenetic traits. This cell line, as a research model, has a high clinical value and would facilitate the understanding of the pathogenesis of cholangiocarcinoma sarcoma.


Time is money: Examining the time cost and associated charges of common performance validity tests.
Objective: This study presents data on the time cost and associated charges for common performance validity tests (PVTs). It also applies an approach from cost effectiveness research to comparison of tests that incorporates cost and classification accuracy. Method: A recent test usage survey was used to identify PVTs in common use among adult neuropsychologists. Data on test administration and scoring time were aggregated. Charges per test were calculated. A cost effectiveness approach was applied to compare pairs of tests from three studies using data on test administration time and classification accuracy operationalized as improvement in posterior probability beyond base rate. Charges per unit increase in posterior probability over base rate were calculated for base rates of invalidity ranging from 10 to 40%. Results: Ten commonly used PVTs measures showed a wide range in test administration and scoring time from 1 to 3 minutes to over 40 minutes with associated charge estimates from $4 to $284. Cost effectiveness comparisons illustrated the nuance in test selection and benefit of considering cost in relation to outcome rather than prioritizing time (i.e. cost minimization) classification accuracy alone. Conclusions: Findings extend recent research efforts to fill knowledge gaps related to the cost of neuropsychological evaluation. The cost effectiveness approach warrants further study in other samples with different neuropsychological and outcome measures.


How the Media Places Responsibility for the COVID-19 Pandemic-An Australian Media Analysis.
Global pandemics are likely to increase in frequency and severity, and media communication of key messages represents an important mediator of the behavior of individuals in response to public health countermeasures. Where the media places responsibility during a pandemic is therefore important to study as blame is commonly used as a tool to influence public behavior but can also lead to the subjective persecution of groups. The aim of this paper is to investigate where the media places responsibility for COVID-19 in Australia. Specifically, we identify the key themes and frames that are present and observe how they changed over the course of the COVID-19 pandemic in relation to government actions and progression of the pandemic. Understanding media representations of the COVID-19 pandemic will provide insights into ways in which responsibility is framed in relation to health action. Newspaper articles from the Australian and the Sydney Morning Herald were sampled between January 20 and March 31 2020 on every second Monday. Factiva was used to identify and download newspaper articles using the following search criteria: "COVID-19" OR coronavirus OR "Wuhan virus" OR "corona virus" OR "Hebei virus" OR "wet market" OR (Wuhan AND virus) OR (market AND Wuhan and virus) or (China AND Virus) or (Novel AND Virus). Articles were imported into Nvivo and thematic and framing analyses were used. The results show that framing of the pandemic was largely based on societal issues with the theme of economic disruption prevalent throughout the study time period. Moral evaluations of the pandemic were infrequent initially but increased co-incident with the first signs of "flattening of the curve." Explicit examples of blame were very rare but were commonly implied based on the causal origin of the virus. The Australian printed media were slow to report on the COVID-19 pandemic, in addition they were reluctant to apportion blame until the end of the study period, after confirmed case rates had begun to slow. This is interpreted as being due to an evaluation of the pandemic risks as low by the media and therefore the tools of othering and blame were not used until after the study period when the actual risks had begun to abate, more consistent with an inquiry than a mediating mechanism.


Interleukin-34 is expressed by giant cell tumours of bone and plays a key role in RANKL-induced osteoclastogenesis.
Interleukin-34 (IL-34) is a newly discovered regulator of myeloid lineage differentiation, proliferation, and survival, acting via the macrophage-colony stimulating factor receptor (M-CSF receptor, c-fms). M-CSF, the main ligand for c-fms, is required for osteoclastogenesis and has been already identified as a critical contributor of the pathogenesis of giant cell tumours of bone (GCTs), tumours rich in osteoclasts. According to the key role of M-CSF in osteoclastogenesis and GCTs, the expression of IL-34 in human GCTs was first assessed. Quantitative analysis of IL-34 mRNA expression in 14 human GCTs revealed expression of this cytokine in GCTs as well as M-CSF and c-fms. Immunohistochemistry demonstrated that osteoclast-like cells exhibited a huge immunostaining for IL-34 and that mononuclear stromal cells were slightly positive for this protein. In contrast to osteoblasts, bone-resorbing osteoclasts showed very strong staining for IL-34, suggesting its potential role in the pathogenesis of GCTs by facilitating osteoclast formation. The role of IL-34 in osteoclastogenesis was then studied in murine and human models. IL-34 was able to support RANKL-induced osteoclastogenesis in the absence of M-CSF in all models. Multinucleated cells generated in the presence of IL-34 and RANKL expressed specific osteoclastic markers and resorbed dentine. IL-34 induced phosphorylation of ERK 1/2 and Akt through the activation of c-fms, as revealed by the inhibition of signalling by a specific c-fms tyrosine kinase inhibitor. Furthermore, IL-34 stimulated RANKL-induced osteoclastogenesis by promoting the adhesion and proliferation of osteoclast progenitors, and had no effect on osteoclast survival. Overall, these data reveal that IL-34 can be entirely substituted for M-CSF in RANKL-induced osteoclastogenesis, thus identifying a new biological activity for this cytokine and a contribution to the pathogenesis of GCTs.


Neural circuit of tail-elicited siphon withdrawal in Aplysia. II. Role of gated inhibition in differential lateralization of sensitization and dishabituation.
In the preceding report, we observed that tail-shock-induced sensitization of tail-elicited siphon withdrawal reflex (TSW) of Aplysia was expressed ipsilaterally but that dishabituation induced by an identical tail shock was expressed bilaterally. Here we examined the mechanisms of this differential lateralization. We first isolated the modulatory pathway responsible for the induction of contralateral dishabituation by making selective nerve cuts. We found that an intact pleural-abdominal connective, the descending pathway connecting the ring ganglia with the abdominal ganglion, ipsilateral to the shock was required for contralateral dishabituation. We examined whether network inhibition suppresses the contralateral effects of tail shock in nonhabituated preparations. We found that blockade of inhibitory transmission in the CNS by the nicotinic ACh inhibitor d-tubocurarine (d-TC) rendered tail shock capable of inducing bilateral sensitization. We next asked whether serotonin (5-HT), a neuromodulator released in the CNS in response to tail shock, was affected by d-TC. We found that d-TC does not alter 5-HT processes in the ring ganglia: it had no effect on the lateralized pattern of tail nerve shock-induced changes in tail sensory neuron excitability, a 5-HT-dependent process, and it did not alter tail nerve shock-evoked release of 5-HT. By contrast, d-TC enhanced 5-HT release in the abdominal ganglion. Consistent with this observation, restricting d-TC to the abdominal ganglion rendered tail nerve shock capable of producing bilateral sensitization. Together with the results of the preceding paper, our results suggest a model in which TSW sensitization and dishabituation can be dissociated both anatomically and mechanistically.


Effects of the local alcohol environment on adolescents' drinking behaviors and beliefs.
To examine relationships between characteristics of the local alcohol environment and adolescent alcohol use and beliefs in 50 California cities. The study used longitudinal survey data collected from adolescents; city-level measures of local alcohol policy comprehensiveness, policy enforcement, adult drinking and bar density; and multi-level modeling with three levels (city, individual, time), allowing for random effects. Models included interaction terms (time × alcohol environment characteristics) and main effects, controlling for city and youth demographic characteristics. Analyses also examined possible mediating effects of alcohol-related beliefs. Fifty California cities (50000-500000 population). Random samples of 1478 adolescents and 8553 adults. Past-year alcohol use and heavy drinking, and alcohol-related beliefs (e.g. perceived alcohol availability) among adolescents; past 28-day alcohol use among adults; ratings of local alcohol control policies; funding for enforcement activities; bars per roadway mile. Local alcohol policy comprehensiveness and enforcement were associated with lower levels of past-year alcohol use (betas=-0.003 and -0.085, P<0.05). Bar density was associated with a higher level of past-year alcohol use (beta=1.086, P<0.01). A greater increase in past-year alcohol use and heavy drinking over time was observed among adolescents living in cities with higher levels of adult drinking (betas=0.224 and 0.108, P<0.01). Effects of bar density appeared to be mediated through perceived alcohol availability and perceived approval of alcohol use. Adolescent alcohol use and heavy drinking are related to characteristics of the local alcohol environment, including alcohol control policies, enforcement, adult drinking and bar density. Change in adolescents' drinking appears to be influenced by community-level adult drinking. Bar density effects appear to be mediated through perceived alcohol availability and approval of alcohol use.


Quantifying the economic impact of communication inefficiencies in U.S. hospitals.
Care delivery is a complex enterprise that involves multiple interactions among multiple stakeholders. Effective communication between these dispersed parties is critical to ensuring quality and safety and improves operational efficiencies. Time and motion studies in hospital settings provide strong evidence that care providers-doctors and nurses-spend a significant proportion of their time obtaining or providing information (i.e., communicating). Yet, surprisingly, no studies attempt to quantify the economic waste associated with communication inefficiencies in hospital settings at a national level. Our research focuses on developing models for quantifying the economic burden on hospitals of poor communications. We developed a conceptual model of the effects of poor communications in hospitals that isolates four outcomes: (1) efficiency of resource utilization, (2) effectiveness of core operations, (3) quality of work life, and (4) service quality, identifying specific metrics for each outcome. We developed estimates of costs associated with wasted physician time, wasted nurse time, and increase in length of stay caused by communication inefficiencies across all U.S. hospitals, using primary data collected from interviews in seven hospitals and secondary data from a literature review, the Bureau of Labor Statistics (BLS), and the Agency for Healthcare Research and Quality (AHRQ). We find that U.S. hospitals waste over $12 billion annually as a result of communication inefficiency among care providers. Increase in length of stay accounts for 53 percent of the annual economic burden. A 500-bed hospital loses over $4 million annually as a result of communication inefficiencies. We note that our estimates are conservative as they do not include all dimensions of economic waste arising from poor communications. The economic burden of communication inefficiency in U.S. hospitals is substantial. Information technologies and process redesign may help alleviate some of this burden.


Who and What Does Involvement Involve? A Multi-Sited Field Study of Involvement of Relatives in Danish Psychiatry.
This article gives an account of aspects of a multi-sited field study of involvement of relatives in Danish psychiatry. By following metaphors of involvement across three sites of the psychiatric system-a family site, a clinical site and a policy site-the first author (J.O.) investigated how, and on what grounds, involvement of relatives is perceived in Danish psychiatry. Paradoxically, the current understanding of involvement of relatives fails to take into consideration the perspectives of the relatives per se and families that were being studied. By analyzing involvement from a discourse theoretical perspective laid out by Ernesto Laclau and Chantal Mouffe, the aim of this study is to show how the dominant discourse about involvement at the political and clinical sites is constituted by understandings of mentally ill individuals and by political objectives of involvement. The analysis elucidates how a psycho-ideological discourse positions the mentally ill person as weak, incapable, and ineffective. By contrast, the supporting relative is positioned as a strong, capable, and effective co-therapist. Furthermore, the analysis considers how this dominant discourse of involvement is constituted by a broader discourse of neoliberalism and market orientation, which justifies involvement as a subtle institutionalization of social control. The article highlights that the role of the relative as a co-therapist may be contested by the families' discourse, which emphasizes issues concerning the responsibility toward the mental health of the ill individual as well as toward the psychological milieu of the family.


Identifying potential engaging leaders within medical education: The role of positive influence on peers.
Previous research has paid little to no attention towards exploring methods of identifying existing medical student leaders. Focusing on the role of influence and employing the tenets of the engaging leadership model, this study examines demographic and academic performance-related differences of positive influencers and if students who have been peer-identified as positive influencers also demonstrate high levels of genuine concern for others. Three separate fourth-year classes were asked to designate classmates that had significant positive influences on their professional and personal development. The top 10% of those students receiving positive influence nominations were compared with the other students on demographics, academic performance, and genuine concern for others. Besides age, no demographic differences were found between positive influencers and other students. High positive influencers were not found to have higher standardized exam scores but did receive significantly higher clinical clerkship ratings. High positive influencers were found to possess a higher degree of genuine concern for others. The findings lend support to (a) utilizing the engaging model to explore leaders and leadership within medical education, (b) this particular method of identifying existing medical student leaders, and


Cochlear Synaptopathy Changes Sound-Evoked Activity Without Changing Spontaneous Discharge in the Mouse Inferior Colliculus.
Tinnitus and hyperacusis are life-disrupting perceptual abnormalities that are often preceded by acoustic overexposure. Animal models of overexposure have suggested a link between these phenomena and neural hyperactivity, i.e., elevated spontaneous rates (SRs) and sound-evoked responses. Prior work has focused on changes in central auditory responses, with less attention paid to the exact nature of the associated cochlear damage. The demonstration that acoustic overexposure can cause cochlear neuropathy without permanent threshold elevation suggests cochlear neuropathy per se may be a key elicitor of neural hyperactivity. We addressed this hypothesis by recording responses in the mouse inferior colliculus (IC) following a bilateral, neuropathic noise exposure. One to three weeks post-exposure, mean SRs were unchanged in mice recorded while awake, or under anesthesia. SRs were also unaffected by more intense, or unilateral exposures. These results suggest that neither neuropathy nor hair cell loss are sufficient to raise SRs in the IC, at least in 7-week-old mice, 1-3 weeks post exposure. However, it is not clear whether our mice had tinnitus. Tone-evoked rate-level functions at the CF were steeper following exposure, specifically in the region of maximal neuropathy. Furthermore, suppression driven by off-CF tones and by ipsilateral noise were reduced. Both changes were especially pronounced in neurons of awake mice. This neural hypersensitivity may manifest as behavioral hypersensitivity to sound - prior work reports that this same exposure causes elevated acoustic startle. Together, these results indicate that neuropathy may initiate a compensatory response in the central auditory system leading to the genesis of hyperacusis.


Integrative analysis reveals the recurrent genetic etiologies in idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is increasingly recognized as a chronic, progressive, and fatal lung disease with an unknown etiology. Current studies focus on revealing the genetic factors in the risk of IPF, making the integrative analysis of genetic variations and transcriptomic alterations of substantial value. This study aimed to improve the understanding of the molecular basis of IPF through an integrative analysis of whole-exome sequencing (WES), bulk RNA sequencing (RNA-seq), and single-cell RNA sequencing (scRNA-seq) data. WES is a powerful tool for studying the genetic basis of IPF, allowing for the identification of genetic variants that may be associated with the development of the disease. RNA-seq data provide a comprehensive view of the transcriptional changes in IPF patients, while scRNA-seq data offer a more granule view of cell-type-specific alterations. In this study, we identified a comprehensive mutational landscape of recurrent genomic and transcriptomic variations, including SNPs, CNVs, and differentially expressed genes, in IPF populations, which may play a significant role in the development and progression of IPF. Our study provided valuable insights into the genetic and transcriptomic variations associated with IPF, revealing changes in gene expression that may contribute to disease development and progression. These findings highlight the importance of an integrative approach to understanding the molecular mechanisms underlying IPF and may pave the way for identifying potential therapeutic targets.