Levels of soluble vascular cell adhesion molecule-1 and soluble intercellular adhesion molecule-2 in plasma of patients with hemorrhagic fever with renal syndrome, and significance of the changes in level.
Hemorrhagic fever with renal syndrome (HFRS) is an acute viral disease characterized by endothelial dysfunction. Vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-2 provide costimulatory signals for the activation of T lymphocytes; these adhesion molecules play key roles in leukocyte adherence and propagation of inflammatory responses. They may be involved in the immunologic response that leads to vascular endothelial cell (VEC) and kidney damage of HFRS patients, and increased levels of soluble (s)VCAM-1 and sICAM-2 in plasma may indicate the severity of HFRS. We examined the presence of sVCAM-1 and sICAM-2 in 52 plasma samples collected from 52 patients. We tested these plasma samples for sVCAM-1 and sICAM-2 by double-antibody sandwich ELISA. We found variable, but persistently elevated, levels of sVCAM-1 and sICAM-2 throughout the various phases and types of the disease, which suggested sVCAM-1 may play an important role in the immunopathological lesions of HFRS and is closely correlated to the severity of HFRS and the degree of kidney damage. sICAM-2 may be associated with the hyperfunctioning of the cellular immune response.


Genotypic and phenotypic diversity of cyanobacteria assigned to the genus Phormidium (Oscillatoriales) from different habitats and geographical sites.
In this study, 30 strains of filamentous, non-heterocystous cyanobacteria from different habitats and different geographical regions assigned to diverse oscillatorian genera but here collectively referred to as members of the Phormidium group have been characterized using a polyphasic approach by comparing phenotypic and molecular characteristics. The phenotypic analysis dealt with cell and filament morphology, ultrastructure, phycoerythrin content, and complementary chromatic adaptation. The molecular phylogenetic analyses were based on sequences of the 16S rRNA gene and the adjacent intergenic transcribed spacer (ITS). The sequences were located on multiple branches of the inferred cyanobacterial 16S rRNA tree. For some, but not all, strains with identical 16S rDNA sequences, a higher level of discrimination was achieved by analyses of the less conserved ITS sequences. As shown for other cyanobacteria, no correlation was found between position of the strains in the phylogenetic tree and their geographic origin. Genetically similar strains originated from distant sites while other strains isolated from the same sampling site were in different phylogenetic clusters. Also the presence of phycoerythrin was not correlated with the strains' position in the phylogenetic trees. In contrast, there was some correlation among inferred phylogenetic relationship, original environmental habitat, and morphology. Closely related strains came from similar ecosystems and shared the same morphological and ultrastructural features. Nevertheless, structural properties are insufficient in themselves for identification at the genus or species level since some phylogenetically distant members also showed similar morphological traits. Our results reconfirm that the Phormidium group is not phylogenetically coherent and requires revision.


Disrupted Brain Functional Network Topology in Essential Tremor Patients With Poor Sleep Quality.
Sleep disturbances, especially poor quality of sleep (QoS), are common among essential tremor (ET) patients and may have adverse effects on their quality of life, but the etiology driving the poor QoS in these individuals remains inadequately understood. Few data are available on the neuroimaging alterations of ET with poor QoS. Thirty-eight ET patients with poor QoS (SleET), 48 ET patients with normal QoS (NorET), and 80 healthy controls (HCs) participated in this study. All subjects underwent a 3.0-T magnetic resonance imaging (MRI) scan for resting-state functional MRI data collection. Then, the whole-brain functional connectome was constructed by thresholding the partial correlation matrices of 116 brain regions. Graph theory and network-based statistical analyses were performed. We used a non-parametric permutation test for group comparisons of topological metrics. Partial correlation analyses between the topographical features and clinical characteristics were conducted. The SleET and NorET groups exhibited decreased clustering coefficients, global efficiency, and local efficiency and increased the characteristic path length. Both of these groups also showed reduced nodal degree and nodal efficiency in the left superior dorsolateral frontal gyrus, superior frontal medial gyrus (SFGmed), posterior cingulate gyrus (PCG), lingual gyrus, superior occipital gyrus, right middle occipital gyrus, and right fusiform gyrus. The SleET group additionally presented reduced nodal degrees and nodal efficiency in the right SFGmed relative to the NorET and HC groups, and nodal efficiency in the right SFGmed was negatively correlated with the Pittsburgh Sleep Quality Index score. The observed impaired topographical organizations of functional brain networks within the central executive network (CEN), default mode network (DMN), and visual network serve to further our knowledge of the complex interactions between tremor and sleep, adding to our understanding of the underlying neural mechanisms of ET with poor QoS.


A Precision Medicine Agenda in Traumatic Brain Injury.
Traumatic brain injury remains a leading cause of death and disability across the globe. Substantial uncertainty in outcome prediction continues to be the rule notwithstanding the existing prediction models. Additionally, despite very promising preclinical data, randomized clinical trials (RCTs) of neuroprotective strategies in moderate and severe TBI have failed to demonstrate significant treatment effects. Better predictive models are needed, as the existing validated ones are more useful in prognosticating poor outcome and do not include biomarkers, genomics, proteonomics, metabolomics, etc. Invasive neuromonitoring long believed to be a "game changer" in the care of TBI patients have shown mixed results, and the level of evidence to support its widespread use remains insufficient. This is due in part to the extremely heterogenous nature of the disease regarding its etiology, pathology and severity. Currently, the diagnosis of traumatic brain injury (TBI) in the acute setting is centered on neurological examination and neuroimaging tools such as CT scanning and MRI, and its treatment has been largely confronted using a "one-size-fits-all" approach, that has left us with many unanswered questions. Precision medicine is an innovative approach for TBI treatment that considers individual variability in genes, environment, and lifestyle and has expanded across the medical fields. In this article, we briefly explore the field of precision medicine in TBI including biomarkers for therapeutic decision-making, multimodal neuromonitoring, and genomics.


Human adenovirus serotypes 4p and 11p are efficiently expressed in cell lines of neural tumour origin.
Most currently used adenovirus vectors are based upon adenovirus serotypes 2 and 5 (Ad2 and Ad5), which have limited efficiencies for gene transfer to human neural cells. Both serotypes bind to the known adenovirus receptor, CAR (coxsackievirus and adenovirus receptor), and have restricted cell tropism. The purpose of this study was to find vector candidates that are superior to Ad5 in infecting human neural tumours. Using flow cytometry, the vector candidates Ad4p, Ad11p and Ad17p were compared to the commonly used adenovirus vector Ad5v for their binding capacity to neural cell lines derived from glioblastoma, medulloblastoma and neuroblastoma cell lines. The production of viral structural proteins and the CAR-binding properties of the different serotypes were also assessed in these cells. Computer-based models of the fibre knobs of Ad4p and Ad17 were created based upon the crystallized fibre knob structure of adenoviruses and analysed for putative receptor-interacting regions that differed from the fibre knob of Ad5. The non CAR-binding vector candidate Ad11p showed clearly the best binding capacity to all of the neural cell lines, binding more than 90% of cells of all of the neural cell lines tested, in contrast to 20% or less for the commonly used vector Ad5v. Ad4p and Ad11p were also internalized and produced viral proteins more successfully than Ad5. Ad4p showed a low binding ability but a very efficient capacity for infection in cell culture. Ad17p virions neither bound or efficiently infected any of the neural cell lines studied.


Secondary MGUS following by adenovirus-induced hemorrhagic cystitis after autologous peripheral blood stem cell transplantation in a patient with multiple myeloma.
A 61-year-old man with multiple myeloma (IgG-κ) received autologous peripheral blood stem cell transplantation (PBSCT) after induction of VAD in July 2009, and obtained a very good partial response. In November 2009, he was admitted to our hospital because of adenovirus-induced hemorrhagic cystitis and pneumocystis jiroveci pneumonia. The pneumonia resolved with sulfamethoxazole and steroid pulse therapy, and cystitis subsided spontaneously. In December 2009, serum protein electrophoresis showed two abnormal protein bands (APB)(IgG-λ, IgA-λ), different from the original M-protein, and IgG thereafter increased to 2,771 mg/dl with a concomitant increase in anti-adenovirus antibody to 4,096. In October 2010, APB disappeared. To date, he has been in stable complete remission for five years since PBSCT. The emergence of APB is considered to be a surrogate marker for long-term remission. Immune reconstitution syndrome and APB after high dose chemotherapy following PBSCT are discussed herein.


Ethanol and LPS modulate NF-kappaB activation, inducible NO synthase and COX-2 gene expression in rat liver cells in vivo.
Ethanol and LPS are immunomodulators, whose actions are associated with the activation of the transcription factor, NF-kappaB, that mediates the expression of a number of rapid response genes involved in the whole body inflammatory response to injury, including transcriptional regulation of iNOS and COX-2. We investigated modulation by acute ethanol (EtOH) intoxication, LPS and LPS tolerance of NF-kappaB activation in hepatocytes, Kupffer cells and sinusoidal endothelial cells (SEC), concurrent regulation of iNOS and COX-2 gene expression and the influence of gender on these mechanisms. In vivo EtOH alone or with LPS significantly activates NF-kappaB in Kupffer cells and SEC. iNOS gene expression in these cells is modulated by LPS+EtOH in a gender- dependent manner. Acute EtOH administration enhanced iNOS mRNA in hepatocytes and Kupffer cells.LPS tolerance decreased LPS-induced NF-kappaB activation in Kupffer cells, but markedly raised iNOS mRNA in all three cell types with gender differences (females being higher). In LPS tolerant rats EtOH decreased elevated iNOS mRNA in all cells studied. LPS tolerance significantly reduced LPS-induced COX-2 mRNA in SEC, but only moderately in Kupffer cells of females, and not at all in males. Since NO is a known scavenger of superoxide and therefore protective against oxidative injury associated with LPS and acute EtOH intoxication, the gender differential effect of LPS+EtOH on iNOS gene expression (reduced only in females) may contribute to the greater susceptibility of females to alcoholic liver disease. Suppression of COX-2 gene expression in SEC may cause detrimental effects in the hepatic microcirculation, associated with cirrhosis.


Disinfection of Virtual Reality Devices in Health Care Settings: In Vitro Assessment and Survey Study.
Virtual reality (VR) devices are increasingly used in health care settings. The use among patients has the potential to unintentionally transmit pathogens between patients and hospital staff. No standard operating procedure for disinfection exists to ensure safe use between patients. This study aims to determine the efficacy of disinfectants on VR devices in order to ensure safe use in health care settings. Three types of bacteria were inoculated onto porous and nonporous surfaces of 2 VR devices: the Meta Oculus Quest and Meta Oculus Quest 2. Disinfection was performed using either isopropyl alcohol or alcohol-free quaternary ammonium wipes. A quantitative culture was used to assess the adequacy of disinfection. A survey was separately sent out to VR device technicians at other pediatric health care institutes to compare the methods of disinfection and how they were established. Both products achieved adequate disinfection of the treated surfaces; however, a greater log-kill was achieved on nonporous surfaces than on the porous surfaces. Alcohol performed better than quaternary ammonium on porous surfaces. The survey respondents reported a wide variability in disinfection processes with only 1 person reporting an established standard operating procedure. Disinfection can be achieved through the use of either isopropyl alcohol or quaternary ammonium products. Porous surfaces showed lesser log-kill rates than the nonporous surfaces, indicating that the use of an added barrier may be of benefit and should be a point of future research. Given the variability in the disinfection process across health care systems, a standard operating procedure is proposed.


Total venous obstruction--a possible complication of transvenous dual-chamber pacing.
Transvenous endocardial pacing has been widely accepted as an effective means to treat patients with bradycardia, though there are some complications unique to this approach. For example, occlusion of the major vessels can be induced by the presence of a single pacing electrode, though it is an extremely rare occurrence. In this paper, we describe 2 cases of venous obstruction complications caused by dual-chamber pacemaker implantation. Venographic studies were useful to confirm the diagnosis, and immediate anticoagulant therapy resulted in a good course. It is speculated that this phenomenon will increase as physiological, dual-chamber pacing becomes more widely performed. Physicians must pay careful attention to the complication of venous obstruction when managing patients with implanted transvenous dual-chamber pacemakers.


Proliferation and micromilieu during fractionated irradiation of human FaDu squamous cell carcinoma in nude mice.
Previous functional radiobiological experiments demonstrated a significant acceleration of repopulation after 3 weeks and reoxygenation after 12 days of radiotherapy of FaDu tumours. Owing to the temporal coincidence between repopulation and reoxygenation, it was hypothesized that the improved oxygenation status during fractionated irradiation might be the preceding stimulus for increased proliferation. The study investigated whether these changes in repopulation and re-oxygenation are reflected by histological parameters of proliferation and the tumour micromilieu. Human FaDu squamous cell carcinomas in nude mice were irradiated with three to 18 fractions of 3 Gy daily or every second day under normal blood flow and clamp hypoxia. At different time points, tumours were excised and stained for Ki67, BrdUrd, epidermal growth factor receptor (EGFR) and markers of the micromilieu (HOECHST 33342, pimonidazole, ER-MP12). On average, Ki67 and BrdUrd labelling indices decreased initially and increased again at later times during the course of fractionated radiotherapy. A similar kinetic pattern was found for the staining intensity of the EGFR. The vascular density in the viable tumour area remained constant during the whole course of irradiation, while the perfused fraction of vessels decreased within the first week of irradiation and returned to baseline values after 2 weeks. There was a corresponding increase in perfusion and a decrease in cellular hypoxia. The histological results were in surprisingly good agreement with the kinetics of clonogen repopulation and re-oxygenation determined previously using functional assays. The results support that the kinetics of repopulation of FaDu squamous cell carcinoma in response to fractionated irradiation are determined not only by intracellular processes, but also by a complex interaction of proliferation parameters with a changing microenvironment.


Oxaliplatin and raltitrexed in the treatment of inoperable malignant pleural mesothelioma: results of a pilot study.
The treatment of inoperable malignant pleural mesothelioma is a challenge for the oncologist. Available chemotherapy regimens achieve poor results, therefore new agents or combinations are needed. In a phase I study, the combination of oxaliplatin and raltitrexed was shown to be active against malignant pleural mesothelioma. We herein report the results of a pilot study about the treatment of this disease. From April 1999 to June 2000, we enrolled 11 chemotherapy-naïve patients with inoperable malignant pleural mesothelioma suitable to receive the following combination chemotherapy: raltitrexed, 3 mg/m2 iv, and oxaliplatin, 130 mg/m2, as a 2-hr infusion every 3 weeks. Four partial responses, 1 regression of disease (objective response rate, 45%; 95% CI, 15.6-74.4%), 4 stable diseases and 2 progressions of disease were observed. An improvement in disease-related symptoms was recorded in all responders and in 2 patients with stable disease. Toxicity was mild, with no toxic-related death and only 1 episode of grade 4 neurotoxicity. We consider the combination promising and worthy of further studies.


A review of systems for continued education and training in the substance abuse field.
Continued education of professionals is a major factor for service improvement and evidence-based good practice. This project explores the strategies used for this purpose across countries (CET = continued education and training in the substance abuse field). A structured questionnaire was circulated internationally by an expert committee of the Swiss Federal Office of Public Health. Reports from 11 countries were collected in 2005. The following review is based on these reports and structured according to the questionnaire (questions in italics). The authors of the reports are listed in the acknowledgements. The countries are Australia, Austria, Finland, France, Germany, Greece, Italy, The Netherlands, Scotland, Switzerland, and the United States. As a result of this project, an international think tank on continued education and training was established and is briefly described.


NBQX, a competitive non-NMDA receptor antagonist, reduces degeneration due to focal spinal cord ischemia.
We have used the laser-induced photochemical thrombosis model in adult rats to evaluate the significance of the non-N-methyl-D-aspartate (non-NMDA) subtype of glutamate receptors in situations of focal spinal cord ischemia. The animals were pretreated with the selective non-NMDA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)-quinoxaline (NBQX) or, for comparison, the NMDA antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5-10-imine (MK-801). Neurological function was quantified using evaluations of motor score and inclined plane. The MK-801-treated rats had higher motor scores during the 3-week observation period while NBQX-treated rats only performed significantly better at 1 week. Both treatments caused significantly better performance in the inclined plane test. NBQX and MK-801 reduced the volume of necrosis by approximately 47% at 3 weeks postlesion. We conclude that blockade of both NMDA and non-NMDA subtypes of glutamate receptors reduces ischemic necrosis, possibly by preventing excessive stimulation of these receptors by released excitatory amino acids in the lesion area.


Comparison between healthy and reduced hand function using ranges of motion and a weighted fingertip space model.
Detection and quantification of changes in hand function are important for patients with loss of function and clinicians who are treating them. A recently developed model, the weighted fingertip space (WFS) quantifies the hand function of individuals in three-dimensional space and applies kinematic weighting parameters to identify regions of reachable space with high and low hand function. The goal of this research was to use the WFS model to compare and contrast the functional abilities of healthy individuals with the abilities of individuals with reduced functionality due to arthritis (RFA). Twenty two individuals with no reported issues with hand function and 21 individuals with arthritis affecting the hand were included in the research. Functional models were calculated from the ranges of motion and hand dimension data for each individual. Each model showed the volume of reachable space for each fingertip of each hand, the number of ways to reach a point in space, the range of fingertip orientations possible at each point, and the range of possible force application directions (FADs) at each point. In addition, two group models were developed that showed how many individuals in both the healthy and RFA groups were able to reach the same points in space. The results showed differences between the two groups for the range of motion (ROM) measurements, the individual model calculations, and the group models. The ROM measurements showed significant differences for the joints of the thumb, extension of the nonthumb metacarpophalangeal (MCP) joints, and flexion of the distal interphalangeal (DIP) joints. Comparing the models, the two groups qualitatively showed similar patterns of functional measures in space, but with the RFA group able to reach a smaller volume of space. Quantitatively, the RFA group showed trends of smaller values for all of the calculated functional weighting parameters and significantly smaller reachable volume for all of the fingers. The group models showed that all healthy individuals were able to reach an overlapping space, while 18 of 21 RFA individuals were able to reach similar spaces. Combined, the results showed that the WFS model presents the abilities of the hand in ways that can be quantitatively and qualitatively compared. Thus, the potential of this hand model is that it could be used to assess and document the changes that occur in hand function due to rehabilitation or surgery, or as a guide to determine areas most accessible by various populations.


Identifying well-folded de novo proteins in the new era of accurate structure prediction.
Computational de novo protein design tailors proteins for target structures and oligomerisation states with high stability, which allows overcoming many limitations of natural proteins when redesigned for new functions. Despite significant advances in the field over the past decade, it remains challenging to predict sequences that will fold as stable monomers in solution or binders to a particular protein target; thereby requiring substantial experimental resources to identify proteins with the desired properties. To overcome this, here we leveraged the large amount of design data accumulated in the last decade, and the breakthrough in protein structure prediction from last year to investigate on improved ways of selecting promising designs before experimental testing. We collected de novo proteins from previous studies, 518 designed as monomers of different folds and 2112 as binders against the Botulinum neurotoxin, and analysed their structures with AlphaFold2, RoseTTAFold and fragment quality descriptors in combination with other properties related to surface interactions. These features showed high complementarity in rationalizing the experimental results, which allowed us to generate quite accurate machine learning models for predicting well-folded monomers and binders with a small set of descriptors. Cross-validating designs with varied orthogonal computational techniques should guide us for identifying design imperfections, rescuing designs and making more robust design selections before experimental testing.


Sports-medical assessment for athletes with a disability.
The purpose of this article is to describe a Sports-Medical Assessment Protocol (SMAP) for athletes with a disability. The purposes of the SMAP are to identify medical problems and therapeutic goals for supplementary training programmes for athletes with a disability, and to provide baseline data for future follow up. The SMAP includes an interview, cardiorespiratory assessment and physical and functional examination. Data were collected from assessment protocols of 14 male athletes with various neurological disorders who qualified to participate in the Atlanta Paralympic Games in 1996. Nine of the athletes had some range of motion (ROM) limitations, one had shoulder pain and one low back pain following physical stress. Two athletes with postpolio presented muscle fasciculation and one of them also presented bilateral Carpal Tunnel Syndrome. Based on the results we concluded that utilizing the SMAP may contribute to trainers' and athletes' (with a disability) awareness of the physical needs of elite athletes as well as participants in leisure sport activities.


Self-serving judgments about winning the lottery.
Although myths and stereotypes about lottery winners tend to be negative (e.g., winners become extravagant), people continue to spend billions of dollars buying lottery tickets in the hope of winning. The authors applied findings from the self-enhancement literature to understand this paradox. Eighty college students received class credit for their participation, in which they read a scenario that asked them to imagine that they, or a target other, had won a lottery. Participants' responses to a 34-item questionnaire displayed a self-serving bias, such that changes to the self were expected to be more positive than changes to the other. For several items, this effect was moderated by the participant's gender. The present research indicates that the pervasive tendency to display self-serving biases can apply to future-oriented processing, an under-researched topic.


Organization, financing, promotion, and cost of U.S. quitlines, 2004.
Quitlines have been established as an effective, evidence-based, population-wide strategy to deliver smoking-cessation treatment, and are now available in most states across America. However, little is known about the organization, financing, promotion, and cost of state quitlines. In 2004, the North American Quitline Consortium surveyed the 50 states and Washington DC to obtain information about state quitlines. Data were analyzed in fall 2005 through spring 2006. Analyses of these data are reported in this paper. Analyses were limited to the 38 states that reported having a quitline in 2004. State governments funded most (89.5%) quitlines. Median state quitline operating budgets in 2004 were 500,000 dollars; this translates into a modest annual median operating cost of 0.14 dollar per capita or 0.85 dollar per adult smoker. A lesser amount was spent for quitline promotion. Quitline services varied, with 97.4% of respondents providing mailed self-help resources, 89.5% providing proactive telephone counseling, and 89.2% providing referrals to other services. Many quitlines provide services in languages other than English. Only 21.1% of quitlines reported providing cessation medication at no cost. Promotional strategies varied widely. A large majority of U.S. smokers live in states with tobacco quitlines, which provide cessation treatment at a remarkably modest per capita cost. There is a great deal of congruence in services and promotional strategies among states. Further research is required to determine how external factors such as the federal National Network of Tobacco Cessation Quitlines funding for state quitlines and the availability of a national portal number (1-800-QUITNOW), both implemented in 2004, affect state quitlines. Additional research to evaluate the cost effectiveness of quitline services is also warranted.


Axoplasmic flow of tritiated proline in the corticospinal tract of the rat.
The rates of axoplasmic transport were studied in the corticospinal tract of the rat by injecting tritiated proline into the sensory-motor cortex and subsequently analyzing the distribution of incorporated label in the spinal cord at intervals after injection. A mathematical model of the anatomy of the corticospinal tract was developed and used in analysis of the data. The rate of a fast component was calculated to be 240-420 mm per day, which is comparable with rates of fast components in the peripheral nervous system (PNS), but considerably greater than rates in other tracts in the central nervous system. A slow component was calculated to have a transport rate of 3-8 mm per day which is greater than rates found either in the CNS or PNS. This higher rate may be related to the greater length of the corticospinal tract as compared to other CNS tracts studied.


Twin births and their complications in women of low socioeconomic profile.
To determine the frequency of twin births and their foetomaternal complications in women of low socioeconomic profile. The cross-sectional study was conducted from January 2009 to December 2010 at the Obstetrics and Gynaecolgy Unit I, Civil Hospital, Karachi. Patients with twin pregnancy giving birth beyond 24 weeks, were selected by non-probability purposive sampling. Data on patient characteristics, gestation, antepartum and peripartum complications, chorionicity, mode of delivery and perinatal outcome was recorded and analysed through SPSS 16. Out of 6077 deliveries during the study period, 119 twin births gave a frequency of 19.58/1000 births. Patients' mean age was 27.51+/-4.2 years, mean parity 2.4+/-2.2 and mean gestational age was 34.76+/-3.4 weeks. Unbooked and referred patients were 96 (80.67%). Final paired outcome was alive twin pairs in 74 (62.18%) cases, stillbirth in 7 (5.88%), neonatal deaths in 10 (8.40%). Perinatal mortality rate was 277/1000 twin births. Most frequent foetal complications were low birth weight (n=84; 70.58%), pre-term births (n=70; 58.82%) and intrauterine growth restriction (n=59; 49.57%). The second twin was at significantly higher risk (p< 0.05). Monochorionic twins had significantly high rates of stillbirths than dichorionic (p = 0.023). Most frequent maternal complications comprised pre-term labour (n=56; 47.05%), severe anaemia (n=22; 18.48%), hypertensive disorders (n=19; 15.96%) and postpartum haemorrhage (n=10; 8.40%). Twin pregnancies in women of low socioeconomic profile result in very high rates of low birthweight, pre-term births, intrauterine growth restriction, anaemia, hypertensive disorders and postpartum haemorrhage. Monochorionic pregnancies result in high rates of stillbirths and second twin is more likely to be compromised.


Identification and validation of a prognostic signature of cuproptosis-related genes for esophageal squamous cell carcinoma.
Esophageal squamous cell carcinoma (ESCC) is a highly lethal form of cancer. Cuproptosis is a recently discovered form of regulated cell death. However, its significance in ESCC remains largely unknown. In this study, we observed significant expression differences in most of the 12 cuproptosis-related genes (CRGs) in the TCGA-ESCC dataset, which was validated using GSE20347, GSE38129, and individual ESCC datasets. We were able to divide patients in the TCGA-ESCC cohort into two subgroups based on disease, and found significant differences in survivor outcomes and biological functions between these subgroups. Additionally, we identified 11 prognosis-related genes from the 12 CRGs using LASSO COX regression analysis and constructed a CRGs signature for ESCC. Patients were categorized into high- and low-risk subgroups based on their median risk score, with those in the high-risk subgroup having significantly worse overall survival than those in the low-risk subgroup. The CRGs signature was also highly accurate in predicting prognosis and survival outcomes. Univariate and multivariate Cox regression analyses revealed that 8 of the 11 CRGs were independent prognostic factors for predicting survival in ESCC patients. Furthermore, our nomogram performed well and could serve as a useful tool for predicting prognosis. Finally, our risk model was found to be relevant to the sensitivity of targeted agents and immune infiltration. Functional enrichment analysis demonstrated that the risk model was associated with biological pathways of tumor migration and invasion. In summary, our study may provide a promising prognostic signature based on CRGs and offers potential targets for personalized therapy.


[The morphofunctional organization of the accessory olfactory organ in mammals].
The study was performed in 180 fetuses of albino rat aged 12-21 d, cat--5-120 mm parietococcygeal length and man--4-70 mm parietococcygeal length, divided into histological slices. Vomeronasal organ of mammals, human included was found to be closely connected with nasal cavity, being its derivative. Within the period of primary palate formation in animals vomeronasal organ opens up into primary choanae, being linked both with oral and nasal cavities in similar extent. In following stages of development the period of secondary palate formation vomeronasal organ displays specific features of its structure.


Development of the cardiac coronary vascular endothelium, studied with antiendothelial antibodies, in chicken-quail chimeras.
The endothelium of the coronary vascular system has been described in the literature as originating from different sources, varying from aortic endothelium for the main coronary stems, endocardium for the intramyocardial network, and sinus venosus lining for the venous part of the coronary system. Using an antibody against quail endothelial cells (alpha-MB1), we investigated the development of the coronary vascular system in the quail (Hamburger and Hamilton stages 15 to 35) and in a series of 36 quail-chicken chimeras. In the chimeras, pieces of quail epicardial primordium and/or liver tissue were transplanted into the pericardial cavity of a chicken host. The results showed that the coronary vascular endothelial distribution closely followed the formation of the epicardial covering of the heart. However, pure epicardial primordium transplants did not lead to endothelial cell formation, whereas a liver graft with or without an epicardial contribution did have this capacity. The first endothelial cells were seen to reach the heart at the sinus venosus region, subsequently spreading through the inner curvature to the atrioventricular sulcus and the outflow tract and, last of all, over the ventricular surfaces. At these sites, the precursor cells and small vessels were seen to invade the sinus venosus wall, the ventricular and atrial myocardium, and the mesenchymal border of the aortic orifice. Connections with the endocardium of the heart tube were only observed in the right ventricular outflow region. Initially, the connections with the aortic endothelium were multiple, but later in development only two of these connections persisted to form the proximal part of the two main coronary arteries. Connections to the pulmonary orifice were never observed. Our transplantation data showed that the entire coronary endothelial vasculature originated from an extracardiac source. Moreover, using the developing subepicardial layer as a matrix, we showed that the endothelial cells reached the heart from the liver region. Ingrowth into the various cardiac segments was also observed. Implications for the relation to specific congenital cardiac malformations are discussed.


St. Gallen/Vienna 2017: A Brief Summary of the Consensus Discussion about Escalation and De-Escalation of Primary Breast Cancer Treatment.
For the second time, the St. Gallen Consensus Conference on early breast cancer treatment standards took place in Vienna, Austria, where it will remain for the foreseeable future (next date: March 20-23, 2019). With the probably most prominent line-up of global breast cancer experts and more than 3,000 participants from over 100 countries, the 2017 St. Gallen/Vienna conference again was a huge success. A generation change took place with respect to the Conference Co-Chairpersons. Traditionally, the experts from all continents reviewed publications from the past 2 years, and discussed whether new diagnostic or therapeutic means were ready for routine everyday practice. This year, the conference's main theme was 'Escalating and Deescalating Treatment', and the traditional panel votings clarified a number of issues in this respect. Several subjects of all breast cancer modalities were further de-escalated (surgery: 'no ink on tumor' clearly confirmed as standard; resection within new limits after neoadjuvant systemic therapy; axillary dissection may also be avoided after mastectomy under certain circumstances; radiotherapy: hypofractionation is standard of care in breast conserving therapy; chemotherapy: can be avoided in low-risk patients). However, others were escalated: surgery: after neoadjuvant treatment and after mastectomy a positive sentinel node leads to axillary dissection; radiotherapy: regional nodes have to be irradiated in 4+ nodes situations; adjuvant therapy: bisphosphonates as standard for postmenopausal women. There was no clear panel opinion on the optimal use of multigenomic assays. As always, the panel recommendations are strictly opinion-based, and try to depict the 'usual' treatment for the 'average' patients. This rapid report by the editors-in-chief of Breast Care summarizes the results of the 2017 international panel votings with respect to loco-regional systemic treatment, and does not intend to replace the official St. Gallen Consensus publication.


[MONITORING OF INTRACRANIAL PRESSURE IN PATIENTS WITH MASSIVE ISCHEMIC STROKE].
To assess the role of monitoring of intracranial pressure (ICP) in patients with massive ischemic stroke within the first 5 days of the onset of the disease. We have analyzed the results of monitoring of intracranial pressure in 10 patients with massive ischemic stroke and compared dynamics of ICP with the dynamics of intracranial pressure and the level of consciousness and dislocation of the brain according to CT RESULTS: Dislocation syndrome decompensation occurred in 6 patients, of which only 3 patients had increased intracranial pressure greater than 20 mm Hg with oppression of the level of consciousness to moderate coma and deeper The average value of transverse dislocation in these patients at the same time amounted to 17 mm. In 2 patients with atrophy of the brain we observed ICP increase over 20 mmHg. The average value of transverse dislocation in these patients was 12 mm. Conclusion: Increased intracranial pressure greater than 20 mm Hg in patients with massive ischemic stroke can occur even when the oppression of the level of consciousness to moderate coma and deeper on the background of the dislocation of the brain. In case of an atrophy of the brain, the level of ICP may not exceed 20 mm Hg even with dislocation syndrome decompensation.


TRIM14 Promotes Breast Cancer Cell Proliferation by Inhibiting Apoptosis.
Tripartite motif-containing 14 (TRIM14) is abnormally expressed in several human cancers. However, the function and expression of TRIM14 in human breast cancer are still largely unknown. To understand the biological function of TRIM14 in breast cancer, we measured the expression level of TRIM14. Cell proliferation and cell apoptosis were measured after TRIM14 overexpression or knockdown. Upregulation of TRIM14 was found in human breast cancer specimens and cell lines. Reduction of TRIM14 inhibited cell proliferation but increased cell apoptosis in the BT474 and MDA-MB-231 cell lines. Further study showed that knockdown of TRIM14 upregulated the expression of BAX while downregulating the expression of BCL2. In addition, the expression of SHP-1 was increased, and the phosphorylation of STAT3 (p-STAT3) was inhibited. Conversely, overexpression of TRIM14 had the opposite effects. Additionally, cryptotanshinone, a STAT3 inhibitor, inhibited cell proliferation but increased cell apoptosis in the BT474 and MDA-MB-231 cell lines. In conclusion, TRIM14 may act as an oncogene in human breast cancer and may be a novel strategy for human breast cancer.


United Complex Centrality for Identification of Essential Proteins from PPI Networks.
Essential proteins are indispensable for the survival or reproduction of an organism. Identification of essential proteins is not only necessary for the understanding of the minimal requirements for cellular life, but also important for the disease study and drug design. With the development of high-throughput techniques, a large number of protein-protein interaction data are available, which promotes the studies of essential proteins from the network level. Up to now, though a series of computational methods have been proposed, the prediction precision still needs to be improved. In this paper, we propose a new method, United complex Centrality (UC), to identify essential proteins by integrating the protein complexes with the topological features of protein-protein interaction (PPI) networks. By analyzing the relationship between the essential proteins and the known protein complexes of S. cerevisiae and human, we find that the proteins in complexes are more likely to be essential compared with the proteins not included in any complexes and the proteins appeared in multiple complexes are more inclined to be essential compared to those only appeared in a single complex. Considering that some protein complexes generated by computational methods are inaccurate, we also provide a modified version of UC with parameter alpha, named UC-P. The experimental results show that protein complex information can help identify the essential proteins more accurate both for the PPI network of S. cerevisiae and that of human. The proposed method UC performs obviously better than the eight previously proposed methods (DC, IC, EC, SC, BC, CC, NC, and LAC) for identifying essential proteins.


Survival of patients with lung cancer and diabetes mellitus.
Diabetes mellitus (DM) and lung cancer are two highly globally prevalent diseases. The current study aimed to determine the prognostic significance of DM comorbidity in patients with lung cancer. All patients diagnosed at Tsukuba Medical Center Hospital and Mito Medical Center, (University of Tsukuba, Ibaraki, Japan) between April 1999 and March 2012 were followed up to 2015 and were retrospectively analyzed. DM was defined as a fasting plasma glucose (FPG) level ≥126 mg/dl, a non-FPG level ≥200 mg/dl, or a hemoglobin (Hb) A1c level ≥6.5%. Additionally, patients taking medication for diabetes and those with a history of using such medications were also classified as having DM. During the study period, 1,798 patients with lung cancer were diagnosed. Within this cohort, 338 (18.8%) were classed as having lung cancer and DM. In univariate and multivariate analyses, smoking status, poorer performance status, small cell lung cancer pathology, metastatic disease and supportive care were the only unfavorable prognostic factors (all P=0.001). Additionally, multivariate analysis revealed that existing DM was an unfavorable disease-modifying factor (P=0.03612). Therefore, DM comorbidity adversely affects lung cancer outcomes. To provide prolonged quality of survival, appropriate pre-evaluation of lung cancer, as well as the patient's medical condition, including DM, is required.


Retron for the 67-base multicopy single-stranded DNA from Escherichia coli: a potential transposable element encoding both reverse transcriptase and Dam methylase functions.
The region (retron-Ec67) required for the biosynthesis of a branched-RNA-linked multicopy single-stranded DNA (msDNA-Ec67) from a clinical isolate of Escherichia coli was mapped at a position equivalent to 19 min on the K-12 chromosome. The element containing the retron consisted of a unique 34-kilobase sequence that was flanked by direct repeats of a 26-base-pair sequence found in the K-12 chromosomal DNA. This suggests that the 34-kilobase element was probably integrated into the E. coli genome by a mechanism related to transposition or phage integration. In the 34-kilobase sequence an open reading frame of 285 residues was found, which displays 44% sequence identity with the E. coli Dam methylase. Interestingly, there are three GATC sequences, the site of Dam methylation, in the promoter region of the gene for reverse transcriptase.


Analyses of alpha/beta-type gliadin genes from diploid and hexaploid wheats.
The alpha/beta-gliadin genes isolated from both hexaploid wheat (cv. Yamhill) and the diploid A genome progenitor Triticum urartu had remarkably similar sequences and differ by only a few point mutations. Primer extension analysis indicated that the transcriptional start points for individual genes in the family cluster within a few nucleotides. Comparison of the promoter region of several alpha/beta-gliadin and B-hordein genes reveals two conserved regions at about -130 and -250 bp. DNA from the hexaploid cultivars, Cheyenne and Chinese Spring, and the diploid progenitors T. urartu and Aegilops squarrosa was analysed by Southern blotting. Restriction fragment lengths of the alpha/beta-gliadin genes varied only slightly between the various wheats, although the overall copy number varied significantly. A region between approx. -1700 and -700 bp upstream from the TATA box was highly repeated in all three wheat genomes. For the hexaploid-derived gene, over 1700 bp of sequence upstream from the TATA box was determined, revealing an additional open reading frame between approx. -1550 and -1250 bp relative to the gliadin TATA box. Northern blot analysis indicated that RNA homologous to this repeated sequence family was present only in developing seed and accumulated to a maximum at late stages of maturation.


Comparison of endocytosis pathways of Duck Tembusu virus in BHK-21 and duck embryo fibroblasts.
The Duck Tembusu virus (DTMUV) is a zoonotic flavivirus characterized by nonsuppurative encephalitis and decreasing egg production that has adversely affected the poultry industry. While the way of invasion of DTMUV into different host cells, especially primary cells, remains elusive. In the present study, the ultrastructural pathological characteristics showed that DTMUV underwent a typical maturation and replication process: progeny virus particles gathered in rough endoplasmic reticulum (RER) cisternae, reached the cell membrane via Golgi body's endocrine channel, then were released in the infected baby hamster kidney-21 (BHK-21) and duck embryo fibroblast (DEF). Endoplasmic reticulum vesicles in BHK-21 were short rods and densely arranged like honeycombs, whereas vesicles in DEF were round and dispersed. Further study showed that the virus replication peak in mammalian BHK-21 cells was at 48 hpi, whereas in avian DEF cells was at 24 hpi. DTMUV entry into BHK-21 and DEF cells was blocked by clathrin inhibitor, chlorpromazine (CPZ), indicating that the flavivirus DTMUV enters BHK-21 and DEF both via a clathrin-mediated endocytosis (CME) pathway rather than caveola-mediated endocytosis or micropinocytosis. The endocytic difference in DTMUV entry into BHK-21 and DEF cells might provide insight into understanding the underlying virulence difference between passaged cells and cultured cells.


A computational model of open-irrigated radiofrequency catheter ablation accounting for mechanical properties of the cardiac tissue.
Radiofrequency catheter ablation (RFCA) is an effective treatment for cardiac arrhythmias. Although generally safe, it is not completely exempt from the risk of complications. The great flexibility of computational models can be a major asset in optimizing interventional strategies if they can produce sufficiently precise estimations of the generated lesion for a given ablation protocol. This requires an accurate description of the catheter tip and the cardiac tissue. In particular, the deformation of the tissue under the catheter pressure during the ablation is an important aspect that is overlooked in the existing literature, which resorts to a sharp insertion of the catheter into an undeformed geometry. As the lesion size depends on the power dissipated in the tissue and the latter depends on the percentage of the electrode surface in contact with the tissue itself, the sharp insertion geometry has the tendency to overestimate the lesion obtained, which is a consequence of the tissue temperature rise overestimation. In this paper, we introduce a full 3D computational model that takes into account the tissue elasticity and is able to capture tissue deformation and realistic power dissipation in the tissue. Numerical results in FEniCS-HPC are provided to validate the model against experimental data and to compare the lesions obtained with the new model and with the classical ones featuring a sharp electrode insertion in the tissue.


Inhibition of mid-cycle gonadotrophin release in healthy women by pimozide and fusaric acid.
The effects of pimozide, a drug blocking dopamine receptors, and fusaric acid, an inhibitor of dopamine beta-hydroxylase, on mid-cycle release of FSH and LH were studied in 8 healthy women 20-25 years of age. None had used contraceptive drugs for the preceding 10 months. From the menstrual history and serum LH determinations during the normal cycle, mid-cycle gonadotrophin bursts were predicted for the following three cycles. Two days before and after the expected gonadotrophin surge were regarded as sufficient for the drug tests. Pimozide (initially 2 mg, then 1 mg/day) and fusaric acid (600 mg/day) were administered in a randomized cross-over study. The mid-cycle LH values were reduced from the control level of 56 +/- 10 mIU/ml (mean +/- SE) to 22 +/- 4 mIU/ml by pimozide (P less than 0.001) and to 17 +/- 5 mIU/ml by fusaric acid (P less than 0.001). The serum FSH level was 9 +/- 2 mIU/ml on the day of the LH surge and did not change significantly during treatment with either drug. The LH and FSH responses to synthetic LRF (100 mug iv) were not changed by pimozide or fusaric acid. The rise of basal temperature associated with ovulation was not affected by the drugs. These results suggest that suprapituitary noradrenergic and dopaminergic neurotransmitters are involved in the regulation of mid-cycle gonadotrophin secretion in women.


The coding of underlying cause of death from fetal death certificates: issues and policy considerations.
Recently, plans to implement nationwide coding of underlying cause of fetal death have been promulgated. To examine the validity and potential utility of nationwide coding, this paper presents data from a five-state (Wisconsin, Arkansas, Maine, North Carolina, California) analysis of underlying causes of fetal death from vital records for 1985 through 1987. Nosological coding rules varied somewhat from state to state. Underlying causes were grouped into categories; distributions were similar for each state. Many deaths (20.3% to 32.9%) were coded as unspecified conditions. Congenital anomalies accounted for only 6.9% to 10.3% of fetal deaths, including implausible and nonspecific causes. In total, 29.5% to 42.8% of the reports were not valid or useful. To obtain better data, researchers must focus on improving fetal death reporting, which will entail the promotion of comprehensive autopsy, placental and laboratory evaluation, systematic vital records query procedures, and implementation of multiple-cause-of-fetal-death coding.


Antigen-induced proliferation and immunoglobulin A secretion by a human-human hybridoma.
The capacity of membrane immunoglobulin A (IgA)-bearing B cells to respond to specific antigen in the absence of T cell influences has not been defined. A human-human hybridoma, constructed from an Epstein-Barr virus transformed tonsil B cell that secreted IgA anti-phosphorycholine (PC) and a human plasmacytoma cell, was utilized to examine this issue. The cloned hybridoma expressed membrane IgA and secreted IgA specific for PC. Stimulation of the hybridoma cells with PC conjugated to Sepharose beads (PC-Sepharose) but not glycine-conjugated Sepharose resulted in an increase in DNA synthesis. Affinity purified goat anti-human IgA bound to Sepharose also augmented DNA synthesis. Soluble PC did not increase DNA synthesis and inhibited the increase in DNA synthesis resulting from PC-Sepharose. IgA secretion was augmented in response to PC-Sepharose, as demonstrated by an increase in the number of Ig-secreting cells detected by a reverse hemolytic plaque assay and by quantitation of the IgA secreted per cell by enzyme-linked immunosorbent assay. Mitogen-stimulated T cell supernatants increased IgA secretion of the hybridoma cells but did not cause synergistic stimulation of the cells in the presence of PC-Sepharose. These data indicate that Sepharose-bound antigen was sufficient to induce proliferation and augment IgA secretion by this membrane IgA anti-PC-bearing hybridoma. The results suggest that cross-linking of membrane IgA by specific antigen may be a sufficient stimulus for proliferation and differentiation of B cells at this stage of maturation.


Culture of human retinal pigment epithelial cells from peripheral scleral flap biopsies.
We studied various methods for harvesting retinal pigment epithelium (RPE) biopsies from cadaver human eyes of donors over age 60 years. Our goal was to harvest cells for possible autologous RPE cell transplantation in patients with age-related macular degeneration and to test the viability of the RPE after isolation by evaluating explant growth in culture. Choroid-RPE biopsies were excised from enucleated human eyes. The RPE was separated from the choroid by treatment with type IV collagenase. RPE patches were cultured. After 100-500 cells had grown out from the explant, the primary cultures were passaged. There was no clear effect of donor age on the ability to establish primary RPE cultures with good morphology from biopsies 2 x 2-10 x 10 mm2 in size. Biopsies 6 x 6 mm2 or larger produced satisfactory primary cultures more than 70% of the time. The number of viable RPE cells (defined as the number of cells adherent to the culture dish 24 h after plating) obtained after enzymatic separation of the RPE and choroid was an important determinant of our ability to establish primary cultures and passage the cells. Primary cultures with good cellular morphology were obtained 100% of the time when RPE explants > 4 mm2 in size were obtained from the biopsy specimen. Seventy-three percent of the biopsies yielding explants > 4 mm2 in size were successfully passaged. These results suggest that peripheral scleral flap biopsies in aging donors can be used to establish RPE explant primary cultures. These cultures may be suitable as a source for autologous RPE transplantation in patients.


Novel chikungunya virus variant in travelers returning from Indian Ocean islands.
Chikungunya virus (CHIKV) emerged in Indian Ocean islands in 2005 and is causing an ongoing outbreak that involves >260,000 patients, including travelers returning home from these islands. We investigated cases in 4 patients returning from Mayotte and Reunion Islands with CHIKV infection and a nurse infected in metropolitan France after direct contact with the blood of a traveler. Four patients had tenosynovitis and pain at wrist pressure, and 1 had life-threatening manifestations. Four CHIKV strains were isolated, including 1 from the patient with the autochthonous case. The complete genomic sequence identified a new CHIKV variant emerging from the East/ central African evolutionary lineage. Aedes albopictus, the implicated vector of CHIKV in Indian Ocean islands, has dispersed worldwide in recent decades. High viral loads in patients returning from Indian Ocean islands to countries where Ae. albopictus is prevalent may be a source of epidemics.


Vaccination and anaphylaxis: a forensic perspective.
To review the available literature pertaining to fatalities following vaccine administration and, in particular, cases of vaccine-related fatal anaphylaxis. The MEDLINE database was systematically searched up to March 2016 to identify all relevant articles pertaining to fatal cases of anaphylaxis following vaccine administration. Six papers pertaining to fatal anaphylaxis following vaccination were found relevant. Mast cell tryptase and total IgE concentration was assessed exclusively in one case. Laryngeal edema was not detected in any of these cases, whereas eosinophil or mast cell infiltration was observed in lymphoid organs. In one case, immunohistochemical investigations using anti-tryptase antibodies allowed pulmonary mast cells and degranulating mast cells with tryptase-positive material outside to be identified. In any suspected IgE-mediated fatal anaphylactic cases, biochemical investigations should be systematically performed for forensic purposes. Splenic tissue should be routinely sampled for immunohistochemical investigations in all suspected anaphylaxis-related deaths and mast cell/eosinophil infiltrations should be systematically sought out in the spleen, myocardium, and coronary artery wall. The hypothesis of fatal anaphylaxis following vaccination should be formulated exclusively when circumstantial data, available medical records, laboratory investigations, and autopsy or histology findings converge in a consistent pattern. The reasonable exclusion of alternative causes of death after all postmortem investigations is also imperative in order to establish or rule out a cause-and-effect relationship between vaccine administration and any presumptive temporarily-related death.


Protein-polymer supramolecular assemblies: a key combination for multifunctionality.
2D/3D structures resulting from self-assembly of amphiphilic block copolymers can be combined with bioactive compounds, such as proteins and enzymes, to create supramolecular assemblies with specific desired properties and functionality. Chemical tuning of the architecture and properties of supramolecular assemblies to accommodate sensitive biomolecules allows the development of new soft hybrid materials that benefit from the robustness of polymers and from the functionality of biomolecules. The encapsulation/insertion of biomolecules (enzymes, mimics, proteins) in self-assembling block copolymer vesicles enables design of 'nanoreactors' both in solutions and at surfaces for highly diverse applications, ranging from production of antibiotics to creation of artificial organelles. When membrane proteins are inserted into polymer membranes, it is possible to generate functional membranes or active surfaces with a rapid and specific response. In addition, the selective binding of ligand-terminated polymers holds potential for targeted delivery of drugs, or for immobilization on solid support, to provide functional 3D assemblies on an extended surface.


Endothelium and the effect of activated neutrophils on arterial smooth muscle.
The aim of the study was to analyze the involvement of the endothelium in the effects of neutrophils (PMNL) on phenylephrine-precontracted isolated rings of the rat thoracic aorta and to compare their effects with those of peroxynitrite (ONOO(-)) and hypochlorous acid (HOCl). Activated PMNL-induced contraction of the precontracted aorta was prevented by the blockade of NO-synthase and by endothelium removal. In the endothelium-free preparations, the effect of PMNL reappeared in the presence of sodium nitroprusside. The effect of ONOO(-) and HOCl significantly differed from that of activated PMNL both in the presence and absence of the endothelium. It is therefore likely that neither ONOO(-) nor HOCl generated by transformation of superoxide anion radical (O2 (•-)) produced by PMNL is involved in their action. Reduction of the relaxant effect of nitric oxide derived from the endothelium by O2 (•-) seems to be the keystone mechanism in generation of PMNL-induced contraction.


"Two-dimensional" molecularly imprinted solid-phase extraction coupled with crystallization and high performance liquid chromatography for fast semi-preparative purification of tannins from pomegranate husk extract.
In this study, "two dimensional" molecularly imprinted solid-phase extraction (2D-MIP-SPE) of semi-preparative grade was constructed to fast purify ellagitannins in pomegranate husk extract with the help of crystallization and reverse-phase liquid chromatgoraphy (RPLC). Ellagic acid and punicalagin imprinted polymers were synthesized in batch mode and two semi-preparative MIP-SPE columns were individually packed. After investigaing "functional complementation", 2D-MIP-SPE was constructed using ellagic acid MIP and punicalagin MIP-SPE as the first and second dimension, respectively. Then, pomegranate husk extract was fast divided into four fractions individually enriching in ellagic acid, granatin A, punicalagin and ellagic acid glucoside by 2D-MIP-SPE. With the aid of crystallization and RPLC, ellagic acid (13.5mg) and punicalagin (53.4mg) were fast obtained in 30min. Ellagic acid glucoside was purified to the purity near 100% with a recovery of 86.1%. Granatin A (92%) was directly obtained by 2D-MIP-SPE with the recovery of 81.8%. All above indicated that 2D-MIP-SPE was highly efficient in natural product purification. The concept of "functional complementation" was expected to be a useful tool in the construction of 2D-MIP-SPE.


X-ray Phase-Contrast Imaging and Metrology through Unified Modulated Pattern Analysis.
We present a method for x-ray phase-contrast imaging and metrology applications based on the sample-induced modulation and subsequent computational demodulation of a random or periodic reference interference pattern. The proposed unified modulated pattern analysis (UMPA) technique is a versatile approach and allows tuning of signal sensitivity, spatial resolution, and scan time. We characterize the method and demonstrate its potential for high-sensitivity, quantitative phase imaging, and metrology to overcome the limitations of existing methods.


Recovery of older patients undergoing ambulatory anaesthesia with isoflurane or sevoflurane.
Delayed recovery of cognitive function is a well-recognized phenomenon in older patients. The potential for the volatile anaesthetic used to contribute to alterations in postoperative cognitive function in older patients following minor surgical procedures has not been determined. We compared emergence from isoflurane and sevoflurane anaesthesia in older surgical patients undergoing urological procedures of short duration. Seventy-one patients, 60 yr of age or older, undergoing anaesthesia expected to last less than 60 min for ambulatory surgery, were randomly assigned to receive isoflurane or sevoflurane. A standardized anaesthetic protocol was used, with intravenous fentanyl 1 microg kg(-1) and propofol 1.5-2.0 mg kg(-1) administered to induce anaesthesia. Anaesthesia was maintained with either sevoflurane or isoflurane in 65% nitrous oxide and oxygen. Early and intermediate recovery times were recorded. The Mini Mental State Examination and digit repetition forwards and backwards were administered at baseline, and at 1, 3 and 6 h postoperatively, to assess cognitive function. There were no between-group differences in (sevoflurane vs. isoflurane, mean +/- standard error of the mean) times to removal of the laryngeal mask airway (7.7 +/- 0.6 vs. 7.1 +/- 0.4 min), verbal response time (10.1 +/- 0.7 vs. 9.9 +/- 0.7 min) and orientation (12.1 +/- 0.7 vs. 12.1 +/- 0.7 min). Intermediate recovery, as measured by time to readiness for discharge from the post anaesthesia care unit (44.9 +/- 1.5 vs. 44.3 +/- 1.5 min), was similar in the two groups. Postoperative indices of cognitive function and attention were comparably reduced at 1 h, but returned to baseline in both groups at 6 h. Isoflurane and sevoflurane anaesthesia resulted in similar clinical and neurocognitive recovery profiles in older patients undergoing ambulatory surgical procedures of short duration.


Implications of subcellular steroid binding sites in endometrial cancer, determined by an immunofluorescent steroid-antibody technique and biochemical assay.
A discrepancy has been found between the progestogen level necessary for treatment of endometrial cancer and the steroid receptor level detected for the response indicator. Therefore the relationships between the steroid binding quantity detected biochemically and the steroid reactivity determined immunofluorescently was evaluated subcellularly in the endometrial cancers. Estradiol-17 beta and progesterone fluorescences were not always related to the classical steroid receptor binding quantities. These two steroids bound to the nuclear components directly, but heterogeneously. In the biochemical method using fractionated dispersed cancer cells, cellular heterogeneity of the steroid receptor mechanism in a given endometrial cancer tissue was proved. Steroid fluorescence was not related to the steroid-receptor complex quantity in the normal endometrial nucleus. This suggests that the binding of steroid antibody to the steroid-receptor bound already to the nucleus seems to be inhibited due to steric hindrance. Therefore the nuclear steroid fluorescence did not always give the nuclear steroid-receptor complex quantity. These results indicate heterogeneity in the estrogen and progestogen receptor mechanism in endometrial cancer, when studied by the biochemical and immunofluorescent techniques, and that these steroids bind to the nucleus directly and may influence the nuclear mechanism. Therefore, in endometrial cancer progestogen does not always have a therapeutic effect through the progestogen receptor and does not affect the therapeutic effect on any of the cells.


Beneficiary activation in the Medicare population.
Patient activation questions from a major national Medicare survey are used to highlight characteristics of Medicare beneficiaries with low activation. We demonstrate that Medicare Current Beneficiary Survey (MCBS) data is an untapped resource for further research on patient activation within Medicare beneficiaries and programs. Data are from the 2012 MCBS Access to Care file and include 10,650 beneficiaries. Patient Activation levels were derived by taking the weighted average responses to the Patient Activation Supplement. Cut points for high, moderate, and low activation were assigned at +/- ½ standard deviation of the mean. Data were analyzed using SAS survey procedures. Within group comparisons were tested using chi-square tests with post hoc pairwise comparisons. Logistic regression identified predictors of low patient engagement. In a multiple logistic regression, beneficiary characteristics associated with low activation included Hispanic origin, being widowed or never married, select age groups, male gender, fair or poor health, difficulty with an IADL or ADLs, and having no usual source of care, with failure to complete high school as the strongest predictor (OR=2.22, p<.001). Utilization and costs were also examined in descriptive analyses. Overall, findings on the characteristics of low activation patients in the Medicare population resemble previous research. In a regression analysis, less education and no usual source of care are the strongest predictors of low activation levels in Medicare beneficiaries. The MCBS Patient Activation Supplement is a rich resource for examining patient activation in the Medicare population, and can be used for a wide range of analyses.


The effect of bacterial toxins on levels of intracellular adenosine nucleotides and human ciliary beat frequency.
Toxins that slow ciliary beat are virulence determinants of bacteria that infect or invade ciliated epithelial surfaces. We have previously shown that the effect of the Pseudomonas aeruginosa toxin pyocyanin on ciliary beat is associated with a fall in intracellular cAMP and ATP. We have now investigated whether reduction in intracellular adenosine nucleotides might be a common mechanism of action of other bacterial toxins which slow ciliary beat. Two other P. aeruginosa toxins, 1-hydroxyphenazine (1-HP) and rhamnolipid, and two Haemophilus influenzae fractions produced by gel filtration of broth cultures were tested. The effect on human nasal epithelium ciliary beat frequency (CBF), and intracellular cAMP and ATP were measured, and the effect of two pharmacological agents, dibutyryl cAMP and salmeterol, on these changes was assessed. 1-HP, rhamnolipid and the two H. influenzae fractions slowed CBF before there was significant release of lactate dehydrogenase from the cells. The toxins also caused a fall in intracellular cAMP and ATP. Dibutyryl cAMP and salmeterol at the concentrations used do not increase baseline CBF, but diminished the fall in CBF and intracellular adenosine nucleotides. The cAMP and ATP levels in these studies were combined with those previously obtained with pyocyanin. there was a good correlation between cAMP and ATP levels and CBF. Bacterial toxins which slow CBF may act by causing a fall in intracellular adenosine nucleotides, and agents which stimulate cAMP may prevent toxin-induced slowing of ciliary beat.


Similarities and Distinctions of Cancer and Immune Metabolism in Inflammation and Tumors.
It has been appreciated for nearly 100 years that cancer cells are metabolically distinct from resting tissues. More recently understood is that this metabolic phenotype is not unique to cancer cells but instead reflects characteristics of proliferating cells. Similar metabolic transitions also occur in the immune system as cells transition from resting state to stimulated effectors. A key finding in immune metabolism is that the metabolic programs of different cell subsets are distinctly associated with immunological function. Further, interruption of those metabolic pathways can shift immune cell fate to modulate immunity. These studies have identified numerous metabolic similarities between cancer and immune cells but also critical differences that may be exploited and that affect treatment of cancer and immunological diseases.


Genetic variation in mouse apolipoprotein A-IV expression is determined pre- and post-transcriptionally.
Among inbred mouse strains there is a striking genetic variation in the levels of apolipoprotein A-IV (apoA-IV) mRNA in the liver, although intestinal mRNA levels vary only twofold in these strains. In the present study we have characterized the apoA-IV expression phenotypes in strains C57BL/6J and 129/J, and investigated the molecular basis for the genetic variation. We report that the two strains differ eight- to tenfold both in the levels of apoA-IV mRNA and in the rate of apoA-IV protein synthesis in liver. Presumably due to the increased synthetic rate, strain 129 exhibits a threefold higher concentration of apoA-IV protein in the circulation. mRNA synthesis and turnover studies indicate that both transcriptional and post-transcriptional events contribute to the genetic variation in steady state apoA-IV mRNA levels. An analysis of the levels of apoA-IV mRNA derived from 129 and C57BL/6 alleles in F1 mice indicates that the genetic control of apoA-IV mRNA levels involves both cis-acting elements linked to the apoA-IV gene, and genetically distinct trans-acting factors.


The disability process: is there a place for frailty?
frailty and disability are very common in older adults; they share some risk factors and pathophysiological mechanisms. Yet, they are different clinical entities. this study aimed to explore a potential hierarchical relationship between frailty and disability along the continuum of the disablement process. prospective cohort study. the French Three-City (3C) study. the sample included 943 participants aged 75 and older. the Fried frailty phenotype, Instrumental Activities of Daily Living (IADL) and basic Activities of Daily Living (ADL) were used. We distinguished between four mutually excluding groups: (i) robust (no frailty and no disability); (ii) pure frailty (no disability); (iii) frailty with IADL disability (no ADL disability) and (iv) frailty with IADL and ADL disabilities. We used Cox's regression models to study the 4-year mortality risk associated with each status. Eight-two per cent of participants were classified according to the assumed hierarchy: 61.3% was robust, 5.4% frail, 10.5% frail and IADL-disabled and 4.8% frail, IADL and ADL-disabled. An extra group of 17% was identified with IADL-disabled individuals without frailty. This extra group was similar to pure frailty in terms of characteristics and risk of death, placing them along the continuum at an intermediate stage between robustness and the two most disabled sub-groups. our findings suggest that including frailty along the continuum could be relevant to describe the whole disablement process. Frailty would occur upstream of the process and might be relevant to identify an opportune time window, where specific monitoring and clinical interventions could be implemented in order to interrupt the process at a potentially more reversible stage.


Adenocarcinoma arising in vulvar breast tissue.
A patient with adenocarcinoma arising in vulvar ectopic breast tissue is described. Hormonal receptors of the tumor are analyzed. This is the first case in which an intensive treatment with combined surgery, radiation, hormonal therapy, and cytotoxic chemotherapy was given. Five cases reported previously in the literature are reviewed.


Contribution of rotational diffusion to pulsed field gradient diffusion measurements.
NMR diffusion experiments employing pulsed field gradients are well established as sensitive probes of the displacement of individual nuclear spins in a sample. Conventionally such measurements are used as a measure of translational diffusion, but here we demonstrate that under certain conditions rotational motion will contribute very significantly to the experimental data. This situation occurs when at least one spatial dimension of the species under study exceeds the root mean square displacement associated with translational diffusion, and leads to anomalously large apparent diffusion coefficients when conventional analytical procedures are employed. We show that in such a situation the effective diffusion coefficient is a function of the duration of the diffusion delay used, and that this dependence provides a means of characterizing the dimensions of the species under investigation.


School collective efficacy and gambling: A multilevel study of 11th grade students in Stockholm.
The aim of the present study was to investigate variations between schools when it comes to gambling and risk gambling, and, in particular, to analyse the links between school collective efficacy and student gambling and risk gambling. The data consists of official register information on schools as well as survey data collected in 2016 among 1,061 teachers and 5,191 students in 46 Stockholm upper secondary schools. School collective efficacy was operationalized on the basis of teacher responses, which were aggregated to the school level. Gambling and risk gambling were based on students' self-reports. Two-level binary logistic regression analyses were performed. The results show that there is between-school variation in gambling and in all the study's indicators of risk gambling. Both gambling and risk gambling were more commonly reported by students attending schools with weak collective efficacy, even when adjusting for student- and school-level sociodemographic characteristics. The findings suggest that conditions at school may counteract students' engagement in gambling and risk gambling.


Spanish adaptation and validation of the Family Quality of Life Survey.
Assessing the quality of life (QOL) for families that include a person with a disability have recently become a major emphasis in cross-cultural QOL studies. The present study examined the reliability and validity of the Family Quality of Life Survey (FQOL) on a Spanish sample. The sample comprised 385 families who were administered the FQOL in Cali, Columbia. The FQOL showed adequate temporal stability (r = 0.68 on Importance and r = 0.78 on Satisfaction) and excellent internal consistency: Cronbach's alpha of 0.96 for Importance and 0.95 for Satisfaction. The confirmatory factor analysis yielded high fit indices, thus confirming that the factor structure of the FQOL as adapted for Spanish people fitted the five-factor model proposed by the survey's authors. The study provides a valid instrument for the research of the QOL of those families that have a child with a disability within Spanish-speaking community.


Windows to their world: the effect of sensory impairments on social engagement and activity time in nursing home residents.
This study examined relationships between three sensory and communication abilities and two areas of nursing home resident behavior. Data from 18,873 nursing home residents include measures of hearing, visual, and communication abilities, and social engagement and time spent in activities. Increasing level of visual impairment is associated with low levels of social engagement and low time in activities. Both moderate and severe hearing impairment are associated with low time in activities, while inadequate communication is associated with limits in both social engagement and time in activities. The combined effects of visual and communications impairments are associated with low social engagement. Increasing attention to sensory and communication losses may lead to improve quality of life in this population.


Ionic basis of cold receptors acting as thermostats.
When temperature (T) of skin decreases stepwise, cold fibers evoke transient afferent discharges, inducing cold sensation and heat-gain responses. Hence we have proposed that cold receptors at distal ends of cold fibers are thermostats to regulate skin T against cold. Here, with patch-clamp techniques, we studied the ionic basis of cold receptors in cultured dorsal root ganglion (DRG) neurons of rats, as a model of nerve endings. Cells that increased cytosolic Ca(2+) level in response to moderate cooling were identified as neurons with cold receptors. In whole-cell current-clamp recordings of these cells, in response to cooling, cold receptors evoked a dynamic receptor potential (RP), eliciting impulses briefly. In voltage-clamp recordings (-60 mV), step cooling induced an inward cold current (I(cold)) with inactivation, underlying the dynamic RP. Ca(2+) ions that entered into cells from extracellular side induced the inactivation. Analysis of the reversal potential implied that I(cold) was nonselective cation current with high Ca(2+) permeability. Threshold temperatures of cooling-induced Ca(2+) response and I(cold) were different primarily among cells. In outside-out patches, when T decreased, single nonselective cation channels became active at a critical T. This implies that a cold receptor is an ion channel and acts as the smallest thermostat. Because these thermal properties were consistent with that in cold fibers, we conclude that the same cold receptors exist at nerve endings and generate afferent impulses for cold sensation and heat-gain behaviors in response to cold.


Positive correlation between NLR and PLR in 10,458 patients with endometriosis in reproductive age in China.
The platelet-lymphocyte ratio (PLR) and neutrophil-lymphocyte ratio (NLR), which can be easily measured from whole blood counts, are composite reflections of significant inflammatory response pathways. However, the relationship between PLR and NLR in patients with ovarian endometriosis is only partially supported by clinical evidence. This study aimed at identifying useful markers for early diagnosis by examining the relationship between PLR and NLR in patients with ovarian endometriosis. Between June 2015 and December 2022, we gathered clinical data of 10,458 endometriosis patients who visited the Gynecology Division of the Affiliated Hospital of Jining Medical University. All statistical analyses were performed using the R statistical package. The results of the univariate analysis, smoothed curve fitting, multiple regression analysis, and subgroup analysis revealed that NLR was always positively correlated with PLR. Further analysis based on the curve fitting threshold effect revealed a significant positive correlation between NLR and PLR when NLR < 2.07 (β: 34.49). Furthermore, when NLR > 2.07, there was a significant positive correlation between NLR and PLR (β: 16.93). The finding that NLR and PLR have a positive correlation confirms that inflammation plays a role in the pathogenesis of ovarian endometriosis. Therefore, PLR and NLR could be used as new biomarkers for the diagnosis of endometriosis.


Problems with continuous-time malaria models in describing gametocytogenesis.
Most mathematical models of malaria infection represent parasites as replicating continuously at a constant rate whereas in reality, malaria parasites replicate at a fixed age. The behaviour of continuous-time models when gametocytogenesis is included, in comparison to a more realistic discrete-time model that incorporates a fixed replication age was evaluated. Both the infection dynamics under gametocytogenesis and implications for predicting the amount parasites should invest into gametocytes (level of investment favoured by natural selection) are considered. It is shown that the many malaria models with constant replication rates can be represented by just 3 basic types. For these 3 types, it is then shown that under gametocytogenesis (i) in 2 cases, parasite multiplication and gametocyte production is mostly much too low, (ii) in the third, parasite multiplication and gametocyte production is mostly much too high, (iii) the effect of gametocyte investment on parasite multiplication is mostly too high, (iv) the effect of gametocyte investment on gametocyte production is nearly always too low and (v) with a simple approximation of fitness, the predicted level of gametocyte investment is mostly much too low. However, a continuous model with 48 age-compartments compares well to the discrete model. These findings are a further argument for modelling malaria infections in discrete time.


[Termination of the series 'From gene to disease'].
In 2000, a series of articles began which illustrated the rapidly expanding knowledge of the molecular basis of many diseases. At this point, the clinical, molecular and epidemiological aspects of more than 100 genetic diseases have been described. The series has achieved its goal. Hence, contributions will no longer be considered for publication.


Testing a Beverage and Fruit/Vegetable Education Intervention in a University Dining Hall.
To test the effect of a nutrition intervention that included education and 2 labeling components on students' food choices. Repeat cross-sectional study taking place on 6 dinner occasions before and 6 afterward. The study was conducted during dinner meals in a buffet-style dining hall in a university campus residence, where students paid a set price and consumed all they cared to eat. University students (n = 368 to 510) visited the cafeteria on each of the data collection dates. Fruit and vegetable consumption were encouraged; sugar-sweetened beverage consumption was discouraged using physical activity calorie equivalent labeling. Beverage choices and vegetable/fruit bar visits. Logistic regression was used to compare the proportion of student who selected each beverage, fruit, or vegetable before and after the intervention, while controlling for menu and gender as covariates. There was a significant decrease in the proportion of students selecting a sugar-sweetened beverage before vs after the intervention (49% vs 41%, respectively; P = .004) and an increase in students choosing water (43% vs 54%, respectively; P < .001). There was a significant increase in students who took fruit after the intervention (36%; P < .001) vs before (30%). The number of students visiting the vegetable bar significantly increased from 60% to 72% (P < .001). This intervention may be a way to encourage healthy dietary choices in campus dining halls.


Sequential interaction of glia maturation factor with insulin.
Astroblasts in culture proliferated when exposed to glia maturation factor for at least 2 hours and then to insulin, but not when exposed in the reverse order. The sequential relation suggests that glia maturation factor is a competence factor.


Regenerative Therapy by Suprachoroidal Cell Autograft in Dry Age-related Macular Degeneration: Preliminary In Vivo Report.
This study is aimed at examining whether a suprachoroidal graft of autologous cells can improve best corrected visual acuity (BCVA) and responses to microperimetry (MY) in eyes affected by dry Age-related Macular Degeneration (AMD) over time through the production and secretion of growth factors (GFs) on surrounding tissue. Patients were randomly assigned to each study group. All patients were diagnosed with dry AMD and with BCVA equal to or greater than 1 logarithm of the minimum angle of resolution (logMAR). A suprachoroidal autologous graft by Limoli Retinal Restoration Technique (LRRT) was carried out on group A, which included 11 eyes from 11 patients. The technique was performed by implanting adipocytes, adipose-derived stem cells obtained from the stromal vascular fraction, and platelets from platelet-rich plasma in the suprachoroidal space. Conversely, group B, including 14 eyes of 14 patients, was used as a control group. For each patient, diagnosis was verified by confocal scanning laser ophthalmoscope and spectral domain-optical coherence tomography (SD-OCT). In group A, BCVA improved by 0.581 to 0.504 at 90 days and to 0.376 logMAR at 180 days (+32.20%) postoperatively. Furthermore, MY test increased by 11.44 dB to 12.59 dB at 180 days. The different cell types grafted behind the choroid were able to ensure constant GF secretion in the choroidal flow. Consequently, the results indicate that visual acuity (VA) in the grafted group can increase more than in the control group after six months.


The Exercising Brain: An Overlooked Factor Limiting the Tolerance to Physical Exertion in Major Cardiorespiratory Diseases?
"Exercise starts and ends in the brain": this was the title of a review article authored by Dr. Bengt Kayser back in 2003. In this piece of work, the author highlights that pioneer studies have primarily focused on the cardiorespiratory-muscle axis to set the human limits to whole-body exercise tolerance. In some circumstances, however, exercise cessation may not be solely attributable to these players: the central nervous system is thought to hold a relevant role as the ultimate site of exercise termination. In fact, there has been a growing interest relative to the "brain" response to exercise in chronic cardiorespiratory diseases, and its potential implication in limiting the tolerance to physical exertion in patients. To reach these overarching goals, non-invasive techniques, such as near-infrared spectroscopy and transcranial magnetic stimulation, have been successfully applied to get insights into the underlying mechanisms of exercise limitation in clinical populations. This review provides an up-to-date outline of the rationale for the "brain" as the organ limiting the tolerance to physical exertion in patients with cardiorespiratory diseases. We first outline some key methodological aspects of neuromuscular function and cerebral hemodynamics assessment in response to different exercise paradigms. We then review the most prominent studies, which explored the influence of major cardiorespiratory diseases on these outcomes. After a balanced summary of existing evidence, we finalize by detailing the rationale for investigating the "brain" contribution to exercise limitation in hitherto unexplored cardiorespiratory diseases, an endeavor that might lead to innovative lines of applied physiological research.


The Hagfish Gland Thread Cell: A Fiber-Producing Cell Involved in Predator Defense.
Fibers are ubiquitous in biology, and include tensile materials produced by specialized glands (such as silks), extracellular fibrils that reinforce exoskeletons and connective tissues (such as chitin and collagen), as well as intracellular filaments that make up the metazoan cytoskeleton (such as F-actin, microtubules, and intermediate filaments). Hagfish gland thread cells are unique in that they produce a high aspect ratio fiber from cytoskeletal building blocks within the confines of their cytoplasm. These threads are elaborately coiled into structures that readily unravel when they are ejected into seawater from the slime glands. In this review we summarize what is currently known about the structure and function of gland thread cells and we speculate about the mechanism that these cells use to produce a mechanically robust fiber that is almost one hundred thousand times longer than it is wide. We propose that a key feature of this mechanism involves the unidirectional rotation of the cell's nucleus, which would serve to twist disorganized filaments into a coherent thread and impart a torsional stress on the thread that would both facilitate coiling and drive energetic unravelling in seawater.


Interrelations that foster learning: An investigation of two correlational studies.
The theoretical tenets of academic engagement, as outlined by Schaufeli and colleagues, have received limited attention. There is credence to indicate that Schaufeli et al.'s conceptualization has educational implications. Extending this avenue of inquiry, we report two longitudinal studies that explore the motivation-related attributes of engagement within the framework of self-efficacy. A number of research questions were developed for examination-for example, does enactive learning experience influence academic achievement, via students' engrossment (i.e. absorption) of a subject matter? Does students' sense of resilience and persistence (i.e. vigor) heighten their self-efficacy beliefs for academic learning? For the two studies (Study 1: 311 Year 11 students; Study 2: 249 Year 12 students), utilizing different cohorts, we measured these constructs at multiple time points. Existing Likert-scale inventories were administered repeatedly, and data collected were analysed using causal modeling procedures. MPlus 7.2 yielded a number of key findings-for example: (a) the positive impact of Time 1 enactive learning experience on Time 2 absorption and vigor, (b) the positive impact of Time absorption on Time 3 self-efficacy, (c) the positive impact of Time 2 absorption on Time 4 achievement and (d) the positive impact of Time 1 self-efficacy on Time 2 absorption and vigor.


Student perspective on outcomes and process - Recommendations for implementing competency-based medical education.
Competency-based medical education (CBME) seeks to prepare undergraduate and postgraduate trainees for clinical practice. Its major emphasis is on outcomes, but questions about how best to reach these remain. One key issue is the need to integrate what matters most to students when setting educational goals: this is crucial if we are to design curricula that trainees understand and engage with, and that promote successful achievement of competencies. We interviewed medical students in years 4 and 6 of a 6-year medical degree and used thematic analysis to understand their main educational priorities and how these fit with the aims of CBME. Two major themes emerged: features of content and process. For content, students wanted clear guidance on what constitutes competence, finding broad outcome statements abstract and difficult to understand as novices. They also attach critical importance to features of process such as being welcomed, included in clinical teams and being known personally - these promote motivation, understanding, and professional development. We present recommendations for those designing CBME curricula to emphasize the student perspective: what kind of guidance on outcomes is required, and features of process that must not be neglected if competence is to be achieved.


Consumer recommendations for enhancing the Safewards model and interventions.
This paper critiques the Safewards model through the lens of lived experiences of psychiatric hospitalization, diagnosis of mental illness, and distress. Special focus is given to the model's tested 10 interventions and to five lesser known interventions, identifying the impact they can have on hospitalized consumers. We highlight the role and prevalence of trauma, as well as the need to prevent harm in hospital settings. We draw upon notions of hospital as a sanctuary for people and the importance of providing a safe ward. 'Sanctuary harm' and 'Sanctuary trauma' are thus defined, with emphasis placed on the Safewards interventions as means by which sanctuary can be achieved. Finally, the consumer-perspective authors propose expansions to the model, critiquing the defining literature and moving towards a consumer experience of safety that is beyond the model's original intention: to reduce seclusion and restraint practices. Throughout the paper, the term 'consumer' is used in this context to mean people who have experienced or are experiencing psychiatric inpatient care.


Intravascular aggregation after acute intracranial hypertension by epidural balloon compression in cats.
The authors have studied the effect of acute intracranial hypertension produced by placement of an epidural balloon (control group) in cats, on cerebral perfusion, evoked responses, and hematological parameters. These elements were measured in similarly injured animals which underwent isovolemic hemodilution with dextran 75, after relief of intracranial hypertension. Four hours after balloon deflation, perfusion was markedly impaired in 30% of the control group, and was reduced to 11% in the dextran-infused group. The suppressed N1 amplitude of somatosensory evoked responses on the compression side, the reduced platelet aggregability, and the erythrocyte-deformability by intracranial hypertension were all significantly more restored in the dextran-infused group after decompression. The percentage of platelets with volumes between 21.75 and 48.75 cu mu (normal 9.75 to 12.75 cu mu) significantly increased after decompression. Activation of platelets during intracranial hypertension leads to an increase in platelet volume from platelet aggregation, and correlates with a decrease in platelet aggregability. It was also suggested that reduction of erythrocyte deformability was not caused by erythrocyte aggregation. The authors emphasize the role of intravascular factors such as vascular obstruction by platelet aggregates, and difficulty in passage of erythrocytes through capillaries due to reduced deformability, in the disturbance of the microcirculation following acute intracranial hypertension. The protective effect of dextran 75 by inhibition of platelets as well as hemodilution is stressed.


Is signal transduction modulated by an interaction between heterotrimeric G-proteins and tubulin?
Although it is generally accepted that tubulin plays an important role in G-protein-mediated signal transduction in a variety of systems, the mechanism of this phenomenon is not completely understood. G-protein-tubulin interaction at the cell membrane and the cytosol, and the influence of such an interaction on cellular signaling are discussed in this review article. Because the diameter of a microtubule is 25 nm and the plasma membrane is 9-11 nm thick, it is not possible for membrane-associated tubulin to assemble into a complete microtubule in the membrane environment. However, tubulin heterodimers may be able to function in the membrane environment as individual heterodimers or as polymers arranged into short protofilaments. At the cell membrane, membrane-associated tubulin may influence hormone-receptor interaction, receptor-G-protein coupling, and G-protein-effector coupling. Structural proteins, such as tubulin, can participate in cellular signaling by communicating through physical forces. By virtue of its interaction with the submembranous network of cytoskeletal proteins, tubulin, when perturbed in one locus, can transmit large changes in conformations to other points. Thus, GTP binding to membrane-associated tubulin might lead to a conformational change in either receptors or G proteins. This may, in turn, influence the binding of an agonist to its receptor. On the other hand, in the cell cytosol, subsequent to agonist-induced translocation of G-proteins from the membrane compartment to the cytosol, G-proteins may affect microtubule formation. In GH3 and AtT-20 cells (stably expressing TRH receptor), transiently transfected with Gq alpha cDNA, soluble tubulin levels decreased in Gq alpha-transfected GH3 and AtT-20 cells, by 33% and 52%, respectively. These results suggest that G-proteins may have a direct effect on the microtubule function in vivo. Because tubulin and G-protein families are ubiquitous and highly conserved, an interaction between these two protein families may occur in vivo, and this, in turn, can have an impact on signal transduction. However, the physiological significance of this interaction remains to be demonstrated.


Alpha1-adrenoceptor subtype activation increases proto-oncogene mRNA levels. Role of protein kinase C.
Noradrenaline increased the mRNA levels of c-fos and c-jun in rat-1 fibroblast lines stably expressing the cloned alpha1-adrenoceptor subtypes. The efficacy to induce the expression of c-fos mRNA was similar for the three cell lines (alpha1d = alpha1b = alpha1a) but different for c-jun (alpha1a > or = alpha1b > alpha1d). The EC50 values were also different: approximately 5 nM (c-fos) and approximately 300 nM (c-jun) for cells transfected with the alpha1a subtype, approximately 30 nM (c-fos) and approximately 300 nM (c-jun) for cells transfected with the alpha1b subtype and approximately 300 nM (c-fos and c-jun) for those transfected with the alpha1d subtype. Staurosporine and protein kinase C down-regulation blocked such effects, indicating a role of this protein kinase. Endothelin-1 (10 nM) also increased the levels of c-fos and c-jun mRNAs. These actions of endothelin-1 were unaffected by staurosporine and protein kinase C down-regulation. It is concluded that activation of any of the three cloned subtypes can increase the levels of c-fos and c-jun mRNAs and that protein kinase C plays a major role in mediating such effects.