Computational Cardiac Modeling Reveals Mechanisms of Ventricular Arrhythmogenesis in Long QT Syndrome Type 8: CACNA1C R858H Mutation Linked to Ventricular Fibrillation.
Functional analysis of the L-type calcium channel has shown that the CACNA1C R858H mutation associated with severe QT interval prolongation may lead to ventricular fibrillation (VF). This study investigated multiple potential mechanisms by which the CACNA1C R858H mutation facilitates and perpetuates VF. The Ten Tusscher-Panfilov (TP06) human ventricular cell models incorporating the experimental data on the kinetic properties of L-type calcium channels were integrated into one-dimensional (1D) fiber, 2D sheet, and 3D ventricular models to investigate the pro-arrhythmic effects of CACNA1C mutations by quantifying changes in intracellular calcium handling, action potential profiles, action potential duration restitution (APDR) curves, dispersion of repolarization (DOR), QT interval and spiral wave dynamics. R858H "mutant" L-type calcium current (ICaL ) augmented sarcoplasmic reticulum calcium content, leading to the development of afterdepolarizations at the single cell level and focal activities at the tissue level. It also produced inhomogeneous APD prolongation, causing QT prolongation and repolarization dispersion amplification, rendering R858H "mutant" tissue more vulnerable to the induction of reentry compared with other conditions. In conclusion, altered ICaL due to the CACNA1C R858H mutation increases arrhythmia risk due to afterdepolarizations and increased tissue vulnerability to unidirectional conduction block. However, the observed reentry is not due to afterdepolarizations (not present in our model), but rather to a novel blocking mechanism.


The clinical endocrinology workforce: current status and future projections of supply and demand.
Many changes in health care delivery, health legislation, and the physician workforce that affect the supply and demand for endocrinology services have occurred since the first published workforce study of adult endocrinologists in 2003. The objective of the study was to assess the current adult endocrinology workforce data and provide the first analysis of the pediatric endocrinology workforce and to project the supply of and demand for endocrinologists through 2025. A workforce model was developed from an analysis of proprietary and publicly available databases, consultation with a technical expert panel, and the results of an online survey of board-certified endocrinologists. The Endocrine Society commissioned The Lewin Group to estimate current supply and to project gaps between supply and demand for endocrinologists. A technical expert panel of senior endocrinologists provided context, clinical information, and direction. The following were measured: 1) the current adult and pediatric endocrinology workforce and the supply of and demand for endocrinologists through 2025 and 2) the number of additional entrants into the endocrinology work pool that would be required to close the gap between supply and demand. Currently there is a shortage of approximately 1500 adult and 100 pediatric full-time equivalent endocrinologists. The gap for adult endocrinologists will expand to 2700 without an increase in the number of fellows trained. An increase in the prevalence of diabetes mellitus further expands the demand for adult endocrinologists. The gap can be closed in 5 and 10 years by increasing the number of fellowship positions by 14.4% and 5.5% per year, respectively. The gap between supply and demand for pediatric endocrinologists will close by 2016, and thereafter an excess supply over demand will develop at the current rate of new entrants into the work force. There are insufficient adult endocrinologists to satisfy current and future demand. A number of proactive strategies need to be instituted to mitigate this gap.


Regulation of flowering time by histone acetylation in Arabidopsis.
The Arabidopsis autonomous floral-promotion pathway promotes flowering independently of the photoperiod and vernalization pathways by repressing FLOWERING LOCUS C (FLC), a MADS-box transcription factor that blocks the transition from vegetative to reproductive development. Here, we report that FLOWERING LOCUS D (FLD), one of six genes in the autonomous pathway, encodes a plant homolog of a protein found in histone deacetylase complexes in mammals. Lesions in FLD result in hyperacetylation of histones in FLC chromatin, up-regulation of FLC expression, and extremely delayed flowering. Thus, the autonomous pathway regulates flowering in part by histone deacetylation. However, not all autonomous-pathway mutants exhibit FLC hyperacetylation, indicating that multiple means exist by which this pathway represses FLC expression.


Reconstruction of Large Postburn Facial-Scalp Scars by Expanded Pedicled Deltopectoral Flap and Random Scalp Flap: Technique Improvements to Enlarge the Reconstructive Territory.
The scars of face and scalp caused by burning often show as 1 large facial-scalp scar. The deltopectoral flap was recognized as one of the first choices for the facial scar reconstruction. However, this flap cannot cross the level of zygomatic arch traditionally when it was transferred with pedicle. When the flap reconstructed the facial-scalp scars with expanded random scalp flap, another flap was often needed to reconstruct the remaining temple and forehead scars. The authors reviewed 24 patients of large facial-scalp scars reconstructed by expanded pedicled deltopectoral flap and scalp flap with several technique improvements. The seaming scar between the deltopectoral flap and scalp flap in the temple region formed the new hairline. The technique improvements included ligation of the perforating branches of the transverse cervical artery and thoracoacromial artery when dissecting the pocket, the partial bolster compressive dressing to the distal part of the flap and dividing the pedicle partly as a delaying procedure before dividing the pedicle completely. Good skin compliance, normal contours, and emotional expression were noted. There were complications including expander exposure in 3 patients, stretch marks in 5 patients, flap tip necrosis in 2 patients, and mild postoperative hypertrophic scars in 3 patients. In conclusion, the expanded pedicled deltopectoral flap can enlarge the reconstructive territory in face successfully with the technique improvements. The combination of the expanded pedicled deltopectoral flap and scalp flap is a reliable and excellent reconstructive option for large postburn facial-scalp scars.


Cloning, mapping, expression, function, and mutation analyses of the human ortholog of the hamster putative tumor suppressor gene Doc-1.
doc-1 is a putative tumor suppressor gene isolated and identified from the hamster oral cancer model. Here, we report the molecular cloning and the functional characterization of the human ortholog of the hamster doc-1 gene. Human doc-1 cDNA is 1.6 kilobase pairs in length and encodes for a 115-amino acid polypeptide (12.4 kDa, pI 9. 53). Sequence analysis showed 98% identity between human and hamster doc-1 protein sequences. DOC-1 is expressed in all normal human tissues examined. In oral keratinocytes, expression of DOC-1 is restricted to normal oral keratinocytes. By immunostaining of normal human mucosa, DOC-1 is detected in both the cytoplasm and nuclei of basal oral keratinocytes; while in suprabasilar cells, it is primarily found in the nuclei. Human oral cancers in vivo did not exhibit immunostaining for DOC-1. Like murine DOC-1, human DOC-1 associates with DNA polymerase alpha/primase and mediates the phosphorylation of the large p180 catalytic subunit, suggesting it may be a potential regulator of DNA replication in the S phase of the cell cycle. Using a human doc-1 cosmid as a probe, human doc-1 is mapped to chromosome 12q24. We identified four exons in the entire human doc-1 gene and determined the intron-exon boundaries. By polymerase chain reaction and direct sequencing, we examined premalignant oral lesion and oral cancer cell lines and found no intragenic mutations.


Ventricular arrhythmias during Swan-Ganz catheterization of the critically ill.
The incidence of ventricular arrhythmias in critically-ill patients during bedside right-sided heart catheterization with a flow-directed balloon-tipped catheter was determined. Twenty-nine of 60 catheterizations (48 percent) were associated with premature ventricular contractions and 20 (33 percent) were associated with ventricular tachycardia. Two patients required antiarrhythmic therapy or a precordial thump to convert ventricular tachycardia. One patient developed ventricular tachycardia and fibrillation and died. Serious catheter-induced arrhythmias, including sustained ventricular tachycardia, may occur during Swan-Ganz catheterization of the critically ill.


The Comorbidity of Chronic Obstructive Pulmonary Disease and Peripheral Artery Disease - A Systematic Review.
The comorbidity of peripheral arterial disease (PAD) and chronic obstructive pulmonary disease (COPD) is obvious from a clinical point of view, especially as smoking is an important risk factor for both. Another factor connecting these two clinical conditions is chronic inflammation, which plays a crucial role in their pathophysiology. The aim of this study was to present the prevalence of COPD in patients with PAD, as well as the prevalence of PAD in COPD patients confirmed in all patients by two reliable methods: spirometry and ankle-brachial index (ABI), respectively. The MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews were searched to identify the potentially eligible publications from the previous 10 years. The published characteristics of different PAD and COPD populations were analyzed. A database search identified 894 records. Reliable criteria of both COPD and PAD diagnosis were used only in seven publications. The prevalence of PAD among patients with COPD ranged from 8.5 to 81.4%. The severity of the disease and the exclusion of nonsmokers or symptomatic patients from the analyses were important factors affecting this parameter. The prevalence of COPD in patients with PAD was measured reliably only in one study and assessed as 27.2%. The comorbidity of COPD and PAD is a relatively common occurrence. There are very few publications addressing this issue based on reliable diagnostic criteria, especially in the field of PAD. In the case of COPD and PAD patients, spirometry and ABI measurements are worth considering as noninvasive screening tests for COPD and PAD, respectively.


Translational control of NKT cell cytokine production by p38 MAPK.
NKT cells are known to rapidly produce a large amount of cytokines upon activation. Although a number of signaling pathways that regulate the development of NKT cells have been identified, the signaling pathways involved in the regulation of NKT cell cytokine production remain unclear. In this study, we show that the p38 MAPK pathway is dispensable for the development of NKT cells. However, NKT cell cytokine production and NKT-mediated liver damage are highly dependent on activation of this pathway. p38 MAPK does not substantially affect cytokine gene expression in NKT cells, but it regulates the synthesis of cytokines through the Mnk-eIF4E pathway. Thus, in addition to gene expression, translational regulation by p38 MAPK could be a novel mechanism that contributes to the overall production of cytokine by NKT cells.


Comparison of the efficacy between conventional moxibustion and smoke-free moxibustion on knee osteoarthritis: study protocol of a randomized controlled trial.
Conventional moxibustion is a representative non-drug intervention in traditional Chinese medicine, and it has been reported to produce encouraging results and benefits in relieving symptoms and improving the quality of life for patients with knee osteoarthritis (KOA) in previous clinical trials and systematic reviews. Given that increasing concerns on the safety of generated smoke from conventional moxibustion have received much attention, smoke-free moxibustion is regarded as a potential alternative. However, whether smoke-free moxibustion would display a similar efficacy to that of conventional moxibustion still remains unclear. Therefore, this randomized controlled trial attempts to investigate the difference of efficacy between conventional moxibustion and smoke-free moxibustion in patients with KOA. This is a multicenter, randomized, single-blinded, parallel-group clinical trial. A total of 138 eligible participants with KOA will be randomly allocated to two groups (conventional moxibustion group and smoke-free moxibustion group) in seven hospitals in China. Participants will receive 12 sessions of moxibustion treatment at three acupoints (EX-LE4, ST35, and ST36) over a period of 4 weeks (3 sessions per week). A smoke-removing device is placed at the top of the moxibustion device for the smoke-free moxibustion group (n = 69), while the conventional moxibustion group (n = 69) is treated with traditional moxibustion. The primary outcome measure will be the change of the global scale of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) from the baseline to 4 weeks. Secondary outcomes include the visual analog scale VASand Patient Global Assessment scores. Follow-up measurements will be performed on the 8th and 12th weeks after random allocation. This study will contribute to providing a solid foundation for the selection of moxibustion in clinical application as well as future research in moxibustion therapy. ClinicalTrials.gov, NCT02772055 . Registered on 12 May 2016.


Ecological Determinants of Sporotrichosis Etiological Agents.
Ecological determinants of sporotrichosis etiological agents remain poorly understood. For this reason, we performed explorations using local climate estimates to determine the temperature and humidity ranges of the environment where clinically relevant Sporothrix species occur and to identify what plant species are associated with them, using data collected from the published literature. We performed a literature search to identify all publications on environmental isolations of medically relevant species of Sporothrix in the PubMed, SCOPUS, and EMBASE databases. All those studies were included in the analysis where medically relevant species of Sporothrix have been isolated from soil samples, and described a specific geographical location that could be precisely georeferenced. We approximated temperature and humidity from local climate estimates, integrating geospatial data, temperature, and water vapor pressure from regions or provinces where medically relevant species of Sporothrix have been isolated from soil. Sporothrix spp. were more commonly isolated from soil of different regions or provinces of 16 countries. Most environmental isolates were identified as S. schenckii, whereas S. pallida, S. brasiliensis, S. globosa, and S. mexicana were rare. We estimate that medically relevant Sporothrix spp. grow in the soil at temperatures of 6.6 °C to 28.84 °C and 37.5% to 99.06% relative humidity. These findings indicate that sporotrichosis etiological agents grow in soil in ecological niches from soil with wide ranges of temperature and humidity, but they are also associated with a variety of plants, flowers, woody debris, reed leaves, corn stalks, leaves, and wood crumbs, potentially facilitating its establishment and proliferation in the environment.


Regional Arch Measurements Differ Between Imaging Modalities in Infants with Aortic Coarctation.
Aortic arch measurements provide a framework for surgical decision-making in neonatal aortic coarctation, specifically in the determination of approach for arch repair by lateral thoracotomy versus median sternotomy. The purpose of this study was to evaluate our experience with transthoracic echocardiography (TTE) and computed tomographic angiography (CTA) in the pre-operative evaluation of infants with aortic coarctation, specifically comparing arch dimensions as a function of imaging modality. Imaging data were reviewed for all infants undergoing surgical repair of aortic coarctation at our institution from 2012-2022. Infants with both TTE and CTA evaluations were included. Aortic measurements were compared at pre-defined anatomic regions including ascending, proximal arch, distal arch, and isthmus. 372 infants underwent surgical coarctation repair during the study period. 72 (19.4%) infants had TTE and CTA arch evaluations pre-operatively. Significant discrepancies between imaging modalities were defined by poor correlation coefficients and absolute measurement differences and were most prominent in the proximal aortic arch (R2=0.23, -4.4 to 3.2mm) and isthmus regions (R2=0.11, -4.2 to 1.7mm). Improved correlation was demonstrated in the ascending aorta (R2=0.63) and distal aortic arch (R2=0.54). Significant variability exists between TTE- and CTA-derived aortic measurements in infants with coarctation, with proximal arch measurements demonstrating the poorest correlation. This anatomic location represents a commonly utilized arch region for the determination of approach for repair of neonatal aortic coarctation. Thus, these findings have important implications for current preoperative surgical decision-making paradigms and future prospective study to minimize the risk of residual or recurrent arch obstruction.


Influenza and pneumococcal vaccination demand responses to changes in infectious disease mortality.
To test the hypothesis that individuals are more likely to receive a vaccination against influenza or pneumonia as the perceived disease threat increases. This study uses two different national datasets. Individual-level information about the vaccination rates of 38,768 elderly persons are from the Behavioral Risk Factor Surveillance System, 1993-1998. Information on the combined influenza and pneumonia state mortality rates are measured from the Compressed Mortality File. Using both cross-sectional and state fixed-effects panel data estimators, we model an individual's probability of having an influenza or pneumococcal vaccination as a function of the lagged state mortality rate. Multiyear lags are specified in order to estimate the duration of the effect of disease mortality on individual vaccination behavior. Results support our hypothesis that influenza vaccination behavior responds positively to disease mortality, even after a one-year lag. We further find that cross-sectional estimators used in previous work yield downward-biased estimates, although even for our preferred panel data models, the estimated effects are small. The findings indicate that behavioral demand responses can help to limit infectious disease epidemics, and suggest further research on how public awareness campaigns can mediate this disease threat responsiveness behavior.


Ready to Make A Decision: A Model of Informational Aids to Improve Informed Participation in Clinical Trial Research.
Enrollment rates for cancer clinical trials remain low, affecting the generalizability of new treatments. Research shows that many patients face significant challenges in understanding basic clinical trial vocabulary and making informed decisions about participation. Informational aids (IA) are developed to address these challenges and support decision making of cancer clinical trial participation. The present study proposed and tested a structural path model to explain the efficacy of three (i.e., interactive, non-interactive, non-cancer control) IAs. The results revealed that clinical trial participation intention was associated with attitudes and social constructs (i.e., social norm, social sharing, and cues to action). Ease of use, rather than knowledge, was the primary communication feature of IA that influenced the outcome variables. The path relations linking messages features, mediators, and outcome variables were different across all three IAs. The results therefore provide theoretical and practical implications for the use and development of IAs to support clinical trial accrual.


Carbon nanotube-based robust steamphobic surfaces.
The wetting behavior of a surface under steam condensation depends on its intrinsic wettability and micrometer or nanoscale surface roughness. A typical superhydrophobic surface may not be suitable as a steamphobic surface because of the nucleation and growth of water inside the valleys and thus the failure to form an air-liquid-solid composite interface. Here, we present the results of steam condensation on chemically modified nanostructured carbon nanotube (CNT) mats. We used a plasma-enhanced chemical vapor deposition (PECVD) process to modify the intrinsic wettability of nanostructured CNT mats. The combination of low surface energy achieved by PECVD and the nanoroughness of the surface provides a mechanism to retain the superhydrophobicity of the CNT mats under steam condensation. The ability to withstand steam temperature and pressure for as long as 10 h implies the remarkably improved stability of the superhydrophobic state of the surface. The thermodynamic calculations carried out using a unit cell model clearly explain the steamphobic wetting behavior of the surface.


Management of refractory or relapsed primary central nervous system lymphoma (Review).
Primary central nervous system lymphoma (PCNSL) is a non-Hodgkin's lymphoma arising in the central nervous system. Combined methotrexate-based chemoradiotherapy is the standard treatment for PCNSL, resulting in a median overall survival of 25-51 months. Failure of first-line treatment has been reported in most patients with PCNSL. Salvage therapy improves outcome; however, since many different treatments have been applied, conclusions cannot be drawn regarding an optimal treatment schedule. This review analyzes the efficacy of different salvage therapies that have been reported in the literature. These well-designed, randomized trials may help elucidate issues such as the best chemotherapy regimen for second-line treatment.


DGCR8-mediated disruption of miRNA biogenesis induces cellular senescence in primary fibroblasts.
The regulation of gene expression by microRNAs (miRNAs) is critical for normal development and physiology. Conversely, miRNA function is frequently impaired in cancer, and other pathologies, either by aberrant expression of individual miRNAs or dysregulation of miRNA synthesis. Here, we have investigated the impact of global disruption of miRNA biogenesis in primary fibroblasts of human or murine origin, through the knockdown of DGCR8, an essential mediator of the synthesis of canonical miRNAs. We find that the inactivation of DGCR8 in these cells results in a dramatic antiproliferative response, with the acquisition of a senescent phenotype. Senescence triggered by DGCR8 loss is accompanied by the upregulation of the cell-cycle inhibitor p21CIP1. We further show that a subset of senescence-associated miRNAs with the potential to target p21CIP1 is downregulated during DGCR8-mediated senescence. Interestingly, the antiproliferative response to miRNA biogenesis disruption is retained in human tumor cells, irrespective of p53 status. In summary, our results show that defective synthesis of canonical microRNAs results in cell-cycle arrest and cellular senescence in primary fibroblasts mediated by specific miRNAs, and thus identify global miRNA disruption as a novel senescence trigger.


Immunohistochemical studies of fetal trophoblast and maternal decidua in hydatidiform mole and choriocarcinoma.
Immunohistochemical techniques have been used to investigate the expression of fetal trophoblast antigens and the maternal leucocytic response in molar pregnancy and choriocarcinoma. The antigenic phenotype of morphologically defined trophoblast populations in complete, partial and invasive moles was analogous to that in normal pregnancy. All trophoblast phenotypes described in normal pregnancy were also identified in choriocarcinoma, suggesting that extensive differentiation into heterogeneous subgroups occurs in malignant trophoblast. The maternal leucocytic infiltrate in molar pregnancy consisted of T lymphocytes and class II MHC-positive macrophages. CD2-positive, CD3-negative lymphocytes were identified in molar decidua but not in uterine tissue in choriocarcinoma. Similarly, endometrial granulocytes were present in molar decidua but not in choriocarcinoma; these cells were associated with decidualization rather than with fetal trophoblast.


Celebrity chefs put their left cheek forward: Cover image orientation in celebrity cookbooks.
Portrait pose orientations influence perception: the left cheek is more emotionally expressive; females' right cheeks appear more attractive. Posing biases are established in paintings, photographs, and advertisements, however, book covers have not previously been examined. This paper assesses cover image orientation in a book genre that frequently features a cover portrait: the celebrity cookbook. If marketers intuitively choose to enhance chefs' emotional expressivity, left cheek poses should predominate; if attractiveness is more important, right cheek poses will be more frequent for females, with a left or no cheek bias for males. Celebrity cookbook covers (N = 493) were sourced online; identity, portrait orientation, photo type, and sex were coded. For celebrity cookbooks, left cheek covers (39.6%) were more frequent than right cheek (31.6%) or midline covers (28.8%); sex did not predict pose orientation. An interaction between photo type and sex bordered on significance: photo type did not influence females' pose orientation; for males, the left cheek bias present for head and torso images was absent for full body and head only photos. Overall, the left cheek bias for celebrity cookbook covers implies that marketers intuitively select images that make the chefs appear happier and/or more emotionally expressive, enhancing engagement with the audience.


Predictors of false-positive stroke thrombectomy transfers.
Most patients with large vessel occlusion (LVO) stroke need to be transferred to receive thrombectomy. To save time, the decision to transfer often relies on clinical scales as a surrogate for LVO rather than imaging. However, clinical scales have been associated with high levels of diagnostic error. The aim of this study is to define the susceptibility to overdiagnosis of our current transfer decision process by measuring the rate of non-treatment transfers, the most common reasons for no treatment and potential predictors. Clinical and transfer data on consecutive patients transferred to a single endovascular capable centre for possible thrombectomy via stroke code activation were retrospectively reviewed. Whether patients underwent the procedure, why they did not undergo the procedure, and other clinical and logistical predictors were recorded. χ2 tests and multivariate logistic regression analysis were performed. From 2015 to 2016, 105/192 transferred patients (54%) did not undergo thrombectomy and the most common reason was absence of a LVO found on CTA after transfer (71/104 (68%)). 14/16 (88%) with a National Institutes of Health Stroke Scale (NIHSS) score <10 did not undergo thrombectomy while 41/78 (52%) with a NIHSS>20 underwent thrombectomy (p<0.001). Helicopter use was associated with no treatment (p=0.004) while arrival within 5 hours was associated with treatment (p<0.001). Clinical scales appear to overdiagnose LVO and may be responsible for the majority of our stroke code transfers not undergoing thrombectomy. Primary stroke centres therefore have reason to develop the capability to rapidly acquire and interpret a CTA in patients with suspected LVO prior to transfer. Such efforts may reduce the costs associated with unnecessary thrombectomy transfers.


Characterization of the order-disorder dielectric transition in the hybrid organic-inorganic perovskite-like formate Mn(HCOO)(3)[(CH(3))(2)NH(2)].
We have found that the hybrid organic-inorganic perovskite-like formate Mn(HCOO)(3)[(CH(3))(2)NH(2)] shows a dielectric transition around 190 K. According to single crystal X-ray diffraction, the compound shows rhombohedral symmetry at room temperature and monoclinic symmetry at low temperature (100 K), and the main difference between both structures is that the (CH(3))(2)NH(2)(+) (DMA) cations are disordered in the high temperature phase but cooperatively ordered in the low temperature one. The vibrational spectra of this compound reveal that significant changes take place in the vibrations ascribed to the DMA cation (changes in the frequency of certain vibrations, splitting of particular vibrations, and changes in the intensities), while no significant changes have been observed in those attributed to the formate anion. On the basis of all this information, we attribute the origin of the dielectric transition to the dynamics of the DMA cations: above 190 K these cations can rotate inside the cubooctahedral cavity created by the [Mn(HCOO)(3)](-) framework, while for lower temperatures such rotation gets frozen, and their cooperative arrangement inside the cavities give rise to the observed dielectric transition.


Completely foldable electronics based on homojunction polymer transistors and logics.
An increase in the demand for completely foldable electronics has motivated efforts for the development of conducting polymer electrodes having extraordinary mechanical stability. However, weak physical adhesion at intrinsic heterojunctions has been a challenge in foldable electronics. This paper reports the completely foldable polymer thin-film transistors (PTFTs) and logic gate arrays. Homojunction-based PTFTs were fabricated by selectively doping p-type diketopyrrolopyrrole-based semiconducting polymer films with FeCl3 to form source/drain electrodes. The doping process caused a gradual work function change with depth, which promoted charge injection to semiconducting regions and provided a low contact resistance. In addition, the interfacial adhesion in the PTFTs was improved by interfacial cross-linking between adjacent component layers. The electrical performance of the resulting PTFTs was maintained without noticeable degradation even after extreme folding, suggesting that the proposed fabrication strategy can further be applied to various semiconducting polymers for the realization of foldable electronics.


Enveloped virus-like particles as vaccines against pathogenic arboviruses.
Arthropod-borne arboviruses form a continuous threat to human and animal health, but few arboviral vaccines are currently available. Advances in expression technology for complex, enveloped virus-like particles (eVLPs) create new opportunities to develop potent vaccines against pathogenic arboviruses. In this short review, I highlight the successes and challenges in eVLP production for members of the three major arbovirus families: Flaviviridae (e.g., dengue, West Nile, Japanese encephalitis); Bunyaviridae (e.g., Rift Valley fever); and Togaviridae (e.g., chikungunya). The results from pre-clinical testing will be discussed as well as specific constraints to the large-scale manufacture and purification of eVLPs, which are complex assemblies of membranes and viral glycoproteins. Insect cells emerge as ideal substrates for correct arboviral glycoprotein folding and posttranslational modification to yield high quality eVLPs. Furthermore, baculovirus expression in insect cell culture is scalable and has a proven safety record in industrial human and veterinary vaccine manufacturing. In conclusion, eVLPs produced in insect cells using modern biotechnology have a realistic potential to be used in novel vaccines against arboviral diseases.


Netrin-1 is a novel myelin-associated inhibitor to axon growth.
We investigated the influence of the bifunctional guidance molecule netrin-1 on axonal growth in the injured adult spinal cord. In the adult, netrin-1 is expressed on mature oligodendrocytes, cells of the central canal, and the meninges. Netrin-1 protein in white matter is selectively enriched adjacent to paranodal loops of myelin in nodes of Ranvier. The repulsion-mediating netrin-1 uncoordinated-5 (UNC5) receptors are expressed by neurons of the corticospinal and rubrospinal projections, and by intrinsic neurons of the spinal cord, both before and after spinal cord injury. Neutralization of netrin-1 in myelin prepared from adult rat spinal cord using UNC5 receptor bodies increases neurite outgrowth from UNC5-expressing spinal motor neurons in vitro. Furthermore, axon regeneration is inhibited in a netrin-1-enriched zone, devoid of other myelin-associated inhibitors, within spinal cord lesion sites in vivo. We conclude that netrin-1 is a novel oligodendrocyte-associated inhibitor that can contribute to axonal growth failure after adult spinal cord injury.


Toward assessment of resection margins using hyperspectral diffuse reflection imaging (400-1,700 nm) during tongue cancer surgery.
There is a clinical need to assess the resection margins of tongue cancer specimens, intraoperatively. In the current ex vivo study, we evaluated the feasibility of hyperspectral diffuse reflectance imaging (HSI) for distinguishing tumor from the healthy tongue tissue. Fresh surgical specimens (n = 14) of squamous cell carcinoma of the tongue were scanned with two hyperspectral cameras that cover the visible and near-infrared spectrum (400-1,700 nm). Each pixel of the hyperspectral image represents a measure of the diffuse optical reflectance. A neural network was used for tissue-type prediction of the hyperspectral images of the visual and near-infrared data sets separately as well as both data sets combined. HSI was able to distinguish tumor from muscle with a good accuracy. The diagnostic performance of both wavelength ranges (sensitivity/specificity of visual and near-infrared were 84%/80% and 77%/77%, respectively) appears to be comparable and there is no additional benefit of combining the two wavelength ranges (sensitivity and specificity were 83%/76%). HSI has a strong potential for intra-operative assessment of tumor resection margins of squamous cell carcinoma of the tongue. This may optimize surgery, as the entire resection surface can be scanned in a single run and the results can be readily available. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.


Coping Skills Training and Acceptance and Commitment Therapy for Symptom Management: Feasibility and Acceptability of a Brief Telephone-Delivered Protocol for Patients With Advanced Cancer.
Patients with advanced cancer face a life-limiting condition that brings a high symptom burden that often includes pain, fatigue, and psychological distress. Psychosocial interventions have promise for managing symptoms but need additional tailoring for these patients' specific needs. Patients with advanced cancer in the community also face persistent barriers-availability of interventions in community clinics as well as financial and illness-related factors-to accessing psychosocial interventions. The aim of the present study was to assess the feasibility and acceptability of telephone implementation of Engage, a novel brief combined Coping Skills Training and Acceptance and Commitment Therapy protocol, for reducing symptoms and increasing quality of life in community patients with advanced cancer. Adult patients with advanced cancer receiving care in the community received Engage, four 60-minute manualized telephone sessions delivered by a trained psychotherapist and completed pretreatment and post-treatment assessments. Engage was feasible, achieving 100% accrual (N = 24) of a heterogeneous sample of patients with advanced cancer, with good retention (88% completed). Acceptability was demonstrated via satisfaction (mean 29 of 32; SD 2), engagement (95% attendance), and use of skills. Secondary analyses pointed to reductions in pain interference, fatigue, psychological distress, and improvements in psychological acceptance and engagement in value-guided activity after treatment. Engage, our brief novel combined Coping Skills and Acceptance and Commitment Therapy intervention, demonstrated initial feasibility and acceptability when delivered over the telephone and increased access for community clinic patients with advanced cancer. Future research will assess the comparative efficacy of Engage in larger randomized trials.


Usability Evaluation of a Mobile Phone-Based System for Remote Monitoring and Management of Chemotherapy-Related Side Effects in Cancer Patients: Mixed-Methods Study.
As most chemotherapy is administered in the outpatient setting, patients are required to manage related side effects at home without direct support from health professionals. The Advanced Symptom Management System (ASyMS) has been developed to facilitate the remote monitoring and management of chemotherapy-related toxicity in patients with cancer, using patient-reported outcomes questionnaires and a clinician alerting system. This study aims to evaluate the usability of the ASyMS, a mobile phone-based technology, from the perspective of Canadian patients with cancer receiving chemotherapy to identify existing design, functionality, and usability issues and elicit their views, experiences, and satisfaction with the ASyMS. We used a mixed-method approach to data collection with user-based testing, a think-aloud technique, semistructured interviews, and short answer questionnaires with a purposive sample of 10 patients with cancer. Participants attended usability testing sessions at the Centre for Global eHealth Innovation, University Health Network, and performed specific tasks on the ASyMS device. The test was videorecorded and each task was timed during the test. After the usability sessions, participants completed a posttest questionnaire and participated in a semistructured qualitative interview. A thematic analysis was used to code and categorize the identified issues into themes that summarized the type and frequency of occurrence. The thematic analysis generated 3 overarching themes as follows: ASyMS user-friendliness; usefulness of ASyMS (content quality and richness); and intention to use. Results from the posttest questionnaire indicated that 80% (8/10) of participants had great motivation to use the ASyMS, 70% (7/10) had positive perceptions of the successful use of the ASyMS, and all (10/10, 100%) had a positive attitude toward using the ASyMS in the future. Most identified design and functionality issues were related to the navigation of the ASyMS device and a desire for a more attractive design with advanced functionality and features. The main general design recommendations were as follows: enhance the readability of the screen; implement advance options (eg, search option); and support better navigation. The ASyMS has shown positive perceptions of patients in usability testing and qualitative interviews. An evaluation of the effects of the ASyMS on symptom outcomes in a clinical trial is needed.


Anterior cruciate ligament deficiency alters the in vivo motion of the tibiofemoral cartilage contact points in both the anteroposterior and mediolateral directions.
Quantifying the effects of anterior cruciate ligament deficiency on joint biomechanics is critical in order to better understand the mechanisms of joint degeneration in anterior cruciate ligament-deficient knees and to improve the surgical treatment of anterior cruciate ligament injuries. We investigated the changes in position of the in vivo tibiofemoral articular cartilage contact points in anterior cruciate ligament-deficient and intact contralateral knees with use of a newly developed dual orthogonal fluoroscopic and magnetic resonance imaging technique. Nine patients with an anterior cruciate ligament rupture in one knee and a normal contralateral knee were recruited. Magnetic resonance images were acquired for both the intact and anterior cruciate ligament-deficient knees to construct computer knee models of the surfaces of the bone and cartilage. Each patient performed a single-leg weight-bearing lunge as images were recorded with use of a dual fluoroscopic system at full extension and at 15 degrees , 30 degrees , 60 degrees , and 90 degrees of flexion. The in vivo knee position at each flexion angle was then reproduced with use of the knee models and fluoroscopic images. The contact points were defined as the centroids of the areas of intersection of the tibial and femoral articular cartilage surfaces. The contact points moved not only in the anteroposterior direction but also in the mediolateral direction in both the anterior cruciate ligament-deficient and intact knees. In the anteroposterior direction, the contact points in the medial compartment of the tibia were more posterior in the anterior cruciate ligament-deficient knees than in the intact knees at full extension and 15 degrees of flexion (p < 0.05). No significant differences were observed with regard to the anteroposterior motion of the contact points in the lateral compartment of the tibia. In the mediolateral direction, there was a significant lateral shift of the contact points in the medial compartment of the tibia toward the medial tibial spine between full extension and 60 degrees of flexion (p < 0.05). The contact points in the lateral compartment of the tibia shifted laterally, away from the lateral tibial spine, at 15 degrees and 30 degrees of flexion (p < 0.05). In the presence of anterior cruciate ligament injury, the contact points shift both posteriorly and laterally on the surface of the tibial plateau. In the medial compartment, the contact points shift toward the medial tibial spine, a region where degeneration is observed in patients with chronic anterior cruciate ligament injuries.


Women's experiences with domestic violence and their attitudes and expectations regarding medical care of abuse victims.
Although domestic violence (DV) is recognized as a serious crime, only recently has it been acknowledged as a critical public health problem. To develop appropriate medical intervention methods to stop abuse, we interviewed 406 female patients in the ambulatory clinics at the Miami Veterans Affairs Medical Center, using a standardized questionnaire. We assessed their experiences with DV and their expectations of physicians in treating victims. Of the 406 women, 40% have had emotional/physical abuse by a partner, 7% were currently in abusive relationships, and 3% had forced sex within the past year. Although 68% of the women could tell their doctors they were abuse victims, only 12% have been asked about abuse. Even when told of abuse, the doctors did nothing for 20% of the patients. The majority of the respondents believe that doctors should routinely screen for abuse. As part of treatment, all women strongly recommended that doctors provide information on community and legal resources and assistance in seeking protective services. Domestic violence is a significant problem for female patients in the ambulatory care setting. Women expect physicians to act as their advocates and, in partnership with other community professionals, to assist abuse victims and stop the violence.


U.S. policy: keeping children with special needs safe in America.
This paper reviews the major efforts being made to reform the child welfare system for children with special needs who are in protective placements. Barriers to finding permanent and loving homes result in putting these children at high risk of institutionalization, poor physical and emotional health, and abuse and neglect. Education for prospective parents, foster parents and the child service provider workforce is necessary to minimize these poor outcomes.


Repression of zygotic gene expression in the Xenopus germline.
Primordial germ cells (PGCs) in Xenopus are specified through the inheritance of germ plasm. During gastrulation, PGCs remain totipotent while surrounding cells in the vegetal mass become committed to endoderm through the action of the vegetal localized maternal transcription factor VegT. We find that although PGCs contain maternal VegT RNA, they do not express its downstream targets at the mid-blastula transition (MBT). Transcriptional repression in PGCs correlates with the failure to phosphorylate serine 2 in the carboxy-terminal domain (CTD) of the large subunit of RNA polymerase II (RNAPII). As serine 5 is phosphorylated, these results are consistent with a block after the initiation step but before the elongation step of RNAPII-based transcription. Repression of PGC gene expression occurs despite an apparently permissive chromatin environment. Phosphorylation of CTD-serine 2 and expression of zygotic mRNAs in PGCs are first detected at neurula, some 10 hours after MBT, indicating that transcription is significantly delayed in the germ cell lineage. Significantly, Oct-91, a POU subclass V transcription factor related to mammalian Oct3/4, is among the earliest zygotic transcripts detected in PGCs and is a likely mediator of pluripotency. Our findings suggest that PGCs are unable to respond to maternally inherited endoderm determinants because RNAPII activity is transiently blocked while these determinants are present. Our results in a vertebrate system further support the concept that one strategy used repeatedly during evolution for preserving the germline is RNAPII repression.


[Emergency psychiatric departments are not refusing admissions].
The staff at the psychiatric emergency out-patient clinic in Oslo evaluated the services of the acute psychiatric wards when admitting patients to the hospital. Of 93 admittances during three months in 1998, the referring doctor was satisfied with the hospital's response in 84% of the cases. The mean time from contact was taken with the hospital till the admittance was accepted was 19 minutes. The admittance of patients in acute psychiatric hospitals in Oslo is straightforward, and reasonably well organized.


A self-supervised classification model for endometrial diseases.
Ultrasound imaging is the preferred method for the early diagnosis of endometrial diseases because of its non-invasive nature, low cost, and real-time imaging features. However, the accurate evaluation of ultrasound images relies heavily on the experience of radiologist. Therefore, a stable and objective computer-aided diagnostic model is crucial to assist radiologists in diagnosing endometrial lesions. Transvaginal ultrasound images were collected from multiple hospitals in Quzhou city, Zhejiang province. The dataset comprised 1875 images from 734 patients, including cases of endometrial polyps, hyperplasia, and cancer. Here, we proposed a based self-supervised endometrial disease classification model (BSEM) that learns a joint unified task (raw and self-supervised tasks) and applies self-distillation techniques and ensemble strategies to aid doctors in diagnosing endometrial diseases. The performance of BSEM was evaluated using fivefold cross-validation. The experimental results indicated that the BSEM model achieved satisfactory performance across indicators, with scores of 75.1%, 87.3%, 76.5%, 73.4%, and 74.1% for accuracy, area under the curve, precision, recall, and F1 score, respectively. Furthermore, compared to the baseline models ResNet, DenseNet, VGGNet, ConvNeXt, VIT, and CMT, the BSEM model enhanced accuracy, area under the curve, precision, recall, and F1 score in 3.3-7.9%, 3.2-7.3%, 3.9-8.5%, 3.1-8.5%, and 3.3-9.0%, respectively. The BSEM model is an auxiliary diagnostic tool for the early detection of endometrial diseases revealed by ultrasound and helps radiologists to be accurate and efficient while screening for precancerous endometrial lesions.


[Dynamics of protein synthesis in several organs of mice with fluorosis].
Proceeding from the time course of 3H-leucine incorporation during chronic fluoride administration the mouse organs were distributed conventionally into three groups. The first group included the organs which did not manifest significant alterations in protein synthesis. On the contrary, the second group of the organs manifested pronounced oscillations in the synthetic activity during poisoning. However, the majority of the organs studied (the third group) was characterized by a sharp inhibition of isotope incorporation.


Hierarchical classifier design using mutual information.
A nonparametric algorithm is presented for the hierarchical partitioning of the feature space. The algorithm is based on the concept of average mutual information, and is suitable for multifeature multicategory pattern recognition problems. The algorithm generates an efficient partitioning tree for specified probability of error by maximizing the amount of average mutual information gain at each partitioning step. A confidence bound expression is presented for the resulting classifier. Three examples, including one of handprinted numeral recognition, are presented to demonstrate the effectiveness of the algorithm.


Modeling UV-Vis spectra of low dimensional materials using electrostatic embedding: The case of CdSe.
We present a generalization of a self-consistent electrostatic embedding approach (SC-Ewald) devised to investigate the photophysical properties of 3D periodic materials, to systems in one- or two-dimensional (2D) reduced periodicity. In this approach, calculations are carried out on a small finite molecular cluster extracted from a periodic model, while the crystalline environment is accounted for by an array of point charges which are fitted to reproduce the exact electrostatic potential (at ground or the excited state) of the infinite periodic system. Periodic density functional theory (DFT) calculations are combined with time dependent DFT calculations to simulate absorption and emission properties of the extended system under investigation. We apply this method to compute the UV-Vis. spectra of bulk and quantum-confined 0D quantum dots and 2D extended nanoplatelets of CdSe, due to their relevance as sensitizers in solar cells technologies. The influence of the size and shape of the finite cluster model chosen in the excited state calculations was also investigated and revealed that, although the long-range electrostatics of the environment are important for the calculation of the UV-Vis, a subtle balance between short- and long-range effects exists. These encouraging results demonstrate that this self-consistent electrostatic embedding approach, when applied in different dimensions, can successfully model the photophysical properties of diverse material classes, making it an attractive low-cost alternative to far more computationally demanding electronic structure methods for excited state calculations.


Expansion of mature thymocyte subsets before emigration to the periphery.
A small population of DNA-synthesizing mature thymocytes could be defined by analyzing cell surface markers and 5-bromo-2'-deoxyuridine (BrdUrd) labeling by four-color cytofluorometry. These cells have a completely mature phenotype (CD4- CD8+ or CD4+ CD8- TCR(high), HSA-, Qa-2(high)) and expand only weakly after BrdUrd incorporation. They recovered immediately in total number and in DNA synthesis rate after treatment with the antimitotic drug demecolcin, thus much faster than immature CD4+ CD8+ thymocytes. These data demonstrate the existence of a late intrathymic expansion phase, independent of that of developing CD4+ CD8+ immature cells, and involving phenotypically mature cells renewed each day. In mixed chimeras prepared by transfer of bone marrow and lymph node cells into RAG-2(-/-) mice, all cycling mature thymocytes were bone marrow derived. They are thus produced in situ and do not correspond to peripheral T cells reentering the thymus. Double FITC/BrdUrd detection showed that a high proportion (10-20%) of recent thymic emigrants were BrdUrd+ just postcycling cells and that around 50% of cycling mature thymocytes are just ready to emigrate to the periphery in the few hours after DNA synthesis. The late intrathymic expansion phase demonstrated here increases the daily thymic cell export by at least 30%. It could play a role in the adjustment of the T cell repertoire before emigration and in the regulation of the thymic cell output into the peripheral T cell pool.


Impact of diabetes on epidemiology, treatment, and outcomes of patients with heart failure.
The prevalence of patients with concomitant heart failure (HF) and diabetes mellitus (DM) continues to increase with the general aging of the population. In patients with chronic HF, prevalence of DM is 24% compared with 40% in those hospitalized with worsening HF. Patients with concomitant HF and DM have diverse pathophysiologic, metabolic, and neurohormonal abnormalities that potentially contribute to worse outcomes than those without comorbid DM. In addition, although stable HF outpatients with DM show responses that are similar to those of patients without DM undergoing evidence-based therapies, it is unclear whether hospitalized HF patients with DM will respond similarly to novel investigational therapies. These data support the need to re-evaluate the epidemiology, pathophysiology, and therapy of HF patients with concomitant DM. This paper discusses the role of DM in HF patients and underscores the potential need for the development of targeted therapies.


The COX-2/PGI2 receptor axis plays an obligatory role in mediating the cardioprotection conferred by the late phase of ischemic preconditioning.
Pharmacologic studies with cyclooxygenase-2 (COX-2) inhibitors suggest that the late phase of ischemic preconditioning (PC) is mediated by COX-2. However, nonspecific effects of COX-2 inhibitors cannot be ruled out, and the selectivity of these inhibitors for COX-2 vs. COX-1 is only relative. Furthermore, the specific prostaglandin (PG) receptors responsible for the salubrious actions of COX-2-derived prostanoids remain unclear. To determine the role of COX-2 and prostacyclin receptor (IP) in late PC by gene deletion. COX-2 knockout (KO) mice (COX-2(-/-)), prostacyclin receptor KO (IP(-/-)) mice, and respective wildtype (WT, COX-2(+/+) and IP(+/+)) mice underwent sham surgery or PC with six 4-min coronary occlusion (O)/4-min R cycles 24 h before a 30-min O/24 h R. There were no significant differences in infarct size (IS) between non-preconditioned (non-PC) COX-2(+/+), COX-2(-/-), IP(+/+), and IP(-/-) mice, indicating that neither COX-2 nor IP modulates IS in the absence of PC. When COX-2(-/-) or IP(-/-) mice were preconditioned, IS was not reduced, indicating that the protection of late PC was completely abrogated by deletion of either the COX-2 or the IP gene. Administration of the IP selective antagonist, RO3244794 to C57BL6/J (B6) mice 30 min prior to the 30-min O had no effect on IS. When B6 mice were preconditioned 24 h prior to the 30-min O, IS was markedly reduced; however, the protection of late PC was completely abrogated by pretreatment of RO3244794. This is the first study to demonstrate that targeted disruption of the COX-2 gene completely abrogates the infarct-sparing effect of late PC, and that the IP, downstream of the COX-2/prostanoid pathway, is a key mediator of the late PC. These results provide unequivocal molecular genetic evidence for an essential role of the COX-2/PGI2 receptor axis in the cardioprotection afforded by the late PC.


Molecular breakpoint mapping of 6q11-q14 interstitial deletions in seven patients.
Interstitial deletions involving 6q11-q14 have been reported in less than 20 patients, with the breakpoints studied by G-banding alone. We report on seven patients with 6q11-q14 interstitial deletions of variable size. The breakpoints were studied by G-banding, dual-color BAC-FISH and SNP array. The results showed the molecular breakpoints differed significantly from the ones obtained from G-banding. The breakpoints studied by BAC-FISH were consistent with the ones from SNP array. Some characteristics from this cohort are consistent with previous reports, but many typical features are lacking in our patients. The cardinal features of 6q11-q14 interstitial deletions in this cohort include: umbilical hernia, hypotonia, short stature, characteristic facial features of upslanting palpebral fissures, low set and/or dysplastic ears, high arched palate, urinary tract anomalies, and skeletal/limb anomalies.


The OncoLifeS data-biobank for oncology: a comprehensive repository of clinical data, biological samples, and the patient's perspective.
Understanding cancer heterogeneity, its temporal evolution over time, and the outcomes of guided treatment depend on accurate data collection in a context of routine clinical care. We have developed a hospital-based data-biobank for oncology, entitled OncoLifeS (Oncological Life Study: Living well as a cancer survivor), that links routine clinical data with preserved biological specimens and quality of life assessments. The aim of this study is to describe the organization and development of a data-biobank for cancer research. We have enrolled 3704 patients aged ≥ 18 years diagnosed with cancer, of which 45 with hereditary breast-ovarian cancer (70% participation rate) as of October 24th, 2019. The average age is 63.6 ± 14.2 years and 1892 (51.1%) are female. The following data are collected: clinical and treatment details, comorbidities, lifestyle, radiological and pathological findings, and long-term outcomes. We also collect and store various biomaterials of patients as well as information from quality of life assessments. Embedding a data-biobank in clinical care can ensure the collection of high-quality data. Moreover, the inclusion of longitudinal quality of life data allows us to incorporate patients' perspectives and inclusion of imaging data provides an opportunity for analyzing raw imaging data using artificial intelligence (AI) methods, thus adding new dimensions to the collected data.


The impact of cognitive impairment on self-management in chronic obstructive pulmonary disease: A systematic review.
To determine the characteristics of persons with cognitive impairment being able to self-manage in chronic obstructive pulmonary disease (COPD). In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance this systematic review examined all studies in English from 1st January 2000 to 20 February 2016, describing the relationship between cognition and COPD self-management domains in older community dwelling persons with dementia or cognitive impairment. Of 4474 studies identified, thirteen studies were eligible for inclusion. No studies differentiated populations into recognized dementia subtypes. Study aims were variable; most (n = 7) examined inhaler competency alone. Studies identified a link between worsening cognition and the need for assistance in activities of daily living. Only one study evaluated the impact of cognition on overall self-management and found no association between cognitive impairment and self-rated self-management. Mild degrees of cognitive impairment were associated with reduced symptom recall. Cognitive impairment in COPD was associated with high degrees of inhaler incompetency. Basic cognitive screening tests were able to predict inhaler incompetence with reduced overall cognitive function, dyspraxia, and/or executive function identified as predictors of incompetency. Multiple measures of disability consistently demonstrated that cognitive impairment in COPD significantly increased the need for assistance in many aspects of daily living, treatment adherence, and effective self-management. Given the nature of neuropsychological deficits seen in COPD, dedicated screening tools are required. Future research should investigate the impact of cognitive dysfunction in COPD and identify how to support those that lack capacity to self-manage.


Safety of early oral ambulatory treatment of adult patients with bloodstream infections discharged from the emergency department.
This study evaluates the safety of early oral ambulatory treatment of adult patients diagnosed with bacteremia after their discharge from the emergency department. A cohort of 206 febrile ambulatory patients was assessed. Bacteremic low-risk patients were recommended an oral treatment and were compared with matched febrile non-bacteremic outpatients. Rates of 14-day mortality and unplanned re-consultations were similar and below 5% in both cohorts, highlighting the safety of oral therapy of low-risk bacteremia, even from its onset.


Intersubject variability of foveal cone photoreceptor density in relation to eye length.
Adaptive optics scanning laser ophthalmoscopy (AOSLO) under optimized wavefront correction allows for routine imaging of foveal cone photoreceptors. The intersubject variability of foveal cone density was measured and its relation to eye length evaluated. AOSLO was used to image 18 healthy eyes with axial lengths from 22.86 to 28.31 mm. Ocular biometry and an eye model were used to estimate the retinal magnification factor. Individual cones in the AOSLO images were labeled, and the locations were used to generate topographic maps representing the spatial distribution of density. Representative retinal (cones/mm(2)) and angular (cones/deg(2)) cone densities at specific eccentricities were calculated from these maps. The entire foveal cone mosaic was resolved in four eyes, whereas the cones within 0.03 mm eccentricity remained unresolved in most eyes. The preferred retinal locus deviated significantly (P < 0.001) from the point of peak cone density for all except one individual. A significant decrease in retinal density (P < 0.05) with increasing axial length was observed at 0.30 mm eccentricity but not closer. Longer, more myopic eyes generally had higher angular density near the foveal center than the shorter eyes, but by 1°, this difference was nullified by retinal expansion, and so angular densities across all eyes were similar. The AOSLO can resolve the smallest foveal cones in certain eyes. Although myopia causes retinal stretching in the fovea, its effect within the foveola is confounded by factors other than cone density that have high levels of intersubject variability.


Factors associated with regular episodes of dysuria among women in one rural general practice.
The aim of this study was to ascertain the factors associated with frequency-dysuria (urethral) syndrome in a population of women. The study included all women aged 25 years and over on 1 May 1987 who had been registered with one rural, dispensing practice over the study period, 1 May 1985 to 1 May 1989. A self-administered questionnaire was sent to the women on 1 May 1987 and a second, similar, questionnaire was sent two years later. A total of 721 women responded to the two questionnaires (response rate 97%). Regular symptoms of frequency and dysuria were reported by 8% of women in 1987 and 14% in 1989. Four percent of women reported symptoms throughout the four year study period. Symptoms were found to be least common in the 55-74 years age group. Although none of the women who were sexually inactive reported regular symptoms no association was reported between recent sexual intercourse and symptoms. Neither was an association demonstrated between type of contraception used and symptoms. However, it was found that premenopausal women reported significantly more symptoms than postmenopausal women. The number of women involved in this study was too small to allow the importance of change of sexual partner to be determined. Significantly more of the women who reported regular symptoms had been treated for urinary tract infection than of those who did not report regular symptoms. Although a history of regular frequency and dysuria points to a diagnosis of urethral syndrome, general practitioners must assess each case in order to exclude urinary tract infection.


Gender and Social Inequalities in Awareness of Coronary Artery Disease in European Countries.
Coronary artery disease (CAD) is the single leading cause of death in Europe and the most common form of cardiovascular disease. Little is known about awareness in the European population. A cross-sectional telephone survey of 2609 individuals from six European countries was conducted to gather information on perceptions of CAD, risk factors, preventive measures, knowledge of heart attack symptoms and ability to seek emergency medical care. Level of awareness was compared according to gender, age, socioeconomic status (SES) and educational level. Women were approximately five times less likely than men to consider heart disease as a main health issue or leading cause of death (OR = 0.224, 95% CI: 0.178-0.280, OR = 0.196, 95% CI: 0.171-0.226). Additionally, women were significantly less likely to have ever had a cardiovascular screening test (OR = 0.515, 95% CI: 0.459-0.578). Only 16.3% of men and 15.3% of women were able to spontaneously identify the main symptoms of a heart attack. Almost half of the sample failed to state that they would call emergency services in case of a cardiac event. Significant differences according to age, SES and education were found for many indicators amongst both men and women. Development of a European strategy targeting improved awareness of CAD and reduced gender and social inequalities within the European population is warranted.


Successful Use of Phage and Antibiotics Therapy for the Eradication of Two Bacterial Pathogens from the Respiratory Tract of an Infant.
Phage therapy can be a useful approach in a number of clinical cases associated with multidrug-resistant (MDR) bacterial infections. In this study, we describe a successful consecutive phage and antibiotic application to cure a 3-month-old girl suffering from severe bronchitis after tracheostomy. Bronchitis was associated with two bacterial agents, MDR Pseudomonas aeruginosa and a rare opportunistic pathogen Dolosigranulum pigrum. The phage cocktail "Pyobacteriophage" containing at least two different phages against isolated MDR P. aeruginosa strain was used via inhalation and nasal drops. Topical application of the phage cocktail removed most of P. aeruginosa cells and contributed to a change in the antimicrobial resistance profile of surviving P. aeruginosa cells. As a result, it became possible to choose and administer an appropriate antibiotic that was effective against both infectious agents. Complete recovery of the infant was recorded.


The development of a metabolizable energy system for horses.
The development of a metabolizable energy (ME) system for horses is described. Predictive equations for gross energy and digestible energy (DE) are revisited. The relationship between feed protein content and renal energy losses and the relationship between feed fibre content and methane energy losses were analysed in a literature review to develop predictive equations for ME. In horses, renal energy losses are much higher than losses by methane energy. Renal energy losses were correlated more strictly to protein intake than to digestible protein intake. The reason probably is that per gram of digestible crude protein energy losses are higher for roughage than for concentrates presumably because phenolic acids of forage cell walls contribute to higher urinary energy losses. However, digestibility of protein is lower in forages than in concentrates. The net result is a rather constant urinary energy loss of 0.008 MJ/g of crude protein in the feed. Methane losses in horses are smaller than in ruminants, presumably because of reductive acidogenesis in hind gut fermentation. Methane energy losses in equines are closely related to crude fibre intake. The mean methane energy losses amount to 0.002 MJ ME/g of crude fibre which can be used to correct for methane losses. Both corrections can be made for any predictive equation for DE. Metabolizable energy is then calculated as follows: ME MJ/kg = DE MJ/kg - 0.008 MJ/g crude protein - 0.002 MJ/g crude fibre. The equation of Zeyner and Kienzle (2002) to predict DE was adapted as mentioned above to predict ME: ME (MJ/kg dry matter) = -3.54 + 0.0129 crude protein+0.0420 crude fat-0.0019 crude fibre+0.0185 N-free extract (crude nutrients in g/kg dry matter).


Effect of light on enzymes of phenylpropanoid metabolism and hispidin biosynthesis in Polyporus hispidus.
The effects of light on growth, pigmentation and the activities of enzymes involved in the deamination of phenylalanine and tyrosine and in the biosynthesis of hispidin were examined in Polyporus hispidus. Evidence is presented for the stimulation of phenylalanine ammonia-lyase activity by light. Tyrosine ammonia-lyase activity and aminotransferase activities for phenylalanine and tyrosine were higher in the dark. Tracer studies showed that conversion of cinnamate into p-coumarate is enhanced by light. p-Coumaric acid hydroxylase, catalysing the conversion of p-coumarate into caffeate, could be detected only in cultures exposed to light. These results suggest that the cinnamate pathway for the metabolism of phenylalanine, leading to hispidin synthesis, is regulated by light in P. hispidus.


Sphingosine kinase inhibitor suppresses IL-18-induced interferon-gamma production through inhibition of p38 MAPK activation in human NK cells.
Natural killer (NK) cells play an important role in the innate immune response. Interleukin-18 (IL-18) is a well-known interferon-gamma (IFN-gamma inducing factor, which stimulates immune response in NK and T cells. Sphingosine kinase (SPHK) catalyzes the formation of sphingosine 1-phosphate (S1P), which acts as a second messenger to function as an anti-apoptotic factor and proliferation stimulator of immune cells. In this study, to elucidate whether SPHK is involved in IL-18-induced IFN-gamma production, we measured IL-18-induced IFN-gamma production after pre-treatment with SPHK inhibitor (SKI) in NK-92MI cells. We found that IL-18-induced IFN-gamma expression was blocked by SKI pre-treatment in both mRNA and protein levels. In addition, the increased IFN-gamma production by stimulation with IL-18 is mediated through both SPHK and p38 MAPK. To determine the upstream signals of SKI and p38 MAPK in IL-18-induced IFN-gamma production, phosphorylation levels of p38 MAPK was measured after SKI pre-treatment. As a result, inhibition of SPHK by SKI blocked phosphorylation of p38 MAPK, showing that SPHK activation by IL-18 is an upstream signal of p38 MAPK activation. Inhibition of SPHK by SKI also inhibited IL-18-induced IFN-gamma production in human primary NK cells. In conclusion, SPHK activation is an essential factor for IL-18-induced IFN-gamma production via p38 MAPK.


Postinvasive Bacterial Resistance Conferred by Open Stomata in Rice.
Stomata are leaf pores that regulate gas exchange and water transpiration in response to environmental cues. They also function in innate immunity by limiting pathogen entry through actively closing in so-called stomatal defense. However, roles of stomata in plant disease resistance are not fully elucidated, especially in monocots. Here, we report that non-race specific resistance of the rice abscisic acid-deficient mutant Osaba1 to Xanthomonas oryzae pv. oryzae is due to increased stomatal conductance. Reducing stomatal conductance in the Osaba1 mutant increases its susceptibility to X. oryzae pv. oryzae. Artificial opening of stomata in wild-type plants leads to enhanced resistance to X. oryzae pv. oryzae. The rice mutant es1-1 with constitutively higher stomatal conductance exhibits strong resistance to X. oryzae pv. oryzae. Additionally, Osaba1 and es1-1 are resistant to X. oryzae pv. oryzicola. The data support that open stomata confer postinvasive resistance against bacterial pathogens in rice, and such resistance probably results from decreased leaf water potential. Our findings reveal a novel role of stomata in plant immunity through modulation of leaf water status, which provides physiological insight into the interactions between plant, pathogen, and environment.


Safety of nifedipine GITS in stable angina: the ACTION trial.
We describe the safety profile of nifedipine GITS as assessed from adverse events reported in the ACTION trial in which 7,665 patients with stable, symptomatic coronary artery disease were randomly assigned nifedipine GITS or placebo and followed for a mean of 4.9 years. All adverse events were coded using the COSTART coding dictionary. The incidence rate for each event was calculated as the number of patients with the event concerned divided by the total time 'at risk'. Hazard ratios comparing nifedipine with placebo and their 95% confidence intervals were obtained by Cox proportional-hazards analysis. As reported previously, nifedipine significantly reduced the incidence of cardiovascular events and procedures [hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.83-0.95]. Apart from the known side effects of nifedipine, which include peripheral oedema, vasodilatation, hypotension, asthenia, constipation, leg cramps, non-specific respiratory complaints, impotence and polyuria, and which were reported more frequently in patients assigned nifedipine, the incidence rates of most other adverse events were similar. There were no differences in the occurrence of gastrointestinal haemorrhage, myocardial infarction and suicide. The rate of occurrence of death or new cancer excluding non-melanoma skin cancer for patients with no history of cancer at baseline was 2.53/100 patient years for patients assigned nifedipine and 2.37/100 patient years for patients assigned placebo (HR 1.06, 95% CI 0.93-1.22). Overall nifedipine GITS was well tolerated by patients with stable symptomatic angina.


The impact of duration of organ dysfunction on the outcome of patients with severe sepsis and septic shock.
This study aimed to assess the impact of the duration of organ dysfunction on the outcome of patients with severe sepsis or septic shock. Clinical data were collected from hospital charts of patients with severe sepsis and septic shock admitted to a mixed intensive care unit from November 2003 to February 2004. The duration of organ dysfunction prior to diagnosis was correlated with mortality. Results were considered significant if p<0.05. Fifty-six patients were enrolled. Mean age was 55.6+/-20.7 years, mean APACHE II score was 20.6+/-6.9, and mean SOFA score was 7.9+/-3.7. Thirty-six patients (64.3%) had septic shock. The mean duration of organ dysfunction was 1.9+/-1.9 days. Within the univariate analysis, the variables correlated with hospital mortality were: age (p=0.015), APACHE II (p=0.008), onset outside the intensive care unit (p=0.05), blood glucose control (p=0.05) and duration of organ dysfunction (p=0.0004). In the multivariate analysis, only a duration of organ dysfunction persisting longer than 48 hours correlated with mortality (p=0.004, OR: 8.73 (2.37-32.14)), whereas the APACHE II score remained only a slightly significant factor (p=0.049, OR: 1.11 (1.00-1.23)). Patients who received therapeutic interventions within the first 48 hours after the onset of organ dysfunction exhibited lower mortality (32.1% vs. 82.1%, p=0.0001). These findings suggest that the diagnosis of organ dysfunction is not being made in a timely manner. The time elapsed between the onset of organ dysfunction and initiation of therapeutic intervention can be quite long, and this represents an important determinant of survival in cases of severe sepsis and septic shock.


[Fever masks of malignant tumors].
During 5 years, the authors followed up 129 patients referred to the clinic with a diagnosis of fever of unclear genesis. In 36.4% of cases, fever masked malignant neoplasms. Hyperthermia was ahead of the emergence of the symptoms of a tumor (maximally up to 12 years), dominated or was the only symptom for a time being. However, in most cases it combined with other paraneoplastic masks (rheumatic, hematological, hepatological, etc), was resistant to the treatment and disappeared after radical treatment.


Major changes in chromatin condensation suggest the presence of an apoptotic pathway in plant cells.
A large decrease in fluorescence intensity of propidium iodide (PI)-stained nuclei is observed during senescence of plant cells. The phenomenon reflects a decrease in accessibility of DNA to this fluorochrome and is a consequence of chromatin condensation. This decrease is substantially greater than usually found in animal nuclei whose chromatin undergoes condensation, e.g., during differentiation or quiescence. Chromatin condensation was confirmed by analyses of (i) DNA accessibility to DNase I, (ii) histone disassociation induced by HCl, (iii) saturation of binding sites by the PI fluorochrome (iv), and (v) visual inspection by fluorescence and confocal microscopy. The extent of changes revealed by these assays was used to map progressive changes in chromatin condensation which allowed us to identify different stages in an apoptosis-like pathway in plants. The initial step of chromatin condensation which occurred prior to endonucleolytic DNA degradation was detected by fluorescence and confocal microscopy and confirmed by a variety of assays employing flow cytometry. The initial chromatin condensation appears to be a reversible step in the early stage of apoptosis. The loss of reversibility of chromatin condensation observed subsequently may be a critical point in the cascade of apoptotic events, leading to further irreversible changes during apoptosis in plants.


Natural history of nonketotic hyperglycinemia in 65 patients.
Glycine encephalopathy, also known as nonketotic hyperglycinemia (NKH), is an autosomal recessive disorder caused by a defect in the glycine cleavage system. NKH is classically associated with neonatal apnea, lethargy, hypotonia, and seizures, followed by severe psychomotor retardation in those who survive. To determine the natural history of NKH, the authors mailed a 44-question survey to 170 households in the International NKH Family Network. Data for 65 patients (36 boys, 29 girls) were collected from 58 families. One-third of the subjects died; 8 girls died during the neonatal period, and 14 patients died thereafter (2 girls, 12 boys). Median age of death for boys was 2.6 years vs <1 month for girls (p = 0.02). Mean birth weight and length, occipitofrontal circumference, and gestation duration were normal. Two-thirds of infants were ventilated during the neonatal period; of these, 40% died. Ninety percent had confirmed seizures, 75% during the first month of life. Interestingly, three NKH patients never developed seizures. An abnormal corpus callosum and/or hydrocephalus were associated with especially poor gross motor and speech development. Of 25 patients living > or =3 years, 10 were able to walk and say/sign words; all were boys. In six families with more than one affected child, disease course and mortality were similar within each family. This study reveals a striking and unexpected gender difference in mortality and developmental progress. Of the two-thirds of nonketotic hyperglycinemia patients surviving the newborn period, up to 20% (mostly boys) may learn to walk and communicate by saying or signing words.


Cloning and expression of canine glycoprotein Ibalpha.
The interaction of the glycoprotein (GP) Ib-IX-V complex with von Willebrand factor (vWF) is critical in initiation of haemostasis and thrombosis through platelet adhesion to damaged endothelium. The binding site for vWF resides within the GPIbalpha subunit of the complex. To further define the physiological function of platelet GPIbalpha we cloned and expressed the canine GPIbalpha cDNA. A canine platelet cDNA library was constructed and screened with a randomly primed 32P-labeled 1041-base-pair restriction fragment of the human GPIbalpha cDNA. Analysis of 23 clones demonstrated that the canine GPIbalpha cDNA is 2530 nucleotides in length and includes a short 5' untranslated segment of 42 nucleotides followed by a signal peptide of 16 amino acids, a mature peptide of 645 amino acids and a 3' noncoding region of 455 nucleotides. A single intron of 142 nucleotides, 6 nucleotides upstream from the ATG translation initiation codon was identified in the canine gene in a similar location to that present in the human gene. Chinese hamster ovary cells that stably express human GPIbbeta and GPIX were transfected with the canine GPIbalpha cDNA. Canine GPIbalpha was expressed on the surface of these cells and bound vWF in the presence of botrocetin. The binding of vWF was inhibited by an anti-vWF human monoclonal antibody known to inhibit vWF binding to GPIbalpha. The results of this investigation will allow the development of reagents to study the physiological function of GPIbalpha in an animal model.


Reflective aperiodic multilayer filters for metrology at XUV sources.
We present a general method for designing XUV aperiodic multilayer mirrors that can mimic a given target spectrum, specifically, the spectral transmission of an XUV optical system. The method is based on minimizing a merit function and using fidelity parameters that quantify the matching of the multilayer reflectivity spectrum with that of the target spectrum. To assess the feasibility of fabricating such a system, we show how to reduce the layer-to-layer thickness variations throughout the aperiodic layer stack. We demonstrate the design method using an example of an EUV optical system composed of 12 identical Mo/Si multilayer mirrors having a reflectivity peak at 13.5 nm. We found that the target spectrum can be mimicked with high fidelity either with a single reflection at an aperiodic multilayer mirror combined with standard absorbing filters or, if required, with two subsequent reflections at a mimic mirror. These examples demonstrate the applicability for metrology at XUV sources, including spectrally proper source imaging. Because our approach is of general applicability, the process can be used to mimic any other narrowband, single-peaked target spectrum in the XUV region.


Enzyme-mediated site-specific bioconjugation of metal complexes to proteins: sortase-mediated coupling of copper-64 to a single-chain antibody.
The enzyme-mediated site-specific bioconjugation of a radioactive metal complex to a single-chain antibody using the transpeptidase sortase A is reported. Cage amine sarcophagine ligands that were designed to function as substrates for the sortase A mediated bioconjugation to antibodies were synthesized and enzymatically conjugated to a single-chain variable fragment. The antibody fragment scFv(anti-LIBS) targets ligand-induced binding sites (LIBS) on the glycoprotein receptor GPIIb/IIIa, which is present on activated platelets. The immunoconjugates were radiolabeled with the positron-emitting isotope (64)Cu. The new radiolabeled conjugates were shown to bind selectively to activated platelets. The diagnostic potential of the most promising conjugate was demonstrated in an in vivo model of carotid artery thrombosis using positron emission tomography. This approach gives homogeneous products through site-specific enzyme-mediated conjugation and should be broadly applicable to other metal complexes and proteins.


Multilayer contactless dielectrophoresis: theoretical considerations.
Dielectrophoresis (DEP), the movement of dielectric particles in a nonuniform electric field, is of particular interest due to its ability to manipulate particles based on their unique electrical properties. Contactless DEP (cDEP) is an extension of traditional and insulator-based DEP topologies. The devices consist of a sample channel and fluid electrode channels filled with a highly conductive media. A thin insulating membrane between the sample channel and the fluid electrode channels serves to isolate the sample from direct contact with metal electrodes. Here we investigate, for the first time, the properties of multilayer devices in which the sample and electrode channels occupy distinct layers. Simulations are conducted using commercially available finite element software and a less computationally demanding numerical approximation is presented and validated. We show that devices can be created that achieve a similar level of electrical performance to other cDEP devices presented in the literature while increasing fluid throughput. We conclude, based on these models, that the ultimate limiting factors in device performance resides in breakdown voltage of the barrier material and the ability to generate high-voltage, high-frequency signals. Finally, we demonstrate trapping of MDA-MB-231 breast cancer cells in a prototype device at a flow rate of 1.0 mL/h when 250 V(RMS) at 600 kHz is applied.


Behavioral methods for the functional assessment of hair cells in zebrafish.
Zebrafish is an emerging animal model for studies on auditory system. This model presents high comparability with humans, good accessibility to the hearing organ, and high throughput capacity. To better utilize this animal model, methodologies need to be used to quantify the hearing function of the zebrafish. Zebrafish displays a series of innate and robust behavior related to its auditory function. Here, we reviewed the advantage of using zebrafish in auditory research and then introduced three behavioral tests, as follows: the startle response, the vestibular-ocular reflex, and rheotaxis. These tests are discussed in terms of their physiological characteristics, up-to-date technical development, and apparatus description. Test limitation and areas to improve are also introduced. Finally, we revealed the feasibility of these applications in zebrafish behavioral assessment and their potential in the high-throughput screening on hearing-related genes and drugs.


[Immunological reactions in acute destructive pneumonia in children].
Clinical examinations of 512 children with acute destructive pneumonia have shown high incidence (27.1%) of medicamentous allergic reactions, high level of sensibilization to antigens of the lung tissue. The use of small doses of polyglucin in experiment prevents the appearance of anaphylactic shock, and in patients with a destructive pneumonia it made the incidence of medicamentous allergic reactions 7 times less frequent.


Altered Expression of Astrocyte-Related Receptors and Channels Correlates With Epileptogenesis in Hippocampal Sclerosis.
Hippocampal sclerosis (HS) is one of the major causes of intractable epilepsy. Astrogliosis in epileptic brain is a peculiar condition showing epileptogenesis and is thought to be different from the other pathological conditions. The aim of this study is to investigate the altered expression of astrocytic receptors, which contribute to neurotransmission in the synapse, and channels in HS lesions. We performed immunohistochemical and immunoblotting analyses of the P2RY1, P2RY2, P2RY4, Kir4.1, Kv4.2, mGluR1, and mGluR5 receptors and channels with the brain samples of 20 HS patients and 4 controls and evaluated the ratio of immunopositive cells and those expression levels. The ratio of each immunopositive cell per glial fibrillary acidic protein-positive astrocytes and the expression levels of all 7 astrocytic receptors and channels in HS lesions were significantly increased. We previously described unique astrogliosis in epileptic lesions similar to what was observed in this study. This phenomenon is considered to trigger activation of the related signaling pathways and then contribute to epileptogenesis. Thus, astrocytes in epileptic lesion may show self-hyperexcitability and contribute to epileptogenesis through the endogenous astrocytic receptors and channels. These findings may suggest novel astrocytic receptor-related targets for the pharmacological treatment of epilepsy.


Translatability score revisited: differentiation for distinct disease areas.
Translational science supports successful transition of early biomedical research into human applications. In 2009 a translatability score to assess risk and identify strengths and weaknesses of a given project has been designed and successfully tested in case studies. The score elements, in particular the contributing weight factors, are heterogeneous for different disease areas; therefore, the score was individualized for six areas (cardiovascular, oncology, psychiatric, anti-viral, anti-bacterial/fungal and monogenetic diseases). FDA reviews and related literature were used for modifications of the score with emphasis on biomarkers, personalized medicine and animal models. 113 new medical entities approved by FDA from 2012 through 2016 were evaluated and metrics obtained for companion diagnostics and animal models as starting points for author-based individualization of the score. Most drugs approved in this period were related to oncology (46%), while the approvals were lowest for psychiatrics (4%). The evaluation of the FDA package inserts revealed that companion diagnostics play an important role in every field except psychiatrics. Further the analysis of the FDA reviews showed the weakness of animal models in psychiatrics and anti-virals, while useful animal models were present for all other fields. Consequently the scoring system was adapted to the different fields, resulting in increased weights for animal models, biomarker and personalized medicine in oncology. For psychiatrics the weights for animal models, biomarker and personalized medicine were decreased, while the weight for model compounds, clinical trials and surrogate or endpoint strategy were increased. For anti-viral drugs weights for in vitro data and personalized medicine were increased, while the weight for animal models was decreased. Further, for anti-bacterial/fungal drugs weights for animal models and personalized medicine were increased. Weights were increased for genetics and personalized medicine and decreased for model compounds for monogenetic orphans. Adaptation of the score to different disease areas should help to support a structured and diverse approach to translation and encourage researchers in the private or public sectors to further customize the score.


Physical activity and the regulation of neurogenesis in the adult and aging brain.
The discovery that exercise regulates adult hippocampal neurogenesis, that is, the production of new neurons in the adult brain, was surprising news and changed quite fundamentally our view on how physical activity affects the brain. The everyday experience that not all athletes are necessarily smarter than more sedentary fellows and the scientific insight that adult hippocampal neurogenesis is actually a process that ranges on a very small scale raised important questions on the relevance of this finding. We propose that the exercise-related regulation of adult hippocampal neurogenesis is a qualitative rather than a quantitative event and that it is a particularly prominent and suggestive example of activity-dependent cellular plasticity. For rodents, the animals, in which most of this research has been done, cognition is almost inseparable from locomotion. Physical activity, especially exerted over longer periods of time, might indicate to the brain an increased chance of experience those situations rich in complexity and novelty that presumably benefit from more new neurons. We thus propose that it is not isolated physical activity that is "good for the brain", but physical activity in the context of cognitive challenges. This would also explain why few new neurons could be beneficial for successful aging. We here review the current stage of the knowledge how this exercise-induced regulation of neurogenesis might work.


Barbiturate effects on acute experimental intracranial hypertension.
Acute intracranial hypertension was induced in cats by progressive inflation of an epidural balloon. Changes in intracranial pressure (ICP), mean arterial pressure (MAP), cerebral perfusion pressure (CPP), heart rate (HR), electroencephalogram (EEG), and pupil size were studied in untreated animals and in animals that had received barbiturates at different stages during the experiment. In animals pretreated with barbiturates, the increase in ICP during balloon expansion was significantly less than in untreated animals (p less than 0.001). The CPP, initially higher in untreated animals, was not significantly different (P less than 0.05) as the mass lesion pressure-volume curve exceeded the inflection point. In the postdeflation period, the untreated animals developed a significant increase in ICP, whereas, in the barbiturate-pretreated group, the ICP returned to preinflation values, suggesting a protective effect of barbiturates against postcompression brain swelling. Barbiturates affected ICP and CPP differently in animals with intracranial hypertension due to the presence of an epidural balloon that was maintained inflated compared to those with postdeflation brain swelling. In the latter group, pentobarbital reduced ICP (p less than 0.05) without significantly decreasing the CPP, whereas, in the mass lesion group, barbiturates failed to reduce the ICP and caused a deterioration in CPP (p less than 0.025). Brain gross pathological changes were significantly less in the pretreated animals as compared with all other groups. The results suggest that if barbiturate treatment is to have therapeutic value, the timing of the therapy and the criteria for its initiation should be determined.


Abnormal course of left testicular artery in relation to an abnormal left renal vein: a case report.
The testis is an important organ upon which the survival of the human species depends. Any compression of testicular artery may lead to loss of gametogenesis and hormone production. We found a left testicular artery entrapped between two divisions of a left renal vein in an approximately 50 year old cadaver. The left renal vein was formed by union of two veins coming from the kidney, left suprarenal vein, left testicular vein and an abnormally enlarged lumbar vein. This case may be of particular importance to surgeons who transplant kidneys, radiologists and orthopaedic surgeons dealing with the spine repairs.


The effect of concentrate supplementation on milk production and cow traffic in early and late lactation in a pasture-based automatic milking system.
The objective of this experiment was to establish the effect of low-concentrate (LC) and high-concentrate (HC) supplementation in the early and late periods of lactation on milk production and cow traffic in a pasture-based automatic milking (AM) system. In total, 40 cows (10 primiparous and 30 multiparous) were randomly assigned to one of the two treatments. The experimental periods for the early and late lactation trials extended from 23 February to 12 April 2015 and 31 August to 18 October 2015, respectively (49 days in each trial period). The early lactation supplement levels were 2.3 and 4.4 kg/cow per day for LC and HC, respectively, whereas the late lactation supplement levels were 0.5 and 2.7 kg/cow per day for LC and HC, respectively. Variables measured included milking frequency, milking interval, milking outcome and milking characteristics, milk yield/visit and per day, wait time/visit and per day, return time/visit and the distribution of gate passes. As the herd was seasonal (spring) calving, the experimental periods could not run concurrently and as a result no statistical comparison between the periods was conducted. There was no significant effect of treatment in the early lactation period on any of the milk production, milking characteristics or cow traffic variables. However, treatment did significantly affect the distribution of gate passes, with the HC cows recording significantly more gate passes in the hours preceding the gate time change such as hours 7 (P<0.01), 15 (P<0.05), 20, 21 (P<0.001), and 22 (P<0.05), whereas the LC treatment recorded significantly more gate passes in the hours succeeding the gate time change, such as time points 2 (P<0.01) and 10 (P<0.05). There was a significant effect of treatment in late lactation, with HC having a greater milk yield (P<0.01), milking duration and activity/day (P<0.05), while also having a significantly shorter milking interval (P<0.05) and return time/visit (P<0.01). The distribution of gate passes were similar to the early lactation period, with HC also recording a significantly greater number of gate passes during the early morning period (P<0.01) when visitations were at their lowest. Any decision regarding the supplementing of dairy cows with concentrates needs to be examined from an economic perspective, to establish if the milk production and cow traffic benefits displayed in late lactation outweigh the cost of the concentrate; thereby ensuring that the decision to supplement is financially prudent.


Human cytomegalovirus pUL79 is an elongation factor of RNA polymerase II for viral gene transcription.
In this study, we have identified a unique mechanism in which human cytomegalovirus (HCMV) protein pUL79 acts as an elongation factor to direct cellular RNA polymerase II for viral transcription during late times of infection. We and others previously reported that pUL79 and its homologues are required for viral transcript accumulation after viral DNA synthesis. We hypothesized that pUL79 represented a unique mechanism to regulate viral transcription at late times during HCMV infection. To test this hypothesis, we analyzed the proteome associated with pUL79 during virus infection by mass spectrometry. We identified both cellular transcriptional factors, including multiple RNA polymerase II (RNAP II) subunits, and novel viral transactivators, including pUL87 and pUL95, as protein binding partners of pUL79. Co-immunoprecipitation (co-IP) followed by immunoblot analysis confirmed the pUL79-RNAP II interaction, and this interaction was independent of any other viral proteins. Using a recombinant HCMV virus where pUL79 protein is conditionally regulated by a protein destabilization domain ddFKBP, we showed that this interaction did not alter the total levels of RNAP II or its recruitment to viral late promoters. Furthermore, pUL79 did not alter the phosphorylation profiles of the RNAP II C-terminal domain, which was critical for transcriptional regulation. Rather, a nuclear run-on assay indicated that, in the absence of pUL79, RNAP II failed to elongate and stalled on the viral DNA. pUL79-dependent RNAP II elongation was required for transcription from all three kinetic classes of viral genes (i.e. immediate-early, early, and late) at late times during virus infection. In contrast, host gene transcription during HCMV infection was independent of pUL79. In summary, we have identified a novel viral mechanism by which pUL79, and potentially other viral factors, regulates the rate of RNAP II transcription machinery on viral transcription during late stages of HCMV infection.