A Clinical Approach to Semiautomated Three-Dimensional Fetal Brain Biometry-Comparing the Strengths and Weaknesses of Two Diagnostic Tools: 5DCNS+TM and SonoCNSTM.
(1) Objective: We aimed to evaluate the accuracy and efficacy of AI-assisted biometric measurements of the fetal central nervous system (CNS) by comparing two semiautomatic postprocessing tools. We further aimed to discuss the additional value of semiautomatically generated sagittal and coronal planes of the CNS. (2) Methods: Three-dimensional (3D) volumes were analyzed with two semiautomatic software tools, 5DCNS+™ and SonoCNS™. The application of 5DCNS+™ results in nine planes (axial, coronal and sagittal) displayed in a single template; SonoCNS™ depicts three axial cutting sections. The tools were compared regarding automatic biometric measurement accuracy. (3) Results: A total of 129 fetuses were included for final analysis. Our data indicate that, in terms of the biometric quantification of head circumference (HC), biparietal diameter (BPD), transcerebellar diameter (TCD) and cisterna magna (CM), the accuracy of SonoCNS™ was higher with respect to the manual measurement of an experienced examiner compared to 5DCNS+™, whereas it was the other way around regarding the diameter of the posterior horn of the lateral ventricle (Vp). The inclusion of four orthogonal coronal views in 5DCNS+™ gives valuable information regarding spatial arrangements, particularly of midline structures. (4) Conclusions: Both tools were able to ease assessment of the intracranial anatomy, highlighting the additional value of automated algorithms in clinical use. SonoCNS™ showed a superior accuracy of plane reconstruction and biometry, but volume reconstruction using 5DCNS+™ provided more detailed information, which is needed for an entire neurosonogram as suggested by international guidelines.


Femtosecond laser pulse driven melting in gold nanorod aqueous colloidal suspension: identification of a transition from stretched to exponential kinetics.
Many potential industrial, medical, and environmental applications of metal nanorods rely on the physics and resultant kinetics and dynamics of the interaction of these particles with light. We report a surprising kinetics transition in the global melting of femtosecond laser-driven gold nanorod aqueous colloidal suspension. At low laser intensity, the melting exhibits a stretched exponential kinetics, which abruptly transforms into a compressed exponential kinetics when the laser intensity is raised. It is found the relative formation and reduction rate of intermediate shapes play a key role in the transition. Supported by both molecular dynamics simulations and a kinetic model, the behavior is traced back to the persistent heterogeneous nature of the shape dependence of the energy uptake, dissipation and melting of individual nanoparticles. These results could have significant implications for various applications such as water purification and electrolytes for energy storage that involve heat transport between metal nanorod ensembles and surrounding solvents.


Exploring the fast food and planning appeals system in England and Wales: decisions made by the Planning Inspectorate (PINS).
The National Planning Policy Framework advocates the promotion of 'healthy communities'. Controlling availability and accessibility of hot food takeaways is a strategy which the planning system may use to promote healthier environments. Under certain circumstances, for example, local authorities can reject applications for new hot food takeaways. However, these decisions are often subject to appeal. The National Planning Inspectorate decide appeals - by upholding or dismissing cases. The aim of this research is to explore and examine the National Planning Inspectorate's decision-making. The appeals database finder was searched to identify hot food takeaway appeal cases. Thematic analysis of appeals data was carried out. Narrative synthesis provided an overview of the appeals process and explored factors that were seen to impact on the National Planning Inspectorate's decision-making processes. The database search identified 52 appeals cases. Results suggest there is little research in this area and the appeals process is opaque. There appears to be minimal evidence to support associations between the food environment and health and a lack of policy guidance to inform local planning decisions. Furthermore, this research has identified non-evidence-based factors that influence the National Planning Inspectorate's decisions. Results from this research will provide public health officers, policy planners and development control planners with applied public health research knowledge from which they can draw upon to make sound decisions in evaluating evidence to ensure they are successfully equipped to deal with and defend hot food takeaway appeal cases.


[Long-term results of surgical treatment of commissural intestinal obstruction].
Long-term results of operations for acute commissural intestinal obstruction (ACIO) were studied in 128 patients 2 to 10 years after surgery. Only patients with uncomplicated forms of ACIO (without intestinal necrosis and generalized peritonitis) have been included into the analysis. The results of the treatment were assessed both in the group and individually after 87 operations of total adheolysis and 39 cases of partial comissurotomies. Clinical symptoms of abdominal commissures after elimination of ACIO were seen in 44.2% patients, including recurrence of ileus in 20.3% patients. Interintestinal commissures and conglomerations were the causes of ACIO in 44.5% cases that should be taken into account at adheolysis made laparoscopically. It is demonstrated that long-term results of ACIO treatment depend on surgical trauma and associated recurrence of adhesive process.


Rheological aspects of red blood cell aggregation.
The rheological aspects of red blood cell aggregation include molecular phenomena, cell viscoelasticity, and bulk flow rheology. At the molecular level, rates at which bonds are formed and broken, the chemical energy liberation from bond formation, the elasticity of the cross-bridges and lateral mobility of cross-linking molecules must all be considered for a complete description of bond formation and distribution. Lateral migration of binding molecules occurs due to diffusion in the surface of the membrane but may also be influenced by the stresses in the membrane during separation of adhering cells. In red blood cell disaggregation, fluorescent probes have shown concentration of ligands in the region of contact close to the line of separation. The chemical potential decrement that occurs when a bond is formed provides the energy source that may deform red blood cells in the process of aggregation. The degree of aggregation and the extent of cell deformation depends on the viscoelastic properties of the cell as well as the dynamics of bond formation and repulsive potential of surface charges present, which is governed by an equation representing a balance of these energies. In flowing blood, the hydrodynamic forces applied by the plasma and surrounding cells must be added to the bond forces and elastic response of the cell. Under sufficiently strong aggregation, plug flow or large aggregates may result. At high shear rates, aggregation may be prevented due to the small contact time and high shear stresses so that no effects of aggregation may be observed. At intermediate shear stresses, transitory contact, adhesion and disaggregation may occur between neighboring cells. Such phenomena have not been analyzed in detail, but simplified models suggest that plug-like flow can occur due to hydrodynamic cell-cell interaction even when cells are not aggregated.


Proteolytic maturation of α2δ controls the probability of synaptic vesicular release.
Auxiliary α2δ subunits are important proteins for trafficking of voltage-gated calcium channels (CaV) at the active zones of synapses. We have previously shown that the post-translational proteolytic cleavage of α2δ is essential for their modulatory effects on the trafficking of N-type (CaV2.2) calcium channels (Kadurin et al., 2016). We extend these results here by showing that the probability of presynaptic vesicular release is reduced when an uncleaved α2δ is expressed in rat neurons and that this inhibitory effect is reversed when cleavage of α2δ is restored. We also show that asynchronous release is influenced by the maturation of α2δ-1, highlighting the role of CaV channels in this component of vesicular release. We present additional evidence that CaV2.2 co-immunoprecipitates preferentially with cleaved wild-type α2δ. Our data indicate that the proteolytic maturation increases the association of α2δ-1 with CaV channel complex and is essential for its function on synaptic release.


[Morphological diagnosis of renal cell carcinoma. Histo-cytological parallels].
A detailed parallel histo-cytological investigation of 100 observations on renal cell carcinoma showed that these tumours had a various macro- and microscopic structure. For the substantiation of correct diagnosis material should be taken from several places of the tumour of different microscopic structure. In diagnosis all detected variants of the structure of the tumour and the degree of cellular anaplasia should be mentioned. A clear-cell variant in the pure form was revealed in 52% of cases, other one-type variants were very rare (7%). In tumours of a mixed structure (41%) there were observed various combinations of all the variants occurring in the order: clear-cell, granular-cell, sarcoma-like, glandular. Collation of Histological and cytological data showed that in the overwhelming majority of cases (97%) there was a complete coincidence in determination of the morphological type of renal cell carcinoma.


Validation of dabrafenib-trametinib prognostic groups in patients treated with vemurafenib and cobimetinib for advanced BRAF-mutated melanoma.
Prognostic groups defined by lactate dehydrogenase concentration and number of organ sites containing metastases have been reported for patients treated with dabrafenib and trametinib for advanced melanoma. We aimed to validate these prognostic groups for patients treated with vemurafenib and cobimetinib in the coBRIM and BRIM-3 clinical studies. Eight hundred nine patients were included, 240 treated with vemurafenib plus cobimetinib and 569 with vemurafenib. For patients treated with vemurafenib and cobimetinib, both overall survival (P < 0.001, c-statistic = 0.72) and progression-free survival (P < 0.001, c-statistic = 0.65) differed markedly between prognostic groups. Two-year progression-free survival ranged from 3 (lactate dehydrogenase ≥2 times the upper limit of normal) to 50% (normal lactate dehydrogenase and ≤3 sites), and two-year overall survival ranged from 7 to 71%. For patients treated with vemurafenib monotherapy, overall survival (P < 0.001, c-statistic = 0.66) and progression-free survival (P < 0.001, c-statistic = 0.62) also differed significantly between prognostic groups. In conclusion, prognostic groups identified for patients treated with dabrafenib and trametinib are also applicable to patients treated with vemurafenib and cobimentinib.


Electrophoresis of proteins on filter paper.
A simplified procedure for filter paper electrophoresis is described in which disturbing factors such as evaporation, heating, buffer concentration gradients, and pH changes in the electrode vessels were reduced to a minimum. Artificial mixtures of highly purified proteins could be separated and the components isolated. The application of the method to a variety of studies on serum proteins is demonstrated. Protein concentration in paper segments was determined by two different methods of protein estimation. Curves were obtained showing the same five major peaks for normal serum as found by the classical methods of free electrophoresis. Comparisons were made of the areas of the various components under the curves obtained with the different methods. Two dimensional electrophoresis was applied to serum and serum components. It proved of value in demonstrating the heterogeneity of fractions such as the gamma-globulin of serum. The polysaccharide dextran was used as an index of the extent of electro-osmotic flow during the course of the various experiments. The ratio of the distance of electroosmotic flow and the distance of protein migration was shown to be constant for a given type of paper. For serum albumin on Munktell 20 paper this ratio was 0.35. A formula for mobilities applicable to liquid in a highly porous supporting medium is presented. Mobility values for human serum albumin at various pH levels on paper showed approximate agreement with those obtained in free solution giving a similar isoelectric point.


Periodontal profile classes predict periodontal disease progression and tooth loss.
Current periodontal disease taxonomies have limited utility for predicting disease progression and tooth loss; in fact, tooth loss itself can undermine precise person-level periodontal disease classifications. To overcome this limitation, the current group recently introduced a novel patient stratification system using latent class analyses of clinical parameters, including patterns of missing teeth. This investigation sought to determine the clinical utility of the Periodontal Profile Classes and Tooth Profile Classes (PPC/TPC) taxonomy for risk assessment, specifically for predicting periodontal disease progression and incident tooth loss. The analytic sample comprised 4,682 adult participants of two prospective cohort studies (Dental Atherosclerosis Risk in Communities Study and Piedmont Dental Study) with information on periodontal disease progression and incident tooth loss. The PPC/TPC taxonomy includes seven distinct PPCs (person-level disease pattern and severity) and seven TPCs (tooth-level disease). Logistic regression modeling was used to estimate relative risks (RR) and 95% confidence intervals (CI) for the association of these latent classes with disease progression and incident tooth loss, adjusting for examination center, race, sex, age, diabetes, and smoking. To obtain personalized outcome propensities, risk estimates associated with each participant's PPC and TPC were combined into person-level composite risk scores (Index of Periodontal Risk [IPR]). Individuals in two PPCs (PPC-G: Severe Disease and PPC-D: Tooth Loss) had the highest tooth loss risk (RR = 3.6; 95% CI = 2.6 to 5.0 and RR = 3.8; 95% CI = 2.9 to 5.1, respectively). PPC-G also had the highest risk for periodontitis progression (RR = 5.7; 95% CI = 2.2 to 14.7). Personalized IPR scores were positively associated with both periodontitis progression and tooth loss. These findings, upon additional validation, suggest that the periodontal/tooth profile classes and the derived personalized propensity scores provide clinical periodontal definitions that reflect disease patterns in the population and offer a useful system for patient stratification that is predictive for disease progression and tooth loss.


Pan-protective anti-alphavirus human antibodies target a conserved E1 protein epitope.
Alphaviruses are emerging, mosquito-transmitted pathogens that cause musculoskeletal and neurological disease in humans. Although neutralizing antibodies that inhibit individual alphaviruses have been described, broadly reactive antibodies that protect against both arthritogenic and encephalitic alphaviruses have not been reported. Here, we identify DC2.112 and DC2.315, two pan-protective yet poorly neutralizing human monoclonal antibodies (mAbs) that avidly bind to viral antigen on the surface of cells infected with arthritogenic and encephalitic alphaviruses. These mAbs engage a conserved epitope in domain II of the E1 protein proximal to and within the fusion peptide. Treatment with DC2.112 or DC2.315 protects mice against infection by both arthritogenic (chikungunya and Mayaro) and encephalitic (Venezuelan, Eastern, and Western equine encephalitis) alphaviruses through multiple mechanisms, including inhibition of viral egress and monocyte-dependent Fc effector functions. These findings define a conserved epitope recognized by weakly neutralizing yet protective antibodies that could be targeted for pan-alphavirus immunotherapy and vaccine design.


Physiology without Borders: US and Cuban Scientists Meet in Space.
Over 400 delegates from 28 countries gathered recently in Havana for the 2nd Pan-American Congress of Physiological Sciences (May, 2019). It was quite an event, the level of science attesting to the quality of participants from the world over. The conference attracted more US scientists to Cuba than any other in the field of medicine over the last several years: 228. I find this number particularly noteworthy amidst the pressures they faced to keep them from coming.


Pneumonia. Treatment and diagnosis.
Pneumonia remains a leading cause of morbidity and mortality despite advances in treatment and therapy. The "Pneumonia: Treatment and Diagnosis" session of the Pittsburgh International Lung Conference examined topics related to improving care of patients with pneumonia. These topics included the process and quality of care for community-acquired pneumonia (CAP), diagnosis and treatment of emerging fungal pathogens, an overview of the strengths and weaknesses of different diagnostic modalities, and an example of how basic science is exploring immunomodulatory strategies for pneumonia treatment. Systematic health care provider and institutional improvements can decrease mortality rates in CAP, particularly in patients with increasingly complex comorbidities. Aspects of current guidelines for the diagnosis and treatment of fungal pneumonia were reviewed through a series of case presentations. Proper treatment of pneumonia hinges on correct pathogen identification but is complicated by the variety of diagnostic assays with variable specificity, sensitivity, and interpretation. In addressing this topic, Dr. Patrick Murray, Ph.D., discussed a range of diagnostic tests for a variety of pathogens and guidelines for their use. In addition to the current state of CAP treatment, Bill (Beibei) Chen, M.D., Ph.D., presented a new potential therapeutic agent called forsythin, an immunomodulatory compound derived from a plant used in traditional Chinese medicine. These topics, ranging from institution-sized policy to interactions at the molecular scale, paint a broad perspective of the efforts against pneumonia.


In situ study of SV40 virus DNA in lytic infection by mild loosening of nucleoproteins.
We have studied SV40 (simian virus40) nucleoprotein in permissively infected monkey kidney cell cultures (CV1) by a procedure which does not require the isolation of the SV40 chromosomes. Treatment of the cells by a low ionic strenght medium containing Photo flo produces a mild loosening of nucleoproteins, and permits the in situ study in ultrathin sections of virus components and their relationships with host cell chromatin. RNP and DNP could be distinguished by uranyl-EDTA-lead staining (for RNP) and by DNase digestion. SV40 DNA was observed as circular molecules, either free or connected with either RNP fibrils or virus capsids. These three aspects were interpreted, respectively, as viral minichromosomes, transcription of virus genome and partially encapsidated virus DNA. During encapsidation a few virus particles appear to be bound to host chromatin. Many, if not all, seemingly mature viruses, singly or in small linear clusters, are also aligned on host chromatin. Some of these observations were corroborated by the Miller spreading technique. They are consistent with a role for the host cell chromatin in the production of nuclear viruses.


Traditional Chinese Medicine Compound (Tongxinluo) and Clinical Outcomes of Patients With Acute Myocardial Infarction: The CTS-AMI Randomized Clinical Trial.
Tongxinluo, a traditional Chinese medicine compound, has shown promise in in vitro, animal, and small human studies for myocardial infarction, but has not been rigorously evaluated in large randomized clinical trials. To investigate whether Tongxinluo could improve clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI). Randomized, double-blind, placebo-controlled clinical trial was conducted among patients with STEMI within 24 hours of symptom onset from 124 hospitals in China. Patients were enrolled from May 2019 to December 2020; the last date of follow-up was December 15, 2021. Patients were randomized 1:1 to receive either Tongxinluo or placebo orally for 12 months (a loading dose of 2.08 g after randomization, followed by the maintenance dose of 1.04 g, 3 times a day), in addition to STEMI guideline-directed treatments. The primary end point was 30-day major adverse cardiac and cerebrovascular events (MACCEs), a composite of cardiac death, myocardial reinfarction, emergent coronary revascularization, and stroke. Follow-up for MACCEs occurred every 3 months to 1 year. Among 3797 patients who were randomized, 3777 (Tongxinluo: 1889 and placebo: 1888; mean age, 61 years; 76.9% male) were included in the primary analysis. Thirty-day MACCEs occurred in 64 patients (3.4%) in the Tongxinluo group vs 99 patients (5.2%) in the control group (relative risk [RR], 0.64 [95% CI, 0.47 to 0.88]; risk difference [RD], -1.8% [95% CI, -3.2% to -0.6%]). Individual components of 30-day MACCEs, including cardiac death (56 [3.0%] vs 80 [4.2%]; RR, 0.70 [95% CI, 0.50 to 0.99]; RD, -1.2% [95% CI, -2.5% to -0.1%]), were also significantly lower in the Tongxinluo group than the placebo group. By 1 year, the Tongxinluo group continued to have lower rates of MACCEs (100 [5.3%] vs 157 [8.3%]; HR, 0.64 [95% CI, 0.49 to 0.82]; RD, -3.0% [95% CI, -4.6% to -1.4%]) and cardiac death (85 [4.5%] vs 116 [6.1%]; HR, 0.73 [95% CI, 0.55 to 0.97]; RD, -1.6% [95% CI, -3.1% to -0.2%]). There were no significant differences in other secondary end points including 30-day stroke; major bleeding at 30 days and 1 year; 1-year all-cause mortality; and in-stent thrombosis (<24 hours; 1-30 days; 1-12 months). More adverse drug reactions occurred in the Tongxinluo group than the placebo group (40 [2.1%] vs 21 [1.1%]; P = .02), mainly driven by gastrointestinal symptoms. In patients with STEMI, the Chinese patent medicine Tongxinluo, as an adjunctive therapy in addition to STEMI guideline-directed treatments, significantly improved both 30-day and 1-year clinical outcomes. Further research is needed to determine the mechanism of action of Tongxinluo in STEMI. ClinicalTrials.gov Identifier: NCT03792035.


Covalent binding to DNA in vitro of 2',3'-oxides derived from allylbenzene analogs.
Epoxidation at the allylic side chain is a major metabolic pathway for allylbenzene and its naturally occurring analogs safrole, estragole, and eugenol. We demonstrate herein that the epoxide metabolites of allylbenzene, estragole, and safrole can form covalent adducts with DNA in vitro, binding primarily to guanine, but also to the other three DNA bases. Epoxide hydrolases can prevent the binding of allylbenzene 2',3'-oxide to DNA in vitro. Four distinct adducts were detected by analytical TLC after the reaction of 2'-deoxyguanosine with allylbenzene 2',3'-oxide. One unstable adduct was formed rapidly, but gradually disappeared, whereas the other three adducts were formed more slowly but persisted. The major persistent adduct, which was isolated by preparative chromatography, was examined by MS and NMR. The structure of this adduct is 3'-N1-deoxyguanosyl-(2'-hydroxypropylbenzene). In addition, a generally applicable paradigm for the identification of deoxyguanosine or guanosine adducts by 13C and 1H NMR spectroscopy is presented.


Likely country of origin in publications on randomised controlled trials and controlled clinical trials during the last 60 years.
The number of publications on clinical trials is unknown as well as the countries publishing most trial reports. To try to examine these questions we performed an ecological study. We searched the 454,449 records on publications in The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, Issue 3, 2005 (CD-ROM version) for possible country of origin. We inspected a random sample of 906 records for information on country and type of trial. There was an exponential growth of publications on randomised controlled trials and controlled clinical trials since 1946, but the growth seems to have seized since 2000. We identified the possible country of origin of 210,974 publications (46.4%). The USA is leading with about 46,789 publications followed by UK, Germany, Italy, the Netherlands, Canada, and France. Sweden becomes the leader with 891 publications per million inhabitants during the last 60 years followed by Denmark (n = 864), New Zealand (n = 791), Finland (n = 781), the Netherlands (n = 570), Switzerland (n = 547), and Norway (n = 543). In depth assessment of the random sample backed these findings. Many records lacked country of origin, even after the additional scrutiny. The number of publications on clinical trials increased exponentially until the turn of the century. Rather small, democratic, and wealthy countries take the lead when the number of publications on clinical trials is calculated based on million inhabitants. If all countries produced the same number of trials as these countries, this could mean thousands of new effective treatments during the next 60 years.


Diagnostic value of clinical examination and radiographic imaging in identification of intraocular foreign bodies in open globe injury.
To evaluate the diagnostic accuracy of clinical eye examination and radiographic imaging in the identification of intraocular foreign bodies (IOFBs) in open-globe traumatic injuries. This was a retrospective chart review of open-globe traumatic injuries with IOFBs presenting to University Hospital (UH) at New Jersey Medical School between 1998 and 2008. A total of 527 patients with traumatic open globe injuries presented to UH, Newark, New Jersey, USA, between 1998 and 2008. Of these, 74 patients had surgically confirmed IOFBs. Mean age of patients with traumatic open globe injury and an IOFB was 33 years (range, 8-69 years); mean follow-up was 17.6 months (range, 1 day-90 months). Foreign bodies were identified as glass (13), metal (58), wood (1), plastic (0), and other (2). There were 24 anterior segment (AS) IOFBs, 45 posterior segment (PS) IOFBs, and 5 noted in both segments. Clinical eye examination at presentation identified an IOFB in 34 (45.6%) of 74 patients. B-scan echography revealed an IOFB in 14 (51.9%) of 27 cases. Computed tomography scan of the orbits identified IOFBs in 56 (94.9%) of 59 cases. Clinical eye examination was performed in all (100%) patients. B-scan was performed only when posterior segment pathology was suspected. Computed tomography scan was performed when an IOFB or orbital fracture was suspected. Computed tomography scan was the most reliable method for identifying IOFBs in patients presenting with open globe injuries in comparison to clinical eye examination and B-scan echography. This result was consistent regardless of IOFB location within the globe.


The role of the renin-angiotensin system in atrial fibrillation and the therapeutic effects of ACE-Is and ARBS.
Atrial fibrillation (AF) is the most common rhythm disturbance in medical practice and represents a very expensive health problem. AF can be managed with the prevention of thromboembolism and either a rate control of rhythm strategy. As both strategies have important limitations, probably a preventative strategy in patients at risk of developing arrhythmia can be a more attractive option. The renin-angiotensin system (RAS) seems to be involved in the genesis of arrhythmia by the following two mechanisms: 1. the induction of atrial fibrosis and structural remodelling by mitogen-activated protein kinase (MAPK) expression and reduction of collagenase activity; 2. the induction of electrical remodelling by shortening of the atrial effective refractory period (AERP) and of the action potential duration. For these reasons it has been hypothesized that angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin-II receptor blockers (ARBs) may play a role in preventing AF recurrence. The aim of the present review was to analyse evidence supporting the usefulness of RAS inhibition in patients with AF in order to focus on which specific subset of patients it would most favour. After reviewing the literature, we conclude that, although many studies and meta-analysis have supported the advantage of RAS block in preventing AF recurrence, it is premature to recommend the use of ACE-Is and ARBs specifically for the prevention of AF. However we believe that as these drugs are safe and manageable, they should be considered the drugs of choice in patients with AF and coexisting clinical conditions such as hypertension, coronary disease, heart failure and diabetes mellitus.


Mammals in which females are larger than males.
Females are larger than males in more species of mammals than is generally supposed. A provisional list of the mammalian cases is provided. The phenomenon is not correlated with an unusually large degree of male parental investment, polyandry, greater aggressiveness in females than in males, greater development of weapons in females, female dominance, or matriarchy. The phenomenon may have evolved in a variety of ways, but it is rarely, if ever, the result of sexual selection acting upon the female sex. The most common selective pressures favoring large size in female mammals are probably those associated with the fact that a big mother is often a better mother and those resulting from more intense competintion among females for some resource than among males. It appears that, in general, more than one such pressure must affect the females of a species, and that their combined effects must not be countered by even stronger selective pressures favoring large size in males, before the result is that of larger size in the female sex. Sexual selection may often be operating upon the male sux in mammals even when it is smaller. Present knowledge about the species of mammals in which females are lager than males is quite rudimentary. Much more information is needed before we will be able to speak of the selective pressures accounting for the phenomenon with any reasomable degree of certainty. Perhaps the most fruitful approach would be a series of field studies of groups of related species in which females are larger in some species and males are larger in others.


Development of selected reaction monitoring-MS methodology to measure peptide biomarkers in prostate cancer.
Prostate cancer is a leading cause of cancer-related death. The current modality of diagnosis, the measurement of serum PSA, not only suffers from lack of specificity, but does not distinguish clinical cases in which current treatment measures would be most successful, i.e. aggressive, life-threatening tumors. A multiplexed MS methodology, selected reaction monitoring-MS/MS coupled with stable isotope dilution (SID), was developed and tested in both cells lines and clinical tissue samples. Standard curves were generated for two peptides representing PSA and one peptide from each of two additional orthogonally validated biomarkers, AMACR and EZH2. The standard curves show high reproducibility, sensitivity, and good linearity. All four peptides were then measured in six clinically relevant cell lines and are in agreement with the biochemical characteristics of each individual cell line. The SID selected reaction monitoring-MS/MS methodology was then transferred to tissue samples, in which the assay shows potential to differentiate benign disease from localized cancer and localized cancer from aggressive metastatic disease. These results establish the preliminary development of a rational targeted MS platform that strives to bridge the gap between discovery and validation of biomarkers for the detection of prostate cancer.


Comparison of Direct Oral Anticoagulants for Acute Hospital Mortality in Venous Thromboembolism.
The choice of direct oral anticoagulants (DOACs) for venous thromboembolism (VTE) is at the physician's discretion; however, it is useful to know the differences in the clinical data of DOACs to help physicians choose. We aimed to compare the mortality associated with the use of rivaroxaban, edoxaban, and apixaban in clinical practice. We identified 38,245 patients with first hospitalization for VTE from the Diagnosis Procedure Combination database in the Japanese Registry of All Cardiac and Vascular Datasets (JROAD-DPC). We classified patients into three groups by DOAC (rivaroxaban and edoxaban group, rivaroxaban and apixaban group, and edoxaban and apixaban group) and compared the in-hospital mortality and bleeding risk by propensity score (PS) matching in each group. After PS matching, patients with rivaroxaban use had significantly lower total in-hospital mortality (1.2% vs. 2.1%; odds ratio [OR] 0.55, p = 0.012) and in-hospital mortality within 21 days (0.4% vs. 1.0%; OR 0.41, p = 0.020) and 28 days (0.7% vs. 1.3%; OR 0.53, p = 0.042) than patients with apixaban use. In the subanalysis, significant differences were only observed in patients younger than 80 years of age, patients with pulmonary embolism, and patients without heart failure. There was no significant difference in in-hospital mortality in the other groups and in the rate of bleeding events among the three groups. On PS-matched analysis, there was a difference in in-hospital mortality, especially in the rivaroxaban and apixaban group. Identifying the clinical characteristics of patients associated with each DOAC, as well as prognosis, will be useful in determining treatment strategies for VTE.


Evaluation of Intoxication Level with EOG Analysis and Machine Learning: A Study on Driving Simulator.
Driving after consuming alcohol can be dangerous, as it negatively affects judgement, reaction time, coordination, and decision-making abilities, increasing the risk of accidents and putting oneself and other road users in danger. Therefore, it is critical to establish reliable and accurate methods to detect and assess intoxication levels. One such approach is electrooculography (EOG), a non-invasive technique that measures eye movements, which has been linked to intoxication levels and holds promise as a method of estimating them. In recent years, machine learning algorithms have been utilized to analyze EOG signals to estimate various physiological and behavioural states. The purpose of this study was to investigate the viability of using EOG analysis and machine learning to estimate intoxication levels in a simulated driving scenario. EOG signals were measured using JINS MEME_R smart glasses and the level of intoxication was simulated using drunk vision goggles. We employed traditional signal processing techniques and feature engineering strategies. For classification, we used boosted decision trees, obtaining a prediction accuracy of over 94% for a four-class classification problem. Our results indicate that EOG analysis and machine learning can be utilized to accurately estimate intoxication levels in a simulated driving scenario.


Antifungal properties of wheat histones (H1-H4) and purified wheat histone H1.
Wheat ( Triticum spp.) histones H1, H2, H3, and H4 were extracted, and H1 was further purified. The effect of these histones on specific fungi that may or may not be pathogenic to wheat was determined. These fungi included Aspergillus flavus , Aspergillus fumigatus , Aspergillus niger , Fusarium oxysporum , Fusarium verticillioides , Fusarium solani , Fusarium graminearum , Penicillium digitatum , Penicillium italicum , and Greeneria uvicola . Non-germinated and germinating conidia of these fungi were bioassayed separately. The non-germinated and germinating conidia of all Fusarium species were highly susceptible to the mixture (H1-H4) as well as pure H1, with viability losses of 99-100% found to be significant (p < 0.001) at ≤10 μM or less for the histone mixture and pure H1. F. graminearum was the most sensitive to histone activity. The histones were inactive against all of the non-germinated Penicillium spp. conidia. However, they significantly reduced the viability of the germinating conidia of the Penicillium spp. conidia, with 95% loss at 2.5 μM. Non-germinated and germinating conidia viability of the Aspergillus spp. and G. uvicola were unaffected when exposed to histones up to 10 μM. Results indicate that Fusarium spp. pathogenic to wheat are susceptible to wheat histones, indicating that these proteins may be a resistance mechanism in wheat against fungal infection.


Modulation of angiotensin II signaling following exercise training in heart failure.
Sympathetic activation is a consistent finding in the chronic heart failure (CHF) state. Current therapy for CHF targets the renin-angiotensin II (ANG II) and adrenergic systems. Angiotensin converting enzyme (ACE) inhibitors and ANG II receptor blockers are standard treatments along with β-adrenergic blockade. However, the mortality and morbidity of this disease is still extremely high, even with good medical management. Exercise training (ExT) is currently being used in many centers as an adjunctive therapy for CHF. Clinical studies have shown that ExT is a safe, effective, and inexpensive way to improve quality of life, work capacity, and longevity in patients with CHF. This review discusses the potential neural interactions between ANG II and sympatho-excitation in CHF and the modulation of this interaction by ExT. We briefly review the current understanding of the modulation of the angiotensin type 1 receptor in sympatho-excitatory areas of the brain and in the periphery (i.e., in the carotid body and skeletal muscle). We discuss possible cellular mechanisms by which ExT may impact the sympatho-excitatory process by reducing oxidative stress, increasing nitric oxide. and reducing ANG II. We also discuss the potential role of ACE2 and Ang 1-7 in the sympathetic response to ExT. Fruitful areas of further investigation are the role and mechanisms by which pre-sympathetic neuronal metabolic activity in response to individual bouts of exercise regulate redox mechanisms and discharge at rest in CHF and other sympatho-excitatory states.


Phenotype Profiling and Allergy in Otitis-Prone Children.
Background: Otitis-prone children can present some distinctive clinical patterns and although a number of known risk factors for recurrent acute otitis media (RAOM) are known, no dedicated epidemiological models have been developed to explain clinical heterogeneity. Methods: A preliminary retrospective pilot study was planned to evaluate the possible effect of allergic disease in the development of different disease phenotypes in otitis-prone children aged 3-10 years, particularly the absence (simple RAOM), or presence of episodes of otitis media with effusion between acute infections (RAOM with OME). Results: Analysis was based on the data contained in 153 charts (55.6% males, mean age of 59.4 ± 16.4 months). 75.8% of children had a simple RAOM and 24.2% a RAOM with OME. Atopy or allergy were documented in respectively 47.7 and 41.3% of children considered as a whole. The prevalence of atopy or allergy was significantly higher in the children with a RAOM with OME (atopy: 73.0 vs. 39.5%, p < 0.001; allergy: 60.0 vs. 36.1%, p = 0.049), who also more frequently showed adenoidal hypertrophy (p = 0.016), chronic adenoiditis (p = 0.007), conductive hearing loss (p = 0.004), and impaired tympanometry (p < 0.001). Conclusions: These data suggest that children with a RAOM with OME are clinically different from children with simple RAOM, as they have a more complex clinical presentation that includes not only adenoidal disease and audiological impairment, but also an underlying allergy or atopy. The possibility that the factors mentioned above may be differently involved in the heterogeneous clinical manifestations occurring in otitis-prone children needs to be further investigated in ad hoc epidemiological studies.


[Self-rated health and physical disabilities due to health (corrected) problems].
To evaluate self-rated health and physical disabilities due to health problems. Population-based cross-sectional study carried out in 18 Brazilian cities between 2002 and 2005. There were interviewed 26,424 residents (aged 15 years or more) of households selected by a two-stage probabilistic sampling. Percentages and confidence intervals were calculated considering the study design effects. Poorer self-rated health status and physical disabilities were found among women, those aged 50 years old or more and those with lower education. In addition, higher percentages of fair or poor self-rated health were found in cities in Northern and Northeastern Brazil compared to those in Southern and Southeastern Brazil. Poorer health conditions in the North/Northeast compared to the South/Southeast regions reflect factors related to social inequalities, mainly lower education.


Pyrrolizidine Alkaloids in the Food Chain: Is Horizontal Transfer of Natural Products of Relevance?
Recent studies have raised the question whether there is a potential threat by a horizontal transfer of toxic plant constituents such as pyrrolizidine alkaloids (PAs) between donor-PA-plants and acceptor non-PA-plants. This topic raised concerns about food and feed safety in the recent years. The purpose of the study described here was to investigate and evaluate horizontal transfer of PAs between donor and acceptor-plants by conducting a series of field trials using the PA-plant Lappula squarrosa as model and realistic agricultural conditions. Additionally, the effect of PA-plant residues recycling in the form of composts or press-cakes were investigated. The PA-transfer and the PA-content of soil, plants, and plant waste products was determined in form of a single sum parameter method using high-performance liquid chromatography mass spectroscopy (HPLC-ESI-MS/MS). PA-transfer from PA-donor to acceptor-plants was frequently observed at low rates during the vegetative growing phase especially in cases of close spatial proximity. However, at the time of harvest no PAs were detected in the relevant field products (grains). For all investigated agricultural scenarios, horizontal transfer of PAs is of no concern with regard to food or feed safety.


Behavioral risk, emotional risk, and child abuse among adolescents in a nonclinical setting.
In this replication study of adolescents in a nonclinical setting, the prevalence of reported problem behaviors, emotions, and abuse is evaluated, and the impact of abuse on multivariate emotional and behavioral risk is assessed. A total of 3998 students (69%) in a rural midwestern community in grades 7 to 12 participated in the study. Almost 20% of the students reported some form of physical and/or sexual abuse, with more girls than boys reporting sexual abuse (chi 2 = 48.5, P less than .001). Some problem behaviors (alcohol use) and emotions (trouble sleeping, difficulty with anger) were common among all adolescents and some were strongly associated with a history of abuse (especially, considering or attempting suicide, running away, laxative use, and vomiting to lose weight). Higher emotional and behavioral risk scores among abused students were confirmed. The effects of physical and sexual abuse on risk scores were independent and additive; no interaction was observed. An interaction of gender and sexual abuse on problem behavior was observed, with problem behavior being significantly greater among sexually abused boys. The results confirm increased risk of problem behaviors and negative feelings among abused adolescents when compared with nonabused peers, and better define influences of gender and abuse type on emotional and behavioral risks.


Hyaluronic Acid-Conjugated Carbon Nanomaterials for Enhanced Tumour Targeting Ability.
Hyaluronic acid (HA) has been implemented for chemo and photothermal therapy to target tumour cells overexpressing the CD44+ receptor. HA-targeting hybrid systems allows carbon nanomaterial (CNM) carriers to efficiently deliver anticancer drugs, such as doxorubicin and gemcitabine, to the tumour sites. Carbon nanotubes (CNTs), graphene, graphene oxide (GO), and graphene quantum dots (GQDs) are grouped for a detailed review of the novel nanocomposites for cancer therapy. Some CNMs proved to be more successful than others in terms of stability and effectiveness at removing relative tumour volume. While the literature has been focused primarily on the CNTs and GO, other CNMs such as carbon nano-onions (CNOs) proved quite promising for targeted drug delivery using HA. Near-infrared laser photoablation is also reviewed as a primary method of cancer therapy-it can be used alone or in conjunction with chemotherapy to achieve promising chemo-photothermal therapy protocols. This review aims to give a background into HA and why it is a successful cancer-targeting component of current CNM-based drug delivery systems.


Myeloid-derived suppressor cells predict survival of patients with advanced melanoma: comparison with regulatory T cells and NY-ESO-1- or melan-A-specific T cells.
To analyze the prognostic relevance and relative impact of circulating myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) compared with functional tumor antigen-specific T cells in patients with melanoma with distant metastasis. The percentage of CD14(+)CD11b(+)HLA-DR(-/low) MDSCs, CD4(+)CD25(+)FoxP3(+) Tregs, and the presence of NY-ESO-1- or Melan-A-specific T cells was analyzed in 94 patients and validated in an additional cohort of 39 patients by flow cytometry. Univariate survival differences were calculated according to Kaplan-Meier and log-rank tests. Multivariate analyses were performed using Cox regression models. NY-ESO-1-specific T cells, the M-category, and the frequency of MDSCs were associated with survival. The absence of NY-ESO-1-specific T cells and the M-category M1c independently increased the risk of death. In a second Cox model not considering results on antigen-specific T cells, a frequency of >11% MDSCs showed independent impact. Its association with survival was confirmed in the additional patient cohort. Median survival of patients with a lower frequency of MDSCs was 13 months versus 8 months for others (P < 0.001, combined cohorts). We observed a strong correlation between high levels of MDSCs and the absence of melanoma antigen-specific T cells implying a causal and clinically relevant interaction. No prognostic impact was observed for Tregs. Circulating CD14(+)CD11b(+)HLA-DR(-/low) MDSCs have a negative impact on survival and inversely correlate with the presence of functional antigen-specific T cells in patients with advanced melanoma. Our findings provide a rationale to investigate MDSC-depleting strategies in the therapeutic setting especially in combination with vaccination or T-cell transfer approaches.


The mediating effect of difficulties in emotion regulation on the association between childhood maltreatment and borderline personality disorder.
Childhood maltreatment and difficulties in emotion regulation are common in patients with Borderline Personality Disorder (BPD) and Depressive Disorders (DD). This study examines differences between patients with BPD and patients with DD, regarding childhood maltreatment and difficulties in emotion regulation as well as the mediating effect of different aspects of emotion regulation deficits on the association between childhood maltreatment and BPD-symptoms. A total of 305 participants, 177 with BPD and 128 with DD completed an assessment including the Childhood Trauma Questionnaire (CTQ), the Emotion Regulation Scale (DERS), the Brief Symptom Inventory (BSI), and the Structured Clinical Interview for DSM-IV (SCID). Data was analyzed using multiple analyses of variances and mediation analyses. Patients with BPD reported more childhood maltreatment and more difficulties in emotion regulation than patients with DD. When general symptom severity, age, and gender were included in the analysis as covariates only group differences regarding 'impulse control difficulties' (F(1,299) = 38.97, p < .001, ηp2 = .115), 'limited access to emotion regulation strategies' (F(1,299) = 4.66, p = .032, ηp2 = .015), and 'lack of emotional clarity' (F(1,299) = 9.38, p = .002, ηp2 = .030) remained statistically significant. A mediation analysis, including above-mentioned covariates, indicated an association between emotional abuse and BPD-symptoms, which was mediated by difficulties in emotion regulation (indirect effect B = .012, 95% CI [.001; .031], R2 = .429). Subscale analyses revealed 'impulse control difficulties' as the aspect of difficulties in emotion regulation that has the greatest impact on this association (B = .021, 95% CI [.003; .045]). Patients with BPD display more childhood maltreatment and difficulties in emotion regulation than patients with DD. Difficulties in emotion regulation, especially difficulties in impulse control, seem to play an important role in the association between childhood emotional abuse and BPD-symptoms.


Kinetin modulates physio-hormonal attributes and isoflavone contents of Soybean grown under salinity stress.
Crop productivity continues to decline due to a wide array of biotic and abiotic stresses. Salinity is one of the worst abiotic stresses, as it causes huge losses to crop yield each year. Kinetin (Kn) has been reported as plant growth regulator since long, but its role in improving plant growth and food quality under saline conditions through mediating phytohormonal cross-talk is poorly studied. Current study was designed to evaluate the impact of exogenously applied Kn on growth, isoflovones and endogenous phytohormones of soybean grown under NaCl induced salt stress. Soybean plants were grown in perlite (semi hydroponic), and under controlled green-house conditions. Elevated levels of exogenous Kn significantly mitigated the adverse effect of NaCl and rescued plant growth attributes, i.e., plant height, fresh and dry biomass of soybean plants grown in all treatments. Higher diadzen, glycitin, and genistin contents were observed in plants treated with elevated Kn in the presence or absence of NaCl induce salt stress. The gibberellins (GAs) biosynthesis pathway was up-regulated by Kn as the bioactive GA1 and GA4 contents were significantly higher in Kn treated plants, as compared to control, while GAs level reduced in NaCl treated plants. Contrary to GAs, the abscisic acid contents declined with Kn but promoted in NaCl stressed soybean plants. The endogenous jasmonic acid and salicylic acid contents of soybean enhanced with elevated Kn application, but they showed an antagonistic response under salt stress. Current study supports the active role of Kn to ameliorate the adverse effects of salt stress on the growth and food quality of soybean. The favorable role of Kn toward soybean growth under salt stress may be attributed to its potential to modulate cross-talk between the various phytohormones involved in soybean growth and its resistance to salinity stress.


Replication-directed sister chromosome alignment in Escherichia coli.
Non-replicating Escherichia coli chromosomes are organized as sausage-shaped structures with the left (L) and the right (R) chromosome arms (replichores) on opposite cell halves and the replication origin (oriC) close to midcell. The replication termination region (ter) therefore passes between the two outer edges of the nucleoid. Four alignment patterns of the two <LR> sister chromosomes within a cell have been detected in an asynchronous population, with the <LRLR> pattern predominating. We test the hypothesis that the minority <LRRL> and <RLLR> patterns arise because of pausing of DNA replication on the right and left replichores respectively. The data resulting from transient pausing or longer-term site-specific blocking of replication show that paused/blocked loci remain close to midcell and the normally replicated-segregated loci locate to the outer regions of the nucleoid, therefore providing experimental support for a direct mechanistic link between DNA replication and chromosome organization.


Motonuclear changes after cranial nerve injury and regeneration.
Little is known about the mechanisms at play in nerve regeneration after nerve injury. Personal studies are reported regarding motonuclear changes after regeneration of injured cranial nerves, in particular of the facial and oculomotor nerves, as well as the influence that the natural molecule acetyl-L-carnitine (ALC) has on post-axotomy cranial nerve motoneuron degeneration after facial and vagus nerve lesions. Adult and newborn animal models were used. Massive motoneuron response after nerve section and reconstruction was observed in the motonuclei of all nerves studied. ALC showed to have significant neuroprotective effects on the degeneration of axotomized motoneurons. Complex quantitative, morphological and somatotopic nuclear changes occurred that sustain new hypotheses regarding the capacities of motoneurons to regenerate and the possibilities of new neuron proliferation. The particularities of such observations are described and discussed.


"That makes all the difference": Aboriginal and Torres Strait Islander health-seeking on social media.
Little is known about the complex relationships between Australian Indigenous people's use of social media and "health-seeking" - seeking help for issues related to health and well-being. This paper has emerged from a broader sociological research project focusing on the help-seeking and help-giving practices of Aboriginal and Torres Strait Islander people on social media, specifically aiming to unlock its potential to create vital and creative connections between help-seekers and help-givers. Semi-structured interviews were conducted with 52 Indigenous Facebook users from five sites across Australia. The use of grounded theory and Indigenous-centred methodologies for analysis showed clearly that users draw on the connections made possible through Facebook to health-seek. We identify five primary health-seeking strategies that differ in form, purpose and directness: soliciting health-related information, gaining emotional support, producing social health-seeking collectives, engaging in motivational and "eudaimonic" content, and connecting with formal health sources. While far from being a panacea to health disparities, these findings show that Facebook does provide unique opportunities for many Indigenous help-seekers and help-givers in times of need. SO WHAT?: Social media offers pathways for health-seeking both beyond and outside the dominant western biomedical models of public health promotion. These already-existing pathways should be considered by people working on social media public health promotion campaigns for Aboriginal and Torres Strait Islander people.


Structural and thermodynamic characterization of the interaction of the SH3 domain from Fyn with the proline-rich binding site on the p85 subunit of PI3-kinase.
The interaction of the Fyn SH3 domain with the p85 subunit of PI3-kinase is investigated using structural detail and thermodynamic data. The solution structure complex of the SH3 domain with a proline-rich peptide mimic of the binding site on the p85 subunit is described. This indicates that the peptide binds as a poly(L-proline) type II helix. Circular dichroism spectroscopic studies reveal that in the unbound state the peptide exhibits no structure. Thermodynamic data for the binding of this peptide to the SH3 domain suggest that the weak binding (approximately 31 microM) of this interaction is, in part, due to the entropically unfavorable effect of helix formation (delta S0 = -78 J.mol-1.K-1). Binding of the SH3 domain to the intact p85 subunit (minus its own SH3 domain) is tighter, and the entropic and enthalpic contributions are very different from those given by the peptide interaction (delta S0 = +252 J.mol-1.K-1; delta H0 = +44 kJ.mol-1). From these dramatically different thermodynamic measurements we are able to conclude that the interaction of the proline-rich peptide does not effectively mimic the interaction of the intact p85 subunit with the SH3 domain and suggest that other interactions could be important.


Voltage threshold and excitability among variously sized cat hindlimb motoneurons.
Intracellular recording has been performed to examine whether any differences in apparent initial-segment voltage threshold exist between types F and S cat triceps surae motoneurons. Voltage threshold was estimated using orthodromic action potentials initiated by large, monosynaptic excitatory postsynaptic potentials (EPSPs) evoked by dorsal root stimulation. No significant differences in voltage threshold could be detected between types F and S motoneurons. Further, voltage thresholds did not covary with motoneuron input resistance, afterhyperpolarization duration, or the twitch contraction time of functionally isolated muscle units. Significant positive correlations were observed between voltage threshold and the motoneuron resting potential. Utilizing a compartmental neuron model, a theoretical analysis has been performed that examines the influence of specific passive membrane properties on current threshold for action potentials initiated by large, monosynaptic EPSPs. This analysis indicates that total membrane capacitance will be the primary determinant of these thresholds. Further analysis of available data suggests that active membrane properties will play a minimal role in setting these thresholds. Since specific membrane capacitance is likely to be similar among cat motoneurons, it is concluded that only size or surface area-related current threshold differences will exist among these cells for activation with brief currents such as those underlying large EPSPs. For motoneurons thus activated, it is suggested that variations in the excitatory/inhibitory balance or density of synaptic input would be the major mechanisms for producing differential recruitment thresholds among the motoneuron population. Other available evidence is discussed that indicates that factors intrinsic to the motoneurons themselves will contribute to the setting of functional recruitment thresholds for activation with longer duration currents.


Treatment with chemotherapy and dendritic cells pulsed with multiple Wilms' tumor 1 (WT1)-specific MHC class I/II-restricted epitopes for pancreatic cancer.
We performed a phase I trial to investigate the safety, clinical responses, and Wilms' tumor 1 (WT1)-specific immune responses following treatment with dendritic cells (DC) pulsed with a mixture of three types of WT1 peptides, including both MHC class I and II-restricted epitopes, in combination with chemotherapy. Ten stage IV patients with pancreatic ductal adenocarcinoma (PDA) and 1 patient with intrahepatic cholangiocarcinoma (ICC) who were HLA-positive for A*02:01, A*02:06, A*24:02, DRB1*04:05, DRB1*08:03, DRB1*15:01, DRB1*15:02, DPB1*05:01, or DPB1*09:01 were enrolled. The patients received one course of gemcitabine followed by biweekly intradermal vaccinations with mature DCs pulsed with MHC class I (DC/WT1-I; 2 PDA and 1 ICC), II (DC/WT1-II; 1 PDA), or I/II-restricted WT1 peptides (DC/WT1-I/II; 7 PDA), and gemcitabine. The combination therapy was well tolerated. WT1-specific IFNγ-producing CD4(+) T cells were significantly increased following treatment with DC/WT1-I/II. WT1 peptide-specific delayed-type hypersensitivity (DTH) was detected in 4 of the 7 patients with PDA vaccinated with DC/WT1-I/II and in 0 of the 3 patients with PDA vaccinated with DC/WT1-I or DC/WT1-II. The WT1-specific DTH-positive patients showed significantly improved overall survival (OS) and progression-free survival (PFS) compared with the negative control patients. In particular, all 3 patients with PDA with strong DTH reactions had a median OS of 717 days. The activation of WT1-specific immune responses by DC/WT1-I/II combined with chemotherapy may be associated with disease stability in advanced pancreatic cancer.


Current status of newborn screening for Pompe disease in Japan.
Pompe disease is an autosomal recessive inherited metabolic disorder caused by a deficiency of the acid α-glucosidase (GAA). Pompe disease manifests as an accumulation of lysosomal glycogen in the skeletal and heart muscle. We conducted newborn screening (NBS) for Pompe disease in Japan from April 2013 to October 2020 to determine the feasibility and utility of NBS for Pompe disease. From the 296,759 newborns whose enzyme activity was measured, 107 of which underwent GAA analysis, we found one patient with infantile-onset Pompe disease (IOPD) and seven with potential late-onset Pompe disease (LOPD). We identified 34 pseudodeficient individuals and 65 carriers or potential carriers. The frequency of patients with IOPD was similar to that in the United States, but significantly lower than that in Taiwan. One patient with IOPD underwent early enzyme replacement therapy within a month after birth before presenting exacerbated manifestations, whereas those with potential LOPD showed no manifestations during the follow-up period of six years. The frequency of IOPD in Japan was similar to that in the United States, where NBS for Pompe disease is recommended. This indicates that NBS for Pompe disease may also be useful in Japan. Therefore, it should be used over a wider region in Japan.


Additional behavioural support as an adjunct to pharmacotherapy for smoking cessation.
Pharmacotherapies for smoking cessation increase the likelihood of achieving abstinence in a quit attempt. It is plausible that providing support, or, if support is offered, offering more intensive support or support including particular components may increase abstinence further. To evaluate the effect of adding or increasing the intensity of behavioural support for people using smoking cessation medications, and to assess whether there are different effects depending on the type of pharmacotherapy, or the amount of support in each condition. We also looked at studies which directly compare behavioural interventions matched for contact time, where pharmacotherapy is provided to both groups (e.g. tests of different components or approaches to behavioural support as an adjunct to pharmacotherapy). We searched the Cochrane Tobacco Addiction Group Specialised Register, clinicaltrials.gov, and the ICTRP in June 2018 for records with any mention of pharmacotherapy, including any type of nicotine replacement therapy (NRT), bupropion, nortriptyline or varenicline, that evaluated the addition of personal support or compared two or more intensities of behavioural support. Randomised or quasi-randomised controlled trials in which all participants received pharmacotherapy for smoking cessation and conditions differed by the amount or type of behavioural support. The intervention condition had to involve person-to-person contact (defined as face-to-face or telephone). The control condition could receive less intensive personal contact, a different type of personal contact, written information, or no behavioural support at all. We excluded trials recruiting only pregnant women and trials which did not set out to assess smoking cessation at six months or longer. For this update, screening and data extraction followed standard Cochrane methods. The main outcome measure was abstinence from smoking after at least six months of follow-up. We used the most rigorous definition of abstinence for each trial, and biochemically-validated rates, if available. We calculated the risk ratio (RR) and 95% confidence interval (CI) for each study. Where appropriate, we performed meta-analysis using a random-effects model. Eighty-three studies, 36 of which were new to this update, met the inclusion criteria, representing 29,536 participants. Overall, we judged 16 studies to be at low risk of bias and 21 studies to be at high risk of bias. All other studies were judged to be at unclear risk of bias. Results were not sensitive to the exclusion of studies at high risk of bias. We pooled all studies comparing more versus less support in the main analysis. Findings demonstrated a benefit of behavioural support in addition to pharmacotherapy. When all studies of additional behavioural therapy were pooled, there was evidence of a statistically significant benefit from additional support (RR 1.15, 95% CI 1.08 to 1.22, I² = 8%, 65 studies, n = 23,331) for abstinence at longest follow-up, and this effect was not different when we compared subgroups by type of pharmacotherapy or intensity of contact. This effect was similar in the subgroup of eight studies in which the control group received no behavioural support (RR 1.20, 95% CI 1.02 to 1.43, I² = 20%, n = 4,018). Seventeen studies compared interventions matched for contact time but that differed in terms of the behavioural components or approaches employed. Of the 15 comparisons, all had small numbers of participants and events. Only one detected a statistically significant effect, favouring a health education approach (which the authors described as standard counselling containing information and advice) over motivational interviewing approach (RR 0.56, 95% CI 0.33 to 0.94, n = 378). There is high-certainty evidence that providing behavioural support in person or via telephone for people using pharmacotherapy to stop smoking increases quit rates. Increasing the amount of behavioural support is likely to increase the chance of success by about 10% to 20%, based on a pooled estimate from 65 trials. Subgroup analysis suggests that the incremental benefit from more support is similar over a range of levels of baseline support. More research is needed to assess the effectiveness of specific components that comprise behavioural support.


Healing of elderly patients with diabetic foot ulcers, venous stasis ulcers, and pressure ulcers.
Although elderly patients have physiologic impairments in wound healing, their wounds should be expected to heal with the same frequency of closure as those in younger populations, albeit at a slower rate. However, compared to the general population, the elderly population has a higher incidence of chronic wounds: diabetic foot ulcers, pressure ulcers, and venous stasis ulcers. Experimental and clinical data indicate physiologically impaired healing is characterized by decreased angiogenesis and synthesis of critical growth factors. Further, compared to younger populations, the elderly have a higher rate of mortality associated with specific morbidities, such as sepsis and acute respiratory distress. As these morbidities may develop directly from the wound, early intervention is mandated. In this report, 40 consecutive elderly patients (65-102 years old) with chronic wounds were analyzed. All patients were provided the same treatment protocol and healing was defined as 100% epithelization and no drainage. Despite the wounds presenting in a nonhealing and/or infected state, 73% of these chronic wounds in elderly patients healed. This suggests that elderly patients with diabetic foot ulcers, pressure ulcers, and venous stasis ulcers close their wounds at a similar frequency as younger patients. Therefore, early intervention and comprehensive treatment that includes safe topical therapies, in addition to growth factors and cellular therapy used for chronic wounds, ensure these patients will be spared the morbidities of pain, amputation, osteomyelitis, and even death. We hypothesize that if all elderly patients with chronic wounds are provided early treatment, morbidities (e.g., amputation, sepsis, pain) and associated costs will decrease.


Consecutive 1127 therapeutic echocardiographically guided pericardiocenteses: clinical profile, practice patterns, and outcomes spanning 21 years.
To evaluate consecutive therapeutic echocardiographically (echo)-guided pericardiocenteses performed at Mayo Clinic, Rochester, Minn, from 1979 to 2000 and to determine whether patient profiles, practice patterns, and outcomes have changed over time. Consecutive echo-guided pericardiocenteses performed between February 1, 1979, and January 31, 2000, for treatment of clinically significant pericardial effusions were identified in the Mayo Clinic Echocardiographic-guided Pericardiocentesis Registry. The medical records of these patients were examined, and a follow-up survey was conducted. Clinical profiles, echocardiographic findings, procedural details, and outcomes were determined for 3 periods: February 1, 1979, through January 31, 1986; February 1, 1986, through January 31, 1993; and February 1, 1993, through January 31, 2000. During the 21-year study period, 1127 therapeutic echo-guided pericardiocenteses were performed in 977 patients. The mean +/- SD age at pericardiocentesis increased from 49+/-14 years in period 1 to 57+/-14 years in period 3. In recent years, cardiothoracic surgery replaced malignancy as the leading cause of an effusion requiring pericardiocentesis and together with malignancy and perforation from catheter-based procedures accounted for nearly 70% of all pericardiocenteses performed. The procedural success rate was 97% overall, with a total complication rate of 4.7% (major, 1.2%; minor, 3.5%). These rates did not change significantly over time. The use of a pericardial catheter for extended drainage increased from 23% in period 1 to 75% in period 3 (P<.001), whereas rates of effusion recurrence and pericardial surgery decreased significantly (P<.001). The profile of patients presenting with clinically significant pericardial effusion has changed over time. Increasing numbers of older patients and those who have undergone cardiothoracic surgery or catheter-based procedures develop effusions that can be rapidly, safely, and effectively managed with echo-guided pericardiocentesis. Extended drainage with use of a pericardial catheter has become standard practice, and concomitantly, recurrence rates and need for surgical management have decreased considerably.


Fluorine-18 fluorodeoxyglucose PET-CT for extranodal staging of non-Hodgkin and Hodgkin lymphoma.
We aimed to evaluate the role of fluorine-18 fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) involving care-dose unenhanced CT to detect extranodal involvement in patients with non-Hodgkin and Hodgkin lymphoma. Lymphoma patients (35 Hodgkin lymphoma, 75 non-Hodgkin lymphoma) who were referred for 18F-FDG PET-CT imaging, following a diagnostic contrast-enhanced CT (CE-CT) performed within the last month, were included in our study. A total of 129 PET-CT images, and all radiologic, clinical, and pathological records of these patients were retrospectively reviewed. In total, 137 hypermetabolic extranodal infiltration sites were detected by 18F-FDG PET-CT in 62 of 110 patients. There were no positive findings by CE-CT that reflected organ involvement in 40 of 137 18F-FDG-positive sites. The κ statistics revealed fair agreement between PET-CT and CE-CT for the detection of extranodal involvement (κ=0.60). The organs showing a disagreement between the two modalities were the spleen, bone marrow, bone, and thyroid and prostate glands. In all lesions that were negative at CE-CT, there was a diffuse 18F-FDG uptake pattern in the PET-CT images. The frequency of extranodal involvement was 51% and 58% in Hodgkin and non-Hodgkin lymphoma patients, respectively. There was a high positive correlation between the maximum standardized uptake values of the highest 18F-FDG-accumulating lymph nodes and extranodal sites (r=0.67) in patients with nodal and extranodal involvement. 18F-FDG PET-CT is a more effective technique than CE-CT for the evaluation of extranodal involvement in Hodgkin and non-Hodgkin lymphoma patients. PET-CT has a significant advantage for the diagnosis of diffusely infiltrating organs without mass lesions or contrast enhancement compared to CE-CT.


Health communication in primary health care -a case study of ICT development for health promotion.
Developing Information and Communication Technology (ICT) supported health communication in PHC could contribute to increased health literacy and empowerment, which are foundations for enabling people to increase control over their health, as a way to reduce increasing lifestyle related ill health. However, to increase the likelihood of success of implementing ICT supported health communication, it is essential to conduct a detailed analysis of the setting and context prior to the intervention. The aim of this study was to gain a better understanding of health communication for health promotion in PHC with emphasis on the implications for a planned ICT supported interactive health channel. A qualitative case study, with a multi-methods approach was applied. Field notes, document study and focus groups were used for data collection. Data was then analyzed using qualitative content analysis. Health communication is an integral part of health promotion practice in PHC in this case study. However, there was a lack of consensus among health professionals on what a health promotion approach was, causing discrepancy in approaches and practices of health communication. Two themes emerged from the data analysis: Communicating health and environment for health communication. The themes represented individual and organizational factors that affected health communication practice in PHC and thus need to be taken into consideration in the development of the planned health channel. Health communication practiced in PHC is individual based, preventive and reactive in nature, as opposed to population based, promotive and proactive in line with a health promotion approach. The most significant challenge in developing an ICT supported health communication channel for health promotion identified in this study, is profiling a health promotion approach in PHC. Addressing health promotion values and principles in the design of ICT supported health communication channel could facilitate health communication for promoting health, i.e. 'health promoting communication'.


Development and Evaluation of Lyophilized Methotrexate Nanosuspension using Quality by Design Approach.
With the application of the quality by design (QbD) approach, a high-pressure homogenizer (HPH) methodology was employed to develop methotrexate nanosuspension (MTX-NS) to boost bioavailability. The Ishikawa diagram was used to analyze potential risk factors in formulation development. To screen and study the impact of various formulation and process factors on the critical quality attributes (CQA), the Placket-Burman design and central composite design were utilized. The number of HPH cycles, poloxamer 188 concentration, and tween 80 concentration were shown to be significant parameters (P<0.05), that were further optimized using Central Composite Design. The zeta potential of optimized lyophilized MTX-NS was determined to be -11.6 ± 7.52 mV and the average particle size was 260 ± 0.25 nm. In vitro cytotoxicity experiments revealed a greater than 80% inhibition, with apoptotic cells shrinking, fragmentation, and cell death. Furthermore, the Cmax and AUC0-t were increased by 2.53 and 8.83 folds, respectively. The relative bioavailability of MTX-NS was found to be 8.83 times higher than that of MTX-aqueous dispersion. As a result, the QbD method resulted in the development of a lyophilized MTX-NS with process understanding and control based on quality risk management.


The use of glass ionomer cements in both conventional and surgical endodontics.
The capacity to bond to dental tissues, especially to dentine, their long-term fluoride release and their biocompatibility make glass ionomer cements (GICs) advantageous for use in endodontics, as well as in restorative dentistry. This review provides information on the basic properties of GICs, such as adhesion, antimicrobial effects and biocompatibility, particularly as they relate to use in endodontics. Indications for the use of GICs in endodontics are orthograde root canal sealing, root-end filling, repair of perforations and root resorption defects, treatment of vertical fractures and maintenance of the coronal seal. The paper includes a review on each of these indications. It is concluded that in spite of the critical handling characteristics and the inconclusive findings regarding sealing ability and antimicrobial activity, there is substantial evidence to confirm their satisfactory clinical performance. Both soft tissue and bone compatibility make them suitable for use during endodontic surgery.


What makes music memorable? Relationships between acoustic musical features and music-evoked emotions and memories in older adults.
Music has a unique capacity to evoke both strong emotions and vivid autobiographical memories. Previous music information retrieval (MIR) studies have shown that the emotional experience of music is influenced by a combination of musical features, including tonal, rhythmic, and loudness features. Here, our aim was to explore the relationship between music-evoked emotions and music-evoked memories and how musical features (derived with MIR) can predict them both. Healthy older adults (N = 113, age ≥ 60 years) participated in a listening task in which they rated a total of 140 song excerpts comprising folk songs and popular songs from 1950s to 1980s on five domains measuring the emotional (valence, arousal, emotional intensity) and memory (familiarity, autobiographical salience) experience of the songs. A set of 24 musical features were extracted from the songs using computational MIR methods. Principal component analyses were applied to reduce multicollinearity, resulting in six core musical components, which were then used to predict the behavioural ratings in multiple regression analyses. All correlations between behavioural ratings were positive and ranged from moderate to very high (r = 0.46-0.92). Emotional intensity showed the highest correlation to both autobiographical salience and familiarity. In the MIR data, three musical components measuring salience of the musical pulse (Pulse strength), relative strength of high harmonics (Brightness), and fluctuation in the frequencies between 200-800 Hz (Low-mid) predicted both music-evoked emotions and memories. Emotional intensity (and valence to a lesser extent) mediated the predictive effect of the musical components on music-evoked memories. The results suggest that music-evoked emotions are strongly related to music-evoked memories in healthy older adults and that both music-evoked emotions and memories are predicted by the same core musical features.


How much does defensive medicine cost?
Many key health reform bills in the 103rd Congress include proposals to overhaul the medical malpractice system. One of the factors motivating such legislation is the practice of defensive medicine, or care that does not benefit the patient and is provided solely to avoid malpractice claims. Estimating the costs of defensive medicine is difficult because of the many conflicting and overlapping motivations facing physicians. Although our estimates delineate a wide range of potential savings, systemwide savings from aggressive malpractice reform could approach $41 billion over five years.


Sensitivity of Listeria monocytogenes to Sanitizers after Exposure to a Chemical Shock.
We tested the hypothesis that exposure of Listeria monocytogenes to sublethal levels of sanitizers (chemical shock) could affect survival to a subsequent exposure to lethal levels and the ability of the cells to attach to stainless steel surfaces. L. monocytogenes was exposed to an acidic anionic sanitizer, a chlorine-based sanitizer, an iodophor, and a quaternary ammonium compound, as well as to citric, lactic, and propionic acids. The cells were exposed to sublethal levels of each sanitizer for up to 60 min (chemical shock), followed by exposure to either the minimum inhibitory concentration (MIC) for 48 h, to the lethal level for 48 h, or to the MIC for 40 min followed by the lethal level for 48 h. No significant difference in survival was observed with most of the sanitizers used. However, exposure to a chemical shock with the acid anionic sanitizer for at least 10 min resulted in survival of the cells in the MIC of this sanitizer, as well as in the lethal level, but only when the cells were first exposed to the MIC for 40 min. Deliberate dissociation of citric acid by pH adjustment also resulted in survival of chemically shocked cells to lethal levels of this acid, suggesting that exposure to the dissociated form somehow enabled cells to survive exposure to lethal levels of the acid. Chemical shock did not affect attachment of the cells to stainless-steel chips.


Methylated tin toxicity a reappraisal using rodents models.
Trimethyltin-induced intoxication has a great impact on human health due to the widespread occurrence of methyltin compounds. Acute TMT intoxication in humans leads to a variety of neurological symptoms which involve primarily the limbic system. In the present review we summarized the neuromorphological correlates of this neurological syndrome extending the analysis to various extra-limbic regions and detailing the fine ultrastructure of TMT-induced neuronal alterations. In order to comprehend the pathophysiology of TMT-induced neuronal damage we analysed the various experimental models of TMT-induced neurotoxicity. When comparing various animal species, it seems that the variety of neuropathological correlates are not related to species difference in the sensitivity to TMT toxicity but to a different susceptibility to secondary effects produced by TMT. In fact, apart from a primary neurotoxic damage induced by TMT at neuronal level, this compound promotes the onset of limbic and generalized seizures, which in turn add a secondary damage to that induced immediately by TMT. Thus, the different neuropathology observed in different animal species is produced mainly by a different sensitivity to epilepsy-induced brain damage.


Parallel line assays of endotoxins with the LAL chromogenic substrate method.
All endotoxins from the gram negative microorganisms studied sofar contain lipid A, which is considered to be responsible for the biological activity. Endotoxins may therefore react in a similar way in quantitative assays. The varying non-lipid A part of different endotoxins may potentiate or reduce the activity of the identical lipid A part without changing the slope of the log-dose vs. response curve of these endotoxins. To test whether 13 endotoxins from different microorganisms react similarly with amoebocyte lysate (LAL) log-dose response curves were made using a chromogenic substrate method. A balanced incomplete block design with 13 blocks and four replications of each endotoxin was applied. A group of eight endotoxins with a common slope was defined with the Student-Newman-Keuls procedure. Two independent potency estimates of these endotoxins were in good agreement.


Vibronic Quantum Beating between Electronic Excited States in a Heterodimer.
Energy transfer in multichromophoric molecules can be affected by coherences that are induced by the electronic and vibrational couplings between chromophore units. Coherent electron-vibrational dynamics can persist at the subpicosecond time scale even at room temperature. Furthermore, wave-like localized-delocalized motions of the electronic wave function can be modulated by vibrations that actively participate in the intermolecular energy transfer process. Herein, nonadiabatic excited state molecular dynamics simulations have been performed on a rigid synthetic heterodimer that has been proposed as a simplified model for investigating the role and mechanism of coherent energy transfer in multichromophoric systems. Both surface hopping (SH) and Ehrenfest approaches (EHR) have been considered. After photoexcitation of the system at room temperature, EHR simulations reveal an ultrafast beating of electronic populations between the two lowest electronic states. These oscillations are not observed at low temperature and have vibrational origins. Furthermore, they cannot be reproduced using SH approach. This periodic behavior of electronic populations induces oscillations in the spatial localization of the electronic transition density between monomers. Vibrations whose frequencies are near-resonant with energy difference between the two lowest electronic excited states are in the range of the electronic population beating, and they are the ones that contribute the most to the coherent dynamics of these electronic transitions.


Interferon regulatory factor 7 (IRF7) is required for the optimal initial control but not subsequent clearance of lymphocytic choriomeningitis virus infection in mice.
The role of IRF7 in the host response to lymphocytic choriomeningitis virus (LCMV) Armstrong 53b infection of mice was investigated. Intracranial infection of IRF7 KO mice was associated with delayed onset of LCM, increased survival and significantly reduced expression of the Ifng gene in the brain but not in the periphery. IRF7 KO mice showed impaired control of LCMV replication and delayed clearance of LCMV. Similar numbers of activated anti-LCMV-GP(33-41) CD8+ T cells were present in the brain and spleens of infected WT and IRF7 KO mice. While plasma IFN-β was increased to similar levels, IFN-α was markedly reduced in IRF7 KO compared with WT mice. Compared with IFN-β, IFN-α was a less potent inhibitor of LCMV infection in vitro. In conclusion, IRF7 (1) is required for the early innate control of LCMV infection, likely through the regulation of the appropriate type I IFN response, and (2) is not required for the antiviral CD8+ T cell-dependent clearance of LCMV from infected tissues.


Dataset of trend-preserving bias-corrected daily temperature, precipitation and wind from NEX-GDDP and CMIP5 over the Qinghai-Tibet Plateau.
A bias-corrected dataset containing daily meteorological data over the Qinghai-Tibet Plateau has been generated using a trend-preserving bias correction, the Inter-Sectoral Impact Model Intercomparison Project (ISI-MIP) approach, with a high-quality gridded meteorological dataset based on ground observations (CN05.1). The dataset contains daily bias-corrected values of maximum/minimum near-surface air temperature, precipitation and mean near-surface wind speed from 15 models from the Fifth Phase of the Coupled Model Intercomparison Project (CMIP5) and a downscaled high-resolution dataset (NEX-GDDP), based on CMIP5 models, over the Qinghai-Tibet Plateau (QTP) during 1986-2095. This dataset provides an important reference for the study of future climate change and its impacts in the Qinghai-Tibet Plateau region.


Chronic toxicity study of neosaxitoxin in rats.
Neosaxitoxin (NeoSTX) is a specific reversible blocker of voltage gated sodium channels on excitable cells. In the last decade, it has been tested in a number of interesting clinical trials, however there is still little information available on mammalian toxicity. Rats were treated for 12 weeks with doses of 1, 3 or 6 μg/kg of subcutaneous NeoSTX. At weeks 12 and 17, animals were sacrificed and blood samples collected for hematological and biochemical analysis. Organs were harvested for weight determination and histopathological assessments. The lowest acute toxicity via the intraperitoneal (ip) route was (30.35 μg/kg) and there was no significant difference between intramuscular and subcutaneous routes (11.4 and 12.41 μg/kg). The NeoSTX adiministration did not produce lethality at week 12 and after five weeks of suspension. NeoSTX 6 μg/kg ip produced reductions (p < 0.05) in body weight and food intake, and increased blood level of total and direct bilirubin, GGT and SGOT at week 12; all of these were reversed in the recovery period. NeoSTX 1 and 3 μg/kg ip did not show significant changes with the control group. Histopathological presentations were normal in all groups. This study revealed that NeoSTX is safe in vivo, giving a reliable security margin for its use like a local anesthetic.


Large Computational Survey of Intrinsic Reactivity of Aromatic Carbon Atoms with Respect to a Model Aldehyde Oxidase.
Aldehyde oxidase (AOX) and other related molybdenum-containing enzymes are known to oxidize the C-H bonds of aromatic rings. This process contributes to the metabolism of pharmaceutical compounds and, therefore, is of vital importance to drug pharmacokinetics. The present work describes an automated computational workflow and its use for the prediction of intrinsic reactivity of small aromatic molecules toward a minimal model of the active site of AOX. The workflow is based on quantum chemical transition state searches for the underlying single-step oxidation reaction, where the automated protocol includes identification of unique aromatic C-H bonds, creation of three-dimensional reactant and product complex geometries via a templating approach, search for a transition state, and validation of reaction end points. Conformational search on the reactants, products, and the transition states is performed. The automated procedure has been validated on previously reported transition state barriers and was used to evaluate the intrinsic reactivity of nearly three hundred heterocycles commonly found in approved drug molecules. The intrinsic reactivity of more than 1000 individual aromatic carbon sites is reported. Stereochemical and conformational aspects of the oxidation reaction, which have not been discussed in previous studies, are shown to play important roles in accurate modeling of the oxidation reaction. Observations on structural trends that determine the reactivity are provided and rationalized.


Connections of the anterior ectosylvian visual area (AEV).
We have previously described a visual area situated in the cortex surrounding the deep infolding of the anterior ectosylvian sulcus of the cat (Mucke et al. 1982). Using orthograde and retrograde transport methods we now report anatomical evidence that this anterior ectosylvian visual area (AEV) is connected with a substantial number of both cortical and subcortical regions. The connections between AEV and other cortical areas are reciprocal and, at least in part, topographically organized: the rostral AEV is connected with the bottom region of the presylvian sulcus, the lower bank of the cruciate sulcus, the rostral part of the ventral bank of the splenial sulcus, the rostral portion of the lateral suprasylvian visual area (LS) and the lateral bank of the posterior rhinal sulcus; the caudal AEV is connected with the bottom region of the presylvian sulcus, the caudal part of LS, the ventral part of area 20 and the lateral bank of the posterior rhinal sulcus. Subcortically, AEV has reciprocal connections with the ventral medial thalamic nucleus (VM), with the medial part of the lateralis posterior nucleus (LPm), as well as with the lateralis medialis-suprageniculate nuclear (LM-Sg) complex. These connections are also topographically organized with more rostral parts of AEV being related to more ventral portions of the LPm and LM-Sg complex. AEV also projects to the caudate nucleus, the putamen, the lateral amygdaloid nucleus, the superior colliculus, and the pontine nuclei. It is concluded that AEV is a visual association area which functionally relates the visual with both the motor and the limbic system and that it might play a role in the animal's orienting and alerting behavior.


[Medusae (Cnidaria: Hydrozoa) from a coastal upwelling zone, Culebra Bay, Pacific, Costa Rica].
The hydromedusae have an important role in marine trophic webs due to their predatory feeding habits. This is the first study of this group of gelatinous marine zooplankton in a coastal upwelling area of Central America. The composition and abundance variability of hydromedusae were studied during six months in 1999 at four stations in Culebra Bay, Gulf of Papagayo, Pacific coast of Costa Rica (10 degrees 37' N-85 degrees 40' W). A total of 53 species were identified, of which 26 are new records for Costa Rica, 21 are new records for Central America, and eight are new records for the Eastern Tropical Pacific. The more abundant species (more than 30% of the total abundance) were Liriope tetraphylla, Solmundella bitentaculata and Aglaura hemistoma. Six species occurred throughout the sampling period, 10 were present only during the dry season (December-April), and 17 were so during the rainy season (May-November). Significant differences of medusan abundances were found between seasons (dry vs. rainy). Maximum abundance (2.1 +/- 4.3ind./m3) was recorded when upwelled deeper water influenced the Bay, as indicated by local higher oxygen concentrations and lower water temperatures. The relatively high species richness of medusae found in Culebra Bay is probably related to factors like the pristine condition of the Bay, the arrival of oceanic species transported by the Equatorial Counter Current (ECC), the eastward shoaling of the Costa Rica Dome, and local currents. Illustrations of the 15 more important species are included to facilitate their identification and foster future work in the region.


Evaluation of ovarian POMC mRNA through quantitative RT-PCR analysis in Rana esculenta.
The evaluation of changes in the expression of specific genes requires accurate measurement of the corresponding mRNA concentration, especially when the gene is expressed at a very low level. We previously showed that the proopiomelanocortin (POMC) gene is expressed in the ovary of the frog Rana esculenta, and, to evaluate its mRNA content in frog ovary, we have now developed a sensitive quantitative RT-PCR method. This study provides evidence for the validation of this method and for the effects of captivity and hypophysectomy on POMC gene expression in the ovary of this anuran. Our data indicate that ovarian POMC gene is involved in short-term captivity stress response and seems not influenced by pituitary. These results are discussed taking into account the knowledge of the role played by opioids in stress response; moreover, a local control of POMC gene expression is also suggested.


[Methods for fixation of the rotator cuff].
Rotator cuff repair has gained increasing popularity in recent years. Fixation of the tendon to the bone presents challenging difficulties like those in many parts of the human body. There is ongoing research concerning clinical and biomechanical features of open and arthroscopic repair methods, though accumulated evidence in the past years suggests that the latter may provide a more secure fixation. Considering the general advantages of arthroscopy, we may propose that arthroscopic rotator cuff repair with anchor fixation will gain more acceptance. This article reviews the most recent literature on the subject.


The Biosynthesis and Transport of Ophiobolins in Aspergillus ustus 094102.
Ophiobolins are a group of sesterterpenoids with a 5-8-5 tricyclic skeleton. They exhibit a significant cytotoxicity and present potential medicinal prospects. However, the biosynthesis and transport mechanisms of these valuable compounds have not been fully resolved. Herein, based on a transcriptome analysis, gene inactivation, heterologous expression and feeding experiments, we fully explain the biosynthesis pathway of ophiobolin K in Aspergillus ustus 094102, especially proved to be an unclustered oxidase OblCAu that catalyzes dehydrogenation at the site of C16 and C17 of both ophiobolin F and ophiobolin C. We also find that the intermediate ophiobolin C and final product ophiobolin K could be transported into a space between the cell wall and membrane by OblDAu to avoid the inhibiting of cell growth, which is proved by a fluorescence observation of the subcellular localization and cytotoxicity tests. This study completely resolves the biosynthesis mechanism of ophiobolins in strain A. ustus 094102. At the same time, it is revealed that the burden of strain growth caused by the excessive accumulation and toxicity of secondary metabolites is closely related to compartmentalized biosynthesis.


Molecular characterization of transcriptome-wide interactions between highly pathogenic porcine reproductive and respiratory syndrome virus and porcine alveolar macrophages in vivo.
Porcine reproductive and respiratory syndrome virus (PRRSV) infects mainly the porcine alveolar macrophages (PAMs) and causes porcine reproductive and respiratory syndrome (PRRS). Previous studies have analyzed the global gene expression profiles of lung tissue in vivo and PAMs in vitro following infection with PRRSV, however, transcriptome-wide understanding of the interaction between highly pathogenic PRRSV (HP-PRRSV) and PAMs in vivo has not yet been established. In this study, we employed Affymetrix microarrays to investigate the gene expression patterns of PAMs isolated from Tongcheng piglets (a Chinese indigenous breed) after infection with HP-PRRSV. During the infection, Tongcheng piglets exhibited typical clinical signs, e.g. fever, asthma, coughing, anorexia, lethargy and convulsion, but displayed mild regional lung damage at 5 and 7 dpi. Microarray analysis revealed that HP-PRRSV infection has affected PAMs in expression of the important genes involved in cytoskeleton and exocytosis organization, protein degradation and folding, intracellular calcium and zinc homeostasis. Several potential antiviral strategies might be employed in PAMs, including upregulating IFN-induced genes and increasing intracellular zinc ion concentration. And inhibition of the complement system likely attenuated the lung damage during HP-PRRSV infection. Transcriptomic analysis of PAMs in vivo could lead to a better understanding of the HP-PRRSV-host interaction, and to the identification of novel antiviral therapies and genetic components of swine tolerance/susceptibility to HP-PRRS.


A case of proteinuria with analbuminuria.
A 46-year-old black man with diabetes mellitus and hypertension was hospitalized because of myocardial ischemia and chronic renal failure. The electrophoretogram for protein in urine revealed proteins only in the alpha 1, alpha 2, and beta regions. These protein fractions were identified as small molecules by sodium dodecyl sulfate/polyacrylamide gel electrophoresis. No albumin was detected in the urine. The molecular mass of albumin, the protein present in highest concentration in serum, is near the glomerular filtration threshold, and this protein is not reabsorbed by renal tubules; therefore, albumin is consistently present in proteinuric specimens. Thus this analbuminuric pattern is highly unusual. Although the mechanism of the analbuminuria in this case is not fully understood, we wished to document this extremely rare electrophoretic pattern to alert clinical chemists and pathologists of its existence.