beta-cell neogenesis during prolonged hyperglycemia in rats.
beta-cell neogenesis from ductal precursors, and possibly from other pancreatic cell types, contributes to the expansion of beta-cell mass during development and after diabetogenic insults in rodents. Using a mathematical model-based analysis of beta-cell mass, replication, and size, we recently demonstrated that neogenesis is also quantitatively important to the expansion of beta-cell mass during prolonged hyperglycemia. In the present study, we examined the morphological appearance of neogenic focal areas, duct cell replication, and beta-cell cluster size distribution in male Sprague Dawley rats infused with either saline or 50% glucose (2 ml/h) for 0, 1, 2, 3, 4, 5, or 6 days. Pancreatic tissue characterized by a high density of small duct-like structures, previously described as neogenic focal areas, were present in glucose-infused rats after 2, 3, or 4 days of infusion. The cross-sectional area of the pancreas characterized as focal tissue peaked after 3 days of infusion at 2.9 +/- 0.8%. In contrast to the partial pancreatectomy model of beta-cell regeneration, duct cell replication was not increased before or during focal area formation. However, the replication rate of cells in the duct-like structures of the focal areas was twofold greater than in cells of the common pancreatic duct and 15- to 40-fold greater than in cells of small, medium, and large ducts. Duct-cell replication was significantly reduced in small, medium, and large ducts of glucose as compared to saline-infused rats (0.21 +/- 0.02 vs. 0.48 +/- 0.04%; P < 0.03). Duct-associated beta-cell mass was not different in glucose- and saline-infused rats (P = 0.78), whereas the number of acinar-associated single beta -cells increased by 70% after 3 and 4 days of glucose infusion. In addition to small duct-like structures, focal areas had considerable T-cell infiltration (151 +/- 30 T-cells/ mm(2)). There was also an increase in T-cell infiltration in acinar tissue of glucose as compared to saline-infused rats (0.43 +/- 0.11 vs. 0.03 +/- 0. 01 T-cells/mm(2); P < 0.0001). In conclusion, these data suggest that neogenic focal areas in these glucose-infused rats do not arise from replication and differentiation of ductal progenitor cells. Rather, acinar cell transdifferentiation into beta-cells and acinar cell dedifferentiation into neogenic focal areas lead to new beta-cell formation during prolonged hyperglycemia.


The University of North Carolina Medical Center pharmacy resident leadership certificate program.
The development and implementation of a certificate program for pharmacy residents are described. University of North Carolina (UNC) Medical Center met the call for increased efforts in the area of pharmacy residency leadership training through the design, implementation, and evaluation of a leadership certificate program. The purpose of the UNC certificate program is to develop leaders who will serve others, improve their communities, and advance the profession. The program is designed to (1) foster self-awareness, social awareness, and altruism, (2) provide transferable and individualized leadership experiences, (3) enrich other residency components through integration of leadership development opportunities, and (4) create role models for departmental leadership. A team of preceptors and residents implemented the certificate program by integrating program components into the existing pharmacy residency infrastructure. The certificate program includes required and flexible components to allow residents to set and achieve their determined leadership development goals. Overall, residents are satisfied with the program and perceive it as worthwhile. During the first 3 years since implementation of the certification initiative, program facilitators improved the feasibility of, participant engagement in, and sustainability of the program. Future directions include an effectiveness evaluation and a "scale-up" to other institutions. The need for a pharmacy residency leadership certificate was met by designing, implementing, and evaluating such a program at UNC. Through its first 3 years, the program was feasible, sustainable, and valued by program participants.


Elimination of leukemia cells from human bone marrow using floating beads.
A new in vitro immunophysical method of removing leukemia or lymphoma cells from autologous bone marrow is described. This new technique makes use of low-density polypropylene beads (density: 0.91) coated with a monoclonal antibody anti-CALLA (antibody ALB2). To ascertain its ability to selectively remove human B/pre-B hematopoietic cells, this technique was applied to normal human bone marrow cell suspensions contaminated with 1-5% of tumor cells. Samples were incubated with the floating beads at 4 degrees C on a rotating wheel for 60 min, followed by a 10-min decantation period, after which the beads bearing the tumor cells floated on the surface, whereas unbound normal marrow cells remained in suspension and were easily recovered free of beads. To demonstrate the feasibility of our method, 2 types of assays were carried out, one using target cell radiolabeled with 111indium, and the other a clonogenic assay. The first assays were to calibrate the different parameters (cellular density, quantity of beads, incubation time) with tumor cell lines: Namalwa (CALLA+) and Molt 4 (CALLA-). These 2 cells lines being able to clone, it is hard to envisage clonogenic assays. In this case, it is very hazardous to evaluate correctly the remaining clonogenic units of Namalwa cells. It is why radiolabelling assays were used for these first experiments. The second assays were to study a model close to the clinical setting and to control the safety of the beads on normal bone marrow cells. In this case, the mixture experiments in which only Namalwa cells were able to clone were evaluated with clonogenic assays, which are more sensitive than radiolabeling assays. A 3- to 4-log reduction of tumor load was achieved with 1-step treatment, and an average of 5-log depletion was obtained by repeating the process twice, as ascertained by the clonogenic assay. Viability, average recovery of nucleated cells, and stem cells potential following the purge were excellent.


DMAP-Catalyzed One-Pot Synthesis of Quinazoline-2,4-diones from 2-Aminobenzamides and Di-tert-butyl Dicarbonate.
The one-pot synthesis of quinazoline-2,4-diones was developed in the presence of 4-dimethylaminopyridine (DMAP) by metal-free catalysis. The commercially available (Boc)2O acted as a key precursor in the construction of the 2-position carbonyl of quinazolinediones. The p-methoxybenzyl (PMB)-activated heterocyclization could smoothly proceed at room temperature instead of the microwave condition. This strategy is compatible with a variety of substrates with different functional groups. Furthermore, this protocol was utilized to smoothly prepare Zenarestat with a total yield of 70%.


Effect of mutations in the nucleocapsid protein (NCp7) upon Pr160(gag-pol) and tRNA(Lys) incorporation into human immunodeficiency virus type 1.
COS-7 cells were transfected with DNAs containing mutations in the NCp7 sequences of human immunodeficiency virus. Selective incorporation into the virus of tRNA(Lys) was measured by two-dimensional polyacrylamide gel electrophoresis, and Pr160(gag-pol) incorporation into the virus was detected in Western blots of viral protein. Mutations tested included cysteine and histidine mutations in either of the Cys-His boxes, as well as mutations in the N- and C-terminal flanking regions and in the linker region between the two Cys-His boxes. Of 10 mutations tested, only 2 inhibited tRNA(Lys) incorporation: a P31L mutation in the linker region and a deletion which removed both Cys-His boxes and the linker region (deltaK14-T50). The P31L mutation prevents the incorporation of Pr160(gag-pol) into the virus. Cotransfection of COS cells with both P31L DNA and a plasmid coding only for unprocessed Pr160(gag-pol) resulted in the viral incorporation of Pr160(gag-pol) and the rescue of selective packaging of tRNA(Lys) into the virion. In the deltaK14-T50 mutant, Pr160(gag-pol) is incorporated into the virus. Selective tRNA(Lys) packaging is not rescued by cotransfection with a plasmid coding for Pr160(gag-pol) but is rescued by cotransfection with DNA coding for wild-type Pr55(gag). Since Pr55(gag) does not by itself selectively package tRNA(Lys), the deltaK14-T50 mutation may be affecting tRNA(Lys) binding to a cytoplasmic Pr55(gag)/Pr160(gag-pol) complex.


Female breast cancer mortality in relation to puberty on Staten Island, New York.
Pursuant to a Congressional act in 2008, the Department of Health and Human Services established the Interagency Breast Cancer and Environmental Research Coordinating Committee to address the burden of breast cancer in the United States. Subsequently, the Committee recommended researchers study the timing of exposure to breast cancer risk factors. Given the high breast cancer mortality rate on Staten Island, this paper presents a case-control study investigating breast cancer risk associated with puberty while living on Staten Island. The dataset combined New York City Department of Health and Mental Hygiene female death certificate information between 1985 and 2006, with life history information from newspaper obituaries. Data analyzed included: age, length of residence on Staten Island, birth on Staten Island, and residence on Staten Island during puberty. Cases were individuals who died of breast cancer and controls were individuals who died of non-malignant causes. Analysis included multivariate logistic regression on the full dataset and multiple replicates of randomized one case to two controls simulations. Results indicated that living on Staten Island during puberty (ages 9-19) was associated with an elevated risk of dying from breast cancer (odds ratio 1.35, p < 0.001, 95% CI = 1.18, 1.55). This paper suggests the importance of studying puberty as a window of susceptibility for breast cancer risk.


Ocular irritation: pathological changes occurring in the rat with surfactants of unknown irritancy.
We believe the development and validation of in vitro alternatives to eliminate the need to use animals in ocular irritation testing must be based on a thorough understanding of the mechanisms of ocular irritation. We have recently undertaken the task of developing such an understanding for a panel of surfactants. The purpose of this study was to expand our current panel of surfactants for which the microscopic changes occurring over time have been characterized. Macroscopic and microscopic findings regarding the ocular irritation of 6 surfactants of relatively unknown irritancy were compared to those of 6 surfactants of known irritancy. The right eye of each rat was treated by placing 10 microliters of a surfactant directly on the cornea. Untreated left eyes served as the controls. At 3 hr and on days 1, 3, and 35, eyes and eyelids were collected for microscopic examination. Collectively, the macroscopic and microscopic findings revealed 3 surfactants to be similar to the mildly irritating surfactants previously studied, and 3 surfactants to be similar to the moderately irritating surfactant previously studied. Information such as this will be important to develop mechanistically based in vitro alternatives to replace the use of animals for ocular irritation testing.


[Clinical experience of bromazepam for psychogenic impotence patients].
A clinical trial was performed with the tranquilizer Bromazepam on 39 patients undergoing diagnosis of psychogenic impotence, and the drug effect was evaluated according to the criteria based on our protocol. The protocol specifies 8 tests (1 for libido, 4 for erection, 2 for ejaculation, 1 for orgasm) which are scored according to an arbitrary logarithmic scoring system. At the end of the study the points made in the 8 tests were added to obtain the total score as the basis for evaluation of the overall drug effect. After treatment all tests showed an improvement, and the improvement in erection during masturbation, reflective erection, and condition of ejaculation was statistically significant. The total score also improved from 16.77 +/- 2.62 (mean +/- S.D.) before treatment to 11.42 +/- 1.96 after treatment, and the change was again statistically significant (P less than 0.05). The rate of satisfaction as a subjective symptom of improvement also increased from 25.38 +/- 4.40% to 39.10 +/- 4.53%. The results of the present study provide evidence to indicate that Bromazepam is beneficial for psychogenic impotence.


Flash NanoPrecipitation for the Encapsulation of Hydrophobic and Hydrophilic Compounds in Polymeric Nanoparticles.
The formulation of a therapeutic compound into nanoparticles (NPs) can impart unique properties. For poorly water-soluble drugs, NP formulations can improve bioavailability and modify drug distribution within the body. For hydrophilic drugs like peptides or proteins, encapsulation within NPs can also provide protection from natural clearance mechanisms. There are few techniques for the production of polymeric NPs that are scalable. Flash NanoPrecipitation (FNP) is a process that uses engineered mixing geometries to produce NPs with narrow size distributions and tunable sizes between 30 and 400 nm. This protocol provides instructions on the laboratory-scale production of core-shell polymeric nanoparticles of a target size using FNP. The protocol can be implemented to encapsulate either hydrophilic or hydrophobic compounds with only minor modifications. The technique can be readily employed in the laboratory at milligram scale to screen formulations. Lead hits can directly be scaled up to gram- and kilogram-scale. As a continuous process, scale-up involves longer mixing process run time rather than translation to new process vessels. NPs produced by FNP are highly loaded with therapeutic, feature a dense stabilizing polymer brush, and have a size reproducibility of ± 6%.


Knowledge, Attitudes, and Practices of School Teachers Regarding Dental Trauma and its Emergency Management in Madinah, Saudi Arabia: A Questionnaire-Based Online Cross-Sectional Survey.
Traumatic dental injuries (TDIs) are a common occurrence in the general population, and they are one of the most severe dental public health issues among children. This cross-sectional study aims to assess the knowledge, attitude, and practices of school teachers in Madinah, Saudi Arabia, regarding dental trauma and its emergency management. This cross-sectional study included teachers of elementary and middle schools both male and female in Madinah. Each teacher received a study questionnaire and was briefed about the procedure of filling it. The questionnaire contained 17 questions which are related to the knowledge, attitude, and practices relating to TDIs. A total of 294 teachers participated in the present study, which includes 163 males (55.4%) and 131 females (44.6%). When we asked the respondents if an avulsed tooth may be replanted, 49.7% answered in the positive and men show more awareness compared to women. When questioned regarding the storage media, 31.3% of participants said they will store the tooth in a cloth or tissue which was the wrong answer and 60.9% of males and 39.1% of females were unaware of appropriate storage media. A percentage of 68.4 of the teachers were not willing to replant a knocked-out tooth (tooth avulsion), 59.7% of these were males, and 40.3% were females. A percentage of 59.2 of participants consider that the dental trauma is an emergency situation, while 25.9% did not consider it as an emergency situation and 15% were not aware of the same. The majority of the participants were not aware of dental trauma and its emergency management. Children indulge in contact sports and play at schools posing the risk for a significant amount of dental trauma. Affirmative action from teachers is critical for successful treatment outcomes.


On the intensity distribution function of blazed reflective diffraction gratings.
We derive from first principles the expression for the angular/wavelength distribution of the intensity diffracted by a blazed reflective grating, according to a scalar theory of diffraction. We considered the most common case of a groove profile with rectangular apex. Our derivation correctly identifies the geometric parameters of a blazed reflective grating that determine its diffraction efficiency, and fixes an incorrect but commonly adopted expression in the literature. We compare the predictions of this scalar theory with those resulting from a rigorous vector treatment of diffraction from one-dimensional blazed reflective gratings.


Infliximab in steroid-dependent ulcerative colitis: effectiveness and predictors of clinical and endoscopic remission.
Up to 20% of patients with ulcerative colitis (UC) become steroid-dependent during their course. Thiopurines are recommended in steroid-dependent UC, but their efficacy is debated. Data exploring the use of infliximab in these patients are scarce. Aims of this study were to evaluate the effectiveness of infliximab in steroid-dependent UC and identify predictors of steroid-free remission, mucosal healing (MH), and colectomy. Steroid-dependent UC patients were enrolled and intentionally treated with infliximab. The prospectively designed analyses evaluated (1) steroid-free clinical remission at 6 and 12 months, (2) steroid-free clinical remission and MH at 12 months, and (3) colectomy within 12 months. One hundred and twenty-six active steroid-dependent UC patients were studied. Of the 126 patients, 36 patients were retrospectively included and 90 patients prospectively enrolled. Steroid-free remission was 53% and 47% at 6 and 12 months, respectively. Predictors of steroid-free remission at 6 and 12 months were thiopurine-naive status (hazard ratio [HR], 2.5 and HR, 2.8, respectively) and combination therapy (HR, 2.1 and HR, 2.2, respectively). At 12 months, 32% were in steroid-free remission and MH. Thiopurine-naive status predicted steroid-free remission and MH (odds ratio, 3.6). C-reactive protein drop to normal after infliximab induction was predictive of steroid-free remission at 6 (HR, 5.9) and 12 months (HR, 4.6) and steroid-free remission and MH at 12 months (odds ratio, 6.0). Twelve patients underwent colectomy after a median of 4.7 months. Steroid sparing significantly reduced the risk of colectomy within 12 months (HR, 0.14). Infliximab seems effective in steroid-dependent UC. Thiopurine-naive status and combination therapy significantly increase the rate of steroid-free remission up to 12 months.


Reconciling different infectivity estimates for HIV-1.
In our article, "HIV-1 Epidemics Driven by Late Stage Disease," we conclude that the probability of transmission of HIV through promiscuous or casual sexual contacts is significantly higher in the third or symptomatic stage of the disease. Our results differ greatly from those of the current literature. The primary stage or first stage has been reported to be the most infectious based on an article by Jacquez et al. More recently, the Wawer et al study of monogamous heterosexual couples in Rakai, Uganda found that the transmission of HIV was most likely to occur in the first 5 months after infection. We describe how the findings of the Wawer et al study might be compatible with our results. We also respond to a response by Koopman and Simon, who seem to criticize their own paper severely and choose not to defend it against our remarks.


Violation of Boltzmann Equipartition Theorem in Angular Phonon Phase Space Slows down Nanoscale Heat Transfer in Ultrathin Heterofilms.
Heat transfer through heterointerfaces is intrinsically hampered by a thermal boundary resistance originating from the discontinuity of the elastic properties. Here, we show that with shrinking dimensions the heat flow from an ultrathin epitaxial film through atomically flat interfaces into a single crystalline substrate is significantly reduced due to violation of Boltzmann equipartition theorem in the angular phonon phase space. For films thinner than the phonons mean free path, we find phonons trapped in the film by total internal reflection, thus suppressing heat transfer. Repopulation of those phonon states, which can escape the film through the interface by transmission and refraction, becomes the bottleneck for cooling. The resulting nonequipartition in the angular phonon phase space slows down the cooling by more than a factor of 2 compared to films governed by phonons diffuse scattering. These allow tailoring of the thermal interface conductance via manipulation of the interface.


High-throughput molecular analysis of urine sediment for the detection of bladder cancer by high-density single-nucleotide polymorphism array.
The detection of urothelial malignancies remains challenging. The majority of patients diagnosed with bladder cancer require life-long surveillance for disease recurrence. Monitoring strategies rely predominantly on invasive endoscopic techniques, which are inconvenient and uncomfortable. Multiple in vitro diagnostic technologies have been developed to supplant the contemporary standard of care. The U.S. Food and Drug Administration has approved several assays, but [because of inferior performance characteristics (low sensitivity and specificity)] these tests have not made a significant impact on practice, to date. We sought to develop a test for bladder cancer with better performance characterization detection based on a novel molecular approach. Matched urine and peripheral blood lymphocyte samples were obtained before surgery from 31 patients with bladder cancer (10 pTa, 4 pT1, and 17 pT2>or). DNA from these samples was subjected to allelic imbalance analysis using HuSNP chips and was validated in parallel with microsatellite analysis for loss of heterozygosity and microsatellite instability. Peripheral blood lymphocyte and urine DNA obtained from 14 individuals without clinical evidence of genitourinary malignancy served as controls. Thirty-one of 31 (100%) urine DNA samples from patients with bladder tumors were found to have 24 or more single-nucleotide polymorphism (SNP) DNA alterations. In general, SNP alterations were more common in urine samples from pT2>or tumors than pTa or pT1 tumors. SNP alterations were not identified in nine normal control subjects and in four of five patients with hematuria. These data support the noninvasive HuSNP chip assay in urine DNA as a valuable tool for the detection of bladder cancer (on a high-throughput-automated platform).


Health Services Research and Development: the Veterans Administration Program.
Health expenditures are rising inexorably; health status shows relatively little gain; technological possibilities are outstripping our ability or willingness to provide a commensurate level of resources. Clinical and administrative managers face increasingly difficult choices among alternative interventions in attempting to resolve these problems. If health services research is to succeed as a tool for assisting these decisions, clinicians, administrators, and researchers must view it as an integral part of management. This paper describes this concept of health services research and its implementation by the VA HSR&D Service, results from 1981 to date, and future directions. Four programs implement the Service's system to make relevant, valid information accessible to VA staff who can use it to improve veterans' health care: Investigator-Initiated Research (IIR) Program; HSR&D Field Program, which implements the Service's mission in various local areas VA-wide; Special Projects Program, responsive to system-wide issues, including technology assessment and transfer; and Resources Program, the Service's own management system. The Service's impact on improving veterans health care is already apparent. However, the true value of the HSR&D system will become apparent only in the 1990s, after the capacity for conducting health services research has been built and integrated fully with clinical and administrative practice. The VA, the nation's largest health care system, has a unique opportunity to demonstrate how health services research can improve health care.


Study of the efficacy of an inactivated virus vaccine against porcine parvovirus.
The efficacy of an inactivated virus vaccine against porcine parvovirus has been studied by immunizing 4 sows during pregnancy. A parvovirus virulent strain has been inoculated to these sows and to two other unvaccinated sows used as controls. The infection was performed between the 52nd and the 57th day of gestation. In the litters born from the vaccinated sows, 82% of the piglets were alive and normal. Neither PPV antibodies nor antigen could be revealed in the stillborn fetuses born from the 4 vaccinated sows. Reversely, only 9.5% of the piglets born from the 2 unvaccinated sows were alive at birth, although they were probably infected during pregnancy. In total, 86% of fetuses in these 2 litters were mummified. A field study allowed to show that the double vaccination antibodies induced, persisted with constant titers for, at least, 13 months. Moreover, the reproductive performance of 413 gilts, vaccinated twice before mating, were not affected by this treatment.


Surgical abortion.
This review of surgically-induced abortion focuses on conventional first trimester suction evacuation. Manual vacuum aspiration at early gestations and dilatation and evacuation at more advanced gestation are also considered. The place of surgical abortion in contemporary abortion practice is reviewed alongside developments in medical abortion. There is still debate about the best method for later abortions. Patient choice and pre-procedure assessment are considered fundamental to practice. The importance of antibiotic prophylaxis or infection screening is highlighted. The value of ultrasound emerges. The need for cervical priming is considered along with choice of suitable pharmacological agents. Current practice and the procedure of surgical abortion is outlined. Complications and strategies to minimize risk are detailed. The overview concludes with consideration of the impact on future reproductive health.


A CD18 monoclonal antibody increases the incidence and severity of subcutaneous abscess formation after high-dose Staphylococcus aureus injection in rabbits.
Monoclonal antibody (MAb) 60.3 blocks CD18-dependent polymorphonuclear neutrophil adherence to endothelium and has been shown to be of benefit in preventing tissue injury in a variety of inflammatory conditions. However, concern exists that interference with normal polymorphonuclear neutrophil host-defense functions may increase susceptibility to bacterial infection. We compared the development of subcutaneous Staphylococcus aureus abscesses in rabbits pretreated with MAb 60.3 to those pretreated with saline placebo. Bacterial inoculation with 10(6) or 10(7) colony-forming units (CFU) did not result in abscess formation in either control or antibody-treated groups. However, inoculation with 10(8) CFU resulted in more frequent and larger abscesses in antibody-treated rabbits than in controls. Abscess incidence was similar for inoculation with 10(9) CFU, although antibody-treated rabbits developed larger abscesses than did controls. The difference in abscess development is due to delayed leukocyte migration into inoculated tissue. The results of these experiments suggest that subjects treated with MAb 60.3 and exposed to massive S. aureus inocula may be at serious risk of infection. However, despite inhibited leukocyte adhesion, inocula of up to 10(7) CFU were well tolerated in this model. Whether these findings are clinically important remains to be determined, although exposure to bacterial concentrations of 10(8) CFU or greater occurs only rarely in clinical practice.


Coupling diversity across human behavior spaces.
The heterogeneous nature of human behaviors contributes to the complexity of human-activated systems. Empirical observations and theoretical models reveal the temporal and spatial heterogeneity of many aspects of human behaviors, including social connections and geographic movements, while little is known whether and how human individual's behavioral diversities are correlated across different aspects. With statistical analysis on large-scale data of aligned online and offline human behaviors, we show that behavior spaces are coupled, independent from the specific choice of measurements. The coupling further expands to individual's direct and indirect social contacts. This finding provides insight into understanding homophily in different social systems and further improving the predictability of human online and offline behaviors.


What do ras oncogenes do?
The ras oncogenes play a crucial role in the regulation of cellular proliferation, probably by coupling growth factor receptors to the PI second messenger pathway. Additional experiments are needed to verify and detail this mechanism, and to examine the question of differing roles for the three ras variants.


Extracting microRNA-gene relations from biomedical literature using distant supervision.
Many biomedical relation extraction approaches are based on supervised machine learning, requiring an annotated corpus. Distant supervision aims at training a classifier by combining a knowledge base with a corpus, reducing the amount of manual effort necessary. This is particularly useful for biomedicine because many databases and ontologies have been made available for many biological processes, while the availability of annotated corpora is still limited. We studied the extraction of microRNA-gene relations from text. MicroRNA regulation is an important biological process due to its close association with human diseases. The proposed method, IBRel, is based on distantly supervised multi-instance learning. We evaluated IBRel on three datasets, and the results were compared with a co-occurrence approach as well as a supervised machine learning algorithm. While supervised learning outperformed on two of those datasets, IBRel obtained an F-score 28.3 percentage points higher on the dataset for which there was no training set developed specifically. To demonstrate the applicability of IBRel, we used it to extract 27 miRNA-gene relations from recently published papers about cystic fibrosis. Our results demonstrate that our method can be successfully used to extract relations from literature about a biological process without an annotated corpus. The source code and data used in this study are available at https://github.com/AndreLamurias/IBRel.


Predicting multiplanar cervical spine injury due to head-turned rear impacts using IV-NIC.
Intervertebral Neck Injury Criterion (IV-NIC) hypothesizes that dynamic three-dimensional intervertebral motion beyond physiological limit may cause multiplanar soft-tissue injury. Present goals, using biofidelic whole human cervical spine model with muscle force replication and surrogate head in head-turned rear impacts, were to: (1) correlate IV-NIC with multiplanar injury, (2) determine IV-NIC injury threshold at each intervertebral level, and (3) determine time and mode of dynamic intervertebral motion that caused injury. Impacts were simulated at 3.5, 5, 6.5, and 8 g horizontal accelerations of T1 vertebra (n = 6; average age: 80.2 years; four male, two female donors). IV-NIC was defined at each intervertebral level and in each motion plane as dynamic intervertebral rotation divided by physiological limit. Three-plane pre- and post-impact flexibility testing measured soft-tissue injury; that is significant increase in neutral zone (NZ) or range of motion (RoM) at any intervertebral level, above baseline. IV-NIC injury threshold was average IV-NIC peak at injury onset. IV-NIC extension peaks correlated best with multiplanar injuries (P < 0.001): extension RoM (R = 0.55) and NZ (R = 0.42), total axial rotation RoM (R = 0.42) and NZ (R = 0.41), and total lateral bending NZ (R = 0.39). IV-NIC injury thresholds ranged between 1.1 at C0-C1 and C3-C4 to 2.9 at C7-T1. IV-NIC injury threshold times were attained between 83.4 and 150.1 ms following impact. Correlation between IV-NIC and multiplanar injuries demonstrated that three-plane intervertebral instability was primarily caused by dynamic extension beyond the physiological limit during head-turned rear impacts.


Spectroscopy of the OC-HF hydrogen-bonded complex at vHF=3.
The v(HF)=3 levels of the linear OC-HF complex are observed in the range of 10,800-11,500 cm(-1) using intracavity Ti-sapphire laser-induced fluorescence. The vibrational predissociation linewidths of both (30000) and (3001(1)0) states exceed 5 GHz; thus, the measured spectra are not rotationally resolvable. Under the assumption that these levels are not strongly perturbed, the rotational constants of the two levels are determined to be 0.1100(1) cm(-1) for (30000), 0.1081(1), and 0.1065(1) cm(-1) for f and e sublevels of (3001(1)0), respectively, through band contour fitting. The (30000)<--(00000) band origin is at 10,894.46(1) cm(-1), showing a HF wave number redshift of 478.3 cm(-1). The 4.07 redshift ratio of v(HF)=3 to that of v(HF)=1 indicates a significantly nonlinear increase of the intermolecular interaction energy through HF valence excitation. An ab initio interaction potential surface for HF valence coordinates varying from 0.8 to 1.25 A is used to examine vibrational dynamics. The HF valence vibration v(1) is treated perturbatively, showing that the vibrational redshifts are determined essentially in first order with only a very small second-order contribution. The (3001(1)0)<--(00000) combination transition is observed with the band origin at 11,432.66(1) cm(-1), giving the HF intermolecular bending mode to be 538.2 cm(-1). The high frequency of this vibration, compared to that in similar HF complexes, shows the strong angular anisotropy of the intermolecular interaction potential of OC-HF with respect to the HF subunit. The lifetime of the (3001(1)0) level increases to 28 ps from 14 ps for (30000).


Influence of pontic material on alveolar mucosal conditions.
The purpose of the present study was to investigate plaque accumulation and inflammatory changes in the mucosa beneath fixed bridge pontics of various materials, in patients cleaning the infrapontic space daily. Fixed bridges with a tight but non-compressive contact to the mucosa in the pontic area and with interchangeable test specimens placed in the pontic base were constructed for five patients. During 4-wk periods the following materials were tested: alloys with a high or a low gold content, silver-palladium, cobalt-chromium, nickel-chromium and also a dental porcelain or a composite restorative resin. Between the test periods a "sanitary pontic" was used to enable recovery of the alveolar mucosa. Clinical examinations including exudate measurements demonstrated that the alveolar mucosa remained healthy irrespective of the material used when the dental floss was used regularly. The amount of plaque on the test specimens of the seven dental materials showed no consistent differences. The composition of the bacterial deposits showed no regular pattern. This investigation has demonstrated that patients maintaining a high standard of oral hygiene are able to prevent the development of inflammatory changes in the alveolar mucosa in contact with fixed bridge pontics irrespective of the pontic material used.


Communicating a Plan for Involuntary Psychiatric Admission: A Standardized Patient Workshop Intervention for General Psychiatry Residents.
One important and often difficult act of communication common in psychiatry is communication regarding the need for involuntarily commitment for psychiatric treatment. Thus, we designed an educational workshop for psychiatry residents on how to communicate the plan for involuntarily commitment to a psychiatric hospital. Using faculty expertise, we created a protocol to guide trainees on how to structure conversations around involuntary commitment. Residents first attended a didactic on the protocol, followed by a 1-hour workshop with standardized patients (SPs) 1 week later. The workshop consisted of three 14-minute simulated scenarios with the SP with debriefing. Trainees filled out pre- and postworkshop surveys. Fifteen and 12 residents completed the pre- and postworkshop surveys, respectively. Residents' perceived comfort level in their ability to deliver involuntary commitment news significantly improved after the workshop when compared to before (3.0 vs. 3.7 for pre- and postworkshop surveys, respectively). Residents trended toward intending to make more changes to their approach after the workshop when compared to before (2.2 vs. 2.6, respectively). Feedback on the didactic and workshop were largely positive. To our knowledge, our intervention is the first designed specifically to teach psychiatry residents how to communicate to patients that they are being involuntarily committed to emergent psychiatric treatment. This educational model has potential for improving resident skills and confidence in having difficult conversations around involuntary commitment.


Adverse impact of intermittent portal clamping on long-term postoperative outcomes in hepatocellular carcinoma.
Introduction To evaluate the impact of intermittent portal clamping (IPC) on long-term postoperative outcomes in patients with hepatocellular carcinoma (HCC). Methods Clinical records of 355 patients underwent curative liver resection for HCC in January 2007 to December 2010 were retrospectively reviewed. According to how portal clamping was performed, patients were grouped as: IPC, n=113; other portal clamping (OPC), n=190; and no portal clamping (NPC), n=52. Results Median recurrence-free survival (RFS) was statistically significantly shorter in the IPC (39.4 months) than OPC (47.3 months, p=0.010) and NPC groups (51.4 months, p=0.008). Median overall survival (OS) was also significantly shorter with IPC (46.3 months), versus 52.9 months with OPC (p=0.022) and 56.2 months with NPC (p=0.015). Kaplan-Meier survival analysis revealed that 5-year cumulative RFS was much lower in the IPC (42.5%) than OPC (50.9%, p=0.014) and NPC groups (49.6%, p=0.013). Five-year cumulative OS was also much lower in the IPC (44.9%) than OPC (58.0%, p=0.020) and NPC groups (57.7%, p=0.025). On univariate analysis, tumour grade, size and number, TNM stage, blood transfusion, vascular invasion and IPC were significantly inversely correlated with RFS and OS. On multivariate analysis, tumour size and number, blood transfusion, vascular invasion and IPC remained significant. Conclusions Our study suggests that IPC is an independent risk factor for poor long-term postoperative outcomes in patients with HCC.


Strength and Power Correlates of Throwing Velocity on Subelite Male Cricket Players.
Throwing velocity is an important aspect of fielding in cricket to affect run-outs and reduce the opponent's run-scoring opportunities. Although a relationship between strength and/or power and throwing velocity has been well established in baseball, water polo, and European handball, it has not been adequately explored in cricket. Consequently, this study aimed to determine the relationship between measures of strength and/or power and throwing velocity in cricket players. Seventeen male cricket players (mean ± SD; age, 21.1 ± 1.6 years; height, 1.79 ± 0.06 m; weight, 79.8 ± 6.4 kg) from an elite athlete program were tested for maximal throwing velocity from the stretch position and after a 3-meter shuffle. They were also assessed for strength and power using a range of different measures. Throwing velocity from the stretch position (30.5 ± 2.4 m·s) was significantly related to dominant leg lateral-to-medial jump (LMJ) distance (r = 0.71; p < 0.01), dominant shoulder internal rotation (IR) strength (r = 0.55; p ≤ 0.05), and dominant (r = 0.73; p < 0.01) and nondominant (r = 0.54; p ≤ 0.05) medicine ball rotation (MB Rot) throw velocity and medicine ball chest pass (MB CP) distance (r = 0.67; p < 0.01). A nonsignificant trend was observed for vertical jump (VJ) height (p = 0.06), whereas no significant relationships were observed for nondominant LMJ distance (p = 0.97), nondominant shoulder IR strength (p = 0.80), 1 repetition maximum (RM) squat strength (p = 0.57), 1RM bench press strength (p = 0.90), height (p = 0.33), or weight (p = 0.29). Multiple regression analysis revealed that dominant MB Rot and MB CP explained 66% of the variance. The results were similar for velocity after a shuffle step (31.8 ± 2.1 m·s); however, VJ height reached statistical significance (r = 0.51; p ≤ 0.05). The multiple regression was also similar with MB Rot and MB CP explaining 70% of the variance. The cricketers in this study threw with greater velocity than elite junior and subelite senior cricketers but with lower velocities than elite senior cricketers and collegiate level and professional baseball players. This is the first study to demonstrate a link between strength and/or power and throwing velocity in cricket players and highlight the importance of power development as it relates to throwing velocity. Exercises that more closely simulated the speed (body weight jumps and medicine ball throws) or movement pattern (shoulder IR) of overhead throwing were greater predictors of throwing velocity. Strength and conditioning staff should assess and develop power to enhance throwing performance in cricket players. Exercises with greater movement and speed specificity to throwing should be used in preference over exercises that are slower and have less movement specificity to the throwing motion. Cricket players should engage in power training to bridge the gap in performance between them and baseball players.


ABL kinase inhibition promotes lung regeneration through expansion of an SCGB1A1+ SPC+ cell population following bacterial pneumonia.
Current therapeutic interventions for the treatment of respiratory infections are hampered by the evolution of multidrug resistance in pathogens as well as the lack of effective cellular targets. Despite the identification of multiple region-specific lung progenitor cells, the identity of molecules that might be therapeutically targeted in response to infections to promote activation of progenitor cell types remains elusive. Here, we report that loss of Abl1 specifically in SCGB1A1-expressing cells leads to a significant increase in the proliferation and differentiation of bronchiolar epithelial cells, resulting in dramatic expansion of an SCGB1A1+ airway cell population that coexpresses SPC, a marker for type II alveolar cells that promotes alveolar regeneration following bacterial pneumonia. Furthermore, treatment with an Abl-specific allosteric inhibitor enhanced regeneration of the alveolar epithelium and promoted accelerated recovery of mice following pneumonia. These data reveal a potential actionable target that may be exploited for efficient recovery after pathogen-induced infections.


Picroside II Shows Protective Functions for Severe Acute Pancreatitis in Rats by Preventing NF-κB-Dependent Autophagy.
Picroside II, from the herb Picrorhiza scrophulariiflora Pennell, has antioxidant and anti-inflammatory activities. However, its function on severe acute pancreatitis (SAP) and molecular mechanism remains unknown. The effects of picroside II on the SAP induced by cerulean were investigated. SAP rats were treated with picroside II (25 mg/kg). The severity of SAP was evaluated by using biochemical and histological analyses. Pancreatic cancer cell PANC-1 was transfected with ptfLC3 (an indicator of autophagic activity), pcDNA3.1-NF-κB (nuclear factor kappa B), and pTZU6+1-NF-κB-shRNA and then treated with picroside II. Relative molecules related with NF-κB-dependent autophagy were detected by using Western blot. Autophagic activities were observed by phase-contrast and fluorescent microscopes. Acetylated LC3 was detected by immunoprecipitation. The results showed that picroside II treatment reduced the level of ALT, AST, NF-κB, IL-1β, IL-6, TNF-α, and SIRT1 (NAD+-dependent deacetylase) and increased the level of SOD and GSH. The autophagic activity was reduced when NF-κB was silenced, and the levels of TNF-α and SIRT1 were reduced. In contrast, the overexpression of NF-κB increased autophagic activity and the level of TNF-α, which activated SIRT1. SIRT1 deacetylated LC3 and increased autophagic activities. Picroside II ameliorates SAP by improving antioxidant and anti-inflammtory activities of SAP models via NF-κB-dependent autophagy.


Effects of concurrent therapy with policosanol and omega-3 fatty acids on lipid profile and platelet aggregation in rabbits.
Policosanol is a mixture of high-molecular-weight aliphatic primary alcohols isolated from sugarcane wax with cholesterol-lowering and antiplatelet effects. Omega-3 fatty acids (FA) from fish oil can protect against coronary disease. An antiarrhythmic mechanism is emerging as the most convincing explanation for omega-3 FA cardiovascular protection, but triglyceride (TG)-lowering effects and inhibition of platelet function could play a role. In view of the effects of policosanol and omega-3 FA on lipid profile and platelet function, potential benefits of combined therapy were expected. To investigate whether combined therapy with policosanol and omega-3 FA would offer some benefit, compared with policosanol or omega-3 FA alone, on serum lipid profile and platelet aggregation in rabbits. Male rabbits were randomly distributed in four groups (n = 9 per group). A control group received vehicle, one group was treated with policosanol 5 mg/kg and one with omega-3 FA (eicosapentaenoic acid; EPA [47.0%], docosahexaenoic acid; DHEA [41%]) 250 mg/kg, and the fourth received policosanol 5 mg/kg + omega-3 FA 250 mg/kg. Treatments were orally administered for 60 days. Bodyweight, food consumption and animal behaviour were performed at baseline and study completion. Policosanol significantly lowered low-density lipoprotein cholesterol (LDL-C) [42.7%; p < 0.01] and total cholesterol (TC) [29.4%; p < 0.05], increased high-density lipoprotein (HDL-C) [15.4%; p < 0.05], but left TG levels unchanged. Omega-3 FA significantly lowered TG (47.1%; p < 0.05), but left TC, LDL-C and HDL-C unchanged. Combined therapy decreased LDL-C (38.7%; p < 0.05). Changes in TC, LDL-C and HDL-C obtained with combined therapy were greater (p < 0.05) than those with omega-3 FA, but similar to those with policosanol, whereas the opposite applied to TG reduction. No significant changes in lipid profile were observed in the control group. Policosanol and omega-3 FA significantly (p < 0.05) but moderately inhibited platelet aggregation induced with arachidonic acid (13.3% and 12.4%, respectively); combined therapy achieved greater inhibition (23.9%; p < 0.05). All groups showed similar food consumption and bodyweight gain. No toxic signs were observed in any animal. Concurrent therapy with policosanol 5 m/kg and omega-3 FA 250 mg/kg lowered LDL-C, TC and TG and increased HDL-C. All treatments inhibited platelet aggregation, but better effects were observed with policosanol + omega-3 FA compared with either treatment alone. Combined therapy was well tolerated. These results suggest that treatment with policosanol + omega-3 FA could be useful for regulating lipid profile and inhibiting platelet aggregation, but conclusive demonstration of such effects requires further experimental and clinical studies.


Myelitis associated with influenza A virus infection.
We report a patient presenting with myelitis after respiratory symptoms. A high level of antibodies to influenza A virus was measured in serum and cerebrospinal fluid (CSF), and the serum/CSF antibody ratio was 1.7, suggesting specific antibody production in the central nervous system. Magnetic resonance imaging of the spinal canal showed a contrast-enhanced swelling on the cervical medulla. Such a case would have warranted the use of antiviral therapy and calls to mind the neurotropic potential of influenza A viruses.


Pathogenesis of disseminated intravascular coagulation in sepsis.
To review new insights in the pathogenetic mechanisms involved in the development of disseminated intravascular coagulation (DIC) in septic patients, in order to develop new directions for therapeutic intervention. Articles and published peer-reviewed abstracts on the mechanism of the initiation of DIC in sepsis. Studies selected for detailed review were those reporting specifics about the mechanism of activation of coagulation and fibrinolysis in experimental human and animal models of sepsis. Data extraction guidelines for assessing data quality included validity of the model, quality of the laboratory assessment of activation of coagulation and fibrinolysis, and methodological considerations, such as the presence of control experiments and statistical analysis. After the presence of endotoxin in the circulation, significant coagulation activation can be detected. This activation is preceded by an increase in the serum levels of various cytokines, such as tumor necrosis factor and interleukins. Inhibition of the increase in tumor necrosis factor results in inhibition of coagulation activation. Measurement of molecular markers for the activation of coagulation proteins at various levels indicates that the activation of coagulation is mediated by the tissue factor-dependent pathway, which is further confirmed by experiments in which the inhibition of the tissue factor-dependent pathway resulted in complete inhibition of coagulation activation. The activation of coagulation seems to be amplified by impaired function of the protein C-protein S inhibitory pathway. An imbalance between coagulation and fibrinolysis, ultimately leading to plasminogen activator inhibitor type 1-mediated inhibition of fibrinolysis, may further promote the procoagulant state. The increased knowledge of the various pathogenetic mechanisms of coagulation activation and fibrinolysis in sepsis may have therapeutic implications; however, their efficacy needs to be assessed in appropriate clinical trials.


The Colours of Octopus: Using Spectral Data to Measure Octopus Camouflage.
No animal can so effectively camouflage in such a wide range of environments as the octopus. Thanks to their highly malleable skin, they are capable of adapting their body patterns to the brightness and texture of their immediate environment, and they often seemingly match the colour of background objects. However, octopuses are colour-blind as their eyes have only one type of visual pigment. Therefore, chromatophores in their skin are likely to respond to changes in brightness, not chromaticity. To determine whether octopuses actually match background colours, we used a SpectraScan® PR-655 spectroradiometer to measure the reflectance spectra of Octopus tetricus skin in captivity. The spectra were compared with those of green algae, brown algae, and sponges-all of these being colourful objects commonly found in the octopus's natural environment. Even though we show that octopuses change both lightness and chromaticity, allowing them to potentially camouflage in a wide range of backgrounds in an effective manner, the overall octopus colours did not reach the same level of saturation compared to some background objects. Spectra were then modelled under the visual systems of four potential octopus predators: one dichromatic fish (Heller's barracuda), two trichromatic fish (blue-spotted stingray and two-spotted red snapper), and one tetrachromatic bird (wedge-tailed shearwater). We show that octopuses are able to match certain background colours for some visual systems. How a colour-blind animal is capable of colour-matching is still unknown.


Assessment of dietary intake among university students: 24-hour recall verses weighed record method.
The purpose of this study was to assess the dietary intake of University Putra Malaysia students using the weighed record method and the 24 hour-dietary recall method. The validity of the 24-hour recall method was studied by comparing it with the weighed record method. A total of 40 male and 25 female students age between 18-29 years volunteered to participate in this study. All the subjects were required to weigh and record the foods they ate for 1 day. Without prior knowledge of the purpose of the visit , the 24-hour recall was carried out the following day. The nutrients analysed were calorie, carbohydrates, protein, fat, calcium, iron, vitamin A and vitamin C. Comparisons of the nutrient intake between these two methods were determined. The paired t-test indicated no significant difference in group's mean nutrient intake between the weighed record method for all nutrients. The differences in group mean intake for all nutrients between weighed record and 24-hour recall method ranged from -3% to 3.6%. A total of 4 nutrients were underestimated, namely energy, protein, vitamin C and iron. The correlation coefficients showed a strong positive relationships between the two methods (ranged from r = 0.88-0.98, p < 0.01) for all of the nutrients analysed. In conclusion, the agreement between nutrient values from two different methods indicated that the 24 hour recall is a suitable method for the dietary assessment of university students.


Personality, Resilience, and Calling in Students Undertaking a Medical Degree Across Two Continents: Disparate Pathways to the Healing Profession.
Background: An educational partnership between The University of Queensland (UQ) in Australia and Ochsner Health in the United States developed the UQ-Ochsner medical program that trains American citizens to practice medicine in the United States. This program provides the opportunity to explore and compare the personal characteristics of UQ-Ochsner students with their domestic (Australian citizen) and international classmates not enrolled in the Ochsner program. Findings may offer some insights into the types of students who choose to study medicine across multiple countries. Methods: We used a quantitative cross-sectional design for our study. A first-year cohort of domestic, international, and UQ-Ochsner students completed a survey comprising demographic questions and measures of temperament and character personality, resilience, and calling to medicine. Univariate statistics were used to compare groups for all variables. Results: The whole sample response rate was 72.1% (375/520). Domestic students represented the greatest proportion of students <25 years, and UQ-Ochsner students represented the greatest proportion of students of ≥26 years. Gender did not differ significantly between groups. The majority first degree for all students was science, although 23% of UQ-Ochsner students reported arts/law/humanities degrees. In comparison to all other students (domestic and international combined), UQ-Ochsner students scored significantly lower in levels of harm avoidance (P=0.039) and higher in self-directedness and self-transcendence, resilience, and calling with medium to strong effect sizes (d>0.3). Conclusion: UQ-Ochsner students have a personality profile similar to their classmates but with levels of certain traits-higher self-directedness and lower harm avoidance-that in combination contribute to higher resilience and a strong sense of calling to medicine. Being slightly older may allow for more development of self-directedness, but low harm avoidance suggests an innate degree of confidence in and acceptance of risk to achieving goals.


Efficacy and safety of autologous adipose tissue-derived stem cell therapy for children with refractory Crohn's complex fistula: a Phase IV clinical study.
Autologous adipose tissue-derived stem cells (ASCs) have been proposed for patients with refractory Crohn disease, but research is lacking in pediatric patients. This Phase IV study evaluated the efficacy and safety of ASCs in children with refractory Crohn's fistulae. Patients with a refractory Crohn's fistula who did not have conventional therapy for more than 3 months or with a recurrent complex Crohn's fistula were included. All patients were at least 14 years old. Patients with infection, poor condition, or active Crohn disease with a disease activity index of 450 and above were excluded. Five patients were treated with ASCs from 2014 to 2015 in Asan Medical Center. ASC administration was adjusted according to fistula size (1 mL per cm2). We evaluated the efficacy and safety 8 weeks after injection and followed patients for 6 months. Fistulae were healed in 4 patients by 8 weeks after ASC injection. Of these 4 patients, 1 had complete fistula closure and sustainability after 6 months. The other 3 with healing effects had less than 50% fistula closure by 6 months. None of these 4 patients have persistent fistulae. One patient had no healing effect, and seton ligation was performed 8 months after ASC injection. There were no adverse effects related to ASC administration. ASC therapy is a simple and well-tolerated therapeutic option for children with refractory Crohn's complex fistulae. Complete closure was well-sustained. However, more data from a larger number of patients are needed.


Rifampin inhibition of bacteriophage phiX174 parental replicative-form DNA synthesis in an Escherichia coli dnaC mutant.
The Escherichia coli dnaC protein is not absolutely required in vivo for bacteriophage phiX174 parental replicative-form synthesis (Kranias and Dumas, 1974). However, when rifampin is present at a concentration that inhibits DNA-dependent RNA polymerase, phiX174 parental replicative-form synthesis is dependent on the dnaC protein activity. We conclude that E. coli DNA-dependent RNA polymerase can substitute for the dnaC protein in phiX174 parental replicative-form DNA synthesis, presumably in its initiation. The implications of this result with respect to the in vitro synthesis of the complementary strand of phiX174 DNA are discussed.


Cremimycin, a novel 19-membered macrocyclic lactam antibiotic, from Streptomyces sp.
A novel 19-membered macrocyclic lactam antibiotic, cremimycin, was isolated from the culture broth of an actinomycete strain. The producing organism, designated MJ635-86F5, was identified as a member of Streptomyces. Cremimycin was isolated from the mycelial cake by extraction with CHCl3-MeOH and precipitation with hexane-MeOH. The structure of cremimycin was determined by spectroscopic study. Cremimycin showed broad antimicrobial activities against Gram-positive bacteria including MRSA.


Expression and trafficking of placental microRNAs at the feto-maternal interface.
During pregnancy, placental trophoblasts at the feto-maternal interface produce a broad repertoire of microRNA (miRNA) species. These species include miRNA from the primate-specific chromosome 19 miRNA cluster (C19MC), which is expressed nearly exclusively in the placenta. Trafficking of these miRNAs among the maternal, placental, and fetal compartments is unknown. To determine miRNA expression and trafficking patterns during pregnancy, we sequenced miRNAs in triads of human placenta and of maternal and fetal blood and found large subject-to-subject variability, with C19MC exhibiting compartment-specific expression. We therefore created humanized mice that transgenically express the entire 160-kb human C19MC locus or lentivirally express C19MC miRNA members selectively in the placenta. C19MC transgenic mice expressed a low level of C19MC miRNAs in diverse organs. When pregnant, female C19MC mice exhibited a strikingly elevated (>40-fold) expression of C19MC miRNA in the placenta, compared with other organs, that resembled C19MC miRNAs patterns in humans. Our mouse models showed that placental miRNA traffic primarily to the maternal circulation and that maternal miRNA can traffic to the placenta and even into the fetal compartment. These findings define an extraordinary means of nonhormonal, miRNA-based communication between the placenta and feto-maternal compartments.-Chang, G., Mouillet, J.-F., Mishima, T., Chu, T., Sadovsky, E., Coyne, C. B., Parks, W. T., Surti, U., Sadovsky, Y. Expression and trafficking of placental microRNAs at the feto-maternal interface.


Unusual magnetic properties of mixed-valence system: multiconfigurational method theoretical study on Mn2+ cation.
The geometry structure, dissociation energy, vibrational frequencies, and low-lying spin-state energy spectrum of Mn2+ are investigated by using ab initio CASSCF/ECP10MDF, complete active space self-consistent field/atomic natural orbital basis sets (CASSCF/ANO-s), CASPT2/ECP10MDF, and second-order perturbation theory with CASSCF reference function/atomic natural orbital basis sets (CASPT2/ANO-s) levels of theory. For the ground state the dissociation energy of 1.397 eV calculated at the CASPT2/ANO-s level supports Jarrlod's experimental value of 1.39 eV. The equilibrium bond length and vibrational frequency are 2.940 A calculated at the CASPT2/ANO-s level of theory and 214.4 cm-1 calculated at the CASSCF/ANO-s level of theory, respectively. On the basis of the mixed-valence model, the Heisenberg exchange constant J(-71.2 cm-1) and the double-exchange constant B(647.7 cm-1) are extracted explicitly from the low-lying energy spectrum calculated at the higher levels of theory. The magnetic competition between the weaker Heisenberg exchange interactions and the stronger double-exchange interactions makes the ground state a 12Sigmag+ state, consistent with electron paramagnetic resonance experimental observation, which explains unusual magnetic properties of Mn2+, quite different from the antiferromagnetic ground state of Mn2 and Cr2. On the other hand, the results calculated at the higher levels of theory show the consistent antiferromagnetic Heisenberg exchange interactions between 3d-3d for Cr2, Mn2+, and Mn2.


Fairness versus efficiency: how procedural fairness concerns affect coordination.
We investigate in a laboratory experiment whether procedural fairness concerns affect how well individuals are able to solve a coordination problem in a two-player Volunteer's Dilemma. Subjects receive external action recommendations, either to volunteer or to abstain from it, in order to facilitate coordination and improve efficiency. We manipulate the fairness of the recommendation procedure by varying the probabilities of receiving the disadvantageous recommendation to volunteer between players. We find evidence that while recommendations improve overall efficiency regardless of their implications for expected payoffs, there are behavioural asymmetries depending on the recommendation: advantageous recommendations are followed less frequently than disadvantageous ones and beliefs about others' actions are more pessimistic in the treatment with recommendations inducing unequal expected payoffs.


Analysis of SAW properties in ZnO/AlxGa1-xN/c-Al2O3 structures.
Piezoelectric thin films on high acoustic velocity nonpiezoelectric substrates, such as ZnO, AlN, or GaN deposited on diamond or sapphire substrates, are attractive for high frequency and low-loss surface acoustic wave devices. In this work, ZnO films are deposited on AlxGa1-xN/c-Al2O3 (0 < or = chi < or = 1) substrates using the radio frequency (RF) sputtering technique. In comparison with a single AlxGa1-xN layer deposited on c-Al2O3 with the same total film thickness, a ZnO/AlxGa1-xN/c-Al2O3 multilayer structure provides several advantages, including higher order wave modes with higher velocity and larger electromechanical coupling coefficient (K2). The surface acoustic wave (SAW) velocities and coupling coefficients of the ZnO/AlxGa1-xN/c-Al2O3 structure are tailored as a function of the Al mole percentage in AlxGa1-xN films, and as a function of the ZnO (h1) to AlxGa1-xN (h2) thickness ratio. It is found that a wide thickness-frequency product (hf) region in which coupling is close to its maximum value, K(2)max, can be obtained. The K(2)max of the second order wave mode (h1 = h2) is estimated to be 4.3% for ZnO/GaN/c-Al2O3, and 3.8% for ZnO/AlN/c-Al2O3. The bandwidth of second and third order wave modes, in which the coupling coefficient is within +/- 0.3% of K(2)max, is calculated to be 820 hf for ZnO/GaN/c-Al2O3, and 3620 hf for ZnO/AlN/c-Al2O3. Thus, the hf region in which the coupling coefficient is close to the maximum value broadens with increasing Al content, while K(2)max decreases slightly. When the thickness ratio of AlN to ZnO increases, the K(2)max and hf bandwidth of the second and third higher wave modes increases. The SAW test devices are fabricated and tested. The theoretical and experimental results of velocity dispersion in the ZnO/AlxGa1-xN/c-Al2O3 structures are found to be well matched.


The Effect of Clopidogrel on the Response to Ischemia Reperfusion.
Reperfusion in the setting of acute ischemia is essential in limiting tissue necrosis. However, reperfusion itself is associated with significant adverse effects. There is animal evidence that platelets play a role in the adverse effects of ischemia and reperfusion (IR) injury. We examined whether clopidogrel would have favorable effects on endothelial dysfunction induced by an episode of IR. Using a parallel design, we administered clopidogrel 600 mg or matching placebo to normal volunteers (n = 20) 24 hours before an episode of IR. Flow-mediated dilatation (FMD, radial artery) was assessed before and after 20 minutes of upper arm ischemia. Following IR, there was a highly significant decrease in FMD in the placebo group (7.6% ± 1.3% vs 3.4% ± 0.1%; P < .001). In the clopidogrel group, there was no change in FMD post-IR (8.3% ± 0.8% vs 7.1% ± 1.2%; P = not significant). Following IR, FMD in the placebo group was significantly smaller than that observed in the clopidogrel group ( P < .01). Ischemia and reperfusion caused no change in plasma levels of biomarkers of inflammation (intercellular adhesion molecule 1, chemokine ligand 5, and interleukin 6) in either group. Therefore, a single dose of clopidogrel given 24 hours prior to an episode of IR had protective effects, limiting the adverse effects of ischemia on endothelial function.


Duration of lactational amenorrhoea: a hospital based survey in district Abbottabad.
The study was carried out to investigate the duration of lactational amenorrhoea in women of district Abbottabad. The objective of this survey was to determine the duration of lactational amenorrhoea in female population of district Abbottabad, NWFP, Pakistan. A survey was conducted at Ayub Teaching Hospital from June to August 2006 by selecting admitted females and their attendants at random and subjecting them to questionnaires and interviews to collect relevant data. Majority of the sampled females belonged to different districts of Hazara division. Fifty nine (59) mothers of parity 1-5 were included in the study. The frequency of breast feeding ranged from 60.0% to 100% (mean 66.1%) in different pregnancies; bottle feeding frequencies ranged from 10-12.5% (mean 6.8%); frequencies of combined breast and bottle feeding ranged from 25-30% (mean 27.1%). The mean duration of lactational amenorrhoea for different pregnancies ranged from 6.0 +/- 0.0 weeks to 22.6 +/- 25.1 weeks (overall mean 15.8 +/- 15.2 weeks). Weaning times ranged from 2 to 12 months, with the mean weaning time ranging from 4.8 +/- 1.5 to 5.1 +/- 1.8 months (overall mean 4.8 +/- 1.1 months). Maternal hormonal cycles appear to be more involved in regulating the post partum amenorrhea observed in lactating mothers.


Purification and characterization of a novel sialidase from a strain of Arthrobacter nicotianae.
The nonpathogenic strain Arthrobacter nicotianae produces two sialidase isoenzymes, NA1 and NA2, with molecular masses of 65 kDa and 54 kDa, respectively, as determined by 10% SDS-polyacrylamide gel electrophoresis. NA1 and NA2 exhibit maximum activities at pH 4 and 5, and both show clear thermal optima at 40 degrees C. They are stable at temperatures up to 50 degrees C. The critical temperatures (T (c) = 50 degrees C and 51 degrees C) for the two isoenzymes were determined by fluorescence spectroscopy and correlate well with the temperatures of melting (T (m) = 49 degrees C and 48 degrees C), determined by CD spectroscopy. The isoenzymes are less stable against denaturation with Gdn.HCl, and the free energy of stabilization in water was calculated to be 7.6 and 8.0 kJ mol(-1), respectively. The specific activity (K (m) value) toward glucomacropeptide as a substrate was calculated to be 0.126 mM for NA1 and 0.083 mM for NA2.


Intracellular Ca2+ stores control in vivo neuronal hyperactivity in a mouse model of Alzheimer's disease.
Neuronal hyperactivity is the emerging functional hallmark of Alzheimer's disease (AD) in both humans and different mouse models, mediating an impairment of memory and cognition. The mechanisms underlying neuronal hyperactivity remain, however, elusive. In vivo Ca2+ imaging of somatic, dendritic, and axonal activity patterns of cortical neurons revealed that both healthy aging and AD-related mutations augment neuronal hyperactivity. The AD-related enhancement occurred even without amyloid deposition and neuroinflammation, mainly due to presenilin-mediated dysfunction of intracellular Ca2+ stores in presynaptic boutons, likely causing more frequent activation of synaptic NMDA receptors. In mutant but not wild-type mice, store emptying reduced both the frequency and amplitude of presynaptic Ca2+ transients and, most importantly, normalized neuronal network activity. Postsynaptically, the store dysfunction was minor and largely restricted to hyperactive cells. These findings identify presynaptic Ca2+ stores as a key element controlling AD-related neuronal hyperactivity and as a target for disease-modifying treatments.


Endoscopy: consensus on approving propofol sedation by nonanesthesiologists.
Propofol sedation by nonanesthesiologists is still a highly controversial issue despite the fact that numerous studies have approved this sedation regimen for gastrointestinal endoscopy. A new position statement from a collaboration of four different American gastroenterology and hepatology societies outlines the latest recommendations for nonanesthesiologist administration of propofol.


On target: Rational approaches to KRAS inhibition for treatment of non-small cell lung carcinoma.
Non-small cell lung carcinoma (NSCLC) is a leading cause of cancer death. Approximately one-third of patients with NSCLC have a KRAS mutation. KRASG12C, the most common mutation, is found in ~13% of patients. While KRAS was long considered 'undruggable', several novel direct KRASG12C inhibitors have shown encouraging signs of efficacy in phase I/II trials and one of these (sotorasib) has recently been approved by the US Food and Drug Administration. This review examines the role of KRAS mutations in NSCLC and the challenges in targeting KRAS. Based on specific KRAS biology, it reports exciting progress, exploring the use of novel direct KRAS inhibitors as monotherapy or in combination with other targeted therapies, chemotherapy, and immunotherapy.


Germ line-inherited H3K27me3 restricts enhancer function during maternal-to-zygotic transition.
Gametes carry parental genetic material to the next generation. Stress-induced epigenetic changes in the germ line can be inherited and can have a profound impact on offspring development. However, the molecular mechanisms and consequences of transgenerational epigenetic inheritance are poorly understood. We found that Drosophila oocytes transmit the repressive histone mark H3K27me3 to their offspring. Maternal contribution of the histone methyltransferase Enhancer of zeste, the enzymatic component of Polycomb repressive complex 2, is required for active propagation of H3K27me3 during early embryogenesis. H3K27me3 in the early embryo prevents aberrant accumulation of the active histone mark H3K27ac at regulatory regions and precocious activation of lineage-specific genes at zygotic genome activation. Disruption of the germ line-inherited Polycomb epigenetic memory causes embryonic lethality that cannot be rescued by late zygotic reestablishment of H3K27me3. Thus, maternally inherited H3K27me3, propagated in the early embryo, regulates the activation of enhancers and lineage-specific genes during development.


[Seed and harvest - German psychiatry and psychology in Perú].
The influence of German psychiatry and German psychology in Perú was very strong in the beginning of the 20(th) Century. This is not well-known either in Germany or even in Perú or seems to be forgotten. The basis of it was the influence of German philosophy of the 19(th) and 20(th) centuries. A review is being given of the work of those that we consider to have been the pioneers of the German thought in these disciplines in Perú: Juan (Giovanni) Copello, Hermilio Valdizán (1885 - 1929), Dora Mayer (1868 - 1959), Enrique Encinas (1895 - 1971), Pedro Zulen (1889 - 1925), Honorio Delgado (1892 - 1967), Walter Blumenfeld (1882 - 1967), and some of their pupils. Without these it would not have been possible to advance in the knowledge, neither would it had been possible to set the basis for a national psychology and psychiatry. Due to the development of the American theories that cropped up in the fifties and invaded the theoretical field as much as the practical one in both, psychology and psychiatry, this era has come to an end. These latter theories now prevail in the current university teaching. The "indigenous" sources, which helped to develop the psychological thought in the country were left aside, but are still very vivid in the discussions of international ethnopsychology and ethnopsychiatry.


Regulation by testosterone and serum protein of DNA synthesis in the developing epididymis of the rat.
Rates of DNA synthesis were measured as an index of cellular proliferation during the pubertal development of the rat epididymis. A highly reproducible pattern of DNA synthesis was defined by (1) a prepubertal, testosterone-insensitive peak of DNA synthesis at 25 days; (2) a dramatic decrease in DNA synthesis with the onset of puberty; (3) a major burst of testosterone-dependent synthesis peaking at 40 days in the head of the epididymis and at 40-60 days in the tail; (4) a fall to low levels as the adult organ weight was attained. An organ culture system was defined and utilized to analyse further the hormonal dependence of DNA synthesis in the epididymis. Testosterone and dihydrotestosterone failed to activate DNA synthesis at any stage of development in vitro. DNA synthesis was stimulated 100-300% by insulin at supra-physiological concentrations and by protein serum factor(s) at physiological concentrations. The serum activity was stable to heat treatment at 60 degrees C, destroyed by heating at 70 degrees C, and was present in the sera of hypophysectomized animals. These results indicate a primarily 'permissive' role for the action of testerone on DNA synthesis in the epididymis: testosterone acts to permit the expression of a developmental 'programme' of cell proliferation which is activated by specific protein(s) in serum.


Description of the advertisement calls of four species of Amazophrynella (Anura:Bufonidae).
Amazophrynella comprises 11 small bufonid species with a pan-Amazonian distribution (Fouquet et al. 2012a, b; Rojas et al. 2016, Rojas et al. 2018). All species inhabit the forest leaf litter, breed in seasonal puddles and are diurnally and nocturnally active (Fouquet et al. 2012b; Rojas et al. 2014; 2015; 2016). Until now only one nominal species, A. javierbustamantei, and two putative lineages-A. moisesii (Rio Yuyapichis, Peru) and A. siona (Santa Cecilia, Ecuador)-had their advertisement calls formally described (Duellman 1978; Schlüter 1981; Rojas et al. 2016). Herein, we described for the first time the advertisement calls from additional four species of Amazophrynella.


Interrelationships of Dictyocaulus spp. in Wild Ruminants with Morphological Description of Dictyocaulus cervi n. sp. (Nematoda: Trichostrongyloidea) from Red Deer, Cervus elaphus.
Lungworms from the genus Dictyocaulus cause parasitic bronchitis (dictyocaulosis) characterized by coughing and severe lung pathology in both domestic and wild ruminants. In this study we investigated the interrelationships of Dictyocaulus spp. from European bison (Bison bonasus L.), roe deer (Capreolus capreolus), and red deer (Cervus elaphus) by nucleotide sequence analysis spanning the 18S RNA gene (small subunit [SSU]) and internal transcribed spacer 2 (ITS2) regions of the ribosomal gene array as well as the mitochondrial cytochrome c oxidase subunit 1 (cox1). Molecular analyses of sequence data obtained partly with novel primers from between 10 and 50 specimens from each host were carried out. Bayesian inference analysis revealed that each host species was infected with different genotypes. Analysis of cox1 sequence data showed a diverse genetic background and high evolutionary potential of Dictyocaulus taxa. Data from lungworms of European bison revealed a distinct genotype of Dictyocaulus viviparus, whereas Dictyocaulus capreolus was only found in roe deer. In contrast, red deer were infected with a taxon with unique SSU, ITS2, and cox1 sequences. These results indicate the occurrence of a novel genotype from red deer, which differs significantly from the National Center for Biotechnology Information reference sequence of Dictyocaulus eckerti. The molecular evidence was consistent with a morphological study with description and imaging of Dictyocaulus cervi n. sp. recovered from red deer. Dictyocaulus cervi n. sp. can be distinguished from D. eckerti on the basis of the absence of cervical papillae, the occurrence of a single ring of 4 symmetrical submedian cephalic papillae, length of the tail in females, morphometry of the female reproductive system, and measurements of gubernacula in males. In conclusion, our findings further strengthen the idea that the genetic complexity and diversity among Dictyocaulus lungworms infecting wildlife ruminants is larger than previously believed and warrants further investigation.


Phenotypic Variation in Fitness Traits of a Managed Solitary Bee, Osmia ribifloris (Hymenoptera: Megachilidae).
We investigated fitness in natural populations of a managed solitary bee Osmia ribifloris Cockerell (Hymenoptera: Megachilidae) from sites separated from 400 to 2,700 km. Parental wild bees originated in central Texas (TX), central-northern Utah (UT), and central California (CA). They were then intercrossed and raised inside a mesh enclosure in southern Mississippi (MS). Females from all possible mated pairs of O. ribifloris produced F1 broods with 30-40% female cocoons and outcrossed progeny were 30% heavier. Mitochondrial (COI) genomes of the four populations revealed three distinct clades, a TX-CA clade, a UT clade, and an MS clade, the latter (MS) representing captive progeny of CA and UT bees. Although classified as separate subspecies, TX and CA populations from 30° N to 38° N latitude shared 98% similarity in COI genomes and the greatest brood biomass per nest straw (600- to 700-mg brood). Thus, TX and CA bees show greater adaptation for southern U.S. sites. In contrast, UT-sourced bees were more distantly related to TX and CA bees and also produced ∼50% fewer brood. These results, taken together, confirm that adult O. ribifloris from all trap-nest sites are genetically compatible, but some phenotypic variation exists that could affect this species performance as a commercial blueberry pollinator. Males, their sperm, or perhaps a substance in their sperm helped stabilize our captive bee population by promoting legitimate nesting over nest usurpation. Otherwise, without insemination, 50% fewer females nested (they nested 14 d late) and 20% usurped nests, killing 33-67% of brood in affected nests.


Novel therapeutic targets for autism.
Autism spectrum disorders (ASDs) are pervasive neurodevelopmental disorders, diagnosed in early childhood when acquired skills are lost or the acquisition of new skills becomes delayed. ASDs are associated with varying degrees of dysfunctional communication and social skills, in addition to repetitive and stereotypic behaviors. The diagnosis has increased considerably to approximately one in 180 people, but it is not clear whether this is because of a higher prevalence of the disorder, improved awareness by clinicians or a combination of both. There are no defined mechanisms of pathogenesis or curative therapy presently available. Oxidative stress, overactivation of the hypothalamic-pituitary-adrenal axis and increased gut-blood-brain-barrier permeability might be involved. The scope of this article is to integrate these findings and present the opinion that non-allergic activation of gastrointestinal and brain mast cells could contribute to many of the pathologic findings and provide unique targets for ASD therapy. We make suggestions for new research directives and possible novel therapies from readily available molecules.


Noise-induced resonances in the Hindmarsh-Rose neuronal model.
The behavior of neurons under stimulation is often described by means of dynamical systems having bifurcations from fixed points to limit cycles. In these models, the presence of noise can induce irregular crossings of the bifurcation threshold leading to intrinsic oscillations of the system variables that describe the detection of the otherwise subthreshold signals by the neuron. In this paper, the response of the Hindmarsh-Rose neuronal model to noisy signals is investigated and a variety of noise-induced resonances are described.


Comparison of Pathological Outcomes for Men with Low Risk Prostate Cancer from Diverse Practice Settings: Similar Results from Immediate Prostatectomy or Initial Surveillance with Delayed Prostatectomy.
We compared pathological outcomes after radical prostatectomy for a population based sample of men with low risk prostate cancer initially on active surveillance and undergoing delayed prostatectomy vs those treated with immediate surgery in order to better understand this expectant management approach outside of the context of academic cohorts. We hypothesized that delays in surgery due to initial surveillance would not impact surgical pathological outcomes. We performed a prospective cohort study of 2 groups of patients with NCCN low risk prostate cancer from practices in the Michigan Urological Surgery Improvement Collaborative, that is 1) men who chose initial active surveillance and went on to delayed prostatectomy and 2) men who chose immediate prostatectomy. Diagnoses occurred from January 2011 through August 2015. For these 2 groups we compared radical prostatectomy Gleason scores, and rates of extraprostatic disease, positive surgical margins, seminal vesicle invasion and lymph node metastases. During a median followup of 506 days 79 (6%) of 1,359 low risk men choosing initial surveillance transitioned to prostatectomy. Compared to those treated with immediate prostatectomy (778), men undergoing delayed surgery were more likely to have Gleason score 7 or greater disease (69.2% vs 48.8%, respectively, p=0.004), but were no more likely to have positive margins, extraprostatic extension, seminal vesicle invasion or lymph node metastases. Patients with low risk prostate cancer who enter active surveillance have higher grade disease at prostatectomy compared to those undergoing immediate surgery. However, the lack of difference in other adverse pathological outcomes suggests preservation of the window of curability.


Experimentally induced alterations in periapical tissues of the cat.
Ten cats were immunized with subcutaneous injections of keyhole limpet hemocyanin (KLH). After it was determined that the experimental animals had developed circulating antibodies to KLH, challenge doses of KLH were administered via the root canal system. The radiographic and histologic findings suggest that antigen-antibody complex reactions can occur in periapical tissues of teeth, and that they can play a role in the pathogenesis of periapical lesions. In contrast, no radiographic and histologic changes were noted in non-immunized cats.


Clinical, bacteriological, and histopathological study of toxic puerperal metritis in Iraqi buffalo.
Data were collected from 42 buffalo with toxic puerperal metritis in 2 large herds, with a history of dystocia, prolapse, and retained placenta. All buffalo were subjected to detailed clinical examination including external inspection, vaginoscopy, and transrectal palpation of the cervix, uterus, and ovaries. Swabs for bacteriology and biopsies for histopathology were collected from the uterine lumen from each cow. Character, odor, and estimation of polymorphonuclear cells of the vaginal mucus were scored. Blood samples were collected from cows for creatine kinase and aspartate amino-transferase measurement. The most predisposing factor causing toxic puerperal metritis was retained placenta (52.4%), and the most prevalent bacteria in uterine lumen were Escherichia coli, Arcanobacterium pyogenes, Staphylococcus aureus, and Fusobacterium necrophorum (18.5, 16.7, 13.0, and 9.3%, respectively). High levels of polymorphonuclear cells were observed in buffalo infected with A. pyogenes and gram-negative anaerobic bacteria (62.1 and 76.4%). A high prevalence of gram-negative anaerobes was isolated from uteri harboring A. pyogenes (13.0%). Buffalo with toxic puerperal metritis had significantly higher creatine kinase and aspartate aminotransferase activities than controls (499.2 +/- 23.9 and 208.3 +/- 11.3 vs. 242.7 +/- 12.9 and 166.8 +/- 11.5 U/L, respectively). In a conclusion, gram-negative anaerobes and other facultative pathogens including A. pyogenes were important pathogens that cause severe uterine inflammation.


Medical students' perceptions of their teachers' and their own cultural competency: implications for education.
Enhancing the cultural competency of students is emerging as a key issue in medical education; however, students may perceive that they are more able to function within cross-cultural situations than their teachers, reducing the effectiveness of cultural competency educational efforts. The purpose of our study was to compare medical students' perceptions of their residents, attendings, and their own cultural competency. Cross-sectional study. A questionnaire containing previously validated instruments was administered to end-of-third-year medical students at four institutions throughout the US. Repeated measures multivariate analysis was used to determine differences in student ratings. Three hundred fifty-eight medical students from four schools participated, for an overall response rate of 65%. Analysis indicated overall statistically significant differences in students' ratings (p < 0.001, eta(2) = 0.33). Students rated their own cultural competency as statistically significantly higher than their residents, but similar to their attendings. For reference, students rated the patient care competency of themselves, their residents, and their attendings; they rated their attendings' skills as statistically significantly higher than residents, and residents as statistically significantly higher than themselves. There were differences between cultural competency and patient care ratings. Our results indicate that students perceive the cultural competency of their attendings and residents to be the same or lower than themselves. These findings indicate that this is an important area for future research and curricular reform, considering the vital role that attendings and residents play in the education of medical students.


Inclusion in physical education: a review of the literature from 1995-2005.
The purpose of the review is to critically analyze English-written research articles pertaining to inclusion of students with disabilities in physical education published in professional journals both within and outside of the United States from 1995-2005. Each study included in this review had to meet seven a priori criteria. Findings of the 38 selected studies were divided into six focus areas: (a) support, (b) affects on peers without disabilities, (c) attitudes and intentions of children without disabilities, (d) social interactions, (e) ALT-PE of students with disabilities, and (f) training and attitudes of GPE teachers. Recommendations for future practice and research are embedded throughout the article.


Vaccines for the elderly: current use and future challenges.
Age-related changes of the immune system contribute to increased incidence and severity of infections in the elderly. Vaccination is the most effective measure to prevent infections and vaccination recommendations in most countries include specific guidelines for the elderly. Vaccination against influenza and Streptococcus pneumoniae is usually recommended for persons with underlying diseases and for the elderly with heterogeneous age limits between ≥ 50 years and ≥ 65 years. Some countries also recommend vaccination against herpes zoster. Several vaccines are recommended for all adults, such as regular booster shots against tetanus/diphtheria/pertussis/polio, or for specific groups, e.g. vaccination against tick-borne encephalitis in endemic areas or travel vaccines. These are also relevant for the elderly. Most currently used vaccines are less immunogenic and effective in the elderly compared to younger adults. Potential strategies to improve their immunogenicity include higher antigen dose, alternative routes of administration, and the use of adjuvants, which were all implemented for influenza vaccines, and induce moderately higher antibody concentrations. Research on universal vaccines against influenza and S. pneumoniae is ongoing in order to overcome the limitations of the current strain-specific vaccines. Respiratory syncytial virus causes significant morbidity in the elderly. Novel vaccines against this and other pathogens, for instance bacterial nosocomial infections, have tremendous potential impact on health in old age and are intensively studied by many academic and commercial organizations. In addition to novel vaccine developments, it is crucial to increase awareness for the importance of vaccination beyond the pediatric setting, as vaccination coverage is still far from optimal for the older population.


Immunodiagnosis of meningeal leukemia using the alkaline phosphatase procedure.
To optimalize the diagnosis of meningeal involvement in ALL we adapted the alkaline-phosphatase-anti-alkaline-phosphatase procedure (APAAP) to be used for cerebrospinal fluid (CSF) examination. The study was performed on 19 patients (9 children with leukemia) with CSF hypercellularity. 490 determinations with a panel of 12 monoclonal antibodies were performed. This method was convenient, cell morphology was preserved so that combined morphological and immunological characterization of specific cells was possible in mixed cell populations. The combined study of immunological and morphological criteria produced more accurate results than those based on morphological criteria alone. The APAAP technique is useful for small numbers of cells. The preservation of antigenic reactivity in frozen CSF smears may be of use in reevaluation studies.


Thermodynamics and kinetics of intramolecular water assisted proton transfer in Na+ -1-methylcytosine water complexes.
High-level ab initio predictions of the tautomerization equilibrium and rate constants of water-assisted proton transfer of 1-methyl-cytosine (MeC) to its MeC* imino tautomeric form in the presence of up to two water molecules (W) and the Na(+) cation were carried out. The calculated energy values were used to obtain the thermodynamic parameters and equilibrium concentration of MeC, its rare tautomer, and their complexes with up to two water molecules and the Na (+) cation. The rate constants for the tautomerization were obtained by using the instanton approach (a quasiclassical method based on the least-action principle). Hydration of MeC by one water molecule leads to an increase of the concentration of the MeC* tautomer in the equilibrium mixture and a decrease of the barrier of the MeC* formation (to 15.6 kcal/mol). If the Na(+) cation is present, the tautomeric form is much less favored, and the tautomerization barrier increases to 25.2 kcal/mol. It was found that MeC monohydrate has both the highest equilibrium (2.9 x 10(-2)) and rate (7.9 x 10(5) s(-1)) constants of tautomerization in comparison to the MeC*NaW and MeC*Na2W complexes containing the Na(+) cation. Moreover, this study also allows one to estimate the concentration of MeC present in the cell during DNA synthesis as the unwanted tautomer, which in forming a mismatched base pair can cause spontaneous point mutations. Kinetic simulations have demonstrated that the low values of equilibrium (10(-14)-10(-13)) and rate constants (10(-17)-10(-16) s(-1)) of tautomerization make contribution of the MeC*Na(+)W and MeC*Na(+)2W complexes to the point mutations in DNA unlikely. In contrast to these Na(+) complexes, MeC*W can reach an equilibrium concentration of 2.9 x 10(-2) within 10(-7) s; thus, it can increase the probability of the point mutations.


Abnormal embryonic karyotype is the most frequent cause of recurrent miscarriage.
We previously found that a normal karyotype in a previous miscarriage is a predictor of subsequent miscarriage. However, the prevalence of recurrent miscarriage caused by an abnormal embryonic karyotype has not yet been reported, since embryonic karyotype is not typically analyzed during conventional examinations. A total of 482 patients who underwent both embryonic karyotype determination and conventional examinations for recurrent miscarriage were enrolled in this study. The distribution of the causes and the live birth rate for each cause were examined. The total percentage of subjects in whom conventional causes of recurrent miscarriage could be detected was 29.5%. The prevalence of the abnormal embryonic karyotype was 41.1% in the subjects in whom no conventional causes of miscarriage could be identified. The prevalence of recurrent miscarriage of truly unexplained cause, that is, of subjects without conventional causes in whom the embryonic karyotype was ascertained to be normal, was 24.5%. Among the patients in whom the first determination revealed an abnormal embryonic karyotype, 76.2% (32/42) showed an abnormal embryonic karyotype in the repeat determination as well. The cumulative live birth rate (71.9%) in women with recurrent miscarriages caused by the abnormal embryonic karyotype was significantly higher than that (44.7%) in women with recurrent miscarriages associated with the embryonal euploidy. An abnormal embryonic karyotype was found to represent the commonest cause of recurrent miscarriage, and the percentage of cases with recurrent miscarriage of truly unexplained cause was limited to 24.5%.The two groups should be distinguished for both clinical and research purposes.


Quantitative 3D fluorescence technique for the analysis of en face preparations of arterial walls using quantum dot nanocrystals and two-photon excitation laser scanning microscopy.
Traditional imaging with one-photon confocal microscopy and organic fluorophores poses several challenges for the visualization of vascular tissue, including autofluorescence, fluorophore crosstalk, and photobleaching. We studied human coronary arteries (HCAs) and mouse aortas with a modified immunohistochemical (IHC) "en face" method using quantum dot (Qdot) bioconjugates and two-photon excitation laser scanning microscopy (TPELSM). We demonstrated the feasibility of multilabeling intimal structures by exciting multicolored Qdots with only one laser wavelength (750 nm). Detailed cell structures, such as the granular appearance of von Willebrand factor (VWF) and the subcellular distribution of endothelial nitric oxide synthase, were visualized using green dots (525 nm), even when the emission maximum of these Qdots overlapped that of tissue autofluorescence (510-520 nm). In addition, sensitive fluorescence quantification of vascular cell adhesion molecule 1 expression at areas of varying hemodynamics (intercostal branches vs. nonbranching areas) was performed in normal C57Bl/6 mice. Finally, we took advantage of the photostability of Qdots and the inherent three-dimensional (3D) resolution of TPELSM to obtain large z-stack series without photobleaching. This innovative en face method allowed simple multicolor profiling, highly sensitive fluorescence quantitation, and 3D visualization of the vascular endothelium with excellent spatial resolution. This is a promising technique to define the spatial and temporal interactions of endothelial inflammatory markers and quantify the effects of different interventions on the endothelium.


The secretome from embryonic stem cell cardiomyogenesis: Same signals, different cellular feedbacks.
Ischemic heart diseases are a global health problem that requires the search for alternative therapies to the current treatments. Thus, an understanding of how cardiomyogenic signals can affect cellular behavior would allow us to create strategies to improve the cell recovery in damaged tissues. In this study, we aimed to evaluate the effects of the conditioned medium (CM), collected at different time points during in vitro cardiomyogenesis of human embryonic stem cells (hESCs), to direct cell behavior. We assayed different cell types to demonstrate noncytotoxic effects from the collected CM and that the CM obtained at initial time points of cardiomyogenic differentiation could promote the cell proliferation. Otherwise, the secretome derived from cardiac committed cells during cardiomyogenesis was unable to improve angiogenesis or migration in endothelial cells, and ineffective to stimulate the differentiation of cardioblasts or increase the differentiation efficiency of hESC. Therefore, we demonstrated that the effectiveness of the CM response varies depending on the cell type and the differentiation step of hESC-derived cardiomyocytes.