Decidualized juvenile cystic adenomyoma mimicking a cornual pregnancy.
To demonstrate the laparoscopic excision technique of a juvenile cystic adenomyoma and show how the decidualization of ectopic endometrial tissue can lead to the misdiagnosis of a focus of ectopic pregnancy. Description and step-by-step demonstration of the surgical procedure using a video recording (Canadian Task Force Classification 3). Teaching and research hospital. A 27-year-old gravida 2 parity 1 patient with one previous caesarean delivery presented to the emergency department with symptoms of pelvic pain and delayed menses. Her beta-human chorionic gonadotropin level was 2,161 mIU/mL. On transvaginal ultrasonography the uterine cavity appeared empty without any signs of a gestational sac, and a 42×45 mm heterogeneous mass was observed on the right cornual area. An 18×21 mm cystic area was observed within the mass. A diagnosis of cornual pregnancy was made and two doses of systemic methotrexate treatment were administered. On the 12th day following medical treatment, the patient reported increasing abdominal pain and free fluid was observed in the pouch of Douglas on ultrasonography. The decision to perform laparoscopic cornual excision was made. On laparoscopic exploration a tubal ectopic pregnancy was observed within the left fallopian tube. The presence of two simultaneous ectopic pregnancies, located in the left fallopian tube and the right cornual area, was suspected. However, upon careful inspection, the right fallopian tube appeared normal and the mass initially thought to be a right cornual pregnancy appeared more like a degenerated fibroid. A left salpingectomy was performed and the excision of the mass in the right cornual area was planned. An incision was made over the mass and the cystic inner area containing chocolate-brown colored fluid was drained. As there was no pseudo capsule surrounding the mass, the diagnosis of focal adenomyosis instead of degenerated fibroid was made. No endometriotic foci were observed within the pelvis. Different from the enucleation of a fibroid, the mass was dissected from the middle into two halves until healthy myometrium was reached on the floor of the mass. The two halves of the mass were resected totally by dissecting the adenomyotic tissue from the myometrium starting from the caudal end towards the cranial end. The first layer of the remaining myometrial defect was sutured extracorporeally with No.1 polyglactan sutures. The second and third layers were sutured intracorporeally with V-loc sutures. The resected left fallopian tube containing the ectopic pregnancy and the adenomyotic mass were externalized through a posterior colpotomy incision. The patient was discharged 24 hours postoperatively without any complications. A diagnosis of juvenile cystic adenoma was made upon histopathological examination. The patient reported subsiding of her dysmenorrhea on the postoperative third month. Juvenile cystic adenomyosis (JCA), is a rare form of focal adenomyosis which is usually located in close proximity to the uterine insertion of the round ligament, contains a cystic inner area larger than 1 cm and is encountered before the age of 30 years. Some authors reported JCA to be an accessory and cavitated uterine mass (ACUM) anomaly developing as a result of gubernaculum dysfunction. The only difference between the two conditions is reported to be the presence of a denser area of adenomyosis surrounding the cystic area lined with endometrium in JCA than in ACUM. This case has shown that decidual changes observed in ectopic endometrial tissue within an adenomyotic area may be misdiagnosed as a focus of ectopic pregnancy. Atypical endometriomas demonstrating decidual changes may also be misdiagnosed as ovarian malignancies. In non-emergency situations, waiting for the decidualization effect of ectopic endometrium to subside can help in the definitive diagnosis of such cases. Our technique for JCA excision is different from enucleation of a fibroid and may aid in the total resection and dissection of the adenomyotic tissue from healthy myometrium.


Photophysical properties of crowned porphyrins.
In this study, we evaluated the photophysical properties of 5,10,15,20-tetrakis[4-(1,4,7,10,13-pentaoxacyclopentadecane-2-aminomethyl)2,3,5,6-(tetrafluoro)-phenyl]-porphyrin (H2C4P) and Zn(II)5,10,15,20-tetrakis[4-(1,4,7,10,13-pentaoxacyclopenta-decane-2-aminomethyl)2,3,5,6-(tetrafluoro)-phenyl]-porphyrinate (ZnC4P). We observed that these porphyrins have unique properties when compared with classical porphyrins. The porphyrins H2C4P and ZnC4P showed efficient transfer energy S1 to T1 by intersystem crossing with high and reasonable yields of triplet excited state and singlet oxygen production. These amphiphilic structures of these porphyrins could improve its localization in the tumor cells due to the presence of the crown ether in its framework. We also believed that the crown ether could modulate the change in ion homeostase (Ca(+2), K+, Na+) as already described by some new phthalocyanine dye. This fact makes us believe that it could be reasonably used as a photosensitizer for PDT purposes.


How the sacrum got its name.
The os sacrum (sacred bone) was so named by the Romans as a direct translation from the older Greek hieron osteon. Explanations of the attribute "sacred" or "holy" in the past have included misinterpretation of the Greek word hieron, use of the bone in sacrificial rites, the role of the bone in protecting the genitalia (themselves considered sacred), and the necessity for the intactness of this bone as a nidus for resurrection at the Day of Judgment. A more plausible explanation may be that the holiness of the sacral bone was an attribute borrowed from the ancient Egyptians, who considered this bone sacred to Osiris, the god of resurrection and of agriculture.


A swab technique for sialometry. Normal range.
A modification of the swab method for sialometry is described. The individual secretions from the right parotid gland, left parotid gland and both submandibular glands together were collected, by use of cotton swabs after submaximal stimulation by citric acid. Five evaluation parameters and their normal ranges and variances are described from a material of 150 control individuals without sign of salivary gland impairment. The measurement is performed within five minutes, it is simple and convenient both for the patient and the staff. Therefore the method described is well suited for routine clinical use.


ACE: automated CTF estimation.
We present a completely automated algorithm for estimating the parameters of the contrast transfer function (CTF) of a transmission electron microscope. The primary contribution of this paper is the determination of the astigmatism prior to the estimation of the CTF parameters. The CTF parameter estimation is then reduced to a 1D problem using elliptical averaging. We have also implemented an automated method to calculate lower and upper cutoff frequencies to eliminate regions of the power spectrum which perturb the estimation of the CTF parameters. The algorithm comprises three optimization subproblems, two of which are proven to be convex. Results of the CTF estimation method are presented for images of carbon support films as well as for images of single particles embedded in ice and suspended over holes in the support film. A MATLAB implementation of the algorithm, called ACE, is freely available.


[A case of primary small intestinal malignant lymphoma found based on multiple pulmonary nodules with cavitation].
A 72-year-old man complained of dyspnea and epigastric pain. He was admitted to our hospital with progressive dyspnea and abnormal chest radiograph findings. Chest CT scan on admission showed multiple nodular shadows with and without air-bronchograms, vessels or cavitation. Transbronchial and percutaneous lung biopsy specimens demonstrated poorly differentiated carcinoma. Pulmonary metastases were suspected, but their primary origin was unknown. Chest and abdominal CT scans on the 18th hospital day showed a giant tumor of the small intestine and rapid progression of the pulmonary tumor, forming cavitation. The patient's condition worsened, and he died on the 51st hospital day. At autopsy, a final diagnosis of T-cell lymphoma of the small intestine and pulmonary metastases was obtained. This is a rare case which was found primarily based on the characteristic radiologic features of pulmonary metastases.


Evaluation of restorative materials using a new perfusion system.
1) To test a new perfusion device able to alternate demineralizing/nondemineralizing solutions, as an acid attack system, and 2) to standardize the dentin demineralization procedure, in order to define the in vitro secondary caries inhibiting potential of different restorative materials. A fluoride-containing adhesive/composite resin (group A), an experimental adhesive/composite resin (group B), and a glass-ionomer cement (group C) were used to restore 24 Class II cavities in extracted molars. Optimal conditions to obtain dentin demineralization inside the perfusion device were identified and applied to restored teeth. Dentin demineralization after perfusion was analyzed by microradiography. The output parameters were lesion morphology, dentin mineral volume percentage, and integrated mineral loss (Delta Z, % volume x microm) of the exposed (outer lesions) and marginal (inner lesions or caries inhibition zones, CIZs) dentin. Demineralization increased as follows: group A < group B < group C. Group A behaved better than group B, probably due to fluoride content, as indicated by Delta-Z values, higher number of CIZs, and few inner lesions. Group C showed a marginal protective effect, demonstrated by the frequent CIZs and Delta-Z positive values. This effect, however, was unable to reduce the high demineralization, probably due to the critical handling characteristics, inducingthe worst marginal adaptation. A new dynamic perfusion device was tested and a reproducible procedure was standardized in order to achieve in vitro conditions that could better simulate the pH changes of oral environment. A limited fluoride protective effect was demonstrated by using the perfusion system, whereas a perfect marginal adaptation was shown as a paramount factor to prevent restoration failure.


Characteristics of episodes of ST elevation or ST depression during ambulatory monitoring in patients subsequently undergoing coronary angiography.
Transient ischaemic ST segment changes were studied in 296 consecutive patients with coronary heart disease attending hospital for coronary arteriography. They underwent two channel, frequency modulated ambulatory monitoring for 24 hours. During this time 221 episodes of transient ST elevation (n = 56) or ST depression (n = 165) with a horizontal deviation of at least 1 mm lasting at least 1 min were found in 70 patients (23.6%). Only 34% of episodes were associated with pain. The duration of the episode, the heart rate at the beginning of the episode, or the extent of ST deviation were not related to the occurrence of pain. Episodes of ST elevation were of significantly shorter duration, occurred significantly more often during the early morning, and at significantly lower heart rates than episodes of ST depression. The considerable overlap between the characteristics of episodes of ST elevation and ST depression suggests that in many instances a combination of factors is responsible for transient ischaemic ST segment changes.


Management of malunited fractures of the metacarpal and phalangeal shafts.
Malunions of the tubular bones of the hand should be carefully studied to understand the original deforming forces at the time of injury. Once a three-dimensional concept of the deformity is embraced, a careful plan for osteotomy can be developed and executed. Surgical approach must afford adequate access with the least possible injury to soft tissues. Technique of osteotomy must be tailored to the configuration, location, and biomechanical requirements for proper realignment of the malunited fracture. Important principles in the management of metacarpal and phalangeal malunions are: 1. Rotatory deformities are most disabling yet frequently not appreciated. A 10-degree rotational malalignment in the metacarpal results in a 2-cm overlap at the finger tip. Alignment should always be checked with the fingers flexed into the palm. 2. Adherence to biomechanical principles of fracture repair is mandatory. 3. The appropriate form of osteotomy and subsequent fixation must be carefully chosen and applied to each individual deformity. Familiarity with the osteotomy techniques and alternative forms of fixation affords flexibility in managing complex deformities. 4. The presence of malunion suggests the presence of fracture disease in the soft tissues. They must be delicately handled and carefully inspected for the presence of scarring, adhesions, and contractures. Careful protection of delicate structures should be complemented by judicious tenolysis and arthrolysis at the time of osteotomy. 5. Appropriate, functional postoperative rehabilitation is mandatory. Without adequate therapy the best surgery will produce suboptimal results. Adherence to these principles can avoid further complications and problems and provide a successful ultimate outcome.


The homeobox gene Hex is required in definitive endodermal tissues for normal forebrain, liver and thyroid formation.
The homeobox gene Hex is expressed in the anterior visceral endoderm (AVE) and rostral definitive endoderm of early mouse embryos. Later, Hex transcripts are detected in liver, thyroid and endothelial precursor cells. A null mutation was introduced into the Hex locus by homologous recombination in embryonic stem cells. Hex mutant embryos exhibit varying degrees of anterior truncation as well as liver and thyroid dysplasia. The liver diverticulum is formed but migration of hepatocytes into the septum transversum fails to occur. Development of the thyroid is arrested at the thyroid bud stage at 9.5 dpc. Brain defects are restricted to the rostral forebrain and have a caudal limit at the zona limitans intrathalamica, the boundary between dorsal and ventral thalamus. Analysis of Hex(-/-) mutants at early stages shows that the prospective forebrain ectoderm is correctly induced and patterned at 7.5 days post coitum (dpc), but subsequently fails to develop. AVE markers are expressed and correctly positioned but development of rostral definitive endoderm is greatly disturbed in Hex(-/-) embryos. Chimeric embryos composed of Hex(-/-) cells developing within a wild-type visceral endoderm show forebrain defects indicating that Hex is required in the definitive endoderm. All together, these results demonstrate that Hex function is essential in definitive endoderm for normal development of the forebrain, liver and thyroid gland.


Human skeletal muscle xenograft as a new preclinical model for muscle disorders.
Development of novel therapeutics requires good animal models of disease. Disorders for which good animal models do not exist have very few drugs in development or clinical trial. Even where there are accepted, albeit imperfect models, the leap from promising preclinical drug results to positive clinical trials commonly fails, including in disorders of skeletal muscle. The main alternative model for early drug development, tissue culture, lacks both the architecture and, usually, the metabolic fidelity of the normal tissue in vivo. Herein, we demonstrate the feasibility and validity of human to mouse xenografts as a preclinical model of myopathy. Human skeletal muscle biopsies transplanted into the anterior tibial compartment of the hindlimbs of NOD-Rag1(null) IL2rγ(null) immunodeficient host mice regenerate new vascularized and innervated myofibers from human myogenic precursor cells. The grafts exhibit contractile and calcium release behavior, characteristic of functional muscle tissue. The validity of the human graft as a model of facioscapulohumeral muscular dystrophy is demonstrated in disease biomarker studies, showing that gene expression profiles of xenografts mirror those of the fresh donor biopsies. These findings illustrate the value of a new experimental model of muscle disease, the human muscle xenograft in mice, as a feasible and valid preclinical tool to better investigate the pathogenesis of human genetic myopathies and to more accurately predict their response to novel therapeutics.


[Stress and periodontal health].
Periodontitis and periimplant infections are complex manifestations associated with several disease-modifying factors, such as causative pathogens and smoking. Although research into these factors has led to important progressions in the treatment of these infections in recent decades, the contribution of mental stress in the absence of pathogens or smoking is still unclear. Qualitative and quantitative assessment of mental stress might be an important instrument in periodontal and periimplant therapy.


Mapping of staphylococcal enterotoxin A functional binding sites and presentation by monoclonal antibodies and fusion proteins.
Staphylococal enterotoxins (SE) bind with high affinity to major histocompatibility complex (MHC) class II proteins and stimulate large number of T cells via the Vbeta region of the T-cell receptor (TCR). To map the epitopes of SE type A (SEA) involved in MHC binding and cell proliferation, 20 specific anti-SEA monoclonal antibodies (MAbs) and two large glutathione S-transferase fusion proteins corresponding to the amino and carboxy termini, respectively, of SEA were used. The functionality of these antibodies was tested, by MHC binding inhibition, interleukin-2 production, and T-cell proliferation assays. Moreover, I studied the ability of the MAbs to present SEA in vitro to human and murine cells and their reactivity with the two fusion proteins. This study showed that all of the MAbs have a defined effect on one or both immunological properties of SEA and were able to present SEA to human and murine cells. However, one MAb (4H8) recognized SEA but without any interference with its biological activities. When the MAbs were tested to react with the two fusion proteins representing the SEA molecule, all of the MAbs were negative except for two. These results confirmed the presence of two functionally different binding sites of SEA with MHC class II molecules and the importance of the disulfide loop for the mitogenic activity of SEA. I further demonstrated that MAbs can present SEA to immune cells independent of the site recognized by the antibody and that the integrity of the SEA molecule is very important for its functions.


Cellular and genetic basis for suppression of cytotoxic T cell generation by haloaromatic hydrocarbons.
Generation of allospecific cytotoxic T cells in C57Bl/6 mice is significantly impaired following exposure to TCDD at doses as low as 4 ng/kg. T helper activity, as assessed by the ability to produce Interleukin 2, and frequency of CTL precursors appear unaffected in treated animals and thus the TCDD-induced suppressor cells we have described are primarily responsible for the reduction in the CTL response. Suppression of CTL generation in DBA/2 mice requires a 10--100-fold greater dose than in C57Bl/6, consistent with the observation that the Ah locus gene(s) of DBA/2 mice code for TCDD receptors with low binding affinity for TCDD. Other haloaromatic hydrocarbons (3,3'4,4'-tetrachlorobiphenyl and Aroclor 1254), capable of binding to the TCDD receptor, also suppress CTL generation, whereas the 2,2',4,4',6,6'-hexachlorobiphenyl molecule that lacks affinity for the TCDD receptor does not suppress CTL. The immunotoxic effects of TCDD in C57B/6 and DBA/2 mice occur at dose levels below those required to induce mixed-function oxidase enzymes in the liver. Suppression of CTL by TCDD is associated with increased susceptibility to lethal herpes virus type II infection. These data suggest that low levels of TCDD may interact with cytoplasmic receptors for TCDD in the thymus and induce biologically significant immunosuppression through activation of suppressor cells.


Comparison of the protective efficacy of DNA and baculovirus-derived protein vaccines for EBOLA virus in guinea pigs.
The filoviruses Ebola virus (EBOV) and Marburg virus (MARV) cause severe hemorrhagic fever in humans for which no vaccines are available. Previously, a priming dose of a DNA vaccine expressing the glycoprotein (GP) gene of MARV followed by boosting with recombinant baculovirus-derived GP protein was found to confer protective immunity to guinea pigs (Hevey et al., 2001. Vaccine 20, 568-593). To determine whether a similar prime-boost vaccine approach would be effective for EBOV, we generated and characterized recombinant baculoviruses expressing full-length EBOV GP (GP(1,2)) or a terminally-deleted GP (GPa-) and examined their immunogenicity in guinea pigs. As expected, cells infected with the GPa- recombinant secreted more GP(1) than those infected with the GP(1,2) recombinant. In lectin binding studies, the insect cell culture-derived GPs were found to differ from mammalian cell derived virion GP, in that they had no complex/hybrid N-linked glycans or glycans containing sialic acid. Despite these differences, the baculovirus-derived GPs were able to bind monoclonal antibodies to five distinct epitopes on EBOV GP, indicating that the antigenic structures of the proteins remain intact. As a measure of the ability of the baculovirus-derived proteins to elicit cell-mediated immune responses, we evaluated the T-cell stimulatory capacity of the GPa- protein in cultured human dendritic cells. Increases in cytotoxicity as compared to controls suggest that the baculovirus proteins have the capacity to evoke cell-mediated immune responses. Guinea pigs vaccinated with the baculovirus-derived GPs alone, or in a DNA prime-baculovirus protein boost regimen developed antibody responses as measured by ELISA and plaque reduction neutralization assays; however, incomplete protection was achieved when the proteins were given alone or in combination with DNA vaccines. These data indicate that a vaccine approach that was effective for MARV is not effective for EBOV in guinea pigs.


Stimulation of 2-methylisoborneol (MIB) production by actinomycetes after cyclic chlorination in drinking water distribution systems.
The impact of fluctuation in chlorine residual on actinomycetes and the production of 2-methylisoborneol (MIB) were studied in cast-iron and PVC model distribution systems. Actinomycetes were spiked in each system and continued operation for a 12-day non-chlorine experiment, resulting in no changes in actinomycetes and MIB concentrations. Three cyclic chlorination events were performed and chlorine residuals were maintained as follows: 1.0 mg L(-1) for 24 h, 0 mg L(-1) for 48 h, 0.5 mg L(-1) for 48 h, 0 mg L(-1) for 48 h and 2 mg L(-1) for 24 h. After each chlorination event, 2 -3 log decrease in actinomycetes was noted in both systems. However, within 48 h at 0 mg L(-1) chlorine, the actinomycetes recovered to the pre-chlorination levels. On the contrary, MIB concentration in both systems remained un-impacted after the first cycle and increased by fourfold (< 5 to > 20 mg L(-1)) after the second cycle, which lasted through the third cycle despite the fact that actinomycetes numbers fluctuated 2-3 logs during this time period. For obtaining biofilm samples from field, water meters were collected from municipality drinking water distribution systems located in central Arizona. The actinomycetes concentration in asbestos cement pipe and cast iron pipe averaged 3.1 × 10(3) and 1.9 × 10(4) CFU cm(-2), respectively. The study shows that production of MIB is associated with changes in chlorine residual in the systems. This is the first report of cyclic chlorine shock as a stimulus for MIB production by actinomycetes in drinking water distribution system's ecology.


MultiDimensional ClinOmics for Precision Therapy of Children and Adolescent Young Adults with Relapsed and Refractory Cancer: A Report from the Center for Cancer Research.
We undertook a multidimensional clinical genomics study of children and adolescent young adults with relapsed and refractory cancers to determine the feasibility of genome-guided precision therapy. Patients with non-central nervous system solid tumors underwent a combination of whole exome sequencing (WES), whole transcriptome sequencing (WTS), and high-density single-nucleotide polymorphism array analysis of the tumor, with WES of matched germline DNA. Clinically actionable alterations were identified as a reportable germline mutation, a diagnosis change, or a somatic event (including a single nucleotide variant, an indel, an amplification, a deletion, or a fusion gene), which could be targeted with drugs in existing clinical trials or with FDA-approved drugs. Fifty-nine patients in 20 diagnostic categories were enrolled from 2010 to 2014. Ages ranged from 7 months to 25 years old. Seventy-three percent of the patients had prior chemotherapy, and the tumors from these patients with relapsed or refractory cancers had a higher mutational burden than that reported in the literature. Thirty patients (51% of total) had clinically actionable mutations, of which 24 (41%) had a mutation that was currently targetable in a clinical trial setting, 4 patients (7%) had a change in diagnosis, and 7 patients (12%) had a reportable germline mutation. We found a remarkably high number of clinically actionable mutations in 51% of the patients, and 12% with significant germline mutations. We demonstrated the clinical feasibility of next-generation sequencing in a diverse population of relapsed and refractory pediatric solid tumors. Clin Cancer Res; 22(15); 3810-20. ©2016 AACR.


[Mediterranean diet. Characteristics and health benefits].
The purpose of this article is to define the concept of Mediterranean Diet or Diets and to describe the associated health benefits recognised by the scientific community. The characteristics of the Mediterranean Diet are described as well as the effects the foods comprising it have on the most common pathologies such as cardiovascular disease and cancer. The Spanish Society of Community Nutrition's consensus based Healthy Diet Pyramid, along with Greece's pyramid for food guidelines for the adult population (from the Greek Ministry of Health), are presented and compared. They are the graphic representation of the food and physical activity guides of two typically Mediterranean countries. Nutritional and sociological trends are also discussed and their impact on the evolution of the Mediterranean Diet.


Weighted logrank tests for interval censored data when assessment times depend on treatment.
We consider weighted logrank tests for interval censored data when assessment times may depend on treatment, and for each individual, we only use the two assessment times that bracket the event of interest. It is known that treating finite right endpoints as observed events can substantially inflate the type I error rate under assessment-treatment dependence (ATD), but the validity of several other implementations of weighted logrank tests (score tests, permutation tests, multiple imputation tests) has not been studied in this situation. With a bounded number of unique assessment times, the score test under the grouped continuous model retains the type I error rate asymptotically under ATD; however, although the approximate permutation test based on the permutation central limit theorem is not asymptotically valid under every ATD scenario, we show through simulation that in many ATD scenarios, it retains the type I error rate better than the score test. We show a case where the approximate permutation test retains the type I error rate when the exact permutation test does not. We study and modify the multiple imputation logrank tests of Huang, Lee, and Yu (2008, Statistics in Medicine, 27: 3217-3226), showing that the distribution of the rank-like scores asymptotically does not depend on the assessment times. We show through simulations that our modifications of the multiple imputation logrank tests retain the type I error rate in all cases studied, even with ATD and a small number of individuals in each treatment group. Simulations were performed using the interval R package.


In vitro antioxidant potential study of some synthetic quinoxalines.
In continuation of our study the in vitro antioxidant activity of some novel quinoxaline derivatives was investigated by 1,1-diphenyl-2-picrylhydrazyl (DPPH) method with respect to ascorbic acid. To determine the antioxidant activity, a number of substituted indoxyls (3A-G), cyclic ketones (2A-G), and quinoxalines (1A-G) were synthesized by both microwave and conventional heating methods. The present findings revealed that some quinoxalines and their precursors (1D, 1F, 1G and 2E) exhibited a marked scavenging effect on DPPH radical.


A high-fidelity virtual environment for the study of paranoia.
Psychotic disorders carry social and economic costs for sufferers and society. Recent evidence highlights the risk posed by urban upbringing and social deprivation in the genesis of paranoia and psychosis. Evidence based psychological interventions are often not offered because of a lack of therapists. Virtual reality (VR) environments have been used to treat mental health problems. VR may be a way of understanding the aetiological processes in psychosis and increasing psychotherapeutic resources for its treatment. We developed a high-fidelity virtual reality scenario of an urban street scene to test the hypothesis that virtual urban exposure is able to generate paranoia to a comparable or greater extent than scenarios using indoor scenes. Participants (n = 32) entered the VR scenario for four minutes, after which time their degree of paranoid ideation was assessed. We demonstrated that the virtual reality scenario was able to elicit paranoia in a nonclinical, healthy group and that an urban scene was more likely to lead to higher levels of paranoia than a virtual indoor environment. We suggest that this study offers evidence to support the role of exposure to factors in the urban environment in the genesis and maintenance of psychotic experiences and symptoms. The realistic high-fidelity street scene scenario may offer a useful tool for therapists.


Care Me Too, a Mobile App for Engaging Chinese Immigrant Caregivers in Self-Care: Qualitative Usability Study.
Caregiving and self-care are challenging for Chinese immigrants in the United States due to limited accessible support and resources. Few interventions exist to assist Chinese immigrant caregivers in better performing self-care. To address this gap in the literature, our team developed the Care Me Too app to engage Chinese immigrant caregivers in self-care and conducted a user experience test to assess its usability and acceptability. This paper aims to report the results of the app's usability and acceptability testing with Chinese immigrant caregivers and to solicit participants' feedback of the app design and functions. A total of 22 Mandarin-speaking Chinese caregivers participated in the study, which consisted of 2 parts: the in-lab testing and the 1-week at-home testing. In-depth face-to-face interviews and follow-up phone interviews were used to assess user experience of the app's usability and acceptability and to solicit feedback for app design and functions. Directed content analysis was used to analyze the qualitative data. Among the 22 participants, the average age was 60.5 (SD 8.1) years, ranging from 46 to 80 years; 17 (77%) participants were women and 14 (64%) had an associate degree or higher. Participants reported uniformly positive ratings of the usability and acceptability of the app and provided detailed suggestions for app improvement. We generated guidelines for mobile health (mHealth) app designs targeting immigrant caregivers, including weighing flexibility versus majority preferences, increasing text sizes, using colors effectively, providing engaging and playful visual designs and functions, simplifying navigation, simplifying the log-in process, improving access to and the content on the help document, designing functions to cater to the population's context, and ensuring offline access. The main contribution of this study is the improved understanding of Chinese caregivers' user experiences with a language-appropriate mHealth app for a population that lacks accessible caregiving and self-care resources and support. It is recommended that future researchers and app designers consider the proposed guidelines when developing mHealth apps for their population to enhance user experience and harness mHealth's value.


1-(Prop-2-en-1-yl)-3-{[3-(pyridin-4-yl)-4,5-di-hydro-isoxazol-5-yl]meth-yl}-1H-anthra[1,2-d]imidazole-2,6,11(3H)-trione.
The fused five- and three six-membered rings of the anthra[1,2-d]imidazole-trione part of the title compound, C27H20N4O4, show two different substituents at the imidazole N atoms, viz. an allyl group and a [3-(pyridin-4-yl)-4,5-di-hydro-isoxazol-5-yl]methyl group. The fused-ring system is approximately planar [r.m.s. deviation = 0.232 (2) Å], but is slightly buckled along the common edge of the two pairs of adjacent rings, with a dihedral angle between them of 11.17 (6)°. The isoxazole ring makes dihedral angles of 27.2 (2) and 12.7 (2)° with the imidazole and pyridine rings, respectively. Weak C-H⋯O and C-H⋯N hydrogen bonds ensure the cohesion of the crystal structure, forming a three-dimensional network.


22q11.2 deletion syndrome is associated with increased mortality in adults with tetralogy of Fallot and pulmonary atresia with ventricular septal defect.
22q11.2 Deletion syndrome (22q11.2DS) is common in patients with tetralogy of Fallot (TOF) or pulmonary atresia with ventricular septal defect (PA/VSD) and is associated with worse outcomes in children. Whether this impaired prognosis is also translated into adulthood is unknown, as data in adult patients are limited. We aimed to compare long-term outcomes in adults with TOF or PA/VSD both with and without 22q11.2DS. This study prospectively followed a nationwide multicenter cohort of TOF or PA/VSD patients with genetically confirmed presence or absence of 22q11.2DS, from inclusion in the Dutch national CONCOR registry for adults with congenital heart disease (CHD) onward. Outcome measures included all-cause mortality, cardiac mortality, need for pulmonary valve replacement (PVR), ventricular arrhythmias (VA), pacemaker implantation, and ICD implantation. In total, 479 patients were included (277 (58%) male, median age 28 [IQR; 21-37] years, 62 (13%) with PA/VSD, 34 (7%) with 22q11.2DS). During a median follow-up of 11 [IQR; 6-13] years, 52 (11%) patients died (8 with 22q11.2DS and 44 without 22q11.2DS). Patients with 22q11.2DS had significant decreased survival after 12 years (76% [95% CI; 62-93]) compared to patients without 22q11.2DS (89% [95% CI; 86-92], p = 0.008). 22q11.2DS was associated with increased risk of all-cause mortality and cardiac-mortality, independent of age, sex, and PA/VSD. No association was found between 22q11.2DS and late complications i.e. PVR, VA, pacemaker, or ICD implantation. Adults with TOF or PA/VSD with 22q11.2DS have a significantly worse survival than adults without this deletion. In patients with TOF or PA/VSD, genetic analysis for the presence of 22q11.2DS is important for risk stratification and genetic counseling.


Exploration of correlation of oral hygiene and condition with influenza infection.
Influenza viruses are known to be infected through epithelial cells of the upper respiratory tract. The oral cavity is in close anatomical proximity to the upper respiratory tract, and it is conceivable that the viruses could pass through the oral cavity and infect to the upper respiratory tract. Several researchers have suggested that colonization of certain pathogenic bacteria such as Staphylococcus aureus or Streptococcus pneumoniae might affect the risk of influenza viral disease, indicating that oral hygiene and/or condition might play an important role in respiratory viral infection. Therefore, the purpose of this study was to investigate whether an oral hygiene/condition might impact influenza infection. We conducted a retrospective observational study of Japanese citizens' regional cohort (N = 2,904) consisting of National Health Insurance beneficiaries who underwent annual health/dental examination with data entries in the Kokuho database (KDB). Trained dentists checked the oral hygiene/condition, and saliva specimens were examined using the LION dental saliva multi-test (SMT) kit. Influenza infection was identified from the diagnosis recorded in the KDB. The correlations between influenza infection and oral hygiene, dryness of the mouth, or various salivary test results were examined by a multivariate analysis adjusting for confounding factors such as gender, age, recent smoking, alcohol drinking, BMI, HbA1c, RBC for influenza infection. The logistic regression model showed that age significantly correlated with influenza infection. In addition, oral hygiene status had a nearly significant impact on influenza infection (p = 0.061), whereby, the subjects with poor oral hygiene had a higher risk of influenza infection than those with good oral hygiene (odds ratio: 1.63, 95% confidence interval: 0.89-2.95). Further, the prevalence of influenza infection was lower in the subjects with saliva weakly acidic and/or containing higher protein level. The results of this study suggested that the maintenance of oral health conditions might be one of the pivotal factors for preventing and reducing influenza infection.


Vitamin D, bone mineral density and risk of fracture in people with intellectual disabilities.
People with intellectual disabilities (IDs) have very high rates of osteoporosis and fractures, to which their widespread vitamin D deficiency and other factors could contribute. We aimed to assess in people with IDs previously treated for vitamin D deficiency (1) long-term adherence to vitamin D supplementation and (2) bone mineral density (BMD), as an indicator for risk of fractures, according to vitamin D supplementation and other factors. We recorded height, weight, medical, pharmacological, dietary and lifestyle assessment. Blood sample were taken for vitamin D and related analytes. dual-energy X-ray absorptiometry for BMD was performed. Of 51 study participants (mean [standard deviation, SD] age 51.5 [13.6] years, 57% male), 41 (80.4%) were taking vitamin D and 10 were not. Mean [SD] serum vitamin D was 81.3 [21.3] vs. 25.2 [10.2] nmol/L (P < 0.0001), respectively. Thirty-six participants underwent a dual-energy X-ray absorptiometry scan, which showed osteoporosis in 23.7% and osteopenia in 52.6%. Participants on vitamin D had higher BMD than those who were not, a statistically significant difference when confounders (lack of mobility and hypogonadism) were removed. BMD was significantly different according to mobility, particularly in wheelchair users, in whom hip BMD was 33% lower (P < 0.0001) than in participants with normal mobility. Participants still taking vitamin D showed a 6.1% increase in BMD at the spine (P = 0.003) after mean [SD] 7.4 [1.5] years vitamin D treatment. In people with IDs and previous vitamin D deficiency, BMD increases on long-term vitamin D supplementation. However, additional strategies must be considered for osteoporosis and fracture prevention in this population.


Extraction/Leaching of Metal-Containing Additives from Polyvinyl Chloride, Ethyl Vinyl Acetate, and Polypropylene Bags and Infusion Sets into Infusion Solutions.
Flexible medical devices are primarily made of plasticized polyvinyl chloride (PVC). In recent times, to avoid undesired migration of the PVC plasticizers, ethyl vinyl acetate (EVA) and polypropylene (PP) has replaced PVC. Nevertheless, other additives are necessary to generate useful polymeric materials. Metallic species present in such additives can also leach out into the infusion solutions. The migration of barium (Ba), cadmium (Cd), lead (Pb), tin (Sn), and zinc (Zn) from devices made from PVC, EVA, and PP was evaluated. Bags and infusion sets were decomposed and their metallic contents analyzed. Glucose, NaCl, and Tween 80 were assessed as extraction media. These solutions were stored in PVC, EVA, and PP bags, heat-sterilized, and stored for 8 months at room temperature. Aliquots were taken before and after sterilization and then once per month to determine the contents of the metals. Commercial glucose and NaCl infusions were analyzed by taking aliquots of the solutions from the bags and from the administration set after their administration to patients. The three polymers contained the five metals. Ba was found in the highest concentration in all samples, with a mean of 8.0 mg/kg in PVC, 4.2 mg/kg in EVA, and 4.7 mg/kg in PP samples. Despite this, the only element that migrated into the glucose, NaCl, and Tween 80 solutions was Zn. The same result was found for the commercial glucose and NaCl infusions. Moreover, the Zn concentration in the administration sets was on average 52% higher than that found in the bags.LAY ABSTRACT: Flexible medical devices for infusions and artificial nutrition are made of plastics, such as polyvinyl chloride (PVC), ethyl vinyl acetate (EVA), and polypropylene (PP). These polymers contain additives necessary to generate useful materials. Metallic species present in these additives can leach out into the infusion solutions and come into contact with patients. To assess the risk of patient exposure to these metals, we evaluated the migration behavior of barium (Ba), cadmium (Cd), lead (Pb), tin (Sn), and zinc (Zn) from devices made from PVC, EVA, and PP. Bags and infusion sets were analyzed. Glucose, NaCl, and Tween 80 were investigated as extraction media. The three polymers contained the five metals. Ba was found in the highest concentration in all samples. Despite this, the only element that migrated into the glucose, NaCl, and Tween 80 solutions was Zn.


Continuous Cell Lines from the European Biting Midge Culicoides nubeculosus (Meigen, 1830).
Culicoides biting midges (Diptera: Ceratopogonidae) transmit arboviruses of veterinary or medical importance, including bluetongue virus (BTV) and Schmallenberg virus, as well as causing severe irritation to livestock and humans. Arthropod cell lines are essential laboratory research tools for the isolation and propagation of vector-borne pathogens and the investigation of host-vector-pathogen interactions. Here we report the establishment of two continuous cell lines, CNE/LULS44 and CNE/LULS47, from embryos of Culicoides nubeculosus, a midge distributed throughout the Western Palearctic region. Species origin of the cultured cells was confirmed by polymerase chain reaction (PCR) amplification and sequencing of a fragment of the cytochrome oxidase 1 gene, and the absence of bacterial contamination was confirmed by bacterial 16S rRNA PCR. Both lines have been successfully cryopreserved and resuscitated. The majority of cells examined in both lines had the expected diploid chromosome number of 2n = 6. Transmission electron microscopy of CNE/LULS44 cells revealed the presence of large mitochondria within cells of a diverse population, while arrays of virus-like particles were not seen. CNE/LULS44 cells supported replication of a strain of BTV serotype 1, but not of a strain of serotype 26 which is not known to be insect-transmitted. These new cell lines will expand the scope of research on Culicoides-borne pathogens.


Navigating environmental constraints to injection preparation: the use of saliva and other alternatives to sterile water among unstably housed PWID in London.
The United Kingdom is experiencing an increase in drug-related deaths and serious bacterial infections among its most vulnerable citizens. Cuts to essential services, coupled with a growing homeless population, create a challenging environment to tackle this public health crisis. In this paper, we highlight an underexplored environmental constraint faced by people living and injecting drugs on the streets. Access to water for injection is restricted in the UK, due to legislative and financial barriers. Austerity measures, such as public toilet closures, further restrict the ability of people made homeless to access clean water and protect themselves from health harms. We generated questionnaire (n = 455) and in-depth qualitative interview (n = 32) data with people who inject drugs in London for the Care and Prevent study. Participants provided detail on their life history; drug use, injecting and living environments; health conditions and care seeking practices. A high proportion of the survey sample reported lifetime history of street homelessness (78%), bacterial infections (65%) and related hospitalisation (30%). Qualitative accounts highlight unsafe, potentially dangerous, injection practices in semi-public spaces. Multiple constraints to sourcing sterile water for injection preparation were reported. Alternatives to sterile water included puddle water, toilet cistern water, whisky, cola soda and saliva. Participants who injected heroin and crack cocaine together unanimously reported adding water at two stages during injection preparation: first, adding water as a vehicle for heroin (which was then heated); second, adding cold water to the heroin mixture prior to adding the crack cocaine. This new finding of a stage addition of solvent may represent an additional risk of infection. Currently, harm reduction equipment and resources for safe injecting are not meeting the needs of people who inject drugs who are street homeless or unstably housed. Preparation of injections with non-sterile water sources could precipitate bacterial and fungal infections, particularly when used without the application of heat. It is crucial that water for injection, also skin cleaning, is made available for the unstably housed and that harm reduction messaging is tailored to speak to the everyday realities of people who prepare and inject drugs in public spaces.


Efflux as a mechanism of resistance to antimicrobials in Pseudomonas aeruginosa and related bacteria: unanswered questions.
Pseudomonas aeruginosa is an opportunistic human pathogen exhibiting innate resistance to multiple antimicrobial agents. This intrinsic multidrug resistance is caused by synergy between a low-permeability outer membrane and expression of a number of broadly-specific multidrug efflux (Mex) systems, including MexAB-OprM and MexXY-OprM. In addition to this intrinsic resistance, these and three additional systems, MexCD-OprJ, MexEF-OprN and MexJK-OprM promote acquired multidrug resistance as a consequence of hyper-expression of the efflux genes by mutational events. In addition to antibiotics, these pumps export biocides, dyes, detergents, metabolic inhibitors, organic solvents and molecules involved in bacterial cell-cell communication. Homologues of the resistance-nodulation-division systems of P. aeruginosa have been found in Burkholderia cepacia, B. pseudomallei, Stenotrophomonas maltophilia, and the nonpathogen P. putida, where they play roles in resistance to antimicrobials and/or organic solvents. Despite intensive studies of these multidrug efflux systems over the past several years, their precise molecular architectures, their modes of regulation of expression and their natural functions remain largely unknown.


Does Prolonged Enteral Feeding With Supplemental Omega-3 Fatty Acids Impact on Recovery Post-esophagectomy: Results of a Randomized Double-Blind Trial.
This randomized controlled trial (RCT) hypothesized that prolonged enteral nutrition (EN) with supplemental eicosapentanoic acid (EPA), an omega-3 fatty acid with immune and anabolic properties, may impact on clinical and nutritional outcomes. Esophagectomy is associated with significant weight loss and catabolism, and negatively impacts quality of life (QL). Strategies to counter sustained catabolism have therapeutic rationale. This multicenter, double-blind, placebo-controlled RCT was powered on a 5% difference in lean body mass (LBM) at 1 month. Patients were randomly assigned to receive either EN-EPA (2.2 g EPA/day) (n = 97) or isocaloric isonitrogenous standard EN (EN-S) (n = 94), preoperatively (5 days orally), and postoperatively via a jejunostomy until 1 month postdischarge. Assessments perioperatively, and at 1, 3, and 6 months included weight, body mass index (BMI), body composition, muscle strength, cytokines, complications, and QL. The median (range) nutrition support was for 51 (36 to 78) days, and overall compliance was 96%. For the entire cohort, a significant (P < 0.005) decrease in weight (-7.4 ± 6.6 kg), BMI (-2.6 ± 2.2 kg/m), LBM (-2.5 ± 8.7 kg), and fat mass (-3.4 ± 5.8 kg) was evident from preoperatively to 6 months. The mean (±SD) loss of LBM (kg) at 1 month was -3.7 ± 8.7 in the EN-S group, compared with -5.6 ± 12.1 in the EN-EPA group (P = 0.355). Per-protocol analysis revealed no difference between the EN-EPA and EN-S in any clinical, nutritional, functional, QL or immune parameter at any time point. The thesis that EPA impacts on anabolism, immune function, and clinical outcomes post-esophagectomy was not supported. Compliance with home EN was excellent, but weight, muscle, and fat loss was significant in 30% of patients, highlighting the complexity of postoperative weight loss.


Comparison of virulence of three strains of Cronobacter sakazakii in neonatal CD-1 mice.
Cronobacter sakazakii (Enterobacter sakazakii) is an emerging pathogen that has been isolated from powdered infant formula and associated with outbreaks of infection in infants in neonatal intensive care units. In a previous study, we observed that neonatal CD-1 mice are susceptible to C. sakazakii infection and that the pathogen invades brain, liver, and cecum tissues. The study objective was to compare the virulence of three strains of C. sakazakii in neonatal CD-1 mice. The strains tested were MNW2 (a food isolate), SK81 (a clinical isolate), and 3290 (a clinical isolate). Timed-pregnant CD-1 mice were allowed to give birth on gestation day 19 or 20. Neonatal mice were sexed and culled to 10 per litter, each having five males and five females. Neonates were orally gavaged with C. sakazakii strains MNW2, SK81, or 3290 at doses ranging from 10(2.8) to 10(10.5) CFU on postnatal day 3.5. Pups surviving to postnatal day 10.5 were euthanized, and brain, liver, and cecum tissues were excised. C. sakazakii was isolated from all three tissues in mice treated with C. sakazakii, regardless of strain. C. sakazakii strain 3290 was significantly more invasive in brains (42.1% of mice) than were strains MNW2 (6.7%) and SK81 (15.9%). Mortality was observed for all strains of C. sakazakii tested, with SK81 being significantly more lethal (5.6%) than MNW2 (1.2%) or 3290 (0.6%). Our findings suggest that invasiveness does not necessarily correlate with mortality among different strains of C. sakazakii, and the clinical isolates are more virulent than the food isolate.


Perceptions about sexual risk, HIV and HIV-testing in Cali, Colombia.
In Colombia, 20%-54% of the population with sexual practices at higher risk for HIV infection (men who have sex with men, transgender women, women sex workers) has sometime been tested. To describe perceptions of sexual risk, HIV and HIV testing in people with risky sexual practices and people who identify themselves as heterosexual. Between 2012 and 2014, it was carried a descriptive study using HIV screening out in Cali-Colombia with the voluntary participation of 940 people aged over 18 years. There were used: informed consent, structured questionnaire and HIV testing. Descriptive, bivariate and multivariate Poisson regression models were performed. Average age 28.5 ±10.9 years; 50% men. 357 (38%) were people from the traditional risk group for HIV infection; and 583 (62%) corresponded to the non-traditional risk group (heterosexual men and women). Likewise, 62% and 41% respectively had HIV test. 51% to 53% reported having sex when they consumed liquor; commercial sex was higher in the group with risky sexual practices (32% vs 3%), as well as anal relations (77% vs 23%), consistent use of condom (32% vs 9%), and HIV positive test (14.3% vs 1.6%). The multivariate analysis showed for both groups that having HIV test was associated with being older than 25 years and a history of sexually transmitted infection. Differentiated education strategies are needed based on risky sexual behaviors and that consider the importance of regular HIV tests for early diagnosis and timely enrollment in care and treatment.


Deep convolutional networks do not classify based on global object shape.
Deep convolutional networks (DCNNs) are achieving previously unseen performance in object classification, raising questions about whether DCNNs operate similarly to human vision. In biological vision, shape is arguably the most important cue for recognition. We tested the role of shape information in DCNNs trained to recognize objects. In Experiment 1, we presented a trained DCNN with object silhouettes that preserved overall shape but were filled with surface texture taken from other objects. Shape cues appeared to play some role in the classification of artifacts, but little or none for animals. In Experiments 2-4, DCNNs showed no ability to classify glass figurines or outlines but correctly classified some silhouettes. Aspects of these results led us to hypothesize that DCNNs do not distinguish object's bounding contours from other edges, and that DCNNs access some local shape features, but not global shape. In Experiment 5, we tested this hypothesis with displays that preserved local features but disrupted global shape, and vice versa. With disrupted global shape, which reduced human accuracy to 28%, DCNNs gave the same classification labels as with ordinary shapes. Conversely, local contour changes eliminated accurate DCNN classification but caused no difficulty for human observers. These results provide evidence that DCNNs have access to some local shape information in the form of local edge relations, but they have no access to global object shapes.


3D4K exoscope in epilepsy surgery: a seminal experience.
To report the progressive introduction of the exoscope (EX) from surface lesionectomy to antero-mesial temporal lobectomy (AMTL) in an epilepsy surgery practice. We describe a population of ten consecutive patients undergoing EX surgery, with a minimum follow-up of 6 months, that was compared to a similar population of patients referred to operative microscopic surgery (OM). All surgeries were performed with the use of EX or OM alone. Transient neurological complications for surgery in eloquent regions were recorded in one patient for each population. Nine and seven patients undergoing, respectively, EX and OM surgery resulted in Engel class Ia (90% vs. 70%). The mean duration of EX and OM surgery resulted in 265.5 and 237.9 min, respectively, with a mean of 308.3 and 253.3 min for AMTL cases, respectively. This preliminary study revealed that ORBEYE EX can be safe and effective in different types of epilepsy surgeries. The transition from OM to EX is fast, even though it is slower for the more challenging mesial temporal structure removal. Ergonomic and operative team interaction is improved by the use of EX. Our data need to be confirmed by larger studies.


Modifying Risk Factors: Strategies That Work Diabetes Mellitus.
An estimated 29.1 million Americans are currently diagnosed with diabetes, and this number is expected to increase to 48.3 million Americans by 2050. Correspondingly, the present burden of diabetes among patients undergoing total joint arthroplasty is significant and rising. Diabetes as a chronic condition is a well-established risk factor for complication after total joint arthroplasty. A growing body of evidence also indicates that hyperglycemia in the perioperative period, and not the diagnosis of diabetes alone, is similarly associated with increased complication risk. As a result, a coordinated approach to preoperative screening and optimization, combined with judicious perioperative glycemic control, may present an opportunity to improve outcomes, reduce complications, and avoid complication-related costs for patients undergoing total joint arthroplasty.


Foraging investment in a long-lived herbivore and vulnerability to coursing and stalking predators.
Allocating resources to growth and reproduction requires grazers to invest time in foraging, but foraging promotes dental senescence and constrains expression of proactive antipredator behaviors such as vigilance. We explored the relationship between carnivore prey selection and prey foraging effort using incisors collected from the kills of coursing and stalking carnivores. We predicted that prey investing less effort in foraging would be killed more frequently by coursers, predators that often exploit physical deficiencies. However, such prey could expect delayed dental senescence. We predicted that individuals investing more effort in foraging would be killed more frequently by stalkers, predators that often exploit behavioral vulnerabilities. Further these prey could expect earlier dental senescence. We tested these predictions by comparing variation in age-corrected tooth wear, a proxy of cumulative foraging effort, in adult (3.4-11.9 years) wildebeest killed by coursing and stalking carnivores. Predator type was a strong predictor of age-corrected tooth wear within each gender. We found greater foraging effort and earlier expected dental senescence, equivalent to 2.6 additional years of foraging, in female wildebeest killed by stalkers than in females killed by coursers. However, male wildebeest showed the opposite pattern with the equivalent of 2.4 years of additional tooth wear in males killed by coursers as compared to those killed by stalkers. Sex-specific variation in the effects of foraging effort on vulnerability was unexpected and suggests that behavioral and physical aspects of vulnerability may not be subject to the same selective pressures across genders in multipredator landscapes.


The Pan American Health Organization and the mainstreaming of human rights in regional health governance.
In the absence of centralized human rights leadership in an increasingly fragmented global health policy landscape, regional health offices have stepped forward to advance the rights-based approach to health. Reviewing the efforts of the Pan American Health Organization (PAHO), this article explores the evolution of human rights in PAHO policy, assesses efforts to mainstream human rights in the Pan American Sanitary Bureau (PASB), and analyzes the future of the rights-based approach through regional health governance, providing lessons for other regional health offices and global health institutions. This article explores PAHO's 15-year effort to mainstream human rights through PASB technical units, national capacity-building, the Inter-American human rights system, and the PAHO Directing Council. Through documentary analysis of PAHO policies and semi-structured interviews with key PASB stakeholders, the authors analyze the understandings and actions of policymakers and technical officers in implementing human rights through PAHO governance. Analyzing the themes arising from this narrative, the authors examine the structural role of secretariat leadership, state support, legal expertise, and technical unit commitment in facilitating a rights-based approach to the health in the Americas. Human rights are increasingly framing PAHO efforts, and this analysis of the structures underlying PAHO's approach provides an understanding of the institutional determinants of the rights-based approach to health, highlighting generalizable themes for the mainstreaming of human rights through regional health governance. With this regional-level understanding of health governance, future national-level research can begin to understand the causal forces linking regional human rights work with national policy reforms and public health outcomes.


Churg-Strauss syndrome associated with acalculous cholecystitis and liver involvement.
We describe a 65-year-old man who had liver involvement with Churg-Strauss syndrome. He was admitted to the hospital because of fever, weight loss, dyspnea, abdominal pain, skin lesions and paraesthesias. His past medical history revealed a diagnosis of acalculous cholecystitis that had been made eight months earlier. Microscopic examination of a gall bladder biopsy specimen obtained at that time revealed an increase in extravascular eosinophils. There was evidence of a new bilateral pulmonary disease with bronchoconstriction and a transient infiltrated lesion in the right upper lung. The patient's white cell count was 14 620 per cubic millimetre, with 39% eosinophils (5800 per cubic millimetre) and 39% neutrophils. IgE was 503 g/L (normal range, 0 to 100 g/L). Liver function tests were mildly elevated. Fine needle liver biopsy showed active interface hepatitis. A diagnosis of Churg-Strauss syndrome was made. In this patient the syndrome occurred in a rare association with hepatitis, likely due to immunologic events in the liver. The patient was successfully treated with 60 mg/day of prednisolone monotherapy.


A novel approach to monitoring pulmonary congestion in heart failure: initial animal and clinical experiences using remote dielectric sensing technology.
Despite current therapies and disease management approaches, rates of heart failure (HF) rehospitalization remain high. New tools are needed to assess preclinical (asymptomatic) pulmonary congestion to enable outpatient management. Hence, a novel monitoring system based on noninvasive remote dielectric sensing (ReDS) technology was developed. Validation of the ReDS technology was conducted in preclinical and clinical studies. In a porcine HF model, acute fluid overload followed by administration of diuretics were performed. Changes in ReDS values were correlated to serial computed tomographic (CT) assessments of lung fluid concentrations. In hospitalized decompensated HF patients, changes in ReDS values were correlated to net fluid balance changes. A nearly linear pattern between the changes in ReDS and CT fluid concentration values was observed in 6 discrete experiments (Intraclass correlation=0.95). Results from 24 patients demonstrated a reduction in ReDS values of 17.53%±11% throughout hospitalization, consistent with a reduction in pulmonary congestion. This finding strongly correlated with changes in net fluid balance (Pearson correlation=0.86; 95% confidence interval, 0.68-0.94; R(2) =0.74). These findings suggest that ReDS technology accurately quantifies lung fluid concentration and has potential for monitoring HF patients through hospitalization and possibly at home.


Biophysical and enzymatic properties of the simian and prototype foamy virus reverse transcriptases.
The foamy virus Pol protein is translated independently from Gag using a separate mRNA. Thus, in contrast to orthoretroviruses no Gag-Pol precursor protein is synthesized. Only the integrase domain is cleaved off from Pol resulting in a mature reverse transcriptase harboring the protease domain at the N-terminus (PR-RT). Although the homology between the PR-RTs from simian foamy virus from macaques (SFVmac) and the prototype foamy virus (PFV), probably originating from chimpanzee, exceeds 90%, several differences in the biophysical and biochemical properties of the two enzymes have been reported (i.e. SFVmac develops resistance to the nucleoside inhibitor azidothymidine (AZT) whereas PFV remains AZT sensitive even if the resistance mutations from SFVmac PR-RT are introduced into the PFV PR-RT gene). Moreover, contradictory data on the monomer/dimer status of the foamy virus protease have been published. We set out to purify and directly compare the monomer/dimer status and the enzymatic behavior of the two wild type PR-RT enzymes from SFVmac and PFV in order to get a better understanding of the protein and enzyme functions. We determined kinetic parameters for the two enzymes, and we show that PFV PR-RT is also a monomeric protein. Our data show that the PR-RTs from SFV and PFV are monomeric proteins with similar biochemical and biophysical properties that are in some aspects comparable with MLV RT, but differ from those of HIV-1 RT. These differences might be due to the different conditions the viruses are confronted with in dividing and non-dividing cells.


The vagina has reducing environment sufficient for activation of Trichomonas vaginalis cysteine proteinases.
Trichomonas vaginalis, a worldwide distributed sexually transmitted protozoan, is remarkable for synthesis of numerous, distinct cysteine proteinases, the significance of which is evidenced by the presence in vivo of soluble proteinases in secretions and antiproteinase antibody in serum of patients with trichomonosis. These proteinases purportedly play a role in host parasitism and immune evasion. It is known that for cysteine proteinases to be functional, they must be activated by disulphide reducing reagents. Whether or not the host vaginal environment has the reducing environment essential for activation of the trichomonad cysteine proteinases is unknown. Our goal, therefore, was to determine whether or not vaginal secretions had sufficient reducing power to activate the trichomonad proteinases. 48 vaginal washes (VWs) from patients were assayed for reducing equivalents and a score in dithiothreitol (DTT) reducing equivalents was assigned to each VW. Activation of trichomonad cysteine proteinases was then tested under the range of reducing equivalents detected from VWs. The possible protective effect of hydrogen peroxide, an oxidising agent produced by some Lactobacillus species, on proteinase activity was also determined. Nine of 48 VWs (18.7%) possessed < or = 10 microM DTT reducing equivalents, four VWs (8.3%) had from 20 microM DTT to 40 microM DTT reducing equivalents, and most (50%) were between 10 microM to 15 microM. Overall, the range in VWs was from approximately 10 microM to 40 microM reducing equivalents. Importantly, data suggest differential proteinase activation over this in vivo range of reducing level. Only two T vaginalis cysteine proteinase activities were stimulated at 2.5 microM DTT in contrast with all proteinase activities present at 40 microM DTT, albeit quantitatively diminished compared with the activity at 1 mM DTT, the concentration routinely used in vitro. Finally, hydrogen peroxide reversibly neutralised all trichomonad proteinases. These results show that the vagina of women has a reducing environment adequate for activation of trichomonad proteinases. The data underscore that the host environment plays a role in the host-parasite interrelation. Finally, hypotheses can now be formulated to help explain resistance and susceptibility to infection commonly reported among women and between men and women with trichomonosis.


Primary folding of aspartylglucosaminidase. Significance of disulfide bridges and evidence of early multimerization.
Aspartylglucosaminidase (AGA) is a lysosomal enzyme involved in the degradation of N-linked glycoproteins in lysosomes. AGA is synthesized as an inactive precursor molecule, which is rapidly activated in the endoplasmic reticulum by a proteolytic cleavage into alpha- and beta-subunits. We have recently determined the three-dimensional structure of AGA and shown that it is a globular molecule with a heterotetrameric (alphabeta)2 structure. On the basis of structural and functional analyses, AGA seems to be the first mammalian protein belonging to a newly described protein family, the N-terminal nucleophile hydrolases. Because the activation of the prokaryotic members of the N-terminal nucleophile hydrolase family seems to be triggered by the assembly of the subunits, we have studied the initial folding and oligomerization of AGA and provide evidence that dimerization of two precursor molecules in the endoplasmic reticulum is a prerequisite for the activation of AGA. To gain further information on the structural determinants influencing the early folding of AGA, we used site-specific mutagenesis of cysteine residues to define the role of intrachain disulfide bridges in the folding and activation of the enzyme. The N-terminal disulfide bridges in both the alpha- and beta-subunits seem to have only a stabilizing role, whereas the C-terminal disulfide bridge in both subunits evidently plays an important role in the early folding and activation of AGA.


Experience with the surgical treatment of hepatic hydatidosis: case series with follow-up.
To describe patient characteristics and the results of surgical treatment for hepatic hydatidosis (HH) in the Hospital Hernán Henríquez Aravena from December 2001 to March 2005. Subjects older than 16 years with suspected HH were included based on the clinical picture and radiological studies. Variables examined included clinical and laboratory aspects, outcome, features of the parasite and surgical aspects. Descriptive statistics were used, calculating central tendency, dispersion and extreme tendency. The series was comprised of 122 patients, with an average age of 44 +/- 16.9 years. The most frequently used surgical technique was subtotal cystectomy in 90% of the patients, followed by hepatic resection (hepatectomy, segmentectomy and subsegmentectomy) in 5%. In 2%, a combination of subtotal cystectomy and segmentectomy was performed. In addition, 28% of the series presented complications in the postoperative period and mortality was 2%. The most frequently used surgical technique for HH was subtotal cystectomy and the morbidity and mortality rates in this Chilean series are comparable to other national and international series.


Forage fibre digestion, rates of feed passage and gut fill in juvenile and adult red kangaroos Macropus rufus Desmarest: why body size matters.
Using red kangaroos Macropus rufus Desmarest, a large (>20 kg) marsupial herbivore, we compared the digestive capabilities of juveniles with those of mature, non-lactating females on high-quality forage (chopped lucerne Medicago sativa hay) of 43+/-1% neutral-detergent fibre (NDF) and poorer quality, high-fibre forage (chopped oaten Avena sativa hay) of 64+/-1% NDF. On chopped lucerne apparent dry matter (DM) digestibilities by young-at-foot (YAF) red kangaroos (an age that would normally be taking some milk from their mother), weaned juveniles and mature females were similar (55-59%). On chopped oaten hay apparent DM digestibility was lower in the YAF (35.9+/-2.3%) followed by weaned (43.4+/-2.8%) and mature females (44.6+/-1%). The digestion of NDF and its components (mainly cellulose and hemicellulose) was lowest among the YAF followed by weaned and then mature females. The YAF and weaned kangaroos could not sustain growth on the poor-quality diet, and appeared to be at or near maximal gut fill on both forages; the values being 114-122 g DM for YAF and 151-159 g DM for weaned kangaroos. Mean retention times (MRT) of particle and solute markers were significantly longer for the YAF and weaned kangaroos on oaten hay than on lucerne hay, and DM intake (g d(-1)) was approximately 50% lower on the oaten hay. In contrast, solute and particle MRTs in the mature females were not significantly affected by diet; they maintained DM intakes by increasing DM gut fill from 264+/-24 g on chopped lucerne to 427+/-26 g DM on chopped oaten hay. Clearly, the mature female kangaroos did not maximise gut fill on the high-quality forage, presumably as a consequence of their proportionally lower energy requirements compared with still-growing juveniles. Overall, we have provided the first mechanistic link between the physiological constraints faced by juvenile red kangaroos in relation to their drought-related mortalities, rainfall and forage quality.


Intravenous access devices for supportive care of patients with cancer.
Reliable long-term venous access is crucial as a pathway for the delivery of many current chemotherapeutic agents, as well as for the supportive measures needed to sustain patients during their recovery from the toxic effects of these drugs. Many access devices are now available, but all carry the risk of infection, thrombosis, and complications related to their insertion. Recent advances in technology and the use of antibiotics and anticoagulants offer the opportunity to reduce the rate of many of these complications.


Prolonged, but transient, elevation of liver and biliary function tests in a healthy infant affected with breast milk jaundice.
Unconjugated hyperbilirubinaemia is a common finding in newborns. When it is exaggerated, it is usually investigated in order to exclude several diseases, such as newborn's haemolytic diseases, infections or hypothyroidism. Breast milk jaundice is a form of neonatal jaundice related to breast feeding and it is not usually associated with any clinical issue and/or other laboratory abnormalities. We describe a case of breast milk jaundice being associated, unexpectedly, to significant elevation of plasmatic liver and biliary enzymes. Despite the infant's good clinical condition and growth, several investigations were performed and these ruled out metabolic, infectious and autoimmune liver diseases. All liver function tests normalised by 6-7 months of life. We suggest that the finding of hypertransaminasaemia and hyper-γ-glutamyl transpeptidase in a benign clinical context (similar to what we described) should be followed for 6-7 months before performing sophisticated and expensive diagnostic investigations which aim at excluding some unlikely and severe diseases in a completely asymptomatic infant.


Functional outcomes in patients with brain tumor after inpatient rehabilitation: comparison with traumatic brain injury.
To compare the functional outcome, length of stay, and discharge disposition of individuals with brain tumor versus those with acute traumatic brain injury. In this study, 78 brain tumor patients were one-to-one matched by location of lesion and age with 78 acute traumatic brain injury patients. Outcome was measured by using the Functional Independence Measure (FIM 228) on admission and discharge. The FIM change and FIM efficiency were also calculated. FIM data were analyzed in three subsets, i.e., activities of daily living, mobility, and cognition. Discharge disposition and rehabilitation length of stay were also compared. Demographic variables of race, marital status, and payer source were comparable for the two groups. No significant difference was found between the brain tumor and the traumatic brain injury populations with respect to total admission FIM, total discharge FIM, and FIM efficiency. The brain injury population had a significantly greater change in FIM. The tumor group had a significantly shorter rehabilitation length of stay and a greater discharge to community rate. Thus, individuals with brain tumor can achieve comparable functional outcome and have a shorter rehabilitation length of stay and greater discharge to community rate than individuals with brain injury.


Do children who receive an 'early dose' of MMR vaccine during a measles outbreak return for their regularly scheduled dose? A retrospective population-based study.
Children under the age of 12 months may receive an early dose of measles-mumps-rubella (MMR) vaccine to provide short-term protection in the case of a disease outbreak. Following a measles outbreak in Alberta, Canada, there was concern that children who received an early dose may not be returning for their routinely scheduled dose at 12 months, leaving them vulnerable to disease in the long term. This population-based study of children born between 2006 and 2014 used administrative health data to assess coverage and timeliness of the first routine dose of MMR vaccine administered at age 12-24 months for children who received an early dose of the vaccine due to a disease outbreak. We compared this group to children who received an early dose due to travel to a measles-endemic region and to children who did not receive an early dose. Only 5.5% of 366 351 children received an early dose. Coverage for the routine dose at age 24 months was 96.5% for children receiving an outbreak dose, 92.2% for those travelling to measles-endemic regions and 86.6% for those without an early dose (p<0.0001). The multivariable Cox proportional hazard analysis, controlling for neighbourhood income, place of residence and interaction effects, determined that, as compared to the general cohort, the outbreak group was most likely to obtain the first routine dose (adjusted HR (aHR): 1.52, 95% CI 1.44 to 1.60), followed by the travel group (aHR: 1.26, 95% CI 1.18 to 1.34). It is reassuring that the majority of children who received an early dose returned for their routine dose and did so in a timely manner.


[Classification of combined chest and abdominal wounds].
On the basis of their experience with the treatment of 166 patients with injuries of the chest and abdomen the authors mark out simultaneous thoracoabdominal and abdomino-thoracal wounds. Among thoracoabdominal wounds there are trans- and extrapleural wounds with injuries of the central and peripheral portions of the diaphragm. Abdomino-thoracal wounds may be trans- and extraperitoneal and can penetrate into the pleural, pericardial and mediastinal cavities. This type of associated wounds of the chest and abdomen is most dangerous since in one third of the patients it includes wounds of the heart which are difficult for diagnosis.


Chitosan/PVA Based Membranes Processed by Gamma Radiation as Scaffolding Materials for Skin Regeneration.
Some of the current strategies for the development of scaffolding materials capable of inducing tissue regeneration have been based on the use of polymeric biomaterials. Chitosan, in particular, due to its recognized biological activity has been used in a number of biomedical applications. Aiming the development of chitosan-based membranes with improved cell adhesion and growth properties to be used as skin scaffolds allowing functional tissue replacement, different formulations with chitosan of different molecular weight, poly (vinyl alcohol) and gelatin, were evaluated. To meet the goal of getting ready-to-use scaffolds assuring membranes' required properties and sterilization, preparation methodology included a lyophilization procedure followed by a final gamma irradiation step. Two radiation dose values were tested. Samples were characterized by TGA, FTIR, and SEM techniques. Their hydrophilic properties, in vitro stability, and biocompatibility were also evaluated. Results show that all membranes present a sponge-type inner structure. Chitosan of low molecular weight and the introduction of gelatin are more favorable to cellular growth leading to an improvement on cells' morphology and cytoskeletal organization, giving a good perspective to the use of these membranes as potential skin scaffolds.


Social support processes and the adaptation of individuals with chronic disabilities.
In a qualitative study examining turning points in life, 15 adults with chronic disabilities (cerebral palsy, spina bifida, or attention deficit disorder) provided information about the nature and meaning of their social support experiences. The study revealed three types of psychological support linked to self-perceptions and enabling beliefs: (a) emotional support (valuing and acceptance leading to perceptions of "being believed in" and a sense of self-esteem), (b) instrumental support (guidance and provision of strategies leading to self-efficacy), and (c) cognitive support (affirmation, confirmation, and new perspectives leading to coherence in self-concept and worldview). The findings have important implications for service delivery with respect to understanding client needs for different kinds of support, especially at periods of transition, and for providing optimal experiences and creating supportive environments. In particular, the role of cognitive support deserves more attention in understanding the adaptation of individuals with chronic disabilities.


Phylogenomics reveals subfamilies of fungal nonribosomal peptide synthetases and their evolutionary relationships.
Nonribosomal peptide synthetases (NRPSs) are multimodular enzymes, found in fungi and bacteria, which biosynthesize peptides without the aid of ribosomes. Although their metabolite products have been the subject of intense investigation due to their life-saving roles as medicinals and injurious roles as mycotoxins and virulence factors, little is known of the phylogenetic relationships of the corresponding NRPSs or whether they can be ranked into subgroups of common function. We identified genes (NPS) encoding NRPS and NRPS-like proteins in 38 fungal genomes and undertook phylogenomic analyses in order to identify fungal NRPS subfamilies, assess taxonomic distribution, evaluate levels of conservation across subfamilies, and address mechanisms of evolution of multimodular NRPSs. We also characterized relationships of fungal NRPSs, a representative sampling of bacterial NRPSs, and related adenylating enzymes, including alpha-aminoadipate reductases (AARs) involved in lysine biosynthesis in fungi. Phylogenomic analysis identified nine major subfamilies of fungal NRPSs which fell into two main groups: one corresponds to NPS genes encoding primarily mono/bi-modular enzymes which grouped with bacterial NRPSs and the other includes genes encoding primarily multimodular and exclusively fungal NRPSs. AARs shared a closer phylogenetic relationship to NRPSs than to other acyl-adenylating enzymes. Phylogenetic analyses and taxonomic distribution suggest that several mono/bi-modular subfamilies arose either prior to, or early in, the evolution of fungi, while two multimodular groups appear restricted to and expanded in fungi. The older mono/bi-modular subfamilies show conserved domain architectures suggestive of functional conservation, while multimodular NRPSs, particularly those unique to euascomycetes, show a diversity of architectures and of genetic mechanisms generating this diversity. This work is the first to characterize subfamilies of fungal NRPSs. Our analyses suggest that mono/bi-modular NRPSs have more ancient origins and more conserved domain architectures than most multimodular NRPSs. It also demonstrates that the alpha-aminoadipate reductases involved in lysine biosynthesis in fungi are closely related to mono/bi-modular NRPSs. Several groups of mono/bi-modular NRPS metabolites are predicted to play more pivotal roles in cellular metabolism than products of multimodular NRPSs. In contrast, multimodular subfamilies of NRPSs are of more recent origin, are restricted to fungi, show less stable domain architectures, and biosynthesize metabolites which perform more niche-specific functions than mono/bi-modular NRPS products. The euascomycete-only NRPS subfamily, in particular, shows evidence for extensive gain and loss of domains suggestive of the contribution of domain duplication and loss in responding to niche-specific pressures.


Neuropsychological testing through a Nintendo Wii console.
In recent years, videogames have demonstrated their positive effects in the psychological treatments and cognitive training of the old population. In this paper we present a pilot study in which a group of elderly people in an old people's home was requested to play a set of cognitive tasks administered through a popular videogames console, the Nintendo Wii. The results obtained by comparing the Wii cognitive games with traditional paper and pencil tests are described and discussed to orient further improvements.


[Clinico-statistical patterns in the dynamics of episodes in schizophrenia].
An examination of schizophrenics living in three regions of Moscow and suffering from the disease for over 15 years has shown that the change of the episode form is a probability process exhibiting a tendency to retention of the form of the preceding episode in the subsequent ones. At the same time it has been shown that this tendency is more marked, if the preceding episodes were of one and the same type. When the episode form changed principal trends of that process were revealed. The patients' sex was found to exert no substantial influence on the regularities discovered. The patients getting older, the frequency of depressive episodes became greater at the expense of transformation of depressive-paranoid symptoms into depressive ones.


A participatory approach for building ex ante impact pathways towards a prudent use of antimicrobials in pig and poultry sectors in France.
Antimicrobial resistance (AMR) is a global public health threat responsible for 700,000 deaths per year worldwide. There is scientific evidence of the causal relationship between antimicrobial use (AMU) along the food chain and AMR. Improving AMU in livestock is therefore a key component in the fight against AMR. To improve AMU in livestock, there is no one-size-fits-all solution and strategies must be context-adapted and socially acceptable for actors in order to increase AMU sustainability. AMU decision-making is based on an interdependent set of economic, behavioral, ethical, and cultural factors that need to be assessed to advise on the potential impacts of measures. We hypothesized that a participatory strategic planning approach may increase the plausibility and the efficacy of the strategies formulated by facilitating the dialogue between actors of diverse backgrounds, stimulating innovative thinking and constant considerations of contextual factors, actors and impacts. We adapted and applied the ImpresS ex ante approach (IMPact in reSearch in the South, https://impress-impact-recherche.cirad.fr/) within a Living Lab engaging actors from the French pig and poultry sectors in co-creation of innovative strategies towards improved AMU. We conducted semi-structured interviews and participatory workshops between April 2021 and March 2022. The results describe 1) an initial diagnosis of the current AMU situation in the pig and poultry sectors in France; 2) a common vision of the future to which participants would like to contribute through the intervention; 3) an identification of the current problems opposed to this vision of the future; 4) a defined scope of the intervention; 5) a typology of actors protagonist or impacted by those issues and 6) outcome maps to solve a priority problem related to indicators and monitoring. This study provides recommendations for decision-makers on plausible and innovative strategies to sustainably improve AMU in pig and poultry sectors in France and evidence of the benefits of participatory strategic planning approaches.


Adherence and resource use among patients treated with biologic drugs: findings from BEETLE study.
Systemic administration of anti-tumor necrosis factor alpha (anti-TNF alpha) leads to an anti-inflammatory and joint protective effect in pathologies such as rheumatoid arthritis, psoriasis, and Crohn's disease. The aim of this study was to assess adherence to therapy, persistence in treatment (no switches or interruptions), and consumption of care resources (drugs, outpatient services, hospitalizations). We conducted an observational retrospective cohort analysis using the administrative databases of five local health units. Patients filling at least one prescription for anti-TNF alpha between January 1, 2009 and December 31, 2011 were included and followed up for 1 year. Patients were defined as adherent if >80% of the follow-up period was covered by drugs dispensation. A total of 1,219 patients were analyzed (mean age 49.6±14.6, male 47%). Among enrolled patients, 36% were affected by rheumatoid arthritis, and 31% and 10% were affected by psoriasis and Crohn's disease, respectively; other indications remained below these percentages. Thirty-four percent of patients (420) were treated with adalimumab, 51% (615) with etanercept, and 15% (184) with infliximab. Among the 94% of patients who did not switch, those treated with infliximab had a higher rate of adherence across all indications (51% overall) when compared to that observed in patients treated with etanercept (27%) or adalimumab (23%). The mean annual nonpharmacological expenditure for each patient in analysis was €988 for adherent and €1,255 for nonadherent patients. Infliximab was associated with the lowest cost for all indications as determined by the multivariate generalized linear model. Patients treated with infliximab were associated with higher adherence and persistence in treatment and lower costs, as compared to those treated with adalimumab or etanercept.


Protein Kinase A Deregulation in the Medial Prefrontal Cortex Impairs Working Memory in Murine Oligophrenin-1 Deficiency.
Classical and systems genetics have identified wide networks of genes associated with cognitive and neurodevelopmental diseases. In parallel to deciphering the role of each of these genes in neuronal or synaptic function, evaluating the response of neuronal and molecular networks to gene loss of function could reveal some pathophysiological mechanisms potentially accessible to nongenetic therapies. Loss of function of the Rho-GAP oligophrenin-1 is associated with cognitive impairments in both human and mouse. Upregulation of both PKA and ROCK has been reported in Ophn1-/y mice, but it remains unclear whether kinase hyperactivity contributes to the behavioral phenotypes. In this study, we thoroughly characterized a prominent perseveration phenotype displayed by Ophn1-deficient mice using a Y-maze spatial working memory (SWM) test. We report that Ophn1 deficiency in the mouse generated severe cognitive impairments, characterized by both a high occurrence of perseverative behaviors and a lack of deliberation during the SWM test. In vivo and in vitro pharmacological experiments suggest that PKA dysregulation in the mPFC underlies cognitive dysfunction in Ophn1-deficient mice, as assessed using a delayed spatial alternation task results. Functionally, mPFC neuronal networks appeared to be affected in a PKA-dependent manner, whereas hippocampal-PFC projections involved in SWM were not affected in Ophn1-/y mice. Thus, we propose that discrete gene mutations in intellectual disability might generate "secondary" pathophysiological mechanisms, which are prone to become pharmacological targets for curative strategies in adult patients.SIGNIFICANCE STATEMENT Here we report that Ophn1 deficiency generates severe impairments in performance at spatial working memory tests, characterized by a high occurrence of perseverative behaviors and a lack of decision making. This cognitive deficit is consecutive to PKA deregulation in the mPFC that prevents Ophn1 KO mice to exploit a correctly acquired rule. Functionally, mPFC neuronal networks appear to be affected in a PKA-dependent manner, whereas behaviorally important hippocampal projections were preserved by the mutation. Thus, we propose that discrete gene mutations in intellectual disability can generate "secondary" pathophysiological mechanisms prone to become pharmacological targets for curative strategies in adults.


Epidemiologic typing of nosocomial microorganisms.
Hospital epidemiologists often rely upon "typing" of microorganisms to help determine their genetic relatedness. Most general clinical microbiology laboratories can determine biologic profiles (biotypes) and antimicrobial susceptibility patterns (antibiograms) of bacteria commonly isolated from specimens; occasionally serologic typing (serotype) is also performed. Special interest laboratories can provide serologic typing, bacteriophage susceptibility patterns (phage typing), bacteriocin production patterns, bacteriocin susceptibility patterns, plasmid analyses and chromosomal DNA analyses for a variety of bacteria, mycobacteria and fungi of nosocomial interest. Such laboratories can also provide serologic typing, restriction enzyme analyses and other special studies of viruses and related microorganisms. A useful and effective "typing" system should be (1) standardized, (2) reproducible, (3) sensitive, (4) stable, (5) available, (6) inexpensive, (7) applicable to a wide range of microorganisms, and (8) field tested in conjunction with epidemiologic investigation. Results should be reported in a standard manner with some discussion of the implications and limitations of the reported results. We suggest that a registry of typing methods be established to facilitate application of available methods to appropriate epidemiologic investigations.


Evolution of droplets of perfectly wetting liquid under the influence of thermocapillary forces.
We consider the evolution of sessile droplets of a nonvolatile perfectly wetting liquid on differentially radially heated solid substrates. The heating induces thermocapillary Marangoni forces that affect the contact line dynamics. Our experiments involving a particular heating pattern reveal that the Marangoni effect suppresses the spreading of a drop, typical for perfectly wetting liquids. The result is a rather slow receding motion and a distinctive thinning of the liquid layer in the region close to the contact line. Our theoretical model, based on the lubrication approximation and incorporating the Marangoni effect, recovers the main features observed in the experiments, and in addition predicts novel features that are still to be observed.


Role of Mannheimia haemolytica leukotoxin in the pathogenesis of bovine pneumonic pasteurellosis.
Bovine pneumonic pasteurellosis continues to be a major respiratory disease in feedlot cattle despite the recent advances in our understanding of the underlying complexities of causation. The etiological agent, Mannheimia haemolytica, possesses several virulence factors, including capsule, outer membrane proteins, adhesins, neuraminidase, endotoxin and exotoxic leukotoxin. Accumulating scientific evidence implicates leukotoxin as the primary factor contributing to clinical presentation and lung injury associated with this disease. Unlike other virulence factors, leukotoxin shows cell-type- and species-specific effects on bovine leukocytes. Recent investigations have delineated the mechanisms underlying the target-cell-specificity of leukotoxin and how this contributes to the pathogenesis of lung damage. This review summarizes current understanding of the secretion, regulation, mechanisms of action and evolutionary diversity of leukotoxin of M. haemolytica. Understanding the precise molecular mechanisms of leukotoxin is critical for the development of more effective prophylactic and therapeutic strategies to control this complex disease.


Suppression of HBV replication by the expression of nickase- and nuclease dead-Cas9.
Complete removal of hepatitis B virus (HBV) DNA from nuclei is difficult by the current therapies. Recent reports have shown that a novel genome-editing tool using Cas9 with a single-guide RNA (sgRNA) system can cleave the HBV genome in vitro and in vivo. However, induction of a double-strand break (DSB) on the targeted genome by Cas9 risks undesirable off-target cleavage on the host genome. Nickase-Cas9 cleaves a single strand of DNA, and thereby two sgRNAs are required for inducing DSBs. To avoid Cas9-induced off-target mutagenesis, we examined the effects of the expressions of nickase-Cas9 and nuclease dead Cas9 (d-Cas9) with sgRNAs on HBV replication. The expression of nickase-Cas9 with a pair of sgRNAs cleaved the target HBV genome and suppressed the viral-protein expression and HBV replication in vitro. Moreover, nickase-Cas9 with the sgRNA pair cleaved the targeted HBV genome in mouse liver. Interestingly, d-Cas9 expression with the sgRNAs also suppressed HBV replication in vitro without cleaving the HBV genome. These results suggest the possible use of nickase-Cas9 and d-Cas9 with a pair of sgRNAs for eliminating HBV DNA from the livers of chronic hepatitis B patients with low risk of undesirable off-target mutation on the host genome.


Insomnia in the context of traumatic brain injury.
Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality in the United States. One of the most common comorbidities of TBI is the disruption of normal sleep. While often viewed as a nuisance symptom, sleep disruption can delay TBI recovery and negatively affect many of the psychological (e.g., anxiety, depression) and neuromuscular (e.g., pain) sequelae of TBI, decreasing quality of life. Treatment of sleep disruption in the context of TBI is complicated by issues of an altered neuronal milieu, polypharmacy, and the complex relationship between the various comorbidities often found in patients with TBI. Given the growing number of veterans returning from combat with TBI and the elevated risk of comorbid disrupted sleep, both caused by and independent of TBI, a comprehensive review of sleep disruption and its treatment is of great relevance to the Department of Veterans Affairs.


Effects of Withania somnifera root extract serum application on hair health in healthy adults: A prospective, double-blind, randomized, parallel, placebo-controlled study.
Alopecia is a dermatological condition affecting genders, negatively impacting their personality and quality of life (QoL). The current approved entities are limited, inconsistently effective, and associated with negative side effects. To alleviate this issue, ayurvedic herbs such as Ashwagandha have being explored. As a result, this study was designed to evaluate the efficacy and safety of Ashwagandha (root extract) topical formulation (serum) on hair health in healthy adults. In this prospective, double-blind, randomized, placebo controlled, two arm, parallel, comparative study, the effects of topical Ashwagandha on the hair health was evaluated. Healthy adults between 18 and 45 years with mild to moderate hair loss were randomized to either Ashwagandha (topical) or Placebo (topical) treatment. The participants were assessed at Day-1 and Day-75 for change in efficacy parameters, which included 60 Seconds Hair Comb, Trichoscan analysis, Hair Pull test, Investigator's Global Assessment (IGA) and QoL using Hair-specific Skindex-29. In the per protocol analysis of 61 participants, Ashwagandha group demonstrated significant reduction in hair shedding in the 60 Seconds Hair Comb test compared to Placebo at day 75. Similarly, Ashwagandha substantially enhanced hair density, growth, and thickness compared to the Placebo group (density = 7.3 vs. 2.8, P < 0.001; growth = 21.7 vs. 4.2, P < 0.001; thickness = 1.8 vs. 0.9, P < 0.001). In addition, Ashwagandha significantly improved QOL compared to placebo (Score = -17.3 vs. -6.1, P = 0.011). The study found that topical Ashwagandha (serum) improved hair growth and hair health indicators. Thus, it can be an effective and safer alternative for alopecia. CTRI, Number CTRI/2022/11/047539, Registered on: 23/11/2022.