Assessment and molecular actions of endocrine-disrupting chemicals that interfere with estrogen receptor pathways.
In all vertebrate species, estrogens play a crucial role in the development, growth, and function of reproductive and nonreproductive tissues. A large number of natural or synthetic chemicals present in the environment and diet can interfere with estrogen signaling; these chemicals are called endocrine disrupting chemicals (EDCs) or xenoestrogens. Some of these compounds have been shown to induce adverse effects on human and animal health, and some compounds are suspected to contribute to diverse disease development. Because xenoestrogens have varying sources and structures and could act in additive or synergistic effects when combined, they have multiple mechanisms of action. Consequently, an important panel of in vivo and in vitro bioassays and chemical analytical tools was used to screen, evaluate, and characterize the potential impacts of these compounds on humans and animals. In this paper, we discuss different molecular actions of some of the major xenoestrogens found in food or the environment, and we summarize the current models used to evaluate environmental estrogens.


A marine secondary producer respires and feeds more in a high CO2 ocean.
Climate change mediates marine chemical and physical environments and therefore influences marine organisms. While increasing atmospheric CO(2) level and associated ocean acidification has been predicted to stimulate marine primary productivity and may affect community structure, the processes that impact food chain and biological CO(2) pump are less documented. We hypothesized that copepods, as the secondary marine producer, may respond to future changes in seawater carbonate chemistry associated with ocean acidification due to increasing atmospheric CO(2) concentration. Here, we show that the copepod, Centropages tenuiremis, was able to perceive the chemical changes in seawater induced under elevated CO(2) concentration (>1700 μatm, pH<7.60) with avoidance strategy. The copepod's respiration increased at the elevated CO(2) (1000 μatm), associated acidity (pH 7.83) and its feeding rates also increased correspondingly, except for the initial acclimating period, when it fed less. Our results imply that marine secondary producers increase their respiration and feeding rate in response to ocean acidification to balance the energy cost against increased acidity and CO(2) concentration.


Highly transparent, mechanical, and self-adhesive zwitterionic conductive hydrogels with polyurethane as a cross-linker for wireless strain sensors.
Zwitterionic hydrogels have attracted a myriad of research interests for their excellent flexibility and biocompatibility as flexible wearable sensors. It is desired to create E-skins that integrate high mechanical strength, sensory sensitivity, and broad adhesion, possessing potential in the fields of intelligent robots and bionic prostheses. In this work, a novel macromolecular cross-linker (MPU) based on waterborne polyurethane (WPU) was designed and applied to synthesize multifunctional conductive hydrogels (PASU-Zn hydrogels). Importantly, in the presence of MPU, the hydrogels exhibited well-balanced mechanical properties (elongation at break 1193%, tensile strength 1.02 MPa, outstanding puncture resistance, and self-recovery abilities). When assembled as wireless strain sensors, PASU-Zn sensors displayed distinguished sensing characteristics to detect mechanotransduction signals of human movements in real-time. Specifically, owing to the dipole-dipole interaction and hydrogen bonding of zwitterions and MPU, the hydrogels have remarkable self-adhesion properties to various surfaces of wood, PDMS, and pigskin, allowing them to stick to skins by themselves without using any adhesive tapes when used. It is deemed that the as-designed zwitterionic hydrogels show great promise for wearable devices and bionic skins.


A Novel Stitching Technique: Adjustable Closed-Loop Sewing Machine Lock Stitching Technique to Bend or Unbend Cartilages.
This study aimed to evaluate the effect of a novel adjustable, closed-loop sewing machine lock stitching technique on cartilage shape. This study was performed on 18 rabbits that were divided into 3 groups to evaluate the short- (Group I), medium- (Group II), and long-term (Group III) effects of the technique on cartilage shape. Three cartilage grafts were obtained from the right and left ears of the rabbits and measured angularly. For the cartilage grafts obtained from the right ears, contours were corrected using the stitching technique proposed herein. The cartilage grafts obtained from the left ears were not stitched; these were maintained as the control group. Angular measurements were performed for the stitched cartilage grafts, and all the cartilages grafts obtained were finally embedded into the rabbits' backs. The rabbits in Groups I, II, and III were euthanized at week 2, 6, and 12, respectively, after which the cartilages were reevaluated for angular measurement and submitted for histopathological examination. A significant improvement from baseline was detected in the angular measurements of the stitched cartilage grafts obtained from the rabbits in each group. For the stitched cartilage grafts obtained from Group II and III rabbits, the angular measurements obtained immediately after stitching were found to be better than those obtained after euthanasia. In histopathological evaluation elevated collagen, perichondrium, and connective tissue levels were detected in grafts obtained from Group III rabbits. The novel stitching technique proposed herein appears to have beneficial long-term effects on the maintenance of cartilage contour.


Pain education at the University of Washington School of Medicine.
Contemporary medical education is inadequate to prepare medical students to competently assess and design care plans for patients with acute and chronic pain. The time devoted to pain education in most medical school curricula is brief and not integrated into case-based clinical experiences, and it is frequently nonexistent during clinical clerkships. Medical student pain curricula have been proposed for over 30 years and are commonly agreed upon, though rarely implemented. As a consequence of poor undergraduate pain education, postgraduate trainees and practicing physicians struggle with both competency and practice satisfaction; their patients are similarly dissatisfied. At the University of Washington School of Medicine, a committee of multidisciplinary pain experts has, between 2009 and 2011, successfully introduced a 4-year integrated pain curriculum that increases required pain education teaching time from 6 to 25 hours, and clinical elective pain courses from 177 to 318 hours. It is expected that increased didactic and case-based multidisciplinary clinical training will increase knowledge and competency in biopsychosocial measurement-based pain narrative and risk assessment, improve understanding of persistent pain as a chronic complex condition, and expand the role of patient-centered interprofessional treatment for medical students, residents, and fellows, leading to better prepared practicing physicians. Strategies for improving multidisciplinary pain education at the University of Washington School of Medicine are described and the preliminary results demonstrated.


Amorphous co-doped MoSex effectively enhances photocatalysis in visible light.
Molybdenum selenide has great potential for the degradation of water pollutants, but its performance is limited by the active sites and recombination of photogenerated electron-hole pairs. In this study, an amorphous co-doped MoSex (Co-MoSex) sample was synthesized by a low-temperature hydrothermal method. Three types of unsaturated Se-Se bonds were found in Co-MoSex by Raman spectroscopy: bridging diselenide, shared diselenide, and terminal diselenide. Photocatalytic experimental results revealed that the degradation rate of Co-MoSex to methylene blue was 96.3%, the degradation rate of amorphous MoSex (a-MoSex) was 61.6%, and the degradation rate of crystalline molybdenum selenide (c-MoSe2) was 23.2%. Furthermore, it was found that the band gap of the Co-MoSex photocatalyst was reduced by 0.15 eV compared to the a-MoSex photocatalyst. The photocatalytic activity of the co-doped MoSex was enhanced by increasing the unsaturated Se atom active sites, reducing the recombination of photogenerated electron-hole pairs, and improving light utilization.


The Macroautophagy Machinery in Endo- and Exocytosis.
Macroautophagy and the autophagy-related gene (Atg) machinery execute during their canonical function cytoplasmic constituent degradation in lysosomes. This canonical function contributes to pathogen restriction and intracellular antigen presentation on major histocompatibility complex (MHC) class II molecules to CD4+ T cells. However, in the recent years, it has become clear that the Atg machinery is also used for other membrane transport functions, including endocytosis and exocytosis. This review describes these non-canonical functions in the context of antigen presentation on MHC class I and II molecules to CD8+ and CD4+ T cells, respectively, and during viral replication. Future studies will need to address how the Atg machinery is modified for these non-canonical functions, gets recruited to the respective sites of membrane modification, and recruits alternative Atg interactors to execute endo- and exocytosis instead of macroautophagy.


Fossil evidence for a hyperdiverse sclerophyll flora under a non-Mediterranean-type climate.
The spectacular diversity of sclerophyll plants in the Cape Floristic Region in South Africa and Australia's Southwest Floristic Region has been attributed to either explosive radiation on infertile soils under fire-prone, summer-dry climates or sustained accretion of species under inferred stable climate regimes. However, the very poor fossil record of these regions has made these ideas difficult to test. Here, we reconstruct ecological-scale plant species richness from an exceptionally well-preserved fossil flora. We show that a hyperdiverse sclerophyll flora existed under high-rainfall, summer-wet climates in the Early Pleistocene in southeastern Australia. The sclerophyll flora of this region must, therefore, have suffered subsequent extinctions to result in its current relatively low diversity. This regional loss of sclerophyll diversity occurred at the same time as a loss of rainforest diversity and cannot be explained by ecological substitution of species of one ecological type by another type. We show that sclerophyll hyperdiversity has developed in distinctly non-Mediterranean climates, and this diversity is, therefore, more likely a response to long-term climate stability. Climate stability may have both reduced the intensity of extinctions associated with the Pleistocene climate cycles and promoted the accumulation of species richness by encouraging genetic divergence between populations and discouraging plant dispersal.


Fear appeals in HIV-prevention messages: young people's perceptions in northern Tanzania.
The aims of the study were to elicit the perceptions of young people in Tanzania on the role of fear appeals in HIV-prevention messages and to identify important contextual factors that may influence young people's perceptions of HIV-prevention posters. A total of 10 focus groups were conducted to investigate the role of fear appeals using the extended parallel process model (EPPM) as a guide. Young people were shown a series of images (mostly posters) with alternating high and low-threat messages (fear appeals), and then asked questions about their overall beliefs about HIV and AIDS, as well as about their response in terms of perceived susceptibility to HIV infection, the severity of the message, and their perceptions of self-efficacy and response efficacy. The images and messages that specifically targeted young people were highest in inducing perceived susceptibility to HIV infection, while pictorial descriptions of the physical consequences of HIV infection and those messages related to the stigma and discrimination faced by HIV-infected or affected people induced greater perceptions of severity. The information-based posters rated high in inducing response efficacy, while none of the images seemed to convince young people that they had the self-efficacy to perform the recommended health behaviours. The young people expressed a preference for fear-based appeals and a belief that this could work well in HIV-prevention efforts, yet they also stated a desire for more information-based messages about how to protect themselves. Finally, the messages evoking the most emotional responses were those that had been locally conceived rather than ones developed by large-scale donor-funded campaigns. Finding the appropriate balance between fear and efficacy in HIV-prevention messages is imperative. Further research is needed to better understand how and when fear appeals work and do not work in African settings, especially among young people.


Impact of Institutional Volume on Critical In-Hospital Complications Adjusted for Patient- and Limb-Related Characteristics: An Analysis of a Nationwide Japanese Registry of Endovascular Interventions for PAD.
To investigate the incidence and clinical predictors, including institutional annual case volume, of critical in-hospital complications after endovascular therapy (EVT) for peripheral artery disease (PAD). The data were extracted from the nationwide registry of peripheral interventions in Japan [Japanese EVT (J-EVT)] between 2012 and 2017. A total of 92,224 EVT cases either for chronic limb-threatening ischemia (CLTI) or intermittent claudication were included in the analysis. The primary outcome measure was critical in-hospital complications, which were defined as a composite of urgent surgery and in-hospital death within 30 days after EVT. The institutional volume was classified into quartiles. The association of institutional volume, as well as baseline characteristics, with the critical in-hospital complications was explored using a multivariable logistic regression model with multiple imputation for missing data. Results are presented as the adjusted odds ratio (OR) with the 95% confidence intervals (CI). The estimated prevalence of critical in-hospital complications was 0.3% (95% CI 0.3% to 0.4%). The following 10 patient- and limb-related characteristics were identified as independent risk factors for critical in-hospital complications: (1) female sex (OR 1.75, 95% CI 1.36 to 2.25), (2) age ≥75 years (OR 1.60, 95% CI 1.06 to 2.40), (3) CLTI (OR 2.12, 95% CI 1.47 to 3.05), (4) nonambulatory status (OR 1.66, 95% CI 1.23 to 2.24), (5) regular dialysis (OR 1.35, 95% CI 1.02 to 1.77), (6) cerebrovascular disease (OR 1.76, 95% CI 1.33 to 2.33), (7) urgent revascularization (OR 5.10, 95% CI 3.64 to 7.13), (8) aortoiliac TASC II D lesion (OR 3.65, 95% CI 2.51 to 5.33), (9) femoropopliteal TASC II D lesion (OR 1.77, 95% CI 1.24 to 2.52), and (10) infrapopliteal TASC D lesion (OR 1.52, 95% CI 1.08 to 2.13). In addition, the 4th quartile of the institutional volume (≥158 cases/year), but not the 2nd or 3rd quartile, had a significantly and independently lower risk of critical in-hospital complications than the 1st quartile (OR 0.13, 95% CI 0.07 to 0.23). After EVT for symptomatic PAD, 0.3% of the population encountered critical in-hospital complications. A higher institutional volume was significantly associated with a lower risk of critical in-hospital complications.


GM2 activator protein expression in mouse tissues.
The GM2 activator protein is an essential cofactor of hexosaminidase A in the degradation of GM2 ganglioside and it is responsible for the variant AB of GM2 gangliosidosis in man. In this study GM2 activator protein and its mRNA were determined in different mouse tissues. It was found that this protein is expressed mostly in the spleen and testis followed by brain and kidney which represent the main source in man. It is also interesting that in mouse testis there is a higher expression of the alpha subunit of hexosaminidase, thus suggesting a relationship between alpha subunit and GM2 activator protein. Furthermore the results indicate that the expression of GM2 activator protein is regulated, at least in part, at the transcriptional level.


Frequency and Duration of Incarceration and Mortality Among US Veterans With and Without HIV.
Exposure to incarceration is associated with increased risk of mortality, and HIV is cited as a leading cause of death. Yet, few studies have examined the association between incarceration and mortality among people with HIV (PWH), specifically whether and how increasing exposure to incarceration increases risk of mortality. We compared mortality by different incarceration exposures and HIV status. We conducted a prospective cohort study of participants in the Veterans Aging Cohort Study from January 2011 to August 2017 (N = 5367). The primary exposure was incarceration by 3 measures: (1) any (ever/never); (2) frequency; and (3) cumulative duration. Stratifying by HIV status and controlling for age, race, and sex, we used Cox Proportional Hazard models to estimate adjusted hazard ratios (AHRs) and 95% confidence intervals (CIs). Incarceration was associated with increased risk of mortality compared with those never incarcerated for PWH (AHR 1.37; 95% CI: 1.13 to 1.66) and those uninfected (AHR 1.24; 95% CI: 0.99 to 1.54), but the association was only statistically significant among PWH. Increasing frequency of incarceration was associated with higher risk of mortality in both groups: for PWH, AHRs 1.13, 1.45, and 1.64 for 1, 2-5; 6+ times, respectively, for uninfected, AHRs 0.98, 1.35, and 1.70 for 1, 2-5, and 6+ times, respectively. PWH were at increased risk of mortality after incarceration, and repeated exposure to incarceration was associated with mortality in both groups in a dose-response fashion. This increased risk of mortality may be mitigated by improving transitional health care, especially HIV care, and reducing incarceration.


Human cytomegalovirus infection induces specific hyperphosphorylation of the carboxyl-terminal domain of the large subunit of RNA polymerase II that is associated with changes in the abundance, activity, and localization of cdk9 and cdk7.
Human cytomegalovirus infection in the presence of the cyclin-dependent kinase (cdk) inhibitor roscovitine leads to changes in differential splicing and the polyadenylation of immediate early IE1/IE2 and UL37 transcripts (V. Sanchez, A. K. McElroy, J. Yen, S. Tamrakar, C. L. Clark, R. A. Schwartz, and D. H. Spector, J. Virol. 78:11219-11232, 2004). To determine if this was associated with specific phosphorylation of the C-terminal domain (CTD) of the RNA polymerase II (RNAP II) large subunit by cdk7/cyclin H and cdk9/cyclin T1, we examined the expression and localization of these kinases and the various phosphorylated forms of RNAP II. Infection resulted in increased RNAP II CTD phosphorylated on serines 2 and 5 and increased levels of activity of cdk7 and cdk9. At early times, cdk9 localizes with input viral DNA, and aggregates of cdk9 and cdk7 and a subset of Ser2-phosphorylated RNAP II colocalize with IE1/IE2 proteins adjacent to promyelocytic leukemia protein oncogenic domains. Later, cdk9 and Ser2-phosphorylated RNAP II form a nuclear punctate pattern; cdk7 resides in replication centers, and Ser5-phosphorylated RNAP II clusters at the peripheries of replication centers. Roscovitine treatment leads to decreased levels of hyperphosphorylated RNAP II (RNAP IIo) in infected cells and of hypophosphorylated RNAP II in mock-infected and infected cells. The RNAP IIo decrease does not occur if roscovitine is added 8 h postinfection, as was previously observed for processing of IE transcripts. These results suggest that accurate IE gene expression requires specific phosphorylation of the RNAP II CTD early in infection.


From presentation to follow-up: diagnosis and treatment of cerebral venous thrombosis.
Cerebral venous thrombosis is an uncommon cause of stroke but remains a challenge for physicians faced with this diagnosis largely due to the variability in presentation. Anticoagulation, typically with intravenous heparin, remains the mainstay of treatment for stable patients and is sufficient in the majority of cases. However, a significant mortality rate exists for cerebral venous thrombosis due to patients who deteriorate or do not adequately respond to initial treatments. It is in these patients that more aggressive interventions must be undertaken. The neurosurgeon is often called on, either acutely for initial evaluation of the stroke or venous hemorrhage or after the failure of initial therapy for clot evacuation, hemicraniectomy, or thrombectomy. A proper workup must include a search for an underlying, correctable cause as well as thorough follow-up with correction of identified risk factors to decrease the risk of recurrent disease.


Perspectives on the basis of seizure-induced respiratory dysfunction.
Epilepsy is an umbrella term used to define a wide variety of seizure disorders and sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in epilepsy. Although some SUDEP risk factors have been identified, it remains largely unpredictable, and underlying mechanisms remain poorly understood. Most seizures start in the cortex, but the high mortality rate associated with certain types of epilepsy indicates brainstem involvement. Therefore, to help understand SUDEP we discuss mechanisms by which seizure activity propagates to the brainstem. Specifically, we highlight clinical and pre-clinical evidence suggesting how seizure activation of: (i) descending inhibitory drive or (ii) spreading depolarization might contribute to brainstem dysfunction. Furthermore, since epilepsy is a highly heterogenous disorder, we also considered factors expected to favor or oppose mechanisms of seizure propagation. We also consider whether epilepsy-associated genetic variants directly impact brainstem function. Because respiratory failure is a leading cause of SUDEP, our discussion of brainstem dysfunction focuses on respiratory control.


Protease inhibitor therapy is associated with markedly prolonged time to relapse and improved survival in AIDS patients with cytomegalovirus retinitis.
Prior to the use of highly active antiretroviral therapy (HAART), cytomegalovirus retinitis (CMV-R) in AIDS patients was characterized by multiple relapses and decreased survival. Recent data suggest that CMV-R in patients treated with HAART may remain relapse-free for long periods. We performed a study of the effects of HIV protease inhibitors (PIs) on the incidence of relapse and time to death in AIDS patients with CMV-R treated with anti-CMV therapy. Medical records of all AIDS patients with CMV-R at Parkland Memorial Health and Hospital System treated with anti-CMV agents were reviewed for date of diagnosis of CMV-R, date of CMV-R relapse, type and duration of anti-CMV therapy, and duration of PI therapy. Relapse rates in subjects treated with PIs were compared with the relapse rates in those who were not treated with PIs. The primary endpoint was the time to relapse and death as determined by Kaplan-Meier analysis. Multivariate analysis was performed by Cox proportional hazard model. One hundred and nine cases of CMV-R were identified in 75 patients. Median follow-up time was 247 days (range 31-1818 days). There were 0.54 relapses per 1000 patient days in the group treated with PIs compared with 1.83 relapses per 1000 patient days in the non-PI treatment group (relative risk [RR]=0.29, P<0.01). Time to relapse was increased in the PI treatment group compared with the non-PI treatment group (endpoint not reached vs 182 days, P<0.001, log-rank). Similarly, the time to relapse or death was increased in the PI group compared with the non-PI group (543 days vs 103 days, P<0.001, log-rank). Multivariate analysis utilizing the Cox proportional hazards model demonstrated that only PI therapy but not anti-CMV therapy was associated with decreased risk of CMV-R relapse or death. Only 3 patients with an undetectable HIV viral load and one patient with a CD4 count >120 cells/microl had a relapse. We conclude that patients with CMV-R treated with HAART containing a PI have increased time to relapse and have prolonged survival.


Modulation of actin mechanics by caldesmon and tropomyosin.
The ability of cells to sense and respond to physiological forces relies on the actin cytoskeleton, a dynamic structure that can directly convert forces into biochemical signals. Because of the association of muscle actin-binding proteins (ABPs) may affect F-actin and hence cytoskeleton mechanics, we investigated the effects of several ABPs on the mechanical properties of the actin filaments. The structural interactions between ABPs and helical actin filaments can vary between interstrand interactions that bridge azimuthally adjacent actin monomers between filament strands (i.e. by molecular stapling as proposed for caldesmon) or, intrastrand interactions that reinforce axially adjacent actin monomers along strands (i.e. as in the interaction of tropomyosin with actin). Here, we analyzed thermally driven fluctuations in actin's shape to measure the flexural rigidity of actin filaments with different ABPs bound. We show that the binding of phalloidin increases the persistence length of actin by 1.9-fold. Similarly, the intrastrand reinforcement by smooth and skeletal muscle tropomyosins increases the persistence length 1.5- and 2- fold respectively. We also show that the interstrand crosslinking by the C-terminal actin-binding fragment of caldesmon, H32K, increases persistence length by 1.6-fold. While still remaining bound to actin, phosphorylation of H32K by ERK abolishes the molecular staple (Foster et al. 2004. J Biol Chem 279;53387-53394) and reduces filament rigidity to that of actin with no ABPs bound. Lastly, we show that the effect of binding both smooth muscle tropomyosin and H32K is not additive. The combination of structural and mechanical studies on ABP-actin interactions will help provide information about the biophysical mechanism of force transduction in cells.


Monoclonal antibody Ki-M4 specifically recognizes human dendritic reticulum cells (follicular dendritic cells) and their possible precursor in blood.
Ki-M4, a new IgG3 monoclonal antibody, selectively recognizes dendritic reticulum cells (DRC; follicular dendritic cells) in all human lymphatic organs, as tested by the immunoperoxidase method on the light and electron microscopic level. This antibody was raised against separated lysosomes of the 12-0-tetradecanoyl phorbol-13-acetate (TPA) stimulated permanent cell line, U-937, derived from a human histiocytic lymphoma. No cross-reactivity was encountered in epithelial and mesenchymal cells, including macrophages and other cells detectable in bronchial and peritoneal lavages. In the nonadherent fraction of the mononuclear blood cells collected from the interphase of a Ficoll-Urografin gradient (density = 1.077 g/ml), 0.1 per million of the cells hitherto not classified as monocytes or lymphocytes showed a strong reaction. All other separated blood cell types were devoid of any reactivity. The observation that DRC share a highly restricted, and thus specific, antigen with a small but distinct subpopulation of mononuclear leukocytes implies their blood derivation.


Non-GCB Diffuse Large B-Cell Lymphoma With an Atypical Disease Course: A Case Report and Clinical Exome Analysis.
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid tumor among other non-Hodgkin lymphomas (30-40% of all cases). This type of lymphoma is characterized by significant differences in treatment response and the heterogeneity of clinical traits. Approximately 60% of patients are cured using standard chemotherapy (CT), while in 10-15% of cases, the tumor is characterized by an extremely aggressive course and resistance to even the most high-dose programs with autologous stem cell transplantation (auto-SCT). The activated B-cell (ABC) subtype of DLBCL is characterized by poor prognosis. Here, we describe a clinical case of diffuse ABC-DLBCL with an atypical disease course. Complete remission was achieved after four courses of CT, followed by autologous hematopoietic stem cell transplantation (auto-HSCT). However, early relapse occurred 2 months after the completion of treatment. According to the results of cytogenetic studies, significant chromosome breakdowns were observed. Exome sequencing allowed for the detection of several novel mutations that affect components of the NOTCH2 and NF-κB signaling pathways, a number of epigenetic regulators (KMT2D, CREBBP, EP300, ARID1A, MEF2B), as well as members of the immunoglobulin superfamily (CD58 and CD70). Whether these mutations were the result of therapy or were originally present in the lymphoid tumor remains unclear. Nevertheless, the introduction of genomic technologies into clinical practice is important for making a diagnosis and developing a DLBCL treatment regimen with the use of targeted drugs.


Persistent plus disease after laser in retinopathy of prematurity with tetralogy of Fallot.
We present a patient with retinopathy of prematurity (ROP) who received panretinal photocoagulation (PRP), but in whom plus disease developed, likely secondary to a complicated cardiovascular history, including DiGeorge syndrome and tetralogy of Fallot. Interventional case report with clinical and angiographic correlation. Our patient had been born at 29 weeks and 2 days gestational age with a birthweight of 940 grams, tetralogy of Fallot, DiGeorge syndrome, and major aortopulmonary collaterals. Type 1 Early Treatment for Retinopathy of Prematurity ROP (zone 2, stage 2 with plus) developed, requiring PRP. Worsening plus disease developed and mild further PRP was performed. Despite this, plus disease persisted. We report plus disease even after appropriate PRP therapy for ROP. In this case, it is likely the patient's cardiovascular diseases that caused the persistent plus disease. Vascular tortuosity can be due to a number of different systemic disorders, so it is important to consider an infant's systemic conditions in the evaluation of ROP.


Comparison of Physician Therapeutic Inertia for Management of Patients With Multiple Sclerosis in Canada, Argentina, Chile, and Spain.
There is growing interest in understanding and addressing factors that govern the decision-making process in multiple sclerosis (MS) care. Therapeutic inertia (TI) is the failure to escalate therapy when goals are unmet. Limited data are available on the prevalence of TI and factors affecting therapeutic decisions in the management of patients with MS worldwide. To compare TI across 4 countries (Canada, Argentina, Chile, and Spain) and to identify factors contributing to TI. Prospective cohort study conducted between July 10, 2017, and May 4, 2018. Participants were exposed to behavioral experiments in which instruments were used to assess their risk preferences (eg, aversion to ambiguity) and therapeutic decisions in 10 simulated MS case scenarios. Mixed-effects linear and logistic regression analyses were performed to determine the association between the participants' baseline characteristics and TI. The association of unmeasured confounders was assessed by the E-value and a bootstrapping analysis. This multicenter study included neurologists practicing at academic and community centers in Canada, Argentina, Chile, and Spain who make therapeutic decisions for patients with MS. The primary outcome was the prevalence of TI. The TI score was calculated by dividing the number of case scenarios in which participants showed TI by the number of case scenarios that measured TI. Higher TI scores indicated greater degrees of TI. The secondary outcome was the identification of factors that contributed to TI. Of 300 neurologists with expertise in MS care who were invited to be part of the study, 226 (75.3%) agreed to participate. Among those who initially showed interest in participating, 195 physicians (86.3%) completed the study, while 31 did not. The mean (SD) age of participants was 43.3 (11.2) years; 52.3% were male. Therapeutic inertia was present in 72.8% (142 of 195) of participants, leading to suboptimal decisions in 20.4% (318 of 1560) of case scenarios. The prevalence of TI among the Canadian group was the lowest compared with the other 3 countries (60.0% [33 of 55] vs 77.9% [109 of 140]; P = .01). For the primary outcome, the TI score in the Canadian group (mean [SD], 0.98 [1.15]) was significantly lower compared with groups from other countries (mean [SD], 1.70 [1.43] for Argentina, 2.24 [1.54] for Chile, and 2.56 [1.64] for Spain) (P = .001). The mixed-effects linear models revealed that participants from Argentina, Chile, and Spain (combined) had higher TI scores compared with their Canadian counterparts (β coefficient, 0.90; 95% CI, 0.52-1.28; P < .001). A higher number of patients with MS per week (OR, 0.44; 95% CI, 0.22-0.88), years of practice (OR, 0.93; 95% CI, 0.86-0.99), and participation from Canada (OR, 0.47; 95% CI, 0.23-0.96) were associated with a lower likelihood of TI. Aversion to ambiguity was associated with a 2-fold higher likelihood of TI (OR, 2.25; 95% CI, 1.02-5.00). All 95% CIs of the β coefficients of covariates were lower than the E-value of 2.35, making it unlikely for the results to be due to the association of unmeasured confounders. This study showed that Canadian participants had the lowest prevalence and magnitude of TI. Higher TI scores were associated with a lower expertise in MS care and with a greater tendency for aversion to ambiguity.


Molecular basis of acute intermittent porphyria: mutations and polymorphisms in the human hydroxymethylbilane synthase gene.
Acute intermittent porphyria (AIP) is an autosomal dominant inborn error of metabolism that results from the half-normal activity of the third enzyme in the heme biosynthetic pathway, hydroxymethylbilane synthase (HMB-synthase). AIP is an ecogenetic condition, with life-threatening acute attacks precipitated by various factors including drugs, alcohol, fasting, and certain hormones. Biochemical diagnosis is problematic and the identification of mutations in the HMB-synthase gene provides accurate detection of presymptomatic heterozygotes, permitting avoidance of the acute precipitating factors. Two HMB-synthase isozymes are encoded by the HMB-synthase gene: one unique to erythroid cells and the other a housekeeping isozyme present in all cells. These two isozymes arise from a single gene by alternative splicing. The recent isolation of the cDNAs and entire genomic sequence encoding the HMB-synthase isozymes has facilitated the detection of diagnostically useful intragenic polymorphisms and disease-causing mutations. Of the 36 mutations identified to date, most caused the classic form of AIP. These mutations included small deletions and insertions, point mutations and RNA splice junction alterations and resulted in the half-normal activity of both the erythroid-specific and housekeeping isozymes. Most AIP mutations were private; however, certain mutations were frequently found in Dutch (R116W) and Swedish (W198X) AIP families. A variant form of AIP, in which patients have normal erythroid activity, but half-normal activity of the housekeeping isozyme, resulted from two mutations at the exon 1/intron 1 boundary, each altering splicing of the hepatic-specific transcript. In addition, 10 polymorphisms in the HMB-synthase gene have been identified that are useful for the diagnosis of presymptomatic AIP heterozygotes in families whose specific mutations have not been determined.


[Human adaptation to climatic changes].
The causes for the currently predicted change in climate result from behaviours of the rapidly growing human population consuming more natural resources for fulfillment of more natural resources for fulfillment of basic needs and high demands on health and comfort and interfering with homeostasis mechanisms of nature beyond adaptive capacities. Human adaptive potential is considered and strategies for adaptation are outlined aiming at an equilibrium between human and natural systems by behavioural modification, without loss of basic needs for health.


Modulation of electronic structures in two-dimensional electrocatalysts for the hydrogen evolution reaction.
The electrocatalytic hydrogen evolution reaction (HER) has attracted substantial attention owing to its important role in realizing economic and sustainable hydrogen production via water electrolysis. Designing two-dimensional (2D) materials with large surface area, highly exposed surface sites and facile charge transport pathways is highly attractive for promoting the HER activity of the earth-abundant catalysts, and conducting rational modulations in the electronic structures is considered to be promising in further optimizing the intrinsic HER activity and thus realizing promoted HER performance. In this Feature Article, we systematically summarize recent progress in the modulation of the electronic structures of 2D HER electrocatalysts via multiple strategies including elemental doping, formation of alloyed structures, defect engineering, facet engineering, phase regulation, interface engineering and hybridization of the nanocatalysts with 2D substrates, and discuss the role of electronic structures in optimizing the intrinsic HER activity of 2D HER catalysts. We anticipate that this Feature Article will offer helpful guidance for oriented design and optimization of efficient electrocatalysts for scalable and economic hydrogen production.


First Report of Phoma rhei as a Pathogen of Rheum rhabarbarum in China.
Rheum rhabarbarum L., rhubarb, is a perennial herb planted mainly in Hebei, Hubei, Shanxi, Heilongjiang, and Jilin provinces as well as Inner Mongolia, China. The plant grows about 1,000 meters above sea level (4), and is used widely in China to treat constipation and gout. From June to September 2012, a leaf spot was observed on R. rhabarbarum in the medicinal garden of Jilin Agricultural University, Changchun, Jilin Province, causing significant effects on the leaves of all infected plants. In the early stage of disease development, small red lesions were visible on infected leaves, which subsequently developed into irregularly shaped or circular necrotic spots, each with a light colored center, pink-red alternating concentric rings, and surrounded by a chlorotic halo. Some lesions became perforated in the center. Lesions ranged from 1 to 15 mm in diameter. Extensive spotting resulted in general browning and yellowing of entire leaves. As lesions enlarged and coalesced, some leaves died from the margin inwards. Lesions on the stem were fusiform and sunken. Small pieces of diseased leaves and stems were surface-disinfested in 75% ethanol for 60 s, rinsed twice in distilled water, dried, and plated on potato dextrose agar (PDA). A Phoma species was isolated that produced a gray or dark gray colony after 5 to 7 days. The isolate was transferred to oatmeal agar (OA) (3). Pycnidia were dark brown to black, globose to subglobose, and 121 to 354 × 100 to 262 μm. Conidia were ellipsoidal or reniform, colorless, unicellular, and 3.8 to 6.5 × 1.7 to 4.1 μm. On the basis of these characteristics, the fungus was identified as Phoma rhei (1). A PCR assay with the ITS4 and ITS5 primers was used to amplify the internal transcribed spacer (ITS) region of ribosomal DNA (rDNA) (2). The amplified product (567 bp) was sequenced and the sequence submitted to GenBank (Accession No. KF531831). The ITS sequence exhibited 99% identity to that of a P. rhei isolate in GenBank (GU237743.1), confirming the morphological identification. Pathogenicity of eight isolates on rhubarb was confirmed by spraying a spore suspension (1 × 106 spores/ml) produced on PDA on the leaves of each 6-year-old R. rhabarbarum (cv. Boyedahuang) plant. Each isolate was inoculated onto five plants, and five plants were sprayed similarly with sterilized water as a control treatment. The plants were then covered with plastic bags for 48 h, and kept in a greenhouse (20 to 30°C with a 12-h photoperiod/day). Initial symptoms on inoculated leaves were observed 3 to 4 days after inoculation, while the control plants remained healthy. Re-isolations from lesions on the inoculated leaves, using the same protocol as the original isolations, produced fungal colonies with the same morphological characteristics as the original isolates of P. rhei, but no fungi were re-isolated from the control plants. This fungus has been found on R. rhaponticum in New Zealand (1), but to our knowledge this is the first report of P. rhei on R. rhabarbarum in China. References: (1) G. H. Boerema et al. Phoma Identification Manual. Diffferentiation of Specific and Infra-Specific Taxa in Culture. CABI Publishing. Wallingford, UK, 2004. (2) D. E. L. Cooke et al. Mycol. Res. 101:667, 1997. (3) Z. D. Fang. Research Method of Phytopathology. China Agricultural Press (In Chinese), 1998. (4) A. J. Li et al. Flora Reipublicae Popularis Sinicae. Tomus 25:171, 1998.


Low Dose of Lenalidomide Enhances NK Cell Activity: Possible Implication as an Adjuvant.
Lenalidomide, a synthetic immunomodulatory drug, has a wide range of features including anti-angiogenic and anti-proliferative properties. To date, researchers have shown that lenalidomide is capable of ameliorating the immune system factors and antitumor responses. Most researchers have reported that lenalidomide enhances the immune response in certain cancer patients through several pathways including the stimulation of Natural Killer cells; notwithstanding, it is still crucial to investigate the effect of lenalidomide on the activity of NK cell cytotoxicity both in vitro and in vivo. To evaluate the in vitro impact of lenalidomide, of different doses, on NK cytotoxicity activity and an in vivo investigation to find the adjuvant behavior of lenalidomide. NK cytotoxocity was measured with the lactate dehydrogenase (LDH) release assay via K562 cells. Lenalidomide was prepared at 1 mM, 2 mM, 4 mM and 8 mM for in vitro study. In addition, the adjuvant properties of lenalidomide were assessed in ten mice groups using NS3 HCV DNA vaccine model of antigen pcDNA3.1(+)/NS3. The results showed that, comparisons to other doses, 4 mMol of lenalidomide was able to noticeably increase NK cytotoxicity activity. Furthermore, the animal model indicated that lenalidomide stimulated NK cytotoxicity in vivo, augmenting it from 16.67% ± 2.07% for the control group to 38.17% ± 2.87% for the lenalidomide-treated. Treatment by lenalidomide and pcDNA3.1(+)/NS3 improves NK cytotoxicity up to 66.80% suggesting that lenalidomide can be used in parallel with such therapeutic vaccines as cancer vaccine or virus vaccines.


The impact of managed competition on diversity, innovation and creativity in the delivery of home-care services.
Reforming publicly funded healthcare systems by introducing elements of competition, often by allowing for-profit providers to compete with not-for-profit providers, is a strategy that has become commonplace in Western democracies. It is widely thought that the competitive forces of the marketplace will lead to greater efficiency, diversity and even innovation in the delivery of services. Between 1997 and 2000, a model of 'managed competition' was introduced as a major reform to the delivery of home-care services in Ontario, Canada. It was expected that by allowing greater competition within the home-care sector, this model would constrain costs and encourage provider agencies to become more innovative and creative in meeting service delivery needs. The purpose of this case study is to explore the impact of the managed competition reform on the for-profit and the not-for-profit organisations that provided rehabilitation home-care services, and, more specifically, to assess the extent to which the goal of greater diversity, innovation and creativity was achieved following implementation of the reform. A purposive sample of 49 key informants were selected for in-depth interviews, and a survey of the 36 organisations that provided rehabilitation home-care services and the 43 community care access centres that purchased services from these provider agencies was conducted. Data were collected between November 2002 and May 2003. Findings demonstrate that a combination of coercive, mimetic and normative isomorphic pressures have constrained diversity, innovation and creativity within the home-care sector. The implication is that the features that have traditionally distinguished for-profit and not-for-profit provider agencies from each other are rapidly disappearing, and a new hybrid organisational structure is evolving.


Impact of free verotoxin testing on epidemiology of diarrhea caused by verotoxin-producing Escherichia coli.
During a 10-week period in the summer of 1990, an epidemiologic investigation of the prevalence of verotoxin (VT)-producing Escherichia coli infection was conducted in Calgary, Alberta, Canada. Consecutive stool specimens (n = 3,577) were cultured for E. coli O157:H7, and fecal filtrates were tested for free VTs (FVTs). E. coli O157:H7 was recovered from 22 specimens (0.6%), but VT was detected in 74 specimens (2.1%). Sixty-nine stool specimens positive for FVTs or E. coli O157:H7 were probed for VT genes by colony blot hybridization; 22 of 38 VT gene probe-positive isolates were non-O157:H7 E. coli organisms. Fourteen of 22 strains could not be induced to produce VT in vitro, despite the presence of FVTs in the stool sample, positivity on colony blot hybridization, positive PCR probes with the primers described by Pollard et al. (D. R. Pollard, W. M. Johnson, H. Lior, S. D. Tyler, and K. R. Rozee, J. Clin. Microbiol. 28:540-545, 1990) or Gannon et al. (V. P. Gannon, R. K. King, J. Y. Kim, and E. J. Golsteyn-Thomas, Appl. Environ. Microbiol. 58:3809-3815, 1992) (but not those described by Karch and Meyer [H. Karch and T. Meyer, J. Clin. Microbiol. 27:2751-2757, 1989]), and positive Southern blot analysis of isolates in 10 of 14 strains. The patient survey questionnaire showed that E. coli O157:H7 infection was associated with bloody diarrhea of short duration, whereas infection with other serotypes or persistence of FVT only was associated with longer-duration nonbloody diarrheal illness. We conclude that (i) detection of FVT in stools enhances the diagnosis of VT infection threefold over cultures for E. coli O157:H7, (ii) cultures for E.coli O157:H7 detect the majority of organisms of that serotype, (iii) the spectrum of disease produced by organisms of non-O157:H7 serotypes may include less severe but more protracted illness, and (iv) differences in the in vivo and in vitro expression of toxin and results of genetic probe studies highlight the need to examine control mechanisms of toxin production.


Role of p53 codon 72 polymorphism in chromosomal aberrations and mitotic index in patients with chronic hepatitis B.
Polymorphisms of the p53 gene, which participates in DNA repair, can affect the functioning of the p53 protein. The Arg and Pro variants in p53 codon 72 were shown to have different regulation properties of p53-dependent DNA repair target genes that can affect various levels of cytogenetic aberrations in chronic hepatitis B patients. The present study aimed to examine the frequency of chromosomal aberrations and the mitotic index in patients with chronic hepatitis B and their possible association with p53 gene exon 4 codon 72 Arg72Pro (Ex4+119 G>C; rs1042522) polymorphism. Fifty-eight patients with chronic hepatitis B and 30 healthy individuals were genotyped in terms of the p53 gene codon 72 Arg72Pro polymorphism by PCR-RFLP. A 72-h cell culture was performed on the same individuals and evaluated in terms of chromosomal aberrations and mitotic index. A high frequency of chromosomal aberrations and low mitotic index were detected in the patient group compared to the control group. A higher frequency of chromosomal aberrations was detected in both the patient and the control groups with a homozygous proline genotype (13 patients, 3 control subjects) compared to patients and controls with other genotypes [Arg/Pro (38 patients, 20 control subjects) and Arg/Arg (7 patients, 7 control subjects)]. We observed an increased frequency of cytogenetic aberrations in patients with chronic hepatitis B. In addition, a higher frequency of cytogenetic aberrations was observed in p53 variants having the homozygous proline genotype compared to variants having other genotypes both in patients and healthy individuals.


Clinicopathological, Immunohistochemical, and PMS2 Gene Expression Profiling of Patients with Sporadic Colorectal Cancer.
The DNA mismatch repair (MMR) system is one of the molecular pathways involved in colorectal cancer (CRC) carcinogenesis that consists of several genes, including MLH1 (MutL homolog 1), MSH6 (MutS homolog 6), MSH2 (MutS homolog 2), and MSH3 (MutS homolog 3). The protein encoded by PMS2 (post-meiotic segregation 2) is also essential for MMR. Here, we address the correlation between immunohistochemical and transcriptional expression of PMS2 with the tumor grade and clinical stage of non-hereditary/sporadic CRC disease. This study retrospectively analyzed 67 colorectal resections performed for 38 male and 29 female patients. Random biopsies were taken by a gastroenterologist from patients referring to three hospitals in the cities of Zanjan, Urmia and Qazvin (Iran) during 2017-2019. All specimens were examined and classified for localization of tumor, pathological stage and grade. The PMS2 protein expression was studied immunohistochemically and analysis of mRNA expression was performed in the same tissue sections. Immunohistochemistry and quantitative real-time polymerase chain reaction (PCR) analysis showed a decrease in PMS2 expression compared with paracancerous tissue (P<0.001), which correlated with tumor stage. In addition, reduced PMS2 expression was correlated with the tumor differentiation grade, underlining a connection between downregulation of PMS2 and progression of CRC. Comparing the PMS2 mRNA levels in different groups showed the following results: 0.92 ± 0.18 in patients with Stage I CRC tumor, 0.86 ± 0.38 in Stage Ⅱ, 0.50 ± 0.29 in Stage Ⅲ, and 0.47 ± 0.23 in Stage Ⅳ. These findings suggest that PMS2 may provide a potential reliable biomarker for CRC classification by combined immunohistochemical and mRNA analysis.


Simulating CXCR5 Dynamics in Complex Tissue Microenvironments.
To effectively navigate complex tissue microenvironments, immune cells sense molecular concentration gradients using G-protein coupled receptors. However, due to the complexity of receptor activity, and the multimodal nature of chemokine gradients in vivo, chemokine receptor activity in situ is poorly understood. To address this issue, we apply a modelling and simulation approach that permits analysis of the spatiotemporal dynamics of CXCR5 expression within an in silico B-follicle with single-cell resolution. Using this approach, we show that that in silico B-cell scanning is robust to changes in receptor numbers and changes in individual kinetic rates of receptor activity, but sensitive to global perturbations where multiple parameters are altered simultaneously. Through multi-objective optimization analysis we find that the rapid modulation of CXCR5 activity through receptor binding, desensitization and recycling is required for optimal antigen scanning rates. From these analyses we predict that chemokine receptor signaling dynamics regulate migration in complex tissue microenvironments to a greater extent than the total numbers of receptors on the cell surface.


Characterization of necrosis and ethylene-inducing proteins (NEP) in the basidiomycete Moniliophthora perniciosa, the causal agent of witches' broom in Theobroma cacao.
The hemibiotrophic basidiomycete Moniliophthora perniciosa causes witches' broom disease of Theobroma cacao. Analysis of the M. perniciosa draft genome led to the identification of three putative genes encoding necrosis and ethylene-inducing proteins (MpNEPs), which are apparently located on the same chromosome. MpNEP1 and 2 have highly similar sequences and are able to induce necrosis and ethylene emission in tobacco and cacao leaves. MpNEP1 is expressed in both biotrophic and saprotrophic mycelia, the protein behaves as an oligomer in solution and is very sensitive to temperature. MpNEP2 is expressed mainly in biotrophic mycelia, is present as a monomer in solution at low concentrations (<40 microM) and is able to recover necrosis activity after boiling. These differences indicate that similar NEPs can have distinct physical characteristics and suggest possible complementary roles during the disease development for both proteins. This is the first report of NEP1-like proteins in a basidiomycete.


Proliferative potential and response to nivolumab in clear cell renal cell carcinoma patients.
Biomarkers predicting immunotherapy response in metastatic renal cell cancer (mRCC) are lacking. PD-L1 immunohistochemistry is a complementary diagnostic for immune checkpoint inhibitors (ICIs) in mRCC, but has shown minimal clinical utility and is not used in routine clinical practice. Tumor specimens from 56 patients with mRCC who received nivolumab were evaluated for PD-L1, cell proliferation (targeted RNA-seq), and outcome. For 56 patients treated with nivolumab as a standard of care, there were 2 complete responses and 8 partial responses for a response rate of 17.9%. Dividing cell proliferation into tertiles, derived from the mean expression of 10 proliferation-associated genes in a reference set of tumors, poorly proliferative tumors (62.5%) were more common than moderately (30.4%) or highly proliferative (8.9%) counterparts. Moderately proliferative tumors were enriched for PD-L1 positive (41.2%), compared to poorly proliferative counterparts (11.4%). Objective response for moderately proliferative (29.4%) tumors was higher than that of poorly (11.4%) proliferative counterparts, but not statistically significant (p = .11). When cell proliferation and negative PD-L1 tumor proportion scores were combined statistically significant results were achieved (p = .048), showing that patients with poorly proliferative and PD-L1 negative tumors have a very low response rate (6.5%) compared to moderately proliferative PD-L1 negative tumors (30%). Cell proliferation has value in predicting response to nivolumab in clear cell mRCC patients, especially when combined with PD-L1 expression. Further studies which include the addition of progression-free survival (PFS) along with sufficiently powered subgroups are required to further support these findings.


An experimental study to investigate the feasibility to classify paints according to neurotoxicological risks: occupational air requirement (OAR) and indoor use of alkyd paints.
The concept of occupational air requirement (OAR), representing the quantity of air required to dilute the vapor concentration in the work environment resulting from 1 l product to a concentration below the occupational exposure limit (OEL), was considered to have potential to discriminate between paints that can and cannot be used safely. The OAR is a simple algorithm with the concentration of volatile organic compound (VOC) in the paint, a discrete evaporation factor and the neurotoxicological effects-based OEL. Conceptually, OAR categories of paints for construction and maintenance applications could be identified that can be applied manually without exceeding OELs with no appreciable room ventilation. Five painters volunteered in an exposure study aimed at testing the OAR approach in practice. Total exposure to VOC was assessed in 30 experiments during the application of 0.5 l of paint in a defined 'standard indoor paint job'. Fifteen paints were prepared, reflecting differences in solvents (percentage, volatility, toxicity) with a range of OAR levels from 43 to 819 m(3)/l. Exposure was assessed by personal air sampling (PAS). In addition, real-time air monitoring was performed. All tests were conducted at minimum ventilation rate (< or=0.33 h(-1)). PAS results were expressed as percentage of the nominal OEL and ranged from 8 to 93% for high solids and from 38 to 168% for conventional paints. In general, higher VOC contents resulted in higher exposure. High volatile paints showed a statistically significant faster increase of VOC concentration with time compared with paints containing low volatile solvents. A significant relationship between OAR value and exposure was observed (R(2) = 0.73). The experiments indicate that OAR-based classification of paints predicts and discriminates risk levels for exposure to neurotoxic paint-solvents in indoor painting fairly well.


[Restoration of severed peripheral nerves].
The state of the art in restoration of severed peripheral nerves is outlined. Discussion of the prerequisites for an optimal nerve-repair such as intraneural anatomy of peripheral nerves (topography of nerves in cross-section), techniques for preparation of nerve stumps, lesions in continuity, precise rotational orientation, nerve-suture, interfascicular dissection and nerve-grafting, including harvesting of autologous nerve grafts and finally the postoperative management after restoration of peripheral nerves are discussed.


Antiamoebic and phytochemical screening of some Congolese medicinal plants.
Results from the in vitro antiamoebic activity of some Congolese plant extracts used as antidiarrhoeic in traditional medicine indicated that of 45 plant extracts tested, 35 (77.78%) exhibited an antiamoebic activity and 10 (22.22%) were inactive. The highest activity (MIC < 100 microg/ml) was obtained with extracts from root bark of Paropsia brazzeana, Cryptolepis sanguinolenta, Alchornea cordifolia, Hensia pulchella, Maprounea africana, Rauwolfia obscura and Voacanga africana, leaves and stem bark of Psidium guajava, stem bark of Dialum englerianum, Harungana madagascariensis and Mangifera indica, mature seeds of Carica papaya, and leaves of Morinda morindoides and Tithonia diversifolia. Metronidazole used as reference product showed a more pronounced activity than that of all plant extracts tested.


Chemical sensitivity after intoxication at work with solvents: response to sauna therapy.
The purpose of this case study is twofold. One, to illustrate a simple method of detoxification using heat chamber depuration (sauna). Second, to raise awareness in the practice of medicine of the importance of taking an environmentally oriented history. A patient with a chronic, debilitating multisystem disorder of 20-years' duration related to a chemical sensitivity resulting from low-level exposure to toxic chemicals (solvents) at work. Detoxification treatment consisted of heat chamber depuration (sauna) together with a specific protocol of oral and intravenous therapy. Appropriate advice was offered related to choosing a safe and suitable workplace. Observation of the dynamic interaction and elimination of chlorinated and aromatic hydrocarbons (solvents) from the patient's bloodstream and related clinical improvement during the course of treatment. The patient was able to discontinue, without ill effect, all medications previously prescribed to treat her symptoms. Heat chamber depuration (sauna) detoxification treatment brought substantial release of symptoms and returned the individual to gainful employment. The connection between symptoms of chronic degenerative diseases and environmental and/or nutritional factors is missed in many cases due to lack of obtaining an environmentally oriented medical history. Taking such a history and dealing with the cause of illness using avoidance and/or appropriate therapy is preventive and cost-effective for both the patient and society.


Peptide/Peptoid Hybrid Oligomers: The Influence of Hydrophobicity and Relative Side-Chain Length on Antibacterial Activity and Cell Selectivity.
Previous optimisation studies of peptide/peptoid hybrids typically comprise comparison of structurally related analogues displaying different oligomer length and diverse side chains. The present work concerns a systematically constructed series of 16 closely related 12-mer oligomers with an alternating cationic/hydrophobic design, representing a wide range of hydrophobicity and differences in relative side-chain lengths. The aim was to explore and rationalise the structure-activity relationships within a subclass of oligomers displaying variation of three structural features: (i) cationic side-chain length, (ii) hydrophobic side-chain length, and (iii) type of residue that is of a flexible peptoid nature. Increased side-chain length of cationic residues led to reduced hydrophobicity till the side chains became more extended than the aromatic/hydrophobic side chains, at which point hydrophobicity increased slightly. Evaluation of antibacterial activity revealed that analogues with lowest hydrophobicity exhibited reduced activity against E. coli, while oligomers with the shortest cationic side chains were most potent against P. aeruginosa. Thus, membrane-disruptive interaction with P. aeruginosa appears to be promoted by a hydrophobic surface of the oligomers (comprised of the aromatic groups shielding the cationic side chains). Peptidomimetics with short cationic side chains exhibit increased hemolytic properties as well as give rise to decreased HepG2 (hepatoblastoma G2 cell line) cell viability. An optimal hydrophobicity window could be defined by a threshold of minimal hydrophobicity conferring activity toward E. coli and a threshold for maximal hydrophobicity, beyond which cell selectivity was lost.


Contribution of natural milk culture to microbiota, safety and hygiene of raw milk cheese produced in alpine malga.
Processing of alpine milk in malga farms is carried out under conditions that can favor contamination by coliforms, coagulase-positive staphylococci, or pathogens such as Listeria monocytogenes. With the aim to improve the hygienic characteristics and safety of cheese produced in four malga farms the use of lyophilized Natural Milk Culture prepared with selected strains was tested.. Two cheesemaking tests were carried out in the same day always starting from the same milk: in the first case following the malga recipe that uses either Natural Whey Culture or without the addition of a starter, in the second one using a Natural Milk Culture. Cheesemaking were carried out in four malga farms located in the west area of Trentino region within the same week. For hygienic and safety evaluation, aerobic colony count, coagulase-positive staphylococci, Escherichia coli, staphylococcal toxins, Listeria monocytogenes, and Salmonella spp, pH and aw were determined in raw milk from evening and morning milking, curd in vat, curd after extraction and two months-ripened cheese. Pathogens or toxins, high values of coagulase- positive staphylococci and E. coli were not found in cheese samples. However, in the curd coagulase-positive staphylococci reached values almost of 5 Log CFU/g in the two malga without starter cultures. The use of Natural Milk Culture reduced E. coli counts. In addition, DNA was extracted from cheese samples and from Natural Milk Culture and the composition of the microbial community determined by Next Generation Sequencing method. The determination of cheese microbial communities demonstrated that the use of Natural Milk Culture exerted different effects in the different malga, in any case preserving bacterial biodiversity.


Role for calcium in the insulin hypersecretory state of the endotoxic rat pancreas.
Previous studies have demonstrated that the endotoxic rat pancreas hypersecretes insulin in response to a glucose stimulus. However, the mechanism for this phenomenon is unknown. Since increases in pancreatic beta (B)-cell cytosolic ionic calcium are required for insulin secretion, this study evaluated the role of extracellular calcium on insulin secretion from the isolated, perfused endotoxic pancreas in the presence of and in the absence of extracellular calcium. Isolated pancreas preparations were obtained from control and endotoxin-treated rats and were perfused with either glucose (which primarily utilizes extracellular calcium to trigger insulin secretion) or 3-isobutyl-1-methylxanthine (IBMX, which primarily utilizes intracellular calcium to trigger secretion). In the presence of extracellular calcium, endotoxic pancreases hypersecreted insulin in response to either glucose or IBMX in comparison to control pancreases. In the absence of extracellular calcium, no insulin secretion occurred from control pancreases perfused with either glucose or IBMX. For endotoxic pancreases perfused with calcium-free conditions, insulin secretion was substantially less than that which occurred in the presence of calcium, but a significant amount of insulin secretion occurred from endotoxic pancreases in response to either IBMX or glucose. Insulin secretion from endotoxic pancreases was nearly three times greater with IBMX than with glucose under calcium-free conditions. Owing to the manner in which IBMX triggers insulin release, these data suggest that calcium handling within the endotoxic B-cell differs from that of the normal B-cell. In addition, endotoxic hypersecretion of insulin did not occur in response to endotoxin in vitro. Therefore this study indicates that endotoxin alters the regulation of calcium movements within the pancreatic B-cell via a mediated pathway.


Preliminary report of a Web-based instrument to assess and teach knowledge and clinical thinking to medical student.
We report the preliminary development of a unique Web-based instrument for assessing and teaching knowledge and developing clinical thinking called the "Sequential Questions and Answers" (SQA) test. Included in this feasibility report are physicians' answers to the Sequential Questions and Answers pre- and posttests and their brief questionnaire replies. The authors refined the SQA test case scenario for content, ease of modifications of case scenarios, test uploading and answer retrieval. Eleven geographically distant physicians evaluated the SQA test, taking the pretest and posttest within two weeks. These physicians completed a brief questionnaire about the SQA test. Eleven physicians completed the SQA pre- and posttest; all answers were downloaded for analysis. They reported the ease of website login and navigating within the test module together with many helpful suggestions. Their average posttest score gain was 53% (p=0.012). We report the successful launch of a unique Web-based instrument referred to as the Sequential Questions and Answers test. This distinctive test combines teaching organization of the clinical narrative into an assessment tool that promotes acquiring medical knowledge and clinical thinking. We successfully demonstrated the feasibility of geographically distant physicians to access the SQA instrument. The physicians' helpful suggestions will be added to future SQA test versions. Medical schools might explore the integration of this multi-language-capable SQA assessment and teaching instrument into their undergraduate medical curriculum.


[Research in the past].
The present study based on the literature, has the purpose of exploring research, it stages, and the types of potential problems that can interfere on its achievement. It also tries to bring some studies about Brazilian nursing history, pointing out some considerations, as well as the interrelationship of nursing and its history in the search for science.


Approximate Green's function for a uniaxially anisotropic metamaterial slab, and its application in analyzing a spectrometer.
An analytic solution for a magnetic line source imaged through a uniaxially anisotropic slab is derived for electric fields, and example results are supported by finite element simulations. The analytical result provides a convenient means to evaluate the effect of material parameters in applications. We introduce a spectrometer that can be realized by illuminating a slab composed of a Ag/ZnO multilayer stack through a small aperture, and we use this example to evaluate the performance of the analytic model.


Sylvian fissure and parietal anatomy in children with autism spectrum disorder.
Autism spectrum disorder (ASD) is characterized by deficits in social functioning and language and communication, with restricted interests or stereotyped behaviors. Anatomical differences have been found in the parietal cortex in children with ASD, but parietal subregions and associations between Sylvian fissure (SF) and parietal anatomy have not been explored. In this study, SF length and anterior and posterior parietal volumes were measured on MRI in 30 right-handed boys with ASD and 30 right-handed typically developing boys (7-14 years), matched on age and non-verbal IQ. There was leftward SF and anterior parietal asymmetry, and rightward posterior parietal asymmetry, across groups. There were associations between SF and parietal asymmetries, with slight group differences. Typical SF asymmetry was associated with typical anterior and posterior parietal asymmetry, in both groups. In the atypical SF asymmetry group, controls had atypical parietal asymmetry, whereas in ASD there were more equal numbers of individuals with typical as atypical anterior parietal asymmetry. We did not find significant anatomical-behavioral associations. Our findings of more individuals in the ASD group having a dissociation between cortical asymmetries warrants further investigation of these subgroups and emphasizes the importance of investigating anatomical relationships in addition to group differences in individual regions.


[An experimental study of the effect of immunomodulators on the immune response to the anatoxin components of adsorbed DPT vaccine against a background of poisoning].
An experiment of rabbits subjected to artificial lead intoxication revealed that after the immunization of the animals with adsorbed DPT vaccine myelopid and thymoptin exhibited practically the same immunomodulating activity with respect to antibody response to diphtheria and tetanus toxoids, exceeding that of rabbits without intoxication. Still the immunomodulators used in this experiment did not completely compensate the negative effect of intoxication on antibody response to the toxoids. For the first time after immunization with adsorbed DPT toxoid lymphocytes capable of binding diphtheria toxoid were detected and the specific features of their dynamics in comparison with the activity of antitoxin were established. Myelopid and thymoptin were found to modulate immune response, evaluated by the content of antigen-binding lymphocytes, the injection of thymoptin completely compensating the negative effect of intoxication.


Microbiological assay for vitamin B12 performed in 96-well microtitre plates.
A simplified microbiological assay for vitamin B12 estimation, completed on microtitre plates using a colistin sulphate resistant strain of Lactobacillus leichmannii (NCIB 12519), and cryopreserved cultures is described. The new assay correlated well with a more conventional "tube" assay and was not influenced by the presence of antibiotics in serum. Evaluation of assay performance showed excellent interassay and intra-assay precision with quantitative recovery of added cyanocobalamin over a wide range of additions (94.9%-102.1%). The advantages of short incubation time, easy reading, and minimal reagent costs make this assay an attractive option in the routine clinical laboratory and in research.


Normalization of Peri-Arteriovenous Malformation Hemodynamics Prior to Direct Microsurgery: 2-Dimensional Operative Video.
Arteriovenous malformations (AVMs) are highly complex vascular lesions characterized by abnormal connections between arteries and an intervening nidus. Definitive and safe treatment of AVMs may require the combination of multiple treatment modalities to address the various complex features of the AVM.1 Endovascular embolization can be used as an adjuvant to surgery in order to control deep feeders, reduce flow, and address high-risk features such as aneurysms. In addition, by progressively reducing the AVM flow, staged embolization can lead to normalization of peri-AVM hemodynamics and therefore may decrease the risk of postresection hemorrhage.2,3 In this operative video, we present a case of a 41-yr-old female who presented with progressively worsening left-sided hemiparesis. Magnetic resonance imaging (MRI) and angiography revealed a complex right fronto-parietal AVM with significant associated edema, likely due to the vascular steal phenomenon. The area of edema, which included the motor cortex, was thought to be at high risk for postoperative hemorrhage from normal perfusion pressure breakthrough. We therefore decided to proceed with staged presurgical embolization to gradually normalize the perilesional hemodynamics, and therefore possibly reduce the risk of postoperative morbidity. The patient underwent 3 embolization sessions at 6-wk intervals. An MRI after the last embolization showed near-complete resolution of the fluid-attenuated inversion-recovery (FLAIR) signal around the AVM. Microsurgical resection was performed on the day after the last embolization. The patient tolerated the procedure well and was discharged at her neurological baseline with mild contralateral hemiparesis, which has continued to improve at follow-up. Postoperative angiography showed complete resection of the AVM. The patient consented to the procedure as shown in this operative video and gave informed written consent for use of her images in publication.


Local adaptation of the trematode Fasciola hepatica to the snail Galba truncatula.
Experimental infections of six riverbank populations of Galba truncatula with Fasciola hepatica were carried out to determine if the poor susceptibility of these populations to this digenean might be due to the scarcity or the absence of natural encounters between these snails and the parasite. The first three populations originated from banks frequented by cattle in the past (riverbank group) whereas the three others were living on islet banks without any known contact with local ruminants (islet group). After their exposure, all snails were placed in their natural habitats from the end of October up to their collection at the beginning of April. Compared to the riverbank group, snails, which died without cercarial shedding clearly predominated in the islet group, while the other infected snails were few in number. Most of these last snails released their cercariae during a single shedding wave. In islet snails dissected after their death, the redial and cercarial burdens were significantly lower than those noted in riverbank G. truncatula. Snails living on these islet banks are thus able to sustain larval development of F. hepatica. The modifications noted in the characteristics of snail infection suggest the existence of an incomplete adaptation between these G. truncatula and the parasite, probably due to the absence of natural contact between host and parasite.


A mutant of Francisella tularensis strain SCHU S4 lacking the ability to express a 58-kilodalton protein is attenuated for virulence and is an effective live vaccine.
Francisella tularensis subsp. tularensis (type A) strain SCHU S4 is a prototypic strain of the pathogen that is highly virulent for humans and other mammals. Its intradermal (i.d.) 50% lethal dose (LD50) for mice is <10 CFU. We discovered a spontaneous mutant, designated FSC043, of SCHU S4 with an i.d. LD50 of >10(8) CFU. FSC043 effectively vaccinated mice against challenge with a highly virulent type A strain, and the protective efficacy was at least as good as that of F. tularensis LVS, an empirically attenuated strain which has been used as an efficacious human vaccine. Comparative proteomics was used to identify two proteins of unknown function that were identified as defective in LVS and FSC043, and deletion mutants of SCHU S4 were created for each of the two encoding genes. One mutant, the DeltaFTT0918 strain, failed to express a 58-kDa protein, had an i.d. LD50 of approximately 10(5) CFU, and was found to be less capable than SCHU S4 of growing in peritoneal mouse macrophages. Mice that recovered from sublethal infection with the DeltaFTT0918 mutant survived when challenged 2 months later with >100 LD50s of the highly virulent type A strain FSC033. This is the first report of the generation of defined mutants of F. tularensis subsp. tularensis and their use as live vaccines.


Microalgae biofilm system as an efficient tool for wastewater remediation and potential bioresources for pharmaceutical product production: an overview.
The role of microalgae in wastewater remediation and metabolite production has been well documented, but the limitations of microalgae harvesting and low biomass production call for a more sustainable method of microalgae utilization. The current review gives an insight on how microalgae biofilms can be utilized as a more efficient system for wastewater remediation and as potential source of metabolite for pharmaceutical product production. The review affirms that the extracellular polymeric substance (EPS) is the vital component of the microalgae biofilm because it influences the spatial organization of the organisms forming microalgae biofilm. The EPS is also responsible for the ease interaction between organisms forming microalgae biofilm. This review restate the crucial role play by EPS in the removal of heavy metals from water to be due to the presence of binding sites on its surface. This review also attribute the ability of microalgae biofilm to bio-transform organic pollutant to be dependent on enzymatic activities and the production of reactive oxygen species (ROS). The review assert that during the treatment of wastewater, the wastewater pollutants induce oxidative stress on microalgae biofilms. The response of the microalgae biofilm toward counteracting the stress induced by ROS leads to production of metabolites. These metabolites are important tools that can be harness for the production of pharmaceutical products.


Long-term home cage activity scans reveal lowered exploratory behaviour in symptomatic female Rett mice.
Numerous experimental models have been developed to reiterate endophenotypes of Rett syndrome, a neurodevelopmental disorder with a multitude of motor, cognitive and vegetative symptoms. Here, female Mecp2(Stop) mice [1] were characterised at mild symptomatic conditions in tests for anxiety (open field, elevated plus maze) and home cage observation systems for food intake, locomotor activity and circadian rhythms. Aged 8-9 months, Mecp2(Stop) mice presented with heightened body weight, lower overall activity in the open field, but no anxiety phenotype. Although home cage activity scans conducted in two different observation systems, PhenoMaster and PhenoTyper, confirmed normal circadian activity, they revealed severely compromised habituation to a novel environment in all parameters registered including those derived from a non-linear decay model such as initial exploration maximum, decay half-life of activity and span, as well as plateau. Furthermore, overall activity was significantly reduced in nocturnal periods due to reductions in both fast ambulatory movements, but also a slow lingering. In contrast, light-period activity profiles during which the amount of sleep was highest remained normal in Mecp2(Stop) mice. These data confirm the slow and progressive development of Rett-like symptoms in female Mecp2(Stop) mice resulting in a prominent reduction of overall locomotor activity, while circadian rhythms are maintained. Alterations in the time-course of habituation may indicate deficiencies in cognitive processing.


The Function of Casual Sex Action and Inaction Regret: A Longitudinal Investigation.
In several recent papers the sex difference in regret predicted by sexual strategies theory has been supported: men more than women report regret passing up short-term sexual opportunities (inaction regret), while women regret having had sexual encounters (action regret). However, the adaptive function of regret, to improve future behavioral choices, has not been tested. In this first longitudinal test of behavioral change following regret, we consider whether regret actually results in adaptive shifts of behavior: will men who regret passing up sex engage in more short-term sex following regret? Will women who regret short-term encounters either choose better quality partners, reduce number of one-night stands or shift their strategy to long-term relationships? Across two waves (NT1 = 399, 65.4% women and NT2 = 222, 66.2% women) students responded to questions about casual sex action regret and inaction regret, along with possible outcomes, intrapersonal traits, and concurrent contextual predictors. There was no clear evidence for the proposed functional shifts in sexual behavior. Casual sex regret was associated with respondent sex and stable individual differences, such as sociosexual attitudes, regret processing and metacognitions, but the effect of these predictors were not consistent across the two waves. Among the tested concurrent contextual predictors, sexual disgust was the most consistent across waves. Regret is considered a gauge of the value and quality of the short-term sexual encounter. However, tentatively we conclude that after this first test of function using longitudinal data, we find no evidence of a mating strategy shifting effect following sexual regret.


How to use experience-sampling technology to understand daily functioning: A practical guide for mental health professionals.
Satisfying daily life functioning is essential in mental healthcare. Standard assessments focus on symptoms and are designed to detect underlying vulnerabilities. However, they offer insufficient insight into patterns of contextual variability and resilience. Consequently, interventions are planned using incomplete information. The experience-sampling method (ESM) is a structured moment-to-moment diary assessing the individual's affect, thoughts, perception and behaviour in the daily life context. ESM helps to understand variation in mental states (e.g., anxiety or sleeping problems) as adaptational processes in relation to contextual challenges (functional analysis). Although ESM has been extensively studied across psychological disorders, the adoption by mental health professionals and their patients remains limited because the 'how to' is unclear. This paper presents a practical guide for ESM application in routine clinical care. It integrates empirical knowledge with expert experiences and provides real-world examples and recommendations for successful implementation. The guide comprises how to engage and motivate patients and how to customize assessments to the patient's needs. It also includes instructions to interpret results and create an atmosphere of shared decision-making. Experience-sampling technology has merits for patients with various mental health complaints and across healthcare settings, although the exact use and implementation may vary depending on the individual case.


Document vectorization method using network information of words.
We propose a new method for vectorizing a document using the relational characteristics of the words in the document. For the relational characteristics, we use two types of relational information of a word: 1) the centrality measures of the word and 2) the number of times that the word is used with other words in the document. We propose these methods mainly because information regarding the relations of a word to other words in the document are likely to better represent the unique characteristics of the document than the frequency-based methods (e.g., term frequency and term frequency-inverse document frequency). In experiments using a corpus consisting of 14 documents pertaining to four different topics, the results of clustering analysis using cosine similarities between vectors of relational information for words were comparable to (and more accurate than in some cases) those obtained using vectors of frequency-based methods. The clustering analysis using vectors of tie weights between words yielded the most accurate result. Although the results obtained for the small dataset used in this study can hardly be generalized, they suggest that at least in some cases, vectorization of a document using the relational characteristics of the words can provide more accurate results than the frequency-based vectors.


The impact of lifetime coffee and tea loads on Multiple Sclerosis severity.
The association between lifestyle factors and Multiple Sclerosis (MS) disease severity and progression has been investigated to a lesser extent compared with susceptibility to the disease. We aimed to assess the impact of lifetime coffee and tea consumption on MS severity. Design: cross-sectional study. Two hundred and eight patients (139 females and 69 males) consecutively recruited at the Department of Neurology in Novara, Italy were asked about their lifetime consumption of coffee and tea. The lifetime intensity of consumption (cups/day) was estimated as the weighted sum of the mean number of standard cups drunk per day at different ages. A measure of cumulative lifetime load of the exposure was expressed in terms of cup-years. Disease severity was estimated by the Multiple Sclerosis Severity Score (MSSS). HLA-DRB1∗15 and HLA-A∗02 genotyping was performed in 167 patients. The MSSS was not associated with the status of coffee or tea consumer, or the amount of cups/day or cup-years. The Odds Ratios (OR) for falling in the upper tertile of the MSSS distribution was 1.30 (95% Confidence Interval (CI): 0.47-3.58) for coffee consumers of 1-3 cups/day and 1.14 (95%CI: 0.33-3.95) for 4-8 cups/day vs. non-consumers. The OR was 0.69 (95%CI: 0.35-1.34) for tea consumers vs. non-consumers. However, heavy consumers of coffee (4-8 cups/day) more frequently had a progressive form than small consumers (1-3 cups/day) and non-consumers (19% vs. 14% vs. 0%), and had a significantly higher age at MS onset (36.6 ± 10.3; 31.5 ± 9.5; 28.6 ± 8.1 years, p = 0.001). Although not reaching statistical significance, coffee consumers positive for HLA-A∗02 had a six-fold risk of being in the worst tertile compared to never consumers, whereas the risk was only 1.3 for coffee consumers negative for the same allele. Coffee or tea intake is not associated with different severity of MS. However, we cannot exclude a possible effect of higher doses of coffee for the subgroup of progressive patients.


Assumption weighting for incorporating heterogeneity into meta-analysis of genomic data.
There is now a large literature on statistical methods for the meta-analysis of genomic data from multiple studies. However, a crucial assumption for performing many of these analyses is that the data exhibit small between-study variation or that this heterogeneity can be sufficiently modelled probabilistically. In this article, we propose 'assumption weighting', which exploits a weighted hypothesis testing framework proposed by Genovese et al. to incorporate tests of between-study variation into the meta-analysis context. This methodology is fast and computationally simple to implement. Several weighting schemes are considered and compared using simulation studies. In addition, we illustrate application of the proposed methodology using data from several high-profile stem cell gene expression datasets.


Self-regulation, daily drinking, and partner violence in alcohol treatment-seeking men.
This study builds on research identifying deficits in behavioral self-regulation as risk factors for intimate partner violence (IPV). It also builds on alcohol administration research identifying these deficits as moderators of the association between acute alcohol consumption and aggression in laboratory paradigms. Participants analyzed were 97 men seeking residential treatment for alcohol dependence who were involved in a current or recent heterosexual relationship of at least 1 year. Participants completed a self-report measure of impulsivity, neuropsychological tests of executive function, and computerized delay discounting and behavioral inhibition tasks. With the exception of the self-report measure of impulsivity, performance on measures of behavioral self-regulation was not associated with the occurrence or frequency of past year IPV in this sample. Similarly, self-reported impulsivity moderated the association between daily drinking and IPV in multivariate models controlling for daily drug use, but deficits in performance on other measures did not. Performance on a tower task moderated the association between daily drinking and the occurrence of IPV, but contrary to hypotheses, better task performance was associated with greater likelihood of IPV on drinking days. These results suggest that self-perceived impulsivity is a better predictor of IPV in alcohol treatment seeking men than deficits in performance on behavioral measures of delay discounting, behavioral inhibition, and executive function.


Genetic analysis of the localization of APOBEC3F to human immunodeficiency virus type 1 virion cores.
Members of the APOBEC3 family of cytidine deaminases vary in their proportions of a virion-incorporated enzyme that is localized to mature retrovirus cores. We reported previously that APOBEC3F (A3F) was highly localized into mature human immunodeficiency virus type 1 (HIV-1) cores and identified that L306 in the C-terminal cytidine deaminase (CD) domain contributed to its core localization (C. Song, L. Sutton, M. Johnson, R. D'Aquila, J. Donahue, J Biol Chem 287:16965-16974, 2012, http://dx.doi.org/10.1074/jbc.M111.310839). We have now determined an additional genetic determinant(s) for A3F localization to HIV-1 cores. We found that one pair of leucines in each of A3F's C-terminal and N-terminal CD domains jointly determined the degree of localization of A3F into HIV-1 virion cores. These are A3F L306/L368 (C-terminal domain) and A3F L122/L184 (N-terminal domain). Alterations to one of these specific leucine residues in either of the two A3F CD domains (A3F L368A, L122A, and L184A) decreased core localization and diminished HIV restriction without changing virion packaging. Furthermore, double mutants in these leucine residues in each of A3F's two CD domains (A3F L368A plus L184A or A3F L368A plus L122A) still were packaged into virions but completely lost core localization and anti-HIV activity. HIV virion core localization of A3F is genetically separable from its virion packaging, and anti-HIV activity requires some core localization. Specific leucine-leucine interactions are identified as necessary for A3F's core localization and anti-HIV activity but not for its packaging into virions. Understanding these signals may lead to novel strategies to enhance core localization that may augment effects of A3F against HIV and perhaps of other A3s against retroviruses, parvoviruses, and hepatitis B virus.


[Biosynthesis of testosterone in the gonads in silver fox embryos after long-term selection for domesticated behavior].
Fetal gonad weight and testosterone content in serum and gonads were analyzed in silver fox every five days from the 35th day of pregnancy until delivery. Fetal testicles were also tested for testosterone production induced by chorionic gonadotropin (CG) in vitro. Pregnant females were sampled from an experimental population subjected to selection for domesticated behavior and a commercial population (control). Fetal gonad weight was significantly lower in domesticated animals than in controls. No differences were revealed in the testosterone contents in their serum and gonads and in the basal production of testosterone in fetal testicles. CG-induced production of testosterone was detectable from the 40th day of fetal development in domesticated animals and from the 50th day in controls. The results obtained suggest that domestication results in the hetero-chronic fetal development of the hypophysial-testicular complex in silver fox.


Positive association between epiphytes and competitiveness of the brown algal genus Lobophora against corals.
Observations of coral-algal competition can provide valuable information about the state of coral reef ecosystems. Here, we report contact rates and apparent competition states for six shallow lagoonal reefs in Fiji. A total of 81.4% of examined coral perimeters were found to be in contact with algae, with turf algae (54.7%) and macroalgae of the genus Lobophora (16.8%) representing the most frequently observed contacts. Turf algae competitiveness was low, with 21.8% of coral-turf contacts being won by the algae (i.e. overgrowth or bleaching of coral tissue). In contrast, Lobophora competitiveness against corals was high, with 62.5% of contacts being won by the alga. The presence of epiphytic algae on Lobophora was associated with significantly greater algal competitiveness against corals, with 75.8% and 21.1% of interactions recorded as algal wins in the presence and absence of epiphytes, respectively. Sedimentation rate, herbivorous fish biomass, and coral colony size did not have a significant effect on Lobophora-coral interactions. This research indicates a novel and important role of epiphytes in driving the outcome of coral-algal contacts.


Acculturation, acculturative stressors, and family relationships among Latina/o immigrants.
Family relationships, widely recognized as core to Latino cultures, are known to vary for Latina/o immigrants based on time in the United States. Less is known about (a) how acculturation explains differences in family relationships by time in the US, and (b) whether acculturative stressors influence different aspects of immigrants' family relationships. Drawing on an expanded acculturation framework, we explore whether and how attitudinal familism, family contact, and family conflict among immigrant Latina/os vary based on acculturation and acculturative stressors. Using nationally representative data on foreign-born Latina/os (National Latino and Asian American Study; N = 1,618), ordered logistic and OLS regression analyses examined whether differences in family relationships by time in the US are explained by acculturation factors, and whether acculturative stressors are associated with family relationships when controlling for other important sociodemographic factors. Accounting for acculturation reduces the effect of time in the US on attitudinal familism and family conflict to nonsignificance. Spanish language proficiency and ethnic identity are associated with higher attitudinal familism, while English proficiency is associated with increased family conflict. Additionally, acculturative stressors (involuntary context of exit, hostile context of reception, limited origin country ties) are associated with lower attitudinal familism and higher conflict. Results highlight the importance of (a) examining the ways that migration influences multiple aspects of family relationships, (b) adopting a more comprehensive acculturation framework. Particularly novel are our findings on how acculturative stressors are associated with different family outcomes. (PsycINFO Database Record


Post-procedural Antibiotic Use and Associated Outcomes After Common Urologic Procedures Across a National Healthcare System.
To quantify the benefits and harms of post-procedural antibiotic use after common urologic procedures. This retrospective cohort study included patients who underwent an endoscopic urologic procedure (transurethral resection of bladder tumor, transurethral resection of prostate, or ureteroscopy) within the Veterans Health Administration between January 1, 2017 and June 30, 2021. A post-procedural antibiotic was any qualifying antibiotic prescribed for administration on the day after the procedure. Guidelines generally do not recommend post-procedural antibiotics for surgical prophylaxis. Outcomes included unplanned return visits and Clostridioides difficile infection within 30 days. Log-binomial models with risk-adjustment were used to measure the association between post-procedural antibiotic use and outcomes. Hospital-level observed-to-expected (O:E) ratios were constructed to compare post-procedural antibiotic use. There were 74,629 qualifying procedures across 105 hospitals; 27,422 (36.7%) received post-procedural antibiotics (median 3 days, IQR 3-6). An unplanned return visit occurred in 20.2% of patients who received post-procedural antibiotics vs 17.2% who did not (adjusted RR 1.032, 95% CI 0.999-1.066). C. difficile infection was diagnosed in 0.27% vs 0.10% in those who received and did not receive post-procedural antibiotics (adjusted RR 1.67, 95% CI 1.13-2.45). The O:E ratio for post-procedural antibiotic use ranged from 0.46 among hospitals in the lowest-use quartile to 1.93 in the highest-use quartile. Post-procedural antibiotics were frequently prescribed after urologic procedures with large inter-facility variability even after adjusting for case-mix differences. Post-procedural antibiotic use was associated with increased risk for C. difficile infection but not fewer unplanned return visits. Efforts to reduce guideline-discordant use of post-procedural antibiotics are needed.


Description of Bacillus naganoensis sp. nov.
A new species, Bacillus naganoensis, is proposed for an obligately aerobic, moderately acidophilic, endospore-forming bacterium that produces a thermostable, aciduric pullulanase (EC 220.127.116.11). The organism was isolated from soil by selection on solid, pullulan-containing medium at pH 4.0 and 30 degrees C. The isolate required a medium pH of less than 6.5 for growth initiation. Fatty acid composition studies revealed that the major fatty acid of cells grown in nutrient broth supplemented with 1% starch was 14-methylpentadecanoic acid (iso-C16) at 45 mol%. The guanine-plus-cytosine content of the DNA of this organism was 45 +/- 2 mol%. A type culture has been deposited with the American Type Culture Collection, Rockville, Md., as strain ATCC 53909.