Cardiac hypertrophy in aryl hydrocarbon receptor null mice is correlated with elevated angiotensin II, endothelin-1, and mean arterial blood pressure.
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates toxicity of xenobiotics, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin. Genetic deletion of the AhR leads to cardiac hypertrophy, suggesting a role for the AhR in cardiovascular physiology and disease; however, the pathways involved in the development of cardiac hypertrophy have not been determined. Thus, we investigated the role of (1) pressure overload using indwelling catheters and (2) vasoactive peptides endothelin-1 (ET-1) and angiotensin II (Ang II), assessed by RIA, in the progression of cardiac hypertrophy in AhR-null mice. Histochemical analysis, expression of cardiac hypertrophy marker genes, and echocardiography were used to assess the degree of cardiac hypertrophy. AhR-null mice developed elevated mean arterial pressures (MAP) by 5 months, which was associated with a two- and ninefold increase in plasma ET-1 and Ang II, respectively, compared to wild-type. Captopril-treatment (4 mg/kg) of AhR-null mice from 2 to 5 months of age significantly decreased MAP and plasma Ang II, but did not affect ET-1. Further, captopril improved cardiac function and reduced cardiac hypertrophy as evidenced by reduction in left ventricle mass, left ventricle internal dimension, and molecular cardiac hypertrophy markers. Captopril also decreased fibrosis of the heart and kidney. These findings show that pressure overload is associated with elevated ET-1 and hypertrophic growth of the heart and that cardiac hypertrophy is mediated, in part, by Ang II.


Translating science into policy: mental health challenges during the COVID-19 pandemic.
Several stressors associated with the coronavirus disease 2019 (COVID-19) are expected to affect the mental health of global populations: the effects of physical distancing, quarantine, and social isolation; the emotional suffering of health and other frontline workers; neuropsychiatric sequelae in those affected by the virus; the impact to families of lives lost to the disease; differential effects for those with severe mental disorders; and the consequences of social and economic deterioration. In this context, we sought: to form a panel of Brazilian experts on child and adolescent health, neurodevelopment, health services, and adult and elderly mental health; and to compile evidence-based interventions to support suggested policy changes in Brazil to mitigate the expected increase in mental health disorders during the pandemic and its mental health consequences. The following actions are recommended: 1) invest in prevention programs for the safe return of students to schools; 2) adopt evidence-based psychosocial interventions to maintain an adequate environment for child and adolescent development; 3) target socially vulnerable populations and those experiencing discrimination; 4) train primary care teams to solve common mental health problems, provide needs-based assessments, and manage long-term, at-home care for older patients; 5) invest in technological advancements (e.g., telemedicine, e-Health, and web-based algorithms) to promote coordinated care; 6) increase access to and literacy in the use of computers and mobile phones, especially among older adults; 7) expand protocols for remote, brief psychotherapy interventions and psychoeducation to manage common mental health problems.


[Levels of labile phosphorus-containing metabolites].
The work deals with the investigation of possible use of 31P-NMR for revealing metabolism changes in the mouse liver during the development of leukemia. This method was shown to permit observation of the extreme pattern of relative concentrations of sugar phosphate and bioorganic phosphate in the latent period. This observed increase in the metabolic activity of hepatocytes correlates with biophysical shifts found by other methods.


Matrix Softness-Mediated 3D Zebrafish Hepatocyte Modulates Response to Endocrine Disrupting Chemicals.
Endocrine disrupting chemicals (EDC) include synthetic compounds that mimic the structure or function of natural hormones. While most studies utilize live embryos or primary cells from adult fish, these cells rapidly lose functionality when cultured on plastic or glass substrates coated with extracellular matrix proteins. This study hypothesizes that the softness of a matrix with adhered fish cells can regulate the intercellular organization and physiological function of engineered hepatoids during EDC exposure. We scrutinized this hypothesis by culturing zebrafish hepatocytes (ZF-L) on collagen-based hydrogels with controlled elastic moduli by examining morphology, urea production, and intracellular oxidative stress of hepatoids exposed to 17β-estradiol. Interestingly, the softer gel drove cells to form a cell sheet with a canaliculi-like structure compared to its stiffer gel counterpart. The hepatoids cultured on the softer gel exhibited more active urea production upon exposure to 17β-estradiol and displayed faster recovery of intracellular reactive oxygen species level confirmed by gradient light interference microscopy (GLIM), a live-cell imaging technique. These results are broadly useful to improve screening and understanding of potential EDC impacts on aquatic organisms and human health.


Usefulness of 18 F-fluorodeoxyglucose positron emission tomography/computed tomography for predicting the prognosis and treatment response of neoadjuvant therapy for pancreatic ductal adenocarcinoma.
The Response Evaluation Criteria in Solid Tumors (RECIST) for computed tomography (CT) is preoperatively used to evaluate therapeutic effects. However, it does not reflect the pathological treatment response (PTR) of pancreatic ductal adenocarcinoma (PDAC). The Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) for positron emission tomography (PET)/CT is effective in other cancers. This study aimed to confirm the usefulness of PERCIST and the prognostic utility of PET/CT for PDAC. Forty-two consecutive patients with PDAC who underwent neoadjuvant therapy (NAT) and pancreatectomy at our institution between 2014 and 2018 were retrospectively analyzed. We evaluated the treatment response and prognostic significance of PET/CT parameters and other clinicopathological factors. Twenty-two patients who underwent PET/CT both before and after NAT with the same protocol were included. RECIST revealed stable disease and partial response in 20 and 2 cases, respectively. PERCIST revealed stable metabolic disease, partial metabolic response, and complete metabolic response in 8, 9, and 5 cases, respectively. The PTR was G3, G2, and G1 in 8, 12, and 2 cases, respectively. For comparing the concordance rates between PTR and each parameter, PERCIST (72.7% [16/22]) was significantly superior to RECIST (36.4% [8/22]) (P = .017). The area under the curve survival values of PET/CT parameters were 0.777 for metabolic tumor volume (MTV), 0.500 for maximum standardized uptake value, 0.554 for peak standardized uptake value corrected for lean body mass, and 0.634 for total lesion glycolysis. A 50% cut-off value for the MTV reduction rate yielded the largest difference in survival between responders and nonresponders. On multivariate analysis, MTV reduction rates < 50% were independent predictors for relapse-free survival (hazard ratio [HR], 3.92; P = .044) and overall survival (HR, 14.08; P = .023). PERCIST was more accurate in determining NAT's therapeutic effects for PDAC than RECIST. MTV reduction rates were independent prognostic factors for PDAC.


Adopting a multidisciplinary telemedicine intervention for fall prevention in Parkinson's disease. Protocol for a longitudinal, randomized clinical trial.
Approximately 40-70% of people with Parkinson's disease (PD) fall each year, causing decreased activity levels and quality of life. Current fall-prevention strategies include the use of pharmacological and non-pharmacological therapies. To increase the accessibility of this vulnerable population, we developed a multidisciplinary telemedicine program using an Information and Communication Technology (ICT) platform. We hypothesized that the risk for falling in PD would decrease among participants receiving a multidisciplinary telemedicine intervention program added to standard office-based neurological care. To determine the feasibility and cost-effectiveness of a multidisciplinary telemedicine intervention to decrease the incidence of falls in patients with PD. Ongoing, longitudinal, randomized, single-blinded, case-control, clinical trial. We will include 76 non-demented patients with idiopathic PD with a high risk of falling and limited access to multidisciplinary care. The intervention group (n = 38) will receive multidisciplinary remote care in addition to standard medical care, and the control group (n = 38) standard medical care only. Nutrition, sarcopenia and frailty status, motor, non-motor symptoms, health-related quality of life, caregiver burden, falls, balance and gait disturbances, direct and non-medical costs will be assessed using validated rating scales. This study will provide a cost-effectiveness assessment of multidisciplinary telemedicine intervention for fall reduction in PD, in addition to standard neurological medical care. In this challenging initiative, we will determine whether a multidisciplinary telemedicine intervention program can reduce falls, as an alternative intervention option for PD patients with restricted access to multidisciplinary care. ClinicalTrials.gov Identifier: NCT04694443.


I2Cnet medical image annotation service.
I2Cnet (Image Indexing by Content network) aims to provide services related to the content-based management of images in healthcare over the World-Wide Web. Each I2Cnet server maintains an autonomous repository of medical images and related information. The annotation service of I2Cnet allows specialists to interact with the contents of the repository, adding comments or illustrations to medical images of interest. I2Cnet annotations may be communicated to other users via e-mail or posted to I2Cnet for inclusion in its local repositories. This paper discusses the annotation service of I2Cnet and argues that such services pave the way towards the evolution of active digital medical image libraries.


Disrupted White Matter Microstructure and Mood Disorders after Traumatic Brain Injury.
Traumatic brain injury (TBI) is associated with an elevated frequency of mood disorders that may, in part, be explained by changes in white-matter microstructure. This study is the first to examine the relationship between mood disorders and white-matter pathology in a sample of patients with mild to severe TBI using a standardized psychiatric interview. This study reports on a sub-sample of 29 individuals recruited from a large prospective study that examined the evolution of psychiatric disorders following complicated, mild to severe TBI. Individuals with TBI were also compared with 23 healthy control participants. Individuals were invited to complete the Structured Clinical Interview for DSM-IV Disorders (SCID) to diagnose psychiatric disorders. Participants who developed a mood disorder within the first 3 years were categorized into a TBI-Mood group. Diffusion tensor tractography assessed white matter microstructure using atlas-based tract-averaged and along-tract approaches. Fractional anisotropy (FA) was used as the measure of white-matter microstructure. TBI participants with and without a mood disorder did not differ in regard to injury severity and other background factors. Nevertheless, TBI participants diagnosed with a mood disorder displayed significantly lower tract-averaged FA values for the right arcuate fasciculus (p = 0.011), right inferior longitudinal fasciculus (p = 0.009), and anterior segments I (p = 0.0004) and II (p = 0.007) of the corpus callosum, as well as the left (p = 0.014) and right (p = 0.015) fronto-occipital longitudinal fasciculi. The pattern of white matter disruption identified in the current study provides further support for a neurobiological basis of post-TBI mood disorders. Greater understanding of individuals' underlying neuropathology may enable better characterization and prediction of mood disorders. Integration of neuropathology may also inform the potential efficacy of pharmacological and psychological interventions.


Ascending colon compression by psoas muscle hypertrophy.
Extrinsic compression of the ascending colon was observed on the barium enema of a professional athlete. Ultrasound examination demonstrated psoas muscle enlargement as the cause of this abnormal radiographic finding. The effect of psoas muscle hypertrophy should be considered when extrinsic compression of the colon is observed on the barium enema of muscular individuals. Ultrasound is useful to differentiate anatomic variant from pathological conditions which may deviate the ureters and/or the ascending colon.


Asymptomatic ocular sarcoidosis.
Sarcoidosis, as multisystem disease, may affect the entire visual apparatus and its adnexa: the eye hence is an optimal observation point to confirm diagnosis and assess disease activity. However, the eyes are affected only in one-fourth of cases, and the majority of the lesions are asymptomatic, requiring appropriate examination techniques to be detected. In this paper we reviewed the ophthalmic changes found in a group of 163 Italian patients affected with sarcoidosis, comparing the data collected with those published in the literature. Conjunctival granulomata, chorio-retinal lesions and lacrimal gland involvement were the more common ocular manifestations of the sarcoidosis detected; these were asymptomatic in two patients out of three. Ocular changes in sarcoidosis are more common than generally appreciated even in white patients, but their detection requires meticulous eye examination, the use of 67 Gallium scans of the head, fluorangiography, and the yield of biopsies from available eye tissues.


Vitamin E-Conjugated Phosphopeptide Inhibitor of the Polo-Box Domain of Polo-Like Kinase 1.
Polo-like kinase 1 (Plk1) regulates cell cycle and cell proliferation, and is currently considered a potential biomarker in clinical trials for many cancers. A characteristic feature of Plks is their C-terminal polo-box domain (PBD). Pro-Leu-His-Ser-pThr (PLHS[pT])-the phosphopeptide inhibitor of the PBD of Plk1-induces apoptosis in cancer cells. However, because of the low cell membrane-penetration ability of PLHS[pT], new approaches are required to overcome these drawbacks. We therefore developed a vitamin E (VE) conjugate that is biodegradable by intracellular redox enzymes as an anticancer drug-delivery system. To ensure high efficiency of membrane penetration, we synthesized VE-S-S-PLHS[pT]KY (1) by conjugating PLHS[pT] to VE via a disulfide bond. We found that 1 penetrated cancer cell membranes, blocked cancer cell proliferation, and induced apoptosis in cancer cells through cell cycle arrest in the G2/M phase. We synthesized a radiolabeled peptide (124I-1), and the radioligand was evaluated in in vivo tumor uptake using positron emission tomography. This study shows that combination conjugates are an excellent strategy for specifically targeting Plk PBD. These conjugates have a dual function, with possible uses in anticancer therapy and tumor diagnosis.


Bandwidth enhancement of electro-optic field sensing using photonic down-mixing with harmonic sidebands.
We demonstrate that harmonic sidebands of an electro-optic modulator's driving frequency can be used as the local oscillator in a photonic down-mixing process in order to significantly enhance the bandwidth of near-field, electro-optic, microwave measurements. The creation of second- and third-order-harmonic modulation sidebands on a laser-diode output are described, with heterodyne down-conversion of microwave signals taking place within an electro-optic sensor crystal. The measurement bandwidth of an electro-optic microwave probe can thus be enhanced by as much as a factor of three with respect to the use of conventional, fundamental-harmonic sidebands. Carrier-sideband analysis from the measured optical spectrum indicates that millimeter-wave-frequency local-oscillator sidebands can be created using a Ku-band electro-optic modulator and that the electro-optic-signal-modulation depth can be enhanced by suppressing the light-beam carrier component. Transverse near-field distributions from high frequency patch antennas are extracted using both second- and third-order-harmonic sidebands.


Syphilis evaluation and therapy: a study of current practices in a university hospital.
The incidence of syphilis, after declining for several years, increased by 23% in the first quarter of 1987. The authors reviewed the charts of 100 patients with syphilis in order to determine how such patients were managed in a university setting. Although 77 patients met Centers for Disease Control (CDC) indications for lumbar puncture, only 11 patients had the procedure. Most patients for whom treatment was indicated either were not treated or were treated with inadequate or incorrect medications. Only 30 patients received follow-up serologic tests, and of these, only one received follow-up at the intervals recommended by the CDC. This study indicates that physicians may either be unfamiliar or disagree with the current CDC guidelines for evaluation and management of patients with syphilis. Physicians should know these guidelines and document their reasoning if they choose not to follow them. Long-term follow-up of patients with syphilis is important to ensure effective treatment and to increase understanding of this disease.


Gender and schizophrenia.
Schizophrenia is a chronic psychotic illness that characteristically manifests itself from the early adult years throughout the entirety of life. Its symptoms are well known, its phenomenology has been exhaustively studied, and palliative treatments exist, although they rarely produce complete response. The pathophysiology and the etiology of the illness remain unknown. Clues to the basic understanding of schizophrenia are rare, but they do appear. Gender differences in schizophrenia have always been implicated in the challenge to clearly understand the disorder. Male and female schizophrenics display identical symptomatic features during acute illness, seemingly minimizing the relevance of gender issues. Within the last decade, however, more careful screening has revealed significant gender differences in schizophrenia: in age at onset, premorbid personality, subtype of schizophrenia, psychosocial function, and treatment response. Attention to these differences could be important to answer theoretical and therapeutic questions regarding the disorder.


Dental Public Health in Action: Understanding oral health care needs and oral health-related quality of life in vulnerable adults in Plymouth.
This paper aims to provide a snapshot analysis of the oral health status of vulnerable adults in Plymouth; and to demonstrate the extent to which oral disease impacts on their normal functioning through the implementation of the Oral Health Impact Profile (OHIP). It is acknowledged that gaining a representative sample of a transient population such as people who are homeless, or individuals affected by problematic use of drugs and/or alcohol is difficult. An opportunity was identified to collect data within the Community Engagement Team's (CET) programme of activity within the Peninsula Dental Social Enterprise. The CET works alongside local organisations to enable dental students from Peninsula School of Dentistry to undertake outreach programmes in a variety of settings. A study was designed which aimed to analyse the oral health status of vulnerable adults accessing three day-support services in Plymouth, and to understand the extent to which oral disease impacts on their normal functioning through the OHIP-14. For all impact domains, the 44 patients in this study reported a greater impact than that found in the Adult Dental Health Survey. The most commonly reported impact domains were physical pain and psychological discomfort. The sample was divided into high and low oral health-related quality of life impact groups, and those participants in the high impact group had significantly greater median D₃MFT scores, i.e. higher levels of decay experience. This survey highlights how these vulnerable groups are characterised by a high prevalence of poor oral health, ill-health, deprivation and social exclusion.


Aging alters calcium regulation of serum concentration of parathyroid hormone in healthy men.
We examined the effect of aging on the relationship between the concentrations of blood ionized calcium and of serum parathyroid hormone (PTH) in 22 healthy men [9 elderly (age 74 +/- 2 yr) and 13 young (age 39 +/- 1 yr)] in whom the glomerular filtration rate was > 70 ml/min. Throughout a 24-h period, serum concentrations of PTH in the elderly men were twice those in the young men, whereas blood ionized calcium did not differ between the two groups. With intravenous infusion of calcium gluconate, the minimum PTH concentration was two- to threefold higher in the elderly men. With infusion of NaEDTA. the maximum PTH concentration was 20% higher in the elderly men. The calcium set point for PTH release was higher in the elderly than in the young men (4.71 +/- 0.04 vs. 4.54 +/- 0.03 mg/dl, respectively, P < 0.005). In these healthy men, the age-related increase in serum PTH could not be attributed to a sustained decrease in concentration of either blood ionized calcium or 1,25-hydroxyvitamin D. These findings suggest that, with aging, the relationship between calcium and PTH is altered such that at any given level of calcium, the concentration of PTH is higher.


The dual actions of Paederia scandens extract as a hypouricemic agent: xanthine oxidase inhibitory activity and uricosuric effect.
Hyperuricemia is associated with a number of pathological conditions, such as gout. Lowering of elevated uric acid levels in the blood could be achieved by xanthine oxidase inhibitors and inhibitors of renal urate reabsorption. Some natural compounds isolated from herbs used in traditional Chinese medicine have been previously demonstrated to act as xanthine oxidase inhibitors. In the present investigation, Paederia scandens (Lour.) Merrill (Rubiaceae) extract (PSE; 4.5, 2.25, and 1.125 g/kg) orally for 14 days was demonstrated to possess in vivo potent hypouricemic activity in hyperuricemic rats pretreated with potassium oxonate. In addition, PSE was also demonstrated to be an inhibitor of xanthine oxidase. Lineweaver-Burk analysis of the enzyme kinetics indicated that the inhibition of PSE was of a mixed type. Using an oxonate-induced hyperuricemic rat model, PSE was indeed shown to exhibit uricosuric action in vivo, which could explain, at least in part, the observed hypouricemic effect of PSE in these rats. The potential application of this compound in the treatment of conditions associated with hyperuricemia is discussed.


High-performance nanotube-enhanced perovskite photodetectors.
Organic-inorganic perovskites have already shown a tremendous potential for low-cost light-harvesting devices. Yet, the relatively low carrier mobilities in bulk perovskites still prevent large-area devices with performances competing with state-of-the-art technologies. Here, we tackle this fundamental challenge by incorporating single-wall carbon nanotubes within a perovskite matrix by means of a simple two-step method in ambient air. Using this nano-engineered hybrid film, we demonstrate large-area photodetectors with responsivities up-to 13.8 A.W-1 and a broad spectral response from 300 to 800 nm, indicating that photocurrent generation arises from the charge transfer from the perovskite matrix to the embedded nanotube network. As the nanotubes facilitate the carrier extraction, these photodetectors also show a fast response time of 10 ms. This is significantly faster than most of previous reports on perovskite-based photodetectors, including devices with much smaller photosensitive areas. This approach is also well-suited for large-scale production of other perovskite-based light-harvesting devices.


Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25- T cells.
CD4+CD25+ regulatory T (TR) cells have been described in both humans and mice. In mice, TR are thymically derived, and lack of TR leads to organ-specific autoimmunity. Recently, the forkhead/winged helix transcription factor, FoxP3, has been shown to be important for the function of TR cells in mice. In this study, human TR cells were examined and, in results similar to those of studies done in mice, expression of FoxP3 was found exclusively in CD4+CD25+ T cells and correlated with the suppressive activity of these cells. In contrast to the mouse studies, activation of human CD4+CD25- T cells led to expression of FoxP3. Expression of FoxP3 in activated human CD4+CD25+ cells also correlated with suppression of proliferation by these cells in freshly isolated CD4+CD25- T cells from the same donor. This suppression was cell-contact dependent and cytokine independent. Thus, in humans, during activation of CD4+CD25- T cells in an immune response, two populations of cells may arise, effector CD4+CD25+ and regulatory CD4+CD25+ T cells, with expression of FoxP3 correlated with regulatory activity. These data also raise the possibility that a failure to generate peripheral TR cells properly may contribute to autoimmune disease and suggest a possible therapeutic role for FoxP3 in the treatment of such diseases.


Comparable bronchodilation with hydrofluoroalkane-134a (HFA) albuterol and chlorofluorocarbons-11/12 (CFC) albuterol in children with asthma.
This was an open-label, parallel group, randomized, age-stratified, multicenter study designed to compare the safety and efficacy of regular use of albuterol formulated in hydrofluoroalkane-134a (HFA albuterol) and albuterol formulated in chlorofluorocarbons-11/12 (CFC albuterol) in children with asthma. Children age 4-11 years using a short-acting inhaled beta2-agonist for 6 months to manage stable asthma, and with a prestudy forced expiratory volume in 1 sec (FEV1) of >50% predicted after withholding short-acting inhaled beta2-agonists for at least 6 hr, an increase in FEV1 > or = 12% within 30 min after two puffs of CFC albuterol, and the capability to comply with medication withholding requirements were eligible for study entry. After screening evaluation, patients entered a minimum 7-day run-in period. On study day 1 spirometry and a baseline 12-lead electrocardiogram (ECG) were performed, pulse and blood pressure were measured, and patients self-administered two puffs of their randomized study drug, either HFA albuterol or CFC albuterol. Serial spirometry was performed over 6 hr after study drug dosing. Pulse and blood pressure were measured just prior to each spirometry and a 12-lead ECG was performed at 60 min postdose. Patients took two puffs of their study drug four times a day for 4 weeks. At study week 4, study day 1 procedures were repeated. Patients maintained a daily diary of morning (A.M.) and evening (P.M.) peak expiratory flow (PEF), daytime asthma symptom scores, nighttime asthma sleep disturbance scores, and study drug use. Demographics and baseline characteristics of the 63 patients randomized to HFA albuterol (33) and CFC albuterol (30) were similar. No significant differences were found between the HFA albuterol and CFC albuterol treatment groups for any of the primary or secondary FEV1 efficacy variables either at study day 1 or study week 4. No significant differences were noted between treatment groups for A.M. and P.M. PEF, individual asthma symptom scores, nighttime asthma sleep disturbance scores, and rescue study drug use over the 4-week study. No significant differences were found between the two treatment groups for change from predose in heart rate, systolic and diastolic blood pressure, and 12-lead ECG intervals at either study day 1 or study week 4. Adverse event reporting was similar for the two treatment groups. In this study, with regular use of HFA albuterol in children with asthma, there was a similar safety profile and comparable bronchodilator efficacy as with CFC albuterol.


The gymnosperm ortholog of the angiosperm central cell-specification gene CKI1 provides an essential clue to endosperm origin.
A defining feature of angiosperms is double fertilization involving the female gametophyte central cell and formation of a nutrient-storing tissue called endosperm. The route for the evolutionary origin of endosperm from a gymnosperm ancestor, particularly the molecular steps involved, has remained elusive. Recently, the histidine kinase gene Cytokinin-Independent 1 (CKI1), an activator of cytokinin signaling, was described as a key to specification of the endosperm precursor central cell in Arabidopsis. Here, we have investigated the function and expression of a putative ortholog of CKI1 in the gymnosperm Ginkgo biloba. We demonstrate that Ginkgo CKI1 can partially rescue an Arabidopsis cki1 mutant and promote weak activation of the cytokinin signaling pathway in the Arabidopsis embryo sac, but does not confer central cell specification. Ginkgo CKI1 is expressed in both male and female gametophytes of Ginkgo. In the latter, it is expressed in the ventral canal cell, which is sister to the egg cell in the archegonium. As in Arabidopsis, Ginkgo CKI1 is not expressed in the egg cell. The similarities in expression patterns of CKI1 in Ginkgo and Arabidopsis female gametophytes suggest that extant gymnosperms possess an essential component of the molecular machinery required for angiosperm endosperm development, and provide new insights into endosperm origin from a gymnospermous ancestor.


Impact of Job Insecurity on Psychological Well- and Ill-Being among High Performance Coaches.
The evaluative nature of high performance (HP) sport fosters performance expectations that can be associated with harsh scrutiny, criticism, and job insecurity. In this context, (HP) sport is described as a highly competitive, complex, and turbulent work environment. The aim of this longitudinal, quantitative study was to explore whether HP coaches' perceptions of job insecurity and job value incongruence in relation to work would predict their psychological well- and ill-being over time. HP coaches (n = 299) responded to an electronic questionnaire at the start, middle, and end of a competitive season, designed to measure the following: job insecurity, values, psychological well-being (vitality and satisfaction with work), and psychological ill-being (exhaustion and cynicism). Structural equation model analyses were conducted using Mplus. Experiencing higher levels of job insecurity during the middle of the season significantly predicted an increase in coaches' psychological ill-being, and a decrease in their psychological well-being at the end of the season. However, value incongruence did not have a significant longitudinal impact. These findings cumulatively indicate that coaches' perceptions of job insecurity matter to their psychological health at work. Consequently, it is recommended that coaches and organizations acknowledge and discuss how to handle job security within the HP sport context.


Amiloride-sensitive sodium absorption is different in vertebrates and invertebrates.
Amiloride-sensitive Na+ absorption is a well-described feature of numerous transporting epithelia in vertebrates. Yet, very little is known about this important physiological process regarding invertebrates. In the present paper, we compare vertebrate Na+ absorption mediated by the amiloride-sensitive epithelial Na+ channel (ENaC) and its invertebrate counterpart. We used the dorsal skin of the annelid Hirudo medicinalis as a model for the Na+ absorption of invertebrate epithelia. In applying electrophysiological, molecular, and biochemical techniques we found striking functional and structural differences between vertebrate and invertebrate amiloride-sensitive Na+ absorption. Using modified Ussing chambers, we analyzed the influence of different known blockers and effectors of vertebrate ENaC on leech epithelial Na+ absorption. We demonstrate that the serine protease trypsin had no effect on the Na+ transport across leech integument, while it strongly activates vertebrate ENaC. While protons, and the divalent cations Ni2+ and Zn2+ stimulate vertebrate ENaC, amiloride-sensitive Na+ currents in leech integument were substantially reduced. For molecular studies, we constructed a cDNA library of Hirudo medicinalis and screened it with specific ENaC antibodies. We performed numerous PCR approaches using a vast number of different degenerated and specific ENaC primers to identify ENaC-like structures. Yet, both strategies did not reveal any ENaC-like sequence in leech integument. From these data we conclude that amiloride-sensitive Na+ absorption in leech skin is not mediated by an ENaC-like Na+ channel but by a still unknown invertebrate member of the ENaC/DEG family that we termed lENaTP (leech epithelial Na+ transporting protein).


Changes in mammary caveolin-1 signaling pathways are associated with breast cancer risk in rats exposed to estradiol in utero or during prepuberty.
Developmental stage of rat mammary gland at the time of estrogen exposure determines whether the exposure increases or reduces later breast cancer risk. For example, in utero exposure to 17β-estradiol (E2) increases, whereas prepubertal exposure to this hormone decreases susceptibility of developing carcinogen-induced mammary tumors. E2 mediates its actions by interacting with caveolin-1 (CAV1), a putative tumor suppressor gene in breast cancer. Mammary tissues from 2-month-old rats exposed to E2 in utero contained decreased levels of CAV1, whereas prepubertal E2 exposure increased the levels, when compared to vehicle controls. Low CAV1 expression was associated with increased cell proliferation and estrogen receptor α expression, and reduced apoptosis in the mammary glands of rats exposed to E2 in utero. In contrast, high CAV1 expression correlated with reduced cell proliferation and cyclin D1 and phospho-Akt levels, and increased apoptosis in the mammary glands of rats exposed to E2 during prepuberty. In support of the role of CAV1 as a negative regulator of a variety of pro-growth signaling proteins, we detected decreased levels of Src and ErbB2 in rats exposed to E2 during prepuberty. Thus, estrogen exposure during mammary gland development affects the expression and function of CAV1 in a manner consistent with observed changes in susceptibility to mammary tumorigenesis.


Interaction of large artery stiffness and baroreceptor function explored through multiple measurement techniques - a pilot study.
Baroreceptors, sensors that play a role in controlling arterial blood pressure (BP), are mechanical stretch receptors located in the aortic arch and carotid sinuses. Factors affecting the degree of stretch in the vessel wall with BP, such as increased arterial stiffness, may compromise baroreceptor sensitivity (BRS) to BP changes. Yet, evidence of this is scattered, as both baroreceptor sensitivity (BRS) and arterial stiffness are calculated variables with multiple methodological approaches. This pilot study (n=10) investigates the correlation of arterial stiffness and BRS using multiple BRS calculation techniques (spectral and sequence methodologies at aortic and finger sites) and arterial stiffness measurement [carotid-femoral pulse wave velocity (cfPWV), carotid compliance and distensibility]. BRS was assessed under resting BP conditions and during BP altered by maneuvers (0.1 Hz controlled breathing and leg ischemia). Magnitude of arterial stiffness - BRS correlation was positive for carotid distensibility and compliance, and negative for cfPWV, supporting the theory. A sample size of 100 participants (not rounded - exact figure by power calculation) would be required to confirm or reject all permutations of correlation between BRS by multiple calculation methods and large artery stiffness by PWV and compliance/distensibility measures.


How are parent-child conflict and childhood externalizing symptoms related over time? Results from a genetically informative cross-lagged study.
The present study attempted to determine the direction and etiology of the robust relationship between childhood externalizing (EXT) symptoms and parent-child conflict using a genetically informative longitudinal model and data from the ongoing Minnesota Twin Family Study. Participants consisted of 1,506 same-sex twins assessed at ages 11 and 14, and their parents. The relationship between EXT and parent-child conflict from ages 11 to 14 was examined within a biometrical cross-lagged design. The results revealed three primary findings: first, the stability of conflict and externalizing over time is largely, although not solely, a result of genetic factors. Second, there appears to be a bidirectional relationship between conflict and EXT over time, such that both conflict and EXT at 11 independently predict the other 3 years later. Finally, the results are consistent with the notion that parent-child conflict partially results from parental responses to their child's heritable externalizing behavior, while simultaneously contributing to child externalizing via environmental mechanisms. These results suggest a "downward spiral" of interplay between parent-child conflict and EXT, and offer confirmation of a (partially) environmentally mediated effect of parenting on child behavior.


Gut microbiome predicts gastrointestinal toxicity outcomes from chemoradiation therapy in patients with head and neck squamous cell carcinoma.
Chemoradiation (CRT) in patients with locally advanced head and neck squamous cell cancer (HNSCC) is associated with significant toxicities, including mucositis. The gut microbiome represents an emerging hallmark of cancer and a potentially important biomarker for CRT-related adverse events. This prospective study investigated the association between the gut microbiome composition and CRT-related toxicities in patients with HNSCC, including mucositis. Stool samples from patients diagnosed with locally advanced HNSCC were prospectively collected prior to CRT initiation and analyzed using shotgun metagenomic sequencing to evaluate gut microbiome composition at baseline. Concurrently, clinicopathologic data, survival outcomes and the incidence and grading of CRT-emergent adverse events were documented in all patients. A total of 52 patients were included, of whom 47 had baseline stool samples available for metagenomic analysis. Median age was 62, 83 % patients were men and 54 % had stage III-IV disease. All patients developed CRT-induced mucositis, including 42 % with severe events (i.e. CTCAE v5.0 grade ≥ 3) and 25 % who required enteral feeding. With a median follow-up of 26.5 months, patients with severe mucositis had shorter overall survival (HR = 3.3, 95 %CI 1.0-10.6; p = 0.02) and numerically shorter progression-free survival (HR = 2.8, 95 %CI, 0.8-9.6; p = 0.09). The gut microbiome beta-diversity of patients with severe mucositis differed from patients with grades 1-2 mucositis (p = 0.04), with enrichment in Mediterraneibacter (Ruminococcus gnavus) and Clostridiaceae family members, including Hungatella hathewayi. Grade 1-2 mucositis was associated with enrichment in Eubacterium rectale, Alistipes putredinis and Ruminococcaceae family members. Similar bacterial profiles were observed in patients who required enteral feeding. Patients who developed severe mucositis had decreased survival and enrichment in specific bacteria associated with mucosal inflammation. Interestingly, these same bacteria have been linked to immune checkpoint inhibitor resistance.


Evaluation of gene expression and alginate production in response to oxygen transfer in continuous culture of Azotobacter vinelandii.
Alginates are polysaccharides used as food additives and encapsulation agents in biotechnology, and their functional properties depend on its molecular weight. In this study, different steady-states in continuous cultures of A. vinelandii were established to determine the effect of the dilution rate (D) and the agitation rate on alginate production and expression of genes involved in alginate polymerization and depolymerization. Both, the agitation and dilution rates, determined the partitioning of the carbon utilization from sucrose into alginate and CO2 under oxygen-limiting conditions. A low D (0.07 h(-1)) and 500 rpm resulted in the highest carbon utilization into alginate (25%). Quantitative real-time polymerase chain reaction was used to determine the transcription level of six genes involved in alginate polymerization and depolymerization. In chemostat cultures at 0.07 h(-1), the gene expression was affected by changes in the agitation rate. By increasing the agitation rate from 400 to 600 rpm, the algE7 gene expression decreased tenfold, whereas alyA1, algL and alyA2 gene expression increased between 1.5 and 2.8 times under similar conditions evaluated. Chemostat at 0.07 h(-1) showed a highest alginate molecular weight (580 kDa) at 500 rpm whereas similar molecular weights (480 kDa) were obtained at 400 and 600 rpm. The highest molecular weight was not explained by changes in the expression of alg8 and alg44 (genes involved in alginate polymerization). Nonetheless, a different expression pattern observed for lyases could explain the highest alginate molecular weight obtained. Overall, the results suggest that the control of alginate molecular weight in A. vinelandii cells growing in continuous mode is determined by a balance between the gene expression of intracellular and extracellular lyases in response to oxygen availability. These findings better our understanding of the biosynthesis of bacterial alginate and help us progress toward obtain tailor-made alginates.


Non-adherence to immunosuppressants following renal transplantation: a protocol for a systematic review.
Adherence to immunosuppressant medication is essential for renal transplant recipients. This review aims to summarise what is known about non-adherence, with a view to providing comprehensive evidence to inform strategies aimed at advancing adherent behaviour. A systematic review of quantitative studies that report adherence to immunosuppressants in adult (over 18 years) renal transplant recipients. The review will follow the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines; study quality will be assessed using the Downs and Black checklist. Systematic searches will be completed across relevant databases. Two reviewers will independently extract data using a predefined data extraction form. We will summarise the operationalisation of adherence across studies and use narrative synthesis to identify factors associated with non-adherence. A meta-analysis will be conducted if there is sufficient homogeneity, and available data, across studies to estimate the prevalence of non-adherence in renal transplant recipients. Heterogeneity will be assessed using the I2 test. Survival analysis will be conducted to estimate hazard ratios to explore the impact of non-adherence on graft survival, graft failure and patient survival. Findings will be published in a peer-reviewed journal and disseminated at conferences for professionals and researchers. Review outcomes will help support clinical practice by highlighting the extent of non-adherence among adults, and in doing so, signpost the need for suitable intervention. PROSPERO registration number (CRD42016038751).


Impact of comorbidity on colorectal cancer screening in the veterans healthcare system.
The quality assessment measure of colorectal cancer screening in the veteran's health system reports the proportion of patients aged 52-80 years who were tested. This approach does little to assess for comorbid illnesses, which might limit the utility of screening. Our aim was to determine the relationship between patient comorbidity and screening by fecal occult blood test in a national sample of veterans. We examined the Veterans Health Administration's national databases (October 2003-February 2005) for a random sample of primary care patients, aged > or = 50 years. The Charlson score, a validated measure of comorbidity burden, was calculated from diagnosis codes by the Deyo method. The association between Charlson score and colorectal cancer screening was assessed with logistic regression. The sample of 77,268 was 97% men; mean age was 67 years. Charlson score distribution was 0, 45%; 1, 24%; 2, 14%; 3, 7%; 4, 4%; 5, 2%; 6, 1%; 7, 0.8%; 8, 0.6%; 9, 0.4%; > or = 10, 1%. Overall there was no consistent significant association between Charlson score and use of fecal occult blood testing except in the sickest 1%. There was a strong and incremental relationship between Charlson score and 1-year mortality. Although there was a strong relationship in the veteran population between the Charlson score and survival, colorectal cancer screening utilization was not impacted by Charlson score. Instead, resources were expended evenly throughout the population, rather than directed toward screening the patients with the most life-years at stake. The quality measure for colorectal cancer screening should be modified to account for patient comorbidity.


The influence of sugar-beet fibre, guar gum and inulin on nutrient digestibility, water consumption and plasma metabolites in healthy Beagle dogs.
The aim of the present study was to evaluate the effects of three fibres (sugar-beet fibre, guar gum and inulin) incorporated in the basal diet of healthy dogs at 7 per cent of dry matter (DM). Parameters examined included stool output, water consumption, nutrient digestibility and fasting and postprandial plasma metabolites. All fibres increased wet faecal output; an increase in faecal DM output being observed with sugar-beet fibre only. Sugar-beet fibre and inulin increased daily water consumption. Sugar-beet fibre and guar gum decreased DM digestibility. The three fibres diminished organic matter and crude protein digestibility while ether extract digestibility was decreased by guar gum and inulin. Guar gum induced lower postprandial insulin, alpha-amino-nitrogen and urea plasma concentrations. Guar gum also lowered fasting cholesterolaemia. Sugar-beet fibre and inulin showed no metabolic effects. These physiological properties suggest that guar gum would be a suitable ingredient for dietary therapy of chronic diseases such as diabetes mellitus or hyperlipidaemia in the dog.


Duration of growth depression and pathogen shedding in experimentally reproduced poult enteritis syndrome.
An experimental study was conducted to determine the duration of growth depression and virus shedding in turkey poults after oral inoculation with intestinal contents from birds affected with poult enteritis syndrome (PES). Poults at day 14 of age were divided into four groups (groups A, B, C, and D) of 40 poults each and inoculated orally with unfiltered supernatant, filtered supernatant, sediment suspended in phosphate-buffered saline (PBS), or PBS alone (control), respectively. The poults were observed daily for clinical signs, and their growth response, pathology, and pathogen shedding were examined at 10, 20, 30, 40, and 50 days postinoculation (DPI). Body weights of eight poults in each group were recorded at each of these intervals followed by euthanasia. Dullness, depression, and diarrhea were observed in birds inoculated with supernatant or sediment suspension. All three treatments significantly reduced body weight gain of poults compared with the control group; average weight loss was 14%. Gross pathologic changes consisted of pale distended intestines with watery contents and distended ceca with frothy and watery contents. Astrovirus and rotavirus were detected in the inoculum by reverse transcription (RT)-PCR, whereas Salmonella was identified on bacterial isolation. Both viruses were detected in treated poults by RT-PCR for up to 10 and 40 DPI, respectively. Of the three treatments, sediment suspension caused maximal decrease in weight gain as well as greatest pathologic lesions followed by unfiltered supernatant and filtered supernatant. These findings suggest a role for bacteria in increasing the severity of PES. Lower weight gain in treated poults (compared with controls) at 9 wk of age also indicates that PES-affected poults may not reach normal weight at marketing, leading to economic losses for the producer.


Animal models of post-ischemic forced use rehabilitation: methods, considerations, and limitations.
Many survivors of stroke experience arm impairments, which can severely impact their quality of life. Forcing use of the impaired arm appears to improve functional recovery in post-stroke hemiplegic patients, however the mechanisms underlying improved recovery remain unclear. Animal models of post-stroke rehabilitation could prove critical to investigating such mechanisms, however modeling forced use in animals has proven challenging. Potential problems associated with reported experimental models include variability between stroke methods, rehabilitation paradigms, and reported outcome measures. Herein, we provide an overview of commonly used stroke models, including advantages and disadvantages of each with respect to studying rehabilitation. We then review various forced use rehabilitation paradigms, and highlight potential difficulties and translational problems. Lastly, we discuss the variety of functional outcome measures described by experimental researchers. To conclude, we outline ongoing challenges faced by researchers, and the importance of translational communication. Many stroke patients rely critically on rehabilitation of post-stroke impairments, and continued effort toward progression of rehabilitative techniques is warranted to ensure best possible treatment of the devastating effects of stroke.


Perioperative complications after cemented or uncemented hemiarthroplasty in hip fracture patients.
Both cemented and uncemented hemiarthroplasties are acceptable methods for treating displaced femoral neck fractures. Cemented hemiarthroplasty has traditionally been recommended as being more safe and reliable. However, the cementing process carries a risk of fat embolism and cardiovascular problems. This study attempted to determine whether these complications can be avoided when using a modern uncemented stem. We retrospectively compared 222 hip fracture patients treated with hemiarthroplasty in our hospital. A total of 100 of these patients were treated with a hydroxyapatite-coated uncemented hemiendoprosthesis (Bi-Metric BFx) and 122 patients with a cemented hemiendoprosthesis (Lubinus SPII). Information on mortality and complications during the first 18.7 months was retrieved from patient files. Nine perioperative fat-embolic events were found in the cemented group and none in the uncemented group. During the initial hospital treatment, there were five deaths (4.1%) in the cemented group and one death (1%) in the uncemented group. There were significantly more perioperative fractures in the uncemented versus cemented group (7% versus 0.8%). We conclude that uncemented hemiarthroplasty is associated with more perioperative fractures than cemented hemiarthroplasty. However, perioperative cardiovascular disturbances may be less frequent with uncemented hemiarthroplasty, and early mortality may be lower with uncemented hemiarthroplasty.


A rare case of gastrointestinal stromal tumor presenting with closed perforation of the small intestine.
Gastrointestinal stromal tumors are very rare mesenchymal tumors of the gastrointestinal tract with variable clinical presentations depending on the tumor size and anatomic site. The currently used diagnostic modalities cannot establish a preoperative diagnosis with 100% certainty. The treatment of choice includes complete surgical excision and/or chemotherapy. In this paper, we present a very rare case of gastrointestinal stromal tumor presenting with closed perforation of the small intestine. The patient was successfully managed with surgical excision of the tumor with segmental bowel resection and adjuvant chemotherapy. Although rare, it must be kept in mind that gastrointestinal stromal tumors can also present with closed bowel perforation.


Reduced blood flow in fibromyotic muscles during ultrasound therapy.
The muscle blood flow (MBF) in m. trapezius was studied in 7 subjects with fibromyotic pain syndrome before and during treatment with ultrasound (1 Watt/cm2) and during placebo treatment, using the local 133Xe-washout technique. MBF in the fibromyotic muscles was significantly reduced during ultrasound treatment (p less than 0.05) compared to the blood flow before the treatment and during placebo treatment 1.57 +/- SEM 0.52 and 2.51 +/- SEM 0.43 ml/100 g/min, respectively. In 6 normal trapezius muscles the mean MBF was 2.30 +/- SEM 0.44 ml/100 g/min before ultrasound treatment and 2.31 +/- SEM 0.41 ml/100 g/min during ultrasound therapy. MBF decreased in a lidocaine blocked fibromyotic muscle during ultrasound treatment while no effect on MBF was detectable during ultrasonic treatment a normal lidocaine pretreated muscle. It is concluded that ultrasound treatment decreases MBF in fibromyotic muscles and that this is paradoxical effect of ultrasound might be due to a direct effect on the vessels or a local release of vasoactive substances in the fibromyotic muscles.


Single-row, double-row, and transosseous equivalent techniques for isolated supraspinatus tendon tears with minimal atrophy: A retrospective comparative outcome and radiographic analysis at minimum 2-year followup.
The purpose of this study was to measure and compare the subjective, objective, and radiographic healing outcomes of single-row (SR), double-row (DR), and transosseous equivalent (TOE) suture techniques for arthroscopic rotator cuff repair. A retrospective comparative analysis of arthroscopic rotator cuff repairs by one surgeon from 2004 to 2010 at minimum 2-year followup was performed. Cohorts were matched for age, sex, and tear size. Subjective outcome variables included ASES, Constant, SST, UCLA, and SF-12 scores. Objective outcome variables included strength, active range of motion (ROM). Radiographic healing was assessed by magnetic resonance imaging (MRI). Statistical analysis was performed using analysis of variance (ANOVA), Mann - Whitney and Kruskal - Wallis tests with significance, and the Fisher exact probability test <0.05. Sixty-three patients completed the study requirements (20 SR, 21 DR, 22 TOE). There was a clinically and statistically significant improvement in outcomes with all repair techniques (ASES mean improvement P = <0.0001). The mean final ASES scores were: SR 83; (SD 21.4); DR 87 (SD 18.2); TOE 87 (SD 13.2); (P = 0.73). There was a statistically significant improvement in strength for each repair technique (P < 0.001). There was no significant difference between techniques across all secondary outcome assessments: ASES improvement, Constant, SST, UCLA, SF-12, ROM, Strength, and MRI re-tear rates. There was a decrease in re-tear rates from single row (22%) to double-row (18%) to transosseous equivalent (11%); however, this difference was not statistically significant (P = 0.6). Compared to preoperatively, arthroscopic rotator cuff repair, using SR, DR, or TOE techniques, yielded a clinically and statistically significant improvement in subjective and objective outcomes at a minimum 2-year follow-up. Therapeutic level 3.


Radiation risk in the context of liability for injury.
It is perceived by the man in the street that low-level radiation from a nuclear facility is more dangerous than that from other practices. The radiation protection system, in particular the ALARA principle, leads to concerns that even the smallest exposure to radiation is abnormal and dangerous. Public perception of the radiation risk leads to fear in the minds of the public. A consequence of this fear itself may be damage to health in the form of psychological damage or nervous shock. The paper draws attention to the liability for damages by radiation, in particular under the common law of the UK and US, and how liability, determined by the court, is not necessarily influenced by scientific rationality. A natural conclusion may be that a claimant suffering injury of the type caused by radiation and who had been exposed to radiation, no matter how small a dose, that could be shown to come from a nuclear installation would be awarded damages against the licensee of the site of the installation unless it could be shown that the injury was predominantly caused by another source (radioactive or otherwise).


Maternal and neonatal thyroid status in Saki, Nigeria.
The influence of inadequate iodine intake on maternal and neonatal thyroid status in Saki, a locality known to have environmental iodine deficiency and located within the goitre belt of Southwestern Nigeria was investigated. One hundred and five (105) subjects and ninety (90) controls from Ibadan were recruited into the study. All subjects were apparently healthy with at least thirty-seven (37) completed weeks of gestation. Each subject was assessed for goitre and blood sample obtained by venepuncture for thyroid function tests before onset of labour. Spot urine samples were also obtained from the mothers at the time of examination for urinary iodine estimation. At delivery, cord blood samples were obtained from the babies for thyroid function tests. The mean maternal urinary iodine excretion was significantly less in Saki when compared with Ibadan (144.76 +/- 14.68 vs 213.36 +/- 9.89 ug/L P < 0.01). Maternal total goitre rates (TGR) were 46.8% and 2.2%, while maternal visible goitre rates (VGR) were 26.6% and 1.1% in Saki and Ibadan, respectively. Maternal mean plasma total T3 and total T4 were relatively lower in Saki as compared to Ibadan, though the differences were not statistically significant. Mean maternal plasma TSH in Saki was slightly above our laboratory reference interval (0.3-5.0 mU/L) and higher than the level seen in Ibadan mothers (6.54 +/- 1.58 vs 4.18 +/- 1.37 mU/L,), though the difference was also not statistically significant. Mean neonatal total T3 and T4 were lower in Saki when compared to Ibadan, but the differences were not statistically significant. The mean neonatal plasma TSH in Saki was above the adult reference interval and significantly higher than the level seen in Ibadan (9.82 +/- 1.64 vs 4.18 +/- 1.17 mU/L, P < 0.05). The incidence of neonatal chemical hypothyroidism (NCH) in Saki was 14.7 per 1000 babies. No case of NCH was seen in Ibadan. These results suggest environmental iodine deficiency and relative chemical hypothyroidism of mothers and neonates in Saki when compared to mothers and noenates from non-iodine deficient areas.


Transcriptional changes in the hookworm, Ancylostoma caninum, during the transition from a free-living to a parasitic larva.
Third-stage larvae (L3) of the canine hookworm, Ancylostoma caninum, undergo arrested development preceding transmission to a host. Many of the mRNAs up-regulated at this stage are likely to encode proteins that facilitate the transition from a free-living to a parasitic larva. The initial phase of mammalian host invasion by A. caninum L3 (herein termed "activation") can be mimicked in vitro by culturing L3 in serum-containing medium. The mRNAs differentially transcribed between activated and non-activated L3 were identified by suppression subtractive hybridisation (SSH). The analysis of these mRNAs on a custom oligonucleotide microarray printed with the SSH expressed sequence tags (ESTs) and publicly available A. caninum ESTs (non-subtracted) yielded 602 differentially expressed mRNAs, of which the most highly represented sequences encoded members of the pathogenesis-related protein (PRP) superfamily and proteases. Comparison of these A. caninum mRNAs with those of Caenorhabditis elegans larvae exiting from developmental (dauer) arrest demonstrated unexpectedly large differences in gene ontology profiles. C. elegans dauer exiting L3 up-regulated expression of mostly intracellular molecules involved in growth and development. Such mRNAs are virtually absent from activated hookworm larvae, and instead are over-represented by mRNAs encoding extracellular proteins with putative roles in host-parasite interactions. Although this should not invalidate C. elegans dauer exit as a model for hookworm activation, it highlights the limitations of this free-living nematode as a model organism for the transition of nematode larvae from a free-living to a parasitic state.


DARS2 promotes the occurrence of lung adenocarcinoma via the ERK/c-Myc signaling pathway.
DARS2 expression is upregulated in lung adenocarcinoma (LUAD) which correlates with tumor patient stage and prognosis. The mechanism of DARS2 involvement in LUAD still needs to be further explored. In this study, we found that DARS2 expression in LUAD tissue was significantly higher than that in normal tissue. At the same time, the Kaplan-Meier curve showed that the survival prognosis of LUAD patients with high expression of DARS2 was significantly worse than low expression of DARS2. The expression of DARS2 was detected in LUAD and adjacent normal tissues by IHC staining, histochemical scoring and a survival curve was generated. In addition, we demonstrated that the knockdown and overexpression of DARS2 significantly affected the proliferation, invasion, and migration of LUAD cells in vitro and in vivo. Finally, western blot and rescue assay were performed on LUAD cells to further explore and verify the signaling pathway. DARS2 expression was significantly upregulated in LUAD tissues and cell lines. What is more, the increased expression of DARS2 was closely related to proliferation, invasion and metastasis. The tumorigenic assay in nude mice further showed that the tumorigenic ability of nude mice was significantly improved with the increase in DARS2 expression. Finally, we determined that DARS2 plays its role in LUAD by targeting the ERK/c-Myc signaling pathway. Our data revealed the oncogenic role of DARS2 in LUAD, indicating that DARS2 may be a predictive biomarker and novel therapeutic target for LUAD.


Sex differences in the transmission, prevention, and disease manifestations of sexually transmitted diseases.
Dermatological manifestations of sexually transmitted diseases (STDs) range from full body papulosquamous eruptions to genital ulcers and warts. The transmission, prevalence, and disease burden of STDs are not shared equally between the sexes. Women are more susceptible than men for the acquisition of the human immunodeficiency virus and other dangerous STDs because of economic, biological, and social factors, and often sustain more damage to their health from the disease. Conclusion This review article elucidates the differential effect of STDs on women vs men to better understand what is required to protect women from the morbidity and mortality of STDs.


Laparoscopic percutaneous jejunostomy for long term enteral access.
Patients suffering from upper gastrointestinal pathology may require jejunal feeding for adequate nutrition. A laparoscopically guided percutaneous jejunostomy offers a minimally invasive means of obtaining such feeding access. Laparoscopic jejunostomy was performed in 32 patients. The most common indications were gastroparesis (n = 16), neurological deficits (n = 7), and proximal obstruction (n = 5). The proximal jejunum was affixed to the abdominal wall using intracorporeal and extracorporeal transabdominal sutures, allowing safe insertion of an 18-Fr Silastic dual-lumen tube. Laparoscopic jejunostomy was successfully completed for 28 patients; the procedure was converted to an open operation in four cases. Three of these four were among 14 patients undergoing the procedure who had a history of previous abdominal surgery. Major complications were observed in seven patients, including one reoperation and one death from aspiration pneumonia. Tube feeding was accomplished in all patients; progression to full enteral feeding proceeded without interruption in 20 patients. Laparoscopic jejunostomy can be performed with relative safety. Morbidity, though high, is usually related to preexisting disease. Previous abdominal surgery is not necessarily a contraindication to laparoscopic jejunostomy.


Trimethorpim-sulfamethoxazole in the treatment of chronic prostatitis.
Chronic prostatis is a common condition for which evidence of bacterial etiology is often lacking, possibly because of difficulty in obtaining secretion from the diseased portion of the gland. Aids to diagnosis apart from bacteriologic studies are of little value. It has been shown that trimethoprim reaches high levels in the prostatic fluid and when combined with sulfamethoxazole provides a highly effective antibacterial agent. In a survey of 40 patients with chronic prostatitis treated with TMP-SMX the usefulness of the combination was demonstrated.


Veterans' health and access to care in the year after September 11, 2001.
The goal was to explore veterans' perceptions of their health care in the year after September 11, 2001. A random sample of outpatients seen at a Manhattan (New York City) or Midwestern Veterans Affairs facility between September 12, 2001, and September 30, 2002, received a mailed questionnaire. Regression assessed the effects of site, demographic features, military service, and symptoms of post-traumatic stress disorder (PTSD) on health status, care-seeking, and satisfaction with health care among 490 patients. Veterans from New York City reported better health and more satisfaction that their providers listened to them. Patients with more PTSD symptoms reported poorer health, more September 11-related symptoms, and less satisfaction with care and were more likely to seek care outside the Veterans Affairs system. Proximity to the September 11 terrorist attacks had little relationship to patients' perceptions of their health and health care, whereas PTSD symptoms had a pervasive effect. Patients with PTSD symptoms may require outreach programs to assist them in dealing with catastrophic events, regardless of their proximity to the events.


Genome-Resolved Metagenomics and Metatranscriptomics Reveal Insights into the Ecology and Metabolism of Anaerobic Microbial Communities in PCB-Contaminated Sediments.
Growth of organohalide-respiring bacteria such as Dehalococcoides mccartyi on halogenated organics (e.g., polychlorinated biphenyls (PCBs)) at contaminated sites or in enrichment culture requires interaction and support from other microbial community members. To evaluate naturally occurring interactions between Dehalococcoides and key supporting microorganisms (e.g., production of H2, acetate, and corrinoids) in PCB-contaminated sediments, metagenomic and metatranscriptomic sequencing was conducted on DNA and RNA extracted from sediment microcosms, showing evidence of both Dehalococcoides growth and PCB dechlorination. Using a genome-resolved approach, 160 metagenome-assembled genomes (MAGs), including three Dehalococcoides MAGs, were recovered. A novel reductive dehalogenase gene, distantly related to the chlorophenol dehalogenase gene cprA (pairwise amino acid identity: 23.75%), was significantly expressed. Using MAG gene expression data, 112 MAGs were assigned functional roles (e.g., corrinoid producers, acetate/H2 producers, etc.). A network coexpression analysis of all 160 MAGs revealed correlations between 39 MAGs and the Dehalococcoides MAGs. The network analysis also showed that MAGs assigned with functional roles that support Dehalococcoides growth (e.g., corrinoid assembly, and production of intermediates required for corrinoid synthesis) displayed significant coexpression correlations with Dehalococcoides MAGs. This work demonstrates the power of genome-resolved metagenomic and metatranscriptomic analyses, which unify taxonomy and function, in investigating the ecology of dehalogenating microbial communities.


The correlates of HIV testing and impacts on sexual behavior: evidence from a life history study of young people in Kisumu, Kenya.
HIV counseling and testing is considered an important component of HIV prevention and treatment. This paper examines the characteristics of young males and females at the time of first reported HIV test, including the influence of recent sexual partnerships, and investigates how HIV testing and the cumulative number of tests are associated with sexual behaviors within six months of testing. The study uses data from a random sample of youth aged 18-24 years living in Kisumu, Kenya, who were interviewed using a 10-year retrospective life history calendar. Cox regression models were used to examine the correlates of the timing of first HIV test. Variance-correction models for unordered repeated events were employed to examine whether having an HIV test in the previous six months and the cumulative number of tests predict unsafe sexual practices in a given month. Sixty-four percent of females and 55% of males reported at least one HIV test in the last 10 years and 40% of females were pregnant the month of first test. Significant correlates of first HIV test included marital aspirations among non-pregnant females, unprotected sex in the previous six months among pregnant females, and concurrency in the previous six months among males. Having a recent HIV test was associated with a decreased likelihood of unprotected sex among ever-pregnant females, an increased likelihood of unprotected sex and "risky" sexual partnerships among never-pregnant females, and an increased likelihood of concurrency among males. Repeated HIV testing was associated with a lower likelihood of concurrency among males and involvement in "risky" sexual partnerships among males and never-pregnant females. The high rate of pregnancy at first test suggests that promotion of HIV testing as part of prevention of mother-to-child transmission is gaining success. Further research is warranted to examine how and why behavior change is influenced by client- versus provider-initiated testing. The influence of different sexual partnership variables for males and females suggests that interventions to assess risk and promote testing should be gender- and relationship-specific. The findings also suggest that encouraging repeat or routine testing could potentially increase the uptake of safer sexual behaviors.


Labrys okinawensis sp. nov. and Labrys miyagiensis sp. nov., budding bacteria isolated from rhizosphere habitats in Japan, and emended descriptions of the genus Labrys and Labrys monachus.
Three strains, MAFF 210191(T), G24103(T) and G24116, assumed to be members of two novel species, were isolated from several rhizosphere habitats in different parts of Japan. Phylogenetic analysis based on 16S rRNA gene sequences revealed that the isolates formed a distinct monophyletic group together with the two known species of the genus Labrys, suggesting that the isolates have a close affiliation with this genus. In this study, a polyphasic approach was used to characterize and compare the three isolates with the two species of the genus Labrys, Labrys monachus and Labrys methylaminiphilus. All three isolates were aerobic, Gram-negative, motile and non-sporulating and they ranged in shape from spherical to short rods. The cells multiplied by budding and utilized a wide variety of monosaccharides, disaccharides and sugar alcohols as sole carbon and energy sources, but they did not utilize C(1) compounds, salicin or d-melezitose. The strains were inhibited by dl-alpha-alanine and glycine (both at 10 mM). The major cellular fatty acids were C(19 : 0) cyclo omega8c, C(16 : 0), C(18 : 0) and C(18 : 1)omega7c. The three isolates shared <12 % and <11 % DNA-DNA relatedness with L. monachus DSM 5896(T) and L. methylaminiphilus DSM 16812(T), respectively. The G+C content of the isolates (61-62 mol%) was also significantly lower than those of the two previously characterized species. In spite of many morphological, physiological and chemotaxonomic similarities among the three isolates, strain MAFF 210191(T) could be differentiated from strains G24103(T) and G24116 on the basis of 16S rRNA gene sequence divergence, DNA-DNA relatedness (<46 %) and gelatin hydrolysis. Two novel species are therefore proposed, namely Labrys okinawensis sp. nov., with the type strain MAFF 210191(T) (=DSM 18385(T)), and Labrys miyagiensis sp. nov., with the type strain G24103(T) (=NBRC 101365(T)=NCIMB 14143(T)) and also including strain G24116 (=NBRC 101366=NCIMB 14144). Emended descriptions of the genus Labrys and Labrys monachus are also presented.


Exploration of Physiological and Pathophysiological Implications of miRNA-143 and miRNA-145 in Cerebral Arteries.
Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke with a high short-term mortality rate which leads to cognitive impairments that reduce the quality of life of the majority of patients. The miRNA-143/145 cluster is highly expressed in vascular smooth muscle cells (VSMC) and has been shown to be necessary for differentiation and function, as well as an important determinant for phenotypic modulation/switching of VSMCs in response to vascular injury. We aimed to determine whether miRNA-143 and miRNA-145 are important regulators of phenotypical changes of VSMCs in relation to SAH, as well as establishing their physiological role in the cerebral vasculature. We applied quantitative PCR to study ischemia-induced alterations in the expression of miRNA-143 and miRNA-145, for rat cerebral vasculature, in an ex vivo organ culture model and an in vivo SAH model. To determine the physiological importance, we did myograph studies on basilar and femoral arteries from miRNA-143/145 knockout mice. miRNA-143 and miRNA-145 are not upregulated in the vasculature following our SAH model, despite the upregulation of miR-145 in the organ culture model. Regarding physiological function, miRNA-143 and miRNA-145 are very important for general contractility in cerebral vessels in response to depolarization, angiotensin II, and endothelin-1. Applying an anti-miRNA targeting approach in SAH does not seem to be a feasible approach because miRNA-143 and miRNA-145 are not upregulated following SAH. The knockout mouse data suggest that targeting miRNA-143 and miRNA-145 would lead to a general reduced contractility of the cerebral vasculature and unwanted dedifferentiation of VSMCs.


Epidemiology of pediatric herpes zoster after varicella infection: a population-based study.
There are limited population-based data regarding pediatric herpes zoster (HZ). Children aged <12 years with varicella infections between 2000 and 2006 were identified from a national population-based database and followed-up for a diagnosis of HZ until December 2008. Since a routine varicella vaccination program was started in 2004, vaccinated children without medically attended varicella were identified between 2004 and 2006, and followed-up for a diagnosis of HZ until December 2008. Of 27 517 children with medically attended varicella, 428 developed HZ. The incidence of HZ was 262.1 per 100 000 person-years. Of 25 132 vaccinated children without medically attended varicella, 106 developed HZ. The incidence of HZ was 93.3 per 100 000 person-years. The mean duration from varicella to HZ was 4.12 years. Children diagnosed with varicella at aged <2 years had a higher incidence (P < .001) and shorter duration (P = .04) than those diagnosed aged ≧2 years. Children diagnosed with varicella aged ≥2 but <8 years had a significantly increased incidence of HZ after than before the vaccination program (relative risk = 1.85 at 3 years of follow-up, P = .03). Children with varicella infections had a significantly greater risk of HZ than vaccinated children without a history of varicella (relative risk = 2.31 at 4 years of follow-up, P < .001). This study demonstrates the population-based epidemiologic characteristics of pediatric HZ among those who contracted varicella. In the early postvaricella vaccination period, an increased HZ incidence was observed among children with varicella infection aged ≥2 years.


Complications and consent following decompressive craniectomy: an illustrative case study.
To assess clinical outcome following restoration of cranial contour in a young male who had suffered a severe traumatic brain injury. Case report. A young male was assessed before and after cranial reconstructive surgery with a custom-made titanium plate. The patient had previously required a bifrontal decompressive craniectomy in order to control intractable intracranial hypertension due to neurotrauma. Following an autologous cranioplasty he made very little neurological recovery and remained wheelchair-bound with severe contractures and was only able to follow single stage commands. Over the following 2 years he developed extensive resorption of his bone flap such that it required augmentation. After surgery he clinically improved such that he was able to communicate more effectively and, although he remained severely disabled and fully dependent, he was able to communicate that he would have provided consent for the initial decompressive procedure even if he had known that the eventual outcome would be survival with severe disability and total dependence. Long-term follow-up is required for patients with severe traumatic brain injury not only to assess outcome and complications, but also to assess how acceptable that outcome is for the patient and their families.


Amyloid-beta decreases cell-surface AMPA receptors by increasing intracellular calcium and phosphorylation of GluR2.
alpha-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs) are key regulators of synaptic function and cognition. In Alzheimer's disease (AD), cell-surface AMPARs are downregulated, however the reason for this downregulation is not clear. In the present study, we found that Abeta significantly decreased levels of the cell-surface AMPA-type glutamate receptor subunit 2 (GluR2), and increased the concentration of free cytosolic calcium ion ([Ca2+]i) in hippocampal neurons. Ion channel blockers (nifedipine, tetrodotoxin, SKF96365) decreased [Ca2+ and increased the level of cell-surface GluR2, whereas Bay K 8644, an activator of L-type voltage-gated calcium channels increased [Ca2+]i and decreased cell-surface GluR2. Abeta and Bay K 8644 increased phosphorylation of serine-880 (S880) on GluR2, whereas the nifedipine. tetrodotoxin and SKF96365 decreased S880 phosphorylation. Finally, we found that bisindolylmeimide I (GF 109203X, GFX), an inhibitor of protein kinase C (PKC) blocked both the decrease in cell-surface GluR2 and the increase in phospho-S880 induced by Abeta and Bay K 8644. Taken together, these results demonstrate that Abeta decreases cell-surface GluR2 by increasing PKC-mediated phosphorylation of S880. Our study supports the view that a rise in cytosolic [Ca2+]i induced by Abeta could impair synaptic function by decreasing the availability of AMPARs at the synapse. This decrease in AMPARs may contribute to the decline in cognitive function seen in AD.


Raf-1 oncogenic signaling is linked to activation of mesenchymal to epithelial transition pathway in metastatic breast cancer cells.
Aberrant activation of the Raf/MEK/MAPK pathway plays a key role in breast cancer development and progression. Dysregulation of Raf/MEK/MAPK oncogenic signaling often results from overexpression of the HER-2/Neu tyrosine kinase receptor leading to chemoendocrine resistance, development of distant metastases and ultimately poor prognosis in breast cancer patients. HER-2/Neu overexpression is also linked to activation of the epithelial to mesenchymal transition (EMT) pathway, loss of adhesion molecules and metastasis. Recently, it has been demonstrated that cancer cells that undergo EMT acquire a CD44+/CD24-/low basal cancer stem cell-like phenotype and are characterized by activation of HER-2/Neu and TGFβ oncogenic signaling pathways with increased capacity of self-renewal, drug resistance, invasion and distant metastases. Following metastatic dissemination, cancer cells re-activate certain epithelial properties through mesenchymal to epithelial transition (MET) to establish neoplastic lesions at secondary sites, although the molecular mechanisms regulating MET remain elusive. In this study we demonstrate that constitutive activation of Raf-1 oncogenic signaling induces HER-2/Neu overexpression leading to the development of distant metastases in ERα+ MCF-7 breast cancer xenografts. Importantly, development of distant metastases in xenograft models was linked to activation of the MET pathway characterized by reduced expression of EMT inducer genes (TGFB2, TWIST1 and FOXC1) and overexpression of BMB7, CXCR7 and EGR family of transcription factors. In summary, our results demonstrate for the first time that amplification of Raf/MEK/MAPK oncogenic signaling during tumor growth promotes the genesis of metastatic lesions from primary tumors by activating the mesenchymal epithelial transition.


A comparative study of technetium-99m sestamibi and technetium-99m tetrofosmin single-photon tomography in the detection of nasopharyngeal carcinoma.
The intention of this prospective study was to compare the diagnostic potential of technetium-99m sestamibi (MIBI) and a novel radiotracer, 99mTc-Tetrofosmin (Tetro), for the assessment of primary nasopharyngeal carcinoma (NPC) and the differentiation of residual disease from post-therapy changes. A total of 38 patients underwent MIBI and Tetro single-photon emission tomography (SPET) imaging at initial presentation (n=22) or following therapy (n=16). The findings were correlated with computed tomography or magnetic resonance imaging (MRI) on a site-by-site basis. Tumour/background (Tm/Bkg) ratios were obtained on coronal sections. Biopsy (nine patients) and/or 12- to 24-month clinical follow-up data were available in the post-therapy group. All primary disease sites were accurately detected by both imaging studies. Although there was no statistical difference between the two imaging techniques in the detection of primary disease, MIBI was superior to Tetro in the detection of regional lymph node metastases (sensitivity: 95% vs 79%). Tetro and MIBI SPET were true-positive in all patients (n=7) with proven residual/recurrent disease. In nine patients who had no evidence of residual/recurrent tumour, MRI was false-positive in five while Tetro and MIBI SPET were false-positive in two and three patients, respectively. Tm/Bkg ratios were </=1.7 in all false-positive cases except one. Tetro, MIBI and MRI had specificities of 78%, 67% and 44%, and accuracies of 87.5%, 81% and 69%, respectively. The results of Tetro and of MIBI SPET were not statistically different from one another with regard to the prediction of residual/recurrent or metastatic NPC.


Patient compliance to a new enteric-coated weekly formulation of fluoxetine during continuation treatment of major depressive disorder.
A new formulation of enteric-coated fluoxetine given once weekly could be a useful option for the long-term treatment of depression, but compliance to once-weekly fluoxetine treatment has not been assessed. Patients were adults from the United Kingdom who had responded to fluoxetine treatment for a current episode of depression (DSM-IV criteria). In the baseline assessment phase, all patients (N = 117) were continued on 20 mg of open-label fluoxetine once daily for 4 weeks. In the follow-up phase, patients (N = 109) were randomly assigned to once-weekly or once-daily fluoxetine for 3 months. Patient compliance was monitored by electronic devices during both phases of the study. Compliance to once-weekly fluoxetine treatment was higher than compliance to once-daily fluoxetine (85.9% vs. 79.4%, respectively). Once-weekly fluoxetine treatment allows for new flexibility for both the clinician and the patient, and this study alleviates the concern that patients will forget weekly doses.


Crystal structures of two Bacillus carboxylesterases with different enantioselectivities.
Naproxen esterase (NP) from Bacillus subtilis Thai I-8 is a carboxylesterase that catalyzes the enantioselective hydrolysis of naproxenmethylester to produce S-naproxen (E>200). It is a homolog of CesA (98% sequence identity) and CesB (64% identity), both produced by B. subtilis strain 168. CesB can be used for the enantioselective hydrolysis of 1,2-O-isopropylideneglycerol (solketal) esters (E>200 for IPG-caprylate). Crystal structures of NP and CesB, determined to a resolution of 1.75Å and 2.04Å, respectively, showed that both proteins have a canonical α/β hydrolase fold with an extra N-terminal helix stabilizing the cap subdomain. The active site in both enzymes is located in a deep hydrophobic groove and includes the catalytic triad residues Ser130, His274, and Glu245. A product analog, presumably 2-(2-hydroxyethoxy)acetic acid, was bound in the NP active site. The enzymes have different enantioselectivities, which previously were shown to result from only a few amino acid substitutions in the cap domain. Modeling of a substrate in the active site of NP allowed explaining the different enantioselectivities. In addition, Ala156 may be a determinant of enantioselectivity as well, since its side chain appears to interfere with the binding of certain R-enantiomers in the active site of NP. However, the exchange route for substrate and product between the active site and the solvent is not obvious from the structures. Flexibility of the cap domain might facilitate such exchange. Interestingly, both carboxylesterases show higher structural similarity to meta-cleavage compound (MCP) hydrolases than to other α/β hydrolase fold esterases.


[Preparation of hexokinase isoenzyme II with expressed adsorption properties].
The isolation of the native hexokinase isozyme II possessing a high adsorptive capacity is described. This property underlies the adsorption mechanism responsible for the control of the hexokinase activity in the cell and is realized only under conditions of the structural integrity of the enzyme. The latter is due, primarily, to the functional state of the specific adsorption domain which provides the specific interaction of hexokinase isozyme II with biological membranes. The criteria of nativity of skeletal muscle hexokinase were elaborated. A procedure for obtaining highly purified native hexokinase isozyme II from rat skeletal muscle was developed.


Media representations of pregnancy and childbirth: an analysis of reality television programs in the United States.
Reality-based birth television programs in the United States warrant close analysis because many women watch these shows to learn about birth. The purpose of this study was to understand how reproduction and birth are portrayed in these shows. We hypothesized that women's bodies are displayed as inferior and in need of surveillance and that this inferiority of the female body is solved through technology and a medical approach to birth. We performed a content analysis of 85 reality-based birth television shows, depicting 123 births, aired in the United States on Discovery Health and The Learning Channel in November 2007. The study hypotheses were largely supported. Women's bodies were typically displayed as incapable of birthing a baby without medical intervention. The shows also lacked diversity in the representations of birthing women and, in particular, overrepresented married women and heterosexual women. This research suggests that reality-based birth television programs do not give women an accurate portrayal of how women typically experience birth in the United States, nor are the shows consistent with evidence-based maternity practices.


Treatment Fidelity in Mind-Body Interventions.
To contribute to the treatment fidelity literature by providing real-world examples and suggestion for future research and potential clinical application, this article reports on implementation, assessment, and evaluation of treatment fidelity in mind-body self-care approaches in at-risk women. Aligning with best practices, treatment fidelity was integrated into three randomized clinical trials. The first examined the effects of a tai chi intervention designed to decrease cardiometabolic risk factors in women; the second examined the effects of a tailored guided imagery intervention on pregnancy outcomes in African American women; and the third explored effects of a mindful physical activity intervention (yoga) on psychological outcomes in women with moderate to severe depressive symptoms. Each of the studies successfully designed, implemented, and evaluated strategies to address recommended treatment fidelity components. These strategies provided qualitative and quantitative data that informed intervention refinement, directions for future research, and application in clinical practice. The treatment fidelity framework used here is based on best practices and was a feasible and reliable approach for ensuring and reporting on treatment fidelity, which is contributing to future research to foster translation of potentially effective mind-body self-care approaches into practice.


[Transitory osteoporosis in pregnancy; diagnosis with MRI. Case report].
A case of transitory osteoporosis of the hips in pregnancy is reported. Through knowledge of the typical course of the disease and exact diagnosis with MRI, expensive therapy can be avoided. Suspicion of a transitory osteoporosis in pregnancy is a clear indication for performing an MRI.


Interobserver variance in perceptual performance and learning.
Normal observers and patients with apparent disease usually are tacitly expected to yield homogeneous thresholds in clinical tests of visual perception. The authors tested this assumption. Through training of 70 observers, performance and improvement of performance were tested for different hyperacuity tasks using psychophysical tests. Although the assumption of homogeneous results might be true for many tasks limited by the physical properties of the eye, such as two-point resolution, the authors find a relatively wide variation of performance, especially in untrained observers, for tasks that require more elaborate processing in the visual cortex. Observers vary widely both in their baseline performance and in the extent and speed of learning for tasks such as vernier discrimination and stereoscopic depth perception. On average, speed of learning is inversely correlated to baseline performance, that is better initial performance usually is associated with slower improvement. This finding indicates that retesting of unusually high (pathologic) thresholds in clinical tests of visual perception might improve discrimination between patients whose performance is poor because of lack of familiarity with the task and who improve with training and patients who improve far less if their poor performance results from pathologic conditions.


Regulation of tumour necrosis factor alpha mRNA stability by the mitogen-activated protein kinase p38 signalling cascade.
The translation of tumour necrosis factor alpha (TNFalpha) mRNA is regulated by the stress-activated protein kinase p38, which also controls the stability of several pro-inflammatory mRNAs. The regulation of TNFalpha gene expression in a mouse macrophage cell line RAW264.7 was re-examined using an inhibitor of stress-activated protein kinases. Stimulation of these cells with bacterial lipopolysaccharide resulted in stabilisation of TNFalpha mRNA, which was reversed by specific inhibition of p38. An adenosine/uridine-rich element from the TNFalpha 3' untranslated region conferred p38-sensitive decay in a tetracycline-regulated mRNA stability assay. Therefore the p38 pathway also controls TNFalpha mRNA turnover.


Dry Eye Disease following LASIK, PRK, and LASEK: An Observational Cross-Sectional Study.
Dry eye disease is the most frequent non-refractive postoperative complication following refractive surgery. This prospective study investigated the development of dry eye disease after three common refractive laser surgeries: laser in situ keratomileusis (LASIK), photorefractive keratectomy (PRK), and laser-assisted sub-epithelial keratectomy (LASEK). Patients who underwent uneventful refractive surgery in a single private medical center between May 2017 and September 2020 were included. Ocular surface disease was graded according to the Dry Eye Workshop severity (DEWS) classification. Patients were examined 6 months following refractive surgery. The analysis included 251 eyes of 137 patients: 64 eyes (36 patients) after LASEK, 90 eyes (48 patients) after PRK, and 97 eyes (53 patients) after LASIK. At 6 months post-surgery, the DEWS score was higher for the LASIK than the PRK and LASEK groups (p = 0.01). For the total cohort, severe DEWS score (grades 3 and 4) at 6 months post-surgery was correlated with female gender (p = 0.01) and to the amount of refractive correction (p < 0.001), but not to age (p = 0.87). In conclusion, LASIK surgery and female gender were associated with dry eye. Patients, particularly those with high myopia, should be counseled about the risk of developing dry eye after refractive surgeries.


Multiple transcription factors contribute to inter-chromosomal interaction in yeast.
Chromatin interactions medicated by genomic elements located throughout the genome play important roles in gene regulation and can be identified with the technologies such as high-throughput chromosome conformation capture (Hi-C), followed by next-generation sequencing. These techniques were wildly used to reveal the relative spatial disposition of chromatins in human, mouse and yeast. Unlike metazoan where CTCF plays major roles in mediating chromatin interactions, in yeast, the transcription factors (TFs) involved in this biological process are poorly known. Here, we presented two computational approaches to estimate the TFs enriched in the chromatin physical inter-chromosomal interactions in yeast. Through the Chi-square method, we found TFs whose binding data are differentially distributed in different interaction groups, including Cin5, Stp1 and Sut1, whose binding data are negatively correlated with the chromosome spatial distance. A multivariate linear regression model was employed to estimate the potential contribution of different transcription factors against the physical distance of chromosomes. Rlr1, Set12 and Dig1 were found to be top positively participated in these chromosomal interactions. Ste12 was highlighted to be involved in gene reposition. Overall, we found 10 TFs enriched from both computational approaches, potentially to be involved in inter-chromosomal interactions. No transcription factor (TF) in our study was found to have a dominant impact on the inter-chromosomal interaction as CTCF did in human or other metazoan, suggesting species without CTCF might have different regulatory systems in mediating inter-chromosomal interactions. In summary, we presented a systematic examination of TFs involved in chromatin interaction in yeast and the results provide candidate TFs for future studies.


A systematic review and network meta-analysis of immunotherapy and targeted therapy for advanced melanoma.
Immune and BRAF-targeted therapies have changed the therapeutic scenario of advanced melanoma, turning the clinical decision-making a challenging task. This Bayesian network meta-analysis assesses the role of immunotherapies and targeted therapies for advanced melanoma. We retrieved randomized controlled trials testing immune, BRAF- or MEK-targeted therapies for advanced melanoma from electronic databases. A Bayesian network model compared therapies using hazard ratio (HR) for overall survival (OS), progression-free survival (PFS), and odds ratio (OR) for response rate (RR), along with 95% credible intervals (95% CrI), and probabilities of drugs outperforming others. We assessed the impact of PD-L1 expression on immunotherapy efficacy. Sixteen studies evaluating eight therapies in 6849 patients were analyzed. For OS, BRAF-MEK combination and PD-1 single agent ranked similarly and outperformed all other treatments. For PFS, BRAF-MEK combination surpassed all other options, including CTLA-4-PD-1 dual blockade hazard ratio (HR: 0.56; 95% CrI: 0.33-0.97; probability better 96.2%), whereas BRAF single agent ranked close to CTLA-4-PD-1 blockade. For RR, BRAF-MEK combination was superior to all treatments including CTLA-4-PD-1 (OR: 2.78; 1.18-6.30; probability better 97.1%). No OS data were available for CTLA-4-PD-1 blockade at the time of systematic review, although PFS and RR results suggested that this combination could also bring meaningful benefit. PD-L1 expression, as presently defined, failed to inform patient selection to PD-1-based immunotherapy. BRAF-MEK combination seemed an optimal therapy for BRAF-mutated patients, whereas PD-1 inhibitors seemed optimal for BRAF wild-type patients. Longer follow-up is needed to ascertain the role of CTLA-4-PD-1 blockade. Immunotherapy biomarkers remain as an unmet need.


[Effects of afobasol in the reperfusion arrhythmia model].
Afobasol caused insignificant dose-related decrease of main parameters of cardiac activity in narcotized animals and was similar to pulse-decelerating calcium antagonists in terms of hemodynamic effects. Reperfusion after acute regional myocardial ischemia induced malignant cardiac rhythm disorders and progressive impairment of cardiac pump function. These changes combined with increased peripheral resistance created conditions for the development of cardiac insufficiency. Afobasol administered 5 min before the onset of reperfusion significantly reduced the frequency and intensity of cardiac rhythm disturbances and thereby prevented cardiac insufficiency. It is conjectured that cardioprotectice action of afobasol in these conditions was due to its ability to activate sigma-1 receptors in cardiomyocytes and thereby protected heart cells from excessive accumulation of Ca2+ ions.


Posttraumatic Oculorrhea From the Eyelid.
We report a 21-month-old boy with a sutured laceration of the left upper eyelid with drainage of cerebrospinal fluid. Careful evaluation, including computerized tomography, revealed a penetrating injury of the left orbital wall and a linear bone fracture. The wound was resutured carefully. There was no cerebrospinal fluid leakage in the postoperative follow-up period.