Outreach immunisation services in NewZealand: a review of service delivery models.
INTRODUCTION Outreach Immunisation Services (OIS) enable children who have not been immunised on time at general practice to be immunised in the community, thereby improving immunisation coverage and reducing equity gaps. AIM To identify the most effective service delivery models and make recommendations for more effective and cost-efficient OIS delivery in New Zealand. METHODS Data collection and thematic analysis through a detailed review of OIS contracts and service specifications, an online survey and in-depth interviews with stakeholders and providers, and an analysis of cost data was conducted. RESULTS In total, 28 OIS providers completed survey questionnaires, 28 OIS staff were interviewed, and cost effectiveness data were obtained from 11 providers. The surveys and interviews identified key themes around identifying clients with the highest needs, effective engagement strategies, staffing requirements, and service challenges. On average, each OIS referral costs NZ$361 (median NZ$257), and each vaccination event costs NZ$636, ranging from NZ$145 to NZ$2403. Characteristics for two separate models of service delivery were identified based on provider size. CONCLUSION There is considerable range in costs and style of OIS delivery, and efficiencies can be gained. Models need to fit with locality needs and include adequate resourcing, staff with good local knowledge, close relationships with other key child health services and preferably co-location, sustainable funding, and regular service reviews. OIS are part of an effective integrated service that relies on accurate data, positive relationships and a rapid response when children fail to present for vaccination in a timely fashion.


On convolutional neural networks for selection inference: Revealing the effect of preprocessing on model learning and the capacity to discover novel patterns.
A central challenge in population genetics is the detection of genomic footprints of selection. As machine learning tools including convolutional neural networks (CNNs) have become more sophisticated and applied more broadly, these provide a logical next step for increasing our power to learn and detect such patterns; indeed, CNNs trained on simulated genome sequences have recently been shown to be highly effective at this task. Unlike previous approaches, which rely upon human-crafted summary statistics, these methods are able to be applied directly to raw genomic data, allowing them to potentially learn new signatures that, if well-understood, could improve the current theory surrounding selective sweeps. Towards this end, we examine a representative CNN from the literature, paring it down to the minimal complexity needed to maintain comparable performance; this low-complexity CNN allows us to directly interpret the learned evolutionary signatures. We then validate these patterns in more complex models using metrics that evaluate feature importance. Our findings reveal that preprocessing steps, which determine how the population genetic data is presented to the model, play a central role in the learned prediction method. This results in models that mimic previously-defined summary statistics; in one case, the summary statistic itself achieves similarly high accuracy. For evolutionary processes that are less well understood than selective sweeps, we hope this provides an initial framework for using CNNs in ways that go beyond simply achieving high classification performance. Instead, we propose that CNNs might be useful as tools for learning novel patterns that can translate to easy-to-implement summary statistics available to a wider community of researchers.


Alterations of paraoxonase and platelet-activating factor acetylhydrolase activities in patients on peritoneal dialysis.
The more atherogenic lipid profile seen in peritoneal dialysis (PD) patients cannot fully explain the increased incidence of atherosclerosis in this population. Oxidative modification of low-density lipoproteins (LDL) is considered to play a central role in the atherogenic process, whereas high-density lipoprotein (HDL) protects LDL from oxidation. On the other hand, it has been suggested that the LDL and HDL of PD patients are more resistant to oxidation than those of control subjects, while PD-HDL equally protects LDL from oxidation compared to control-HDL. Two HDL-associated enzymes have been shown to protect both LDL and HDL from oxidation: paraoxonase (PON1) and HDL-associated platelet-activating factor acetylhydrolase (HDL-PAF-AH). Furthermore, low PON1 activity and high total plasma PAF-AH concentration, which represents mainly the LDL-associated enzyme, have been shown to be independent risk factors for coronary artery events in the general population. However, there are limited data regarding possible alterations of these enzymes in PD patients. The aim of our study was to examine the possible alterations of PON1 and PAF-AH activities in patients undergoing PD. A cross-sectional study. A university medical center. 56 PD patients of Caucasian origin and 86 matched controls were studied. In all subjects, serum PON1 activity toward paraoxon (paraoxonase) and phenylacetate (arylesterase), as well as total serum and HDL-PAF-AH activities were measured; PON1 genetic polymorphisms known to influence PON1 activity (Q192R and M55L) were determined. The PD patients exhibited significantly increased serum PON1 (paraoxonase) and PON1 (arylesterase) activities compared to controls, regardless of the PON1 polymorphisms or the levels of HDL cholesterol. Additionally, PD patients had significantly elevated activities of total serum PAF-AH and HDL-PAF-AH, independently of the levels of LDL or HDL cholesterol. The ratio of HDL-PAF-AH/ total PAF-AH, which has recently been suggested to be a potential marker of atherogenicity, was decreased in these patients compared to controls. Moreover, no difference in the prevalence of PON1 polymorphisms between PD patients and controls was found. The elevated activities of PON1 and HDL-PAF-AH could explain the increased resistance of PD-HDL to oxidation; the higher activity of total PAF-AH and the decreased HDL-PAF-AH/ total PAF-AH ratio could contribute to the increased incidence of atherosclerosis in these patients.


Clinical course of gastroesophageal reflux disease and impact of treatment in symptomatic young patients.
In symptomatic young patients with gastroesophageal reflux symptoms, early identification of progressive gastroesophageal reflux disease (GERD) is critical to prevent long-term complications associated with hiatal hernia, increased esophageal acid and nonacid exposure, release of proinflammatory cytokines, and development of intestinal metaplasia, endoscopically visible Barrett's esophagus, and dysplasia leading to esophageal adenocarcinoma. Progression of GERD may occur in asymptomatic patients and in those under continuous acid-suppressive medication. The long-term side effects of proton-pump inhibitors, chemopreventive agents, and radiofrequency ablation are contentious. In patients with early-stage disease, when the lower esophageal sphincter function is still preserved and before endoscopically visible Barrett's esophagus develops, novel laparoscopic procedures, such as magnetic and electric sphincter augmentation, may have a greater role than conventional surgical therapy. A multidisciplinary approach to GERD by a dedicated team of gastroenterologists and surgeons might impact the patients' lifestyle, the therapeutic choices, and the course of the disease. Biological markers are needed to precisely assess the risk of disease progression and to tailor surveillance, ablation, and management.


Temporal properties of spatial frequency tuning of surround suppression in the primary visual cortex and the lateral geniculate nucleus of the cat.
In primary visual cortex (V1) neurons, a stimulus placed in the extraclassical receptive field suppresses the response to a stimulus within the classical receptive field (CRF), a phenomenon referred to as surround suppression. The aim of the present study was to elucidate the mechanisms of surround suppression in V1. Using stationary-flashed sinusoidal grating as stimuli, we observed temporal changes of surround suppression in V1 and the lateral geniculate nucleus (LGN) and of the response to CRF stimulation in V1. The spatial frequency (SF) tuning of surround suppression in V1 neurons changed over time after the stimulus onset. In the early phase (< 50 ms), the SF tuning was low-pass, but later became band-pass that tuned to the optimal SF in response to CRF stimulation. On the other hand, the SF tuning of CRF responses in V1 was band-pass throughout the response time whereas the SF peak shifted slightly toward high SF. Thus, SF tuning properties of the CRF response dissociated from that of surround suppression in V1 only in the early phase. We also confirmed that the temporal changes of the SF tuning of surround suppression in the LGN occurred in the same direction as surround suppression in V1, but the shift from low-pass to band-pass SF tuning started later than that in V1. From these results, we suggest that subcortical mechanisms contribute to early surround suppression in V1, whereas cortical mechanisms contribute to late surround suppression.


[Measurement of physical capacities in the elderly: a secondary analysis of the Quebec longitudinal study NuAge].
To assess the validity of a battery of functional capacity tests in community-living elderly Canadians. cross-sectional study. baseline data from 1793 men and women aged 74.4 +/- 4.1 participating in the NuAge longitudinal study were collected from December 2003 to April 2005 and used for the analyses. A global score measuring functional capacities (BFC) was constructed as the sum of four tests according to a method proposed by Guralnik [Timed Up and Go, walking speed (4 m), chair stands (five times), standing balance]. Multivariate linear regression analysis was used to study the relationship between age, sex, and physical activity, and BFC score. The global functional capacities score had an internal consistency of 0.74. It was significantly associated with age, sex and measures of mental and physical health status including: cognitive function (< 0.001), depressive symptoms (< 0.001), nutritional risk (< 0.001), burden of disease (< 0.001), and level of physical activity (< 0.001) thus supporting the construct validity of the global score. Age related differences in BFC were consistent and similar among men and women. The global score of functional capacity tests provided a valid assessment of physical capacities in the community-living elderly. While men had higher global BFC scores than women, among both sexes the best performance was observed in the youngest age group and in those reporting more physical activity.


Auto-adhesive transdermal drug delivery patches using beetle inspired micropillar structures.
The patch described in this paper combines the principles of wet adhesion, which is a widely adopted biological adhesion system in nature, with transdermal drug delivery. A biologically inspired micropillar patch was fabricated that is self-adhesive, reusable, and can sustain a controlled drug release. We successfully preloaded the commercial non-steroidal anti-inflammatory generic drug unguents indomethacin, ketoprofen, diclofenac sodium and etofenamate into a polydimethylsiloxane elastomeric matrix and fabricated drug-containing micropillar patches. When examining the drug release kinetics and friction of the patches, we observed that these drug unguents can be released calculably and regularly for several days. Additionally, the drug unguents released from the patch to its attached surface are critical to increase the strength of the patch's adhesion, which is based on capillary attractive forces and is inspired by beetle feet. Here, we create a novel system combining biomimetics and drug delivery that can be modified for use across the biomedical and engineering spectra. Motivation: the objective of the present study was to characterize a micropillar PDMS patch that was inspired by a beetle's wet adhesion as a platform for conducting in vitro release studies. Commercially available non-steroid anti-inflammatory drugs (NSAIDs) were used as the model drugs for our delivery systems. An emphasis was put on quantitatively evaluating the drug release and friction manifestation of these patches.


Introduction of Medicare coverage in opioid treatment programs: Findings from the first three years.
Prior to January of 2020, there was no Medicare reimbursement for services delivered in opioid treatment programs (OTPs). OTPs are the only authorized providers of opioid use disorder (OUD) treatment with methadone, a critical tool to address the opioid overdose crisis. While prior research has examined the availability of MOUD other than methadone for Medicare beneficiaries, research has not identified organizational and local Medicare beneficiary characteristics associated with Medicare insurance acceptance among OTPs. This study has two objectives: 1) to determine the extent to which OTPs began accepting Medicare insurance in the first three years following the new Medicare OTP benefit; and 2) to identify organizational characteristics and local Medicare beneficiary characteristics associated with OTP acceptance of Medicare. We used data from the 2021-2023 National Directory of Drug and Alcohol Abuse Treatment Facilities to examine OTP acceptance of Medicare. We used logistic regression to identify organizational characteristics and local Medicare beneficiary characteristics associated with OTP acceptance of Medicare (n = 4630 OTPs). By 2022, about 78.7 % of OTPs accepted Medicare, compared to only 41.1 % of non-OTPs. The odds of Medicare acceptance were lower among for-profit OTPs, compared to non-profit OTPs, and higher among OTPs that accepted Medicaid and private insurance. Additionally, the odds of accepting Medicare were lower for OTPs located in the Northeast, Midwest, and South, compared to OTPs located in the West. Finally, the odds of accepting Medicare were higher for OTPs located in counties with higher percentages of Non-Hispanic White Medicare beneficiaries. We found high rates of Medicare acceptance among OTPs in the first three years of the Medicare OTP benefit, suggesting increased access to OUD treatment via OTPs for Medicare beneficiaries. While promising, results indicate potential geographic and racial/ethnic disparities in access to OTPs.


Isolation of sterol-resistant Chinese hamster ovary cells with genetic deficiencies in both Insig-1 and Insig-2.
Insig-1 and Insig-2, a pair of endoplasmic reticulum (ER) membrane proteins, mediate feedback control of cholesterol synthesis through their sterol-dependent binding to the following two polytopic ER membrane proteins: sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Sterol-induced binding of Insigs to SCAP prevents the proteolytic processing of SREBPs, membrane-bound transcription factors that enhance the synthesis of cholesterol, by retaining complexes between SCAP and SREBP in the ER. Sterol-induced binding of Insigs to reductase leads to the ubiquitination and ER-associated degradation of the enzyme, thereby slowing a rate-controlling step in cholesterol synthesis. Here we report the isolation of a new line of mutant Chinese hamster ovary cells, designated SRD-15, deficient in both Insig-1 and Insig-2. The SRD-15 cells were produced by gamma-irradiation of Insig-1-deficient SRD-14 cells, followed by selection in high levels of the oxysterol, 25-hydroxycholesterol. Sterols neither inhibit SREBP processing nor promote reductase ubiquitination/degradation in SRD-15 cells. Sterol regulation of SREBP processing and reductase ubiquitination/degradation is fully restored in SRD-15 cells when they are transfected with expression plasmids encoding either Insig-1 or Insig-2. These results demonstrate an absolute requirement for Insig proteins in the regulatory system that mediates lipid homeostasis in animal cells.


Allergy and the gastrointestinal system.
The gastrointestinal system plays a central role in immune system homeostasis. It is the main route of contact with the external environment and is overloaded every day with external stimuli, sometimes dangerous as pathogens (bacteria, protozoa, fungi, viruses) or toxic substances, in other cases very useful as food or commensal flora. The crucial position of the gastrointestinal system is testified by the huge amount of immune cells that reside within it. Indeed, gut-associated lymphoid tissue (GALT) is the prominent part of mucosal-associated lymphoid tissue (MALT) and represents almost 70% of the entire immune system; moreover, about 80% of plasma cells [mainly immunoglobulin A (IgA)-bearing cells] reside in GALT. GALT interacts strictly with gastrointestinal functions in a dynamic manner; for instance, by increasing intestinal permeability in replay to particular stimulations, or orientating the immune response towards luminal content, allowing either tolerance or elimination/degradation of luminal antigens, or sometimes provoking damage to the intestinal mucosa, such as in coeliac disease or food allergy. The immune mechanisms implicated in these actions are very complex and belong to both innate and adaptive immunity; innate immunity supplies an immediate non-specific response that is indispensable before specific adaptive immunity, which needs 7-10 days to be efficacious, takes place. The results of their interactions depend upon different contexts in which contact with external agents occurs and may change according to different genetic settings of the hosts.


[The Redox-Catalytic Properties of Cobalamins].
Vitamin B12, or cobalamin, is essential for normal body function and is used in the therapies of different diseases. Vitamin B12 has anti-inflammatory and antioxidant properties that can play an important role in the prevention of some diseases. On the other hand, it has been reported that vitamin B12 in combination with such reducing agents as ascorbate (vitamin C) and thiols showed prooxidant activity. This review provides information on the roles of vitamin B12 in diseases accompanied by inflammation and oxidative stress and the effects of vitamin B12 administrated alone and in combinations with different reducing agents such as ascorbate and thiols on oxidative stress. In addition, the mechanisms of prooxidant actions of combinations of vitamin B12 with these reducing agents depending on the form of vitamin B12 (hydroxocobalamin and cyanocobalamin) are discussed. Understanding the mechanisms of prooxidant action of vitamin B12 is necessary for developing strategies for therapeutic administration of vitamin B12.


Recreational drug consumers: who seeks treatment?
Recreational drug consumption represents a complex issue, because of the lack of a shared definition, settings and patterns of consumptions, and poorness of evidence-based treatments. In spite of the great number of users, just few seek specific treatment, probably representing those at major risk of continuing and problematic use. The general objective of this study was to report the characteristics and main consumption patterns of recreational drug consumers treated in Regione Piemonte (Italy), in order to formulate hypotheses suitable for further research aimed at establishing more effective preventive intervention and treatment. All addiction treatment services in the region were required to fill in, for each user, a questionnaire reporting: contact of the user with the service, socio-demographic data, drugs consumption and interventions/treatments. Among 441 users, 70.3% were new users, 85.5% were males and the average age of consumption onset was 22 years. Psychiatric and traumatics events were present in 13.3% and in 17.9% of cases, respectively. The most frequent primary substances were cocaine (76.9%) and ecstasy (13.8%). Substances taken in association with primary drug are quoted in 75% of cases. The users that get in touch with services are those showing greater problems, representing, therefore, the main target for preventive public health interventions. Some interesting points can be noted: among patients treated, cocaine represents the main issue; females seem to be more sensitive to recreational drug effects; social class (education), settings and use habits are similar for recreational drugs users and heroin users.


Stimulation of Na+-Ca2+ exchange in cardiac sarcolemmal vesicles by proteinase pretreatment.
The Na+-Ca2+ exchange activity of purified canine cardiac sarcolemmal vesicles can be strikingly stimulated if the vesicles are pretreated with a serine or thiol proteinase. The Km (Ca2+) for Na+i-dependent Ca2+ influx is reduced from 22.2 +/- 2.3 to 8.1 +/- 0.3 microM while Vmax is increased from 15.1 +/- 3.6 to 18.9 +/- 5.2 nmol Ca2+ . mg protein-1 . s-1. Na+o-dependent Ca2+ efflux is also stimulated by proteinase pretreatment although passive (Na+-independent) Ca2+ efflux from the sarcolemmal vesicles is unaffected. Proteinase treatment reduces the sensitivity of Na+-Ca2+ exchange to the inhibitors chlorpromazine and polymyxin B, but not to the inhibitor, palmitylcarnitine. Using a newly developed technique we are able to demonstrate that the Na+-Ca2+ exchange of inside-out sarcolemmal vesicles is being stimulated by proteinase treatment (Philipson, K. D., and A. Y. Nishimoto, J. Biol. Chem: 257, 5111-5117, 1982; this technique uses the ATP-dependent Na+ pump to preload only inside-out vesicles with Na+ prior to Na+-Ca2+ exchange). Right-side-out vesicles may also be stimulated.


Despeckling of medical ultrasound images using data and rate adaptive lossy compression.
A novel technique for despeckling the medical ultrasound images using lossy compression is presented. The logarithm of the input image is first transformed to the multiscale wavelet domain. It is then shown that the subband coefficients of the log-transformed ultrasound image can be successfully modeled using the generalized Laplacian distribution. Based on this modeling, a simple adaptation of the zero-zone and reconstruction levels of the uniform threshold quantizer is proposed in order to achieve simultaneous despeckling and quantization. This adaptation is based on: (1) an estimate of the corrupting speckle noise level in the image; (2) the estimated statistics of the noise-free subband coefficients; and (3) the required compression rate. The Laplacian distribution is considered as a special case of the generalized Laplacian distribution and its efficacy is demonstrated for the problem under consideration. Context-based classification is also applied to the noisy coefficients to enhance the performance of the subband coder. Simulation results using a contrast detail phantom image and several real ultrasound images are presented. To validate the performance of the proposed scheme, comparison with two two-stage schemes, wherein the speckled image is first filtered and then compressed using the state-of-the-art JPEG2000 encoder, is presented. Experimental results show that the proposed scheme works better, both in terms of the signal to noise ratio and the visual quality.


How to control epistaxis.
Epistaxis is a common problem in medical practice. This article outlines the basic techniques used to control it. In severe cases, prompt management is essential and may save life.


Osteoarthritis chondrocytes die by apoptosis. A possible pathway for osteoarthritis pathology.
To determine which kind of cell death occurs in cartilage from patients with osteoarthritis (OA). Seven normal and 16 OA cartilage samples were collected at autopsy or during joint replacement surgery, respectively. A piece of cartilage was cryopreserved until histologic studies were done. The rest of the cartilage was used to isolate chondrocytes. Apoptotic chondrocytes were analyzed by light and fluorescence microscopy using nuclear 4',6-diamidino-2-phenylindole dihydrochloride stain. Apoptotic chondrocytes were quantified by fluorescence-activated cell sorter (FACS) analysis. The TUNEL technique was used to study histologic apoptosis in situ. Superficial cartilage was processed for ultrastructural study by electron microscopy. OA chondrocytes displayed nuclear and cytoplasmic changes consistent with apoptotic cell death. FACS analysis showed that the OA cartilage had a higher proportion of apoptotic chondrocytes than did normal tissue (51% versus 11%; P < 0.01). In situ study of DNA fragmentation in the cartilage showed that apoptotic cells were located in the superficial and middle zones. Ultrastructural analysis of the superficial OA cartilage revealed some empty lacunae, lysosomal-like structures, matrix vesicle-like structures, fragmented chondrocytes, and nuclear condensation. Chondrocytes in OA cartilage demonstrated morphologic changes that are characteristic features of apoptosis. This mechanism of cell death plays an important role in the pathogenesis of OA and could be targeted for new treatment strategies.


Developing catalysts and catalytic processes with industrial relevance.
The catalysis group of Solvias has its roots in the Central Research Laboratories of Ciba-Geigy. Since the early eighties its research has been focused on three areas of catalytic technology: heterogeneous hydrogenation, coupling catalysis, and enantioselective hydrogenation. Today, these are still the catalytic methods with the greatest industrial potential. In this overview a short description will be given how these methods have been developed further since the spin-off of Solvias in 1999. It will be discussed which strategies were successful and what the most important results have been in the first decade of Solvias.


Disordered eating is not associated with musculoskeletal injury in university athletes.
Musculoskeletal injuries and disordered eating are prevalent in varsity-level athletes but are not associated in our participants.


TNF-alpha pretreatment induces protective effects against focal cerebral ischemia in mice.
Cytokines are recognized to play an important role in acute stroke. Tumor necrosis factor-alpha (TNF) is one of the pro-inflammatory cytokines and is expressed in ischemic brain. We hypothesized that TNF might play a role in the regulation of tolerance to ischemia when administered prior to the ischemic episode. We studied the effects of pretreatment of TNF administered intravenously, intraperitoneally, or intracisternally in mice that were subjected to middle cerebral artery occlusion (MCAO) 48 h later. MCAO was performed in BALB/C mice by direct cauterization of distal MCA, which resulted in pure cortical infarction. A significant reduction in infarct size was noted in mice pretreated by TNF at the dose of 0.5 microgram/mouse (p < 0.01) intracisternally. At the doses used in this study, administration of TNF by intravenous or intraperitoneal routes was not effective. Immunohistochemical analysis of brains subjected to 24 h of MCAO revealed a significant decrease in CD11b immunoreactivity after TNF pretreatment compared with control MCAO. Preconditioning with TNF affects infarct size in a time- and dose-dependent manner. TNF induces significant protection against ischemic brain injury and is likely to be involved in the signaling pathways that regulate ischemic tolerance.


Effect of parental overweight and serum leptin levels on the manifestation of overweight in 7-year-old Korean children.
To explore the relationship between children and their parents in terms of various anthropometric parameters and obesity-related hormone levels and to identify early indicators for child obesity. Cross-sectional observational study. Urban areas of Korea in 2005. A total 124 families with 7-year-old children participated. Anthropometric and blood biochemistry data and information concerning the children's lifestyles, dietary habits and parental and grandparental weight status were obtained. The mean values for all anthropometric parameters were greater in overweight children than in children of normal weight. Very close relationships existed between the anthropometric parameters of children and their parents. Children with two overweight parents showed the highest odds for being overweight (OR 7.62). The strong relationship between overweight children and grandparental and parental overweight, especially on the maternal side, suggests gender differences in the intergenerational transmission of body weight. We also noted a greater risk of being overweight in children with a parent with high serum leptin level. Grandparental and parental weight status and parental serum leptin levels enable us to identify childhood obesity at an early age and may help to counter the current epidemic of adult obesity.


Dynamic patterns of marital conflict: Relations to trajectories of adolescent adjustment.
The deleterious effects of marital conflict on youth outcomes are well-documented in both cross-sectional and longitudinal studies. To date, longitudinal studies have focused on repeated measures of youths' outcomes and the temporal dynamics of marital conflict have largely been ignored. Marital conflict changes over time as contextual and relationship characteristics change, and these patterns of change may provide unique predictive power in accounting for differences in youth outcomes. This study provides a novel exploration of an old idea by focusing on dynamic patterns of marital conflict in predicting trajectories of adolescents' adjustment. All variables were measured at ages 16, 17, and 18 with 252 adolescents (53% female) enrolled in the longitudinal Family Stress and Youth Development Study. Latent growth curve models with latent variable interactions were used to determine whether marital conflict at age 16 (intercept), change over time in marital conflict (slope), and the intercept-slope interaction predicted change over time in adolescent internalizing and externalizing symptoms and levels of internalizing and externalizing symptoms at age 18. Youth exposed to high and increasing levels of marital conflict reported high and stable levels of internalizing and externalizing symptoms across adolescence. Adolescents exposed to low and decreasing levels of marital conflict had consistently fewer symptoms. Furthermore, exposure to initially low but increasing levels of marital conflict was associated with increases in problems across adolescence, which contrasted with findings for youth with initially high marital conflict exposure that decreased over time. Findings are discussed in relation to both conceptual and methodological advances. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Modelling Cryptosporidium infection in human small intestinal and lung organoids.
Stem-cell-derived organoids recapitulate in vivo physiology of their original tissues, representing valuable systems to model medical disorders such as infectious diseases. Cryptosporidium, a protozoan parasite, is a leading cause of diarrhoea and a major cause of child mortality worldwide. Drug development requires detailed knowledge of the pathophysiology of Cryptosporidium, but experimental approaches have been hindered by the lack of an optimal in vitro culture system. Here, we show that Cryptosporidium can infect epithelial organoids derived from human small intestine and lung. The parasite propagates within the organoids and completes its complex life cycle. Temporal analysis of the Cryptosporidium transcriptome during organoid infection reveals dynamic regulation of transcripts related to its life cycle. Our study presents organoids as a physiologically relevant in vitro model system to study Cryptosporidium infection.


Dynamic expression and activity of NF-kappaB during post-natal mammary gland morphogenesis.
The Rel/NF-kappaB family of transcription factors has been implicated in such diverse cellular processes as proliferation, differentiation, and apoptosis. As each of these processes occurs during post-natal mammary gland morphogenesis, the expression and activity of NF-kappaB factors in the murine mammary gland were examined. Immunohistochemical and immunoblot analyses revealed expression of the p105/p50 and RelA subunits of NF-kappaB, as well as the major inhibitor, IkappaBalpha, in the mammary epithelium during pregnancy, lactation, and involution. Electrophoretic mobility shift assay (EMSA) demonstrated that DNA-binding complexes containing p50 and RelA were abundant during pregnancy and involution, but not during lactation. Activity of an NF-kappaB-dependent luciferase reporter in transgenic mice was highest during pregnancy, decreased to near undetectable levels during lactation, and was elevated during involution. This highly regulated pattern of activity was consistent with the modulated expression of p105/p50, RelA, and IkappaBalpha.


Major hematological diseases associated with cleft lip and palate.
Cleft lip and palate is among the most common congenital anomalies. Its association with major blood disorders has rarely been reported. The purpose of this study was to report two patients who had major blood diseases associated with cleft lip and palate. From June 1995 to December 1997, there were 2700 patients with cleft lip, cleft palate, or both who received treatment at Chang Gung Memorial Hospital. Two of them were found to have major hematological disorders. In both cases, the disorder was detected by preoperative blood cell counts and white cell differentiation. Case 1 was a 21-year-old woman patient with repaired right cleft lip. She was admitted for alveolar bone grafting and closure of oronasal fistula. Abnormal presentation of blast cells was found, and subsequent bone marrow study confirmed acute lymphocytic leukemia. Case 2 was a 26-year-old man with left secondary cleft lip nasal deformity scheduled to receive staged reconstructive operations. An elevated platelet count was found and subsequently confirmed to represent essential thrombocytosis. In both cases, reconstructive operations for the cleft-related deformities were performed. Association of major hematological disorders and cleft lip, palate, or both is rare and is reported herein.


Echo-planar imaging: magnetic resonance imaging in a fraction of a second.
Progress has recently been made in implementing magnetic resonance imaging (MRI) techniques that can be used to obtain images in a fraction of a second rather than in minutes. Echo-planar imaging (EPI) uses only one nuclear spin excitation per image and lends itself to a variety of critical medical and scientific applications. Among these are evaluation of cardiac function in real time, mapping of water diffusion and temperature in tissue, mapping of organ blood pool and perfusion, functional imaging of the central nervous system, depiction of blood and cerebrospinal fluid flow dynamics, and movie imaging of the mobile fetus in utero. Through shortened patient examination times, higher patient throughput, and lower cost per MRI examination, EPI may become a powerful tool for early diagnosis of some common and potentially treatable diseases such as ischemic heart disease, stroke, and cancer.


Acute regional vascular effects of intravenous captopril in a rat model of myocardial infarction and failure.
The effects of i.v. captopril on regional blood flow (radioactive microspheres, 15 +/- 5 micron), hemodynamics and maximal oxygen consumption were evaluated in conscious rats with congestive heart failure due to large myocardial infarction (n = 9, infarct size 39.5 +/- 2% of left ventricle) and compared to data obtained from rats subjected to sham surgical procedures (n = 8). In both groups data were obtained at rest and during submaximal treadmill exercise during alternate infusion of captopril and saline. In the congestive heart failure group captopril reduced systemic vascular resistance, mean arterial pressure and left ventricular systolic pressure (P less than .05 each). Blood flow to the renal, gastrointestinal and coronary circulations was reduced in the heart failure group treated with saline vehicle. Flow to the renal and gastrointestinal beds of heart failure animals was enhanced to values similar to those observed in sham animals during captopril treatment. Left ventricular coronary flow was also increased significantly by captopril in both sham and heart failure animals. The most prominent effects of captopril occurred in the renal circulation of the heart failure group in which blood flow increased by 55%. Blood flow to skeletal muscle and skin was unchanged by captopril both in sham and heart failure animals at rest and during exercise. Maximal oxygen consumption was not affected by captopril treatment. Thus, captopril induced a differential pattern of vasodilation with the greatest effect in the renal bed and a less intensive effect in the gastrointestinal and coronary beds. The unchanged flow to skeletal muscle may explain the failure of captopril to improve exercise capacity after short-term administration.


Dorsiflexion Range of Motion in Copers and Those with Chronic Ankle Instability.
The Cumberland Ankle Instability Tool (CAIT) is used to classify individuals as ankle sprain copers, or as one suffering from chronic ankle instability (CAI). However, literature examining factors contributing to these classifications on the CAIT is lacking, as the CAIT itself does not offer explanations for specific anthropometric measures that influence a patient's classification. Therefore, the purpose was to determine if there was a difference between dorsiflexion active range of motion (AROM) between copers, those with CAI, and a healthy control group. Twenty-two individuals with recent ankle sprains were recruited by a convenience sampling method and placed in the coper (5 females, 5 males, age: 21.9 ± 1.5 years, height: 173.74 ± 7.69 cm, weight: 69.75 ± 10.50 kg) or CAI (10 females, 2 males, age: 21.8 ± 2.3 years, height: 173.99 ± 10.86 cm, weight: 68.14 ± 10.63 kg) groups. The remaining 10 individuals (4 females, 6 males, age: 23.2 ± 1.5 years, height: 178.05 ± 12.92 cm, weight: 75.65 ± 8.00 kg) who participated in the study served as control, as they had never sustained a previous ankle sprain. Dorsiflexion AROM measurements were evaluated using an inclinometer during a weight-bearing lunge. Three measurements were taken for each participant and used for statistical analysis. There was no statistically significant difference in average dorsiflexion AROM between the coper, control, and CAI groups (F2,29 = 2.063, p = 0.15, ω = 0.06, 1 - β = 0.40). Further research is needed to determine if limited dorsiflexion AROM is indeed a contributing factor to an individual's classification as a coper or suffering from CAI, as defined by the CAIT.


Analysis of Membrane Protein Interactions with a Bacterial Adenylate Cyclase-Based Two-Hybrid (BACTH) Technique.
The bacterial two-hybrid (BACTH, for "Bacterial Adenylate Cyclase-based Two-Hybrid") technique is a simple and fast genetic approach to analyze protein-protein interactions in vivo. In this system, the proteins of interest are genetically fused to two complementary fragments from the catalytic domain of Bordetella pertussis adenylate cyclase and co-expressed in strains of Escherichia coli deficient in adenylate cyclase. Association of the hybrid proteins restores synthesis of cyclic AMP (cAMP), which then triggers the expression of catabolic operons such as the lactose operon or the maltose regulon. As BACTH uses a cAMP second messenger, the association between the chimeric proteins can take place at a distance from the transcription machinery. This technique is therefore particularly appropriate for studying interactions involving integral-membrane or membrane-associated proteins that may not be soluble in the cytoplasm, and/or that may only associate in the plane of the membrane. This unit describes the basic procedures to characterize protein-protein interactions with the BACTH genetic system and to search for potential partners of known proteins. © 2017 by John Wiley & Sons, Inc.


DNA methylation-based signature of CD8+ tumor-infiltrating lymphocytes enables evaluation of immune response and prognosis in colorectal cancer.
Tumor-infiltrating lymphocytes (TILs), especially CD8+ TILs, can be used for predicting immunotherapy responsiveness and survival outcome. However, the evaluation of CD8+ TILs currently relies on histopathological methodology with high variability. We therefore aimed to develop a DNA methylation signature for CD8+ TILs (CD8+ MeTIL) that could evaluate immune response and prognosis in colorectal cancer (CRC). A CD8+ MeTIL signature score was constructed by using CD8+ T cell-specific differentially methylated positions (DMPs) that were identified from Illumina EPIC methylation arrays. Immune cells, colon epithelial cells, and two CRC cohorts (n=282 and 335) were used to develop a PCR-based assay for quantitative analysis of DNA methylation at single-base resolution (QASM) to determine CD8 + MeTIL signature score. Three CD8+ T cell-specific DMPs were identified to construct the CD8+ MeTIL signature score, which showed a dramatic discriminability between CD8+ T cells and other cells. The QASM assay we developed for CD8+ MeTIL markers could measure CD8+ TILs distributions in a fully quantitative, accurate, and simple manner. The CD8+ MeTIL score determined by QASM assay showed a strong association with histopathology-based CD8+ TIL counts and a gene expression-based immune marker. Furthermore, the low CD8+ MeTIL score (enriched CD8+ TILs) was associated with MSI-H tumors and predicted better survival in CRC cohorts. This study developed a quantitative DNA methylation-based signature that was reliable to evaluate CD8+ TILs and prognosis in CRC. This approach has the potential to be a tool for investigations on CD8+ TILs and a biomarker for therapeutic approaches, including immunotherapy.


Autoantibodies by line immunoassay in patients with primary biliary cirrhosis.
We attempted to measure multiple autoantibodies simultaneously using line immunoassay (LIA) in patients with primary biliary cirrhosis (PBC) with or without anti-mitochondrial antibody (AMA) and patients with PBC-autoimmune hepatitis (AIH) overlap, and we examined the clinical significance of measuring these autoantibodies. The study population consisted of 80 patients with PBC (including 12 AMA-negative patients), 16 patients with PBC-AIH overlap and 40 patients with AIH as controls. Nine antibodies (AMA-M2, M2-3E, Sp100, PML, gp210, Ro-52, LKM-1, LC-1 and SLA/LP) were detected by LIA, and AMA-M2 and anti-centromere antibody (ACA) were detected by ELISA. We examined the relationship between these autoantibodies and clinical findings. The positive prevalence of each autoantibody and ACA in the PBC group, as determined by LIA, was as follows: 13.8% for anti-Sp100, 8.7% for anti-PML, 40% for anti-gp210 and 27.5% for anti-Ro-52 antibodies and 32.5% for ACA. In the PBC-AIH overlap group, the prevalence of anti-gp210 antibody (68.7%) and that of anti-Ro-52 antibody (81.2%) were significantly higher than those in the PBC and AIH groups. Only a few patients were positive for 2 or more autoantibodies. Nine patients were determined to be negative for all autoantibodies by LIA, of whom 7 were positive for ACA. Patients positive for anti-gp210 antibody included more patients classified as stage 4 on histology than did the negative group. Those positive for ACA included more patents with varices than did the negative group. LIA can measure multiple autoantibodies simultaneously and thus is considered useful in diagnosing PBC and PBC-AIH overlap. In addition, ACA is a useful marker for identifying AMA-negative PBC.


Cellular, Synaptic and Network Effects of Acetylcholine in the Neocortex.
The neocortex is densely innervated by basal forebrain (BF) cholinergic neurons. Long-range axons of cholinergic neurons regulate higher-order cognitive function and dysfunction in the neocortex by releasing acetylcholine (ACh). ACh release dynamically reconfigures neocortical microcircuitry through differential spatiotemporal actions on cell-types and their synaptic connections. At the cellular level, ACh release controls neuronal excitability and firing rate, by hyperpolarizing or depolarizing target neurons. At the synaptic level, ACh impacts transmission dynamics not only by altering the presynaptic probability of release, but also the magnitude of the postsynaptic response. Despite the crucial role of ACh release in physiology and pathophysiology, a comprehensive understanding of the way it regulates the activity of diverse neocortical cell-types and synaptic connections has remained elusive. This review aims to summarize the state-of-the-art anatomical and physiological data to develop a functional map of the cellular, synaptic and microcircuit effects of ACh in the neocortex of rodents and non-human primates, and to serve as a quantitative reference for those intending to build data-driven computational models on the role of ACh in governing brain states.


Family members' experiences of everyday life when a child is dependent on a ventilator: a metasynthesis study.
Children using mechanical ventilation for survival represent a small, but growing, vulnerable population in society. The aim of this study was to describe the existing qualitative research that examined family members' experiences when a child is dependent on ventilator at home. A metasynthesis is an interpretative integration of qualitative research findings based on a systematic literature search. Twelve original research reports focusing on the life situation of ventilator- and technology-dependent children and their families published between 1998 and 2006 were selected as data. Themes from the metasynthesis included experiences of the ill child, siblings, and parents and the meaning of space and place. These findings provide an understanding of the family members' experiences when a child is dependent on a ventilator for survival. Recommendations for future research with this population of families include a greater focus on professional support systems and family strengths and the use of longitudinal research methods using observation and interviews.


Work potential evaluation in mental health.
A survey was conducted to describe the methods and the degree to which occupational therapists in mental health settings were evaluating the work potential of patients. Of the 231 responses received from a population of 500 therapists, 157 were usable for this study. Results showed that 36% of the respondents performed work potential evaluations using interest inventories, crafts, and miscellaneous nonstandardized measures as their primary sources of information, and they cited observation as the most useful tool to obtain information about a patient. Most respondents identified the need to do more in this area and expressed an interest in expanding their skills and available resources. Implications for occupational therapy were discussed in relationship to new Medicare legislation.


Intrathecal Migration of an Epidural Catheter While Using a Programmed Intermittent Epidural Bolus Technique for Labor Analgesia Maintenance: A Case Report.
We describe a case of intrathecal migration of a wire-reinforced epidural catheter in a parturient who received epidural labor analgesia. Epidural analgesia was initiated with a combined-spinal epidural technique and maintained by programmed intermittent epidural boluses. Epidural catheter aspiration after insertion was negative for cerebrospinal fluid. The patient's response to the first four doses of local anesthetic was consistent with epidural drug delivery. After the fifth dose, she developed a complete lower extremity motor block, hypotension, and high sensory blockade. Catheter aspiration was then positive for cerebrospinal fluid. After symptom resolution, labor pain was successfully managed with this inadvertent intrathecal catheter.


Long-term Antibiotic Treatment in Pouchitis-Patterns of Use and Safety.
Pouchitis, often developing after colectomy and ileal pouch-anal anastomosis for ulcerative colitis, is highly responsive to antibiotics. Ciprofloxacin and/or metronidazole are commonly used, often for prolonged periods. We report patterns of antibiotic use, adverse events, and resistant infections in patients with pouchitis with long-term antibiotic treatment. In a cohort of patients following pouch surgery, a retrospective nested case-control analysis was performed between 2010 and 2017. Ultra-long-term use, defined as the top 10% of users, was compared with the remaining users. Patterns of antibiotic use, adverse events, and resistant infections were analyzed. The cohort included 205 patients with UC, of whom 167 (81.5%) used antibiotics for pouchitis, predominantly ciprofloxacin. The long-term antibiotic use rate was 18% and 42% at 5 and 20 years postsurgery, respectively. Mean antibiotic use of at least 1, 3, and 6 months/year was noted in 54 (26.3%), 31 (15.1%), and 14 (6.8%) patients, respectively. Twenty-two (13.2%) and 4 (2.4%) patients reported mild and severe (transient) adverse events, respectively, without mortalities, tendinopathies or arrhythmias. Adverse event rates for ciprofloxacin and metronidazole were 1per 10,000 and 6 per 10,000 use-days, respectively. Longer, but not ultra-long antibiotic use, was associated with mild adverse events. There was no association between antibiotic use and resistant infections. Thirteen (6.3%) patients required ileostomy procedures-more commonly in the ultra-long-term antibiotic users. Patients with pouchitis may require prolonged antibiotic treatment, reflecting clinical benefit and favorable safety profile. Few adverse events and resistant infections were observed with long-term antibiotics use. However, resistant microbial strains selection, which are potentially transmittable, warrants consideration of different therapeutic alternatives.


Abdominal aortic aneurysm and cytomegalovirus infection.
Cytomegalovirus (CMV) has been implicated in the pathogenesis of atherosclerosis. Abdominal aortic aneurysm is regarded traditionally as a consequence of atherosclerosis. Several microorganisms have been suggested as possible contributing factors for the development of abdominal aortic aneurysm. The relevance of CMV in the processes underlying the development, expansion, and rupture of abdominal aortic aneurysm is unknown. The aim of the present study was to investigate whether CMV infection is related to abdominal aortic aneurysm rupture. One hundred nineteen patients with abdominal aortic aneurysm and 36 matched controls without abdominal aortic aneurysm were investigated prospectively by CMV serology. Patients with ruptured abdominal aortic aneurysm have similar levels of IgG antibodies against CMV as patients with nonruptured abdominal aortic aneurysm, small abdominal aortic aneurysm, and controls without abdominal aortic aneurysm. In conclusion, this study fails to demonstrate a connection between CMV infection and abdominal aortic aneurysm rupture.


Chalcone Derivatives: Promising Starting Points for Drug Design.
Medicinal chemists continue to be fascinated by chalcone derivatives because of their simple chemistry, ease of hydrogen atom manipulation, straightforward synthesis, and a variety of promising biological activities. However, chalcones have still not garnered deserved attention, especially considering their high potential as chemical sources for designing and developing new effective drugs. In this review, we summarize current methodological developments towards the design and synthesis of new chalcone derivatives and state-of-the-art medicinal chemistry strategies (bioisosterism, molecular hybridization, and pro-drug design). We also highlight the applicability of computer-assisted drug design approaches to chalcones and address how this may contribute to optimizing research outputs and lead to more successful and cost-effective drug discovery endeavors. Lastly, we present successful examples of the use of chalcones and suggest possible solutions to existing limitations.


Impact of early psychosocial factors (childhood socioeconomic factors and adversities) on future risk of type 2 diabetes, metabolic disturbances and obesity: a systematic review.
Psychological factors and socioeconomic status (SES) have a notable impact on health disparities, including type 2 diabetes risk. However, the link between childhood psychosocial factors, such as childhood adversities or parental SES, and metabolic disturbances is less well established. In addition, the lifetime perspective including adult socioeconomic factors remains of further interest.We carried out a systematic review with the main question if there is evidence in population- or community-based studies that childhood adversities (like neglect, traumata and deprivation) have considerable impact on type 2 diabetes incidence and other metabolic disturbances. Also, parental SES was included in the search as risk factor for both, diabetes and adverse childhood experiences. Finally, we assumed that obesity might be a mediator for the association of childhood adversities with diabetes incidence. Therefore, we carried out a second review on obesity, applying a similar search strategy. Two systematic reviews were carried out. Longitudinal, population- or community-based studies were included if they contained data on psychosocial factors in childhood and either diabetes incidence or obesity risk. We included ten studies comprising a total of 200,381 individuals. Eight out of ten studies indicated that low parental status was associated with type 2 diabetes incidence or the development of metabolic abnormalities. Adjustment for adult SES and obesity tended to attenuate the childhood SES-attributable risk but the association remained. For obesity, eleven studies were included with a total sample size of 70,420 participants. Four out of eleven studies observed an independent association of low childhood SES on the risk for overweight and obesity later in life. Taken together, there is evidence that childhood SES is associated with type 2 diabetes and obesity in later life. The database on the role of psychological factors such as traumata and childhood adversities for the future risk of type 2 diabetes or obesity is too small to draw conclusions. Thus, more population-based longitudinal studies and international standards to assess psychosocial factors are needed to clarify the mechanisms leading to the observed health disparities.


Large-Scale Functional Brain Network Architecture Changes Associated With Trauma-Related Dissociation.
Dissociative experiences commonly occur in response to trauma, and while their presence strongly affects treatment approaches in posttraumatic spectrum disorders, their etiology remains poorly understood and their phenomenology incompletely characterized. Methods to reliably assess the severity of dissociation symptoms, without relying solely on self-report, would have tremendous clinical utility. Brain-based measures have the potential to augment symptom reports, although it remains unclear whether brain-based measures of dissociation are sufficiently sensitive and robust to enable individual-level estimation of dissociation severity based on brain function. The authors sought to test the robustness and sensitivity of a brain-based measure of dissociation severity. An intrinsic network connectivity analysis was applied to functional MRI scans obtained from 65 women with histories of childhood abuse and current posttraumatic stress disorder (PTSD). The authors tested for continuous measures of trauma-related dissociation using the Multidimensional Inventory of Dissociation. Connectivity estimates were derived with a novel machine learning technique using individually defined homologous functional regions for each participant. The models achieved moderate ability to estimate dissociation, after controlling for childhood trauma and PTSD severity. Connections that contributed the most to the estimation mainly involved the default mode and frontoparietal control networks. By contrast, all models performed at chance levels when using a conventional group-based network parcellation. Trauma-related dissociative symptoms, distinct from PTSD and childhood trauma, can be estimated on the basis of network connectivity. Furthermore, between-network brain connectivity may provide an unbiased estimate of symptom severity, paving the way for more objective, clinically useful biomarkers of dissociation and advancing our understanding of its neural mechanisms.


Sorbitol Minimizes Calcium Carbonate Scale Generation While Maintaining the Disinfection Effect of Heated Scallop-Shell Powder for Fresh Produce.
Scallop shells subjected to heat treatment exhibit antimicrobial activity, and heated scallop-shell powder (HSSP) has recently been reported to be effective for disinfecting food. However, because the main component of these shells is calcium oxide, there is a problem that scales of calcium carbonate (CaCO3) become established on the surface of equipment used for food processing. In this study, we thus investigated whether the addition of sugar to HSSP slurry suppressed CaCO3 scale generation and whether the sugar-supplemented HSSP could be applied to the disinfection and preservation of fresh lettuce. The results showed that glucose, sucrose, and sorbitol could suppress the scale generation in HSSP slurry. However, glucose and sucrose decreased the antibacterial activity of HSSP. Since the addition of sorbitol did not affect the antibacterial activity of HSSP slurry, it was used for subsequent experiments because of its low bioavailability. Sorbitol effectively suppressed scale formation by dissolving it before the addition of HSSP. The disinfection and preservative effects of sorbitol-supplemented HSSP ( S-HSSP) treatment on lettuce did not decrease compared with those upon HSSP treatment and were almost equal to or higher than those of sodium hypochlorite treatment at 200 mg/l. The addition of sorbitol solved the major problem of scale generation by HSSP containing CaO, which contributes to expansion of usage of heated shell powder, such as HSSP, in food processing.


Association of chromosome damage detected as micronuclei with hematological diseases and micronutrient status.
Epidemiological studies reveal strong association between micronutrient deficiencies and development of cancer. Since chromosome breaks and abnormal chromosome segregation, identified as micronuclei (MN), are central to malignant transformation, the influence of micronutrient status upon MN frequency has been the subject of intense research. Motivating this effort is the idea that marginal micronutrient deficiencies lead to allocation of scarce cellular resources towards immediate survival at the expense of maintaining genomic integrity, placing the individual at greater risk for degenerative diseases and cancer in old age. The challenge in identifying an association between individual micronutrients and MN frequency stems from the complexity of human diet, simultaneous presence of multiple micronutrient deficiencies, variable genetic susceptibility and methodological difficulties. A unique model for studying MN in humans is provided by a group of haematological diseases, the chronic haemolytic anaemias associated with high reticulocyte count and absence of splenic function. These disorders may prove valuable for assessing the influence of micronutrient status once the effect of abnormal erythropoiesis on MN formation is adequately understood. Eventually, large population-based studies that can account for the baseline variability in MN frequency, lifestyle and genetic factors may be needed to uncover the DNA-damaging effect of poor diet. Understanding the link between micronutrient status and MN frequency will contribute towards determining optimal micronutrient intake to preserve long-term health.


Influence of nisoldipine on vascular resistance and vasoconstrictor responses in cats.
The influence of nisoldipine, a calcium entry antagonist, on vascular resistance and vasoconstrictor responses was investigated in the anesthetized cat. Nisoldipine, a dihydropyridine calcium entry blocking agent, decreased total peripheral resistance and dilated the intestinal vascular bed. This calcium antagonist blocked intestinal vasoconstrictor responses to BAY K 8644, a nifedipine analogue, which promotes calcium entry. The calcium entry antagonist decreased intestinal vasoconstrictor responses to sympathetic nerve stimulation, norepinephrine, and tyramine. Nisoldipine also reduced intestinal vasoconstrictor responses to potassium chloride and agonists that elicit vasoconstriction by specific receptor-mediated actions including stimulation of alpha 1- and alpha 2-adrenoceptors. The vasodilator and inhibitory effects of nisoldipine on vasoconstrictor responses were reversible, and responses returned to control value over a 60-min period. The present data suggest that an extracellular source of calcium is required for maintenance of tone and for vasoconstriction induced by neuronally released or exogenous norepinephrine as well as a diverse group of agents that act through specific receptor mechanisms or depolarize vascular smooth muscle. The present results suggest that similar sources of calcium are required for vasoconstriction elicited by alpha 1- and alpha 2-adrenoceptor agonists in the feline intestinal vascular bed.


A novel functional cell surface dimer (Kp43) expressed by natural killer cells and T cell receptor-gamma/delta+ T lymphocytes. I. Inhibition of the IL-2-dependent proliferation by anti-Kp43 monoclonal antibody.
In the present study we describe a novel functional cell surface molecule, designated as Kp43, which is expressed among leukocytes by NK cells, TCR-gamma/delta + T lymphocytes, and some CD8+ CD56+TCR-alpha/beta + T cell clones. The Kp43 Ag is a 70-kDa disulfide-linked dimer, which migrates in SDS-PAGE under reducing conditions as a single 43-kDa band. Two-color immunofluorescence staining of fresh PBL revealed that only a fraction of CD16+, and of TCR-gamma/delta + T lymphocytes expressed the Ag. The analysis of TCR-alpha/beta + T cell clones showed that a small proportion (2 out of 20) weakly expressed Kp43 together with the CD8 and CD56 molecules. By immunoperoxidase staining of different tissues the anti-Kp43, reactivity was detected exclusively in lymphoid organs, where a minority of scattered cells was stained, and in some liver sinusoidal cells. Essentially all NK cells acquired Kp43 when stimulated with a B lymphoblastoid cell line. By contrast, the pattern of distribution of Kp43 remained stable upon in vitro culture of T-gamma/delta lymphocytes, thus delineating two subsets according to its expression. In lymphokine-activated killer populations, obtained by culturing either PBL or NK cells with high concentration of IL-2, most CD16+ and CD56+ cells became Kp43+. The Kp43-specific mAb inhibited the IL-2-dependent proliferative response of cultured NK and TCR-gamma/delta + T cells without affecting their non-MHC-restricted cytotoxicity. The partial inhibitory effect, which was mediated as well by pepsin digested F(ab')2 fragments, was lost upon reduction to Fab. The anti-Kp43 mAb did not interfere with the specific binding of IL-2 to its surface receptors. Altogether the data point out that the Kp43 dimer is involved in the regulation of the IL-2-dependent proliferative response of NK cells and a subset of TCR-gamma/delta + T lymphocytes.


Agmatine Administration Effects on Equine Gastric Ulceration and Lameness.
Osteoarthritis (OA) accounts for up to 60% of equine lameness. Agmatine, a decarboxylated arginine, may be a viable option for OA management, based on reports of its analgesic properties. Six adult thoroughbred horses, with lameness attributable to thoracic limb OA, received either daily oral phenylbutazone (6.6 mg/kg), agmatine sulfate (25 mg/kg) or a control for 30 days, with 21-day washout periods between treatments. Subjective lameness, thoracic limb ground reaction forces (GRF), plasma agmatine and agmatine metabolite levels were evaluated using an established rubric, a force platform, and mass spectrometry, respectively, before, during and after each treatment period. Gastric ulceration and plasma chemistries were evaluated before and after treatments. Braking GRFs were greater after 14 and 29 days of agmatine compared to phenylbutazone administration. After 14 days of phenylbutazone administration, vertical GRFs were greater than for agmatine or the control. Glandular mucosal ulcer scores were lower after agmatine than phenylbutazone administration. Agmatine plasma levels peaked between 30 and 60 min and were largely undetectable by 24 h after oral administration. In contrast, plasma citric acid levels increased throughout agmatine administration, representing a shift in the metabolomic profile. Agmatine may be a viable option to improve thoracic limb GRFs while reducing the risk of glandular gastric ulceration in horses with OA.


Metachronous advanced neoplasia after submucosal invasive colorectal cancer resection.
Little is known about the incidence of metachronous advanced neoplasia (AN) following resection of submucosal invasive colorectal cancer (SM-CRC). Here, we aimed to assess the occurrence of metachronous AN following SM-CRC resection. We retrospectively reviewed consecutive patients who underwent SM-CRC resection at an academic medical center between 2005 and 2013. Among 343 patients, 250 (72.9%) underwent surgical resection or endoscopic resection followed by surgical resection and 93 (27.1%) underwent only endoscopic resection. During a median follow-up period of 61.5 months, the overall incidence of metachronous AN was 7.6%, and the cumulative incidence at 5 years was 6.1%. The cumulative incidence was significantly higher in the endoscopic resection group than in surgical resection group, in patients with colonic disease than in those with rectal disease, and in patients with synchronous AN than in those without. Multivariate analysis revealed that synchronous AN was the only significant risk factor for metachronous AN (HR 4.35; 95% CI 1.88-10.1). These findings imply that depending on synchronous AN, a surveillance protocol following SM-CRC resection can be changed for better detection of metachronous AN.


Effects of the addition of t'ai chi to a dietary weight loss program on lipoprotein atherogenicity in obese older women.
To examine the additive effect of t'ai chi (TC) to diet education on the traditional coronary heart disease (CHD) risk factor low-density lipoprotein cholesterol (LDL-C) and on emerging CHD risk factors (apolipoprotein B and LDL particle size) in older obese women. Ancillary study of a randomized clinical trial. University of Rhode Island. 26 obese women (mean age±standard deviation, 61.5±6.0 years; mean body mass index, 34.3±4.0 kg/m(2)) were enrolled and randomly assigned to the diet education group (n=13) or the diet education plus TC group (n=13). All participants received 45 minutes of diet education per week. The diet education plus TC group also received 45 minutes of TC three times per week for 16 weeks. Anthropometrics (height, weight, BMI, waist circumference, and hip circumference), clinical variables (blood pressure), and biochemical variables (standard lipid profile, apolipoprotein B, LDL particle size) were measured. The primary outcome was LDL-C, and the secondary outcomes were apolipoprotein B and LDL particle size. Neither LDL-C nor apolipoprotein B improved in either group. Percentage of large LDL particles after the intervention was increased in the diet education plus TC group compared with the diet education group. Weight, waist circumference, and high-density lipoprotein cholesterol decreased in both groups from baseline to post-intervention. Triacylglycerol and dietary screening tool scores increased in both groups. Additional improvements were seen in the diet education plus TC group, including a significant increase in Dietary Approaches to Stop Hypertension score from baseline to post-intervention. The addition of TC to diet education is more effective than diet education alone at improving diet quality and emerging CHD risk factors, such as LDL particle size, in obese older women.


Iron-binding proteins in sputum of chronic bronchitis patients with Haemophilus influenzae infections.
Airway inflammation during infection is associated with increased transudation of serum proteins and increased production of protein by the airway epithelium. We therefore, assessed whether Haemophilus influenzae infections in patients with chronic bronchitis are associated with increased levels of transferrin and lactoferrin in the sputum compared to uninfected patients. Sputum sol phase and serum samples from 14 infected and 13 uninfected patients with chronic bronchitis and from 12 bronchial asthma patients were included in the study. The median Q-values (the concentration in sputum sol phase/the concentration in serum) x 10(3) of transferrin appeared increased in chronic bronchitis patients with an H. influenzae infection (26.0, n=13) compared to uninfected controls (9.5, n=11) and bronchial asthma patients (4.5, n=6). The ratio of the Q(transferrin)/Q(albumin) was >1 in infected chronic bronchitis patients, indicating local production of transferrin. Growth of H. influenzae was stimulated more in sputum from infected and uninfected patients with chronic bronchitis than in sputum from patients with bronchial asthma. The concentrations of lactoferrin were not significantly different in infected (n=14) and uninfected (n=13) chronic bronchitis patients and bronchial asthma patients (n=12) (median 137.4, 84.6, 87.1 mg x L(-1), respectively). We conclude that in patients with chronic bronchitis with Haemophilus influenzae infections, the levels of transferrin are increased and the levels of lactoferrin are not associated with infections.


Weight-bearing radiographs and cone-beam computed tomography examinations in adult acquired flatfoot deformity.
Optimal characterization of Adult acquired flatfoot deformity (AAFD) on two-dimensional radiograph can be challenging. Weightbearing Cone Beam CT (CBCT) may improve characterization of the three-dimensional (3D) structural details of such dynamic deformity. We compared and validated AAFD measurements between weightbearing radiograph and weightbearing CBCT images. 20 patients (20 feet, right/left: 15/5, male/female: 12/8, mean age: 52.2) with clinical diagnosis of flexible AAFD were prospectively recruited and underwent weightbearing dorsoplantar (DP) and lateral radiograph as well as weightbearing CBCT. Two foot and ankle surgeons performed AAFD measurements at parasagittal and axial planes (lateral and DP radiographs, respectively). Intra- and Inter-observer reliabilities were calculated by Intraclass correlation (ICC) and Cohen's kappa. Mean values of weightbearing radiograph and weightbearing CBCT measurements were also compared. Except for medial-cuneiform-first-metatarsal-angle, adequate intra-observer reliability (range:0.61-0.96) was observed for weightbearing radiographic measurements. Moderate to very good interobserver reliability between weightbearing radiograph and weightbearing CBCT measurements were observed for the following measurements: Naviculocuneiform-angle (ICC:0.47), Medial-cuneiform-first-metatarsal-gapping (ICC:0.58), cuboid-to-floor-distance (ICC:0.68), calcaneal-inclination-angle(ICC:0.7), axial Talonavicular-coverage-angle(ICC:0.56), axial Talus-first-metatarsal-angle(ICC:0.62). Comparing weightbearing radiograph and weightbearing CBCT images, statistically significant differences in the mean values of parasagittal talus-first-metatarsal-angle, medial-cuneiform-first-metatarsal-angle, medial-cuneiform-to-floor-distance and navicular-to-floor-distance was observed (P < 0.05). Moderate to very good correlation was observed between certain weightbearing radiograph and weightbearing CBCT measurements, however, significant difference was observed between a number of AAFD measurements, which suggest that 2D radiographic evaluation could potentially underestimate the severity of AAFD, when compared to 3D weightbearing CT assessment.


[Diversity of Hemiptera Auchenorrhyncha in citrus, coffee and a fragment of native forest of the state of São Paulo].
The population of Hemiptera Auchenorrhyncha was studied in sweet citrus groves (Citrus sinensis), coffee plantations (Coffea arabica) and a semi-deciduous seasonal forest with shrub physiognomy in Bebedouro, SP, to evaluate the influence of the natural ecosystem on the species composition of the agroecosystems. Monitoring was carried out by using yellow stick cards, which were replaced every 15 days and all Auchenorrhyncha collected were counted and identified. Seven families, 11 subfamilies and 98 species were collected, with Cicadellidae being the most abundant. The native forest presented larger wealth, diversity and equitability of Auchenorrhyncha species, demonstrating to be more stable than the other habitats. The high values of similarities obtained between the agroecosystems and the forest demonstrated that great part of Auchenorrhyncha species occurring in the agricultural habitats was also occurring at the forest, indicating that the last may serve as reservoir of species. The abundance of the taxonomic groups of Auchenorrhyncha collected varied with the evaluated habitats, with Proconiini being the most abundant in the coffee plantation next to the forest, Athysanini, Scaphytopiini, Neocoelidiinae and Coelidiinae in the orange orchard and coffee plantation distant from the forest; Cicadellinae and Agalliinae were not related to any of the habitats. The presence of vector insects and possible vectors of plant diseases in the appraised habitats indicate the need of the implementation of strategies for landscape management.


Coexisting micronutrient deficiencies among Sri Lankan pre-school children: a community-based study.
Assessing micronutrient status in children may also have the benefit of addressing the problems of various micronutrient deficiencies with a unified programmatic approach on a public health scale. A cross-sectional survey in the Galle district of the micronutrient and anthropometric status of 248 children of ages 3-5 years was performed to determine the prevalence of micronutrient deficiencies [iron, zinc (Zn), folate, calcium, caeruloplasmin, iodine, vitamin A and vitamin D] and the extent to which multiple micronutrient deficiencies coexist. The prevalence of anaemia [haemogbolin (Hb) < 110.0 g L⁻¹] was 34.0% in males and 33.0% in females (overall 33.5%, gender difference, P = 0.92). In anaemic children, 7.0% of males and 15.0% of females were iron deficient (serum ferritin < 15.0 µg L⁻¹). Folate deficiency (<3.00 ng mL⁻¹) was found in 41.0% and 33.0% of male and female, respectively, whereas Zn deficiency (<9.95 µmol L⁻¹) occurred in 57.0% and 50.0% of male and female, respectively. Serum vitamin D deficiency (<35.0 nmol L⁻¹) was found in 26% and 25% of male and female, respectively. Anaemic males had a 3.0-fold (95% confidence interval (CI) 1.1-8.3) and 2.3-fold (95% CI 0.8-6.6) greater risk of being underweight and thin, whereas the risk among anaemic females was 0.7-fold (95% CI 0.3-1.8) and 0.9-fold (95% CI 0.3-2.6) for being underweight and thin. Only 7.3% of the subjects did not have any micronutrient deficiency, 38.3% were deficient in two micronutrients, 17.7% had three micronutrient deficiencies and 6.0% had four or more micronutrient deficiencies. Multiple micronutrient deficiencies are prevalent in Sri Lankan pre-school children and established baseline data for future studies.


Hypertension in a resource-limited setting: Is it associated with end organ damage in older adults in rural Tanzania?
Few data from sub-Saharan Africa exist on the effects of hypertension on the organs of the human body. We aimed to establish the prevalence of hypertensive end organ damage (EOD) in an elderly cohort of Tanzanians. The population aged 70 years and over of 2 villages in northern Tanzania (n = 246), had blood pressure (BP) data available from 2010 and 2013, and underwent in-depth follow-up for markers of hypertensive EOD in 2016. Assessment included ankle-brachial pressure index, lying-standing BP, electrocardiogram, and mid-stream urine dip. Sustained hypertension (those with hypertension at all 3 assessments) was found in 129 (52.4% subjects). Of the entire cohort, 13.9% had left ventricular hypertrophy and 26.4% had peripheral arterial disease, both of which were associated with sustained hypertension, although orthostatic hypotension, stroke, proteinuria, and arterial stiffening were not. Further investigation, particularly in younger age groups, is merited if hypertension-associated morbidity is to be controlled.


Development and Validation of a Method to Quantify Flavonoids in Leaves of Lithospermum officinale (Boraginaceae).
The common gromwell Lithospermum officinale L. is a valuable medicinal plant that has been used in traditional medicine since ancient times. A method to quantify flavonoids in L. officinale leaves by differential spectrophotometry was developed taking advantage of the flavonoid reaction with aluminum chloride. The optimum duration of the reaction was determined, as well as the optimum volume-to-volume ratio between an aqueous ethanolic extract of L. officinale leaves and 2% aluminum chloride (aqueous ethanolic solution). Rutin was used as a standard. The method was validated in terms of specificity, linearity, precision, and accuracy and proved suitable for analytical purposes. The flavonoid content expressed in terms of rutin was found to exceed 2% of the absolutely dry weight in L. officinale leaves over different years of cultivation.


The Plasmodium falciparum Ca(2+)-ATPase PfATP6: insensitive to artemisinin, but a potential drug target.
The disease malaria, caused by the parasite Plasmodium falciparum, remains one of the most important causes of morbidity and mortality in sub-Saharan Africa. In the absence of an efficient vaccine, the medical treatment of malaria is dependent on the use of drugs. Since artemisinin is a powerful anti-malarial drug which has been proposed to target a particular Ca2+-ATPase (PfATP6) in the parasite, it has been important to characterize the molecular properties of this enzyme. PfATP6 is a 139 kDa protein composed of 1228 amino acids with a 39% overall identity with rabbit SERCA1a (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 1a). PfATP6 conserves all sequences and motifs that are important for the function and/or structure of a SERCA, such as two high-affinity Ca2+-binding sites, a nucleotide-binding site and a phosphorylation site. We have been successful in isolating PfATP6 after heterologous expression in yeast and affinity chromatography in a pure, active and stable detergent-solubilized form. With this preparation, we have characterized and compared with the eukaryotic SERCA1a isoform the substrate (Ca2+ and ATP) -dependency for PfATP6 activity as well as the specific inhibition/interaction of the protein with drugs. Our data fully confirm that PfATP6 is a SERCA, but with a distinct pharmacological profile: compared with SERCA1a, it has a lower affinity for thapsigargin and much higher affinity for cyclopiazonic acid. On the other hand, we were not able to demonstrate any inhibition by artemisinin and were also not able to monitor any binding of the drug to the isolated enzyme. Thus it is unlikely that PfATP6 plays an important role as a target for artemisinin in the parasite P. falciparum.


Neonatal lactocrine deficiency affects the adult porcine endometrial transcriptome at pregnancy day 13.
Reproductive performance of female pigs that do not receive sufficient colostrum from birth is permanently impaired. Whether lactocrine deficiency, reflected by low serum immunoglobulin immunocrit (iCrit), affects patterns of endometrial gene expression during the periattachment period of early pregnancy is unknown. Here, objectives were to determine effects of low iCrit at birth on the adult endometrial transcriptome on pregnancy day (PxD) 13. On the first day of postnatal life, gilts were assigned to high or low iCrit groups. Adult high (n = 8) and low (n = 7) iCrit gilts were bred (PxD 0), and humanely slaughtered on PxD 13 when tissues and fluids were collected. The endometrial transcriptome was defined for each group using mRNAseq and microRNAseq. Reads were mapped to the Sus scrofa 11.1 genome build. Mature microRNAs were annotated using miRBase 21. Differential expression was defined based on fold change (≥ ±1.5). Lactocrine deficiency did not affect corpora lutea number, uterine horn length, uterine wet weight, conceptus recovery, or uterine luminal fluid estrogen content on PxD 13. However, mRNAseq revealed 1157 differentially expressed endometrial mRNAs in high versus low iCrit gilts. Differentially expressed genes had functions related to solute transport, endometrial receptivity, and immune response. Six differentially expressed endometrial microRNAs included five predicted to target 62 differentially expressed mRNAs, affecting similar biological processes. Thus, lactocrine deficiency on the first day of postnatal life can alter uterine developmental trajectory with lasting effects on endometrial responses to pregnancy as reflected at the level of the transcriptome on PxD 13.


Gender differences in patient-provider symptom agreement in reporting respiratory complaints on a questionnaire.
Men and women communicate differently, but it is unclear whether this influences health care outcomes. Because women patients frequently choose women health care providers, we examined whether this preference was affected by communication styles. We focused on communication of disease-specific symptoms, hypothesizing that symptom agreement between women patients and women health care providers would be greater than between other patient-provider gender combinations. Patients attending outpatient clinics were recruited as part of a study of respiratory illness at 7 university-affiliated sites during 3 consecutive influenza seasons (2000-2003). Individuals aged > or = 19 years were offered enrollment if they sought care for cold or flu symptoms at a participating study site. Patients were eligible to participate in the study if they reported any 1 of 6 symptoms: cough, runny nose, fever (subjective), muscle aches, sore throat, and/or exhaustion. Using separate questionnaires, patients and their health care providers recorded the patients' respiratory symptoms (as present or absent). Patients recorded their symptoms before visiting their health care provider, and providers recorded patient symptoms after the visit. Symptom agreement was compared using general estimating equations across all gender combinations. A total of 327 patients (220 women, 107 men) and 84 health care providers (37 women, 47 men) participated in the study. Overall symptom agreement for all patient-provider gender combinations was 81.9% (95% CI, 79.6%-84.2%). For each symptom, the observed agreement significantly exceeded the agreement expected by chance alone (P < 0.001 for all symptoms except "no energy," which was P = 0.023). The male-male pairing of patient and provider was more likely to agree on a symptom than were the other gender combinations, although not statistically significantly more so than the female-female pairing. In this survey of patients with respiratory illness, there was no significant difference in symptom agreement for most symptoms between the male-male and female-female patient-provider combinations. Based on these findings, symptom agreement alone does not explain why women patients select women health care providers.


Silencing the ACAT1 Gene in Human SH-SY5Y Neuroblastoma Cells Inhibits the Expression of Cyclo-Oxygenase 2 (COX2) and Reduces β-Amyloid-Induced Toxicity Due to Activation of Protein Kinase C (PKC) and ERK.
BACKGROUND Acyl-coenzymeA: cholesterol acyltransferase (ACAT) 1, a key enzyme converting excess free cholesterol to cholesterol esters, has been demonstrated to be associated with the pathogenesis of Alzheimer disease (AD). However, the mechanism underlying the protective role of ACAT1 blockage in AD progression remains elusive. MATERIAL AND METHODS Human neuroblastoma SH-SY5Y cells were treated for 24 h with increasing concentrations of aggregated Aβ₂₅₋₃₅ (5, 15, 25, and 45 μmol) with or without the ACAT1 siRNA pretreatment. Cell viability analysis was measured by CCK-8 assay. The genome-wide correlation between ACAT1 and all other probe sets was measured by the Pearson correlation coefficient (r). Western blotting was used to detect the ACAT1 protein expression in the hippocampus of APP/PSN transgenic AD mice. The mRNA level for each target was analyzed by qPCR. Western blotting was used to detect the ACAT1, cyclo-oxygenase-2 (Cox2), Calcium voltage-gated channel subunits (CACNAs), and ERK/PKC proteins in SH-SY5Y cells with or without the ACAT1 siRNA pretreatment in the presence of Aβ₂₅₋₃₅. RESULTS The expression of ACAT1 was significantly increased in the hippocampus of APP/PSN mice, and also showed an increasing trend when SH-SY5Y cells were exposed to Aβ₂₅₋₃₅. Silencing ACAT1 significantly attenuated Aβ-induced cytotoxicity and cell apoptosis in SH-SY5Y cells. The genome-wide correlation analysis showed that Ptgs2 had the most significant correlation with Acat1 in the hippocampus of BXD RI mice. We further determined the regulatory effect of ACAT1 on COX2 expression by silencing or over-expressing ACAT1 in SH-SY5Y cells and found that silencing ACAT1 played a protective role in AD progression by regulating CACNAs and PKC/ERK signaling cascades. CONCLUSIONS Silencing ACAT1 attenuates Aβ₂₅₋₃₅-induced cytotoxicity and cell apoptosis in SH-SY5Y cells, which may due to the synergistic effect of ACAT1 and COX2 through PKC/ERK pathways.


International collaborative study for the calibration of a proposed reference preparation for thromboplastin, human recombinant, plain. On behalf of the Subcommittee on Control of Anticoagulation.
Stocks of the International Reference Preparation (IRP) for thromboplastin, human, plain, coded BCT/253 and held by the World Health Organization (WHO) are nearly exhausted and must be replaced. For practical reasons the choice of the replacement candidate was restricted to two available human recombinant preparations which were coded as X/95 and Y/95 and calibrated in an international collaborative study involving 19 laboratories from Europe, Australia, Canada and Argentina. To minimize the differences between routes of calibration, the two candidates were calibrated against the existing WHO-IRP from human, rabbit and bovine origin and the final ISI was the resultant average value. On the basis of predefined criteria (i.e., within- and between-laboratory precision of the calibration and the conformity to the calibration model), X/95 was the preferred candidate. The assigned ISI (SE of the mean) value is 0.940 (0.0060) and the interlaboratory coefficient of variation 4.7%.


Essential oils chemical composition, antioxidant activities and total phenols of Astrodaucus persicus.
Astrodaucus persicus, Apiaceae, is used as vegetable or food additive in some parts of Iran. The essential oils of different parts of Astrodaucus persicus from Kordestan province were analyzed for the first time and compared with other regions. In this study, antioxidant activities and total phenols determination of aerial parts essential oils and root fractions of A. persicus were investigated. The essential oils were obtained by hydro-distillation from flowers/fruits, leaves/stems, ripe fruits and roots of plant and analyzed by GC-MS. Crude root extract was fractionated with hexane, chloroform, ethyl acetate and methanol. Antioxidant activities by DPPH and FRAP methods and total phenols by Folin-ciocalteu assay were measured. The abundant compounds of flowers/fruits blue essential oil were α-thujene, β-pinene and α-pinene. The predominant components of blue leaves/stems essential oil were α-thujene, α-pinene and α-fenchene. The major volatiles of ripe fruits blue essential oil were β-pinene, α-thujene and α-pinene. The chief compounds of root yellow essential oil were trans-caryophyllene, bicycogermacrene and germacrene-D. Total root extract and ethyl acetate fraction showed potent antioxidant activities and high amount of total phenols in comparison to other samples. Among volatile oils, the flowers/fruits essential oil showed potent reducing capacity. The major compounds of aerial parts essential oils were hydrocarbon monoterpenes while the chief percentage of roots essential oil constituents were hydrocarbon sesquiterpenes. α-Eudesmol and β-eudesmol were identified as responsible for creation of blue color in aerial parts essential oils. A. persicus was known as a potent antioxidant among Apiaceae.


Combined loss of Hey1 and HeyL causes congenital heart defects because of impaired epithelial to mesenchymal transition.
Congenital heart defects affect almost 1% of human newborns. Recently, mutations in Notch ligands and receptors have been found to cause a variety of heart defects in rodents and humans. However, the molecular effects downstream of Notch are still poorly understood. Here we report that combined inactivation of Hey1 and HeyL, two primary target genes of Notch, causes severe heart malformations, including membranous ventricular septal defects and dysplastic atrioventricular and pulmonary valves. These defects lead to congestive cardiac failure with high lethality. We found both genes to be coexpressed with Notch1, Notch2 and the Notch ligand Jagged1 in the endocardium of the atrioventricular canal, representing the primary source of mesenchymal cells forming membraneous septum and valves. Atrioventricular explants from Hey1/HeyL deficient mice exhibited impaired epithelial to mesenchymal transition. Although epithelial to mesenchymal transition was initiated regularly, full transformation into mesenchymal cells failed. This was accompanied by reduced levels of matrix metalloproteinase-2 expression and reduced cell density in endocardial cushions in vivo. We further show that loss of Hey2 leads to very similar deficiencies, whereas a Notch1 null mutation completely abolishes epithelial to mesenchymal transition. Thus, the Hey gene family shows overlap in controlling Notch induced endocardial epithelial to mesenchymal transition, a process critical for valve and septum formation.


Collaborative stepped care v. care as usual for common mental disorders: 8-month, cluster randomised controlled trial.
Thus far collaborative stepped care (CSC) studies have not incorporated self-help as a first step. To evaluate the effectiveness of CSC in the treatment of common mental disorders. An 8-month cluster randomised controlled trial comparing CSC to care as usual (CAU) (Dutch Trial Register identifier NTR1224). The CSC consisted of a stepped care approach guided by a psychiatric nurse in primary care with the addition of antidepressants dependent on the severity of the disorder, followed by cognitive-behavioural therapy in mental healthcare. Twenty general practitioners (GPs) and 8 psychiatric nurses were randomised to provide CSC or CAU. The GPs recruited 163 patients of whom 85% completed the post-test measurements. At 4-month mid-test CSC was superior to CAU: 74.7% (n = 68) v. 50.8% (n = 31) responders (P = 0.003). At 8-month post-test and 12-month follow-up no significant differences were found as the patients in the CAU group improved as well. Treatment within a CSC model resulted in an earlier treatment response compared with CAU.


[Neurophysiological correlates of visual perception].
Structural organization of simple and complex receptive fields of the visual cortex was studied. The bidimensional weight function of the field determining its main properties as a filter of spatial frequencies (the space-frequency and the orientation sensitivity), was investigated. Two types of modules are discussed: the cylinders of cortical neurons whose receptive fields are oriented towards a single area of the visual field and adjusted for different spatial frequencies and orientations. One type of the modules contains neurons whose receptive fields describe the amplitude and phase of a visual signal and give the Fourier-description of a portion of picture; the second type's receptive fields describe the amplitude alone and give the power spectra. Comparison with psychophysical data suggests that the second type serves for texture description. Inhibition in the receptive field induced by frequencies which are lateral in respect to the optimal frequency and by orientations which are perpendicular in respect to the optimal orientation, reveals the mutually inhibiting influences among the module's neurons. Significance of this type of organization for visual perception is discussed.


Locomotor play behavior evolves by random genetic drift but not as a correlated response to selective breeding for high voluntary wheel-running behavior.
Locomotor play is vigorous and seemingly purposeless behavior, commonly observed in young mammals. It can be costly in terms of energy expenditure, increased injury risk, and predator exposure. The main hypothesized benefit of locomotor play is enhancement of neuromuscular development, with effects persisting into adulthood. We hypothesized that levels of locomotor play would have evolved as a correlated response to artificial selection for increased voluntary exercise behavior. We studied mice from 4 replicate lines bred for voluntary wheel running (High Runner or HR) at 6-8 weeks of age and four non-selected Control (C) lines. Mice were weaned at 21 days of age and play behavior was observed for generations 20 (22-24 days old), 68 (22-23 days old), and 93 (15 days old). We quantified locomotor play as (1) rapid, horizontally directed jerk-run sequences and (2) vertical "bouncing." We used focal sampling to continuously record behavior in cages containing 4-6 individuals during the first 2-3 h of the dark cycle. Observations were significantly repeatable between observers and days. A two-way, mixed-model simultaneously tested effects of linetype (HR vs. C), sex, and their interaction. Contrary to our hypothesis, HR and C lines did not differ in any generation, nor did we find sex differences. However, differences among the replicate HR lines and among the replicate C lines were detected, and may be attributed to the effects of random genetic drift (and possibly founder effects). Thus, play behavior did evolve in this selection experiment, but not as a correlated response to selection for voluntary exercise.


Diagnosing Glaucoma Progression with Visual Field Data Using a Spatiotemporal Boundary Detection Method.
Diagnosing glaucoma progression is critical for limiting irreversible vision loss. A common method for assessing glaucoma progression uses a longitudinal series of visual fields (VF) acquired at regular intervals. VF data are characterized by a complex spatiotemporal structure due to the data generating process and ocular anatomy. Thus, advanced statistical methods are needed to make clinical determinations regarding progression status. We introduce a spatiotemporal boundary detection model that allows the underlying anatomy of the optic disc to dictate the spatial structure of the VF data across time. We show that our new method provides novel insight into vision loss that improves diagnosis of glaucoma progression using data from the Vein Pulsation Study Trial in Glaucoma and the Lions Eye Institute trial registry. Simulations are presented, showing the proposed methodology is preferred over existing spatial methods for VF data. Supplementary materials for this article are available online and the method is implemented in the R package womblR.


[Value of routine preoperative tests in children].
To asses the value of preoperative tests in pediatric patients, a retrospective study of 722 surgical patients was undertaken. No unsuspected abnormalities or underlying diseases leading to the cancellation or postposition of surgery were found. Neither anaesthesia nor postoperatory complications were prevented by means of this procedure. We conclude that detailed anamnesis and physical examination are the most effective screening procedures and that radiologic and laboratory tests should be restricted to help in diagnosis and evaluation of the patient in emergency surgery and when the anamnesis, physical examination or a specific kind of surgery recommend it.


Paxillin suppresses the proliferation of HPS rat serum treated PASMCs by up-regulating the expression of cytoskeletal proteins.
Hepatopulmonary syndrome (HPS) is a triad of advanced liver disease, intrapulmonary vasodilatation (IPVD), and arterial hypoxemia. The arterial hypoxemia induces pulmonary vascular remodelling (PVR). In recent studies, the role of the proliferation of pulmonary artery smooth muscle cells (PASMCs) in PVR associated with HPS has been established; the changes in cytoskeletal proteins play an essential role in the proliferation of PASMCs. Little is known about the relevance of cytoskeletal protein expression or the molecular mechanisms of PVR associated with HPS. In addition, it has been identified that paxillin could influence the cytoskeletal protein expression by some important signaling pathways in many diseases, including lung cancer and liver cancer. In this study, we found that HPS rat serum from a common bile duct ligation (CBDL) rat model decreased the expression of cytoskeletal proteins (α-actin, α-tubulin, and destrin) and enhanced the expression levels of paxillin mRNA and protein in PASMCs. After silencing paxillin with siRNA, we found that the down-regulation of cytoskeletal protein expression, induced by the HPS rat serum, was reversed. Additionally, we reported that HPS rat serum improved the proliferation of PASMCs and down-regulation of paxillin could significantly inhibit this variation. These findings suggest that the up-regulation of cytoskeletal protein expression, induced by the paxillin, may cause the dysregulation of PASMC proliferation as well as play a fundamental role in PVR associated with HPS. In conclusion, down-regulation of paxillin by siRNA results in the inhibition of the dysregulation of cytoskeletal proteins and proliferation of PASMCs, suggesting a potential therapeutic effect on PVR associated with HPS.