Synergistic interaction between yeast nucleotide excision repair factors NEF2 and NEF4 in the binding of ultraviolet-damaged DNA.
Saccharomyces cerevisiae RAD4, RAD7, RAD16, and RAD23 genes function in the nucleotide excision repair (NER) of ultraviolet light (UV)-damaged DNA. Previous biochemical studies have shown that the Rad4 and Rad23 proteins are associated in a stoichiometric complex named NEF2, and the Rad7 and Rad16 proteins form another stoichiometric complex named NEF4. While NEF2 is indispensable for the incision of UV-damaged DNA in the in vitro reconstituted system, NEF4 stimulates the incision reaction. Both NEF2 and NEF4 bind UV-damaged DNA, which raises the intriguing possibility that these two complexes cooperate to achieve the high degree of specificity for DNA damage demarcation required for nucleotide excision repair in vivo. Consistent with this hypothesis, we find that NEF2 and NEF4 bind in a synergistic fashion to UV-damaged DNA in a reaction that is dependent on ATP. We also purify the Rad7 protein and show that it binds DNA but has no preference for UV-damaged DNA. Rad7 physically interacts with NEF2, suggesting a role for Rad7 in linking NEF2 with NEF4.


Clinical and sonographic features of uncommon primary ovarian malignancies.
To describe the gray-scale and color Doppler ultrasound features of uncommon (<5% prevalence) primary malignant ovarian tumors. Retrospective analysis of 98 masses in 89 patients (median age: 50.4 years old, ranging from 15 to 81 years) diagnosed as having an uncommon primary ovarian malignancy. All patients had undergone transvaginal color Doppler ultrasound according to a standardized protocol prior to surgical tumor removal. Ultrasound features analyzed were laterality, presence of ascites, tumor volume, morphologic appearance (unilocular, multilocular, unilocular-solid, multilocular-solid, and solid), and color Doppler score (subjective assessment of the amount of flow as absent, scanty, moderate, or abundant). Pathological diagnoses included uncommon epithelial tumors (n = 59), germ cell tumors (n = 10), sex cord-stromal tumors (n = 11), sarcoma (n = 9), and lymphoma (n = 9). Germ cell tumors presented in younger women (p < 0.001). Germ cell tumors, sex cord-stromal tumors, sarcomas, and lymphomas were significantly more often solid as compared with epithelial malignancies, which appeared more frequently as complex (cystic-solid) tumors (p < 0.001). There were no differences in color Doppler score between the various types of tumors. Germ cell tumors, sex cord-stromal tumors, sarcomas, and lymphomas tend to appear as unilateral solid tumors. Color Doppler score is not useful for discriminating among uncommon primary ovarian malignancies.


The cognitive and neural correlates of "tactile consciousness": a multisensory perspective.
People's awareness of tactile stimuli has been investigated in far less detail than their awareness of stimuli in other sensory modalities. In an attempt to fill this gap, we provide an overview of studies that are pertinent to the topic of tactile consciousness. We discuss the results of research that has investigated phenomena such as "change blindness", phantom limb sensations, and numerosity judgments in tactile perception, together with the results obtained from the study of patients affected by deficits that can adversely affect tactile perception such as neglect, extinction, and numbsense. The similarities as well as some of the important differences that have emerged when visual and tactile conscious information processing have been compared using similar experimental procedures are highlighted. We suggest that conscious information processing in the tactile modality cannot be separated completely from the more general processing of spatial information in the brain. Finally, the importance of considering tactile consciousness within the larger framework of multisensory information processing is also discussed.


P-selectin glycoprotein ligand-1 mediates rolling of human neutrophils on P-selectin.
Neutrophils roll on P-selectin expressed by activated platelets or endothelial cells under the shear stresses in the microcirculation. P-selectin glycoprotein ligand-1 (PSGL-1) is a high affinity ligand for P-selectin on myeloid cells. However, it has not been demonstrated that PSGL-1 contributes to the rolling of neutrophils on P-selectin. We developed two IgG mAbs, PL1 and PL2, that appear to recognize protein-dependent epitopes on human PSGL-1. The mAbs bound to PSGL-1 on all leukocytes as well as on heterologous cells transfected with PSGL-1 cDNA. PL1, but not PL2, blocked binding of 125-I-PSGL-1 to immobilized P-selectin, binding of fluid-phase P-selectin to myeloid and lymphoid leukocytes, adhesion of neutrophils to immobilized P-selectin under static conditions, and rolling of neutrophils on P-selectin-expressing CHO cells under a range of shear stresses. PSGL-1 was localized to microvilli on neutrophils, a topography that may facilitate its adhesive function. These data indicate that (a) PSGL-1 accounts for the high affinity binding sites for P-selectin on leukocytes, and (b) PSGL-1 must interact with P-selectin in order for neutrophils to roll on P-selectin at physiological shear stresses.


Some pathogenic fungi involved in serious cases of urinary tract infections in Nigeria.
Three hundred early morning midstream urine samples collected from 200 females and 100 males between the ages of 20 and 60 years, suffering from urinary tract infections (UTI) were studied to determine the etiologic agents. The caliberated loop-direct method used for culturing each sample on both bacterial and fungal media showed significant microbial growth in 117 of the 300 samples. Bacteria were the sole agents of infection in 30% of the cases while pathogenic yeasts were the sole agents of infection in 8% of the cases. Only 1% showed mixed infection. The bacterial pathogens identified from the culture were Escherichia coli (12.7%), Staphylococcus aureus (8.0%), Proteus mirabilis (4.3%), Klebsiella aerogenes (2.7%), Streptococcus faecalis (2.0%) and Pseudomonas aeruginosa (0.3%). The fungal pathogens isolated were Candida albicans (0.3%). While patients between the ages of 20 and 40 years were significantly more susceptible to UTI caused by bacteria (P = 0.05), patients between the ages of 41 and 60 years were more prone to UTI caused by fungi. Also females appeared to contact UTI more often than males.


Impaired white matter connectivity between regions containing mirror neurons, and relationship to negative symptoms and social cognition, in patients with first-episode schizophrenia.
In schizophrenia, abnormalities in structural connectivity between brain regions known to contain mirror neurons and their relationship to negative symptoms related to a domain of social cognition are not well understood. Diffusion tensor imaging (DTI) scans were acquired in 16 patients with first episode schizophrenia and 16 matched healthy controls. FA and Trace of the tracts interconnecting regions known to be rich in mirror neurons, i.e., anterior cingulate cortex (ACC), inferior parietal lobe (IPL) and premotor cortex (PMC) were evaluated. A significant group effect for Trace was observed in IPL-PMC white matter fiber tract (F (1, 28) = 7.13, p = .012), as well as in the PMC-ACC white matter fiber tract (F (1, 28) = 4.64, p = .040). There were no group differences in FA. In addition, patients with schizophrenia showed a significant positive correlation between the Trace of the left IPL-PMC white matter fiber tract, and the Ability to Feel Intimacy and Closeness score (rho = .57, p = 0.034), and a negative correlation between the Trace of the left PMC-ACC and the Relationships with Friends and Peers score (rho = remove -.54, p = 0.049). We have demonstrated disrupted white mater microstructure within the white matter tracts subserving brain regions containing mirror neurons. We further showed that such structural disruptions might impact negative symptoms and, more specifically, contribute to the inability to feel intimacy (a measure conceptually related to theory of mind) in first episode schizophrenia. Further studies are needed to understand the potential of our results for diagnosis, prognosis and therapeutic interventions.


Database-Guided Discovery of Potent Peptides to Combat HIV-1 or Superbugs.
Antimicrobial peptides (AMPs), small host defense proteins, are indispensable for the protection of multicellular organisms such as plants and animals from infection. The number of AMPs discovered per year increased steadily since the 1980s. Over 2,000 natural AMPs from bacteria, protozoa, fungi, plants, and animals have been registered into the antimicrobial peptide database (APD). The majority of these AMPs (>86%) possess 11-50 amino acids with a net charge from 0 to +7 and hydrophobic percentages between 31-70%. This article summarizes peptide discovery on the basis of the APD. The major methods are the linguistic model, database screening, de novo design, and template-based design. Using these methods, we identified various potent peptides against human immunodeficiency virus type 1 (HIV-1) or methicillin-resistant Staphylococcus aureus (MRSA). While the stepwise designed anti-HIV peptide is disulfide-linked and rich in arginines, the ab initio designed anti-MRSA peptide is linear and rich in leucines. Thus, there are different requirements for antiviral and antibacterial peptides, which could kill pathogens via different molecular targets. The biased amino acid composition in the database-designed peptides, or natural peptides such as θ-defensins, requires the use of the improved two-dimensional NMR method for structural determination to avoid the publication of misleading structure and dynamics. In the case of human cathelicidin LL-37, structural determination requires 3D NMR techniques. The high-quality structure of LL-37 provides a solid basis for understanding its interactions with membranes of bacteria and other pathogens. In conclusion, the APD database is a comprehensive platform for storing, classifying, searching, predicting, and designing potent peptides against pathogenic bacteria, viruses, fungi, parasites, and cancer cells.


Exploring the Content of Post-Traumatic Stress Symptoms among Parents after Paediatric Stem Cell Transplant.
In the present study the aim was to explore the content in a trauma reported in a self-report questionnaire by parents of children with a life threatening illness. Semi-structured interviews were performed, with the aim to explore the specific cognitive and behavioral content of the trauma related symptoms reported by the individual informant. The transcripts of the interviews were analyzed with content analysis using a direct approach with a-priori categories according to the B and C categories of the DSM-IV diagnostic criteria for PTSD. The results give us the picture of a complex situation, where the self-report instrument PCL captured a spectrum of qualitatively different cognitions. The parents described traumatic thoughts and images relating not only to experiences in the past (i.e., truly post-traumatic), but also to current stressors and expected future events.


Validation of food store environment secondary data source and the role of neighborhood deprivation in Appalachia, Kentucky.
Based on the need for better measurement of the retail food environment in rural settings and to examine how deprivation may be unique in rural settings, the aims of this study were: 1) to validate one commercially available data source with direct field observations of food retailers; and 2) to examine the association between modified neighborhood deprivation and the modified retail food environment score (mRFEI). Secondary data were obtained from a commercial database, InfoUSA in 2011, on all retail food outlets for each census tract. In 2011, direct observation identifying all listed food retailers was conducted in 14 counties in Kentucky. Sensitivity and positive predictive values (PPV) were compared. Neighborhood deprivation index was derived from American Community Survey data. Multinomial regression was used to examine associations between neighborhood deprivation and the mRFEI score (indicator of retailers selling healthy foods such as low-fat foods and fruits and vegetables relative to retailers selling more energy dense foods). The sensitivity of the commercial database was high for traditional food retailers (grocery stores, supermarkets, convenience stores), with a range of 0.96-1.00, but lower for non-traditional food retailers; dollar stores (0.20) and Farmer's Markets (0.50). For traditional food outlets, the PPV for smaller non-chain grocery stores was 38%, and large chain supermarkets was 87%. Compared to those with no stores in their neighborhoods, those with a supercenter [OR 0.50 (95% CI 0.27. 0.97)] or convenience store [OR 0.67 (95% CI 0.51, 0.89)] in their neighborhood have lower odds of living in a low deprivation neighborhood relative to a high deprivation neighborhood. The secondary commercial database used in this study was insufficient to characterize the rural retail food environment. Our findings suggest that neighborhoods with high neighborhood deprivation are associated with having certain store types that may promote less healthy food options.


[Turner syndrome: the patients' view].
To identify how patients with Turner syndrome perceive their condition. Thirty-six women with Turner syndrome, aged between 15 and 25 years and with over 2 years of medical follow-up, were individually interviewed about: the impact of Turner syndrome at the moment of the diagnosis, their understanding of the syndrome, its effect in their lives, and their expectations for the future. Only 31% of the patients immediately understood the diagnosis. Their feelings associated to that moment were neutral (47%) or concerned (33%). About one third of the interviewed women were unable to explain the etiology of Turner syndrome (42%), did not relate their symptoms with Turner syndrome (36%), and/or believe there might be a cure for it (44%). Although most of the interviewed women affirm that the syndrome has no interference in their lives (67%) and that they consider themselves happy persons (78%), in more than half of the interviews there are evidences of difficulties in social interaction and love relationship, low self-esteem, dissatisfaction with their physical appearances, especially the short stature and infertility. Their hopes for the future refer mainly to study and have a job. Although being, on average, 19 years old, one in two women (53%) still hopes to grow up. Besides medical treatment, it is important that the knowledge of the patients about the syndrome and some issues as infertility, short stature, self-esteem and social interactions receive proper and continuous attention from the moment of the diagnosis. The ideal situation should be a joint-action of a psychologist and the medical team.


Treatment with eldecalcitol positively affects mineralization, microdamage, and collagen crosslinks in primate bone.
Eldecalcitol (ELD), an active form of vitamin D analog approved for the treatment of osteoporosis in Japan, increases lumbar spine bone mineral density (BMD), suppresses bone turnover markers, and reduces fracture risk in patients with osteoporosis. We have previously reported that treatment with ELD for 6 months improved the mechanical properties of the lumbar spine in ovariectomized (OVX) cynomolgus monkeys. ELD treatment increased lumbar BMD, suppressed bone turnover markers, and reduced histomorphometric parameters of both bone formation and resorption in vertebral trabecular bone. In this study, we elucidated the effects of ELD on bone quality (namely, mineralization, microarchitecture, microdamage, and bone collagen crosslinks) in OVX cynomolgus monkeys in comparison with OVX-vehicle control monkeys. Density fractionation of bone powder prepared from lumbar vertebrae revealed that ELD treatment shifted the distribution profile of bone mineralization to a higher density, and backscattered electron microscopic imaging showed improved trabecular bone connectivity in the ELD-treated groups. Higher doses of ELD more significantly reduced the amount of microdamage compared to OVX-vehicle controls. The fractionated bone powder samples were divided according to their density, and analyzed for collagen crosslinks. Enzymatic crosslinks were higher in both the high-density (≥2.0 mg/mL) and low-density (<2.0 mg/mL) fractions from the ELD-treated groups than in the corresponding fractions in the OVX-vehicle control groups. On the other hand, non-enzymatic crosslinks were lower in both the high- and low-density fractions. These observations indicated that ELD treatment stimulated the enzymatic reaction of collagen crosslinks and bone mineralization, but prevented non-enzymatic reaction of collagen crosslinks and accumulation of bone microdamage. Bone anti-resorptive agents such as bisphosphonates slow down bone remodeling so that bone mineralization, bone microdamage, and non-enzymatic collagen crosslinks all increase. Bone anabolic agents such as parathyroid hormone decrease bone mineralization and bone microdamage by stimulating bone remodeling. ELD did not fit into either category. Histological analysis indicated that the ELD treatment strongly suppressed bone resorption by reducing the number of osteoclasts, while also stimulating focal bone formation without prior bone resorption (bone minimodeling). These bidirectional activities of ELD may account for its unique effects on bone quality.


SARS-CoV-2: a storm is raging.
The pandemic coronavirus infectious disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is rapidly spreading across the globe. In this issue of the JCI, Chen and colleagues compared the clinical and immunological characteristics between moderate and severe COVID-19. The authors found that respiratory distress on admission is associated with unfavorable outcomes. Increased cytokine levels (IL-6, IL-10, and TNF-α), lymphopenia (in CD4+ and CD8+ T cells), and decreased IFN-γ expression in CD4+ T cells are associated with severe COVID-19. Overall, this study characterized the cytokine storm in severe COVID-19 and provides insights into immune therapeutics and vaccine design.


Role of primate visual area V4 in the processing of 3-D shape characteristics defined by disparity.
We studied the responses of V4 neurons in awake, fixating monkeys to a diverse set of stereoscopic stimuli, including zero-order disparity (frontoparallel) stimuli, surfaces oriented in depth, and convex and concave shapes presented at various mean disparities. The responses of many V4 cells were significantly modulated across each of these stimulus subsets. In general, V4 cells were broadly tuned for zero-order disparity, and at any given disparity value, about four-fifths of the cells responded significantly above background. The response modulation by flat surfaces oriented in depth was significant for about one-quarter of cells, and the responses of about one-third of the cells were significantly modulated by convex or concave surfaces at various mean disparities. However, we encountered no cells that unambiguously distinguished a given three-dimensional (3-D) shape independent of mean disparity. Thus 3-D shapes defined by disparity are unlikely to be represented explicitly at the level of individual V4 cells. Nonetheless, V4 cells likely play an important role in the processing of 3-D shape characteristics defined by disparity as a part of a distributed network.


Oligonucleotide-Recognizing Topoisomerase Inhibitors (OTIs): Precision Gene Editors for Neurodegenerative Diseases?
Topoisomerases are essential enzymes that recognize and modify the topology of DNA to allow DNA replication and transcription to take place. Topoisomerases are divided into type I topoisomerases, that cleave one DNA strand to modify DNA topology, and type II, that cleave both DNA strands. Topoisomerases normally rapidly religate cleaved-DNA once the topology has been modified. Topoisomerases do not recognize specific DNA sequences, but actively cleave positively supercoiled DNA ahead of transcription bubbles or replication forks, and negative supercoils (or precatenanes) behind, thus allowing the unwinding of the DNA-helix to proceed (during both transcription and replication). Drugs that stabilize DNA-cleavage complexes with topoisomerases produce cytotoxic DNA damage and kill fast-dividing cells; they are widely used in cancer chemotherapy. Oligonucleotide-recognizing topoisomerase inhibitors (OTIs) have given drugs that stabilize DNA-cleavage complexes specificity by linking them to either: (i) DNA duplex recognizing triplex forming oligonucleotide (TFO-OTIs) or DNA duplex recognizing pyrrole-imidazole-polyamides (PIP-OTIs) (ii) or by conventional Watson-Crick base pairing (WC-OTIs). This converts compounds from indiscriminate DNA-damaging drugs to highly specific targeted DNA-cleaving OTIs. Herein we propose simple strategies to enable DNA-duplex strand invasion of WC-OTIs giving strand-invading SI-OTIs. This will make SI-OTIs similar to the guide RNAs of CRISPR/Cas9 nuclease bacterial immune systems. However, an important difference between OTIs and CRISPR/Cas9, is that OTIs do not require the introduction of foreign proteins into cells. Recent successful oligonucleotide therapeutics for neurodegenerative diseases suggest that OTIs can be developed to be highly specific gene editing agents for DNA lesions that cause neurodegenerative diseases.


The effects of cold therapy in the postoperative management of pain in patients undergoing anterior cruciate ligament reconstruction.
This prospective study assessed 54 consecutive arthroscopically assisted ACL reconstructions for the amount of postoperative pain relief provided by cold therapy, using the Hot/Ice Thermal Blanket. Twenty-six randomly selected patients undergoing this procedure were compared to a control group consisting of 28 patients having the identical procedure in which the Hot/Ice unit was not used postoperatively. The initial ACL injury in both groups was sports related with the exception of three patients whose injury occurred while on the job. The Hot/Ice Thermal Blanket consists of two rubber pads (blankets) connected by a hose to the main cooling unit. The pads were applied to either side of the operated knee in the operative suite. The pads received fluid which was circulated from the main unit. The temperature of the fluid was set at 50 degrees in the recovery room and the unit was run continuously until the time of discharge, which was approximately 4 days. Hot/Ice patients required 53% less injectable Demerol and 67% less oral Vistaril than patients in the control group. Hot/Ice patients had made the conversion from injectable to oral pain medication an average of 1.2 days sooner than did their non-Hot/Ice counterparts. There was no appreciable difference in length of hospital stay. Physical therapy and nursing records documented a greater percentage of compliant patients in the Hot/Ice group. According to these records the Hot/Ice patients were more helpful in self-assistance, were out of bed and ambulating in the halls more quickly, and did their range of motion exercises with greater ease.(ABSTRACT TRUNCATED AT 250 WORDS)


Body shape diversification along the benthic-pelagic axis in marine fishes.
Colonization of novel habitats can result in marked phenotypic responses to the new environment that include changes in body shape and opportunities for further morphological diversification. Fishes have repeatedly transitioned along the benthic-pelagic axis, with varying degrees of association with the substrate. Previous work focusing on individual lineages shows that these transitions are accompanied by highly predictable changes in body form. Here, we generalize expectations drawn from this literature to study the effects of habitat on body shape diversification across 3344 marine teleost fishes. We compare rates and patterns of evolution in eight linear measurements of body shape among fishes that live in pelagic, demersal and benthic habitats. While average body shape differs between habitats, these differences are subtle compared with the high diversity of shapes found within each habitat. Benthic living increases the rate of body shape evolution and has led to numerous lineages evolving extreme body shapes, including both exceptionally wide bodies and highly elongate, eel-like forms. By contrast, we find that benthic living is associated with the slowest diversification of structures associated with feeding. Though we find that habitat can serve as an impetus for predictable trait changes, we also highlight the diversity of responses in marine teleosts to opportunities presented by major habitats.


Assessing bone mineralisation in children with chronic kidney disease: what clinical and research tools are available?
Mineral and bone disorder in chronic kidney disease (CKD-MBD) is a triad of biochemical imbalances of calcium, phosphate, parathyroid hormone and vitamin D, bone abnormalities and soft tissue calcification. Maintaining optimal bone health in children with CKD is important to prevent long-term complications, such as fractures, to optimise growth and possibly also to prevent extra-osseous calcification, especially vascular calcification. In this review, we discuss normal bone mineralisation, the pathophysiology of dysregulated homeostasis leading to mineralisation defects in CKD and its clinical consequences. Bone mineralisation is best assessed on bone histology and histomorphometry, but given the rarity with which this is performed, we present an overview of the tools available to clinicians to assess bone mineral density, including serum biomarkers and imaging such as dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. We discuss key studies that have used these techniques, their advantages and disadvantages in childhood CKD and their relationship to biomarkers and bone histomorphometry. Finally, we present recommendations from relevant guidelines-Kidney Disease Improving Global Outcomes and the International Society of Clinical Densitometry-on the use of imaging, biomarkers and bone biopsy in assessing bone mineral density. Given low-level evidence from most paediatric studies, bone imaging and histology remain largely research tools, and current clinical management is guided by serum calcium, phosphate, PTH, vitamin D and alkaline phosphatase levels only.


Prerequisite for treatment planning implant dentistry: periodontal prognostication of compromised teeth.
In this era of increased dental implant use, there is a tendency to underestimate the long-term prognosis of a tooth with a compromised periodontium (treated or untreated). This can result in premature extraction of a tooth because of the rationalization that its retention can damage a future implant site, or its inclusion in prosthesis is too risky. Data in the literature was reviewed to ascertain if clinicians can assign an accurate prognosis to teeth based on currently used clinical periodontal parameters. Clinical trials were selected that addressed the ability of commonly used clinical periodontal parameters to predict disease progression leading to tooth loss. Currently, there is no single clinical parameter that can reliably forecast periodontal disease activity, tooth loss, or conversely, long-term tooth retention. Thus, combinations of parameters are evaluated in concert to guide the need for therapy and to assess treatment outcomes. The data indicate that the absence of clinical inflammation and a stable periodontium (eg, no increasing probing depths, no additional loss of bone, or clinical attachment) are advantageous for retaining teeth. With periodontal therapy, many teeth with an unfavorable periodontal forecast can be converted to teeth with a favorable long-term prognosis; therefore, caution should be taken when considering criteria for tooth removal. Presently, there is no precise way to delineate a quantifiable threshold for tooth removal based on periodontal status that is correct in every circumstance. The decision to extract a tooth will fluctuate depending on its clinical condition, and this action should be supported by the literature, clinical experience, and the patient's declared goals.


Roadmap on biology in time varying environments.
Biological organisms experience constantly changing environments, from sudden changes in physiology brought about by feeding, to the regular rising and setting of the Sun, to ecological changes over evolutionary timescales. Living organisms have evolved to thrive in this changing world but the general principles by which organisms shape and are shaped by time varying environments remain elusive. Our understanding is particularly poor in the intermediate regime with no separation of timescales, where the environment changes on the same timescale as the physiological or evolutionary response. Experiments to systematically characterize the response to dynamic environments are challenging since such environments are inherently high dimensional. This roadmap deals with the unique role played by time varying environments in biological phenomena across scales, from physiology to evolution, seeking to emphasize the commonalities and the challenges faced in this emerging area of research.


Solid pseudopapillary neoplasm of the pancreas: CT imaging features and radiologic-pathologic correlation.
We aimed to evaluate the imaging features of solid pseudopapillary neoplasm (SPN) of the pancreas with an emphasis on radiologic-pathologic correlation. Ten patients (all female; mean age, 32 years) with histologic or cytologic diagnosis of SPN encountered between January 2007 and December 2013 were included in this study. Preoperative computed tomography (CT) images were reviewed for location, attenuation, enhancement pattern, margin, shape, size, morphology, presence of capsule and calcification. CT appearances were correlated with histopathologic findings. Tumors in the distal pancreatic body and tail had a tendency to be larger (mean size 12.6 cm vs. 4.0 cm). Six of the nine tumors that were resected had a fibrous pseudocapsule at histology, five of which could be identified on CT scan. Eight lesions had mixed hypoenhancing solid components and cystic areas corresponding to tumor necrosis and hemorrhage. The two smallest lesions were purely solid and nonencapsulated. Varied patterns of calcification were seen in four tumors. Three of the four pancreatic tail tumors invaded the spleen. At a median follow-up of 53 months, there was no evidence of recurrence in the nine patients who underwent surgical resection of the tumor. A mixed solid and cystic pancreatic mass in a young woman is suggestive of SPN. However, smaller lesions may be completely solid. Splenic invasion can occur in pancreatic tail SPNs; however, in this series it did not adversely affect the long-term outcome.


What is the effect of peer support on diabetes outcomes in adults? A systematic review.
There is increasing interest in the role that peers may play to support positive health behaviours in diabetes, but there is limited evidence to inform policy and practice. The aim of this study was to systematically review evidence of the impact and effectiveness of peer support in adults living with diabetes. We searched the Cochrane Library, MEDLINE, PubMed, EMBASE and CINHAL for the period 1966-2011, together with reference lists of articles for eligible studies. Data were synthesized in a narrative review. Twenty-five studies, including fourteen randomized, controlled or comparative trials, met the inclusion criteria. There was considerable heterogeneity in the design, setting, outcomes and measurement tools. Peer support was associated with statistically significant improvements in glycaemic control (three out of 14 trials), blood pressure (one out of four trials), cholesterol (one out of six trials), BMI/weight (two out of seven trials), physical activity (two out of five trials), self-efficacy (two out of three trials), depression (four out of six trials) and perceived social support (two out of two trials). No consistent pattern of effect related to any model of peer support emerged. Peer support appears to benefit some adults living with diabetes, but the evidence is too limited and inconsistent to support firm recommendations. There remains a need for further well-designed evaluations of its effectiveness and impact. Key questions remain over its suitability to the needs of particular individuals, populations and settings, how best to implement its specific components and the sustainability of its effects.


Hypoxic-ischemic encephalopathy: a review for the clinician.
Hypoxic-ischemic encephalopathy (HIE) occurs in 1 to 8 per 1000 live births in developed countries. Historically, the clinician has had little to offer neonates with HIE other than systemic supportive care. Recently, the neuroprotective therapy of hypothermia has emerged as the standard of care, and other complementary therapies are rapidly transitioning from the basic science to clinical care. To examine the pathophysiology of HIE and the state of the art for the clinical care of neonates with HIE. We performed a literature review using the PubMed database. Results focused on reviews and articles published from January 1, 2004, through December 31, 2014. Articles published earlier than 2004 were included when appropriate for historical perspective. Our review emphasized evidence-based management practices for the clinician. A total of 102 articles for critical review were selected based on their relevance to the incidence of HIE, pathophysiology, neuroimaging, placental pathology, biomarkers, current systemic supportive care, hypothermia, and emerging therapies for HIE and were reviewed by both of us. Seventy-five publications were selected for inclusion in this article based on their relevance to these topics. The publications highlight the emergence of serum-based biomarkers, placental pathology, and magnetic resonance imaging as useful tools to predict long-term outcomes. Hypothermia and systemic supportive care form the cornerstone of therapy for HIE. The pathophysiology of HIE is now better understood, and treatment with hypothermia has become the foundation of therapy. Several neuroprotective agents offer promise when combined with hypothermia and are entering clinical trials.


Recognizing the unconscious.
Recognition memory enables us to discriminate whether an event has occurred in the past, and is widely interpreted to reflect the conscious retrieval of episodic traces or familiarity. Non-conscious mnemonic influences, such as repetition priming, are thought to have a negligible effect on standard tests of recognition memory. A major difficulty with this conclusion is that it is exclusively based on the results from experimental protocols that use stimulus materials available to conscious perception. In eight experiments (N = 144), we tested the necessity of mechanisms related to conscious perception for accurate recognition memory by manipulating observers' awareness of either the encoded event and/or the retrieval cues. Remarkably, observers made accurate objective and subjective recognition memory-guided judgments without visual awareness of the encoded events, retrieval cues or, most strikingly, both. These results demonstrate that non-conscious processes can drive accurate recognition memory, and are a significant challenge to neurobiological accounts centered on the conscious retrieval of episodic traces or familiarity.


Protective role of p70S6K in intestinal ischemia/reperfusion injury in mice.
The mTOR signaling pathway plays a crucial role in the regulation of cell growth, proliferation, survival and in directing immune responses. As the intestinal epithelium displays rapid cell growth and differentiation and is an important immune regulatory organ, we hypothesized that mTOR may play an important role in the protection against intestinal ischemia reperfusion (I/R)-induced injury. To better understand the molecular mechanisms by which the mTOR pathway is altered by intestinal I/R, p70S6K, the major effector of the mTOR pathway, was investigated along with the effects of rapamycin, a specific inhibitor of mTOR and an immunosuppressant agent used clinically in transplant patients. In vitro experiments using an intestinal epithelial cell line and hypoxia/reoxygenation demonstrated that overexpression of p70S6K promoted cell growth and migration, and decreased cell apoptosis. Inhibition of p70S6K by rapamycin reversed these protective effects. In a mouse model of gut I/R, an increase of p70S6K activity was found by 5 min and remained elevated after 6 h of reperfusion. Inhibition of p70S6K by rapamycin worsened gut injury, promoted inflammation, and enhanced intestinal permeability. Importantly, rapamycin treated animals had a significantly increased mortality. These novel results demonstrate a key role of p70S6K in protection against I/R injury in the intestine and suggest a potential danger in using mTOR inhibitors in patients at risk for gut hypoperfusion.


Ultrashort broadband polarization beam splitter based on an asymmetrical directional coupler.
An ultrashort polarization beam splitter (PBS) based on an asymmetrical directional coupler is proposed by utilizing the evanescent coupling between a strip-nanowire and a nanoslot waveguide. In order to be convenient for integration with other components, mode converters between the nanoslot waveguide and the strip-nanowire are introduced and merged into S-bends to achieve an ultracompact PBS. As an example a 6.9 μm long PBS based on a silicon-on-insulator platform is designed, and the length of the coupling region is as small as 1.3 μm. Numerical simulations show that the present PBS has a very broad band (>160 nm) for an extinction ratio of >10 dB.


A Systematic Review of the Sources of Dietary Salt Around the World.
Excess salt intake contributes to hypertension and increased cardiovascular disease risk. Efforts to implement effective salt-reduction strategies require accurate data on the sources of salt consumption. We therefore performed a systematic review to identify the sources of dietary salt around the world. We systematically searched peer-reviewed and gray literature databases for studies that quantified discretionary (salt added during cooking or at the table) and nondiscretionary sources of salt and those that provided information about the food groups contributing to dietary salt intake. Exploratory linear regression analysis was also conducted to assess whether the proportion of discretionary salt intake is related to the gross domestic product (GDP) per capita of a country. We identified 80 studies conducted in 34 countries between 1975 and 2018. The majority (n = 44, 55%) collected data on dietary salt sources within the past 10 y and were deemed to have a low or moderate risk of bias (n = 75, 94%). Thirty-two (40%) studies were judged to be nationally representative. Populations in Brazil, China, Costa Rica, Guatemala, India, Japan, Mozambique, and Romania received more than half of their daily salt intake from discretionary sources. A significant inverse correlation between discretionary salt intake and a country's per capita GDP was observed (P < 0.0001), such that for every $10,000 increase in per capita GDP, the amount of salt obtained from discretionary sources was lower by 8.7% (95% CI: 5.1%, 12%). Bread products, cereal and grains, meat products, and dairy products were the major contributors to dietary salt intake in most populations. There is marked variation in discretionary salt use around the world that is highly correlated with the level of economic development. Our findings have important implications for the type of salt-reduction strategy likely to be effective in a country.


A genetic screen for modifiers of Drosophila caspase Dcp-1 reveals caspase involvement in autophagy and novel caspase-related genes.
Caspases are cysteine proteases with essential functions in the apoptotic pathway; their proteolytic activity toward various substrates is associated with the morphological changes of cells. Recent reports have described non-apoptotic functions of caspases, including autophagy. In this report, we searched for novel modifiers of the phenotype of Dcp-1 gain-of-function (GF) animals by screening promoter element- inserted Drosophila melanogaster lines (EP lines). We screened approximately 15,000 EP lines and identified 72 Dcp-1-interacting genes that were classified into 10 groups based on their functions and pathways: 4 apoptosis signaling genes, 10 autophagy genes, 5 insulin/IGF and TOR signaling pathway genes, 6 MAP kinase and JNK signaling pathway genes, 4 ecdysone signaling genes, 6 ubiquitination genes, 11 various developmental signaling genes, 12 transcription factors, 3 translation factors, and 11 other unclassified genes including 5 functionally undefined genes. Among them, insulin/IGF and TOR signaling pathway, MAP kinase and JNK signaling pathway, and ecdysone signaling are known to be involved in autophagy. Together with the identification of autophagy genes, the results of our screen suggest that autophagy counteracts Dcp-1-induced apoptosis. Consistent with this idea, we show that expression of eGFP-Atg5 rescued the eye phenotype caused by Dcp-1 GF. Paradoxically, we found that over-expression of full-length Dcp-1 induced autophagy, as Atg8b-GFP, an indicator of autophagy, was increased in the eye imaginal discs and in the S2 cell line. Taken together, these data suggest that autophagy suppresses Dcp-1-mediated apoptotic cell death, whereas Dcp-1 positively regulates autophagy, possibly through feedback regulation. We identified a number of Dcp-1 modifiers that genetically interact with Dcp-1-induced cell death. Our results showing that Dcp-1 and autophagy-related genes influence each other will aid future investigations of the complicated relationships between apoptosis and autophagy.


Bayesian analysis of botanical epidemics using stochastic compartmental models.
A stochastic model for an epidemic, incorporating susceptible, latent, and infectious states, is developed. The model represents primary and secondary infection rates and a time-varying host susceptibility with applications to a wide range of epidemiological systems. A Markov chain Monte Carlo algorithm is presented that allows the model to be fitted to experimental observations within a Bayesian framework. The approach allows the uncertainty in unobserved aspects of the process to be represented in the parameter posterior densities. The methods are applied to experimental observations of damping-off of radish (Raphanus sativus) caused by the fungal pathogen Rhizoctonia solani, in the presence and absence of the antagonistic fungus Trichoderma viride, a biological control agent that has previously been shown to affect the rate of primary infection by using a maximum-likelihood estimate for a simpler model with no allowance for a latent period. Using the Bayesian analysis, we are able to estimate the latent period from population data, even when there is uncertainty in discriminating infectious from latently infected individuals in data collection. We also show that the inference that T. viride can control primary, but not secondary, infection is robust to inclusion of the latent period in the model, although the absolute values of the parameters change. Some refinements and potential difficulties with the Bayesian approach in this context, when prior information on parameters is lacking, are discussed along with broader applications of the methods to a wide range of epidemiological systems.


Revealing the synergetic effects in Ni nanoparticle-carbon nanotube hybrids by scanning transmission X-ray microscopy and their application in the hydrolysis of ammonia borane.
The hybrids of carbon nanotubes (CNTs) and the supported Ni nanoparticles (NPs) have been studied by scanning transmission X-ray microscopy (STXM) and tested by the hydrolysis reaction of ammonia borane (AB, NH3BH3). Data clearly showed the existence of a strong interaction between Ni NPs and thin CNTs (C-O-Ni bonds), which favored the tunable (buffer) electronic structure of Ni NPs facilitating the catalytic process. The hydrolysis process of AB confirmed the hypothesis that the hybrids with a strong interfacial interaction would show superior catalytic performance, while the hybrids with a weak interfacial interaction show poor performance. Our results provide a wealth of detailed information regarding the electronic structure of the NP-CNT hybrids and provide guidance towards the rational design of high-performance catalysts for energy applications.


Persistent viral pathogens and cognitive impairment across the life course in the third national health and nutrition examination survey.
Herpesviruses have been linked to cognitive impairment in older individuals but little is known about the association in the general US population. We determined whether cytomegalovirus (CMV) and herpes simplex virus 1 (HSV-1) seropositivity were associated with cognitive impairment among children (aged 6-16 years) and adults aged 20-59 or ≥60 years, using data from the National Health and Nutrition Examination Survey (NHANES) III. Linear and logistic regression models were used to examine the associations between pathogen seropositivity and cognitive impairment. Among children, HSV-1 seropositivity was associated with lower reading and spatial reasoning test scores (β, -0.69; 95% confidence interval [CI], -1.18 to -.21 and β, -0.82; 95% CI, -1.29 to -.36, respectively). Among middle-aged adults, HSV-1 and CMV seropositivity were associated with impaired coding speed (odds ratio [OR], 1.54; 95% CI, 1.13-2.11, and OR, 1.41; 95% CI, 1.09-1.82, respectively). CMV seropositivity was also associated with impaired learning and recall (OR, 1.43; 95% CI, 1.14-1.80). Among older adults, HSV-1 seropositivity was associated with immediate memory impairment (OR, 3.26; 95% CI, 1.68-6.32). Future studies examining the biological pathways by which herpesviruses influence cognitive impairment across the life course are warranted.


Prolactin modulates TRPV1 in female rat trigeminal sensory neurons.
Sex dependency in pain perception is well documented and is thought to be attributable to the effect of reproductive hormones on nociceptive processing. In the present study, we evaluated whether estradiol alters gene transcription in the trigeminal ganglia (TG) of ovariectomized rats (OVX). These experiments demonstrated a dramatic (40-fold) upregulation of prolactin (PRL) expression in TG by 17-beta-estradiol (E2). PRL expression was restricted to TG neurons and was highly overlapped with transient potential receptor vanilloid type 1 (TRPV1) (approximately 90%) in TG. Additionally, PRL is released from neurons during stimulation. Both forms of PRL receptors (PRLRs), short and long, were also present in TG neurons. Moreover, expression of the long PRLRs was under control of estradiol. We next evaluated the novel hypothesis that PRL acts as a neuromodulator of sensory neurons. PRL pretreatment significantly enhanced capsaicin-evoked inward currents, calcium influx, and immunoreactive calcitonin gene-related peptide release from cultured TG neurons. This PRL modulation of capsaicin responses was abolished by withdrawal of E2 from TG cultures. Biochemical analysis demonstrated that PRL increased (>50%) phosphorylation levels of TRPV1 in TG. In a behavioral test, PRL pretreatment significantly potentiated capsaicin-evoked nocifensive behavior in female rats at proestrous and in OVX rats after E2 treatment. The in vivo potentiating effect of PRL on capsaicin responses was also dependent on E2. Collectively, these data demonstrate that PRL is a novel modulator of sensory neurons tightly regulated by E2. These findings are consistent with the hypothesis that PRL could contribute to the development of certain pain disorders, possibly including those modulated by estrogen.


Effects of light therapy on suicidal ideation in patients with winter depression.
Recent case reports suggest that some patients with seasonal affective disorder (SAD) may become suicidal after initial treatment with light therapy. This retrospective study sought to determine the effects of light therapy on suicidal ideation in patients with SAD. The cases of 191 depressed patients with SAD by DSM-III-R or DSM-IV criteria treated with an open trial of morning light therapy using cool white fluorescent light boxes (2500 lux for 2 hours per day or 10,000 lux for 30 minutes per day) for 2 weeks were retrospectively analyzed. Patients had been rated before and after treatment with the expanded Hamilton Depression Rating Scale (SIGH-SAD). Sixty-seven percent of patients were rated as clinical responders to light therapy. There was significant improvement in the SIGH-SAD suicide item score, with 45% of patients showing a reduction in score. Only 6 patients (3%) had slight worsening of suicide scores. No patients attempted suicide or discontinued light therapy because of emergent suicidality. Light therapy relieves suicidal ideation in patients with SAD consistent with overall clinical improvement. Emergence of suicidal ideas or behaviors is very uncommon with light therapy.


Use of Medical Cannabis to Treat Traumatic Brain Injury.
There is not a single pharmacological agent with demonstrated therapeutic efficacy for traumatic brain injury (TBI). With recent legalization efforts and the growing popularity of medical cannabis, patients with TBI will inevitably consider medical cannabis as a treatment option. Pre-clinical TBI research suggests that cannabinoids have neuroprotective and psychotherapeutic properties. In contrast, recreational cannabis use has consistently shown to have detrimental effects. Our review identified a paucity of high-quality studies examining the beneficial and adverse effects of medical cannabis on TBI, with only a single phase III randomized control trial. However, observational studies demonstrate that TBI patients are using medical and recreational cannabis to treat their symptoms, highlighting inconsistencies between public policy, perception of potential efficacy, and the dearth of empirical evidence. We conclude that randomized controlled trials and prospective studies with appropriate control groups are necessary to fully understand the efficacy and potential adverse effects of medical cannabis for TBI.


Malaria control in Timor-Leste during a period of political instability: what lessons can be learned?
Malaria is a major global health problem, often exacerbated by political instability, conflict, and forced migration. To examine the impact of political upheaval and population displacement in Timor-Leste (2006) on malaria in the country. Case study approach drawing on both qualitative and quantitative methods including document reviews, in-depth interviews, focus group discussions, site visits and analysis of routinely collected data. The conflict had its most profound impact on Dili, the capital city, in which tens of thousands of people were displaced from their homes. The conflict interrupted routine malaria service programs and training, but did not lead to an increase in malaria incidence. Interventions covering treatment, insecticide treated nets (ITN) distribution, vector control, surveillance and health promotion were promptly organized for internally displaced people (IDPs) and routine health services were maintained. Vector control interventions were focused on IDP camps in the city rather than on the whole community. The crisis contributed to policy change with the introduction of Rapid Diagnostic Tests and artemether-lumefantrine for treatment. Although the political crisis affected malaria programs there were no outbreaks of malaria. Emergency responses were quickly organized and beneficial long term changes in treatment and diagnosis were facilitated.


Clinical effectiveness of CT-P13 (Infliximab biosimilar) used as a switch from Remicade (infliximab) in patients with established rheumatic disease. Report of clinical experience based on prospective observational data.
To gain clinical experience on the effectiveness and safety of switching from infliximab-Remicade(INX) to infliximab-biosimilar-CT-P13(INB) in patients with established rheumatic disease. Patients receiving INX treatment at a rheumatology clinic consented to switching from INX to INB. Patient reported outcomes (PROs), disease-activity, and inflammatory markers were recorded at every visit. Generalized estimating equation models and time-dependent area under the curve (AUC) before/during INX and INB treatments were employed. Thirty-nine consecutive patients [mean (SD) age 53 (11), 17 F] with various rheumatic diseases were switched to INB after a mean (SD) of 4.1 (2.3) years on INX. Thirty-one patients were on concomitant methotrexate. At a median (range) of 11 (7.5-13) months following the first administration of INB, AUCs for disease activity and PROs were similar for INX and INB. They were better compared to those prior to INX. Eleven patients (28.2%) discontinued INB, due to INX antidrug antibodies detected prior to INB infusion (n = 3); latent tuberculosis (n = 1); new-onset neurofibromatosis (n = 1); subjective reasons with no objective deterioration of disease (n = 6). The clinical effectiveness of INB in both PROs and disease-activity measures was comparable to INX during the first year of switching, with no immediate safety signals. Subjective reasons (negative expectations) may play a role among discontinuations of biosimilars. Larger patient numbers and longer follow-up are necessary for confirming this clinical experience.


AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011.
Therapeutic drug monitoring (TDM), i. e., the quantification of serum or plasma concentrations of medications for dose optimization, has proven a valuable tool for the patient-matched psychopharmacotherapy. Uncertain drug adherence, suboptimal tolerability, non-response at therapeutic doses, or pharmacokinetic drug-drug interactions are typical situations when measurement of medication concentrations is helpful. Patient populations that may predominantly benefit from TDM in psychiatry are children, pregnant women, elderly patients, individuals with intelligence disabilities, forensic patients, patients with known or suspected genetically determined pharmacokinetic abnormalities or individuals with pharmacokinetically relevant comorbidities. However, the potential benefits of TDM for optimization of pharmacotherapy can only be obtained if the method is adequately integrated into the clinical treatment process. To promote an appropriate use of TDM, the TDM expert group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued guidelines for TDM in psychiatry in 2004. Since then, knowledge has advanced significantly, and new psychopharmacologic agents have been introduced that are also candidates for TDM. Therefore the TDM consensus guidelines were updated and extended to 128 neuropsychiatric drugs. 4 levels of recommendation for using TDM were defined ranging from "strongly recommended" to "potentially useful". Evidence-based "therapeutic reference ranges" and "dose related reference ranges" were elaborated after an extensive literature search and a structured internal review process. A "laboratory alert level" was introduced, i. e., a plasma level at or above which the laboratory should immediately inform the treating physician. Supportive information such as cytochrome P450 substrate- and inhibitor properties of medications, normal ranges of ratios of concentrations of drug metabolite to parent drug and recommendations for the interpretative services are given. Recommendations when to combine TDM with pharmacogenetic tests are also provided. Following the guidelines will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems. Thereby, one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data so that, ultimately, the patient can profit from such a joint effort.


Stable, Environmental Specific and Novel QTL Identification as Well as Genetic Dissection of Fatty Acid Metabolism in Brassica napus.
Fatty acid (FA) composition is the typical quantitative trait in oil seed crops, of which study is not only closely related to oil content, but is also more critical for the quality improvement of seed oil. The double haploid (DH) population named KN with a high density SNP linkage map was applied for quantitative trait loci (QTL) analysis of FA composition in this study. A total of 406 identified QTL were detected for eight FA components with an average confidence interval (CI) of 2.92 cM, the explained phenotypic variation (PV) value ranged from 1.49 to 45.05%. Totally, 204 consensus and 91 unique QTL were further obtained via meta-analysis method for the purpose of detecting multiple environment expressed and pleiotropic QTL, respectively. Of which, 74 stable expressed and 22 environmental specific QTL were also revealed, respectively. In order to make clear the genetic mechanism of FA metabolism at individual QTL level, conditional QTL analysis was also conducted and more than two thousand conditional QTL which could not be detected under the unconditional mapping were detected, which indicated the complex interrelationship of the QTL controlling FA content in rapeseed. Through comparative genomic analysis and homologous gene annotation, 61 candidates related to acyl lipid metabolism were identified underlying the CI of FA QTL. To further visualize the genetic mechanism of FA metabolism, an intuitive and meticulous network about acyl lipid metabolism was constructed and some closely related candidates were positioned. This study provided a more accurate localization for stable and pleiotropic QTL, and a deeper dissection of the molecular regulatory mechanism of FA metabolism in rapeseed.


Effect of methylene blue on blood pressure in rats.
Methylene blue (MB) is a soluble guanylate cyclase inhibitor, and known as an endothelium-derived relaxing factor (EDRF) inhibitor in vitro. In the present study, it was demonstrated that intravenous administration of MB caused a dose-dependent hypertensive effect in rats. The hypertensive responses to the higher doses (10 and 20 mg/kg) of MB was followed by a reflex hypotension which did not appear in pithed rats. Noradrenaline depletion by reserpine pretreatment did not inhibit MB-induced hypertension, but abolished the hypotensive response. Both hypertensive and hypotensive phases were not altered by indometacin. These results may suggest that in vivo guanylate cyclase inhibition leads to an increase in blood pressure; prostaglandins and noradrenaline release from sympathetic nerve endings do not contribute to MB-induced hypertension and it may be due in part to the inhibition of EDRF.


The knowns and unknowns of latent Mycobacterium tuberculosis infection.
Humans have been infected with Mycobacterium tuberculosis (Mtb) for thousands of years. While tuberculosis (TB), one of the deadliest infectious diseases, is caused by uncontrolled Mtb infection, over 90% of presumed infected individuals remain asymptomatic and contain Mtb in a latent TB infection (LTBI) without ever developing disease, and some may clear the infection. A small number of heavily Mtb-exposed individuals appear to resist developing traditional LTBI. Because Mtb has mechanisms for intracellular survival and immune evasion, successful control involves all of the arms of the immune system. Here, we focus on immune responses to Mtb in humans and nonhuman primates and discuss new concepts and outline major knowledge gaps in our understanding of LTBI, ranging from the earliest events of exposure and infection to success or failure of Mtb control.


Evaluation of phage display discovered peptides as ligands for prostate-specific membrane antigen (PSMA).
The aim of this study was to identify potential ligands of PSMA suitable for further development as novel PSMA-targeted peptides using phage display technology. The human PSMA protein was immobilized as a target followed by incubation with a 15-mer phage display random peptide library. After one round of prescreening and two rounds of screening, high-stringency screening at the third round of panning was performed to identify the highest affinity binders. Phages which had a specific binding activity to PSMA in human prostate cancer cells were isolated and the DNA corresponding to the 15-mers were sequenced to provide three consensus sequences: GDHSPFT, SHFSVGS and EVPRLSLLAVFL as well as other sequences that did not display consensus. Two of the peptide sequences deduced from DNA sequencing of binding phages, SHSFSVGSGDHSPFT and GRFLTGGTGRLLRIS were labeled with 5-carboxyfluorescein and shown to bind and co-internalize with PSMA on human prostate cancer cells by fluorescence microscopy. The high stringency requirements yielded peptides with affinities KD~1 µM or greater which are suitable starting points for affinity maturation. While these values were less than anticipated, the high stringency did yield peptide sequences that apparently bound to different surfaces on PSMA. These peptide sequences could be the basis for further development of peptides for prostate cancer tumor imaging and therapy.


The joint demand for cigarettes and marijuana: evidence from the National Household Surveys on Drug Abuse.
Recent studies have shown that efforts to curb youths' alcohol use, such as increasing the price of alcohol or limiting youths' access, have succeeded but may have had the unintended consequence of increasing marijuana use. This possibility is troubling in light of the doubling of teen marijuana use from 1990 to 1997. What impact will recent increases in cigarette prices have on the demand for other substances, such as marijuana? To better understand how the demand for marijuana and tobacco responds to changes in the policies and prices that affect their use, we explore the National Household Survey on Drug Abuse (NHSDA) from 1990 to 1996. We find evidence that both higher fines for marijuana possession and increased probability of arrest decrease the probability that a young adult will use marijuana. We also find that higher cigarette taxes appear to decrease the intensity of marijuana use and may have a modest negative effect on the probability of use among males.


Diesel Exhaust Particles Induce Impairment of Vascular and Cardiac Homeostasis in Mice: Ameliorative Effect of Emodin.
There is strong epidemiological and clinical evidence that components of the cardiovascular system are adversely affected by particulate air pollutants through the generation of inflammation and oxidative stress. Emodin (1,3,8-trihydroxy-6- methylanthraquinone), which is commonly found in the roots of rhubarb plant, has strong antioxidant and anti-inflammatory effects. However, its possible protective effect on the cardiovascular effect of particulate air pollutants has never been reported before. We tested, in Tuck-Ordinary mice, the possible ameliorative effect of emodin on the acute (24h) cardiovascular effects of diesel exhaust particles (DEP, 1 mg/kg) or saline (control). Emodin (4 mg/kg) was administered intraperitoneally 1h before and 7h after pulmonary exposure to DEP. Twenty four h following DEP exposure, several cardiovascular endpoints were assessed. Emodin significantly prevented the increase of leukocyte (n=8, P<0.001) and erythrocyte (n=8, P<0.01) numbers caused by DEP. Likewise, emodin abrogated DEP-induced increase of heart tissue levels of interleukin 1β (n=8, P<0.01) and tumour necrosis factor α (n=8, P<0.05), and significantly mitigated the change of the activities of antioxidant enzymes superoxide dismutase (n=8, P<0.001) and glutathione reductase (n=8, P<0.05). Emodin abolished the in vivo prothrombotic effect of DEP in pial arterioles (n=6, P<0.01) and venules (n=6, P<0.001). Similarly, emodin prevented platelet aggregation in vitro in whole blood (n=4-5, P<0.01), and the shortening of activated partial thromboplastin time (n=4, P<0.001) and prothrombin time (n=4, P<0.01) caused by DEP. We conclude that emodin treatment has consistently protected against DEP-induced impairment of vascular and cardiac homeostasis in mice. Our study provides experimental evidence that the use of functional food such as emodin, pending further studies, can be considered a useful agent and may have the potential to protect or mitigate the cardiovascular detrimental effects observed in people living in cities with high concentrations of particulate air pollution.


How women perceive abortion care: A study focusing on healthy women and those with mental and posttraumatic stress.
Objectives To identify perceived deficiencies in the quality of abortion care among healthy women and those with mental stress. Methods This multi-centre cohort study included six obstetrics and gynaecology departments in Sweden. Posttraumatic stress (PTSD/PTSS) was assessed using the Screen Questionnaire-Posttraumatic Stress Disorder; anxiety and depressive symptoms, using the Hospital Anxiety Depression Scale; and abortion quality perceptions, using a modified version of the Quality from the Patient's Perspective questionnaire. Pain during medical abortion was assessed in a subsample using a visual analogue scale. Results Overall, 16% of the participants assessed the abortion care as being deficient, and 22% experienced intense pain during medical abortion. Women with PTSD/PTSS more often perceived the abortion care as deficient overall and differed from healthy women in reports of deficiencies in support, respectful treatment, opportunities for privacy and rest, and availability of support from a significant person during the procedure. There was a marginally significant difference between PTSD/PTSS and the comparison group for insufficient pain alleviation. Conclusions Women with PTSD/PTSS perceived abortion care to be deficient more often than did healthy women. These women do require extra support, relatively simple efforts to provide adequate pain alleviation, support and privacy during abortion may improve abortion care.


The prognostic impact of Akt isoforms, PI3K and PTEN related to female steroid hormone receptors in soft tissue sarcomas.
The PI3K/Akt pathway is involved in cellular survival pathways by inhibiting apoptotic processes and stimulating cell growth and proliferation. Its negative prognostic value has been proven in many types of cancer. In soft tissue sarcomas, the expression profiles of the PI3K/Akt pathway components are poorly defined and their significance uncertain. We aimed to investigate the prognostic impact of Akt (Akt1) phosphorylated at threonine308 and serine473, Akt2, Akt3, PI3K and PTEN, alone and in coexpression with ER and PgR in non-gastrointestinal stromal tumor soft tissue sarcomas (non-GIST STSs). Tumor samples and clinical data from 249 patients with non-GIST STS were obtained, and tissue microarrays (TMAs) were constructed. Immunohistochemistry (IHC) was used to evaluate marker expression in tumor cells. In univariate analyses, the expression levels of p-Akt Thr308 (P = 0.002), Akt2 (P = 0.008) and PI3K (P < 0.001) were significant prognostic factors. In the multivariate analysis, high PI3K expression was an independent negative prognosticator (HR = 1.5, 95% CI = 1.0-2.2, P = 0.042) in addition to advanced age, tumor depth, high malignancy grade, metastasis at diagnosis, surgery and positive resection margins. p-Akt Thr308 expression had strong unfavorable effect in men only (P = 0.009). In contrast, p-Akt Ser473 expression had strong unfavorable impact in women (P = 0.023). PgR-/p-Akt Ser473+ phenotype tended to have less favorable impact in women (P = 0.087), but was the most favorable one in men (P = 0.010). Expression of PI3K was significantly associated with aggressive behavior and shorter DSS in non-GIST STSs. The site of Akt phosphorylation seems to have gender-dependent impact on survival in STS patients.


Pseudouridines and pseudouridine synthases of the ribosome.
psi are ubiquitous in ribosomal RNA. Eubacteria, Archaea, and eukaryotes all contain psi, although their number varies widely, with eukaryotes having the most. The small ribosomal subunit can apparently do without psi in some organisms, even though others have as many as 40 or more. Large subunits appear to need at least one psi but can have up to 50-60. psi is made by a set of site-specific enzymes in eubacteria, and in eukaryotes by a single enzyme complexed with auxiliary proteins and specificity-conferring guide RNAs. The mechanism is not known in Archaea, but based on an analysis of the kinds of psi synthases found in sequenced archaeal genomes, it is likely to involve use of guide RNAs. All psi synthases can be classified into one of four related groups, virtually all of which have a conserved aspartate residue in a conserved sequence motif. The aspartate is essential for psi formation in all twelve synthases examined so far. When the need for psi in E. coli was examined, the only synthase whose absence caused a major decrease in growth rate under normal conditions was RluD, the synthase that makes psi 1911, psi 1915, and psi 1917 in the helix 69 end-loop. This growth defect was the result of a major failure in assembly of the large ribosomal subunit. The defect could be prevented by supplying the rluD structural gene in trans, and also by providing a point mutant gene that made a synthase unable to make psi. Therefore, the RluD synthase protein appears to be directly involved in 50S subunit assembly, possibly as an RNA chaperone, and this activity is independent of its ability to form psi. This result is not without precedent. Depletion of PET56, a 2'-O-methyltransferase specific for G2251 (E. coli numbering) in yeast mitochondria virtually blocks 50S subunit assembly and mitochondrial function (Sirum-Connolly et al. 1995), but the methylation activity of the enzyme is not required (T. Mason, pers. comm.). The absence of FtsJ, a heat shock protein that makes Um2552 in E. coli, makes the 50S subunit less stable at 1 mM Mg++ (Bügl et al. 2000) and inhibits subunit joining (Caldas et al. 2000), but, in this case, it is not yet known whether the effects are due to the lack of 2'-O-methylation or to the absence of the enzyme itself. Is there any role for the psi residues themselves? First, as noted above, the 3 psi made by RluD which cluster in the end-loop of helix 69 are highly conserved, with one being universal (Fig. 2B). In the 70S-tRNA structure (Yusupov et al. 2001), the loop of this helix containing the psi supports the anticodon arm of A-site tRNA near its juncture with the amino acid arm. The middle of helix 69 does the same thing for P-site tRNA. Unfortunately, the resolution is not yet sufficient to provide a more precise alignment of the psi residues with the other structural elements of the tRNA-ribosome complex so that one cannot yet determine what role, if any, is played by the N-1 H that distinguishes psi from U. Second, and more generally, some psi residues in the LSU appear to be near the site of peptide-bond formation or tRNA binding but not actually at it (Fig. 2B) (Nissen et al. 2000; Yusupov et al. 2001). For example, position 2492 is commonly psi and is only six residues away from A2486, the A postulated to catalyze peptide-bond formation. Position 2589 is psi in all the eukaryotes and is next to 2588, which base-pairs with the C75 of A-site tRNA. Residue 2620, which interacts with the A76 of A-site-bound tRNA, is a psi or is next to a psi in eukaryotes and Archaea, and is five residues away from psi 2580 in E. coli. A2637, which is between the two CCA ends of P- and A-site tRNA, is near psi 2639, psi 2640, and psi 2641, found in a number of organisms. Residue 2529, which contacts the backbone of A-site tRNA residues 74-76, is near psi 2527 psi 2528 in H. marismortui. Residues 2505-2507, which contact A-site tRNA residues 50-53, are near psi 2509 in higher eukaryotes, and residues 2517-2519 in contact with A-site tRNA residues 64-65 are within 1-3 nucleotides of psi 2520 in higher eukaryotes and psi 2514 in H. marismortui. A way to rationalize this might be to invoke the concept suggested in the Introduction that psi acts as a molecular glue to hold loose elements in a more rigid configuration. It may well be that this is more important near the site of peptide-bond formation and tRNA binding, accounting for the preponderance of psi in this vicinity. What might be the role of all the other psi in eukaryotes? One can only surmise that cells, having once acquired the ability to make psi with guide RNAs, took advantage of the system to inexpensively place psi wherever an undesirable loose region was found. It might be that in some of these cases, psi performs the role played by proteins in other regions, namely that of holding the rRNA in its proper configuration. Confirmation of this hypothesis will have to await structural determination of eukaryotic ribosomes.


Inhibition of cell growth in vitro by adenosine 3',5'-monophosphate.
Adenosine 3',5'-monophosphate, at a concentration of 40 micrograms per milliliter, inhibits the growth of HeLa and strain L cells in culture. The inhibition becomes progressively greater during the incubation of the cells. Adenosine 5'-monophosphate and adenosine, metabolites of adenosine 3',5'-monophosphate, do not affect the growth of either cell culture. This suggests that 3',5'-monophosphate enters the cell without alteration. Dibutyryl-adenosine 3',5'-monophosphate, reported to have a greater activity than adenosine 3'5'-monophosphate on several tissues, inhibited the growth of the cells much less.


PPARγ activator, rosiglitazone: Is it beneficial or harmful to the cardiovascular system?
Rosiglitazone is a synthetic agonist of peroxisome proliferator-activated receptor γ which is used to improve insulin resistance in patients with type II diabetes. Rosiglitazone exerts its glucose-lowering effects by improving insulin sensitivity. Data from various studies in the past decade suggest that the therapeutic effects of rosiglitazone reach far beyond its use as an insulin sensitizer since it also has other benefits on the cardiovascular system such as improvement of contractile dysfunction, inhibition of the inflammatory response by reducing neutrophil and macrophage accumulation, and the protection of myocardial injury during ischemic/reperfusion in different animal models. Previous clinical studies in type II diabetes patients demonstrated that rosiglitazone played an important role in protecting against arteriosclerosis by normalizing the metabolic disorders and reducing chronic inflammation of the vascular system. Despite these benefits, inconsistent findings have been reported, and growing evidence has demonstrated adverse effects of rosiglitazone on the cardiovascular system, including increased risk of acute myocardial infarction, heart failure and chronic heart failure. As a result, rosiglitazone has been recently withdrawn from EU countries. Nevertheless, the effect of rosiglitazone on ischemic heart disease has not yet been firmly established. Future prospective clinical trials designed for the specific purpose of establishing the cardiovascular benefit or risk of rosiglitazone would be the best way to resolve the uncertainties regarding the safety of rosiglitazone in patients with heart disease.


Projections of cochlear root neurons, sentinels of the rat auditory pathway.
In certain rodents, the root of the cochlear nerve contains a population of large neurons, known as cochlear root neurons (CRNs), an essential element of the primary acoustic startle pathway. To characterize the projections of the CRNs, we made stereotaxically guided, iontophoretic injections of biotinylated tracers into the cochlear nerve root of albino rats. CRN axons, which are remarkably thick, enter the trapezoid body, cross the midline, and ascend in the rostral aspect of the lateral lemniscus to reach the upper levels of the midbrain. As a group, CRN axons produce a characteristic pattern of profusely ramified collaterals that innervate specific brainstem regions. The main target of CRN axons is the contralateral pontine reticular formation, where collaterals terminate in the caudal pontine reticular nucleus (PnC) and, to a lesser degree, in the ventrolateral tegmental area, the oral pontine reticular nucleus, and the rostral and medial paralemniscal regions. Other targets of CRN axons include the lateral paragigantocellular nucleus of both sides, the ipsilateral facial motor nucleus and PnC, and the contralateral intercollicular tegmentum and superior colliculus. Notably, CRNs apparently do not innervate any of the nuclei of the auditory brainstem, as usually defined, even though their axons pass through or in close proximity to them. The fact that CRNs innervate several reticular and tectal structures that mediate auditory alerting and escape behaviors suggests that they are "early warning neurons," i.e., true sentinels of the auditory pathway.


Survival Motor Neuron Protein Participates in Mouse Germ Cell Development and Spermatogonium Maintenance.
The defective human survival motor neuron 1 (SMN1) gene leads to spinal muscular atrophy (SMA), the most common genetic cause of infant mortality. We previously reported that loss of SMN results in rapid differentiation of Drosophila germline stem cells and mouse embryonic stem cells (ESCs), indicating that SMN also plays important roles in germ cell development and stem cell biology. Here, we show that in healthy mice, SMN is highly expressed in the gonadal tissues, prepubertal spermatogonia, and adult spermatocytes, whereas low SMN expression is found in differentiated spermatid and sperm. In SMA-like mice, the growth of testis tissues is retarded, accompanied with gamete development abnormalities and loss of the spermatogonia-specific marker. Consistently, knockdown of Smn1 in spermatogonial stem cells (SSCs) leads to a compromised regeneration capacity in vitro and in vivo in transplantation experiments. In SMA-like mice, apoptosis and accumulation of the R-loop structure were significantly elevated, indicating that SMN plays a critical role in the survival of male germ cells. The present work demonstrates that SMN, in addition to its critical roles in neuronal development, participates in mouse germ cell and spermatogonium maintenance.


Distribution and epitope analysis of the cell membrane glycoprotein (HPCA-1) associated with human hemopoietic progenitor cells.
Monoclonal antibodies My10, BI.3C5, 12.8, and ICH3 identify a monomeric cell surface glycoprotein (HPCA-1) of 100-120 kD, which is selectively expressed on human hemopoietic progenitor cells. Other tissues are nonreactive with the exception of capillary endothelia and basement membrane in some sites. In addition, the antigen can be detected on cell lines that exhibit characteristics associated with early T cell precursors. HPCA-1 is therefore associated with myeloid, B, and T lineage precursors. Sequential immunoprecipitation and Western blotting studies demonstrate that BI.3C5, ICH3, My10, and an antibody directed against endothelial cells, 188.27, all react with the same glycoprotein species, although the epitopes involved may be distinct. The epitope recognized by BI.3C5 is sialic acid dependent, whereas that recognized by ICH3 is not. The My10 epitope has partial sensitivity to neuraminidase. Competitive/additive binding experiments suggest that these epitopes, although probably distinct, may be closely associated.


Best research practices in psychology: Illustrating epistemological and pragmatic considerations with the case of relationship science.
In recent years, a robust movement has emerged within psychology to increase the evidentiary value of our science. This movement, which has analogs throughout the empirical sciences, is broad and diverse, but its primary emphasis has been on the reduction of statistical false positives. The present article addresses epistemological and pragmatic issues that we, as a field, must consider as we seek to maximize the scientific value of this movement. Regarding epistemology, this article contrasts the false-positives-reduction (FPR) approach with an alternative, the error balance (EB) approach, which argues that any serious consideration of optimal scientific practice must contend simultaneously with both false-positive and false-negative errors. Regarding pragmatics, the movement has devoted a great deal of attention to issues that frequently arise in laboratory experiments and one-shot survey studies, but it has devoted less attention to issues that frequently arise in intensive and/or longitudinal studies. We illustrate these epistemological and pragmatic considerations with the case of relationship science, one of the many research domains that frequently employ intensive and/or longitudinal methods. Specifically, we examine 6 research prescriptions that can help to reduce false-positive rates: preregistration, prepublication sharing of materials, postpublication sharing of data, close replication, avoiding piecemeal publication, and increasing sample size. For each, we offer concrete guidance not only regarding how researchers can improve their research practices and balance the risk of false-positive and false-negative errors, but also how the movement can capitalize upon insights from research practices within relationship science to make the movement stronger and more inclusive.


Vitamin C and hyperglycemia in the European Prospective Investigation into Cancer--Norfolk (EPIC-Norfolk) study: a population-based study.
To examine the cross-sectional association between plasma vitamin C, self-reported diabetes, and HbA1c. Data from a population-based study of diet, cancer, and chronic disease were analyzed. A total of 2,898 men and 3,560 women 45-74 years of age who were registered with general practices in Norfolk, U.K., were recruited to the European Prospective Investigation Into Cancer-Norfolk study between 1995 and 1998. Mean plasma vitamin C levels were significantly higher in individuals with HbA1c levels < 7% than in those with self-reported diabetes or prevalent undiagnosed hyperglycemia (HbA1c > or = 7%). An inverse gradient of mean plasma vitamin C was found in both sexes across quintiles of HbA1c distribution < 7%. The odds ratio (95% CI) of having prevalent undiagnosed hyperglycemia per 20 micromol/l (or 1 SD) increase in plasma vitamin C was 0.70 (0.52-0.95) (adjusted for sex, age, BMI, waist-to-hip ratio, tertiary education, any use of dietary supplements, vegetarian diet, alcohol consumption, physical activity, dietary vitamin E, dietary fiber, dietary saturated fat, and smoking history). The unadjusted change in HbA1c per 20 micromol/l increase in vitamin C estimated by linear regression was -0.12% (-0.14 to -0.09) in men and -0.09% (-0.11 to -0.07) in women. After adjusting for the possible confounders, these values were -0.08% (-0.11 to -0.04) in men and -0.05% (-0.07 to -0.03) in women. An inverse association was found between plasma vitamin C and HbA1c. Dietary measures to increase plasma vitamin C may be an important public health strategy for reducing the prevalence of diabetes.


Competitive antagonism of glutamate receptor channels by substituted benzazepines in cultured cortical neurons.
Whole-cell recordings from rat cortical neurons in dissociated cell culture were used to study the antagonism of glutamate receptors by several lipophilic benzazepine analogues of 2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine (DDHB). DDHB and three substituted derivatives, 4-bromo-, 7-methyl-, and 8-methyl-DDHB, inhibited the activation of N-methyl-D-aspartate (NMDA) receptors at both the NMDA recognition site and the glycine allosteric site. In addition, all four compounds blocked the activation of non-NMDA receptors by kainate and L-glutamate. Antagonism by the four benzazepines was equivalent at holding potentials from -80 mV to +50 mV. Both the onset of and recovery from block of the agonist-gated currents were complete within seconds. Antagonist affinity was calculated from the displacement of steady state concentration-response curves for kainate, L-glutamate, glycine, and NMDA, based on the Gaddum-Schild relationship (dose ratio = 1 + [antagonist]/KB). The most potent blocker, 8-Me-DDHB, had an apparent dissociation constant (KB) of 470 nM at the glycine allosteric site and 27 microM at the NMDA recognition site. The apparent dissociation constant of 8-Me-DDHB for non-NMDA receptors was 6.4 microM when kainate was the agonist and 9.6 microM when L-glutamate was the agonist. Unsubstituted DDHB showed slightly higher affinity for the NMDA recognition site (KB = 16 microM) but was less potent than 8-Me-DDHB at the glycine allosteric site and at non-NMDA receptors (KB = 3 and 65 microM, respectively). At all three sites, the inhibitory actions of these benzazepine derivatives were consistent with a simple competitive mechanism of antagonism. In addition, the antagonist potency of the parent compound, DDHB, against kainate, NMDA, and glycine was equal to or greater than that of other bicyclic antagonists, including kynurenic acid, indole-2-carboxylic acid, and quinoxaline-2,3-dione. Substituted benzazepines represent a new class of glutamate receptor antagonists that show competitive action, significant potency at multiple sites, and a high degree of lipophilicity.


Catheter-tract metastases associated with chronic indwelling pleural catheters.
Indwelling pleural catheters are increasingly being used for ambulatory treatment of malignant pleural effusion, particularly for patients unsuitable for pleurodesis. These catheters are often left in situ for the rest of the patient's life. Tumor metastasis along the tract between pleura and skin surface is a potential complication in patients with chronic indwelling pleural catheters that has seldom been reported. We describe four cases of catheter-tract metastasis that developed between 3 weeks and 9 months after catheter insertion. Catheter-tract metastasis occurred in two patients with mesothelioma despite prophylactic irradiation at time of insertion, and in two patients with metastatic adenocarcinoma. All cases were successfully treated using external-beam radiotherapy without necessitating catheter removal. A retrospective audit in our center showed that catheter-tract metastasis occurred in 6.7% of 45 patients treated with indwelling pleural catheters for malignant pleural effusions. Both clinicians and patients should be aware of this potential complication.


Tpl2 ablation promotes intestinal inflammation and tumorigenesis in Apcmin mice by inhibiting IL-10 secretion and regulatory T-cell generation.
To address the role of Tpl2, a MAP3K8 that regulates innate/adaptive immunity and inflammation, in intestinal tumorigenesis, we crossed a Tpl2 KO allele into the Apc(min/+) genetic background. Here, we show that Apc(min/+)/Tpl2(-/-) mice exhibit a fivefold increase in the number of intestinal adenomas. Bone marrow transplantation experiments revealed that the enhancement of polyposis was partially hematopoietic cell-driven. Consistent with this observation, Tpl2 ablation promoted intestinal inflammation. IL-10 levels and regulatory T-cell numbers were lower in the intestines of Tpl2(-/-) mice, independent of Apc and polyp status, suggesting that they were responsible for the initiation of the enhancement of tumorigenesis caused by the ablation of Tpl2. The low IL-10 levels correlated with defects in mTOR activation and Stat3 phosphorylation in Toll-like receptor-stimulated macrophages and with a defect in inducible regulatory T-cell generation and function. Both polyp numbers and inflammation increased progressively with time. The rate of increase of both, however, was more rapid in Apc(min/+)/Tpl2(-/-) mice, suggesting that the positive feedback initiated by inflammatory signals originating in developing polyps is more robust in these mice. This may be because these mice have a higher intestinal polyp burden as a result of the enhancement of tumor initiation.


Interhippocampal synthesis of lateralized place navigation engrams.
Rats were trained in a water maze in a dark room with the extramaze cues restricted to only dimly back-lit shapes. We used lidocaine to reversibly lesion the dorsal hippocampus and this controlled-cue room in order to examine interhippocampal synthesis of lateralized place engrams. Experiment 1 showed that lidocaine injected into both hippocampi effectively abolished place navigation for up to 25 min but not at 45 min. In experiment 2, each day under lidocaine blockade of one hippocampus, pretrained rats were trained in the water maze to locate the target according to two cues (e.g., AB). Two hours later, the contralateral hippocampus was inactivated and the rats were trained to the same location with two other cues (CD). On day 5, intact brain retrieval was tested in one of three conditions: ACQ (e.g., AB), one of the pairs of cues used in acquisition training; SYNTH (e.g., AC), one cue from each of the pairs used in acquisition; CONT (e.g., AE), one cue that was used in acquisition training and a novel cue. The results show that the hippocampi learned the two tasks independently and similarly [latency (L) at the asymptote = 7 s]. Retrieval performance was at the asymptote for ACQ (AB) and SYNTH (AC) (L = 6 and 7, respectively) but was disrupted for CONT (L = 12). In experiment 3 as in experiment 2, the rats were trained, under unilateral blockade, to a new place for 4 days. On day 5, retrieval with the trained hippocampus blocked was worse (L = 11) than with the untrained side blocked (L = 5).(ABSTRACT TRUNCATED AT 250 WORDS)


Health-related social disengagement in elderly diabetic patients: association with subsequent disability and survival.
We examined the relationship between health-related social disengagements, as opposed to disengagements related to financial and other non-health-related factors, and subsequent risk of disability and death among initially nondisabled elderly diabetic patients enrolled in Medicare Managed Care plans. We used data from the Medicare Health Outcomes Survey (HOS) Cohort 1 Baseline (1998) and Cohort 1 Follow-Up (2000). Through mail and telephone surveys, trained interviewers collected information on sociodemographic variables, physical and mental health functioning (using Medical Outcomes Study Short Form-36 [SF-36]), activities of daily living (ADL), and medical conditions. This study reported on diabetic subjects aged >or=65 years with no ADL disability at baseline (n = 8949). Health-related social disengagement (degree to which physical health or emotional problems interfere with social activities) was derived from the social functioning subscale of SF-36 (range 0-100; higher scores depicting better social functioning). For each 10-point increase in social functioning score at baseline, older diabetic subjects in our study experienced an 18% less chance of any ADL disability (odds ratio [OR] 0.82, 95% CI 0.75-0.89; P < 0.001) and a 12% less chance of death (0.88, 0.78-1.00; P = 0.043) over a 2-year period, adjusting for demographic factors, comorbidities, depression, and general health (assessed by the SF-36). Among initially nondisabled older diabetic subjects, health-related interferences with social activities at baseline may be early warning signs of subsequent ADL disability and premature death, independent of other measures of health status.


Associations of sodium, potassium and protein intake with blood pressure and hypertension in Switzerland.
Nutritional factors play an important role in the regulation of blood pressure and in the development of hypertension. In this analysis, we explored the associations of 24-hour urinary Na+, K+ and urea excretion with blood pressure levels and the risk of hypertension in the Swiss population, taking regional linguistic differences into account. The Swiss Survey on Salt is a population based cross-sectional study that included 1336 subjects from the three main linguistic regions (French, German and Italian) of Switzerland. Blood pressure was measured with a validated oscillometric Omron HEM 907 device. Hypertension was defined as current antihypertensive treatment or a mean systolic blood pressure >140 mm Hg and/or diastolic >90 mm Hg, based on eight blood pressure measurements performed at two visits. Na+, K+ and urea excretion were assessed in 24-hour urine collections. We use multiple logistic/linear regressions to explore the associations of urine Na+, K+ and urea with blood pressure / hypertension, taking into account potential confounders and effect modifiers. The prevalence of hypertension was 30%, 26% and 17% in the German-, French- and Italian- speaking regions respectively, (p-value across regions <0.001). In the Swiss adult population, besides age, sex, and body mass index, urinary Na+ excretion was positively associated with systolic blood pressure and hypertension. Urinary K+ excretion tended to be negatively associated with blood pressure but this was not significant (p = 0.08). Hypertensive people had a higher 24-hour urinary Na+/K+ ratio than normotensive people (p = 0.003). Urinary urea excretion was associated with neither blood pressure nor hypertension. Participants from the German-speaking region had a higher likelihood of having a high systolic blood pressure. We confirm a high prevalence of elevated blood pressure in Swiss adults, including regional differences. In Switzerland, urinary Na+ excretion is associated positively with blood pressure and hypertension, independently of urinary K+ and urea excretion. The observed differences in blood pressure levels across linguistic regions are independent of the urinary Na+, K+ and urea excretion.


Segmental glomerulonephritis.
The renal biopsy findings in 40 patients with segmental glomerulonephritis are reported. The term is used to describe a condition in which one or more segments of the glomerular tuft is involved by disease when other segments appear unaffected on light microscopy. The word 'focal' is not used as it may be taken to imply that the changes affect some glomeruli but not others and the evidence for this is not convincing. Segmental glomerulonephritis was a relatively common finding in cases of proteinuria with or without the nephrotic syndrome. The severity of the glomerular changes did not correlate with the ultimate prognosis. On the other hand the tubular and interstitial changes, as assessed by a grading procedure and by point counting, were significantly less severe in those patients who showed clinical recovery than in those who did not.


Membrane selectivity versus sensor response in hydrogenated amorphous silicon CHEMFETs using a semi-empirical model.
Toxic amides, such as acrylamide, are potentially harmful to Human health, so there is great interest in the fabrication of compact and economical devices to measure their concentration in food products and effluents. The CHEmically Modified Field Effect Transistor (CHEMFET) based on amorphous silicon technology is a candidate for this type of application due to its low fabrication cost. In this article we have used a semi-empirical model of the device to predict its performance in a solution of interfering ions. The actual semiconductor unit of the sensor was fabricated by the PECVD technique in the top gate configuration. The CHEMFET simulation was performed based on the experimental current-voltage curves of the semiconductor unit and on an empirical model of the polymeric membrane. Results presented here are useful for selection and design of CHEMFET membranes and provide an idea of the limitations of the amorphous CHEMFET device. In addition to the economical advantage, the small size of this prototype means it is appropriate for in situ operation and integration in a sensor array.


Effect of altitude on urinary leukotriene (LT) E4 excretion and airway responsiveness to histamine in children with atopic asthma.
Asthmatic subjects who are resident at altitude may experience a deterioration in lung function following a stay at sea level. To determine whether measurement of urinary leukotriene E4 (LTE4) reflects changes in asthma severity and airway responsiveness, 14 allergic asthmatic subjects resident at altitude (1560 m, Davos, Switzerland) were studied. Subjects were randomly divided into two groups. Measurements of baseline forced expiratory volume in one second (FEV1), the concentration of histamine producing a 20% decrease in FEV1, (PC20 FEV1), serum total immunoglobulin E (IgE), eosinophil count, and urinary LTE4 concentration were determined prior to and following a 2 week stay in The Netherlands (sea level) in eight subjects (4 males and 4 females, aged 14 +/- 0.5 yrs) (mean +/- SEM) and over a similar time period in six subjects (4 males and 2 females, aged 15 +/- 0.3 yrs) resident in Davos, Switzerland. There was no significant difference in total IgE and eosinophil count, and no significant correlation between urinary LTE4 and PC20FEV1 histamine, FEV1, total IgE, and eosinophil count. In subjects returning to Davos from The Netherlands there was a significant increase in urinary LTE4 from a baseline value of 16.9 pg.mg-1 creatinine (GM, range 0.3-101.7 pg.mg-1 creatinine) to 52.3 pg.mg-1 creatinine (GM, range 8.8-301.6 pg.mg-1 creatinine), a significant decrease in PC20FEV1 from 1.7 mg.ml-1 (GM, range 0.3-16.4 mg.ml-1) to 0.9 mg.ml-1 (GM, range 0.1-->32 mg.ml-1), and a significant fall in FEV1 from 3.0 +/- 0.3 to 2.8 +/- 0.3 l (mean +/- SEM).(ABSTRACT TRUNCATED AT 250 WORDS)