Protein phosphatase inhibitors induce the selective breakdown of stable microtubules in fibroblasts and epithelial cells.
In many cell types, a small subset of microtubules (MTs) are unusually long-lived compared with the majority of the MTs. These "stable" MTs may be important mediators of differentiative events since they are usually found aligned with developing asymmetries of cells undergoing morphogenesis. In addition to their longevity, the stable MTs are more resistant to drug depolymerization and are enriched in post-translationally detyrosinated tubulin (Glu-tubulin). To determine the role of protein phosphorylation in the regulation of these stable MTs, we treated NIH 3T3 fibroblasts and TC-7 monkey kidney epithelial cells with okadaic acid (OA) and calyculin A, potent inhibitors of protein phosphatases 1 and 2A (PP1 and PP2A), and then localized dynamic MTs and stable MTs with antibodies specific for tyrosinated tubulin (Tyrtubulin) and Glu-tubulin, respectively. OA at 0.1-10 microM caused a rapid and complete breakdown of Glu-MTs (MTs enriched in Glu-tubulin) in both cell types without substantially affecting the number of Tyr-MTs. While all concentrations of OA over this range resulted in a complete loss of Glu-MTs, the onset of Glu-MT breakdown was proportional to the logarithm of the OA concentration. The inactive analog of OA, 1-norokadaone, had no effect at any concentration. Calyculin A also caused a selective loss of Glu-MTs but was effective at 10 nM, consistent with its more potent inhibition of PP1. That the loss of Glu-MTs reflected the loss of stable MTs from the cells was shown by the absence of nocodazole-resistant MTs in OA-treated cells. OA did not appear to activate a MT-severing activity, since no MT fragments were observed after OA treatment of cells pretreated with taxol. These results suggest that PP1 and perhaps PP2A are involved in the regulation of MT stability in cells and show that the dynamic and stable subsets of MTs are regulated differentially by protein phosphorylation.


Functional Genomics Uncovers Pleiotropic Role of Rhomboids in Corynebacterium glutamicum.
The physiological role of ubiquitous rhomboid proteases, membrane-integral proteins that cleave their substrates inside the lipid bilayer, is still ill-defined in many prokaryotes. The two rhomboid genes cg0049 and cg2767 of Corynebacterium glutamicum were mutated and it was the aim of this study to investigate consequences in respect to growth phenotype, stress resistance, transcriptome, proteome, and lipidome composition. Albeit increased amount of Cg2767 upon heat stress, its absence did not change the growth behavior of C. glutamicum during exponential and stationary phase. Quantitative shotgun mass spectrometry was used to compare the rhomboid mutant with wild type strain and revealed that proteins covering diverse cellular functions were differentially abundant with more proteins affected in the stationary than in the exponential growth phase. An observation common to both growth phases was a decrease in ribosomal subunits and RNA polymerase, differences in iron uptake proteins, and abundance changes in lipid and mycolic acid biosynthesis enzymes that suggested a functional link of rhomboids to cell envelope lipid biosynthesis. The latter was substantiated by shotgun lipidomics in the stationary growth phase, where in a strain-dependent manner phosphatidylglycerol, phosphatidic acid, diacylglycerol and phosphatidylinositol increased irrespective of cultivation temperature.


MRI in CLN2 disease patients: Subtle features that support an early diagnosis.
Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a rare, paediatric-onset, neurodegenerative disorder characterised in its early stages by language delay, seizures and loss of motor function. It is rapidly progressive and ultimately results in the premature death of patients. We aim to highlight common magnetic resonance imaging (MRI) features seen in early CLN2 disease and increase disease awareness among clinicians in order to facilitate early diagnosis and treatment of patients with disease-modifying enzyme replacement therapy. We obtained MRI scans from 12 Turkish children with CLN2 disease, at symptom onset or time of diagnosis, and at various times during disease progression. Patient details including age at onset of symptoms, age at diagnosis and clinical presentation were collected. MRIs were analysed to identify common features present in patients with CLN2 disease. The median diagnostic delay in this cohort was 2 years, highlighting the need for increased disease awareness among clinicians. Key MRI features suggestive of CLN2 disease that were identified included cerebellar atrophy in 11 patients, linear hyperintensity of central white matter in 10 patients, cerebral atrophy in 8 patients and thinning of the corpus callosum in 6 patients. Thalamic hypointensity was seen in 1 patient and may also indicate CLN2 disease. It is important to consider the presenting symptoms alongside clinical test results in order to support early diagnosis of CLN2 disease. Clinical suspicion of CLN2 disease accompanied by the detection of any of the above-mentioned features on MRI should encourage healthcare professionals to test for CLN2 disease.


Current trends in hormone replacement therapy.
As life span increases, more and more women live longer after the menopause, and see its long-term consequences. The menopause and climacteric have major consequences for the well being of most women, resulting in a variety of symptoms including vasomotor, psychological, sexual symptoms and increased risk of osteoporosis and atherosclerosis. Prevention of osteoporosis and reduction in cardiovascular risks are the long-term goals of post-menopausal hormone replacement therapy. Post-menopausal women who receive hormone replacement therapy have approximately half of the rate of coronary artery disease compared to those who do not take it. Similarly, estrogen replacement alone for 5 years results in 50% reduction in the risk of overall fracture and is a major factor in the prevention and management of osteoporosis. A wide range of estrogen preparations is available for administration by various routes. The choice depends on indications, side effects and convenience. Oral estrogen is the most commonly used preparation followed by transdermal preparation. Controversy still exists over the efficacy and safety of hormone replacement therapy among both the medical and lay authorities. There is overwhelming evidence that hormone replacement therapy improves the quality of life and reduces the morbidity and mortality by reversing the metabolic and pathological changes induced by the menopause. The benefits of hormone replacement therapy out weigh any increased risk of venous thromboembolism or breast, ovarian and endometrial cancers.


Maximizing Magnetic Resonance Contrast in Gd(III) Nanoconjugates: Investigation of Proton Relaxation in Zirconium Metal-Organic Frameworks.
Gadolinium(III) nanoconjugate contrast agents (CAs) provide significant advantages over small-molecule complexes for magnetic resonance imaging (MRI), namely increased Gd(III) payload and enhanced proton relaxation efficiency (relaxivity, r1). Previous research has demonstrated that both the structure and surface chemistry of the nanomaterial substantially influence contrast. We hypothesized that inserting Gd(III) complexes in the pores of a metal-organic framework (MOF) might offer a unique strategy to further explore the parameters of nanomaterial structure and composition, which influence relaxivity. Herein, we postsynthetically incorporate Gd(III) complexes into Zr-MOFs using solvent-assisted ligand incorporation (SALI). Through the study of Zr-based MOFs, NU-1000 (nano and micronsize particles) and NU-901, we investigated the impact of particle size and pore shape on proton relaxivity. The SALI-functionalized Gd nano NU-1000 hybrid material displayed the highest loading of the Gd(III) complex (1.9 ± 0.1 complexes per node) and exhibited the most enhanced proton relaxivity (r1 of 26 ± 1 mM-1 s-1 at 1.4 T). Based on nuclear magnetic relaxation dispersion (NMRD) analysis, we can attribute the performance of Gd nano NU-1000 to the nanoscale size of the MOF particles and larger pore size that allows for rapid water exchange. We have demonstrated that SALI is a promising method for incorporating Gd(III) complexes into MOF materials and identified crucial design parameters for the preparation of next generation Gd(III)-functionalized MOF MRI contrast agents.


Divergent outcomes of gold(I)-catalyzed indole additions to 3,3-disubstituted cyclopropenes.
Depending on the conditions employed, gold(I)-catalyzed addition of indoles to 3,3-disubstituted cyclopropenes can be controlled to yield either 3-(E)-vinylindoles (3) or bis-indolylalkanes (4). If the cyclopropene substituents are sterically bulky, unprecedented gold-catalyzed oxidation under air occurs to yield bis-indolylalkene (5) and epoxide (6) at room temperature.


[Biodegradable polymer microparticles with entraped herbal extracts: preparation with supercritical carbon dioxide and use for tissue repair].
Biodegradable microparticles based on poly-D,L-lactide with entrapped mixture of herbal water-soluble extracts of Plantago major and Calendula officinalis were prepared. For preparation of these microparticles the previously developed method based on the usage of supercritical carbon dioxide (SC-CO2) was proposed. Microparticles were obtained by two techniques: 1) by preparing porous polymer monolith containing entrapped mixture of herbal extracts, which was then reduced to fine microparticles (ca. 0.1 mm) by dry ice grinding (called here as "monolithisation technique") and 2) by spraying of this polymer/extracts mixture through a jet (spray technique). In vitro release kinetic profile of herbal extract mixture was found to depend on the microparticle preparation technique, on the microparticle structure as well as on the initial ratio polymer/extracts (w/w). The microparticles were used for gastric ulcer treatment in a rat model. The extracts released from microparticles were found to accelerate tissue repair.


Repeated allergen challenge as a new research model for studying allergic reactions.
Repeated allergen challenge might be a more relevant model for studying symptomatic disease, because it gives more information on the patient's handling of chronic allergen exposure. Thus, this experimental model has more resemblance to the situation of natural allergen exposure, and the allergen load can be standardized. However, the response to repeated allergen challenge in individual patients can show a large variation, that is from a strongly enhanced response to complete diminution of the response. Successful allergen immunotherapy can change the response pattern of repeated allergen challenge in the skin into down-regulation of the late reaction. Chronic or repeated allergen exposure may result in an enhanced allergen-specific allergic response, involving allergen-specific T-cell activation. Different subsets of T cells can exert either activating or suppressive effects on inflammatory cells involved in subsequent allergic reactions. CD8+ T cells might exert suppressive effects, because they seem to be associated with a subsequent down-regulation of the late skin reaction after repeated allergen challenge (Fig. 4). Further studies are needed to compare the responses to repeated allergen challenge with the response to natural seasonal allergen exposure in the same patients and to explore possible underlying mechanisms using, for example, nasal biopsies.


Porcine lymphotropic herpesvirus (Gammaherpesvirinae) DNA in free-living wild boars (Sus scrofa Linnaeus, 1758) in Brazil.
Suid gammaherpesvirus 3, 4, and 5 (porcine lymphotropic herpesvirus - PLHV-1, -2, and -3) are viruses that infect domestic and feral pigs. This study examined the presence of PLHV DNA in biological samples from free-living wild boars circulating in a Brazilian geographical region with a high density of commercial domestic pigs. Lung samples of 50 free-living wild boars were collected by exotic wildlife controller agents between 2017 and 2019 in the state of Paraná, southern Brazil. Lung and spleen fragments were obtained from six fetuses collected by hysterectomy post mortem from a pregnant sow. A polymerase chain reaction (PCR) assay using consensus primers (pan-herpesviruses) was performed to detect PLHV DNA. The samples showing positive results for PLHV DNA were submitted to single-round PCR assays with the specific primers for identifying PLHV-1 (213-S/215-As), PLHV-2 (208-S/212-As), and PLHV-3 (886s/886As). The specificity of the species-specific PCR products was assessed by nucleotide sequencing of the amplicons. Forty-eight (96%) of the 50 lung samples analyzed were positive for PLHV by PCR using pan-herpesvirus primers. In 33 (68.75%) of the positive samples, at least two PLHV species were identified simultaneously. The DNA of PLHV-1, -2, and -3 was found in free-living wild boars of all ages, but not in the fetuses, even though they were from a sow that tested positive for all three viruses. These viruses are endemic to the population of feral pigs in the Brazilian region evaluated, as well as in domesticated pigs.


Synthesis and biological activity of some amide derivatives of the lantibiotic actagardine.
A series of basic carboxamides of actagardine (1), a lantibiotic possessing good antistreptococcal activity, were synthetized. Some physico-chemical characteristics, in particular charge and lipophilicity, that influence water solubility were determined. The in vitro and in vivo activity was evaluated. The monocarboxamides were generally more active than actagardine against selected Gram-positive bacteria. The 3,3-dimethylamino-1-propylamide hydrochloride (4) showed good water solubility, bactericidal action and favourable antibacterial activity and it appears to be a suitable drug for further investigation.


Allogenic bone marrow transplantation or chemotherapy for patients with acute myeloid leukemia in first complete remission: a decision analysis approach.
The methodology of decision analysis was originally developed to improve clinical decisions of physicians for individual patients. However, it is also well suited to support consensus procedures. We have used this methodology to analyse the question whether allogeneic bone marrow transplantation (BMT) or consolidation chemotherapy (CCT) should be used as first line postremission treatment in patients with acute myeloid leukemia. Main risk factors relevant for the outcome after BMT and CCT are therapy-related mortality and leukemic relapse, respectively. If the possibility of salvage BMT for patients relapsing after CCT is included, the outcomes of the two strategies come rather close. However, they are clearly different in subtypes of leukemia with high or low risk of relapse, and in patients at high risk for BMT-related mortality. Sensitivity analysis considering the variation of more than one risk factor provides valuable information for decision making for both individual patients and particular subgroups of patients with acute myeloid leukemia.


Alloexposed blood donors and transfusion-related acute lung injury: a case-referent study.
Donor white blood cell (WBC) antibodies are thought to increase the risk of transfusion-related acute lung injury (TRALI). WBC antibodies can be present in blood products from donors who have been alloexposed. Alloexposed donors are increasingly excluded from donating plasma, but can still donate plasma-poor products. We aimed to quantify the contribution of alloexposed donors to the occurrence of TRALI for different blood product types. We performed a case-referent study including all reported TRALI patients and all Dutch blood donors. Data on alloexposure status of donors of all TRALI cases reported between January 2004 and October 2008, in the Netherlands, were compared to information on the total donor population. Alloexposure status of all 223 involved donors was compared to the expected status. The overall percentage of TRALI cases that could have been prevented by the deferral of all alloexposed donors (i.e., population-attributable risk [PAR]) was 51% (95% confidence interval [CI], 14%-88%). In 19 recipients of exclusively plasma-poor products (mostly red blood cells [RBCs]), alloexposure of the donors was not associated with TRALI, while in 28 recipients of both plasma-poor and plasma-rich products (>200 mL plasma), the PAR was 94% (95% CI, 34%-100%). Alloexposed donors conferred an increased risk of TRALI in recipients of plasma-rich products, but not in recipients of plasma-poor products. Although WBC antibodies are an important risk factor for TRALI, among RBC recipients another risk factor must be more important.


[Study of estradiol on treatment of preeclampsia in rat model].
To evaluate whether estradiol can inhibit and cure the inflammation of experimental preeclampsia in rats. Experimental preeclampsia was induced in 14-day-pregnant rats by infusion of endotoxin (1.0 microg/kg). Rats with normal pregnancy were infused with sodium chloride solution. A group of preeclampsia rats was injected with 17beta-estradiol (17beta-E(2), 1 mg.kg(-1).d(-1)). Blood pressure, albuminuria, inflammation associated adhesion molecule CD(49d) and tumor necrosis factor-alpha (TNF-alpha) were assessed. On pregnant day 19, for normal pregnancy group (group C) the blood pressure was (120.4 +/- 2.0) mm Hg (1 mm Hg = 0.133 kPa), urinary protein (0.47 +/- 0.06) mg/24 hours; for experimental preeclampsia group (group A) blood pressure was (134.2 +/- 2.4) mm Hg, urinary protein (0.79 +/- 0.10) mg/24 hours; for experimental preeclampsia with 17beta-E(2) treatment group (group B) blood pressure was (123.3 +/- 1.7) mm Hg, urinary protein (0.51 +/- 0.08) mg/24 hours. A significant increase of blood pressure and urinary albumin was observed in group A. CD(49d) expression and TNF-alpha concentration were also increased. 17beta-E(2) reduced the expression of CD(49d), concentration of TNF-alpha, blood pressure and albuminuria of experimental preeclampsia. However, the weight of fetuses in 17beta-E(2) treatment group were less than that in other groups. 17beta-E(2) can improve the symptoms of experimental preeclampsia, but its effects on fetus need to be further studied.


Effects of imiglucerase treatment on traumatic fracture and bone and blood abnormalities in a patient with previously untreated type 1 gaucher disease.
This letter reports on the effect of enzyme replacement therapy with imiglucerase on bone healing and bone and blood abnormalities in a woman with previously untreated type 1 Gaucher disease (GD). The 49-year-old patient had been diagnosed with GD at the age of 28 years and had previously undergone splenectomy. She presented with pseudarthrosis 14 months after sustaining a traumatic fracture of the tibia and fibula. Therapy was begun with imiglucerase 60 U/kg q2wk. The effects of treatment on bone healing were monitored radiographically, and effects on blood and bone marrow biology were monitored by hemograms, myelograms, and hematopoietic and mesenchymal clonogenic assays. Objective bone healing was observed starting in the third month of imiglucerase treatment. Blood abnormalities normalized and bone marrow parameters improved over the first 9 months, including a decrease in Gaucher cells, an increase in bone marrow CD34+ cell cloning efficiency, and the appearance of mesenchymal progenitors. This research letter reports the results of hematologic and bone evaluations during enzyme replacement therapy with imiglucerase in a woman with previously untreated type 1 GD who presented with a traumatic fracture.


The role of the oximes HI-6 and HS-6 inside human acetylcholinesterase inhibited with nerve agents: a computational study.
The oximes 4-carbamoyl-1-[({2-[(E)-(hydroxyimino) methyl] pyridinium-1-yl} methoxy) methyl] pyridinium (known as HI-6) and 3-carbamoyl-1-[({2-[(E)-(hydroxyimino) methyl] pyridinium-1-yl} methoxy) methyl] pyridinium (known as HS-6) are isomers differing from each other only by the position of the carbamoyl group on the pyridine ring. However, this slight difference was verified to be responsible for big differences in the percentual of reactivation of acetylcholinesterase (AChE) inhibited by the nerve agents tabun, sarin, cyclosarin, and VX. In order to try to find out the reason for this, a computational study involving molecular docking, molecular dynamics, and binding energies calculations, was performed on the binding modes of HI-6 and HS-6 on human AChE (HssAChE) inhibited by those nerve agents.


Quantum chemical study of agonist-receptor vibrational interactions for activation of the glutamate receptor.
To understand the mechanism of activation of a receptor by its agonist, the excitation and relaxation processes of the vibrational states of the receptor should be examined. As a first approach to this problem, we calculated the normal vibrational modes of agonists (glutamate and kainate) and an antagonist (6-cyano-7-nitroquinoxaline-2,3-dione: CNQX) of the glutamate receptor, and then investigated the vibrational interactions between kainate and the binding site of glutamate receptor subunit GluR2 by use of a semiempirical molecular orbital method (MOPAC2000-PM3). We found that two local vibrational modes of kainate, which were also observed in glutamate but not in CNQX, interacted through hydrogen bonds with the vibrational modes of GluR2: (i) the bending vibration of the amine group of kainate, interacting with the stretching vibration of the carboxyl group of Glu705 of GluR2, and (ii) the symmetric stretching vibration of the carboxyl group of kainate, interacting with the bending vibration of the guanidinium group of Arg485. We also found collective modes with low frequency at the binding site of GluR2 in the kainate-bound state. The vibrational energy supplied by an agonist may flow from the high-frequency local modes to the low-frequency collective modes in a receptor, resulting in receptor activation.


Neurobehavioral dysfunction in non-alcoholic steatohepatitis is associated with hyperammonemia, gut dysbiosis, and metabolic and functional brain regional deficits.
Non-alcoholic steatohepatitis (NASH) is one of the most prevalent diseases worldwide. While it has been suggested to cause nervous impairment, its neurophysiological basis remains unknown. Therefore, the aim of this study is to unravel the effects of NASH, through the interrelationship of liver, gut microbiota, and nervous system, on the brain and human behavior. To this end, 40 Sprague-Dawley rats were divided into a control group that received normal chow and a NASH group that received a high-fat, high-cholesterol diet. Our results show that 14 weeks of the high-fat, high-cholesterol diet induced clinical conditions such as NASH, including steatosis and increased levels of ammonia. Rats in the NASH group also demonstrated evidence of gut dysbiosis and decreased levels of short-chain fatty acids in the gut. This may explain the deficits in cognitive ability observed in the NASH group, including their depressive-like behavior and short-term memory impairment characterized in part by deficits in social recognition and prefrontal cortex-dependent spatial working memory. We also reported the impact of this NASH-like condition on metabolic and functional processes. Brain tissue demonstrated lower levels of metabolic brain activity in the prefrontal cortex, thalamus, hippocampus, amygdala, and mammillary bodies, accompanied by a decrease in dopamine levels in the prefrontal cortex and cerebellum and a decrease in noradrenalin in the striatum. In this article, we emphasize the important role of ammonia and gut-derived bacterial toxins in liver-gut-brain neurodegeneration and discuss the metabolic and functional brain regional deficits and behavioral impairments in NASH.


Insights into the capping and structure of MoS(2) nanotubes as revealed by aberration-corrected STEM.
Aberration-corrected electron microscopy (STEM-HAADF) has been used for the first time to understand the capping, nature and structure of the MoS(2) nanotubes. The MoS(2) nanotubes that have been obtained have various unusual faceted caps presumably arising from the presence of topological defects. A detailed study of the capping of the nanotubes, along with identification that the MoS(2) nanotubes are of the zigzag type have been carried out using both experimental and simulated STEM images. The presence of 3R-rhombohedral stacking of the MoS(2) nanotubes has been identified.


Characterization of the Complete Mitochondrial Genome of Harpalus sinicus and Its Implications for Phylogenetic Analyses.
In this study, we report the complete mitochondrial genome of Harpalus sinicus (occasionally named as the Chinese ground beetle) which is the first mitochondrial genome for Harpalus. The mitogenome is 16,521 bp in length, comprising 37 genes, and a control region. The A + T content of the mitogenome is as high as 80.6%. A mitochondrial origins of light-strand replication (OL)-like region is found firstly in the insect mitogenome, which can form a stem-loop hairpin structure. Thirteen protein-coding genes (PCGs) share high homology, and all of them are under purifying selection. All tRNA genes (tRNAs) can be folded into the classic cloverleaf secondary structures except tRNA-Ser (GCU), which lacks a dihydrouridine (DHU) stem. The secondary structure of two ribosomal RNA genes (rRNAs) is predicted based on previous insect models. Twelve types of tandem repeats and two stem-loop structures are detected in the control region, and two stem-loop structures may be involved in the initiation of replication and transcription. Additionally, phylogenetic analyses based on mitogenomes suggest that Harpalus is an independent lineage in Carabidae, and is closely related to four genera (Abax, Amara, Stomis, and Pterostichus). In general, this study provides meaningful genetic information for Harpalus sinicus and new insights into the phylogenetic relationships within the Carabidae.


A chemical investigation of the Antarctic sponge Lyssodendoryx flabellata.
From the Antarctic sponge Lyssodendoryx flabellata, a new polycyclic compound, which we named flabellone, related to the oestrogenic hormone oestrone, has been elucidated by spectrometric and spectroscopic means. Along with flabellone, a glycosphingolipid (GSL) mixture featuring an unusual α-fucofuranosyl-3-β-glucopyranoside unit structurally identical to the previously reported terpioside has been isolated and identified. The mixture of GSL homologues exhibited inhibitory effects in mixed lymphocyte reactions on human cells.


Psychologic interventions for the anxious dental patient.
This article asserts that pharmacologic usage can be reduced by understanding that pain is composed of somatic, affective, and cognitive elements; the dentist should be assertive in addressing and dealing with the emotional and psychological aspects of the anxious and fearful patient. The dentist can measure levels of anxiety and fear through self-report and records of dental care; an easily administered test of dental anxiety, such as the Dental Anxiety Scale; and a structured interview in a nonoperatory setting. For those patients exhibiting a moderate amount of anxiety, attention to basic aspects of good clinic care should be sufficient. For those patients manifesting a high level of anxiety, a treatment program implemented by a dental clinical assistant is outlined and recommended. The treatment program is intended to increase patient relaxation, positive cognitive coping statements, sensory information, sense of control, and confidence in handling the dental procedures. At any level of anxiety, it is recommended that patients be abundantly praised for any element of success in dealing with the stress of their dental experience. Lastly, for those patients who do not respond to treatment efforts to reduce anxiety, it is recommended that the dentist establish a regular consultation with a psychologist who is an expert in treating dental fear and anxiety.


The acetyltransferase p300 is recruited in trans to multiple enhancer sites by lncSmad7.
The histone acetyltransferase p300 (also known as KAT3B) is a general transcriptional coactivator that introduces the H3K27ac mark on enhancers triggering their activation and gene transcription. Genome-wide screenings demonstrated that a large fraction of long non-coding RNAs (lncRNAs) plays a role in cellular processes and organ development although the underlying molecular mechanisms remain largely unclear (1,2). We found 122 lncRNAs that interacts directly with p300. In depth analysis of one of these, lncSmad7, is required to maintain ESC self-renewal and it interacts to the C-terminal domain of p300. lncSmad7 also contains predicted RNA-DNA Hoogsteen forming base pairing. Combined Chromatin Isolation by RNA precipitation followed by sequencing (ChIRP-seq) together with CRISPR/Cas9 mutagenesis of the target sites demonstrate that lncSmad7 binds and recruits p300 to enhancers in trans, to trigger enhancer acetylation and transcriptional activation of its target genes. Thus, these results unveil a new mechanism by which p300 is recruited to the genome.


Regulation of synovial cell proliferation and prostaglandin E2 production by combined action of cytokines.
To study the causes of synovitis in rheumatoid arthritis (RA), we have analyzed the effect of several cytokines known to be secreted in RA joints, on synovial cell proliferation and prostaglandin E2 (PGE2) production. Recombinant interleukin-1-beta (IL-1-beta) and tumor necrosis factor-alpha (TNF-alpha) stimulated moderately the DNA synthesis and markedly the production of PGE2. Interferon-gamma (IFN-gamma) was often mitogenic but never induced PGE2 secretion. The association of IL-1-beta and TNF-alpha showed an additive effect on both parameters, whereas addition of IFN-gamma to either monokine reduced the proliferation and increased PGE2 release. Incubation with a crude T cell supernatant or a mixture of cytokines including IL-1-beta, TNF-alpha and IFN-gamma enhanced synovial cell growth and PGE2 production as compared to the effect elicited by each single cytokine. In contrast, interleukin-2 (IL-2) down regulated the synovial cell activation induced by the combined action of the three other cytokines. Taken together, our findings indicate that synovial cell proliferation is weakly stimulated, reaching a two-fold increase over background levels, whatever cytokines are used. Furthermore, proliferation can vary independently of PGE2 production. Nevertheless, the monokines IL-1-beta and TNF-alpha both exert agonistic effects on synovial cell activation, thus contributing to cartilage damage in RA, whereas IFN-gamma, IL-6 or IL-2 may rather play a regulatory role.


Differences in femoral compact bone tissue microscopic structure between adult cows (Bos taurus) and pigs (Sus scrofa domestica).
The purpose of this investigation was to study in detail compact bone tissue microscopic structure of adult cows and pigs with an emphasis to find an adequate key for the species identification. Altogether 18 femurs were analysed. Each of the bones was sectioned at the smallest breadth of their diaphysis. Specimens were prepared using standard histological equipment, producing thin sections approximately 80-100 mum thick. The qualitative differences between investigated species were examined in anterior, posterior, medial and lateral views of thin sections. The quantitative ones were counted using the specific computer software Scion Image. We measured the area, perimeter, minimal and maximal diameter of the Haversian canals, the Haversian systems and the vascular canals of primary osteons. After that a discriminant function analysis was used for the species identification. According to our results the basic structural pattern of femur diaphysis was primary vascular plexiform in both species. However, non-vascular bone tissue was identified in cows and resorption lacunae were found between the secondary osteons in pigs. The measured variables of the Haversian canals, the Haversian systems and the primary osteon's vascular canals were higher in most cases in cows. Classification functions for investigated species give a correct classification of 64.69% of cases. This percentage value can be increased by integrating conclusions from the qualitative analysis.


Single- and multiple-clade influenza A H5N1 vaccines induce cross protection in ferrets.
The rapid evolution, genetic diversity, broad host range, and increasing human infection with avian influenza A (H5N1) viruses highlight the need for an efficacious cross-clade vaccine. Using the ferret model, we compared induction of cross-reactive immunity and protective efficacy of three single-clade H5N1 vaccines and a novel multiple-clade H5N1 vaccine, with and without MF59 adjuvant. Reverse genetics (rg) was used to generate vaccine viruses containing the hemagglutinin (HA) and neuraminidase genes of wild-type H5N1 viruses. Ferrets received two doses of inactivated whole-virus vaccine separated by 3 weeks. Single-clade vaccines (7.5 microg HA per dose) included rg-A/Vietnam/1203/04 (clade 1), rg-A/Hong Kong/213/03 (clade 1), and rg-A/Japanese White Eye/Hong Kong/1038/06 (clade 2.3). The multiple-clade vaccine contained 3.75 microg HA per dose of each single-clade vaccine and of rg-A/Whooper Swan/Mongolia/244/05 (clade 2.2). Two doses of vaccine were required to substantially increase anti-HA and virus neutralizing antibody titers to H5N1 viruses. MF59 adjuvant enhanced induction of clade-specific and cross-clade serum antibody responses, reduced frequency of infection (as determined by upper respiratory tract virus shedding and seroconversion data), and eliminated disease signs. The rg-A/Hong Kong/213/03 vaccine induced the highest antibody titers to homologous and heterologous H5N1 viruses, while rg-A/Japanese White Eye/Hong Kong/1038/06 vaccine induced the lowest. The multiple-clade vaccine was broadly immunogenic against clade 1 and 2 viruses. The rg-A/Vietnam/1203/04 vaccine (the currently stockpiled H5N1 vaccine) most effectively reduced upper respiratory tract virus shedding after challenge with clade 1 and 2 viruses. Importantly, all vaccines protected against lethal challenge with A/Vietnam/1203/04 virus and provided cross-clade protection.


Experiences of healthcare providers during the coronavirus pandemic and its impact on them: protocol for a mixed-methods systematic review.
Frontline healthcare providers are redeployed to areas outside their clinical expertise and assigned high-loading workload to address the surge of patients with each coronavirus outbreak. Their importance in crisis is not in doubt. However, they experienced considerable physical distress and psychological stressors, even leading to psychological illness and infection in this environment. There is an urgent need to accurately, comprehensively and objectively understand their experiences, perceptions and current situation of burnout, post-traumatic stress disorder (PTSD), anxiety, depression, insomnia and coronavirus infection. Therefore, this protocol is to conduct a mixed-methods systematic review to summarise the evidence on the experiences of healthcare providers and impacts of the coronavirus on their psychological status and infection during the pandemics. Published studies on experience, perspective, impact, burnout, PTSD, anxiety, depression, insomnia, and infection of healthcare providers with SARS, Middle East respiratory syndrome and COVID-19, and written in English and Chinese will be accepted. Databases (MEDLINE, EMBASE, CENTRAL, Web of Science, PubMed, Psychology Information, WanFang and SinoMed) from inception until 30 July 2020 will be searched. Two reviewers will select, screen, extract data and assess the risk of bias independently. Risk of bias of results will be using the Mixed-Methods Appraisal Tool. Using a convergent integrated approach on qualitative/quantitative studies, we will synthesise qualitative and quantitative data separately. The incidence and number of cases about burnout, PTSD, anxiety, depression, insomnia and coronavirus infection among medical staff will be extracted. Then we will transform quantitative data to synthesise narrative findings. This protocol will be reported per the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines. Ethical assessment is not required due to the nature of the proposed systematic review. Findings of our research will be disseminated at conferences related to this field and through publication in peer-reviewed journals. CRD42020198506.


Allergic complication in operated gastroduodenal ulcers: pathogeny and morphoclinical significance.
1660 gastric and duodenal ulcers were examined, of which 61 per cent showed allergic complications. The eosinophilic infiltrate associated with endarteritis and fibrinoid necrosis in the area, more accentuated than in ulcers without eosinophils is produced through a mechanism of atopic hypersensitization to food antigens. A more frequent appearance of allergic complications in the gastrointestinal tract explains why some ulcers do not heal and why certain groups of food tolerated by some patients, are rejected by others. It also imposes in some cases a desensitization treatment concomitantly with the antiulcerous one.


Association between Neighborhood Social Deprivation and Stage at Diagnosis among Breast Cancer Patients in South Carolina.
The purpose of this study was to examine the association between neighborhood social deprivation and individual-level characteristics on breast cancer staging in African American and white breast cancer patients. We established a retrospective cohort of patients with breast cancer diagnosed from 1996 to 2015 using the South Carolina Central Cancer Registry. We abstracted sociodemographic and clinical variables from the registry and linked these data to a county-level composite that captured neighborhood social conditions-the social deprivation index (SDI). Data were analyzed using chi-square tests, Student's t-test, and multivariable ordinal regression analysis to evaluate associations. The study sample included 52,803 female patients with breast cancer. Results from the multivariable ordinal regression model demonstrate that higher SDI (OR = 1.06, 95% CI: 1.02-1.10), African American race (OR = 1.35, 95% CI: 1.29-1.41), and being unmarried (OR = 1.17, 95% CI: 1.13-1.22) were associated with a distant stage at diagnosis. Higher tumor grade, younger age, and more recent year of diagnosis were also associated with distant-stage diagnosis. As a proxy for neighborhood context, the SDI can be used by cancer registries and related population-based studies to identify geographic areas that could be prioritized for cancer prevention and control efforts.


High incidence of invasive group B streptococcal infections in HIV-exposed uninfected infants.
The occurrence of an unusual number of group B streptococcal (GBS) infections in HIV-exposed uninfected (HEU) infants who were followed in our center prompted this study. The objective of this study was to describe and compare the incidence and clinical presentation of GBS infections in infants who were born to HIV-infected and -uninfected mothers. All cases of invasive GBS infections in infants who were born between 2001 and 2008 were identified from the database of HEU infants and from the microbiology laboratory records. The medical charts of all infants with GBS infection were reviewed. GBS invasive infections were described for 5 (1.55%) infants who were born to 322 HIV-infected mothers who delivered in our center. The incidence of GBS infections during the same period was 16 (0.08%) of 20 158 infants who were born to HIV-uninfected mothers. One HEU infant presented a recurrent infection 28 days after completion of treatment for the first episode. Late-onset infection was more frequent in HEU infants (5 of 6 vs 2 of 16 episodes in the control population). The diseases were also more severe in HEU infants with 5 of 6 sepsis or sepsis shock in HEU infants versus 10 of 16 in control subjects, and most HEU infants had leukopenia at onset of infection. The incidence of GBS infection was significantly higher in HEU infants than in infants who were born to HIV-uninfected mothers. These episodes of GBS sepsis in HEU infants were mostly of late onset and more severe than in the control population, suggesting an increased susceptibility of HEU infants to GBS infection.


Recent trends in the birth prevalence of Down syndrome in China: impact of prenatal diagnosis and subsequent terminations.
This study aims to analyze recent trends in Down syndrome (DS) prevalence in China and evaluate the impact of prenatal diagnosis and subsequent terminations. A birth defects surveillance-based retrospective study was adopted. On the basis of the 1996 to 2011 surveillance data for DS from Chinese Birth Defects Monitoring Network, we examined the total prevalence ratio (TPR), perinatal prevalence ratio (PPR) and percentages of prenatally identified cases and of terminations by periods (before and after 2003), birth area, gender and maternal-age classifications. Down syndrome TPR was 3.05 per 10 000 births during 2003 to 2011, with significant differences between urban-rural, gender and maternal-age groups. DS PPR during 1996 to 2011 was 1.99 per 10 000, presenting an increasing trend till 2003 but a decreasing tendency since then. The proportion of DS diagnosed prenatally increased from 7.55% during 1996 to 2002 to 47.70% during 2003 to 2011, varying by birth area and maternal age. During 2003 to 2011, the high termination rate led to 55% reduction in the overall DS PPR and 62% and 36% decreases in urban and rural PPRs. The important reduction in the PPR suggests that current strategies in China for the prenatal screening and diagnosis of DS are effective. However, significant urban-rural variations in TPR and PPR indicate an urgent need to strengthen prenatal care for DS in rural regions.


Stresses as First-Line Tools for Enhancing Lipid and Carotenoid Production in Microalgae.
Microalgae can produce high-value-added products such as lipids and carotenoids using light or sugars, and their biosynthesis mechanism can be triggered by various stress conditions. Under nutrient deprivation or environmental stresses, microalgal cells accumulate lipids as an energy-rich carbon storage battery and generate additional amounts of carotenoids to alleviate the oxidative damage induced by stress conditions. Though stressful conditions are unfavorable for biomass accumulation and can induce oxidative damage, stress-based strategies are widely used in this field due to their effectiveness and economy. For the overproduction of different target products, it is required and meaningful to deeply understand the effects and mechanisms of various stress conditions so as to provide guidance on choosing the appropriate stress conditions. Moreover, the underlying molecular mechanisms under stress conditions can be clarified by omics technologies, which exhibit enormous potential in guiding rational genetic engineering for improving lipid and carotenoid biosynthesis.


Optimization of pressure-induced germination of Bacillus sporothermodurans spores in water and milk.
Bacillus sporothermodurans produces highly resistant endospores that can survive ultra-high-temperature treatment in milk. The induction of endospore germination before a heat treatment could be an efficient method to inactivate these bacteria and ensure milk sterility. In this work, the rate of spore germination of B. sporothermodurans LTIS27 was measured in distilled water after high-pressure treatments with varying pressure (50-600 MPa), treatment temperature (20-50 °C), pressure-holding time (5-30 min) and post-pressurization incubation time (30-120 min) at 37 °C or 4 °C. The results showed that pressure-induced germination was maximal (62%) after a treatment at 200 MPa and 20 °C and increased with pressure-holding time and post-pressurization incubation time. Treatment temperature had no significant effect on germination. A central composite experimental design with three factors (pressure, pressure-holding time, and post-pressurization incubation time) using response surface methodology was used to optimize the germination rate in distilled water and in skim milk. No factor interaction was observed. Germination was induced at lower pressure and was faster in milk than in distilled water, but complete germination was not reached. The optimum germination obtained with experimental data was 5.0 log cfu/mL in distilled water and 5.2 log cfu/mL in milk from 5.7 log cfu/mL of spores initially present in the suspension. This study shows the potential of using high hydrostatic pressure to induce the germination of B. sporothermodurans spores in milk before a heat treatment.


Micrometastases in esophagogastric cancer: high detection rate in resected rib segments.
Micrometastases within bone marrow indicate a poor prognosis. We prospectively examined micrometastases in patients undergoing resection of esophagogastric cancers for (1) prevalence in rib marrow; (2) comparative detection rates in rib and iliac crest marrow; (3) responsiveness to neoadjuvant therapy; and (4) viability and tumorigenicity. In 50 consecutive patients, marrow was obtained before manipulation of the primary tumor. Micrometastatic cells were detected by staining contaminant cytokeratin-18-positive cells. Viability and tumorigenicity were determined by culture and xenograft. Micrometastases were detected in rib marrow from 88% of patients (44 of 50). When bilateral iliac crest marrow was also obtained, micrometastases were found in 15% (4 of 27) compared with 89% (24 of 27) for ribs (P < 0.001). Detection rates were independent of histological type or nodal status and were similar in patients with and without neoadjuvant therapy. Metastatic cells were cultured from rib marrow of 5 of 7 patients and were tumorigenic in nude mice. Most patients undergoing resection of esophagogastric malignancies have micrometastases in rib marrow. Detection rates based on iliac crest marrow are underestimates. Hematogenous spread of metastatic cells is independent of histological type or nodal status. The metastatic cells are viable, tumorigenic, and resistant to neoadjuvant therapy.


Ribociclib Nanostructured Lipid Carrier Aimed for Breast Cancer: Formulation Optimization, Attenuating In Vitro Specification, and In Vivo Scrutinization.
The current investigation is on the explicit development and evaluation of nanostructured lipidic carriers (NLCs) through the oral route to overcome the inherent lacuna of chemotherapeutic drug, in which Ribociclib (RBO) was used for breast cancer to diminish the bioavailability issue. The RBO-NLCs were prepared using the solvent evaporation method and optimized method by the Box-Behnken design (BBD). Various assessment parameters characterized the optimized formulation and their in vivo study. The prepared NLCs exhibited mean particle size of 114.23 ± 2.75 nm, mean polydispersity index of 0.649 ± 0.043, and high entrapment efficiency of 87.7 ± 1.79%. The structural analysis by TEM revealed the spherical size of NLCs and uniform drug distribution. An in vitro drug release study was established through the 0.1 N HCl pH 1.2, acetate buffer pH 4.5, and phosphate buffer pH 6.8 with % cumulative drug release of 86.71 ± 8.14, 85.82 ± 4.58, and 70.98 ± 5.69%, was found respectively, compared with the RBO suspension (RBO-SUS). In vitro intestinal gut permeation studies unveiled a 1.95-fold gain in gut permeation by RBO-NLCs compared with RBO-SUS. In vitro lipolysis suggests the drug availability at the absorption site. In vitro haemolysis study suggests the compatibility of NLCs to red blood cells compared to the suspension of the pure drug. The confocal study revealed the depth of penetration of the drug into the intestine by RBO-NLCs which was enhanced compared to RBO-SUS. A cell line study was done in MCF-7 and significantly reduced the IC50 value compared to the pure drug. The in vivo parameters suggested the enhanced bioavailability by 3.54 times of RBO-NLCs as compared to RBO-SUS. The in vitro, ex vivo, and in vivo results showed a prominent potential for bioavailability enhancement of RBO and effective breast cancer therapy.


Posttranscriptional regulation of glucose-6-phosphate dehydrogenase by dietary polyunsaturated fat.
The activity of glucose-6-phosphate dehydrogenase (G6PD) is inhibited by the addition of polyunsaturated fat (PUFA) to a high carbohydrate diet. To define the regulated step, we measured enzyme activity, accumulation of G6PD mRNA, and transcriptional activity of the gene. At steady-state, G6PD activity and mRNA abundance were inhibited by 80% in the livers of mice fed a high-fat diet (6% safflower oil) compared to mice fed a low-fat diet (1% safflower oil). Inhibition of mRNA accumulation was 20% by 4 h and was maximal by 9 h after beginning the high-fat diet. Changes in mRNA accumulation preceded changes in enzyme activity, indicating pretranslational regulation. The rapid kinetics of G6PD mRNA accumulation depended on prior dietary history of the mice. In meal-trained mice, abundance of G6PD mRNA increased by twofold within 4 h of the onset of a low-fat meal and was maximal by 12 h. In contrast, an increase in G6PD mRNA was not observed until 12 h after refeeding starved mice and the increase was maximal (12-fold) by 27 h. Transcriptional activity of the gene was measured using the nuclear run-on assay. The G6PD probes were rigorously screened for repetitive elements and for transcription of the noncoding strand of the gene. Throughout the time course of changes in G6PD mRNA accumulation due to PUFA or refeeding, transcriptional activity of the gene did not change. Therefore, regulation of G6PD expression by nutritional status occurs at a posttranscriptional step.


Repeated measurement of mechanical properties in viable osteochondral explants following a single blunt impact injury.
The objective of this work was to develop a method for repeated same-site measurement of mechanical properties suitable for the detection of degenerative changes in a biologically active explant model after a single blunt impact injury. Focal blunt impact injuries to articular surfaces lead to local cartilage degeneration and loss of mechanical properties. We employed a repeated measurement methodology to determine variations in mechanical same-site properties before and after injury in living cartilage, with the hypothesis that normalization with initial mechanical properties may provide a clearer evaluation of impact effects and improve our understanding of the biologic responses to impact injury. Bovine osteochondral explants were cultured for up to 14 days after impact injury. Indentation tests were performed before and after impact injury to assess relative changes in mechanical properties. Creep strain increased significantly in impacted explants after 7 days and in both impacted and control explants after 14 days. Further analysis at 14 days revealed decreases in stretch factor beta, creep time constant and local compressive modulus. A repeated measures methodology reliably detected changes in the mechanical behaviour of viable osteochondral explants after a single impact injury.


Psycho-Trauma, Psychosocial Adjustment, and Symptomatic Post-Traumatic Stress Disorder among Internally Displaced Persons in Kaduna, Northwestern Nigeria.
In April 2011, a post election violent conflict in Northern Nigeria led to resettlement of internally displaced persons (IDPs) in a camp in Kaduna, the worst affected state. We set out to determine prevalence and socio-demographic factors associated with post-traumatic stress disorder (PTSD) among IDPs. We also determined types of psycho-trauma experienced by the IDPs and their psychosocial adjustment. Cross-sectional systematic random sampling was used to select 258 adults IDPs. We used Harvard trauma questionnaire to diagnose "symptomatic PTSD," composite international diagnostic interview (CIDI) for diagnosis of depression, and communal trauma event inventory to determine exposure to psycho-trauma. We assessed social adjustment using social provision scale. Multiple logistic regression analysis was used to determine independent predictors of PTSD. Of the 258 IDPs, 109 (42.2%) had a diagnosis of PTSD, 204 (79.1%) had poor living conditions, and only 12 (4.7%) had poor social provision. The most frequent psycho-traumas were destruction of personal property (96.1%), been evacuated from their town (96%) and witnessing violence (88%). More than half (58%) of IDPs had experienced 11-15 of the 19 traumatic events. Independent predictors of PTSD among respondents were having a CIDI diagnosis of depression (adjusted odds ratios 3.5, 95% confidence interval 1.7-7.5; p = 0.001) and witnessing death of a family member (3.7, 1.2-11.5; p = 0.0259). We concluded that exposure to psycho-trauma among IDPs in Kaduna led to post conflict PTSD. Death of a family member and co-morbid depression were independent predictors of PTSD among IDPs. Though their living condition was poor, the IDPs had good psychosocial adjustment. We recommended a structured psychosocial intervention among the IDP targeted at improving living condition and dealing with the psychological consequences of psycho-trauma.


Granulocyte transfusions for neonates with confirmed or suspected sepsis and neutropenia.
Neonates have immature granulopoiesis, which frequently results in neutropenia after sepsis. Neutropaenic septic neonates have a higher mortality than non-neutropenic septic neonates. Therefore, granulocyte transfusion to septic neutropenic neonates may improve outcomes. The primary objective was to determine the effect of granulocyte or buffy coat transfusions as adjuncts to antibiotics, after confirmed or suspected sepsis in neutropenic neonates, on all-cause mortality during hospital stay and neurological outcome at ≥ year of age. Secondary objectives were to determine the effects of granulocyte transfusions on length of hospital stay in survivors to discharge, adverse effects and immunologic outcomes at ≥ year of age. The Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE, EMBASE and CINAHL, proceedings of the PAS conferences and ongoing trials at clinicaltrials.gov and clinical-trials.com were searched in July 2011. Studies where neutropenic neonates with suspected or confirmed sepsis were randomised or quasi-randomised to granulocyte or buffy coat transfusions at any dose or duration, and reporting any outcome of interest were included. Relative risk (RR) and risk difference (RD) with 95% confidence intervals using the fixed effects model were reported for dichotomous outcomes. Pre-specified subgroup analyses were performed. Four trials were eligible for inclusion. Forty-four infants with sepsis and neutropenia were randomised in three trials to granulocyte transfusions or placebo/no transfusion. In another trial, 35 infants with sepsis and neutropenia on antibiotics were randomised to granulocyte transfusion or IVIG.When granulocyte transfusion was compared with placebo or no transfusion, there was no significant difference in 'all-cause mortality' (three trials; typical RR 0.89, 95% CI 0.43 to 1.86; typical RD -0.05, 95% CI -0.31 to 0.21).When granulocyte transfusion was compared with intravenous immunoglobulin (one trial), there was a reduction in 'all-cause mortality' of borderline statistical significance (RR 0.06, 95% CI 0.00 to 1.04; RD -0.34, 95% CI -0.60 to -0.09; NNT 2.7, 95% CI 1.6 to 9.1).Pulmonary complications were the only adverse effect reported in the trials that used buffy coat transfusions. None of the trials reported on neurological outcome at one year of age or later, length of hospital stay in survivors to discharge or immunological outcome at one year of age or later. Currently, there is inconclusive evidence from randomised controlled trials (RCTs) to support or refute the routine use of granulocyte transfusions in neutropenic, septic neonates. Researchers are encouraged to conduct adequately powered multi-centre trials of granulocyte transfusions in neutropenic septic neonates.


Discovery of novel, dual mechanism ERK inhibitors by affinity selection screening of an inactive kinase.
An affinity-based mass spectrometry screening technology was used to identify novel binders to both nonphosphorylated and phosphorylated ERK2. Screening of inactive ERK2 identified a pyrrolidine analogue 1 that bound to both nonphosphorylated and phosphorylated ERK2 and inhibited ERK2 kinase activity. Chemical optimization identified compound 4 as a novel, potent, and highly selective ERK1,2 inhibitor which not only demonstrated inhibition of phosphorylation of ERK substrate p90RSK but also demonstrated inhibition of ERK1,2 phosphorylation on the activation loop. X-ray cocrystallography revealed that upon binding of compound 4 to ERK2, Tyr34 undergoes a rotation (flip) along with a shift in the poly-Gly rich loop to create a new binding pocket into which 4 can bind. This new binding mode represents a novel mechanism by which high affinity ATP-competitive compounds may achieve excellent kinase selectivity.


The metabolic disposition of plasma 5 alpha-dihydroprogesterone (5 alpha-pregnane-3,20-dione) in women and men.
This study was conducted 1) to ascertain whether the high levels of plasma 5 alpha-dihydroprogesterone (5 alpha DHP) during the luteal phase of the human ovarian cycle and pregnancy are attributable to high rates of production or, alternatively, low rates of clearance, and 2) to estimate the relative distribution of the irreversible metabolism of 5 alpha DHP, i.e. hepatic compared with extrahepatic clearance of plasma 5 alpha DHP. The concentration of 5 alpha DHP in plasma of women during the luteal phase of the ovarian cycle and pregnancy is very high, viz. 12-40% that of progesterone. Thus, a potentially large source of steroid precursor is available for the formation of bioactive 5 alpha-pregnanolone metabolites. We found that the MCR of 5 alpha DHP in women and men is 4187 +/- 312 L plasma/24 h (range, 3181-5506; n = 6). The MCR of 5 alpha DHP as a function of body surface area was 2406 +/- 240 L/24 h.m2. The MCR of 5 alpha DHP, therefore, is the greatest of any steroid reported, except for that of the catechol estrogens, which are metabolized intravascularly by erythrocyte catechol-O-methyltransferase. Based on estimated rates of liver plasma flow (1500 L/24 h) and hepatic extraction (75-85%) of lipophilic steroids that are not specifically bound in plasma with high affinity to binding proteins as determined by other investigators (e.g. 5 alpha DHP), we estimate that approximately 1200 L plasma/24 h are cleared of 5 alpha DHP by liver and approximately 2800 L plasma/24 h are cleared of 5 alpha DHP (70%) by metabolism in extrahepatic tissues. Thus, 5 alpha DHP can serve as a precursor for bioactive 5 alpha-pregnanolone(s).


Resolution on the recognition and effectiveness of the right to social security health assistance for children in foster care, 16 September 1987.
This Resolution provides that children placed in foster care in Spain by associations and foundations recognized for such purposes have the right to receive social security health assistance benefits in conformity with Article 2 of Decree 2766/1967 of 16 November 1967.


A Two-Step Feature Selection Method to Predict Cancerlectins by Multiview Features and Synthetic Minority Oversampling Technique.
Cancerlectins have an inhibitory effect on the growth of cancer cells and are currently being employed as therapeutic agents. The accurate identification of the cancerlectins should provide insight into the molecular mechanisms of cancers. In this study, a new computational method based on the RF (Random Forest) algorithm is proposed for further improving the performance of identifying cancerlectins. Hybrid feature space before feature selection is developed by combining different individual feature spaces, CTD (Composition, Transition, and Distribution), PseAAC (Pseudo Amino Acid Composition), PSSM (Position-Specific Scoring Matrix), and disorder. The SMOTE (Synthetic Minority Oversampling Technique) is applied to solve the imbalanced data problem. To reduce feature redundancy and computation complexity, we propose a two-step feature selection process to select informative features. A 5-fold cross-validation technique is used for the evaluation of various prediction strategies. The proposed method achieves a sensitivity of 0.779, a specificity of 0.717, an accuracy of 0.748, and an MCC (Matthew's Correlation Coefficient) of 0.497. The prediction results are also compared with other existing methods on the same dataset using 5-fold cross-validation. The comparison results demonstrate the high effectiveness of our method for predicting cancerlectins.


Effect of different rest intervals, between sets, on muscle performance during leg press exercise, in trained older women.
The purpose of this study was to assess the effect of different rest intervals (RI) between sets on number of repetitions, sustainability of repetitions, and total volume during a leg press exercise. Seventeen resistance-trained older women (68.0 ± 5.9 years, 71. 2 ± 11.7 kg, 1.58 ± 0.07 m) participated in the study. All participants performed three sets to voluntary exhaustion, with loads that corresponded to 15 maximum repetitions, in two experimental sessions (that ranged from 48 to 72 hours apart). In each session, one of two RI (one-minute: RI-1 and three minute: RI-3) was tested, employing a randomized and counterbalanced design. For both RI, significant reductions (p < 0.05) were observed in the number of repetitions and sustainability of repetitions, from the first to the second and third sets. Differences (p < 0.05) between the RI also were observed in the two final sets. The total volume for the RI-3 session was statistically higher (29.4%, p < 0.05) as compared to the RI-1 session. The length of the RI between sets influenced the number of repetitions, sustainability of repetitions, and total volume. The longer RI should be used, therefore, when the goal of training is to increase the total volume. Key pointsThis study examined the influence of rest intervals, between sets, on muscle performance during leg press exercise, in trained older women.When multiple sets were performed to voluntary exhaustion, neither short and long rest interval (1 and 3 minutes, respectively) promoted the sustainability of repetitions in subsequent sets.A longer rest interval seems to be necessary for a higher number of repetitions in subsequent sets, and with increase in time of tension and total volume.


[Survival Analysis of Non-Small Cell Lung Cancer in Patients aged 70 and over.].
With a trend of worldwide increasing incidence of elderly population, more and more people pay close attention to diseases in the elderly. Lung cancer is a typical disease of the elderly patients. Around one- third of all patients with non-small cell lung cancer (NSCLC) are over the age of 70. Many authors use the age 70 to define the elderly patients in lung cancer. The objective of this study is to evaluate the survival of patients older than 70 with NSCLC and explore the independent prognostic factors in this group of patients. 148 elderly patients with NSCLC were reviewed. All the potential prognostic factors, including sex, age, smoke, symptoms, pathological types, clinical stage, ECOG performance status, complication, focus resection, radiotherapy and chemotherapy were analyzed by COX regression in SPSS 13.0 software. After 5-168 months follow-up, 119 patients died, the overall survival rate was 19.6%. 1,2,3,5-year survival rates were 43.2%, 19.0%,9.0% and 5.4% respectively. Median survival time (MST) was 9.29 moths. COX regression showed clinical stage(P =0.002), ECOG performance status(P =0.000), focus resection(P =0.012) and radiotherapy of primary site(P =0.012) were the independent prognostic factors. The elderly patients with NSCLC in early stage and good performance status tend to have longer life expectance, whereas resection and radiotherapy of primary site can prolong the survival time (P <0.05).


[The role of polymerase protein genes of influenza A virus in the transition from the early to late stage of replication].
Regulation of influenza virus RNA replication was studied with the use of A/FPV/Rostock/34 strain ts-mutants. Mutants C44, C15, C45 possessing the ts-defects in the PB2, PB1 and PA genes respectively were used for the infection of chick embryo cultured cells and H-uridine-labelled nucleocapsid-associated RNA was analysed in polyacrylamide gel electrophoresis to assess the kinetics of vRNA synthesis. A typical early-late transition of the pattern of vRNA synthesis was observed in the cells infected with C44, whereas the other two mutants exhibited a slightly changed (C15) or strongly distorted (C45) pattern. In shift up experiments after the transfer to non-permissive temperature all the mutants exhibited partial reversion to an early pattern of vRNA synthesis. The results are discussed in connection with the mechanism of the early-late transition of influenza virus-specific RNA synthesis.


Determination of cerebral blood flow with a phase-contrast cine MR imaging technique: evaluation of normal subjects and patients with arteriovenous malformations.
This study evaluated a phase-contrast cine magnetic resonance (MR) imaging technique capable of simultaneously allowing determination of velocity and volume flow rate (VFR) in both carotid arteries and the basilar artery. Forty patients were studied; 24 were neurologically normal, and 16 had intracerebral arteriovenous malformations (AVMs). In the normal group, mean basilar flow was significantly less than mean carotid flow. Mean velocity and VFR showed a significant decline with age in the basilar artery. Carotid artery flow and total cerebral blood flow did not decline with age. In the AVM patients, flow and velocity measurements were significantly elevated in all three arteries. Flow in the carotid artery ipsilateral to the AVM was significantly greater than flow in the contralateral carotid artery. VFR increased in all three arteries with increasing AVM volume. Four patients underwent partial embolization, and a corresponding decrease in flow was observed. Phase-contrast cine MR imaging provides rapid, simultaneous, noninvasive velocity and VFR measurement in the major intracranial arteries.


Postural adjustments and bearing angle use in interceptive actions.
The experiment investigates the effect of ball velocity and walking direction on the adherence to the bearing angle (BA) strategy in adults. Adult participants (N=12) approached a moving ball in order to manually intercept it at a predefined target area. Results revealed that during locomotion the BA strategy was implemented, but on reaching the point of interception, this strategy broke down and the BA strategy of the wrist compensated for the movement requirements relative to the ball velocity and approach angle. Larger deviations from the BA occurred when the angle of approach was decreased and when the ball velocity increased. When the BA strategy was adhered to, postural adjustments were reduced. Increased movements occurred in a proximal-distal direction with an increasing approach angle and a faster ball velocity.


[A case-control study on depression and anxiety in hypertensive patients].
To study the current situation of depression and anxiety from patients with hypertension as well as to provide reference for the development of control and prevention program. Participants older than 35-year including both hypertensive patients and healthy controls were randomly selected in 2 communities of Pukou district in Nanjing through Health Behavior Survey. All the subjects were assessed by the Zung's self-rating depression scale (SDS) and the Zung's self-rating anxiety scale (SAS). Raw score and index score of SDS and SAS were both significantly (P < 0.01) greater in hypertensive patients than in healthy control group. The prevalence of depression of 17.9% and anxiety of 9.5% in patient group were found significantly higher than that in healthy control group as 11.5% and 4.3%. Data from logistic regression model analysis showed that depression and anxiety were possible risk factors of hypertension (OR = 1.677, 95% CI: 1.013-2.776; OR = 2.451, 95% CI: 1.228-4.894). There was a combined effect seen between depression and anxiety (OR = 5.238, 95% CI: 2.356-11.664) but interaction did not appear. Depression and anxiety were possibly associated with hypertension and more attention needs to be paid to the mental health situation of hypertensive patients in order to improve their quality of life.


Actinobacillus pleuropneumoniae RTX-toxins: uniform designation of haemolysins, cytolysins, pleurotoxin and their genes.
The three different pore-forming RTX-toxins of Actinobacillus pleuropneumoniae are reviewed, and new and uniform designations for these toxins and their genes are proposed. The designation ApxI (for Actinobacillus pleuropneumoniae RTX-toxin I) is proposed for the RTX-toxin produced by the reference strains for serotypes 1, 5a, 5b, 9, 10 and 11, which was previously named haemolysin I (HlyI) or cytolysin I (ClyI). This protein is strongly haemolytic and shows strong cytotoxic activity towards pig alveolar macrophages and neutrophils; it has an apparent molecular mass in the range 105 to 110 kDa. The genes of the apxI operon will have the designations apxIC, apxIA, apxIB, and apxID for the activator, the structural gene and the two secretion genes respectively. The designation ApxII is proposed for the RTX-toxin which is produced by all serotype reference strains except serotype 10 and which was previously named App, HlyII, ClyII or Cyt. This protein is weakly haemolytic and moderately cytotoxic and has an apparent molecular mass between 103 and 105 kDa. The genes of the apxII operon will have the designations apxIIC for the activator gene and apxIIA for the structural toxin gene. In the apxII operon, no genes for secretion proteins have been found. Secretion of ApxII seems to occur via the products of the secretion genes apxIB and apxID of the apxI operon. The designation ApxIII is proposed for the nonhaemolytic RTX-toxin of the reference strains for serotypes 2, 3, 4, 6 and 8, which was previously named cytolysin III (ClyIII), pleurotoxin (Ptx), or macrophage toxin (Mat).(ABSTRACT TRUNCATED AT 250 WORDS)


Release of Sucrose from Vicia faba L. Leaf Discs.
The release of sucrose from leaf discs of Vicia faba L. to a bathing medium was studied for evidence of a relationship between this release and mesophyll export of photosynthate in vivo. Sucrose was released specifically over hexoses and represented over 85% of total photosynthate released. The sucrose appeared to be derived from the mesophyll tissue directly and release did not require concurrent photosynthesis. The data indicated two separate channels for sucrose release. The first was sensitive to inhibition by 1 millimolar p-chloromercuribenzenesulfonic acid and the second was promoted by lowering the Ca(2+) concentration below 0.1 millimolar. Flow through both channels was about equal when tissue that had been actively photosynthesizing for several hours was used. The rate of release was not dependent on the extracellular pH, but was inhibited by 10 micromolar carbonylcyanide p-trifluromethoxyphenylhydrazone. Lowering the Ca(2+) concentration below 0.1 millimolar or raising the K(+) concentration above 100 millimolar stimulated sucrose release. The stimulation by high K(+) was not reversed by adding Ca(2+). The data supported the postulate that Ca(2+) removal or K(+) addition changed the permeability of the mesophyll plasma membrane to sucrose.


The impact of meteorological factors on the onset of myocardial infarction in the coastal region of middle Dalmatia.
The influence of mediterranean climate on the onset of acute myocardial infarction (AMI) has been investigated in a study group comprised of 1306 AMI patients from the coastal part of middle Dalmatia (Croatia) admitted to the two Split hospitals in the 1981-1987 period. AMI incidence during the southern wind (0.62 per day) was significantly greater than during the northern wind (0.50 per day; p < 0.05), as well as during all non-southern-wind days (0.49 per day; p < 0.01). The coefficients of partial correlation showed a significant association of AMI incidence with increased air temperature (p < 0.05) and relative humidity (p < 0.05). Cross-correlation showed a positive link of AMI incidence to increased air temperature four days before, and on the day of the incident (p < 0.05). Analysis of the synoptic situations revealed characteristics of unstable weather in the days with 4 or more AMI patients. The results suggest that during the southern wind or the passing atmospheric front, coronary patients should stay at home, avoid both physical and psychological stress, and take antianginal drugs more frequently.


Leptomonas seymouri as a model system for the analysis of gene expression in trypanosomatids.
Leptomonas seymouri, a monogenetic trypanosomatid originally isolated from Dysdercus suturellus (Hemiptera), was used to develop a reverse genetic system for trypanosomatid flagellates. In many eukaryotic cell types, reverse genetics has proven to be a powerful tool for defining structure/function relationships within genes. The mini-exon genes of trypanosomatids encode key components of all cellular mRNAs. This component is a 5' "leader" RNA that is spliced onto all mRNA precursors during mRNA formation within the cell nucleus. The data presented here indicate that structure/function relationships within the mini-exon gene can be probed using the molecular genetic system developed and characterized for L. seymouri.


Increased arterial adrenaline is highly correlated to blood pressure and in vivo platelet function in pre-eclampsia.
Compared with normotensive pregnant women (n = 13), patients with severe pre-eclampsia (n = 13) had increased arterial plasma adrenaline (P < 0.001), peripheral venous adrenaline (P < 0.01), arterio-venous differences of adrenaline (P < 0.001) and venous concentration of the platelet release product beta-thromboglobulin (P < 0.001). In the pre-eclamptic group, arterial adrenaline correlated with mean blood pressure (r = 0.90, P < 0.001), heart rate (r = 0.78, P < 0.01) and beta-thromboglobulin (r = 0.82, P < 0.001), while in the normotensives adrenaline correlated only with beta-thromboglobulin (r = 0.76, P < 0.01). According to these results, sympathetic adrenal tone is increased in pre-eclampsia and may play a role in the pathogenesis of high blood pressure and platelet activation in this disease.


Binge eating as escape from self-awareness.
This article proposes that binge eating is motivated by a desire to escape from self-awareness. Binge eaters suffer from high standards and expectations, especially an acute sensitivity to the difficult (perceived) demands of others. When they fall short of these standards, they develop an aversive pattern of high self-awareness, characterized by unflattering views of self and concern over how they are perceived by others. These aversive self-perceptions are accompanied by emotional distress, which often includes anxiety and depression. To escape from this unpleasant state, binge eaters attempt the cognitive response of narrowing attention to the immediate stimulus environment and avoiding broadly meaningful thought. This narrowing of attention disengages normal inhibitions against eating and fosters an uncritical acceptance of irrational beliefs and thoughts. The escape model is capable of integrating much of the available evidence about binge eating.


Mathematical disabilities: cognitive, neuropsychological, and genetic components.
Cognitive, neuropsychological, and genetic correlates of mathematical achievement and mathematical disability (MD) are reviewed in an attempt to identify the core deficits underlying MD. Three types of distinct cognitive, neuropsychological, or cognitive and neuropsychological deficits associated with MD are identified. The first deficit is manifested by difficulties in the representation or retrieval of arithmetic facts from semantic memory. The second type of deficit is manifested by problems in the execution of arithmetical procedures. The third type involves problems in the visuospatial representation of numerical information. Potential cognitive, neuropsychological, and genetic factors contributing to these deficits, and the relationship between MD and reading disabilities, are discussed. Finally, suggestions for the subtyping of mathematical disorders are offered.


Changes in ambulatory utilization after switching from Medicaid fee-for-service to managed care.
To observe any change in ambulatory care utilization after switching from Medicaid fee-for-service (FFS) to Medicaid managed care (MC). We conducted a statewide longitudinal study of 21,048 adult Medicaid beneficiaries in New York State who switched from FFS to MC in 2011 or 2012, with 2 sets of controls (n = 21,048 with continuous FFS; n = 21,048 with continuous MC) who were matched on age, gender, dual-eligible status, and number of chronic conditions. We measured ambulatory care utilization in the 12 months before and 12 months after the switch date, using regression to adjust for case mix and account for matching. Overall, switching from Medicaid FFS to Medicaid MC was associated with greater absolute decreases over time in ambulatory visits and providers compared with controls (-1.49 visits vs continuous FFS and -1.60 visits vs continuous MC; each P <.0001; -0.10 providers vs continuous FFS and -0.12 providers vs continuous MC; each P <.0001). The subset of switchers with 5 or more chronic conditions had the greatest absolute decreases in visits (-5.88 visits vs continuous FFS and -5.98 visits vs continuous MC; each P <.0001) and providers (-1.37 providers vs continuous FFS and -1.39 providers vs continuous MC; each P <.0001). Significant decreases in visits and providers were also observed for switchers with 3 to 4 chronic conditions but not for those with 0 to 2 chronic conditions. Switching from Medicaid FFS to Medicaid MC was associated with a decrease in ambulatory utilization, especially for the sickest patients.


Therapeutic monoclonal antibodies: trends in development and approval in the US.
Monoclonal antibodies have significant potential as therapeutic agents because of their ability to bind to specific antigens. To determine trends in the clinical development and approval processes for therapeutic mAbs, data on 199 mAbs that entered clinical study from 1980 to 2001 were collected and analyzed. Of the 199 mAbs, 75 are in clinical development, two are undergoing Food and Drug Administration (FDA) review, and 11 are FDA approved. Approval success rates for murine, chimeric and humanized mAbs, and clinical and approval phase lengths for mAbs, are presented. In addition, mAbs that are either in phase III, FDA-review, or are FDA approved for antineoplastic or immunological indications are described.


Cyclin gene amplification and overexpression in breast and ovarian cancers: evidence for the selection of cyclin D1 in breast and cyclin E in ovarian tumors.
Evidence of the involvement of cyclin genes in genetic alterations in human cancer is growing. In the present study, we investigated the amplification, in human breast and ovarian cancer, of 5 cyclin genes; cyclin A, cyclin D1, cyclin D2, cyclin D3 and cyclin E. For this purpose, a series of 1,171 breast and 237 ovarian tumors tested for DNA amplification by Southern blotting and a subset of 132 breast and 22 ovarian cancers were analyzed for RNA expression levels by slot-blot and Northern blotting. In breast tumors, only cyclin D1 was found to be activated in a sizeable fraction of the tumors (amplification 12.6%, overexpression 19%). Cyclin A, D2, D3, and E genes never, or only on rare occasions, showed increased DNA copy numbers and were never found overexpressed at the RNA level. Amplification of cyclin D1 correlated with ER+ breast cancer and the presence of lymph-node metastasis. Interestingly, we were also able to determine an association with invasive lobular carcinoma. Our data suggest that cyclin D1 activation determines the evolution of a particular subset of estrogen-responsive tumors. Data obtained in ovarian tumors contrasted with observations in breast cancer. Cyclin D1 DNA amplification was much less frequent in ovarian than in breast tumors (3.3% vs. 12.6%), whereas cyclin E amplification and overexpression were observed in a significant number of cases (12.5% and 18.0% respectively). Cyclin A, cyclin D2 and D3 rarely showed anomalies at the DNA level and were never overexpressed. No clear correlation could be observed between amplification of the cyclin E gene and tumor type, stage or grade in ovarian cancer. Data presented here suggest distinct pathways of cyclin activation in human breast and ovarian cancer.


Compact U^{k}(1) Chern-Simons Theory as a Local Bosonic Lattice Model with Exact Discrete 1-Symmetries.
We propose a bosonic U^{κ}(1) rotor model on a three dimensional spacetime lattice. With the inclusion of a Maxwell term, we show that the low-energy properties of our model can be obtained reliably via a semiclassical approach. Those properties are the same as that of the Chern-Simons field theory, S=∫d^{3}x(K_{IJ}/4π)A_{I}dA_{J}. We require the lattice variables on each link to be compact (i.e., take values on circles), which enforces the quantization of the K matrix as a symmetric integer matrix with even diagonals. Our lattice model also has exact 1-symmetries, which gives rise to the 1-form symmetry in the Chern-Simons field theory. In particular, some of those 1-symmetries are anomalous (i.e., non-on-site) in the expected way. The anomaly can be probed via the breaking of those lattice 1-symmetries by the boundaries.


A simulation study on the importance of size-related changes in leaf morphology and physiology for carbon gain in an epiphytic bromeliad.
This study addresses the question of how size-related changes in leaf morphology and physiology influence light absorption and carbon gain of the epiphytic bromeliad Vriesea sanguinolenta. A geometrically based computer model, Y-plant, was used for the three-dimensional reconstruction of entire plants and for calculation of whole plant light interception and carbon gain. Plants of different sizes were reconstructed, and morphological and physiological attributes of young and old leaves, and small and large plants were combined to examine the individual effects of each factor on light absorption and carbon gain of the plant. The influence of phyllotaxis on light absorption was also explored. Departure of measured divergence angles between successive leaves from the ideal 137.5 degrees slightly decreased light absorption. The only morphological parameter that consistently changed with plant size was leaf shape: larger plants produced more slender foliage, which substantially reduced self-shading. Nevertheless, self-shading increased with plant size. While the maximum rate of net CO(2) uptake of leaves increased linearly with plant size by a factor of two from the smallest to the largest individual, the potential plant carbon gain (based on total foliage area) showed a curvilinear relationship, but with similar numerical variation. We conclude that leaf physiology has a greater impact on plant carbon gain than leaf and plant morphology in this epiphytic bromeliad.


Localization and properties of ribulose diphosphate carboxylase from castor bean endosperm.
A substantial portion of the ribulose 1,5-diphosphate carboxylase activity in the endosperm of germinating castor beans (Ricinus communis var. Hale) is recovered in the proplastid fraction. The partially purified enzyme shows homology with the enzyme from spinach (Spinacia oleracea) leaves, as evidenced by its reaction against antibodies to the native spinach enzyme and to its catalytic subunit. The enzyme from the endosperm of castor beans has a molecular weight of about 500,000 and, with the exception of a higher affinity for ribulose 1,5-diphosphate, has similar kinetic properties to the spinach enzyme. The castor bean carboxylase is inhibited by oxygen and also displays ribulose 1,5-diphosphate oxygenase activity with an optimum at pH 7.5.


Identification of a new adapter protein that may link the common beta subunit of the receptor for granulocyte/macrophage colony-stimulating factor, interleukin (IL)-3, and IL-5 to phosphatidylinositol 3-kinase.
Binding of human granulocyte/macrophage colony-stimulating factor (hGM-CSF) to its receptor induces the rapid activation of phosphatidylinositol-3 kinase (PI 3-kinase). As hGM-CSF receptor (hGMR) does not contain a consensus sequence for binding of PI 3-kinase, hGMR must use a distinct mechanism for its association with and activation of PI 3-kinase. Here, we describe the identification of a tyrosine-phosphorylated protein of 76-85 kDa (p80) that associates with the common beta subunit of hGMR and with the SH2 domains of the p85 subunit of PI 3-kinase in hGM-CSF-stimulated cells. Src/Yes and Lyn were tightly associated with the p80.PI 3-kinase complex, suggesting that p80 and other phosphotyrosyl proteins present in the complex were phosphorylated by Src family kinases. Tyrosine phosphorylation of p80 was only detected in hGM-CSF or human interleukin-3-stimulated cells, suggesting that activation of p80 might be specific for signaling via the common beta subunit. We postulate that p80 functions as an adapter protein that may participate in linking the hGM-CSF receptor to the PI 3-kinase signaling pathway.


Injury/illness physician referral profile from a youth university-sponsored summer sport camp program.
Participation at university-sponsored summer sport camps is popular among youth athletes; however, there is a dearth of information to describe the injuries/illnesses experienced by camp participants. Data from a university-sponsored sport camp program from 2008 to 2011 were accessed retrospectively. The sport camp program had approximately 80 camps for 28 sports over 12 weeks annually. Male and female participants were 10 to 17 years old. Athletic trainers maintained medical documentation and provided medical referrals. Referrals were made for 9.9% (n=478) of all injuries/illnesses. Emergency department referrals were made for 2.9% of injuries/illnesses. University health services received 42.5% of referrals. There were 1.1 referrals per 100 participants. Boys comprised 60.7% of referrals. Rugby had the highest referral rate--5.0 per 100 participants. These data help increase physician preparedness and guide the delivery of sports medicine services for related sport camp programs as a means to improve quality of care delivered to participants.


County wide employment and population growth: an analysis of the 1980s.
"Regional scientists remain interested in studying interregional differences in the growth rates of population and employment. Following the earlier work of Carlino and Mills, this paper examines growth trends at the county level in the U.S. during the period 1981-1989. Five major sectors of employment are examined. A partial adjustment model is developed that captures intercounty differences in amenities, business and fiscal conditions, demography, employment structure, and relative location. Some evidence is given that population and employment growth was simultaneous, although feedback effects apparently were not strong."


A rapid and simple chemiluminescence method for screening levels of inosine and hypoxanthine in non-traumatic chest pain patients.
A rapid and simple chemiluminescence method was developed for detection of inosine and hypoxanthine in human plasma. The method utilized a microplate luminometer with direct injectors to automatically dispense reagents during sample analysis. Enzymatic conversions of inosine to hypoxanthine, followed by hypoxanthine to xanthine to uric acid, generated superoxide anion radicals as a useful metabolic by-product. The free radicals react with Pholasin(®) , a sensitive photoprotein used for chemiluminescence detection, to produce measurable blue-green light. The use of Pholasin(®) and a chemiluminescence signal enhancer, Adjuvant-K™, eliminated the need for plasma clean-up steps prior to analysis. The method used 20 μL of heparinized plasma, with complete analysis of total hypoxanthine levels (inosine is metabolized to hypoxanthine using purine nucleoside phosphorylase) in approximately 3.7 min. The rapid chemiluminescence method demonstrated the capability of differentiating total hypoxanthine levels between healthy individuals, and patients presenting with non-traumatic chest pain and potential acute cardiac ischemia. The results support the potential use of chemiluminescence methodology as a diagnostic tool to rapidly screen for elevated levels of inosine and hypoxanthine in human plasma, potential biomarkers of acute cardiac ischemia.


Demographics and outcome of metatarsal fractures.
Although metatarsal fractures are amongst the most common injuries of the foot, this is the first study on outcome after metatarsal fractures. All consecutive patients with metatarsal fractures treated between January 2006 and September 2008 were re-evaluated. Patients aged 16 to 75 were sent a questionnaire consisting of the American Orthopaedic Foot Ankle Society midfoot score and a Visual Analogue Scale (VAS) for patient satisfaction. Four-hundred metatarsal fractures were identified in 322 patients. The fifth metatarsal was involved in more than 50% of patients. Most fractures were caused by an inversion injury or fall from height (75%). Out of 247 patients between 16 and 75 years, a total of 166 patients (67.2%) returned the questionnaire with a median follow-up of 33 months. All patients were treated conservatively. The median AOFAS score was 100 points (P(25)-P(75), 87-100), the median VAS was 9 points (P(25)-P(75), 8-10). The AOFAS and VAS scores correlated negatively with the body mass index (BMI) (R (s) = -0.409 and -0.305; p < 0.001). Patients with diabetes reported lower VAS (p = 0.010) and AOFAS scores (p = 0.020). Females reported a lower AOFAS score (p = 0.034). An increase in dislocation (>2 mm) resulted in a decrease in VAS score (p = 0.017). Multivariable analysis indicated that the VAS score was significantly affected by BMI and dislocation >2 mm (p = 0.013). The AOFAS score was affected by BMI (p = 0.011). This is the first investigation using two validated outcome scoring systems to determine functional outcome in metatarsal fractures. Overall outcome in metatarsal fractures is high, as almost all fractures healed without complaints at 33 months. Outcome is dependent on BMI, diabetes, gender, and dislocation at the fracture site.


Literature, philosophy, and medical ethics: let the dialogue go on.
This is a reply to Dan Clouser's philosophical commentary on the essays in this issue. Important assumptions that condition his perspective on the essays are identified and analyzed. Attention is drawn to his unhistorical emphasis on the exclusive importance of philosophy in ethical thought, and his resulting insistence that any discipline wishing to contribute to biomedical discourse must adopt the assumptions and methodologies of philosophy. Clouser's "three tenets" are examined, and then the question of what literature, considered in terms of its own aims and methodologies, has to offer to medical ethics. Genuine dialogue about medical ethics between philosophers and literary scholars is both desirable and important, but becomes possible only if the methods and insights of each discipline are honored in the pursuit of the overall goals they hold in common.


Recommendations for the diagnosis and management of Prader-Willi syndrome.
The objective of the study was to provide recommendations for the diagnosis and management of Prader-Willi syndrome throughout the life span to guide clinical practice. An open international multidisciplinary expert meeting was held in October 2006 in Toulouse, France, with 37 invited speakers and session chairs (see Acknowledgments) and 85 additional registered participants. The meeting was supported by an unrestricted educational grant from Pfizer. Invited participants with particular expertise reviewed the published evidence base for their specialist topic and unpublished data from personal experience, previous national and international PWS conferences, and PWS Association clinical advisory groups. Sessions covered epidemiology, psychiatric, and behavioral disorders; breathing and sleep abnormalities; genetics; endocrinology; and management in infancy, childhood, transition, and adulthood. This included group meetings including open discussion after each session. The guidelines were written by the Scientific Committee (authors), using the conclusions provided by the sessions chairs and summary provided by each speaker, including incorporation of changes suggested after review by selected meeting participants (see Acknowledgments). The diagnosis and management of this complex disorder requires a multidisciplinary approach with particular emphasis on the importance of early diagnosis using accredited genetic testing, use and monitoring of GH therapy from early childhood, control of the food environment and regular exercise, appropriate management of transition, consideration of group home placement in adulthood, and distinction of behavioral problems from psychiatric illness.


Percutaneous extra-anatomic nephrovesical diversion: preliminary report.
We propose a new approach to total ureteric replacement based on the use of a new spiraled composite tube. This tube is inserted percutaneously into the renal pelvis, then tracked subcutaneously and introduced into the bladder via a short incision. The tube is maintained in place by anchoring its spirals along the subcutaneous tract, and only the two silicone extremities are in continuous contact with the urine. We have used this technique for total replacement of the ureter in one renal transplant patient with a follow-up of 8 months and no complication. A longer follow-up is obviously necessary, but this new, minimally invasive approach, using a newly designed tube, would appear to give a new lease of life to an old, abandoned principle.


Uropathogens and their antimicrobial resistance patterns: Relationship with urinary tract infections.
This study was performed to determine the prevalence of uropathogens causing urinary tract infections (UTIs) and to determine their pattern of antimicrobial resistance. This study was conducted on 273 urine samples collected from outpatient departments (OPDs) of Qassim University affiliated hospitals. Fully automated VITEK 2 compact system was used in the identification and antimicrobial susceptibility testing of causative microorganisms. Of 273 urine samples, only 89 (32.6%) were found to show significant growth for UTI, and overall, drug resistance was found in 92% (n = 82/89) of samples, with most (80%) being resistant to at least two drugs. Antibiotic resistance was commonly observed in ampicillin (88.3%), piperacillin (72.7%), clindamycin (66.7%), amoxicillin/clavulanic acid (66.2%), and trimethoprim/sulfamethoxazole (50%). The commonly isolated microorganisms were Escherichia coli 24 (27%), Klebsiella pneumoniae 11 (12.4%), Proteus mirabilis 4 (4.5%), Pseudomonas aeruginosa 4 (4.5%), Enterobacter cloacae 5 (5.6%), Enterococcus faecalis 5 (5.6%), and Staphylococcus saprophyticus 3 (3.4%). This research work has shown that patients with UTI in Qassim are at high risk of antibiotic resistance. The work also showed that multidrug-resistant bacteria can lead to momentous therapeutic problems in OPD patients.


Assessing diabetes dietary goals and self-management based on in-depth interviews with Latino and Caucasian clients with type 2 diabetes.
Latino (n = 10) and Caucasian (n = 8) clients with type 2 diabetes receiving care at a community health clinic participated in individual in-depth interviews assessing diabetes dietary self-management goal behaviors. Themes from interviews were identified using content analysis, which revealed current and future goals, influencing factors, and motivators and barriers to dietary modification for diabetes management. Implications for practice include simplifying goal setting to those goals with the greatest potential clinical impact or the greatest significance to the patient, in a socially supportive environment. Results contribute to future survey development and understanding how to optimize diabetes education for these populations.


Platelet reactivity in vitro in relation to thromboxane in healthy pregnancy.
There is substantial evidence of increased platelet reactivity in vivo and in vitro during pregnancy. Previous in vitro studies suggest that platelets from pregnant women show increased sensitivity to agonists, the response to which has a thromboxane dependent component. The aim of this study was to determine whether this is due to increased activity of the thromboxane biosynthetic pathway or to increased platelet sensitivity to the effects of thromboxane. During pregnancy, platelets were more sensitive to the pro-aggregatory effects in vitro of the thromboxane mimetic U46619, in whole blood and in platelet rich plasma, compared to those from non-pregnant controls. The difference in extent of U46619-induced platelet aggregation between groups was abolished in the presence of a high concentration of the specific thromboxane antagonist ICI 192605, but not by prior incubation of blood with aspirin. Platelets from pregnant women were significantly less sensitive to inhibition of arachidonic acid induced activation by the thromboxane synthetase inhibitor dazmegrel, but there was no change in platelet cyclic AMP accumulation under these conditions. Arachidonic acid induced platelet thromboxane B2 production was similar in pregnant and non-pregnant subjects. In conclusion, platelets are more sensitive to the activating effects of thromboxane during pregnancy, but there is no change in the intrinsic reactivity of the thromboxane biosynthetic pathway.