Effects of estradiol on glucoprivic transactivation of catecholaminergic neurons in the female rat caudal brainstem.
Hyperphagic and hypothalamic neuroendocrine responses to acute glucose deprivation are modified by the ovarian steroid estradiol (E). Observations of genomic activation of catecholaminergic (CA) neurons in the hindbrain lateral reticular nucleus, nucleus of the solitary tract, and area postrema (AP) by glucopenia support their potential function in pathways mediating regulatory effects of this metabolic challenge within the brain. Expression of E receptors by these cells suggests that their activity may be sensitive to steroid modulation during glucopenia. The present studies investigated the role of E on transcriptional activation of caudal brainstem CA neurons by the glucose antimetabolite, 2-deoxy-D-glucose (2DG). Ovariectomized rats were implanted with s.c. Silastic capsules containing E (30 or 250 microg/ml) or sesame oil, and injected i.p. 7 days later with 400 mg 2DG/kg or saline. Tyrosine hydroxylase (TH)-immunoreactive (-ir) neurons in the C(1)/A1, C2, C3, A2, A5, and A6 cell groups and AP were colabeled for Fos following antimetabolite administration, whereas vehicle injection resulted in negligible nuclear staining of these cells. With the exception of A2, A6, and AP cells, mean numbers of Fos- and TH-/Fos-ir-positive neurons in these brain sites did not differ between E- and sesame oil-implanted groups. Numbers of TH-positive A2 and A6 neurons that expressed Fos in response to 2DG were significantly greater in rats implanted with the high E dose vs. either the low steroid dose or sesame oil. These results show that the magnitude of cellular Fos labeling within discrete hindbrain CA neuron populations varies in accordance with circulating E levels. These findings suggest that E may exert potential modulatory effects on glucoprivic activation of the Fos stimulus/transcription cascade and consequent compensatory genomic responses within specific areas of the female rat caudal brainstem.


Alterations in the Timing of Huperzine A Cerebral Pharmacodynamics in the Acute Traumatic Brain Injury Setting.
Traumatic brain injury (TBI) may affect the pharmacodynamics of centrally acting drugs. Paired-pulse transcranial magnetic stimulation (ppTMS) is a safe and noninvasive measure of cortical gamma-aminobutyric acid (GABA)-mediated cortical inhibition. Huperzine A (HupA) is a naturally occurring acetylcholinesterase inhibitor with newly discovered potent GABA-mediated antiepileptic capacity, which is reliably detected by ppTMS. To test whether TBI alters cerebral HupA pharmacodynamics, we exposed rats to fluid percussion injury (FPI) and tested whether ppTMS metrics of cortical inhibition differ in magnitude and temporal pattern in injured rats. Anesthetized adult rats were exposed to FPI or sham injury. Ninety minutes post-TBI, rats were injected with HupA or saline (0.6 mg/kg, intraperitoneally). TBI resulted in reduced cortical inhibition 90 min after the injury (N = 18) compared to sham (N = 13) controls (p = 0.03). HupA enhanced cortical inhibition after both sham injury (N = 6; p = 0.002) and TBI (N = 6; p = 0.02). The median time to maximum HupA inhibition in sham and TBI groups were 46.4 and 76.5 min, respectively (p = 0.03). This was consistent with a quadratic trend comparison that projects HupA-mediated cortical inhibition to last longer in injured rats (p = 0.007). We show that 1) cortical GABA-mediated inhibition, as measured by ppTMS, decreases acutely post-TBI, 2) HupA restores lost post-TBI GABA-mediated inhibition, and 3) HupA-mediated enhancement of cortical inhibition is delayed post-TBI. The plausible reasons of the latter include 1) low HupA volume of distribution rendering HupA confined in the intravascular compartment, therefore vulnerable to reduced post-TBI cerebral perfusion, and 2) GABAR dysfunction and increased AChE activity post-TBI.


Abscission: characterization of light control.
Exposure of mung bean (Vigna radiata [L.] Wilczek cv Jumbo) cuttings to low level red light inhibits dark-induced leaf abscission. A 12-hour daily light requirement for maximum inhibition of abscission was equally effective as a continuous red light treatment or shorter light-dark cycles. Transfer of cuttings from dark to light stopped the abscission process at the time of transfer. The available evidence suggests a light receptor located in the leaves with an abscission inhibitor translocated from lighted leaf to the abscission zone.


Spontaneous network activity of cerebellar granule neurons: impairment by in vivo chronic cannabinoid administration.
Synchronized activity of neuronal networks has been proposed to be essential for cerebellar function. To examine the occurrence and organization of spontaneous neuronal activity in the cerebellum in vivo, we imaged mouse cerebellar slices loaded with the intracellular Ca2+ concentration indicator, fura-2. Recordings were then analysed statistically to identify correlated network activity. Ca2+ imaging revealed consistent spontaneous correlated network activity of granule cells (GC), which often occurred in clusters of coactivated GC. The number of spontaneously active GC, their activation frequency and correlation, were controlled by glutamate and GABA ionotropic receptors. These findings indicate that distinctive patterns of correlated activity between GC networks may be relevant for cerebellar circuit function. Cannabinoid antagonist-precipitated delta9-tetrahydrocannabinol (THC) withdrawal impaired motor coordination. Given that the cerebellum has been suggested recently to be a main substrate for cannabinoid withdrawal, we used imaging of spontaneous network activity to examine whether GC, which contain CB1 cannabinoid receptors, respond to chronic THC treatment and withdrawal. Acute administration of THC had no effect on patterns of spontaneous GC network activity. In contrast, chronic THC administration severely impaired GC activity and network coordination. Incubation of cerebellar slices, from chronically THC-treated mice, with the cannabinoid antagonist, SR141716A increased the number and network correlation of active GC. These data provide physiological evidence of the involvement of cerebellar circuits in the adaptive changes occurring during chronic THC exposure and withdrawal.


Acceptability of smartphone text- and voice-based ecological momentary assessment (EMA) methods among low income housing residents in New York City.
This study aimed to evaluate the acceptability of smartphone-based text message- and voice-based ecological momentary assessment (EMA) methods among a sample of low-income housing residents in New York City. Using data from the community-based NYC Low Income Housing, Neighborhoods and Health Study (n = 112), the acceptability of text message- and voice-based EMA methods were assessed via survey. Overall, 88.4% of participants reported that they would participate in a study that utilized text message-based EMA. These analyses showed no appreciable differences by sub-groups (p > .05). Overall, 80.2% of participants reported that they would participate in a study that used voice-based EMA. This voice-based method was least acceptable among participants younger than 25 years old compared to participants of all other ages, χ2(2) = 10.107, p = .006 (among the younger participants 60.7% reported "yes" regarding the anticipated acceptability of voice-based EMA and 39.3% reported "no"). Overall, this work suggests that text message- and voice-based EMA methods are acceptable for use among low-income housing residents. However, the association between age and the acceptability of voice-based EMA suggests that these methods may be less suited for younger populations.


Conformal hypofractionated and accelerated radiotherapy with cytoprotection (HypoARC) for high risk prostatic carcinoma: rationale, technique and early experience.
Recent radiobiological analysis of the radiotherapy results for prostate cancer revealed that prostate carcinoma behaves as a late responding tissue, sharing an alpha/beta ratio lower than 2Gy. These findings suggest that hypofractionation may be more effective. Reduction of the overall treatment time could further increase response by abrogating the effect of rapid tumor repopulation. In the present study we report a conformal technique applied (to pelvis and prostate) for the treatment of high-risk prostate cancer, using hypofractionated and accelerated radiotherapy (3.4Gy x 15 consecutive fractions) supported with high-dose daily amifostine (1000mg subcutaneously) to protect normal tissues against early and late effects. The biological dose delivered to the prostate cancer by this HypoARC (hypofractionated accelerated radiotherapy with cytoprotection) technique is estimated to be 71.4Gy (alpha/beta= 1.5 Gy). The time-adjusted biological dose is estimated to 77-94 Gy. Amifostine tolerance was excellent. All seven patients recruited up to now have accomplished their treatment with grade 0-1 cystitis or diarrhoea (5/7 grade 0). The study is ongoing to assess efficacy and late effects of HypoARC.


Identification of Legionella pneumophila rcp, a pagP-like gene that confers resistance to cationic antimicrobial peptides and promotes intracellular infection.
In the course of characterizing a locus involved in heme utilization, we identified a Legionella pneumophila gene predicted to encode a protein with homology to the product of the Salmonella enterica serovar Typhimurium pagP gene. In Salmonella, pagP increases resistance to the bactericidal effects of cationic antimicrobial peptides (CAMPs). Mutants with insertions in the L. pneumophila pagP-like gene were generated and showed decreased resistance to different structural classes of CAMPs compared to the wild type; hence, this gene was designated rcp for resistance to cationic antimicrobial peptides. Furthermore, Legionella CAMP resistance was induced by growth in low-magnesium medium. To determine whether rcp had any role in intracellular survival, mutants were tested in the two most relevant host cells for Legionnaires' disease, i.e., amoebae and macrophages. These mutants exhibited a 1,000-fold-decreased recovery during a Hartmannella vermiformis coculture. Complementation of the infectivity defect could be achieved by introduction of a plasmid containing the intact rcp gene. Mutations in rcp consistently reduced both the numbers of bacteria recovered during intracellular infection and their cytopathic capacity for U937 macrophages. The rcp mutant was also more defective for lung colonization of A/J mice. Growth of rcp mutants in buffered yeast extract broth was identical to that of the wild type, indicating that the observed differences in numbers of bacteria recovered from host cells were not due to a generalized growth defect. However, in low-Mg(2+) medium, the rcp mutant was impaired in stationary-phase survival. This is the first demonstration of a pagP-like gene, involved in resistance to CAMPs, being required for intracellular infection and virulence.


Epidemiological characteristics of brucellosis in sheep and goats in Bulgaria: 2005-2008.
To analyse and present the epidemiological and epizootological situation of brucellosis in humans, sheep and goats caused by Brucella melitensis. The veterinary health services analyzsd epidemiological reports, as well as other official documents, in relation to the epidemiology and the measures undertaken for control of brucellosis in Bulgaria, 2005-08. In Bulgaria animal infections caused by Brucella melitensis have been eradicated since 1941. In 2005 several Bulgarian citizens with Brucella infection were diagnosed in the National Reference Laboratory. All the cases were imported, mostly by employees on sheep and goat farms in Greece. For a period of four years, the number of infected humans was 120 and distributed in 12 districts. Epidemiological investigations suggested that 45 persons (37.5%) were infected in Greece and 4 in Cyprus, Turkey, Italy and Tanzania respectively. All other patients were considered to be infected in Bulgaria. They were owners of infected sheep and goats or consumers of contaminated dairy products with Brucella melitensis. In June 2006, the first outbreaks of brucellosis in sheep and goat farms were recorded in the Smolyan district. By the end of 2008, the infection was registered in 16 villages of 4 districts. The average prevalence rate in the infected herds was 12.2% in goats and 1.8% in sheep. In order to achieve eradication 496 goats and 117 sheep were slaughtered. A farm where goats from Greece were introduced illegally in 2005 was identified as the primary source of the infection. the negative epidemiological aspects of free movement of goods and persons in the European Union are considered.


Evidence for a major gene controlling susceptibility to tegumentary leishmaniasis in a recently exposed Bolivian population.
Tegumentary leishmaniasis due to Leishmania braziliensis is a parasitic disease that occurs in two stages after the infected sandfly bite: (1) a primary cutaneous lesion followed by (2) a secondary mucosal involvement generally resulting in severe facial deformities. In order to investigate the genetic and environmental factors involved in the development of the cutaneous lesion, a familial study was performed in a region of Bolivia in which the disease is endemic. Complete selection of 118 nuclear families (703 subjects, with 241 patients), each with at least one cutaneous affected subject, was achieved; 41 families were of native origin, and 77 (herein designated "migrant") recently had settled in the area. For the analysis, the trait under study was the time to onset of the primary cutaneous lesion. The start of the follow-up was birth, for native population, or date of arrival in the endemic area, for migrant population. Segregation analysis was performed by use of a model based on survival analysis methods that allows joint estimation of genetic and environmental effects and accounts for gene x covariate interactions. A significant effect of gender, home-forest distance, and forest-related activity was found. In the 77 migrant families there was evidence for a recessive major gene controlling the onset of the primary cutaneous lesion, with residual familial dependences and age x genotype interaction. Penetrance estimations show that young subjects are genetically more susceptible than older subjects, suggesting that this genetic component could concern mechanisms involved in the development of individual protection during childhood. There was also a significant genetic heterogeneity of the sample according to the native/migrant origin of the families, and no major-gene effect was found in the native subsample.


Echocardiographic evaluation of dogs with dysautonomia.
To describe echocardiographic findings in dogs with dysautonomia. Prospective case series: 20 dogs with dysautonomia (13 confirmed during necropsy and 7 with results of antemortem testing [tear production, pilocarpine response test, atropine response test, and ID histamine response] supportive of the diagnosis). Dogs with dysautonomia were evaluated by use of echocardiography, and M-mode measurements were obtained on all dogs. A dobutamine response test was performed on 1 dog, starting at a rate of 1 microg/kg/min and doubling the rate every 15 minutes until fractional shortening (FS) increased to > 2 times the baseline value. Evidence of systolic dysfunction was detected in 17 of 20 dogs with dysautonomia, as determined on the basis of FS (median, 17.9%; range, 4.0% to 31.1%). Left ventricular internal dimension during diastole or left ventricular internal dimension during systole was enlarged in 4 of 20 and 14 of 20 dogs, respectively. Enlargement of the left atrium or aorta was identified in 3 of 15 and 1 of 15 dogs in which it was measured, respectively. Administration of dobutamine at a rate of 4 microg/kg/min resulted in dramatic improvement in FS (increase from 4% to 17%) in the 1 dog tested. Results suggested that echocardiographic evidence of diminished systolic function was common in dogs with dysautonomia. Whether the diminished function was a result of sympathetic denervation or myocardial hibernation was unclear, although myocardial hibernation was more likely.


Comparison of aromatase activity in human prostatic, testicular and placental tissues.
The aromatase enzyme was quantified by the release of tritiated water from [1 beta-3H] androstenedione. Tritiated water was released by the crude homogenates in 4 of 18 samples of benign prostatic hyperplasia tissue and one of 5 samples of prostate carcinoma tissue. However, this apparent aromatase activity was not inhibited by 4-hydroxyandrostenedione (0.5 and 5.0 microM), and none of the particulate fractions (100,000 g pellet) prepared from each of the prostatic tissues exhibited aromatase activity. Particulate fractions from rat ovary (n = 3) and human testes (n = 6) displayed significant aromatase activity (mean values of 9.9 and 0.033 nmol estrone formed/g protein/h, respectively). The testicular aromatase was inhibited by aminoglutethimide, 4-hydroxyandrostenedione and CGS 16949A with IC50 values of 6.4, 0.17 and 0.0017 microM, respectively. These are of a similar order to values obtained with the aromatase enzyme from human placental microsomes (14, 0.43 and 0.0075 microM, respectively).


Mechanisms underlying metabolic and neural defects in zebrafish and human multiple acyl-CoA dehydrogenase deficiency (MADD).
In humans, mutations in electron transfer flavoprotein (ETF) or electron transfer flavoprotein dehydrogenase (ETFDH) lead to MADD/glutaric aciduria type II, an autosomal recessively inherited disorder characterized by a broad spectrum of devastating neurological, systemic and metabolic symptoms. We show that a zebrafish mutant in ETFDH, xavier, and fibroblast cells from MADD patients demonstrate similar mitochondrial and metabolic abnormalities, including reduced oxidative phosphorylation, increased aerobic glycolysis, and upregulation of the PPARG-ERK pathway. This metabolic dysfunction is associated with aberrant neural proliferation in xav, in addition to other neural phenotypes and paralysis. Strikingly, a PPARG antagonist attenuates aberrant neural proliferation and alleviates paralysis in xav, while PPARG agonists increase neural proliferation in wild type embryos. These results show that mitochondrial dysfunction, leading to an increase in aerobic glycolysis, affects neurogenesis through the PPARG-ERK pathway, a potential target for therapeutic intervention.


Tunable channel-drop filters consisting of polymeric Bragg reflectors and a mode sorting asymmetric X-junction.
A tunable channel-drop filter as essential component for the wavelength-division-multiplexing optical communication system has been demonstrated, which is based on polymer waveguide Bragg reflectors. For an ordinary Bragg reflector, the filtered signal is reflected toward the input waveguide. Thus an external circulator is required to separate the filtered signal from the input port, though it increases the total footprint and cost. For this purpose, we employed dual Bragg reflectors and a mode sorting asymmetric X-junction. The Bragg reflector exhibited a maximum reflectivity of 94% for a 6-mm long grating, a 3-dB bandwidth of 0.39 nm and a 20-dB bandwidth of 2.6 nm. The mode sorting crosstalk in asymmetric X-junction was less than -20 dB, and linear wavelength tuning was achieved over 10 nm at the applied thermal power of 377 mW.


Qualitative and quantitative analysis of locus coeruleus neurons in Parkinson's disease.
The analysis of qualitative changes in the locus coeruleus (LC) was performed on brains from 21 cases of Parkinson's disease. Eleven cases were selected for quantitative analysis of the loss of LC noradrenergic pigmented neurons. The qualitative studies revealed uneven dissemination of the noradrenergic cells loss of overall structure of the LC. Few preserved neurons showed degenerative changes. Extracellular neuromelanine granules, traces of dying neurons, were also observed. A weak astro- and microglia proliferation corresponded with neuronal loss. Lewy bodies were found in the LC in all cases. The quantitative analysis revealed that the average loss of adrenergic neurons in the LC accounts for about 70% in relation to the control group. The degenerative changes were observed in the whole LC, but they were most intensive in its caudal and next in the middle segment. The results suggest also that the degenerative process began in the middle segment and then it spread towards caudal segment of the LC as the stages of disease advanced.


Widespread siRNA "off-target" transcript silencing mediated by seed region sequence complementarity.
Transfected siRNAs and miRNAs regulate numerous transcripts that have only limited complementarity to the active strand of the RNA duplex. This process reflects natural target regulation by miRNAs, but is an unintended ("off-target") consequence of siRNA-mediated silencing. Here we demonstrate that this unintended off-target silencing is widespread, and occurs in a manner reminiscent of target silencing by miRNAs. A high proportion of unintended transcripts silenced by siRNAs showed 3' UTR sequence complementarity to the seed region of the siRNA. Base mismatches within the siRNA seed region reduced the set of original off-target transcripts but generated new sets of silenced transcripts with sequence complementarity to the mismatched seed sequence. An inducible shRNA silenced a subset of transcripts that were silenced by an siRNA of the same sequence, demonstrating that unintended silencing is sequence mediated and is independent of delivery method. In all cases, off-target transcript silencing was accompanied by loss of the corresponding protein and occurred with dependence on siRNA concentration similar to that of silencing of the target transcript. Thus, short stretches of sequence complementarity to the siRNA or shRNA seed region are key to the silencing of unintended transcripts.


Factors associated with development of ileal impaction in horses with surgical colic: 78 cases (1986-2000).
Deal impaction is prevalent in the south-eastern USA, where feeding of Coastal Bermuda hay has been implicated as a risk factor. Alternatively, infection with the tapeworm Anoplocephala perfoliata has been identified as a risk factor for ileal impaction in the UK. We hypothesised that feeding Coastal Bermuda hay and failure to administer routinely an anthelmintic with efficacy against tapeworms would place horses at risk of developing ileal impaction in the USA. Seventy-eight horses, with surgically confirmed ileal impaction and 100 horses admitted for colic that did not have an ileal impaction, were selected retrospectively for logistic regression analysis. Using odds ratios (OR) as an index of risk, feeding Coastal Bermuda hay (OR = 2.9) and failure to administer a pyrantel salt within 3 months of admission (OR = 3.1) placed horses at risk of development of ileal impaction. This study confirms the belief that feeding Coastal Bermuda hay places horses at risk of ileal impaction, although the quality of the hay may also play a role. Periodic administration of anthelmintics with efficacy against tapeworms should be considered to reduce risk of ileal impaction.


[Rhythm analysis in CPR].
It's necessary to interrupt cardiopulmonary resuscitation (CPR) for a reliable automatic external defibrillator (AED) rhythm analysis, because the mechanical activity from the chest compressions introduces artifacts in the electrocardiogram (ECG) that substantially lower the capacity of an AED to judge cardio-electric rhythm. However, repeated interruptions of compression will reduce the quality of CPR, which in turn affect the prognosis of patients with cardiac arrest (CA). In order to improve the quality of CPR, reduce the interruptions of chest compression and implement accurate defibrillation, people have made many efforts on identifying ECG rhythm in CPR. The studies can be grouped into two broad categories: those based on the artificial mixture of ECG data and CPR artifacts and those based on CA data recorded during CPR. This article introduced researches for rhythm recognition in CPR, including sources and characteristics of CPR artifacts, methods of rhythm analysis, and provided a basis for the study of how to improve the accuracy of cardio-electric rhythm recognition.


The design and implementation of a picklist authoring tool.
It is well recognized that controlled medical terminologies play a critical role in Health Information Systems and Clinical Patient Record systems, but the creation and management of customized lists of terms ("picklists") remains a potential obstacle. We have been developing a sophisticated authoring tool that is fully integrated with our terminology server and that will be made available to our system analysts and clinicians.


Estimating analytical variances in measurement of polycyclic aromatic hydrocarbons and application to monitoring contaminants in American lobster (Homarus americanus).
A method is presented for estimating replicate polycyclic aromatic hydrocarbon (PAH) concentrations in American lobster (Homarus americanus) digestive gland tissue based on recoveries of added perdeuterated surrogates from a single satisfactory analysis. PAH concentrations demonstrated a large interanimal variance, even in specimens captured at the same time in the same place. Principal component analysis showed that the variability of the total system of biological variables (carapace length, lobster weight, and digestive gland weight) could be adequately summarized by the first principal component alone in each data set. Ranks provide ordered classification of individuals, allowing data analysis by statistical methods for continuous variables (i.e., analysis of variance). PAH concentrations in individual lobsters were generally highly sensitive to animal size, sex, and fishing area. Efficient monitoring would result from analyzing individual animals of a single sex from a study area, using as small a geographical study area as possible, measuring a single biological variable, and using individual specimens of as narrow a size range as possible.


Local anesthetics for the Nephrologist.
Several specialists in medicine use local anesthetics. In patients with kidney disease, these agents are used during catheter insertions for hemodialysis and peritoneal dialysis, arteriovenous fistula and graft procedures, kidney transplantation, parathyroidectomy, kidney biopsies, and dental and skin procedures. Patients on chronic hemodialysis use a topical application prior to use of needles for arteriovenous fistula cannulation before starting dialysis. They are also used to manage acute and chronic pain conditions, in regional nerve blockade and in multi-modal enhanced recovery protocols. Despite their frequent use by both physicians and patients, data on the use of local anesthetics in patients with kidney impairment are not well reported. This review will summarize the use of local anesthetics in chronic kidney disease, describe their pharmacology and the impact of lower estimated glomerular filtration rate on their pharmacokinetics, and suggest dose regulation in those with kidney dysfunction.


Production of Agu piglets after transfer of embryos produced in vitro.
The present study was conducted to examine the feasibility of in vitro embryo production and transfer technologies for producing piglets of Agu, an Okinawan indigenous pig breed. After collection of oocytes from surgically dissected ovaries, they were subjected to in vitro maturation. After in vitro maturation/fertilization, a total of 616 putative embryos were transferred into four commercial Western pig recipients, one of which became pregnant and farrowed a total of eight Agu piglets. These results demonstrate that in vitro embryo production using ovaries from Agu females is useful for breeding management and conservation of indigenous breeds.


Preliminary study on the effects of Buchholzia coriacea seed extract on male reproductive parameters in rats.
The effects of methanol extract of Buchholzia coriacea seed was studied on male reproductive system of albino rats. Administration of 200mg/kg b.w.(p.o.) of the extract for 6 weeks resulted in significant reduction (P˂0.05) in the weight of the epididymis and seminal vesicle, but not the testes and prostate gland. Also the weight of the visceral organs- lungs, liver, heart and kidney were unaffected. A marked decrease (P<0.05) in sperm motility and volume was also observed in sperm collected from the caudal epididymis of the treated animals. Sperm count and morphology were not significantly affected (P<0.05). Total tissue protein of the epididymis and testes of the treated rats was significantly increased (P<0.05) and fertility was zero in the treated rats. Histological section showed that the epididymal ducts were mostly empty, though the epithelial lining appeared normal. There were fewer spermatozoa and late stage spermatids in the testes, with normal testicular epithelium. The results suggest that the extract of Buchholzia coriacea may have antifertility effects in male rats, the site of action most probably the epididymis.


Heat capacity peak in solid 4He: effects of disorder and 3He impurities.
Heat capacity measurements with significantly improved resolution find the presence of a peak in a solid 4He sample in coexistence with liquid. With improved crystallinity, the peak decreases in height and moves to lower temperature. A hysteretic heat capacity signature consistent with 3He-4He phase separation, not detected in an earlier work is clearly observed.


Premature failure of Kinemax Plus total knee replacements.
We describe a cohort of patients with a high rate of mid-term failure following Kinemax Plus total knee replacement inserted between 1998 and 2001. This implant has been recorded as having a survival rate of 96% at ten years. However, in our series the survival rate was 75% at nine years. This was also significantly lower than that of subsequent consecutive series of PFC Sigma knee replacements performed by the same surgeon. No differences were found in the clinical and radiological parameters between the two groups. At revision the most striking finding was polyethylene wear. An independent analysis of the polyethylene components was therefore undertaken. Scanning electron microscopy revealed type 2 fusion defects in the ultra-high molecular weight polyethylene (UHMWPE), which indicated incomplete boundary fusion. Other abnormalities consistent with weak UHMWPE particle interface strength were present in both the explanted inserts and in unused inserts from the same period. We consider that these type 2 fusion defects are the cause of the early failure of the Kinemax implants. This may represent a manufacturing defect resulting in a form of programmed polyethylene failure.


Socio-Cultural Constraints in Protecting Child Rights in a Society in Transition: A Review and Synthesis from Oman.
In line with international best practice, the Arabian Gulf countries have ratified the Convention on the Right of the Child (CRC), which has some clauses on child abuse and neglect. The present discourse, made from within an Arabian Gulf society, specifically Oman, reviews the socio-cultural differences of the region and explores the potential regional challenges for effectively implementing the CRC mandated child protection legislation. The international best practices evolved for individualistic, "guilt-based" societies, which may need to be modified to suit the "shame-based" collective societies in the Arabian Gulf where the individual autonomy is overridden by that of the family and society. This may mean that the entire spectrum of child abuse may need to be studied in-depth, starting from what constitutes child abuse and neglect, the methods adopted for identifying cases, setting preventive measures in place, applying penal and corrective action on the perpetrators, and helping the victims recover. It is posited that while modifying the laws may be straightforward, implementation of certain clauses may initially come into conflict with deeply engrained socio-cultural conventions on these societies which have different parenting styles and child-rearing practices. The country in focus is Oman. Pointing out the sparsity of research on the topic in the region, the study suggests additional research to understand how to reconcile these sociocultural constraints with the international best practices of protecting child rights.


Dietary lipid and intestinal brush border membrane phospholipid fatty acid composition and glucose transport of channel catfish.
Although the influences of dietary carbohydrate and protein on intestinal brush border membrane functions are well known, the responses to different dietary lipids are less clear, particularly for ectotherms. Therefore, we examined intestinal brush border membrane phospholipid fatty acid composition and rates of glucose transport of catfish fed two diets with different fatty acid profiles. Intestinal brush border membranes of fish fed a diet containing stearic acid had higher concentrations of monoenes, dienes, and trienes but were lower in polyenes and had a lower unsaturation index than those of fish fed a diet with menhaden oil. Rates of glucose transport at low, mid, and high temperatures were higher for intact tissues and vesicles prepared from the brush border membrane of fish fed the stearic acid diet. Our findings indicate that dietary lipids influence intestinal brush border membrane fatty acid composition and the relationship between temperature and rates of glucose transport. However, we can not exclude the possibility that dietary lipids can induce changes in transporter site densities and/or the physical characteristics of membrane microdomains in which the transporters might reside.


Kinetic comparison of cytokinin nucleosidase activity isolated from normally ripening and mutant tomato varieties.
Kinetic parameters for cytokinin nucleosidase activity which catalyzes the deribosylation of N(6)(Delta(2)-isopentenyl)adenosine (I(6)Ado) to produce the more "active" free base N(5)(Delta(2)-isopenetyl)adenine (I(6)Ade) were compared for a normally ripening tomato (Lycopersicon esculentum L.) cultivar Rutgers, and two mutant tomato varieties (Nor and Rin). K(m) for nucleosidase activity in Rutgers was lower (K(m) = 0.1 millimolar) than that in either Nor (K(m) = 0.14 millimolar) or Rin (K(m) = 0.13 millimolar).


Profile and genetic parameters of dairy cattle locomotion score and lameness across lactation.
This study investigated the profile of locomotion score and lameness before the first calving and throughout the first (n=237) and second (n=66) lactation of 303 Holstein cows raised on a commercial farm. Weekly heritability estimates of locomotion score and lameness, and their genetic and phenotypic correlations with milk yield, body condition score, BW and reproduction traits were derived. Daughter future locomotion score and lameness predictions from their sires��� breeding values for conformation traits were also calculated. First-lactation cows were monitored weekly from 6 weeks before calving to the end of lactation. Second-lactation cows were monitored weekly throughout lactation. Cows were locomotion scored on a scale from one (sound) to five (severely lame); a score greater than or equal to two defined presence of lameness. Cows��� weekly body condition score and BW was also recorded. These records were matched to corresponding milk yield records, where the latter were 7-day averages on the week of inspection. The total number of repeated records amounted to 12 221. Data were also matched to the farm���s reproduction database, from which five traits were derived. Statistical analyses were based on uni- and bivariate random regression models. The profile analysis showed that locomotion and lameness problems in first lactation were fewer before and immediately after calving, and increased as lactation progressed. The profile of the two traits remained relatively constant across the second lactation. Highest heritability estimates were observed in the weeks before first calving (0.66 for locomotion score and 0.54 for lameness). Statistically significant genetic correlations were found for first lactation weekly locomotion score and lameness with body condition score, ranging from ���0.31 to ���0.65 and from ���0.44 to ���0.76, respectively, suggesting that cows genetically pre-disposed for high body condition score have fewer locomotion and lameness issues. Negative (favourable) phenotypic correlations between first lactation weekly locomotion score/lameness and milk yield averaged ���0.27 and ���0.17, respectively, and were attributed to management factors. Also a phenotypic correlation between lameness and conception rate of ���0.19 indicated that lame cows were associated with lower success at conceiving. First-lactation daughter locomotion score and/or lameness predictions from sires��� estimated breeding values for conformation traits revealed a significant linear effect of rear leg side view, rear leg rear view, overall conformation, body condition score and locomotion, and a quadratic effect of foot angle.


Evolution of pathological changes in the gastrocnemius of the mdx mice correlate with utrophin and beta-dystroglycan expression.
Utrophin can function in muscle as a substitute for dystrophin and its over-expression has been used successfully to ameliorate mdx muscle pathology. Despite of this fact, there are no detailed studies on the expression of endogenous skeletal muscle utrophin- and dystrophin-associated glycoproteins throughout the life span of mdx mice. We have monitored, sequentially, the expression of matrix metalloproteinase-9 (MMP-9), myosin heavy chain, utrophin and beta-dystroglycan, as well as the mRNA expression of utrophin and of structurally related proteins, in mdx and control mice. We found an inverse relationship between concentration of muscle utrophin and abundance of groups of degenerative-regenerative fibers and of MMP-9 expression. There was also temporal correlation between the decline of utrophin at 15 days of age and the onset of muscle necrosis. Conversely, reappearance of utrophin, with a peak around 2 months of age, was followed by a progressive decline of necrosis. A lineal correlation between utrophin and beta-dystroglycan levels, not seen in controls, indicates that improvement of mdx is due to utrophin binding to dystrophin-associated glycoproteins. Utrophin and other structurally related protein transcripts were not up-regulated, suggesting a post-transcriptional regulation for utrophin in skeletal muscle.


Powered Toothbrushes: An Opportunity for Biofilm and Gingival Inflammation Control.
The present review aimed at a broad investigation on the potential of powered as compared to manual toothbrushes in different aspects of clinical dentistry. Studies evaluating plaque and gingival inflammatory parameters were included, as well as those that investigated adverse effects. Emphasis was given separately to adults, youngsters, special-needs patients, and those under fixed orthodontic therapy. In general, comparisons favored powered toothbrushes. In summary, approximately 68% of the included studies, in terms of plaque/gingival inflammation in adults, presented better results for powered toothbrushes. In children and special-needs populations, approximately 40% of the included studies favored powered toothbrushes for plaque/gingival inflammation, and none favored manual ones. In orthodontic individuals, 50% of the studies also demonstrated a better effect of powered toothbrushes on plaque and gingival inflammation. All included studies that assessed adverse events did not demonstrate a difference in these effects when comparing manual vs. powered toothbrushes. It is concluded that the use of powered toothbrushes is an opportunity to enhance patterns of plaque control and associated gingival inflammation.


Shedding of herpes simplex virus type 1 into saliva.
The shedding of herpes simplex virus Type 1 (HSV-1) into saliva was studied in 110 healthy individuals, 55 patients who were undergoing oral surgery, and 21 immunocompromised patients in an asymptomatic Japanese population. Specimens were collected regularly for up to 2 months from each individual. Virus was recovered on at least one occasion from 4.5% of the healthy individuals, 20% of the patients undergoing oral surgery and 38% of the immunocompromised patients. In those individuals that shed virus, the duration of shedding varied from a mean of 1.2 days in the healthy individuals to 5.8 days in patients undergoing oral surgery, and was 3 days in the immunocompromised patients. The majority of oral surgery patients shed HSV-1 into saliva within 7 days after surgery and immunocompromised patients shed virus almost continuously. The role of surgery in triggering the reactivation of latent HSV-1, and the differences in rates of viral shedding between American and Japanese are discussed.


Plasmin, plasminogen activators and inhibitor in human osteoarthritic cartilage.
Osteoarthritis (OA) is characterized by a progressive erosion of cartilage, which is mediated by the protease degradation of the extracellular matrix components. Plasmin, plasminogen activators (PA) and the inhibitor of plasminogen activator (PAI) are thought to play an important role in the regulation of the OA pathophysiology process. Our study determined the activity of plasmin and PA in OA and normal cartilage. Moreover, the presence and the content of each form of PA, uPA and tPA, as well as the inhibitor PAI-1, were determined using immunohistological techniques and ELISA. Our studies were carried out on fresh cartilage, cultured tissue explants and chondrocytes. OA cartilage demonstrates about 5 times more plasmin activity than the controls (p less than 0.001). Moreover, a statistically significant correlation was found between the plasmin activity and the free collagenolytic form in OA specimens showing severe lesions (r = 0.50; p less than 0.05). Our study revealed that PA content and activity increase in OA cartilage following culture explant experiments. Immunohistochemical studies showed the presence of both uPA and tPA forms in OA cartilage lesions only. Protein determinations revealed uPA as the predominant form. PAI-1 was significantly decreased (p less than 0.04) in OA, and was located mainly extracellularly. Chondrocyte cultures showed the ability to synthesize both forms of PA and PAI-1. Our study demonstrated an increased level of plasmin activity in OA cartilage. This is likely related to increased PA activity, in which the urokinase type appeared to be predominant in OA.(ABSTRACT TRUNCATED AT 250 WORDS)


Lack of emergency medical services documentation is associated with poor patient outcomes: a validation of audit filters for prehospital trauma care.
Our previous Delphi study identified several audit filters considered sensitive to deviations in prehospital trauma care and potentially useful in conducting performance improvement, a process currently recommended by the American College of Surgeons Committee on Trauma. This study validates 2 of those proposed audit filters. We studied 4,744 trauma patients using the electronic records of the Central Region Trauma registry and Emergency Medical Services (EMS) patient logs for the period January 1, 2002, to December 31, 2004. We studied whether requests by on-scene Basic Life Support (BLS) for Advanced Life Support (ALS) assistance or failure by EMS personnel to record basic patient physiology at the scene was associated with increased in-hospital mortality. We performed multivariate analyses, including a propensity score quintile approach, adjusting for differences in case mix and clustering by hospital. Overall mortality was 6.1%. A total of 28.2% (n = 1,337) of EMS records were missing patient scene physiologic data. Multivariate analysis revealed that patients missing 1 or more measures of patient physiology at the scene had increased risk of death (adjusted odds ratio = 2.15; 95% CI, 1.13 to 4.10). In 17.4% (n = 402) of cases BLS requested ALS assistance. Patients for whom BLS requested ALS had a similar risk of death as patients for whom ALS was initially dispatched (odds ratio = 1.04; 95% CI, 0.51 to 2.15). Failure of EMS to document basic measures of scene physiology is associated with increased mortality. This deviation in care can serve as a sensitive audit filter for performance improvement. The need by BLS for ALS assistance was not associated with increased mortality.


Solution conformational preferences of immunogenic peptides derived from the principal neutralizing determinant of the HIV-1 envelope glycoprotein gp120.
With standard one- and two-dimensional proton NMR techniques, a common structural motif has been identified in water solutions of short peptide sequences derived from the envelope glycoprotein gp120 of HIV-1. Three peptides of lengths 12, 24, and 40 residues (termed RP342, RP142, and RP70, respectively) were synthesized, each containing a central amino acid sequence common to many HIV-1 isolates. In addition, RP70 contained a disulfide bond between cysteine residues close to the ends of the molecule, forming a loop that is thought to constitute an important structural and immunological component of the intact glycoprotein. Peptides RP70 and RP142 showed evidence for the presence of a significant population of conformations containing a beta-turn in the conserved sequence Gly-Pro-Gly-Arg. Strong nuclear Overhauser effect (NOE) connectivities were observed between the amide protons of the arginine and the adjacent glycine. A weak NOE connectivity was observed between the C alpha H of the proline residue and the NH of the Arg [a d alpha N(i,i + 2) NOE connectivity], confirming the presence of a conformational preference for a turn conformation in this sequence. The remainder of the peptide showed evidence of conformational averaging: no NMR evidence for a uniquely folded structure was obtained for any of the peptides in water solution. Circular dichroism (CD) spectra indicated that no ordered helix was present in water solutions of RP70, although a CD spectrum that indicated the presence of approximately 30% helix could be induced by the addition of trifluoroethanol.(ABSTRACT TRUNCATED AT 250 WORDS)


Towards a personalised treatment approach for asthma attacks.
Asthma attacks (exacerbations) are common, accounting for over 90 000 UK hospital admissions per annum. They kill nearly 1500 people per year in the UK, have significant associated direct and indirect costs and lead to accelerated and permanent loss of lung function. The recognition of asthma as a heterogeneous condition with multiple phenotypes has revolutionised the approach to the long-term management of the condition, with greater emphasis on personalised treatment and the introduction of the treatable traits concept. In contrast asthma attacks are poorly defined and understood and our treatment approach consists of bronchodilators and systemic corticosteroids. This review aims to explore the current limitations in the description, assessment and management of asthma attacks. We will outline the risk factors for attacks, strategies to modify this risk and describe the recognised characteristics of attacks as a first step towards the development of an approach for phenotyping and personalising the treatment of these critically important events. By doing this, we hope to gradually improve asthma attack treatment and reduce the adverse effects associated with recurrent courses of corticosteroids.


Transcriptional control of human papillomavirus (HPV) oncogene expression: composition of the HPV type 18 upstream regulatory region.
The malignant transformation potential of high-risk human papillomaviruses (HPVs) is closely linked to the expression of the viral E6 and E7 genes. To elucidate the molecular mechanisms resulting in HPV oncogene expression, a systematic analysis of the cis-regulatory elements within the HPV type 18 (HPV18) upstream regulatory region (URR) which regulate the activity of the E6/E7 promoter was performed. As the functional behavior of a given cis-regulatory element can be strongly influenced by the overall composition of a transcriptional control region, individual elements were inactivated by site-directed mutagenesis in the physiological context of the complete HPV18 URR. Subsequently, the effects of these mutations on the activity of the E6/E7 promoter were assessed by transient transfection assays. We found that the transcriptional stimulation of the E6/E7 promoter largely depends on the integrity of cis-regulatory elements bound by AP1, SP1, and in certain epithelial cells, KRF-1. In contrast to previous reports by implying a key role for NF1 and Oct-1 recognition motifs in the stimulation of papillomavirus oncogene expression, the inactivation of these elements in the context of the HPV18 URR did not strongly affect the transcriptional activity of the E6/E7 promoter. Mutation of a promoter-proximal glucocorticoid response element completely abolished dexamethasone inducibility of the HPV18 E6/E7 promoter and resulted in an increase of its basal activity. Functional dissection of the HPV18 constitutive enhancer region indicates that its transcriptional activity is largely generated by functional synergism between a centrally located AP1 module and thus far undetected cis-active elements present in the 5' flank of the enhancer. Furthermore, comparative analyses using homologous and heterologous promoters show that the transcriptional activity of HPV18 enhancer elements is influenced by the nature of the test promoter in a cell-type-specific manner.


[Disability and rehabilitation problems in Russian Federation].
The authors considered theoretic topics, including terminology aspects, of disablement and rehabilitation. The results are up-to-date approaches and measures helping to solve disablement problem that remains among priorities in the state social policies.


Polydopamine Particle as a Particulate Emulsifier.
"Pickering-type" emulsions were prepared using polydopamine (PDA) particles as a particulate emulsifier and n-dodecane, methyl myristate, toluene or dichloromethane as an oil phase. All the emulsions prepared were oil-in-water type and an increase of PDA particle concentration decreased oil droplet diameter. The PDA particles adsorbed to oil⁻water interface can be crosslinked using poly(ethylene imine) as a crosslinker, and the PDA particle-based colloidosomes were successfully fabricated. Scanning electron microscopy studies of the colloidosomes after removal of inner oil phase revealed a capsule morphology, which is strong evidence for the attachment of PDA particles at the oil⁻water interface thereby stabilizing the emulsion. The colloidosomes after removal of inner oil phase could retain their capsule morphology, even after sonication. On the other hand, the residues obtained after oil phase removal from the PDA particle-stabilized emulsion prepared in the absence of any crosslinker were broken into small fragments of PDA particle flocs after sonication.


Spider Telangiectases and Palmar Erythema as Harbingers of Structural Liver Changes in Three Breast Cancer Patients on Ado-trastuzumab Emtansine.
Objective: We describe three patients treated with ado-trastuzumab emtansine who developed either palmar flushing or spider angiomas. We then correlate these findings with radiologic imaging results of the liver. Design: Three consecutive referrals to dermatology for patient skin complaints while taking ado-trastuzumab emtansine were evaluated and found to have either telangiectases or palmar flushing. Two patients who did not have prominent nodularity on computed tomography of the liver underwent transient elastography. Results: All three patients with stigmata of liver disease that developed during the course of ado-trastuzumab emtansine demonstrated parenchymal liver abnormalities. Conclusion: Patients presenting with spider angiomas and/or palmar flushing on adotrastuzumab emtansine should be considered for elastography studies to ensure early structural damage is not occurring. Further investigation is needed to define the precise etiology for these telangiectases and the role of elastography imaging in monitoring patients on long-term adotrastuzumab emtansine.


Negative effects of Microcystis blooms on the crustacean plankton in an enclosure experiment in the subtropical China.
Effects of Microcystis blooms on the crustacean plankton were studied using enclosure experiments during July-September, 2000. Eight enclosures were set in the hypereutrophic Donghu Lake. Different nutrient concentrations through additional nutrient and sediment in enclosures were expected to result in different abundance of Microcystis. From July to early August, the phytoplankton community was dominated by Chlorophyta, Cryptophyta, Bacillariophyta and Cyanophyta other than Microcystis aeruginosa. M. aeruginosa showed a rapid increase during early August in all enclosures and predominated. Crustacean plankton was dominated by the herbivorous Moina micrura, Diaphanosoma brachyurum and Ceriodaphnia cornuta, and the predaceous Mesocyclops sp. and Thermocyclops taihokuensis. During the pre-bloom period, the dynamics of M. micrura population appeared to be mainly affected by the predaceous cyclopoids. With the development of Microcystis blooms, such interaction between M. micrura and cyclopoids seemed weakened, especially when the Microcystis biomass was high. But there was no apparent influence on the interaction between Leptodora kindti and its zooplanktonic prey. The density of two cyclopoids decreased with the enhancement of Microcystis. The density decline of M. micrura was caused by both predation and inhibition by Microcystis. The low food availability of other edible phytoplankton during the blooms led to low densities of both C. cornuta and D. brachyurum by late August. It appears that dense Microcystis blooms exert strong negative effects on the herbivorous cladocerans and the predaceous cyclopoids.


What is the actual cost of providing the intrauterine system for contraception in a UK community sexual and reproductive health setting?
The anticipated increase in uptake of intrauterine system (IUS) fittings is slower than predicted by the National Institute for Health and Clinical Excellence (NICE). There is evidence to suggest that this is because of a high perceived cost of providing this contraceptive method. Whereas studies to date have all guessed at these costs, we calculated the actual costs of providing the IUS. We tracked the notes of 283 women who had an IUS fitted in our community sexual and reproductive health service for 5 years. We recorded duration of use, measured the actual cost of all appointments and interventions over the lifespan of the device, and compared our findings with NICE predicted costs. With 70% complete follow-up, the average duration of use of the IUS was 3.44 years compared to NICE's prediction of 3.32. The average annual cost of providing an IUS for contraception in community clinics was £54.55 per woman; this compares with £70.49 modelled by NICE for provision in primary care. Most (80%) of the cost is incurred in the first year. The cost of managing problems is small. Providing the IUS for contraception was 23% cheaper in the present study than that predicted by NICE and cheaper than providing combined oral contraception in our service. Fitting IUSs in community clinics may be cheaper than in primary care. Streamlining the patient pathway will reduce costs further. Restricting access to the IUS because of initial cost is a false economy.


Synthesis of (S)-alpha-amino oleic acid.
An efficient synthesis of (S)-alpha-amino oleic acid was developed. The fully protected FA derivative was obtained in four steps starting from methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-oxopentanoate. These steps are (i) olefination of the starting aldehyde with the appropriate phosphonate anion, (ii) hydrogenation of the double bonds, (iii) controlled reduction of omega-ethyl ester to an aldehyde in the presence of alpha-methyl ester, and (iv) a Wittig reaction of the latter aldehyde with the suitable ylide. Free alpha-amino oleic acid was prepared after deprotection of the amino group followed by saponification in a total yield of 24%. N-tert-Butoxycarbonyl-protected amino oleic acid and the corresponding amino alcohol were prepared in high yield. The structures of the products have been established by various spectroscopic techniques.


Psychosocial well-being of patients with inoperable non-small cell lung cancer. The importance of treatment- and disease-related factors.
Patients with inoperable non-small cell lung cancer, limited disease, were randomized to either chemotherapy (cisplatin and etoposide) or radiotherapy of the thorax. A set of questionnaires, covering 4 areas: psychosocial well-being, medical side effects, physical function, and everyday activity was filled out by 101 patients. The correlations between psychosocial well-being (dependent variable) on the one hand, and medical side effects, physical function, and everyday activity (independent variables) on the other were subjected to multiple regression analysis. No significant correlation was found between psychosocial well-being and chemotherapy- or radiotherapy-related subjective side effects. The disease-related symptoms correlated highly with psychosocial well-being during the observation period. Psychosocial well-being and the independent variables tended to be more strongly correlated during the follow-up period (14-52 weeks) than during the treatment period.


Papaya Leaf Curl Virus (PaLCuV) Infection on Papaya (Carica papaya L.) Plants Alters Anatomical and Physiological Properties and Reduces Bioactive Components.
Papaya leaves are used frequently for curing scores of ailments. The medicinal properties of papaya leaves are due to presence of certain bioactive/pharmacological compounds. However, the papaya leaf curl virus (PaLCuV), a geminivirus, is a major threat to papaya cultivation globally. During the present investigation, we observed that PaLCuV infection significantly altered the anatomy, physiology, and bioactive properties of papaya leaves. As compared to healthy leaves, the PaLCuV-infected leaves were found to have reduced stomatal density (76.83%), stomatal conductance (78.34%), photosynthesis rate (74.87%), water use efficiency (82.51%), chlorophyll (72.88%), carotenoid (46.63%), osmolality (48.55%), and soluble sugars (70.37%). We also found lower enzymatic activity (superoxide dismutase (SOD), ascorbate peroxidase (APX), and catalase (CAT)-56.88%, 85.27%, and 74.49%, respectively). It was found that the size of guard cells (50%), transpiration rate (45.05%), intercellular CO2 concentration (47.81%), anthocyanin (27.47%), proline content (74.17%), malondialdehyde (MDA) (106.65%), and electrolyte leakage (75.38%) was elevated in PaLCuV-infected leaves. The chlorophyll fluorescence analysis showed that the infected plant leaves had a significantly lower value of maximal quantum yield of photosystem II (PSII (Fv/Fm), photochemical quantum yield of photosystem I (PSI (Y(I)), and effective quantum yield of PSII (Y(II)). However, in non-photochemical quenching mechanisms, the proportion of energy dissipated in heat form (Y(NPQ)) was found to be significantly higher. We also tested the bioactivity of infected and healthy papaya leaf extracts on a Caenorhabditis elegans (C. elegans) model system. It was found that the crude extract of papaya leaves significantly enhanced the life span of C. elegans (29.7%) in comparison to virus-infected leaves (18.4%) on application of 100 µg/mL dose of the crude extract. Our research indicates that the PaLCuV-infected leaves not only had anatomical and physiological losses, but that pharmacological potential was also significantly decreased.


Sexual health policies in other industrialized countries: are there lessons for the United States?
Health professionals have been concerned about the high rates of unwanted and unplanned pregnancy, teenage pregnancy, abortion, and sexually transmitted diseases in the U.S. A major concern has been why these rates in the U.S. are so much higher than in most other western industrialized countries. In this article I summarize major national and comparative studies that have attempted to understand how the U.S. can do better in providing for the sexual health of its citizens. I also discuss approaches to sexual health in countries that do substantially better on the aforementioned indicators of sexual health. This review indicates that the recommendations of health and social science experts in the U.S. are consistent with approaches in countries where programs have done a better job in meeting the sexual health needs of their populations.


Assessing the dynamic range and peak capacity of nanoflow LC-FAIMS-MS on an ion trap mass spectrometer for proteomics.
Proteomics experiments on complex mixtures have benefited greatly from the advent of fast-scanning ion trap mass spectrometers. However, the complexity and dynamic range of mixtures analyzed using shotgun proteomics is still beyond what can be sampled by data-dependent acquisition. Furthermore, the total liquid chromatography-mass spectrometry (LC-MS) peak capacity is not sufficient to resolve the precursors within these mixtures, let alone acquire tandem mass spectra on all of them. Here we describe the application of a high-field asymmetric waveform ion mobility spectrometry (FAIMS) device as an interface to an ion trap mass spectrometer. The dynamic range and peak capacity of the nanoflow LC-FAIMS-MS analysis was assessed using a complex tryptic digest of S. cerevisiae proteins. By adding this relatively simple device to the front of the mass spectrometer, we obtain an increase in peak capacity >8-fold and an increase in dynamic range of >5-fold, without increasing the length of the LC-MS analysis. Thus, the addition of FAIMS to the front of a table-top mass spectrometer can obtain the peak capacity of multidimensional protein identification technology (MudPIT) while increasing the throughput by a factor of 12.


Di-μ-azido-κN:N-bis-{aqua-[bis-(1H-benzimidazol-2-ylmeth-yl)amine]-copper(II)} dinitrate.
In the centrosymmetric dinuclear title complex, [Cu(2)(N(3))(2)(C(16)H(15)N(5))(2)(H(2)O)(2)](NO(3))(2), the Cu(II) ion is in a distorted octa-hedral coordination environment with long axial Cu-N(azide) [2.821 (6) Å] and Cu-O(water) [2.747 (5) Å] bonds as a result of the Jahn-Teller effect. Two symmetry-related azide ligands bridge in μ(2)-modes giving a Cu⋯Cu distance of 3.533 (2) Å. In the crystal, N-H⋯O and O-H⋯O hydrogen bonds link the components into a three-dimensional network. In addition, there are weak inter-molecular C-H⋯N hydrogen bonds and π-π stacking inter-actions with centroid-centroid distances ranging from 3.562 (2) to 3.974 (2) Å.


[Research Progress of Skin-substitute and Its Effectiveness Evaluation].
Skin-substitute has developed rapidly and it is essential to evaluate its effectiveness before clinical use.This paper reviews the development of skin-substitute,methods to evaluate the effectiveness of skin-substitute and relevant standards.This paper highlights the in vitro and in vivo means of preclinical effectiveness evaluation and provides theoretical basis for preclinical safety evaluation of skin-substitute.


Incident atrial fibrillation and risk of death in adults with chronic kidney disease.
Atrial fibrillation (AF) frequently occurs in patients with chronic kidney disease (CKD); however, the long-term impact of development of AF on the risk of death among patients with CKD is unknown. We studied adults with CKD (glomerular filtration rate <60 mL/min per 1.73 m(2) by the Chronic Kidney Disease Epidemiology Collaboration equation) identified between 2002 and 2010 who were enrolled in Kaiser Permanente Northern California and had no previously documented AF. Incident AF was identified using primary hospital discharge diagnoses or ≥2 outpatient visits for AF. Death was comprehensively ascertained from health plan administrative databases, Social Security Administration vital status files, and the California death certificate registry. Covariates included demographics, comorbidity, ambulatory blood pressure, laboratory values (hemoglobin, proteinuria), and longitudinal medication use. Among 81 088 adults with CKD, 6269 (7.7%) developed clinically recognized incident AF during a mean follow-up of 4.8±2.7 years. There were 2388 cases of death that occurred after incident AF (145 per 1000 person-years) compared with 18 865 cases of death during periods without AF (51 per 1000 person-years, P<0.001). After adjustment for potential confounders, incident AF was associated with a 66% increase in relative rate of death (adjusted hazard ratio 1.66, 95% CI 1.57 to 1.77). Incident AF is independently associated with an increased risk of death in adults with CKD. Further study is needed to understand the mechanisms by which CKD is associated with AF and to identify potentially modifiable risk factors to decrease the burden of AF and subsequent risk of death in this high-risk population.


Gatekeepers and sentinels. Their consolidated effects on inpatient medical care.
Evaluations assessing precertification by nurse gatekeepers and onsite monitoring by nurse sentinels report inconclusive unique effects of these programs on the utilization, expense, and appropriateness of inpatient medical care. By applying the fixed- and random-effects paradigm of meta-analysis, this article consolidates the results of all relevant quasi-experiments conducted by an evaluation group of a large private insurer from 1986 to 1990. It determines the difference in effect between the target and comparison groups, reports this effect and its statistical range, and determines the pooled effect and its range. The random effects indicate that precertification will reduce admissions, and onsite, concurrent review will reduce length of stay, bed days, and inpatient ancillary expense. The precertification and onsite programs may reduce negative iatrogenic effects, thereby enhancing the patients' well-being. If applied to privately insured populations who are still served on a fee-for-service basis, the gatekeeper and sentinel effects of these programs may reduce utilization and expense; however, inference of these results to Medicare fee-for-service care remains problematical.


A day in the life of a junior doctor: everyday ethical encounters.
This paper presents a hypothetical 'day in the life' of junior doctors working on a busy hospital ward. It illustrates the fact that, although the everyday ethical encounters faced by doctors are generally not as dramatic as some of the ethical issues discussed at medical school, the underlying principles, such as consent, confidentiality and resource allocation, are highly relevant to daily practice. After presenting some of the ethical challenges faced by junior doctors, from patients confused by poor explanations to inadequate consent procedures, the paper ends with suggestions on how to improve the situation.


Population pharmacokinetics of ponesimod and its primary metabolites in healthy and organ-impaired subjects.
Ponesimod, a selective, orally active S1P1 receptor modulator, reduces total blood lymphocyte counts by blocking the egress of lymphocytes from lymphoid organs. It is currently in clinical development for the treatment of relapsing-remitting multiple sclerosis. Ponesimod has two primary metabolites, M12 and M13, that circulate in human plasma. The work presented in this paper predicts and quantifies the accumulation of ponesimod and both metabolites in healthy and organ-impaired subjects. Based on clinical data including studies in renally and hepatically impaired subjects, a population pharmacokinetic (PK) model was developed to characterize the PK of ponesimod and its primary metabolites and to qualify and quantify the influence of organ impairment on the concentration-time profiles of these compounds. As hepatic and renal function are critical for the elimination of the majority of drugs, being able to quantify their influence is important for the treatment in these populations. The PK of ponesimod and its metabolites were characterized by 2 compartments for each of the analytes, inter-connected via a liver compartment that serves as a physiologically meaningful approach to model first-pass metabolism. Absorption and elimination were described by first-order processes whereas metabolism was found to be saturable at supratherapeutic doses. Body weight and hepatic impairment were identified as significant covariates. Whereas the effect of body weight is small and within the margins of between-subject variability, hepatic impairment markedly affects the PK of ponesimod and its metabolites with up to 9-fold higher steady-state exposure in subjects with severe hepatic impairment.


Estrogen receptor beta is expressed in human stomach adenocarcinoma.
In stomach adenocarcinoma, the role of the hormonal receptor, estrogen receptor (ER), has been controversial. Recently, a new estrogen receptor, called estrogen receptor beta (ER beta), was found to be expressed in various tissues including normal gastrointestinal tract. In this paper, the expression of ER beta in stomach adenocarcinomas has been investigated for the first time, specifically in signet ring cell adenocarcinomas, together with surrounding non-cancerous tissues. By immunohistochemistry the expression of ER alpha and beta was studied in 29 stomach adenocarcinomas, ten signet ring cell adenocarcinomas, and 19 other adenocarcinomas. Western blotting was performed to examine the immunohistochemical result. Statistical studies (Student's t test and chi(2)-test) explored the relation between the immunohistochemical result and clinicopathological characteristics. All 29 adenocarcinomas, including the signet ring cell ones, demonstrated clear ER beta nucleus staining. Lymphocytes, venous endothelial cells, smooth muscle, and non-cancerous stomach glands also showed strong ER beta staining, while no staining was observed in the immunohistochemistry of ER alpha. Western blotting showed equivalent ER beta protein levels in cancerous and non-cancerous tissues, which was consistent with the results of immunohistochemical staining. Among signet ring cell adenocarcinomas of the stomach, cytoplasm were stained in addition to nuclei, specifically in patients under the age of 40 years. Our results imply that the effects of estrogen in stomach cancer, as well as those in normal stomach, may be mediated by ER beta, and that the role of ER beta may differ by the subtype of stomach adenocarcinoma - specifically signet ring cell adenocarcinomas and other ones - although large scale samples are needed to confirm these findings.


Theoretical structure-activity study of mutagenic allyl chlorides.
Ab initio molecular orbital calculations at the STO-3G and 3-21G levels were used to clarify the mechanism of mutagenic action of various substituted allyl chlorides. Computed molecular properties were compared with experimental mutagenic potentials of these allylic compounds. In agreement with experiment, the computational results suggest that the primary mechanism of action involves the SN1 formation of allylic cations which then react with nucleophilic centers of nucleic acid bases. The usefulness of computed properties in estimating the degree of alkylating activity and mutagenicity was evaluated. In general, stability of the allylic carbocation intermediate and the degree of charge delocalization in the allyl system correlate well with observed mutagenic potentials.


A 41-year-old male with cough, wheeze, and dyspnea poorly responsive to asthma therapy.
Reactive airway disease is often triggered by an upper respiratory viral infection and readily responds to anti-inflammatory and bronchodilator therapy. The differential diagnosis for unresponsive disease includes poorly controlled asthma, noncompliance with medical regimen, vocal cord dysfunction, rhinosinusitis, gastroesophageal reflux disease or recurrent aspiration, foreign body aspiration, allergic bronchopulmonary aspergillosis, Churg-Strauss vasculitis, cardiac disorders such as congestive heart failure or mitral stenosis, or other pulmonary disorders such as chronic obstructive pulmonary disease, alpha-1 antitrypsin deficiency, interstitial lung disease, bronchiectasis, sarcoidosis, hypersensitivity pneumonitis, pulmonary embolism, cystic fibrosis, airway neoplasms, or laryngotracheomalacia. As is often the case, a meticulous history can expeditiously direct the clinician to the diagnosis, especially in a patient without a smoking, asthmatic, or atopic history.


The combinatorial centre of excellence - a unique industrial academic partnership.
The Combinatorial Centre of Excellence (CCE) offers a unique opportunity for the exploitation of a broad range of combinatorial methodologies. Many areas of activity are under investigation, including high-throughput X-ray of small molecules, parallel polymer chemistry and the development of new multi-component reactions.


Wildlife conservation status and disease trends: ten years of reports to the Worldwide Monitoring System for Wild Animal Diseases.
Disease is an increasingly recognised threat to wild animal populations and the conservation of endangered species. The World Organisation for Animal Health (OIE) Worldwide Monitoring System for Wild Animal Diseases (WAHIS-Wild) serves as the main global information portal for wildlife disease events, compiled via voluntary reporting by countries on non-OIE-listed diseases. The first decade of reports to WAHIS-Wild were analysed to identify trends and examine their relevance for conservation. Between 2008 and 2018, a total of 4,229 wildlife disease events were reported, with the majority from the European continent. When standardised for nomenclature changes, 54 unique previous or current non-OIE-listed diseases were reported. The most common disease events (collectively representing > 50% of reports) were chemical poisoning (12.5% of events reported), infection with low pathogenic avian influenza viruses (11.9%), infection with Salmonella enterica (10.8%), infection with Pasteurella spp. (8.4%) and infection with Trichomonas spp. in birds and reptiles (7.5%). Reports indicated disease in 501 unique species, 19.2% of which are listed as endangered species based on the International Union for Conservation of Nature (IUCN) Red List of Threatened Species, and 30.7% of which are protected under the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES). The findings suggest reporting gaps, including likely geographical area and other biases. More systematic reporting of wildlife disease and use of this information in biodiversity assessment and decision-making would result in better animal health and conservation coordination in a One Health context.


[Clinical effect and safety of 144-week treatment with entecavir capsules in treatment-naïve HBeAg-positive patients with chronic hepatitis B].
Objective: To investigate the clinical effect and safety of entecavir capsules in the treatment of treatment-naïve HBeAg-positive patients with chronic hepatitis B (CHB). Methods: A total of 158 HBeAg-positive CHB patients were given oral entecavir capsules at a dose of 0.5 mg/time once a day for 144 weeks. Clinical outcome and safety were evaluated at baseline and at 24, 48, 72, 96, 120, and 144 weeks of treatment respectively. The Fisher's exact test was used for the analysis of categorical data. Results: After 144 weeks of treatment, 90.91% of all patients achieved virologic response (< 69 IU/ml), the normalization rate of alanine aminotransferase was 88.18%, the clearance rate of HBeAg was 33.33%, and the seroconversion rate of HBeAg was 24.07%. Of all patients, 2 dropped out due to adverse events and 5 experienced serious adverse reactions. Conclusion: Entecavir capsules can inhibit viral replication and have good safety in treatment-naïve HBeAg-positive CHB patients.


Extensive porosity at the cement-femoral prosthesis interface: a preliminary study.
This study is the first description of the extensive porosity which is preferentially located at the cement-prosthesis interface of cemented femoral components of total hip replacements. The observation is important because the interfacial porosity may decrease the strength of the cement-femoral prosthesis interface and jeopardize the mechanical integrity of the cement mantle. We examined the cement-metal interfaces from a multiplicity of in vivo and in vitro specimens using both optical and scanning electron microscopy. These samples included several stem designs, implants made from either Co-Cr or Ti alloy, implants made with a variety of surface finishes and both centrifuged and uncentrifuged cement. All in vivo and in vitro samples had marked porosity in the cement focally concentrated at the cement-metal interface. The amount of porosity at the interface greatly exceeded the amount of general porosity found throughout the bulk cement. Centrifuging did not affect the interfacial porosity, and neither did alloy nor surface finish. The presence of these pores may be explained by the rheological characteristics of the cement.


Alterations of chondroitin sulfate synthesized by chick embryo cartilage cultured in the presence of 6-aminonicotinamide.
Treatment of day-4 chick embryos with 6-aminonicotinamide (6-AN) impairs limbs chondrogenesis and produces micromelia. Interference with limb cartilage development may be related to decreased NAD-dependent synthesis of ATP due to the fact that chondrogenesis is dependent upon anaerobic metabolism. To better understand the effect of 6-AN on chondrogenesis, isolated cartilage epiphyses from day-11 chick embryos were treated in vitro. Sulfate incorporation into total glycosaminoglycans of treated epiphyses was 30% of control. Incorporation of [3H]glucosamine was normal. Fractionation by gel chromatography showed that 40% of the glycosaminoglycans synthesized by treated cells had a molecular weight of less than 15000 compared with 5% of that of the control. A decrease in amount of chondroitin 6-sulfate, an increase of chondroitin 4-sulfate and no change in amount of unsulfated polysaccharide were observed. These results suggest that, upon exposure to 6-AN, chondrocytes produce shorter than normal chondroitin sulfate chains that are preferentially sulfated in the 4 position. Since endochondral bone formation plays an integral role in growth and development of the limb, a defect in production of chondroitin sulfate, a major constituent of cartilage matrix, appears to be involved in 6-AN-induced micromelia.


Artificial Intelligence Models Do Not Ground Negation, Humans Do. GuessWhat?! Dialogues as a Case Study.
Negation is widely present in human communication, yet it is largely neglected in the research on conversational agents based on neural network architectures. Cognitive studies show that a supportive visual context makes the processing of negation easier. We take GuessWhat?!, a referential visually grounded guessing game, as test-bed and evaluate to which extent guessers based on pre-trained language models profit from negatively answered polar questions. Moreover, to get a better grasp of models' results, we select a controlled sample of games and run a crowdsourcing experiment with subjects. We evaluate models and humans against the same settings and use the comparison to better interpret the models' results. We show that while humans profit from negatively answered questions to solve the task, models struggle in grounding negation, and some of them barely use it; however, when the language signal is poorly informative, visual features help encoding the negative information. Finally, the experiments with human subjects put us in the position of comparing humans and models' predictions and get a grasp about which models make errors that are more human-like and as such more plausible.


Endothelium and high blood pressure.
Due to its strategic anatomical position, the endothelium is constantly exposed to the different risk factors for atherosclerosis. During the last decade it has become clear that hypertension profoundly affects endothelial function. Depending on the form of hypertension, endothelium-dependent relaxation is impaired in most vascular beds. In spontaneous hypertension, the production of nitric oxide, which in endothelial cells is formed from L-arginine via the constitutively expressed enzyme endothelial nitric oxide synthase, represents the main mediator of endothelium-dependent vasodilation and seems to be enhanced. On the other hand, the release of endothelium-dependent contracting factors such as prostaglandin H2 and thromboxane A2 have been demonstrated in this model of hypertension. Similar results have been obtained in the forearm circulation of patients with essential hypertension. In contrast, in models of salt-sensitive hypertension no release of vasoconstrictor prostanoids can be found indicating a decreased production of nitric oxide. Thus, in spontaneous hypertension an increased production of nitric oxide seems to occur, which is ineffective due to either the simultaneous release of endothelium-dependent vasoconstrictors and/or inactivation of nitric oxide, or due to anatomical changes such as hypertension-induced intimal thickness which inhibits its action on vascular smooth muscle cells. In summary, in hypertension, endothelium-dependent vasodilation is blunted and the endothelial L-arginine nitric oxide pathway is altered. These changes seem to represent a consequence rather than a cause of hypertension.


Assessment of frailty syndrome using Edmonton frailty scale in Polish elderly sample.
The aim of the study was to assess the incidence and severity of the frailty syndrome assessed with the Edmonton Frailty Scale. This is a cross-sectional study conducted among 382 patients (236 men and 146 women, mean age 71.9 years). The Edmonton Frailty Scale was administered during the patient's admission to the hospital. The Polish adaptation was performed using the standard methodology. The Cronbach's alpha coefficient for the whole Edmonton Frailty Scale was 0.709. The mean correlation between positions and the overall result was r = 0.180. There were no statistically significant differences between women and men in the area of Edmonton Frailty Scale mean score (p < 0.05). The socio-clinical analysis, showed statistically significant differences in the age of respondents, educational attainment, occupational activity, number of drugs taken and co-occurrence of chronic diseases. A higher values of the Edmonton Frailty Scale were indicated for individuals >70 years than for those <70 years (p < 0.001). The Edmonton Frailty Scale proved to be a reliable tool which may be used in the Polish population. The use of this questionnaire for frailty syndrome may be helpful in everyday clinical practice.


Presentation and experimental verification of a physico-mathematical model describing the migration across functional barrier layers into foodstuffs.
For several years there has been an ongoing controversial scientific discussion about the so-called functional barrier concept which, although mostly connected with the re-use of recycled plastics for food packaging, has general relevance and is principally applicable to any type of multilayer structure. Concerning the definition of the efficiency of a functional barrier there exists different understandings, ranging from the absolute physical barrier requirement over the acceptance of toxicologically insignificant migration to a completely lag time-related definition. The starting point of this work was the fact that functional barriers are in most cases already in-situ-contaminated due to the thermally extreme coextrusion conditions of the manufacturing process. As a consequence, middle layer contaminants may already have penetrated the functional barrier of a food package and may provide direct contact with the foodstuff at the time when the package is filled. Nevertheless, depending on the individual food package parameters, the remaining functional barrier efficiency can still prevent inadmissible migration. To meet this real-life situation and to describe the underlying migration process a theoretical migration model was developed and experimentally verified in this work using artificially-contaminated multilayer HIPS sheets with different functional barrier thicknesses. An important result of this study was the finding that compared with the interdiffusion between the package's layers in situ during their formation in the coextrusion process, the interdiffusion at ambient temperature until the filling time point of the package is able to be neglected.


Parathyroid hormone-related peptide-secreting pancreatic neuroendocrine tumours: case series and literature review.
Parathyroid hormone-related peptide (PTHrP) was discovered in 1987 as the tumour product responsible for humoral hypercalcaemia of malignancy (HHM). Pancreatic neuroendocrine tumours (NETs) are uncommon malignancies with an incidence of 1:100,000 population. PTHrP-secreting NETs are rare but are being recognised as a cause of HHM in NETs. We describe the largest series to date and the management of these rare tumours. One male and 4 female patients were seen in our unit from 1998 to 2006. The average duration of follow-up was 86 months from initial diagnosis. All patients had a histologically confirmed diagnosis of pancreatic NET, all of which were low-grade tumours. PTHrP assay was performed in 4 of 5 cases and was elevated in these patients. Initial management involved surgery in 2 of 5 cases, whilst 2 cases underwent chemotherapy and 1 case was commenced on interferon-alpha. We discuss the further therapies that all patients underwent and the complexities that arose in managing disease progression as well as resistant hypercalcaemia. PTHrP-secreting tumours should be considered in the differential diagnosis of patients with NETs who present with hypercalcaemia and a disproportionately low PTH. PTHrP tumours may well be underestimated as the assay is difficult to perform and may not be requested. In hypercalcaemic patients the standard management acutely includes intravenous fluids, diuretics and intravenous bisphosphonate. In the further management, somatostatin analogue therapy is the first medical option to consider and we discuss the role of other therapies.


[Effect of hypoxia-inducible factor-1alpha inhibition caused by RNA interference on permeability of hypoxic endothelial cells].
To study the effect of hypoxia-inducible factor-1alpha (HIF-1alpha) inhibition caused by RNA interference on permeability of hypoxic vascular endothelial (VE) cells. Plasmid pcDNA6.2-GW/EmGFP-miR was applied to construct the RNA interference expression vector targeted to human HIF-1alpha gene. VE cells were divided into normal control group (NC), hypoxia group (H, cells were treated for hypoxia in mixed gas with 1% O(2) for 6 hours), transfection group (T), and transfection hypoxia group (TH, transfected with vector and treated with hypoxia). Expression of HIF-1alpha mRNA in NC and T groups were determined with RT-PCR. Expression of HIF-1alpha protein in each group was determined with Western blot. The permeability of VE cell monolayer was detected by fluorospectrophotometer. Another sample of VE cells were divided into dimethyloxallyl glycine (DMOG) group, transfected with DMOG group (TD), normal control group (NC), and transfection group (T), with 1 mmol/L DMOG (HIF-1alpha specific derivant) replacing hypoxia treatment. The expression of HIF-1alpha protein in each group was determined with Western blot. All data were recorded as density value ratio except for permeability data, which was recorded as fluorescence intensity value. Data were processed with t test (pairwise comparison among groups). The relative content of HIF-1alpha mRNA of cells in NC group (0.765 +/- 0.069) was significantly higher than that of cells in T group (0.093 +/- 0.007, t = 16.696, P < 0.05). Content of HIF-1alpha protein of cells in TH group (0.591 +/- 0.029) was significantly lower than that of cells in H group (2.612 +/- 0.259, t = 13.415, P < 0.05). Content of HIF-1alpha protein of cells in TD group (0.566 +/- 0.008) was significantly lower than that of cells in DMOG group (3.243 +/- 0.551, t = 6.975, P < 0.05). The permeability of cell monolayer in H group (41.6 +/- 11.1) was significantly higher than that of cell monolayer in NC group (9.4 +/- 1.5, t = 6.238, P < 0.05). The permeability of cell monolayer in TH group (13.3 +/- 4.5) was markedly lower than that of cell monolayer in H group (t = 5.430, P < 0.05). The expression of HIF-1alpha gene in vascular endothelial cells is effectively inhibited by specific RNA interference, which significantly prevents the hypoxia-induced increase in vascular endothelial cell permeability.


The Evolution of Nephrectomy and Patient Characteristics in Metastatic Renal Cell Carcinoma Patients Enrolled Into First-Line Tyrosine Kinase Inhibitors Clinical Trials.
The objective of this study was to compare rates of nephrectomy (Nx) in, and characteristics of, patients with metastatic renal cell carcinoma (mRCC) enrolled in prospective clinical trials of tyrosine kinase inhibitors (TKIs) that were completed through (Group 1) versus after (Group 2) 2007. Searching online databases, we retrospectively identified phase I to III trials with ≥ 15 patients with mRCC treated with first-line TKIs, alone or in combination with other agent(s). Of 70 trials identified, 42 were included in the analysis (n = 6074 patients). Compared with Group 1, Group 2 patients had significantly less Nx (85.7% vs. 93.7%; P < .001) and prior cytokine therapy (11.1% vs. 46.8%; P < .001). Group 2 also had significantly fewer patients with good prognostic risk (based on Memorial Sloan-Kettering Cancer Center criteria) or performance status (both P < .001). Group 2 patients had a significantly greater objective response rate than Group 1 patients (intent-to-treat analysis: 28.6% vs. 23.1%, respectively; P < .001), whereas Group 1 patients had significantly more stable disease. Clinical benefit was similar in both groups (P = .157), and the means of median progression-free survival were comparable (8.2 and 9.0 months in Groups 1 and 2, respectively; P = .2528). Use of Nx in mRCC patients participating in clinical trials has declined in the TKI era. More patients with worse prognostic risk profiles are participating in first-line TKI trials after 2007, but objective response rates are higher. Despite patient characteristics that favor the earlier group, progression-free survival is similar as TKIs have replaced cytokines as first-line therapy.


Influence of air pollutants on allergic sensitization: the paradox of increased allergies and decreased resistance to infection.
Air pollution has long been associated with health risks such as increased susceptibility to respiratory infections and potentiation of asthmatic-type responses. Experimental evidence in rodents indicates that air pollutants including diesel exhaust particles (DEPs), gases, and metals cause lung injury, inflammation, reduce aspects of host defense, and may potentiate allergic airway responses. Here we present evidence that diesel exhaust particles delivered by inhalation or aspiration can exacerbate allergic lung disease depending on the material's chemical properties. Genomic analysis of mouse lungs following instillation or inhalation of DEPs shows an alteration spectrum of pathways associated with immune signaling, cell metabolism, and oxidative stress. Diesel exposure also may worsen respiratory infections through depression of protective immune responses. Here we show that mice exposed to diesel and co-infected with influenza had increased influenza virus titers as well as higher levels of lung injury and inflammation in association with increased Th2 cytokines, and a concomitant decrease in Th1 polarization. A simplified model explains how the potentiation of the Th2 arm of immunity by diesel exhaust results in increased allergic sensitization, whereas cell-mediated (protective) immunity against viral infections is simultaneously reduced.


Brief report: the smiles of a child with autism spectrum disorder during an animal-assisted activity may facilitate social positive behaviors--quantitative analysis with smile-detecting interface.
We quantitatively measured the smiles of a child with autism spectrum disorder (ASD-C) using a wearable interface device during animal-assisted activities (AAA) for 7 months, and compared the results with a control of the same age. The participant was a 10-year-old boy with ASD, and a normal healthy boy of the same age was the control. They voluntarily participated in this study. Neither child had difficulty putting on the wearable device. They kept putting on the device comfortably through the entire experiment (duration of a session was about 30-40 min). This study was approved by the Ethical Committee based on the rules established by the Institute for Developmental Research, Aichi Human Service Center. The behavior of the participants during AAA was video-recorded and coded by the medical examiner (ME). In both groups, the smiles recognized by the ME corresponded with the computer-detected smiles. In both groups, positive social behaviors increased when the smiles increased. Also, negative social behaviors decreased when the smiles increased in the (ASD-C). It is suggested that by leading the (ASD-C) into a social environment that may cause smiling, the child's social positive behaviors may be facilitated and his social negative behaviors may be decreased.


Cysteamine oxygenase: possible involvement of superoxide ion in the catalytic mechanism.
The reaction catalyzed by cysteamine oxygenase on cysteamine in the presence of phenazine methosulphate as cofactor like compound is inhibited by nitroblue tetrazolium, a scavenger of superoxide ions. The reaction is not inhibited by superoxide dismutase and allyl alcohol and it is not activated by superoxide ions produced in solution. Nitroblue tetrazolium is reduced by cysteamine or mercaptoethanol and phenazine methosulphate. This reaction is completely inhibited by superoxide dismutase. In the presence of cysteamine oxygenase the reduction with mercaptoethanol is greatly enhanced and it is only partially inhibited by superoxide dismutase. According to these data a reaction mechanism is proposed in which superoxide ions and thiyl radicals are produced at the active site during catalysis.


Papillary tumor of the pineal region.
Presented is a patient with papillary tumor of the pineal region (PTPR), an uncommon and recently recognized neoplasm. As its name implies, PTPR does not arise from the pineal gland itself. The cell of origin is thought to be the specialized ependymocytes of the subcommissural organ. Primary tumors of the pineal region include pineal parenchymal neoplasms, germ cell neoplasms, and tumors arising from adjacent structures, including meningiomas, astrocytomas, and ependymomas. Like other masses in this location, PTPR often leads to obstructive hydrocephalus. Due to the relative paucity of reported cases of PTPR, its natural history is unknown.


Case-mix reimbursement for nursing home services: simulation approach.
Nursing home reimbursement based on case mix is a matter of growing interest. Several States either use or are considering this reimbursement method. In this article, we present a method for evaluating key outcomes of such a change for Connecticut nursing homes. A simulation model is used to replicate payments under the case-mix systems used in Maryland, Ohio, and West Virginia. The findings indicate that, compared with the system presently used in Connecticut, these systems would better relate dollar payments to measure patient need, and for-profit homes would benefit relative to nonprofit homes. The Ohio methodology would impose the most additional costs, the West Virginia system would actually be somewhat less expensive in terms of direct patient care payments.


Out of programme experience: going away to bring something back: closing the loop.
In the January 2011 edition of Frontline Gastroenterology, I was the lead author of an article: Out of programme experience and training: going away to bring something back. 1 Since then, I have taken time out of my speciality training programme-an out of programme experience. I thought it would be of interest to trainees to read about how I organised my out of programme experience and how this time away has helped me to develop my unique selling point.


Chest wall myositis in a patient with acute coronary syndrome.
We describe a case of a 42-year-old man who presented to the emergency department with severe left-sided chest pain and chest tenderness of 1-day duration. The pain was episodic and was aggravated by any chest wall movement. His initial blood tests and ECG were suggestive of acute coronary syndrome (ACS). However, his pattern of pain, lack of response to opiates, raised creatine kinase and signs of pleurisy on chest radiograph raised a suspicion of an alternative diagnosis. The patient showed a dramatic response in pain relief to non-steroidal anti-inflammatory medication. He was suspected to have chest wall myositis with pleural involvement in the form of pleurodynia. His serology test was positive for coxsackie virus antibodies. We will discuss in this case report the pathognomonic features, diagnosis and treatment of a rare infectious condition known as Bornholm disease.


The influence of client characteristics on psychologists' ethical beliefs: an empirical investigation.
Do psychologists' ethical beliefs depend upon client characteristics? In the current study, licensed psychologists were surveyed regarding their ethical beliefs using an adaptation of a frequently used list of therapist behaviors rated for ethicality (Pope, Tabachnick, & Keith-Spiegel, 1987). In the current survey, the age, sex, and diagnostic severity of the hypothetical client were specified and varied between participants. Results indicated a significant interaction between client age and client sex, such that older male clients elicited lower overall ethicality ratings than did younger male clients, but older female clients elicited higher overall ethicality ratings than did younger female clients. This finding was especially robust when a subset of therapist behaviors involving assertive or discomforting therapist actions was considered.