Non-medical use of prescription pain relievers among high school students in China: a multilevel analysis.
Given the differences between general high school (GHS) and vocational high school (VHS) students, this study aimed to investigate the lifetime prevalence of non-medical use of prescription pain relievers (NMUPPR) among high school students as well as the associations between NMUPPR and individual-level factors and school category. A cross-sectional study was conducted in GHS and VHS students in 2012 in Chongqing, and 11 906 students' questionnaires were completed and qualified for the survey. Self-reported NMUPPR and information regarding individual-level determinants and school category were collected. A multilevel multivariate logistic regression model was fitted to explore independent predictors of NMUPPR. The total lifetime prevalence of NMUPPR was 11.3%, and NMUPPR was more prevalent among VHS students (15.8%) compared with GHS students (9.8%). Overall, the results indicated that VHS students were more likely to be involved in NMUPPR (adjusted OR (AOR)=1.64, 95% CI 1.42 to 1.89). Regarding the individual-level predictors of NMUPPR, below-average family economic status was negatively correlated with NMUPPR (AOR=0.77, 95% CI 0.60 to 0.98), and students with more pocket money were more likely to be engaged in NMUPPR. Students who had difficult family relationships, had poor relationships with teachers, had parents or friends who engaged in non-medical prescription drug use, and considered or attempted suicide were more likely to be engaged in NMUPPR. NMUPPR among high school students is a multidetermined phenomenon. The current findings indicate that VHS students are an important subgroup of adolescents and highlight the need for additional research as well as targeted prevention and intervention programmes for NMUPPR.


Modeling and Parallel Operation of Exchange-Biased Delta-E Effect Magnetometers for Sensor Arrays.
Recently, Delta-E effect magnetic field sensors based on exchange-biased magnetic multilayers have shown the potential of detecting low-frequency and small-amplitude magnetic fields. Their design is compatible with microelectromechanical system technology, potentially small, and therefore, suitable for arrays with a large number N of sensor elements. In this study, we explore the prospects and limitations for improving the detection limit by averaging the output of N sensor elements operated in parallel with a single oscillator and a single amplifier to avoid additional electronics and keep the setup compact. Measurements are performed on a two-element array of exchange-biased sensor elements to validate a signal and noise model. With the model, we estimate requirements and tolerances for sensor elements using larger N. It is found that the intrinsic noise of the sensor elements can be considered uncorrelated, and the signal amplitude is improved if the resonance frequencies differ by less than approximately half the bandwidth of the resonators. Under these conditions, the averaging results in a maximum improvement in the detection limit by a factor of N. A maximum N≈200 exists, which depends on the read-out electronics and the sensor intrinsic noise. Overall, the results indicate that significant improvement in the limit of detection is possible, and a model is presented for optimizing the design of delta-E effect sensor arrays in the future.


Computational quantification of metabolic fluxes from a single isotope snapshot: application to an animal biopsy.
Quantitative determination of metabolic fluxes in single tissue biopsies is difficult. We report a novel analysis approach and software package for in vivo flux quantification using stable isotope labeling. We developed a protocol based on brief, timed infusion of (13)C isotope-enriched substrates for the tricarboxylic acid (TCA) cycle followed by quick freezing of tissue biopsies. NMR measurements of tissue extracts were used for flux estimation based on a computational model of carbon transitions between TCA cycle metabolites and related amino acids. To this end, we developed a computational framework in which metabolic systems can be flexibly assembled, simulated and analyzed. Flux parameters were quantified from NMR multiplets by a partial grid search followed by repeated Nelder-Mead optimizations implemented on a computer grid. We implemented a model of the TCA cycle and showed by extensive simulations that the timed infusion protocol reliably quantitates multiple fluxes. Experimental validation of the method was done in vivo on hearts of anesthetized pigs under two different conditions: basal state (n = 7) and cardiac stress caused by infusion of dobutamine (n = 7). About nine tissue samples (40-200 mg dry-weight) were taken per heart. TCA cycle flux was 6.11 +/- 0.28 (SEM) micromol/min x gdw at baseline versus 9.29 +/- 1.03 micromol/min x gdw for dobutamine stress. Oxygen consumption calculated from the TCA cycle flux and from 'gold standard' blood gas-based measurements were close, correlating with r=0.88 (P < 10(-4)). Spatial heterogeneity in metabolic fluxes is detectable amongst the small samples. We propose that our novel isotope snapshot methodology is suitable for flux measurements in biopsies in vivo. Non-profit organizations will, upon request, be granted a non-exclusive license to use the software for internal research and teaching purposes at no charge. A web interface for using the software on our computer grid is available under http://www.ibi.vu.nl/programs/


In vivo priming of HIV-specific CTLs determines selective cross-reactive immune responses against poorly immunogenic HIV-natural variants.
Degeneracy of the TCR repertoire might allow for cross-recognition of epitope variants. However, it is unclear how the first encounter with HIV Ags determines recognition of emerging epitope variants. This question remains crucial in the choice of HIV vaccine sequences given the virus variability. In this study, we individualized nine natural mutations within an HIV-Nef(180-189) epitope selected from several HIV-infected individuals. These variants of Nef(180-189) sequence display slightly different HLA-A2 binding capacities and stabilities and we have shown that only two induced a strong CTL response in vivo in HLA-A2 transgenic mice after a single injection. We demonstrated that priming with these two immunogenic variants generated a specific pattern of cross-reactive CTL repertoire directed against poorly immunogenic peptides. Thus, the range of peptide variants recognized by HIV-specific CTL depends upon the Ag encountered during primary immunization of CD8 lymphocytes. These data have practical implications in the development of cross-reactive vaccines against HIV.


Extensive multiple test centre evaluation of the VecTest malaria antigen panel assay.
To determine which species and populations of Anopheles transmit malaria in any given situation, immunological assays for malaria sporozoite antigen can replace traditional microscopical examination of freshly dissected Anopheles. We developed a wicking assay for use with mosquitoes that identifies the presence or absence of specific peptide epitopes of circumsporozoite (CS) protein of Plasmodium falciparum and two strains of Plasmodium vivax (variants 210 and 247). The resulting assay (VecTest Malaria) is a rapid, one-step procedure using a 'dipstick' test strip capable of detecting and distinguishing between P. falciparum and P. vivax infections in mosquitoes. The objective of the present study was to test the efficacy, sensitivity, stability and field-user acceptability of this wicking dipstick assay. In collaboration with 16 test centres world-wide, we evaluated more than 40 000 units of this assay, comparing it to the standard CS ELISA. The 'VecTest Malaria' was found to show 92% sensitivity and 98.1% specificity, with 97.8% accuracy overall. In accelerated storage tests, the dipsticks remained stable for > 15 weeks in dry conditions up to 45 degrees C and in humid conditions up to 37 degrees C. Evidently, this quick and easy dipstick test performs at an acceptable level of reliability and offers practical advantages for field workers needing to make rapid surveys of malaria vectors.


Cryptochlorogenic acid and its metabolites ameliorate myocardial hypertrophy through a HIF1α-related pathway.
Cryptochlorogenic acid (4-CQA) is a phenolic acid that has antioxidant and anti-inflammatory activities. Our preliminary study found that 4-CQA has a good effect on isoproterenol (ISO)-induced myocardial hypertrophy, while the mechanism remains largely unknown. This study aimed at delineating the metabolites and metabolic pathways of 4-CQA using liquid mass spectrometry and molecular biotechnology, exploring possible active metabolites and the mechanism of myocardial hypertrophy amelioration in H9c2 cells, and finally, investigating the pharmacokinetics of 4-CQA and its active metabolites in vivo. In summary, 56 potential effective metabolites were distinguished in rat urine, feces, plasma samples and heart tissue after intragastric administration of 4-CQA, and the main metabolic reaction types of 4-CQA included hydrogenation, methylation, glucuronidation, sulfation, hydration and their composite reactions in in vivo biotransformation. Besides, 4-CQA and its main active metabolites, caffeic acid and 4-O-feruloylquinic acid, significantly ameliorated pathological cardiac hypertrophy of H9c2 cells treated with ISO based on the Akt/mTOR/HIF-1α pathway. In addition, this study demonstrated that the prototype drugs 4-CQA and 4-O-ferulylquinic acid generally exhibit similar pharmacokinetic characteristics and caffeic acid presents relatively late peak time and low peak concentration in rats, which make them suitable candidate drugs.


Preparation and properties of Pue-loaded HA-ADH-PS nanomicelles.
Puerarin (Pue) is the most abundant isoflavonoid in kudzu root. It has been widely used as a therapeutic agent for the treatment of cardiovascular diseases. However, poor-bioavailability of puerarin is the main obstacle to its widespread clinical applications. In this paper, HA-ADH-PS nanomicelles were prepared by chemical modification, noncovalent modification and etc, and characterized by means of FT-IR, ultraviolet (UV) and thermogravimetric analysis (TG). The encapsulation efficiency and drug loading of Pue-loaded HA-ADH-PS nanomicelles were 45.1% and 19.89% by UV, respectively. It could be observed from the transmission electron microscopy (TEM) images that HA-ADH-PS micelles appeared obvious spherical structure in the water. The particle size of HA-ADH-PS nanomicelles and Pue-loaded HA-ADH-PS nanomicelles were about 136.8 nm and 119.5 nm with a PDI of 0.237 and 0.272, respectively. The fluorescence probe method was used to characterize the critical micelle concentration, the critical micelle concentration (CMC) value of the nanomicells was 0.002 g/L and the results met the requirements and ensured the stability of micelles after dilution. DPPH assay suggested that Pue-loaded HA-ADH-PS nanomicelles had an obvious radical scavenging effect in vitro. MTT test showed that Pue-loaded HA-ADH-PS nanomicelles was non-toxic and had good biocompatibility. Thus, Pue-loaded HA-ADH-PS nanomicelles could be used as a potential drug carrier for puerarin.


Performance and specificity of monoclonal immunoassays for cyclosporine monitoring: how specific is specific?
Immunoassays designed for the selective measurement of cyclosporin A (CsA) inadvertently show cross-reactivity for CsA metabolites. The extent and clinical significance of the resulting overestimation is controversial. A comprehensive assessment of old and new methods in clinical specimens is needed. In a comprehensive evaluation, CsA was analyzed in 145 samples with the new CEDIA assay and compared with the Emit assay with the old and new pretreatments, the TDx monoclonal and polyclonal assays, the AxSYM, and HPLC. All samples were from patients with liver and/or kidney transplants. The CEDIA offered the easiest handling, followed by the AxSYM, which showed the longest calibration stability. The TDx monoclonal assay provided the lowest detection limit and the lowest CVs. The mean differences compared with HPLC were as follows: Emit, 9-12%; CEDIA, 18%; AxSYM, 29%; and TDx monoclonal, 57%. The CycloTrac RIA paralleled the Emit results. In contrast to the mean differences, substantial (>200%) and variable overestimations of the CsA concentration were observed in individual patient samples. Metabolic ratios, estimates of the overall concentrations of several cross-reacting metabolites (nonspecific TDx polyclonal/specific reference method), correlated with the apparent biases of the various monoclonal assays. Metabolic ratios varied up to 10-fold, which translated into biases for individual samples between -7% and +174%. The higher the cross-reactivity of an assay was, the higher was the range of biases observed. The interindividual differences markedly exceeded other factors of influence (organ transplanted, hepatic function). Because assay bias cannot be predicted in individual samples, substantially erratic CsA dosing can result. The specificity of CsA assays for parent CsA remains a major concern.


How are elderly patients treated after a diagnosis of metastatic colorectal cancer in real-life practice? A study in a French teaching hospital.
Metastatic colorectal cancer (mCRC) is frequent among elderly patients. However, in the era of new targeted therapies, little is known about real-life mCRC treatment in this population. This study aimed to describe elderly mCRC patients and the current real-life treatment practices. mCRC patients aged ≥65 years were identified using the registry of multidisciplinary team meetings, mandatory for all cancer patients, held between January 1, 2013 and June 30, 2014 at the Bordeaux University Hospital. Data were collected from medical records using a standardized questionnaire. Treatment type was defined as follows: at least one anticancer medication administered vs. best supportive care (BSC). A total of 78 patients were included; median age was 74 years and the M/F sex ratio 1.6. Eleven patients (14.1%) were referred to a geriatric oncology consultation. One patient died before treatment initiation, 28 (35.9%) had BSC, and 49 (62.8%) were treated with anticancer medications: 20 (25.6%) had chemotherapy combined with a targeted therapy, and 28 (35.9%) chemotherapy alone (one missing data for treatment). Compared to patients treated with anticancer medications, BSC patients were older (P < 0.0001) and had more often metachronous metastases (P = 0.01), more comorbidities (P = 0.05), and a greater number of concomitant medications (P = 0.004). This study is one of the rare investigations providing insight to treatment practices in all elderly mCRC patients, not just those who receive anticancer medications. Our results suggest that efforts must be pursued to better integrate geriatric oncology in daily clinical practice.


The unintended effects of a boxed warning.
To demonstrate a real-life correlation that after the US Food and Drug Administration introduced a boxed warning concerning malignancies to the labeling for topical calcineurin inhibitors, reluctance to use topical calcineurin inhibitors has led to their substitution with other therapies that have their own risks. An anonymous survey of attendees of the 2007 Fall Clinical Dermatology conference in Las Vegas, Nevada, from October 17-19, 2007. More than 95 percent of attendees were dermatologists; a small number of mid-level practitioners attended as well. Of nearly 700 attendees, the first 504 who agreed to complete the survey were included. More than 40 percent of dermatologists surveyed claimed that more than 20 percent of their atopic dermatitis patients are not adequately controlled since the introduction of the boxed warning. Forty-eight percent claim that more than 20 percent of those patients were adequately controlled with topical calcineurin inhibitors as part of their regimens. Eighty percent of dermatologists surveyed agree that more than 10 precent of those patients were adequately controlled with topical calcineurin inhibitors in their regimens. While caution is usually prudent, the introduction of a boxed warning in the case of topical calcineurin inhibitors has led to the use of treatments that often have greater risks than the topical calcineurin inhibitors that they replaced.


Effects of tocotrienols on cell viability and apoptosis in normal murine liver cells (BNL CL.2) and liver cancer cells (BNL 1ME A.7R.1), in vitro.
The effects of tocotrienols on murine liver cell viability and their apoptotic events were studied over a dose range of 0-32 microg mL(-1). Normal murine liver cells (BNL CL.2) and murine liver cancer cells (BNL 1ME A.7R.1) were treated with tocotrienols (T(3)), alpha tocopherol (alpha-T) and the chemo drug, Doxorubicin (Doxo, as a positive control). Cell viability assay showed that T(3) significantly (P < or = 0.05) lowered the percentage of BNL 1ME A.7R.1 cell viability in a dose-responsive manner (8-16 microg mL(-1)), whereas T did not show any significant (P>0.05) inhibition in cell viability with increasing treatment doses of 0-16 microg mL(-1). The IC(50) for tocotrienols were 9.8, 8.9, 8.1, 9.7, 8.1 and 9.3 microg mL(-1) at 12, 24, 36, 48, 60 and 72 hours respectively. Early apoptosis was detected 6 hours following T(3) treatment of BNL 1ME A.7R.1 liver cancer cells, using Annexin V-FITC fluorescence microscopy assay for apoptosis, but none were observed for the non-treated liver cancer cells at the average IC(50) of 8.98 microg mL(-1) tocotrienols for liver cancer cells. Several apoptotic bodies were detected in BNL 1ME A.7R.1 liver cancer cells at 6 hours post-treatment with tocotrienols (8.98 microg mL(-1)) using Acridine Orange/Propidium Iodide fluorescence assay. However, only a couple of apoptotic bodies were seen in the non-treated liver cancer cells and the BNL CL.2 normal liver cells. Some mitotic bodies were also observed in the T(3)-treated BNL 1ME A.7R.1 liver cancer cells but were not seen in the untreated BNL 1ME A.7R.1 cells and the BNL CL.2 liver cells. Following T(3)-treatment (8.98 microg mL(-1)) of the BNL 1ME A.7R.1 liver cancer cells, 24.62%, 25.53% and 44.90% of the cells showed elevated active caspase 3 activity at 9, 12 and 24 hours treatment period, respectively. DNA laddering studies indicated DNA fragmentation occurred in the T(3)-treated liver cancer cells, BNL 1ME A.7R.1 but not in non-treated liver cancer cells and the T(3)-treated and non-treated normal liver cells. These results suggest that tocotrienols were able to reduce the cell viability in the murine liver cancer cells at a dose of 8-32 microg mL(-1) and that this decrease in percentage cell viability may be due to apoptosis.


Synergistic Effect on Neurodegeneration by N-Truncated Aβ4-42 and Pyroglutamate Aβ3-42 in a Mouse Model of Alzheimer's Disease.
The N-terminally truncated pyroglutamate Aβ3-42 (AβpE3-42) and Aβ4-42 peptides are known to be highly abundant in the brain of Alzheimer's disease (AD) patients. Both peptides show enhanced aggregation and neurotoxicity in comparison to full-length Aβ, suggesting that these amyloid peptides may play an important role in the pathogenesis of AD. The aim of the present work was to study the direct effect of the combination of AβpE3-42 and Aβ4-42 on ongoing AD-related neuron loss, pathology, and neurological deficits in transgenic mice. Bigenic mice were generated by crossing the established TBA42 and Tg4-42 mouse models expressing the N-truncated Aβ peptides AβpE3-42 and Aβ4-42, respectively. After generation of the bigenic mice, detailed phenotypical characterization was performed using either immunostainings to evaluate amyloid pathology or quantification of neuron numbers using design-based stereology. The elevated plus maze was used to study anxiety levels. In order to evaluate sensori-motor deficits, the inverted grid, the balance beam and the string suspension tasks were applied. We could demonstrate that co-expression of AβpE3-42 and Aβ4-42 accelerates neuron loss in the CA1 pyramidal layer of young bigenic mice as seen by reduced neuron numbers in comparison to single transgenic homozygous mice expressing either AβpE3-42 or Aβ4-42. This observation coincides with the robust intraneuronal Aβ accumulation observed in the bigenic mice. In addition, loss of anxiety and motor deficits were enhanced in an age-dependent manner. The sensori-motor deficits correlate with the abundant spinal cord pathology, as demonstrated by robust intracellular Aβ accumulation within motor neurons and extracellular Aβ deposition. Our observations demonstrate that a combination of AβpE3-42 and Aβ4-42 has a stronger effect on ongoing AD pathology than the peptides alone. Therefore, AβpE3-42 and Aβ4-42 might represent excellent potential therapeutic targets and diagnostic markers for AD.


Notes on the genus Xestopus from China, with description of a new species (Carabidae,Sphodrini, Dolichina).
The genus Xestopus Andrewes, 1937 in China is reviewed, with the description of a new species: X. gutangensis Zhu & Kavanaugh, sp. nov. (type locality: Xizang: Mêdog, 29.46414°N, 95.73563°E). The male of X. cyaneus Sciaky & Facchini, 1997 is described for the first time, and the first record of this species in Yunnan, China, represents an eastward range extension for the species. A key is provided for the eight known species of the genus.


Study of Neurodermatitis Circumscripta Patients with Psychological Tests.
2.54 percent of patients attending the dermatology clinic were found to have neurodermatitis circumscripta. Twenty adult male patients with the disease who were p educated at least u to high school were p subjected to detailed psychological testing. They were administered 10 cards of TAT Sinha's anxiety scale,- self-rating depression scale of Zung and Wechsler adult intelligence scale tests. AU the patients were found to have high IO levels. Anxiety of a very high degree was observed in 55.8 percent of the patients. Anxiety levels were high in patients who were eldest in the family. Sixty five per cent of patients showed high degree of depression, which was more apparent in the younger age group. Patients with first and second ordinal position were more depressed. No relationship was found between the disease and the financial and cdcational status, duration and extent of disease and 1.Q., anxiety or depression levels. Need (n) affifiation and (n) achievement were the two most dominant needs expressed.


Mapping blood traits to structural organization of the brain in rhesus monkeys.
Hematological and biochemical blood traits have been linked to brain structural characteristics in humans. However, the relationship between these two domains has not been systematically explored in nonhuman primates, which are crucial animal models for understanding the mechanisms of brain function and developing therapeutics for various disorders. Here we investigated the associations between hematological/biochemical parameters and the brain's gray matter volume and white matter integrity derived from T1-weighted and diffusion magnetic resonance imaging in 36 healthy macaques. We found that intersubject variations in basophil count and hemoglobin levels correlated with gray matter volumes in the anterior cingulum, prefrontal cortex, and putamen. Through interactions between these key elements, the blood parameters' covariation network was linked with that of the brain structures, forming overarching networks connecting blood traits with structural brain features. These networks exhibited hierarchical small-world architecture, indicating highly effective interactions between their constituent elements. In addition, different subnetworks of the brain areas or fiber tracts tended to correlate with unique groups of blood indices, revealing previously unknown brain structural organization. These results provide a quantitative characterization of the interactions between blood parameters and brain structures in macaques and may increase the understanding of the body-brain relationship and the pathogenesis of relevant disorders.


Two SERK genes are markers of pluripotency in Cyclamen persicum Mill.
The genetic basis of stem cell specification in somatic embryogenesis and organogenesis is still obscure. SOMATIC EMBRYOGENESIS RECEPTOR-LIKE KINASE (SERK) genes are involved in embryogenesis and organogenesis in numerous species. In vitro culture of Cyclamen persicum immature ovules provides a system for investigating stem cell formation and maintenance, because lines forming either organs or embryos or callus without organs/embryos are available for the same cultivar and plant growth regulator conditions. The present aim was to exploit this property of cyclamen cultures to understand the role of SERK(s) in stem cell formation and maintenance in somatic embryogenesis and organogenesis in vitro, in comparison with expression in planta. CpSERK1 and CpSERK2 were isolated from embryogenic callus. CpSERK1 and CpSERK2 levels by RT-PCR showed that expression is high in embryogenic, moderate in organogenic, and null in recalcitrant calli. in situ hybridizations showed that the expression of both genes started in clumps of pluripotent stem cells, from which both pre-embryogenic aggregates and organ meristemoids derived, and continued in their trans-amplifying, meristem-like, derivatives. Expression declined in organ meristemoids, in parallel with a partial loss of meristematization. In mature somatic embryos, and in shoot and root primordia, CpSERK1 and CpSERK2 were expressed in meristems, and similar patterns occurred in zygotic embryo and primary meristems in planta. The results point to SERK1 and SERK2 as markers of pluripotency in cyclamen. It is proposed that the high expression of these genes in the trans-amplifying derivatives of the stem cells maintains a pluripotent condition leading to totipotency and, consequently, somatic embryogenesis.


Microbial fermentation of Fossence™, a short-chain fructo-oligosaccharide, under simulated human proximal colonic condition and assessment of its prebiotic effects-a pilot study.
A short-chain fructo-oligosaccharide (sc-FOS) was tested in a simulator of the human gut microbial ecosystem (SHIME) in vitro model to quantify its prebiotic effects according to Prebiotic Index (PI) and Measure of prebiotic effect (MPE) equations. FossenceTM, (sc-FOS, 0.5%) was fermented in a simulated human proximal colonic condition, using a fecal inoculum from a healthy individual. We analysed the pH reduction, substrate utilization, lactate and short-chain fatty acid (SCFA) production and microbial community modulation. Microbial fermentation of sc-FOS strongly reduced the media pH indicating the production of lactate and SCFA with accumulation of lactate and enhanced levels of acetate (34.38 ± 0.38 mM), propionate (20.93 ± 0.56 mM) and butyrate (4.93 ± 0.03 mM) compared to 18.46 ± 0.20 mM, 6.24 ± 0.10 mM and 3.3 ± 0.06 mM in the blank, respectively. Total SCFA production in test media was 61.91 ± 0.87 mM compared to 33.65 ± 0.36 mM in blank and the contribution of free-sugars present in sc-FOS to SCFAs was negligible. Modulation of the microbial community was analysed through 16S rRNA sequencing and we found that sc-FOS greatly stimulated the beneficial bacteria such as Bifidobacteria and Lactobacillus. We report the PI and MPE values for FossenceTM, as 14.9 and 0.01 respectively at the end of 24 h, which is an indicator of a strong prebiotic effect.


Hydrogen sulfide selectively potentiates central preganglionic fast nicotinic synaptic input in mouse superior mesenteric ganglion.
Hydrogen sulfide (H2S) plays important roles in the enteric system in the wall of the gastrointestinal tract. There have been no studies on whether H2S is endogenously generated in peripheral sympathetic ganglia and, if so, its effect on synaptic transmission. In this study, we examined the effect of H2S on cholinergic excitatory fast synaptic transmission in the mouse superior mesenteric ganglion (SMG). Our study revealed that NaHS and endogenously generated H2S selectively potentiated cholinergic fast EPSPs (F-EPSPs) evoked by splanchnic nerve stimulation but not F-EPSPs evoked by colonic nerve stimulation. The H2S-producing enzyme cystathionine-γ-lyase (CSE) was expressed in both neurons and glial cells. The CSE blocker PAG (dl-propargylglycine) significantly reduced the amplitude of F-EPSPs evoked by splanchnic nerve stimulation but not F-EPSPs evoked by colonic nerve stimulation. Inhibiting the breakdown of endogenously generated H2S with stigmatellin potentiated the amplitude of F-EPSPs evoked by splanchnic nerve stimulation but not F-EPSPs evoked by colonic nerve stimulation. Splanchnic F-EPSPs but not colonic F-EPSPs were reduced in CSE knock-out (KO) mice. Functional studies showed that NaHS enhanced the inhibitory effect of splanchnic nerve stimulation on colonic motility. Colonic motility in CSE-KO mice was significantly higher than colonic motility in wild-type mice. We conclude that endogenously generated H2S acted selectively on presynaptic terminals of splanchnic nerves to modulate fast cholinergic synaptic input and that this effect of H2S modulates CNS control of gastrointestinal motility. Our results show for the first time that the facilitatory effect of endogenous H2S in the mouse SMG is pathway specific.


Phase transition in a triplet process.
We argue that the reaction-diffusion process 3A-->4A,3A-->2A exhibits a different type of continuous phase transition from an active into an absorbing phase. Because of the upper critical dimension d(c)> or =4/3 we expect the phase transition in 1+1 dimensions to be characterized by nontrivial fluctuation effects.


[A case of urachal carcinoma associated with elevated levels of CA19-9].
A 53-year-old man was admitted with the chief complaint of gross hematuria. Cystoscopic examination revealed a non-papillary tumor at the dome of the bladder. The plasma level of CA19-9 was markedly elevated before treatment. Total cystectomy with en bloc removal of the tumor and radical lymphadenectomy were performed under the diagnosis of urachal carcinoma. The plasma CA19-9 level decreased to the normal level after operation and was well correlated with postoperative course. The monitoring of CA19-9 may be useful for follow up in patients showing a high elevation of CA19-9.


Formation of a Hydroxymethylfurfural-Cysteine Adduct and Its Absorption and Cytotoxicity in Caco-2 Cells.
Adducts of 5-hydroxymethylfurfural (HMF)-amino acids are formed during food processing and digestion; the elimination capacity of in vitro intestinal digests of biscuits, instant noodles, and potato crisps for HMF is 652, 727, and 540 μg/g, respectively. However, the safety of these adducts is unknown. In this study, an HMF-cysteine adduct named 1-dicysteinethioacetal-5-hydroxymehtylfurfural (DCH), which was found to be produced in the gastrointestinal tract after HMF intake, was prepared to test its effect toward Caco-2 cells. Compared with HMF, the adduct displayed lower cytotoxicity against Caco-2 cells with an IC50 value of 31.26 mM versus 14.95 mM (HMF). The DCH did not induce cell apoptosis, whereas HMF significantly increased the apoptosis rate after incubation at concentrations of 16, 32, and 48 mM for 72 h. DCH showed an absorption rate considerably lower than that of HMF by Caco-2 cells. Lower absorption of DCH may result in lower toxicity compared with HMF against Caco-2 cells. Intracellular transformation of DCH has been observed.


An Exploration of Online Behaviors and Social Media Use Among Hookah and Electronic-Cigarette Users.
The purpose of this study was to explore the relationship between social norms and attitudes towards ENDS and hookah and use of these products. We conducted surveys with hookah and ENDS users who regularly used the Internet and social media and analyzed the primary social media account (e.g. Facebook) of each participant, coding all references to nicotine or tobacco products. The survey included domains on perceived favorability, perceived vulnerability and subjective norms. We surveyed 21 ENDS users and 20 hookah users. Both groups used the Internet to look up information about their respective tobacco product (95% for hookah vs. 90% for ENDS). Seventy percent of hookah users had references to hookah on their social media profiles while 43% of ENDS users had references to ENDS on their page. The majority of both groups were exposed to content posted by friends in their social media network about their respective products online. Those who posted on social media about hookah and those who read about ENDS online had lower perceived vulnerability to the health risks associated with tobacco products. Hookah and ENDS users actively use the Internet and social media to obtain and share information about nicotine/tobacco products. Study participants who use hookah were more likely to share photos and discuss hookah related activities via social media than those who use ENDS. Social networks also represent valuable and untapped potential resources for communicating with this group about risks and harm reduction related to emerging nicotine/tobacco products.


Up-regulation of histamine H4 receptors contributes to splenic apoptosis in septic mice: counteraction of the antiapoptotic action of nuclear factor-kappaB.
The histamine H(4) receptor is the most recently identified receptor and is considered to play a role in a variety of inflammatory diseases. Histamine levels in the plasma are known to be elevated in animal models of sepsis and in septic patients. The aim of this study was to test the hypothesis that the H(4) receptor may play a significant role in the pathophysiology of sepsis. Polymicrobial sepsis was induced by cecal ligation and puncture in BALB/c mice. Although the H(4) receptor gene was undetectable in normal peripheral key organs, with the exception of the spleen, the expression levels of this gene were highly up-regulated in all those organs of septic mice. In vivo transfection of nuclear factor-kappaB (NF-kappaB) decoy oligodeoxynucleotide, but not of its scrambled form, resulted in a great inhibition of sepsis-induced overexpression of the H(4) receptor gene. In septic mice, marked increases in caspase-3 activation and follicular lymphocyte apoptosis in spleens were strongly suppressed by systemic treatment with synthetic small interfering RNA (siRNA) targeted to the H(4) receptor. This was associated with the up-regulation of a number of antiapoptotic proteins. These antiapoptotic effects of H(4) receptor siRNA treatment were all inhibited by further application of NF-kappaB decoy oligonucleotide. Our results suggest that superinduction of the histamine H(4) receptor gene in peripheral key organs, including the spleen, that is promoted by sepsis is transcriptionally controlled by NF-kappaB, whereas stimulation of this receptor is involved in the development of sepsis-induced splenic apoptosis through counteraction of the antiapoptotic action of NF-kappaB.


Sanofi vows to limit price hikes- but will it make much difference?
Sanofi's commitment to limit prices to the rise in the National Health Expenditure Data Accounts--estimated to be 5.6% annually from 2016 to 2025--is not enough, experts said.


Block Copolymer of Flexible and Semi-Flexible Block Confined in Nanopost Array.
Coarse-grained molecular dynamics simulations of a diblock copolymer consisting of a flexible and semi-flexible block in a dense array of parallel nanoposts with a square lattice packing were performed. The mutual interactions between the two blocks of the confined diblock chain were investigated through a comparison of their size, structure, and penetration among nanoposts with the corresponding separate chains. The geometry of a nanopost array was varied at constant post separation or at constant width of the passage between nanoposts. The size of a single interstitial volume was comparable to or smaller than the size of the diblock chain. A comparison of the blocks with their separate analogous chains revealed that the mutual interactions between the blocks were shielded by the nanoposts and, thus, the blocks behaved independently. At constant passage width, competitive effects of the axial chain extension in interstitial volumes and the lateral chain expansion among interstitial volumes led to a nonmonotonic behavior of the axial span. The position of the maximum in the span plotted against the filling fraction for a diblock chain was dictated by the semi-flexible block. The semi-flexible block penetrates among the nanoposts more readily and the expansion of the whole diblock copolymer is governed by the semiflexible block. The main findings were explained using the free energy arguments when an interstitial volume was approximated by a channel geometry and a passage aperture by a slit geometry. Detail knowledge of controlled conformational behavior in a compartmentalized environment can contribute to new processes in the storage and retrieval of information.


Supernova hemorrhage: obliterative hemorrhage of brain arteriovenous malformations following γ knife radiosurgery.
Hemorrhage represents the most feared complication of cerebral arteriovenous malformations (AVMs) in both untreated patients and those treated with gamma knife radiosurgery. Radiosurgery does not immediately lead to obliteration of the malformation, which often does not occur until years following treatment. Post-obliteration hemorrhage is rare, occurring months to years after radiosurgery, and has been associated with residual or recurrent AVM despite prior apparent nidus elimination. Three cases are reported of delayed intracranial hemorrhage in patients with cerebral AVMs treated with radiosurgery in which no residual AVM was found on catheter angiography at the time of delayed post-treatment hemorrhage. That the pathophysiology of these hemorrhages involves progressive venous outflow occlusion is speculated and the possible mechanistic link to subsequent vascular rupture is discussed.


[Relation of ME491/CD63 gene and integrin alpha5 in the invasion and metastases of ovarian cancer].
To explore the expression and significance of ME491/CD(63) and integrin alpha5 protein and mRNA in ovarian cancer. The expression levels of ME491/CD(63) and integrin alpha5 proteins and mRNA were evaluated by using RT-PCR and hybridization in situ (HIS) in normal ovarian tissues (G(1)), ovarian benign tumor tissues (G(2)), ovarian borderline tumor tissues (G(3)) and ovarian cancer tissues (G(4)). The expression levels of ME491/CD(63) genes and proteins were analyzed by multivariant analysis and their effects on the invasion and metastases of ovarian cancer were explored and their correlation with age at surgery, metastatic sites, operation fashions, lymph status, operation pathological staging and pathological typing was studied. The results showed the exact biological effects of ME491/CD(63) and integrin alpha5 in ovarian cancer tissues. The tendency of two methods is coincidence on the whole. There was positive expression of ME491/CD(63) and integrin alpha5, and ME491/CD(63) mRNA expression levels were 1.7 +/- 0.3 and 1.5 +/- 0.3, and integrin alpha5 mRNA expression levels were 1.7 +/- 0.3 and 1.5 +/- 0.3 in G(1) and G(2); ME491/CD(63) is 1.1 +/- 0.5, and integrin alpha5 is 1.1 +/- 0.5 in G(3); ME491/CD(63) is 0.6 +/- 0.4, integrin alpha5 is 0.6 +/- 0.4 in G(4); There was no significant relationship between gene expression and age at surgery or clinical-pathological staging (P > 0.05). There was significant difference between G(1), G(2) and G(3) (P < 0.01), while no difference between G(1) and G(2) (P > 0.05). Low expression levels in G(4) (III, IV) were observed. Significant differences were noted between expression levels in G(4) (III, IV) and in G(2), G(3) or G(4) (I, II; P < 0.01). There was significant difference between expression levels in tissues with lymph metastases and tissues without lymph metastases (P < 0.01). ME491/CD(63) and integrin alpha5 are lowly expressed and negatively correlated with ovarian cancer. Different expression levels exist in tissues of late ovarian cancer, earlier ovarian cancer, benign ovarian tumor and borderline tumor. The changes of two genes are correlated with tumor differentiation degree, but not pathologic typing.


Present and future water scarcity in Switzerland: Potential for alleviation through reservoirs and lakes.
In Alpine regions, future changes in glacier and snow cover are expected to change runoff regimes towards higher winter but lower summer discharge. The low summer discharge will coincide with the highest water demand for irrigation, and local and regional water shortages are expected to become more likely. One possible measure to adapt to these changes can be the extension of current uses of artificial reservoirs and natural lakes to the provision of water for the alleviation of water shortage. This study assesses the potential of reservoirs and natural lakes for the alleviation of water shortages in a nationwide analysis in Switzerland. To do so, we estimated water supply and demand under current and future conditions both under normal and extreme runoff regimes for 307 catchments. Water demand was assessed for various categories including drinking water, industrial use, artificial snow production, agriculture, ecological flow requirements, and hydropower production. The aggregated supply and demand estimates were used to derive water surplus/shortage estimates. These were then compared to the storage capacity of reservoirs and natural lakes within a catchment to determine the potential for alleviating summer water scarcity. Our results show that water shortage is expected mainly in the lowland region north of the Alps, and less in the Alps. In this lowland region, the potential of natural lakes for alleviating water scarcity is high. This potential is lower in the Alps where it is expected to increase or decrease under future conditions depending on the region of interest. Catchments with a high storage capacity can potentially contribute to the alleviation of water shortage downstream. We conclude that a spatial mismatch between water scarcity and storage availability exists since water stored in reservoirs on the southern side of the Alps is often not available for the use on the northern side.


Semi-continuous cultivation of Haematococcus pluvialis for commercial production.
The objectives of the present study on the growth of Haematococcus pluvialis were to indicate the effects of a long-term semi-continuous cultivation, sterilization, carbon dioxide, and different culture media by using artesian well water. This investigation was an enterprise in order to commercialize the production economically. When the effect of CO(2) was investigated in basal culture medium, the influence of sterilization was also researched in Rudic's culture medium in vertical panel-type photobioreactors for 31 days of semi-continuous cultivation. The maximum cell concentration of 10.55 x 10(5) cells ml(-1), which corresponds to the growth rate of 0.271 day(-1) with the areal productivity of 3.531 g m(-2) day(-1), was found in non-sterilized RM medium on the 24th day of the third run of semi-continuous cultivation at a renewal rate of 50% in a vertical panel-type photobioreactor.


From fancy to reason: scaling deaf and hearing children's understanding of theory of mind and pretence.
We examined deaf and hearing children's progression of steps in theory of mind (ToM) development including their understanding of social pretending. Ninety-three children (33 deaf; 60 hearing) aged 3-13 years were tested on a set of six closely matched ToM tasks. Results showed that deaf children were delayed substantially behind hearing children in understanding pretending, false belief (FB) and other ToM concepts, in line with their delayed uptake of social pretend (SP) play. By using a scaling methodology, we confirmed previous evidence of a consistent five-step developmental progression for both groups. Moreover, by including social pretence understanding, both deaf and hearing children's ToM sequences were shown to extend reliably to six sequential developmental steps. Finally and focally, even though both groups' sequences were six steps long, the placement of pretence relative to other ToM milestones varied with hearing status. Deaf children understood social pretending at an earlier step in the ToM sequence than hearing children, albeit at a later chronological age. Theoretically, the findings are relevant to questions about how universal developmental progressions come together along with culturally distinctive inputs and biological factors (such as hearing loss) to set the pace for ToM development.


Screening a heterogeneous elderly South African population for cognitive impairment: the utility and performance of the Mini- Mental State Examination, Six Item Screener, Subjective Memory Rating Scale and Deterioration Cognitive Observee.
The aim of this study was to report on the prevalence of cognitive impairment, and to assess the performance and utility of subjective, objective and informant screening tools in a heterogeneous community sample. A sample of 302 elderly participants (>60 years) living in residential homes in a large city in South Africa were screened for the presence of cognitive impairment using objective (Mini-Mental State Examination [MMSE] and Six Item Screener-[SIS]), subjective (Subjective Memory Complaint [SMC]and Subjective Memory Rating Scale [SMRS]) and informant (Deterioration Cognitive Observee [DECO]) screening tools. All tools were compared to the MMSE and the influence of demographic variables on the performance on these tools was considered. Significantly lower MMSE scores were found in participants aged 80-89 years (p=.023) and those who had 8-11 years of education (p=.002). For every one additional year of education, participants were 0.71 times less likely to screen positive on the MMSE. Differential item functioning on various components of the MMSE was demonstrated due to the effects of education, race and gender. There was significant differential performance between the recommended and alternate attention/concentration items (p<.001) with the alternate item favouring better performance. Based on the MMSE cutoff score of < 23, the prevalence of cognitive impairment was 16.9%; the prevalence yielded by the remaining tools ranged from 10.5% using the DECO to 46% as determined by the presence of a SMC. Using the MMSE as the reference standard for the presence of cognitive impairment, the SIS, SMC, SMRS and DECO had sensitivities of 82.3%, 54.6%, 17.0% and 37.5%, and specificities of 71.3%, 57.6%, 87.4% and 96.7% respectively. Age and race influenced performance on the MMSE, SIS and SMRS. Different types of cognitive screening tools yielded varying sensitivities and specificities for identifying cognitive impairment when compared to the MMSE. The influence of race, age and education on test performance highlights the need for suitable, culture-fair screening tools. Locally, the alternate item for attention/concentration should be preferred.


[Microscopic tumor cells in re-excision tissue by conservative surgery in breast cancer].
Conservative procedures in early breast carcinoma are a safe alternative to mastectomy. The resection line is controversial, as well as the presence of residual malignant cells in the breast after excision and their influence on local recurrence. The aim of the study was to assess the presence of residual cells in re-excised tissues near positive resection lines, in the distance up to 2 mm, and 2-5 mm. The distance of more than 5 mm was evaluated as free margin. All patients operated on in Atlas Hospital from 2004 to 2008 using conservative surgery were included in study. The resection line and the presence of residual malignant cells were followed in positive margins and in the distance of the resection line from the tumour up to 2 mm, and 2-5 mm. The conservative procedure was indicated 330 times, and 78 patients were re-operated for insufficiently free margins. The conservative procedure was completed 311 times, and mastectomy was done as the final procedure in 19 cases. Positive resection line was found 10 times. Distance up to 2 mm occurred 12 times and 25 mm 56 times. In all re-operated patients, presence of malignant cells in the re-excised tissue was found 31 times (39.7%). Repeated surgery for positive line, i.e. tumour present in the resection line, was done 10 times while malignant cells were found in all patients; for the distance up 2 mm, repeated surgery was done 12 times and 3 cases were positive (25%). For the distance of 2-5 mm, repeated excision occurred 56 times and 18 cases were positive, i.e. 32.1%. For the resection line "no tumour in contact with ink", presence of malignant cells in breast tissue must be expected in one third of the cases.Key words: breast carcinoma - conservative surgery - residual malignant cells.


Serum total gangliosides level: clinical prognostic implication.
The gangliosides overexpression contributes to the development of skin melanoma. The purpose of this study was to determine if the total gangliosides serum levels might predict the tumor growth in patients with melanoma or if the transfer of shed cell gangliosides reflects the implication in the clinical prognostic of these patients. Total gangliosides serum levels were measured in the cryopreserved serum by estimating lipid-associated sialic acid in 761 patients before surgical resection of melanoma, in 406 patients with precancerous pigmentary lesions, and in 410 healthy individuals. This study was performed at the Dermatovenereological Research Center, Bucharest, Romania, during 1991-2010. All sera obtained after surgical resection of melanocytic tumors were analyzed to see if adjuvant therapy (chemo-, immuno-, immunochemo-therapy) induced gangliosides changes in melanoma patients and if the responses were correlated with survival. Total gangliosides serum levels were higher in melanoma patients than in precancerous melanocytic lesions patients or in healthy individuals. Larger tumors in Breslow index and more advanced stage of disease were correlated with higher total gangliosides serum values. Augmented total gangliosides serum levels after melanoma adjuvant treatment were predictive for decreased overall survival, whereas decreased total gangliosides serum levels were predictable for improved overall survival. A marker for early melanoma complications and survival may be the total gangliosides serum level.


Prevention of early-onset familial/hereditary colon cancer: new models and mechanistic biomarkers (review).
Human colon cancer is a multi-factorial, multi-step disease wherein genetic and dietary factors represent important regulators of initiation, promotion and progression. While the etiology of sporadic colon cancer remains largely unidentified, familial adenomatous polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC) represent predisposing genetic syndromes for early-onset familial/hereditary colon cancer. These syndromes are characterized by germ-line mutations in the adenomatous polyposis coli (APC) and/or DNA mismatch repair genes, respectively. Currently available preclinical animal models for human FAP and HNPCC syndromes, expressing clinically relevant germ-line mutations, exhibit adenomas in the small intestine rather than in the colorectum. These models are, therefore, subject to extrapolation for direct clinical translatability of the data for colon carcinogenesis and chemoprevention. Experimental models expressing clinically relevant genetic defects (APC and/or DNA mismatch repair gene mutations) in an appropriate target site (colon) may represent novel approaches that reduce extrapolation of the data for their clinical relevance. This report provides an overview on carcinogenesis and chemoprevention in preclinical models of FAP and HNPCC syndromes, and summarizes recent data on i) development of new cell culture models for FAP and HNPCC syndromes; and ii) validation of developed models for rapid, mechanism-based screening of new pharmacological or naturally occurring chemopreventive agents.


Global Burden of Atrial Fibrillation and Flutter by National Income: Results From the Global Burden of Disease 2019 Database.
Background Atrial fibrillation (AF) and atrial flutter (AFL) are common conditions that can lead to significant morbidity and death. We aimed to understand the distribution and disparities of the global burden of AF/AFL as well as the underlying risk factors. Methods and Results Data on the AF/AFL burden from the Global Burden of Disease data set were analyzed for the years 1990 to 2019, with countries grouped into low, lower-middle, upper-middle, and high national income classes according to World Bank categories. Data were supplemented with World Health Organization and World Bank information. The prevalence of AF/AFL has more than doubled (+120.7%) since 1990 in all income groups, though with a larger increment in middle-income countries (+146.6% in lower-middle- and +145.2% in upper-middle-income countries). In absolute numbers, 63.4% of AF/AFL cases originate from upper-middle-income countries, although the relative prevalence is highest in high-income countries. Prevalence of AF/AFL appears to be correlated with medical doctor rate and life expectancy. The most relevant AF/AFL risk factors are unevenly distributed among income classes, with elevated blood pressure as the only risk factor that becomes less common with increasing income. The development of these risk factors differed over time. Conclusions The global burden of AF/AFL is increasing in all income groups and is more pronounced in middle-income countries, with further growth to be expected. Underdiagnosis of AF/AFL in low- and middle-income countries may contribute to lower reported prevalence. The risk factor distribution varies between income groups.


Improvements of a spatial frequency analyzer for automated characterization of holographic recording materials.
A spatial frequency analyzer was designed to simplify characterization studies for new holographic recording materials. Mechanical movements were automated and a complete informational system gave rapid characterization results. A good fringe stabilization unit was improved by adding simple holographic optical beam combiners. Experimental characterization of two different recording materials shows the versatility of this automated apparatus. Also we present modulation-transfer-function curves of dichromated gelatin between 500 and 3500 cycles/mm obtained with polarization volume transmission holograms.


COVID-19: dealing with a potential risk factor for chronic neurological disorders.
SARS-CoV2 infection is responsible for a complex clinical syndrome, named Coronavirus Disease 2019 (COVID-19), whose main consequences are severe pneumonia and acute respiratory distress syndrome. Occurrence of acute and subacute neurological manifestations (encephalitis, stroke, headache, seizures, Guillain-Barrè syndrome) is increasingly reported in patients with COVID-19. Moreover, SARS-CoV2 immunopathology and tissue colonization in the gut and the central nervous system, and the systemic inflammatory response during COVID-19 may potentially trigger chronic autoimmune and neurodegenerative disorders. Specifically, Parkinson's disease, multiple sclerosis and narcolepsy present several pathogenic mechanisms that can be hypothetically initiated by SARS-CoV2 infection in susceptible individuals. In this short narrative review, we summarize the clinical evidence supporting the rationale for investigating SARS-CoV2 infection as risk factor for these neurological disorders, and suggest the opportunity to perform in the future SARS-CoV2 serology when diagnosing these disorders.


Risk factors for bronchial hyperresponsiveness in late childhood and early adolescence.
The prevalence of asthma and bronchial hyperresponsiveness (BHR) tends to decrease in male children but increase in female children in the transition from childhood to adolescence. Hormonal factors may be involved in the natural history of asthma during this period. In a prospective study of Montreal school children, the authors examined the determinants of BHR according to the child's pubertal status; 156 male children and 168 female children without a prior diagnosis of asthma were followed for an average of 4.6 yrs. Average age at follow-up was 13.4 yrs and 59% had reached puberty. The prevalence of BHR at follow-up was similar among pre- and postpubertal male children (25.0% versus 29.2%),while BHR was more common among post- compared with prepubertal female children (33.1% versus 14.2%). There were no differences in the determinants (measured in childhood) of BHR at follow-up according to pubertal status. The major determinant of BHR was a positive skin test to dust-mite antigen. BHR was also linked to exposure to gas cooking and the presence of exercise-induced bronchospasm. In conclusion, the results of this study do not support a change in asthma phenotype with the onset of puberty. Pre- and postpuberty, the major determinant of bronchial hyperresponsiveness was skin sensitivity to mite allergen.


Epidemiology and natural history of non-alcoholic fatty liver disease (NAFLD).
The authors summarize and update the most recent knowledge in the field of prevalence, natural history and incidence of Non Alcoholic Fatty Liver Disease (NAFLD) and Non Alcoholic Steatohepatitis (NASH). These novel diseases, firstly recognized at the beginning of the second millennium, arose suddenly to the attention of the clinicians, because they are the hepatic expression of the "so-called" metabolic syndrome. Due to the epidemic burden of obesity, diabetes, and metabolic diseases, NAFLD and NASH will become soon probably the most common hepatic disease worldwide, and they surely will keep busy our future young hepatologists.


Infantile haemangio-endothelioma of liver: a case report.
Infantile haemangio-endothelioma of liver is the most common symptomatic vascular tumour of liver. A 6-month-old female was admitted for evaluation of a mass in the right hypochondrium. It extended 5 cm below the right costal margin. USG of the liver revealed multiple hypo-echoic lesions within the liver. Non-contrast CT images showed multiple hypo-attenuating masses of lower density than the surrounding liver. A postcontrast CT revealed intense enhancement of all the lesions. The findings suggested an infantile haemangio-endothelioma of the liver. On follow-up USG after 8 months near complete involution of the mass was revealed.


Physical activity among Canadian children on school days and nonschool days.
Schools are frequently cited as a favorable venue to promote physical activity (PA), however little data exist describing times when students are least active. Our objective was to overcome this limitation and describe time periods when students are least active. We used a cross-sectional design to assess patterns of PA in 923 grade 5 students [mean age: 10.9 (± 0.4) years] from 30 schools in Alberta, Canada. Students wore time-stamped pedometers for 9 consecutive days, providing 7 full days of data. We compared step counts adjusted for nonwear time between school days and nonschool days as well as during school hours and after school hours. 689 (75%) students provided complete data. The average daily step count was higher on school days (boys 13,476 ± 4123 step/day; girls 11,436 ± 3158 steps/day) than nonschool days (boys 11,009 ± 5542 steps/day; girls 10,256 ± 5206 steps/day). More steps were also taken during school hours than nonschool hours (boys +206 ± 420 steps/hour, P < .001; girls 210 ± 347, P < .001 steps/hour). PA levels of children are below Canadian recommended levels for optimal growth and health. Health promotion should emphasize PA particularly among girls, outside school hours, and weekends.


The Relationship Between PSA and Total Testosterone Levels in Men With Prostate Cancer.
Prostate-specific antigen (PSA) secretion is a testosterone (T) dependent process. Published data suggest that a low T level is an independent predictor of higher-grade prostate cancer (PC). To evaluate the relationship between T and PSA in patients with PC. All men diagnosed with PC with a recorded pre-treatment total T level measurement were included in this analysis. We analyzed demographic, clinical, and pathological data. Patients were stratified according to pretreatment PSA levels: <2 ng/mL, 2-4 ng/mL, >4 ng/mL. Low T was defined as total T < 10.4 nmol/L (300 ng/dL), very low T < 6.9 nmol/L (200 ng/dL). T levels by PSA groups according to the PC pathology. In this retrospective study, mean patient age was 61 years among 646 men. The distribution by PSA group was: 8% (<2), 17% (2-4), and 76% (>4). The mean T level across the entire cohort was 13 nmol/L (374 ng/dL). Overall, 30% had a T level < 10.4 nmol/L (300 ng/dL). The mean total T level by PSA group was: <2 ng/mL, 7 nmol/L (206 ng/dL); 2-4 ng/mL, 13 nmol/L (362 ng/dL); >4 ng/mL, 14 nmol/L (393 ng/dL), P < .001. PSA <4 ng/mL was a significant predictor of low T in men with PC GS ≥8. PSA <2 ng/mL was a significant predictor of very low T independent of the PC pathology. These findings suggest that clinicians should consider measuring T levels when a patient diagnosed with PC GS ≥8 and PSA level <4 ng/mL, and for each patient with PSA level <2 ng/mL independent of the PC pathology. Our study has several strengths including (i) inclusion of a large population of men, (ii) use of a database which is audited and reviewed for accuracy annually, and (iii) use of an accurate T assay (LCMS). Nonetheless, there are limitations: (i) the subjects of the study are from a single institution, and (ii) we did not measure free T levels. In men with PC with GS ≥8, PSA level <4 ng/mL predicts low T. PSA <2 ng/mL predicts very low T independent of the PC pathology. Flores JM, Bernie HL, Miranda E, et al. The Relationship Between PSA and Total Testosterone Levels in Men With Prostate Cancer. J Sex Med 2022;19:471-478.


Decree No. 96.943 on official incentives and credits for agricultural and livestock projects in the Amazon area, 12 October 1988.
This Decree suspends for a period of 90 days 1) the approval of agricultural and livestock projects in the Amazon area in places covered with tropical forests for the purpose of granting incentives related to the Brazilian Investment Fund for the Amazon; 2) the granting of official credits for livestock projects in the same areas; and 3) the granting of official incentives and credits for agricultural and livestock projects in "Mata Atlantica" in areas covered with native forests, including those in the process of regeneration. This suspension includes projects to enlarge, modernize, make technically fit, or reformulate undertakings already approved. Within the 90-day period, new criteria and rules for the granting of official credits and incentives are to be devised.


[A preliminary study on the induction of metallothionein in rats with aluminum administration by different ways].
To study the inductive effects of aluminum (Al) on metallothioneine (MT) in rats. Inductive experiment of MT was conducted with Al administration in 16 SD rats, divided into trial and control groups, for two weeks by subcutaneous injection and gastric tube. Al could induce liver MT in the rats, to certain extent, especially more significantly by subcutaneous injection than by oral administration of Al. Oral administration of Al also could induce MT in the small intestine. Induction of MT by Al reflected the body response to stress, the metal poison Al. It postulated that combination of Al with MT was unstable due to its chemical property, so, its detoxication effect was uncertain. In addition, induction of MT in different sites, such as liver and small intestine, by Al could influence the normal metabolism of metal elements, such as zinc, etc.


State, heal thy physicians: an assessment of the Louisiana Natural Death Act.
In our society, state governments have the major role in regulating physician behavior and actions related to end-of-life decision making. However, in the current confusing and conflicted legal environment, how well are state governments doing with this serious responsibility? The authors of this article report the results of the first statewide survey of Louisiana physicians regarding their knowledge of and compliance with specific parts of one state government's attempt to regulate end-of-life decision making: the Louisiana Natural Death Act (LNDA). Physician respondents were asked to indicate their level of familiarity with the LNDA and several questions examined physician compliance with specific sections contained in the statute. Among many things, the survey revealed most physicians (74%) were not familiar with even the basic provisions of the LNDA, and had not received either medical school or subsequent post graduate training in this area. Based on the results of this survey, the authors offer several policy recommendations that could enhance physician knowledge and subsequent compliance with the LNDA.


Inflammatory response to dental polishing and prophylaxis materials in rats.
To describe the tissue response to implanted polishing and prophylaxis materials using a rat model system. Two polishing pastes (diamond polishing paste and aluminum polishing paste), two prophylaxis materials (prophylaxis paste with fluoride and air polishing prophylaxis powder) and negative and positive controls were subcutaneously implanted in rats. Tissue specimens obtained after 2 days, 1, 4, 6 and 8 weeks after implantation were processed for routine hematoxylin and eosin staining and polarized light evaluation. Air polishing prophylaxis powder produced a mild inflammatory response. A more intense inflammation was elicited by diamond polishing paste, and the prophylaxis paste with fluoride elicited an even greater response. The aluminum polishing paste produced the most severe and persistent tissue response, which was of the granulomatous type. This finding suggests that foreign body reaction should be considered in a gingivitis that does not respond to plaque control or does not represent a mucocutaneous lesion.


Advances in cathepsin S inhibitor design.
Cathepsin S is expressed in antigen-presenting cells and plays a role in invariant chain processing and major histocompatibility complex class II (MHCII) antigen presentation leading to CD4+ T-cell activation. An oral cathepsin S inhibitor that blocks MHCII antigen presentation could result in a T-cell-selective immunosuppressant agent with improved safety over the current standard of care for the treatment of rheumatoid arthritis, psoriasis, multiple sclerosis and other autoimmune-based inflammatory diseases. This review focuses on advances in cathepsin S inhibitor utility and design since January of 2004.


1/2(e^{2}/h) Conductance Plateau without 1D Chiral Majorana Fermions.
We address the question about the origin of the 1/2(e^{2}/h) conductance plateau observed in a recent experiment on an integer quantum Hall (IQH) film covered by a superconducting (SC) film. Since one-dimensional (1D) chiral Majorana fermions on the edge of the above device can give rise to the half quantized plateau, such a plateau is regarded as conclusive evidence for the chiral Majorana fermions. However, in this Letter we give another mechanism for the 1/2(e^{2}/h) conductance plateau. We find the 1/2(e^{2}/h) conductance plateau to be a general feature of a good electric contact between the IQH film and the SC film, and cannot distinguish the existence or the nonexistence of 1D chiral Majorana fermions. We also find that the contact conductance between a superconductor and an IQH edge channel has a non-Ohmic form σ_{SC-Hall}∝V^{2} in the k_{B}T≪eV limit, if the SC and IQH bulks are fully gapped.


Ultrasound-induced blood-brain barrier opening.
Over 4 million U.S. men and women suffer from Alzheimer's disease; 1 million from Parkinson's disease; 350,000 from multiple sclerosis (MS); and 20,000 from amyotrophic lateral sclerosis (ALS). Worldwide, these four diseases account for more than 20 million patients. In addition, aging greatly increases the risk of neurodegenerative disease. Although great progress has been made in recent years toward understanding of these diseases, few effective treatments and no cures are currently available. This is mainly due to the impermeability of the blood-brain barrier (BBB) that allows only 5% of the 7000 small-molecule drugs available to treat only a tiny fraction of these diseases. On the other hand, safe and localized opening of the BBB has been proven to present a significant challenge. Of the methods used for BBB disruption shown to be effective, Focused Ultrasound (FUS), in conjunction with microbubbles, is the only technique that can induce localized BBB opening noninvasively and regionally. FUS may thus have a huge impact in trans-BBB brain drug delivery. The primary objective in this paper is to elucidate the interactions between ultrasound, microbubbles and the local microenvironment during BBB opening with FUS, which are responsible for inducing the BBB disruption. The mechanism of the BBB opening in vivo is monitored through the MRI and passive cavitation detection (PCD), and the safety of BBB disruption is assessed using H&E histology at distinct pressures, pulse lengths and microbubble diameters. It is hereby shown that the BBB can be disrupted safely and transiently under specific acoustic pressures (under 0.45 MPa) and microbubble (diameter under 8 μm) conditions.


Research and Patents on Coronavirus and COVID-19: A Review.
COVID-19 pandemic is a global problem that requires the point of view of basic sciences and medicine as well as social, economics and politics disciplines. Viral particles of coronaviruses including SARS-CoV-2 as well as other enveloped viruses like influenza virus could be considered as an approximation to functional core-shell nanoparticles and therefore, their study enters the realm of nanotechnology. In this context, nanotechnology can contribute to alleviate some of the current challenges posed by COVID-19 pandemic. The present analysis contributed to diverse sources of general information, databases on scientific literature and patents to produce a review affording information on relevant areas where as nanotechnology has offered response to coronavirus challenges in the past and may be relevant now, and has offered an update of the current information on SARS-CoV-2 and COVID-19 issues. This review contribution includes specific information including: 1) An introduction to current research on nanotechnology and related recent patents for COVID-19 responses; 2) Analysis of nonimmunogenic and immunogenic prophylaxis of COVID-19 using Nanotechnology; 3) Tools devoted to detection & diagnosis of coronaviruses and COVID-19: the role of Nanotechnology; and 4) A compilation on the research and patents on nanotechnology dealing with therapeutics & treatments of COVID-19. Among the increasing literature on COVID-19, there are few works analyzing the relevance of Nanotechnology, and giving an analysis on patents dealing with coronaviruses that may provide useful information on the area. This review offers a general view of the current research investigation and recent patents dealing with aspects of immunogenic and non-immunogenic prophylaxis, detection and diagnosis as well as therapeutics and treatments.


What Is the Role of Questioning in Young Children's Fluency?
Most therapy programs for young children who stutter (CWS) involve caregiver counseling and adjustment of caregiver behavior to maximize opportunities for the child to be more fluent. One component sometimes included as a recommended adjustment is a reduction in caregiver question asking, as question asking is hypothesized to increase language formulation demands on the child. However, there is limited research to guide clinician advisement to caregivers that has controlled for numerous potential confounding factors, including utterance length and grammaticality, that may impact potential stressors on children. Our aim was to assess whether there was an empirical basis for such recommendations by comparing disfluency profiles of answers to questions and nonanswer utterances produced by children during spontaneous play with parents and examiners. We analyzed fluency and structural properties as well as pragmatic function of 15,782 utterances from language samples produced by 32 CWS and 32 children who do not stutter (CWNS) who were between 28 and 50 months of age. CWS and CWNS were matched on gender and age within 4 months and were matched as closely as possible on maternal education. For utterances produced by CWS, answers to adult questions were significantly less likely to contain stuttering-like disfluencies than other utterance types, and this was still true after controlling for utterance length and grammaticality. In contrast, for utterances produced by CWNS, answers to questions were significantly more likely to be disfluent than other utterance types after controlling for length and grammaticality. Given the current findings, some prior research, and the documented potential benefits in language development for adult question asking of children, we do not believe that clinicians need to recommend changes to typical question-asking behavior by caregivers of CWS.


Role of interleukin-15 in the development of human CD56+ natural killer cells from CD34+ hematopoietic progenitor cells.
Human natural killer (NK) cells are bone marrow (BM)-derived CD2+CD16+CD56+ large granular lymphocytes (LGL) that lack CD3 yet contain the T-cell receptor zeta-chain (zeta-TCR). NK cells provide requisite interferon-gamma (IFN-gamma) during the early stages of infection in several experimental animal models. A number of studies have shown that human CD3-CD56+ NK cells can be obtained from BM-derived CD34+ hematopoietic progenitor cells (HPCs) cultured in the presence of interleukin-2 (IL-2) and an allogeneic feeder cell layer, or IL-2 and other hematopoietic growth factors such as the c-kit ligand (KL). The failure to detect the IL-2 gene product within the BM stroma and the presence of NK cells in IL-2-deficient mice suggested that cytokines other than IL-2 may participate in NK cell differentiation from HPCs in vivo. IL-15 is a cytokine which, while lacking any sequence homology in IL-2, can activate cells via the IL-2 receptor. Here we show that human BM stromal cells express the IL-15 transcript, and supernatants from long-term BM stromal cell cultures contain IL-15 protein. In vitro, CD3-CD56+ NK cells can be obtained from 21-day cultures of CD34+ HPCs supplemented with IL-15 in the absence of IL-2, stromal cells, or other cytokines. The addition of the KL to these cultures had no effect on the differentiation of the CD3-CD56+ cytotoxic effector cells, but greatly enhanced their expansion. The majority of these cells lack CD2 and CD16, but do express zeta-TCR. Similar to NK cells found in peripheral blood, the CD2-CD16-CD56+ NK cells grown in the presence of IL-15 were found to be potent producers of IFN-gamma in response to monocyte-derived cytokines. Thus IL-15, like KL, appears to be produced by BM stromal cells. IL-15 can induce CD34+ HPCs to differentiate into CD3-CD56+ NK cells, and KL can amplify this. Therefore, IL-15 may be a physiologically relevant ligand for NK cell differentiation in vivo.


Role of the human Y box-binding protein YB-1 in cellular sensitivity to the DNA-damaging agents cisplatin, mitomycin C, and ultraviolet light.
The Y box-binding protein (YB-1) binds to DNA sequences, present in the control regions of many genes, that contain an inverted CCAAT box. The binding activity of a nuclear factor, designated MDR-NF1, to an inverted CCAAT box in the promoter of the multidrug resistance 1 (MDR1) gene has previously been shown to be increased in nuclear extracts of cells exposed to UV radiation or various anticancer agents. The MDR-NF1 cDNA has now been cloned by screening a human colon library with an active fragment of the MDR1 promoter. The amino acid sequence encoded by the cloned cDNA was identical to that of YB-1. Northern blot analysis revealed that YB-1 mRNA was present in all human tissues examined. Rabbit antibodies were generated against synthetic peptides corresponding to YB-1, and indirect immunofluorescence microscopy with these antibodies showed that the concentration of YB-1 in all cisplatin-resistant cell lines examined was higher than that in the respective drug-sensitive parental cells. Transfection of human epidermoid cancer KB cells with a YB-1 antisense construct established two cell lines with reduced concentrations of YB-1. These transfectants showed increased sensitivity to cisplatin, mitomycin C, and UV radiation but not to vincristine, doxorubicin, camptothecin, or etoposide. Thus, YB-1 may protect cells from the cytotoxic effects of agents that induce cross-linking of DNA, suggesting a novel function of this ancestor DNA-binding protein.


[Evaluation of single-stage methods of studying the activity of factor VIII].
Accurate diagnosis of coagulopathies related to changed factor VIII activity, studies of specific activities of antihemophilic cryoprecipitate globulin used for hemostatic correction in patients, and monitoring of therapy efficacy are impossible without a reproducible, sensitive, standard, and available method. The authors have compared two single-stage methods developed by Soviet scientists: that by V. P. Baluda et al. and that by L. P. Papayan and P. V. Khrolova. Both methods have proved sufficiently sensitive and capable to detect factor VIII deep deficiency, but L. P. Papayan and P. V. Khrolova's modification was found higher reproducible, and therefore chosen for further investigation in order to standardize it. Besides the conditions of reproducing the method, reference plasma, substrate plasma deficient for factor VIII, and partial thromboplastin are to be standardized.


Toward meaningful noise research.
The present review considers a series of studies of noise conducted in collaboration with Dr. Michel Loeb. This review attempts to provide a theoretical perspective as well as to summarize the most important findings of those studies. The work reviewed shows that noise effects interact with other variables, such that a noise effect on one sex is reversed for the other, and is also reversed at different times of the day. A second experiment confirmed this finding with a different arithmetic task. Further work indicated parallels between noise and fatigue, with aftereffects depending upon both work and noise. The final experiment repeated some of these findings with a different task battery of information processing tasks while showing that noise effects further depend on the meaningfulness of the noise background.


Effect of continuous positive airway pressure on an atrial arrhythmia in a patient with mild obstructive sleep apnea.
Cardiac arrhythmias have been reported in up to half of individuals with obstructive sleep apnea (OSA) and have been proposed to be one of the factors contributing to their increased mortality. Several studies have demonstrated evidence of an association between OSA and a number of cardiac arrhythmias. The mechanisms of arrhythmogenesis in OSA may be due to enhanced vagal output triggered by a combination of apnea and hypoxemia. This case demonstrates a dose-dependent reduction in atrial ectopy with increasing continuous positive airway pressure (CPAP) in the setting of mild sleep apnea.


Subcutaneous drug infusions: a review of problems and solutions.
Subcutaneous drug infusion using a portable syringe driver has had a significant impact on patient comfort in palliative care. It permits the continuous delivery of a range of drug therapies, so bypassing problems of dysphagia, weakness and the inability of many patients in the terminal phase to take oral medication. The devices are not problem-free, however. Mechanical problems, reactions at the infusion site and difficulties with the mixing of drugs in the syringe are all widely recognized. This article reviews some general issues with the operation of portable syringe drivers, and discusses a range of potential problems and their solutions.


Hydrophobic contact between the two epidermal growth factor-like domains of blood coagulation factor IX contributes to enzymatic activity.
The three-dimensional structure of activated factor IX comprises multiple contacts between the two epidermal growth factor (EGF)-like domains. One of these is a salt bridge between Glu(78) and Arg(94), which is essential for binding of factor IXa to its cofactor factor VIII and for factor VIII-dependent factor X activation (Christophe, O. D., Lenting, P. J., Kolkman, J. A., Brownlee, G. G., and Mertens, K. (1998) J. Biol. Chem. 273, 222-227). We now addressed the putative hydrophobic contact at the interface between the EGF-like domains. Recombinant factor IX chimeras were constructed in which hydrophobic regions Phe(75)-Phe(77) and Lys(106)-Val(108) were replaced by the corresponding sites of factor X and factor VII. Activated factor IX/factor X chimeras were indistinguishable from normal factor IXa with respect to factor IXa enzymatic activity. In contrast, factor IXa(75-77)/factor VII displayed approximately 2-fold increased factor X activation in the presence of factor VIII, suggesting that residues 75-77 contribute to cofactor-dependent factor X activation. Activation of factor X by factor IX(106-108)/factor VII was strongly decreased, both in the absence and presence of factor VIII. Activity could be restored by simultaneous substitution of the hydrophobic sites in both EGF-like domains for factor VII residues. These data suggest that factor IXa enzymatic activity requires hydrophobic contact between the two EGF-like domains.


Investigation of a Worker Death While Agitating Manure in a Non-enclosed Storage.
An in-depth investigation of an unusual, non-enclosed manure storage hydrogen sulfide-induced fatality on a Holstein beef production operation is presented. The case involved several factors that likely played a role in the young farmer's death. These included zero wind movement, a reported temperature inversion in the area, relatively cool late summer outdoor temperatures on the morning of the incident, higher outdoor temperatures the week prior, and a high by-product steer ration containing ingredients that contributed significant sulfur content to the stored manure. Recommendations are offered for future research to determine the combinations of conditions and inputs that have potential to increase human and animal risk around manure storage structures. Based on this case and others recently documented showing unsafe levels of hydrogen sulfide being released from similar outdoor storages, it is critical that agricultural industry experts and input suppliers continue to analyze risk and consequences associated with new management practices, processes, inputs (including feed ingredients and animal bedding), machines, and other technology developed to support animal agriculture. Production practice and educational guidance are also offered based on this case and published literature.


[Hair physiology].
The first hair follicles appear on the body toward the end of the 8th week of intrauterine life. The appearance on the scalp is more tardive 7th month. The hair is a keratin-containing appendage that grows from cavities called follicles. Hair follicles extend from the surface of the skin through the stratum corneum and the epidermis into the dermis. Keratin contains almost all aminoacids but particularly rich in cystein. Hair fibers grow in three distinct stages. The first one, the anagen stage, is the growing phase with a duration of 3 to 5 years. The catagen stage, the transition stage, lasts only a few weeks; it precedes the telogen stage, resting or shedding phase, lasts for 2 months.


How do emergency department patients store and dispose of opioids after discharge? A pilot study.
Opioid abuse and overdose have increased drastically in recent years. Diversion of opioids used to treat pain, either through theft or sharing, is increasing and may contribute to this misuse. Based on these trends, we designed a study to investigate opioid storage and disposal practices of patients who were prescribed these agents in the emergency department. A prospective cohort pilot study was conducted. All adults (aged ≥18 years) with a chief complaint of either minor musculoskeletal trauma, renal colic, or acute back pain who were discharged home with an opioid prescription were eligible for inclusion; persons with chronic pain were excluded. Patients were asked to participate in two home interviews in which the research assistant viewed the storage location of the opioid prescription. Safe storage was defined as being stored in a locked container or cabinet. Safe disposal was defined as returning the drugs to a designated location or mixing unused pills with an undesirable substance, placing in a sealable container, and then in the trash. Patients self-reported disposal methods. Feasibility of study methods evaluated the ability to conduct home interviews after the ED visit. Descriptive statistics were used to analyze the data. Twenty-five subjects consented to participate; 20 patients completed both home interviews. None of the medications were safely stored. Only 1 patient disposed of the medication, yet did so improperly. This pilot study revealed widespread improper storage and disposal of opioids. The study has major implications for education for ED physicians, nurses, and residents.


Importance of multiagent chemotherapy regimens in ovarian carcinoma: dose intensity analysis.
In the previous meta-analysis of dose intensity (dosage) of chemotherapy in advanced ovarian cancer, we analyzed data on cyclophosphamide, altretamine (hexamethylmelamine), doxorubicin, and cisplatin. Only cisplatin showed statistically significant association of complete and partial clinical response with dose intensity. This analysis updates the previous results and further characterizes response to cisplatin alone or in multiagent regimens. We analyzed data from 18 regimens containing platinum (cisplatin or carboplatin) that were used in nine new randomized trials, in addition to data from the 60 groups of patients in our previous study in which responses were reported. Relative dose intensity was calculated as a fraction of the dosage of a drug in the standard regimen of cyclophosphamide, altretamine, doxorubicin, and platinum (CHAP). We performed single and multiple regression analyses to determine the relationship between disease outcome and relative dose intensity for cyclophosphamide, platinum, and doxorubicin alone or in combination. The association between outcome and dose intensity for platinum alone or in multiagent regimens was statistically significant. This association was of borderline significance for cyclophosphamide alone but was not significant for this drug in multiagent regimens. There were insufficient data to test the relationship for doxorubicin as a single agent, but in multiagent regimens, the relationship was borderline (P = .05). Multiagent regimens containing platinum produced greater response rates than platinum alone for any fixed, planned relative dose intensity for platinum. Our results support other published findings that use of cyclophosphamide and doxorubicin increases the efficacy of single-agent platinum. Relative dose intensity values for cyclophosphamide used alone were larger than those used in multiagent regimens, which might explain why the relationship between relative dose intensity and outcome for cyclophosphamide was not significant for use in multiagent regimens. Similarly, none of the multiagent regimens incorporated doxorubicin at a relative dose intensity for which the drug is found to be effective as a single agent. Prospective clinical trials are required to test the effect of higher relative dose intensity for doxorubicin and cyclophosphamide added to platinum in advanced ovarian cancer. An important element in the design of prospective trials will be to test for the relative importance of dose intensity versus total dose. This testing is best achieved in a three-arm study design such as that reported in adjuvant treatment of stage II breast cancer conducted by the Cancer and Leukemia Group B.


Comparative effects of tissue plasminogen activator, streptokinase, and staphylokinase on cerebral ischemic infarction and pulmonary clot lysis in hamster models.
The effects of alteplase (rtPA), streptokinase, and staphylokinase (rSak) on focal cerebral ischemia (FCI) and on pulmonary clot lysis (PCL) were studied in hamsters. ++FCI was produced by ligation of the left middle cerebral artery (MCA) and common carotid artery (CCA) and a 10-minute occlusion of the right CCA. FCI was measured after 24 hours by 2,3, 5-triphenyltetrazolium chloride staining. (125)I-fibrin-labeled plasma clots were injected via the jugular vein, and clot lysis was determined from residual radioactivity at 90 minutes. Study drugs were given intravenously over 60 minutes. FCI increased from 1.2 (0. 27 to 2.3) mm(3) (median and 17th to 83rd percentile range, n=24) in controls to 19 to 27 mm(3) with thrombolytic agent, with maximal rates at 0.13+/-0.05 mg/kg rtPA, 0.23+/-0.09 mg/kg streptokinase, and 0.037+/-0.025 mg/kg rSak. PCL increased from 18+/-2% (mean+/-SEM, n=27) in controls to approximately 85% with thrombolytics, with maximal rates at 0.12+/-0.03 mg/kg rtPA, 0.17+/-0.05 mg/kg streptokinase, and 0.018+/-0.002 mg/kg rSak. All agents caused maximal FCI and PCL rates at similar doses without alpha(2)-antiplasmin and fibrinogen depletion. Injection of 6 mg/kg human plasminogen combined with streptokinase caused a "systemic fibrinolytic state" with fibrinogen depletion. Maximal rates of FCI were obtained with 0.097+/-0.077 mg/kg streptokinase (P=0.26 versus streptokinase alone) and of PCL with 0.010+/-0.002 mg/kg (P=0.006 versus streptokinase alone). Thrombolytic agents cause similar dose-related extension of FCI after MCA ligation and PCL, irrespective of the agent or systemic plasmin generation.


Comparison between traditional and nontraditional add-on devices used with pressurised metered-dose inhalers.
Add-on devices that are attached to metered-dose inhalers (MDIs) were introduced to improve aerosol delivery. The objective of this study was to determine the efficacy of drug delivery from an MDI when attached to different add-on devices at different inhalation volumes. The total emitted dose (TED) of salbutamol was estimated for the MDI alone and the MDI connected to five different add-on devices (Able valved holding chamber, Tips-haler valved holding chamber, Aerochamber plus flow Vu valved holding chamber, Dolphin chamber, and a handmade water bottle spacer), at inhalation flow of 28.3 L·min-1 with flow volume of 1, 2 and 4 L, assuming young child (aged <6 years), old child (>6 years) and adult inhalation volumes, respectively. The TED% ranged between 84.1% and 87.2% at all inhalation volumes from the MDI alone, which was significantly greater than all MDI add-on device combinations (p<0.05). The TED% delivered to MDI sampling apparatus by a homemade water bottle spacer and Dolphin chamber, as non-antistatic add-on devices, ranged between 30.5% and 35.3%. However, washing these non-antistatic add-on devices with a light detergent before use improved their TED to range between 47.6% and 51.2%. Non-antistatic add-on devices had significantly lower TED (p<0.05) than that delivered by most antistatic add-on devices, which ranged from 51.3% to 71.6%. This study suggests that antistatic add-on devices delivered much more aerosol than non-antistatic add-on devices. However, it may be advised to still use a non-antistatic add-on device, for the sake of solving the coordination problem, and wash it with light detergent before use to improve TED.


Immunoscintigraphy with indium-111-capromab pendetide: evaluation before definitive therapy in patients with prostate cancer.
No standard noninvasive diagnostic test reliably differentiates patients with organ-confined prostate cancer from those with lymph node metastases. The ability of a radiolabeled monoclonal antibody, indium-111 (111ln)-capromab pendetide, to identify sites of metastatic disease in patients at moderate to high risk of nodal involvement was investigated. The study prospectively evaluated 160 patients with prostate cancer scheduled to undergo pelvic lymph node dissection (PLND) before or during definitive treatment. All were at relatively high risk of nodal involvement by virtue of significantly elevated baseline prostate-specific antigen (PSA) values, Gleason scores, and/or locally advanced clinical stages of disease. The histologic findings of the PLNDs were compared with the results of immunoscintigraphy, computed tomography, and magnetic resonance imaging. Among the 152 evaluable patientS studied with 111In-capromab pendetide before PLND, the sensitivity of immunoscintigraphy for lymph node detection was 62% and the specificity was 72%; the positive predictive value was 62% and the negative predictive value was 72%. In comparison, the sensitivity of computed tomography and magnetic resonance imaging was 4% and 15%, respectively, and the specificity was 100% for both procedures on the basis of a large number of negative interpretations. Logistic regression analysis revealed that immunoscintigraphy with 111In-capromab pendetide provided strong, independent evidence of the presence of lymph node metastases. Furthermore, the analysis indicated that certain combinations of PSA, Gleason score, and 111In-capromab pendetide were particularly effective at predicting the risk of nodal involvement. Immunoscintigraphy with 111In-capromab pendetide outperformed standard diagnostic imaging techniques in the detection of prostate cancer lymph node metastases and provided independent prognostic information that complemented PSA, Gleason score, and clinical stage.


Theories of international labor migration: an overview.
"Emigration pressures are primarily the result of increasing inequalities between countries which, in turn, are the result of factors internal to less developed countries and their relations with developed countries. Both micro (neoclassical) and macrostructural theories of migration are reviewed. It is argued that the neoclassical theory of migration is often unjustly criticized and is sufficiently robust to incorporate those structural considerations which are at the core of macrostructural theories. Moreover, the neoclassical theory, with slight modification, can incorporate the ¿new economics of migration.' The major empirical problem confronting models of international labor migration is that migration flows are constrained by immigration policy. This policy, in turn, is influenced by various special interest groups. The direction and form of migration flows is conditioned by contemporary and historical relationships between source and destination countries."


Etiology of cerebral palsy.
To register the prevalence of cerebral palsy (CP) and determine etiological factors for the condition. Population based study with registration of CP-cases in children born during the 30-year period 1970-99. Cases with postneonatal etiology were excluded. 166 CP-cases were registered among 70 824 children, a prevalence of 2.3 per 1000 live born infants. The prevalence did not change significantly during the period. 66 (40%) were low birthweight infants (LBWIs; <2500 g), and 100 (60%) normal birthweight infants (NBWIs; > or = 2500 g). The origin was classified as prenatal in 37 (22%), perinatal/neonatal in 78 (47%) and unclassifiable in 51 (31 %). In LBWIs 39/66 (59%) had a perinatal/neonatal etiology, most frequently intra- or periventricular hemorrhages (IVH/PVH) and/or periventricular leukomalacia (PVL) or cerebral infarctions (CI) (17; 44%). In NBWIs 39/100 (39%) had a perinatal etiology, most frequently hypoxic-ischemic encephalopathy (HIE) (31; 79%). In a substantial percentage of CP-cases perinatal/neonatal brain injury was classified as the cause. Among these IVH/PVH/PVL/CI dominated in LBWIs, while HIE dominated in NBWIs. Our data may point to preventability of a larger part of CP than earlier suggested.


Sexual health promotion in Thailand.
Sexuality and power are at the root of most sexual and reproductive health problems in Thailand, including reproductive tract infections, fertility and population control, unwanted pregnancy and abortion, unsafe abortion, unsafe motherhood and violence against women, as well as issues emerging from the mobile and migrant population, including the spreading of HIV/AIDS. In the past three decades, reproductive health services in Thailand have been established and strengthened. Since 1995, reproductive health has become a priority of the Ministry of Public Health. Health system reform in 2000 led to strategies and actions of health performance improvement. Ongoing multisectoral programmes include: (1) political and social involvement; (2) training for professionals; (3) multidimensional services; and (4) research.


Tetrahydrocannabinol fails to reduce hair pulling or skin picking: results of a double-blind, placebo-controlled study of dronabinol.
Body-focused repetitive behaviors (BFRBs) such as trichotillomania and skin picking disorder are associated with decreased self-esteem and poor quality of life. The objective of this study was to evaluate dronabinol, a cannabinoid agonist, for the reduction of BFRB symptoms. Fifty adults with either trichotillomania (n = 34) or skin picking disorder (n = 16) were recruited for a randomized, double-blind, placebo-controlled study. Participants received 10-week treatment with dronabinol (5-15 mg/day) or placebo. The primary efficacy outcome measure was the change on the clinician-rated National Institute of Mental Health scale for hair pulling or skin picking. Both dronabinol and placebo treatment were associated with significant reductions in BFRB symptoms. Dronabinol did not significantly separate from placebo on any efficacy measure. At week 10, 67% of the treatment group were classified as responders (Clinical Global Impressions-Improvement Score of very much or much improved) compared to 50% in the placebo group (P value = 0.459). This study assessed the efficacy of dronabinol, a synthetic form of tetrahydrocannabinol, in the treatment of BFRBs, and found no differences in symptom reductions between dronabinol and placebo.