A potential link between dorsomedial hypothalamic nucleus NPY and energy balance.
The function of dorsomedial hypothalamic neuropeptide Y (NPY) in energy balance has largely been restricted to lactation-induced hyperphagia. In this issue, Chao et al. (2011) expand this role to include inhibition of both brown fat thermogenesis and conversion of white-to-brown adipocytes in a white fat depot, resulting in reduced energy expenditure.


E6/E7-P53-POU2F1-CTHRC1 axis promotes cervical cancer metastasis and activates Wnt/PCP pathway.
Cervical cancer is an infectious cancer and the most common gynecologic cancer worldwide. E6/E7, the early genes of the high-risk mucosal human papillomavirus type, play key roles in the carcinogenic process of cervical cancer. However, little was known about its roles in modulating tumor microenvironment, particular extracellular matrix (ECM). In this study, we found that E6/E7 could regulate multiple ECM proteins, especially collagen triple helix repeat containing 1 (CTHRC1). CTHRC1 is highly expressed in cervical cancer tissue and serum and closely correlated with clinicopathological parameters. CTHRC1 promotes cervical cancer cell migration and invasion in vitro and metastasis in vivo. E6/E7 regulates the expression of CTHRC1 in cervical cancer by E6/E7-p53-POU2F1 (POU class 2 homeobox 1) axis. Futhermore, CTHRC1 activates Wnt/PCP signaling pathway. Take together, E6/E7-p53-POU2F1-CTHRC1 axis promotes cervical cancer cell invasion and metastasis and may act as a potential therapeutic target for interventions against cervical cancer invasion and metastasis.


Probabilistic assessment of fatigue initiation data on highly crosslinked ultrahigh molecular weight polyethylenes.
Ultrahigh molecular weight polyethylenes (UHMWPE) showing wear resistance, oxidative stability and good mechanical performance go on being a relevant research area in biomaterials for total joint replacements, where fatigue happens to be a recurrent damage mode that needs to be investigated. While crack propagation lifetime has been extensively studied, fatigue initiation data are scarcely offered in the literature, often due to the higher costs implied in the experimental programs. Moreover, their analysis is not always suitable to obtain reliable guidance. Different deterministic and probabilistic methods, generally resting on empirical bases have been previously used to analyze the fatigue initiation data. In this work, the probabilistic Weibull regression model of Castillo et al., based on both physical and statistical conditions, such as weakest link principle and the necessary compatibility between life-time and stress range distributions, is applied for the first time in the assessment of fatigue results of polymers, particularly to highly crosslinked UHMWPEs (HXLPEs). Accordingly, different published experimental data corresponding to HXLPE stabilized by thermal treatments and with α-tocopherol (vitamin E) are re-analyzed. Additional data are incorporated to assess the influence of notched HXLPE on fatigue performance. New conclusions are drawn from this revision.


Influence of specificity of reagents and of behaviour of cell surface Ig on the detection and enumeration of immunoglobulin-bearing lymphocytes in humans.
Some parameters likely to influence detection and classification of human B-lymphocytes using anti-immunoglobulin (Ig) sera have been investigated. Of 20 separate mono- and polyspecific native or conjugated anti-Ig sera analysed by a passive haemagglutination technique, 13 exhibited non-specific reactivity. This technique showed no consistent correlation between the titre of individual sera against Fab2 and whole IgG respectively. The indirect immunofluorescence (IF) method applied to detect surface Ig on blood lymphocytes seemed to detect Fc-bearing rather than Ig-bearing cells. The direct method generally yielded fewer reacting cells (5%) than the indirect (10-25%), suggesting that Fc-bearing cells are more numerous than Ig-bearing cells. The Ig-bearing blood lymphocytes seemed to belong preferentially to the IgM class. Passively adsorbed Ig did not appear to contribute significantly to the number of Ig-bearing cells detected. Anti-Ig sera induced redistribution and some endocytosis of surface Ig but this did not markedly affect detection of Ig-bearing cells.


Resistance to ciprofloxacin appearing during therapy.
The development of resistance to ciprofloxacin in nine clinical isolates of Pseudomonas aeruginosa was investigated. Isolates had increases in minimal inhibitory concentrations (MICs) from 0.25 to 16 micrograms/ml. The isolates also became resistant to ofloxacin and norfloxacin, but did not show increases in MICs to aminoglycosides, antipseudomonas penicillins, or cephalosporins. One isolate from a patient with endocarditis showed a reduction in a 43-kD outer membrane protein and simultaneous increase in the imipenem MIC. This isolate also showed impaired uptake of ciprofloxacin. Respiratory isolates from cystic fibrosis patients did not show loss of outer membrane protein. MICs were lowered by ethylene diaminetetra-acetic acid, suggesting changes in lipopolysaccharide. Resistant isolates were synergistically inhibited by combinations of ciprofloxacin plus tobramycin or ceftazidime, but MICs remained beyond the achievable serum level.


Amiloride at pH 7.0 inhibits the Na(+)-driven flagellar motors of Vibrio alginolyticus but allows cell growth.
Amiloride, a specific inhibitor for the Na(+)-driven flagellar motors of alkalophilic Bacillus, is known to inhibit secondarily the growth of alkalophiles. The motility of a marine Vibrio, V. alginolyticus, was almost completely inhibited by 2 mM amiloride either at pH 7.0 or 8.5. We found that this concentration of amiloride inhibited the cell growth completely at pH 8.5 but only slightly at pH 7.0. Kinetic analysis of the inhibition of motility by amiloride at pH 7.0 showed that the inhibition was competitive with Na+ in the medium. Thus, amiloride at pH 7.0 is really a specific and useful tool for the analysis of the Na(+)-driven flagellar motors of Vibrio.


Long-term outcome of the REMAGUS 02 trial, a multicenter randomised phase II trial in locally advanced breast cancer patients treated with neoadjuvant chemotherapy with or without celecoxib or trastuzumab according to HER2 status.
The REMAGUS-02 multicenter randomised phase II trial showed that the addition to neoadjuvant chemotherapy (NAC) of trastuzumab in patients with localised HER2-positive breast cancer (BC) increased the pathological complete response (pCR) rate and that the addition of celecoxib in HER2-negative cases did not increase the pCR rate. We report here the long-term follow-up results for disease-free survival (DFS) and overall survival (OS). From 2004 to 2007, 340 stage II-III BC patients were randomly assigned to receive neoadjuvant EC-T (four cycles of epirubicin-cyclophosphamide followed by four cycles of docetaxel) +/- celecoxib in HER2-negative cases (n = 220) and ± trastuzumab in HER2-positive cases (n = 120). From September 2005, all patients with HER2-positive BC received adjuvant T (n = 106). Median follow-up was nearly 8 years (94.4 months, 20-127 m). In the HER2-negative subgroup, addition of celecoxib was not associated with a DFS benefit. Favourable factors were smaller tumour size, expression of progesterone receptor status (PgR) and pCR. In the HER2-positive population, neoadjuvant trastuzumab was not associated with a DFS benefit. Axillary pCR was the only prognostic factor associated with DFS in this group [HR = 0.44, 95% CI = 0.2-0.97], p = 0.035]. To note, DFS and OS were significantly higher in the HER2-positive than in HER2-negative BC patients (HR = 0.58 [0.36-0.92], p = 0.021). Celecoxib combined with NAC provided neither pCR nor survival benefit in patients with HER2-negative BC. Absence of PgR is a major prognostic factor. Neoadjuvant trastuzumab increased pCR rates without translation into a DFS or OS benefit compared with adjuvant trastuzumab only. Axillary pCR could be a more relevant surrogate of survival than in the breast in HER2-positive population. A retrospective comparison shows that patients with HER2-positive tumours have a better outcome than HER2-negative BC patients showing the impact of trastuzumab on the natural history of BC.


[Correlation of genetic and cytogenetic alterations in pathological aggressiveness urothelial carcinoma of the bladder: Performance of BCA-1, a mini-array comparative genomic hybridisation-based test].
Urothelial carcinomas are the fourth leading cause of cancer in humans. Their incidence is increasing by more than 50% in 25 years. The superficial forms (70% cases) require a close active surveillance to identify frequent recurrences and progression to invasive stage. Our main goal was to identify prognostic molecular markers for bladder cancer that could be used alone or in combination in routine clinical practice. In this aim, we evaluated the capability of the BCA-oligo test based on a CGH array to correctly classify tumoral grade/stage. Urinary DNA was extracted from 81 patients with superficial bladder cancer and has been hybridized on the BCA-oligo array. The results from the molecular analysis were correlated with the tumoral grade and stage. Several chromosomal alterations were significantly more frequent in tumors of higher grade and more advanced stage. A significant association was observed between a high grade and the presence of one of these alterations: loss on 6p, gain on 8q or 13q, loss or gain on 9q or 11q, with an odds ratio of 6.91 (95% CI=2.20-21.64; P=0.0009). Moreover, a significant association was found between a more advanced stage (pT1) and the presence of one of these alterations: loss on 6p, gain on 8q, loss or gain on 5p, with an odds ratio of 15.2 (95% CI=3.71-62.58; P=0.0002). Our results showed that molecular analyses of superficial bladder cancers based on urinary DNA and the BCA-oligo test could be used as prognostic factor for the tumor evolution, allowing then a more adapted clinical management.


Metal-Organic Frameworks (MOFs) as methane adsorbents: From storage to diluted coal mining streams concentration.
Ventilation Air Methane emissions (VAM) from coal mines lead to environmental concern because their high global warming potential and the loss of methane resources. VAM upgrading requires pre-concentration processes dealing with high flow rates of very diluted streams (<1% methane). Therefore, methane separation and concentration is technically challenging and has important environmental and safety concerns. Among the alternatives, adsorption on Metal-Organic Frameworks (MOFs) could be an interesting option to methane selective separation, due to its tuneable character and outstanding physical properties. Most of the works devoted to the methane adsorption on MOFs deal with methane storage. Therefore, these works were reviewed to determine the properties governing methane-MOF interactions. In addition, the metallic ions and organic linkers roles have been identified. With these premises, decisive effects in the methane adsorption selectivity in nitrogen/methane lean mixtures have been discussed, since nitrogen is the most concentrated gas in the VAM stream, and it is very similar to methane molecule. In order to fulfill this overview, the effect of other aspects, such as the presence of polar compounds (moisture and carbon dioxide), was also considered. In addition, engineering considerations in the operation of fixed bed adsorption units and the main challenges associated to MOFs as adsorbents were also discussed.


Individual differences in within-subject weight variability: There's a signal in the noise.
Humans show a high degree of stability in their body weights over time, a phenomenon explained by powerful, redundant homeostatic mechanisms. Nonetheless, human populations are also highly susceptible to develop epidemic levels of overweight in an obesogenic environment. Relatively little is known about the process responsible for the transition from remarkable weight stability to relentless weight gain. We have been studying individual differences in within-subject variability in body weights to learn more about this transition. This research has revealed that those who show greater WV over time are more susceptible to future weight gain; greater WV in those losing weight also predicts poorer weight loss maintenance. All the above findings continue to hold when baseline BMI and weight change over the WV assessment period are controlled. The relation of these newer findings to several trends in existing research was considered; these include the relation of weight cycling and morbidity, WV and eating/affective dysregulation, WV and medical diseases and WV and variability in daily energy intake. It appears that elevated WV per se is a risk factor for unfavorable clinical outcomes but little is known about the mechanisms accounting for these associations.


Current role of radial and curved-linear arrayed EUS scopes for diagnosis of pancreatic abnormalities in Japan.
To elucidate the current status of radial and curved-linear arrayed endoscopic ultrasonography (EUS), the author conducted a survey using a questionnaire at different institutions to assess the following. 1. Number of EUS procedures conducted annually for pancreatic malignancies. 2. Role of radial arrayed EUS for pancreatic abnormalities. 3. Role of curved-linear arrayed EUS for pancreatic abnormalities. 4. Indication of EUS-guided fine-needle aspiration biopsy (EUS-FNA) for pancreatic abnormalities. 5. Percentage of EUS-FNA among the cases carried out with EUS for pancreatic abnormalities. 6. Experience of EUS with contrast harmonic echo for pancreatic malignancies and its indications. 7. Experience of elastography on EUS for pancreatic abnormalities. In Japan, although usage of curved-linear arrayed EUS has become popular for both EUS-FNA and for screening, radial EUS is widely used for diagnosing pancreatic abnormalities. Endosonographers must understand the respective advantages and disadvantages of EUS devices and carry out EUS procedures appropriately.


Gene silencing in parasites: current status and future prospects.
Parasitic diseases cause important losses in public and veterinary health worldwide. Novel drugs, more reliable diagnostic techniques and vaccine candidates are urgently needed. Due to the complexity of parasites and the intricate relationship with their hosts, development of successful tools to fight parasites has been very limited to date. The growing information on individual parasite genomes is now allowing the use of a broader range of potential strategies to gain deeper insights into the host-parasite relationship and has increased the possibilities to develop molecular-based tools in the field of parasitology. Nevertheless, functional studies of respective genes are still scarce. The RNA interference phenomenon resulting in the regulation of protein expression through the specific degradation of defined mRNAs, and more specifically the possibility of artificially induce it, has shown to be a powerful tool for the investigation of proteins function in many organisms. Recent advances in the design and delivery of targeting molecules allow efficient and highly specific gene silencing in different types of parasites, pointing out this technology as a powerful tool for the identification of novel vaccine candidates or drug targets at the high-throughput level in the near future, and could enable researchers to functionally annotate parasite genomes. The aim of this review is to provide a comprehensive overview on the current advances and pitfalls in gene silencing mechanisms, techniques, applications and prospects in animal parasites.


Impact of an accelerated melting of Greenland on malaria distribution over Africa.
Studies about the impact of future climate change on diseases have mostly focused on standard Representative Concentration Pathway climate change scenarios. These scenarios do not account for the non-linear dynamics of the climate system. A rapid ice-sheet melting could occur, impacting climate and consequently societies. Here, we investigate the additional impact of a rapid ice-sheet melting of Greenland on climate and malaria transmission in Africa using several malaria models driven by Institute Pierre Simon Laplace climate simulations. Results reveal that our melting scenario could moderate the simulated increase in malaria risk over East Africa, due to cooling and drying effects, cause a largest decrease in malaria transmission risk over West Africa and drive malaria emergence in southern Africa associated with a significant southward shift of the African rain-belt. We argue that the effect of such ice-sheet melting should be investigated further in future public health and agriculture climate change risk assessments.


Beyond phonological and morphological processing: pure copying as a marker of dyslexia in Chinese but not poor reading of English.
To examine cognitive correlates of dyslexia in Chinese and reading difficulties in English as a foreign language, a total of 14 Chinese dyslexic children (DG), 16 poor readers of English (PE), and 17 poor readers of both Chinese and English (PB) were compared to a control sample (C) of 17 children, drawn from a statistically representative sample of 177 second graders. Children were tested on pure copying of unfamiliar stimuli, rapid automatized naming (RAN), phoneme deletion, syllable deletion, and morphological awareness. With children's ages and Raven's nonverbal reasoning statistically controlled, the PE and PB groups were significantly lower than the C group on phoneme deletion and RAN tasks, while the DG performed significantly better than the PB group on the RAN task. The copying task distinguished the DG group from the C group. Findings particularly highlight the importance of phoneme awareness for word reading in English (but not Chinese), the potential need for fluency training for children with reading difficulties in both Chinese and English, and the important role that copying skills could have specifically in understanding impairment of literacy skills in Chinese (but not English).


The importance of social histories for assessing sexually transmitted disease risk.
Although identifying risk groups for sexually transmitted diseases based on age or race may be useful for targeting screening efforts, clinicians should recognize that even members of most "low-risk" groups include some individuals at higher risk of infection. This case series of generally older people with sexually transmitted diseases illustrates how assumptions regarding age and risk group can lead to missed opportunities for sexually transmitted disease prevention. Records were compiled from two clusters of patients with sexually transmitted diseases seen at a Springfield, Mass., health center between March and September 1992. Nine patients with a sexually transmitted disease (one with syphilis/human immunodeficiency virus co-infection, one with herpes/human immunodeficiency virus co-infection, two with human immunodeficiency virus infections, and five with syphilis) are described. Eight of the patients are linked epidemiologically. A social history is essential during a medical encounter for sexually transmitted disease prevention purposes. Relying on assumptions regarding risk groups, as well as sexual activity, age, or other medical conditions, may lead to a patient's level of risk of infection going unrecognized. Discomfort associated with asking the sensitive questions involved in a social history also is a barrier to recognizing risks or infections. Non-judgmental sexual histories are appropriate when evaluating all patients.


A cross-sectional survey of clinical factors that influence the use of traditional Korean medicine among children with cerebral palsy.
Traditional Korean medicine (TKM) is widely used to treat children with cerebral palsy (CP) in Korea; however, studies investigating factors that influence the use of TKM are scarce. Thus, we investigated the clinical factors that might influence the use of TKM. A population-based, cross-sectional, multicenter survey was performed from August 2014 to May 2016. The history of TKM use, type and severity of CP, current treatment characteristics, presence of accompanying disabilities or other health problems not directly related to CP, and monthly cost for the treatment of CP were surveyed. In total, 182 children were recruited, and 78 children (42.9%) had used TKM. Among these 78 children, 50 (64.1% of the TKM-use group) had used both acupuncture and herbal medication, 15 (19.2%) had used acupuncture only, and 13 (16.7%) had used herbal medication only. Children with non-typical CP, accompanying disabilities and general health problems tended to use TKM. The monthly cost of treatment for CP was significantly higher in the TKM-use group than that in the no-TKM-use group, suggesting that economically disadvantaged children may have difficulty in accessing TKM. Dietary supplements, conventional pharmacological treatments, and rehabilitation therapies did not affect TKM use. Children with non-typical symptoms or those with poor overall health status are likely to use TKM. Additionally, TKM use leads to increased treatment costs. Studies investigating the motivation for starting or ceasing TKM therapy, socioeconomic factors and the attitude of parents towards complementary and alternative medicine should be performed.


Trafficking of NMDA receptors is essential for hippocampal synaptic plasticity and memory consolidation.
NMDA receptor (NMDAR) plays a vital role in brain development and normal physiological functions. Surface trafficking of NMDAR contributes to the modulation of synaptic functions and information processing. However, it remains unclear whether NMDAR trafficking is independent of long-term potentiation (LTP) and whether it regulates behavior. Here, we report that LTP of AMPAR and NMDAR can occur concurrently and that NMDAR trafficking can regulate AMPAR trafficking and AMPAR-mediated LTP. By contrast, AMPAR trafficking does not impact NMDAR-mediated LTP. Using SAP97-interfering peptide and SAP97 knockin (KI) rat, we show that the effect is mediated by GluN2A-subunit-containing NMDARs. At the behavior level, impaired NMDAR trafficking results in deficits in consolidation, but not acquisition, of fear memory. Collectively, our results suggest the essential role of NMDAR trafficking in LTP and memory consolidation.


Myocardial scintigraphy with technetrium-99m pyrophosphate during the early phase of acute infarction.
To determine the sensitivity of myocardial scintigraphy with technetium-99m pyrophosphate during the early phase of acute myocardial infarction, 31 patients admitted to the coronary care unit with prolonged ischemic pain underwent imaging within 4 to 8 hours and again at 24 hours after the onset of symptoms. In 11 of 15 patients with documented acute myocardial infarction, increased focal myocardial uptake was demonstrated on early myocardial scintigraphy. Focal uptake was observed in only 2 of 16 patients with unstable angina pectoris. Three or four patients with normal early scintigrams had massive transmural myocardial infarction. Normal early scintigrams in these three patients may have reflected poor perfusion because the images were abnormal at 24 hours. In four patients the extent of technetium-99m pyrophosphate uptake increased more than 20 percent at 24 hours without other evidence of infarct extension. In the other seven patients, there was no significant change in the area of the abnormal radioactive uptake between early and delayed scintiscans. This study suggests that technetium-99m pyrophosphate scintigraphy can defect acute myocardial infarction as early as 4 hours after the onset of symptoms although the sensitivity rate (73 percent) is less than that at 24 hours.


Quantitative pinch stimulator for exploring evoked nociceptive responses: a pilot study.
A mechanical noxious stimulator is useful for studies of pain, both for clinic and basic research. We propose to use a pinch stimulator that can not only generate a quantitative, reproducible noxious pinch but also simultaneously provide a synchronous external trigger signal, which is essential for acquisition of evoked potentials. For ethical considerations, audible and visual aids were incorporated so that pinch force could be regulated within a predetermined level. Reproducibility of the nociceptive responses evoked by this device was validated. The device was constructed with a simple circuit, and the element build-in was delicately selected for the minimum required to produce evoked potentials. The magnitude of the force output is linearly proportional to the volts produced by the device (i.e., during the pinch). Increases in force correspond to increases in the number of action potentials induced. This device may be useful for studying the mechanisms of nociceptive signal processing in the brain through application of reproducible, noxious pinch stimuli.


Food-grade xylitol production from corncob biomass with acute oral toxicity studies.
Xylitol, a sugar substitute, is widely used in various food formulations and finds a steady global market. In this study, xylitol crystals were produced from corncob by fermentation (as an alternative to the chemical catalytic process) by a GRAS yeast Pichia caribbica MTCC 5703 and characterized in detail for their purity and presence of any possible contaminant that may adversely affect mammalian cell growth and proliferation. The acute and chronic oral toxicity trials demonstrated no gross pathological changes with average weekly weight gain in female Wistar rats at high xylitol loading (LD50 > 10,000 mg/kg body weight). The clinical chemistry analysis supported the evidence of no dose-dependent effect by analyzing blood biochemical parameters. The finding suggests the possible application of the crystals (> 98% purity) as a food-grade ingredient for commercial manufacture pending human trials.


Military carrier choice during the Covid-19 pandemic in Hungary.
Covid-19 pandemic has changed availability of reasonable jobs. To avoid joblessness, many young adults selected military service in Hungary. The aim of this research was to study their motivation, their individual needs and the way they think about the military forces. In this study, half-structured, focus group interviews with standard questions have been qualitatively analyzed by applying the Grounded Theory (GT) method. Three levels of coding were applied: open (basic), axial and selective coding. This process resulted in fewer codes representing larger categories leading to a final concentrated overview of the interviews. Three selective codes (Enrollment, Pathfinding, Fulfillment), and many sub-codes were identified. We could establish that the effect of the Covid-19 pandemic for the military career-choice really can be detected in many individuals. The military force offers for them safe, predictable existence and career image, in which, in addition to continuous learning and development, teamwork and camaraderie provides major motivations.


Motor root conduction block in traumatic brachial plexopathy.
A 31-year old man sustained severe left brachial plexus traction injury. Electrical stimulation demonstrated multilevel motor root conduction block, which reversed after a 4-month period. Motor root conduction studies are useful diagnostic and prognostic adjuncts in the management of brachial plexopathy.


Homogeneous incorporation of secondary cell wall polysaccharides to the cell wall of Thermus thermophilus HB27.
Regular surface protein layers (S-layers) from most Gram-positive bacteria and from the ancestral bacterium Thermus thermophilus attach to pyruvylated polysaccharides (SCWP) covalently bound to the peptidoglycan through their SLH domain. However, it is not known whether the synthesis of SCWP and S-layer is coordinated enough as to follow a similar pattern of incorporation to the cell wall during growth. In this work we analyse the localization of newly synthesized SCWP on the cell wall of T. thermophilus by immunoelectron microscopy. For this, we obtained mutants with a reduced amount of pyruvylated SCWP through mutation of the csaB gene encoding the SCWP-pyruvylating activity, and its upstream gene csaA, a putative sugar transporter. We hypothesized that CsaA would be required for the synthesis of the SCWP. However, we found that csaA mutants showed only a minor decrease in the amount of SCWP immunodetected on the cell walls in comparison with csaB mutants, revealing its irrelevance in the process. Complementation experiments of csaB mutants with CsaB expressed from inducible promoters revealed that newly synthesized SCWP was homogeneously distributed along the cell wall. Fusions with thermostable fluorescent protein revealed that CsaB was distributed also in homogeneous pattern associated with the membrane. These data support that synthesis of SCWP takes place in disperse and homogeneous form all over the cell surface, in contrast to the zonal incorporation at the cell centre recently demonstrated for SlpA.


Antagonism of methomyl-induced toxicosis by diphenhydramine in rats.
The efficacy of diphenhydramine in the prevention and treatment of methomyl-induced toxicosis was evaluated in female rats. Diphenhydramine at 10 and 20 mg/kg subcutaneously (s.c.) given immediately after methomyl increased the LD(50) of methomyl (6.29 mg/kg intraperitoneally (i.p.)) in the rats by 71 and 75% respectively. Diphenhydramine at 20 mg/kg s.c. given immediately after methomyl (6 mg/kg i.p.) decreased the occurrence of cholinergic signs of toxicosis, and prevented convulsions, gasping and death by 100% in comparison with the control (methomyl-saline) group. Diphenhydramine administration at 2.5, 5 and 10 mg/kg s.c. 20 min before methomyl (8 mg/kg i.p.) significantly and dose-dependently decreased the number of convulsion episodes in rats in comparison with the control group. This effect was similar to those of atropine and diazepam pretreatments at 20 mg/kg s.c. Diphenhydramine and atropine at 20 mg/kg i.p. given 5 min after the methomyl administration (8 mg/kg i.p.) were close to each other in reducing the signs of cholinergic toxicity as well as the severity of toxicosis induced by methomyl in rats. Methomyl at 4 and 8 mg/kg i.p. significantly decreased erythrocyte (40 and 43%) and plasma (23 and 31%) cholinesterase activities in comparison with the control group. Diphenhydramine (10 mg/kg s.c.) injected 15 min before methomyl significantly decreased the inhibitory effect of methomyl (4 and 8 mg/kg i.p.) on erythrocyte cholinesterase to 17 and 27%, respectively. The inhibitory effect on plasma cholinesterase was not affected by the diphenhydramine pretreatment. The data suggest that diphenhydramine could be of therapeutic value in reducing the toxic effects of methomyl.


A filtration based technique for simultaneous SEM and TEM sample preparation for the rapid detection of pathogens.
Diagnostic electron microscopy for infectious diseases has the advantage that "everything" in the specimen can be observed, without a priori knowledge of the likely identity of the microorganisms present in the sample. The classical specimen preparation method used employs a droplet of sample, which allows particles to adsorb to a support film, and is subsequently negative stained. This "grid on drop" procedure has a sensitivity range of approximately 106 viruses per mL if no enrichment procedures are used. In the current investigation we present a novel use of filtration that allows us to detect viruses at concentrations as low as 102 viruses per mL. We present here methods based on filtration, in which total virus, and not virus concentration, is the limiting factor for detection. We show that filtration is more sensitive than conventional negative staining and can detect as few as 5 × 103 particles per sample.


Revisiting the malaria hypothesis: accounting for polygenicity and pleiotropy.
The malaria hypothesis predicts local, balancing selection of deleterious alleles that confer strong protection from malaria. Three protective variants, recently discovered in red cell genes, are indeed more common in African than European populations. Still, up to 89% of the heritability of severe malaria is attributed to many genome-wide loci with individually small effects. Recent analyses of hundreds of genome-wide association studies (GWAS) in humans suggest that most functional, polygenic variation is pleiotropic for multiple traits. Interestingly, GWAS alleles and red cell traits associated with small reductions in malaria risk are not enriched in African populations. We propose that other selective and neutral forces, in addition to malaria prevalence, explain the global distribution of most genetic variation impacting malaria risk.


Zika Virus Amplification Using Strand Displacement Isothermal Method and Sequencing Using Nanopore Technology.
Development of novel point of care diagnostic methods in order to help in implementing disease control program and identifying the causative agent of an outbreak is crucial. Classical diagnostic techniques, e.g., real-time polymerase chain reaction (PCR), rely on the presence of the nucleic acid sequence of the target in GenBank. In the case of an emerging new strain of a known or novel pathogen, false-negative results will be recorded by PCR. On the other hand, next-generation sequencing technologies allow rapid whole genome sequencing without previous knowledge of the target. One of these methods is the Oxford Nanopore sequencing technique, which utilizes a portable device named MinION and has a short run time. In this protocol, we describe the development of a novel nanopore sequencing protocol by combining random isothermal amplification technology and nanopore sequencing. The established protocol is rapid (<7 h) and sensitive as less than 4% of the sequenced RNA belonged to the target virus, Zika. Interestingly, we have established an offline BLAST search for the data analysis that facilitates the use of the whole protocol at remote settings without the need of an Internet connection.


Effect of endoscopic resection on short-term surgical outcomes of subsequent laparoscopic gastrectomy: a meta-analysis.
Endoscopic resection (ER) might affect subsequent laparoscopic gastrectomy (LG) because of the electrical coagulation, but the effect remains controversial. The purpose of this meta-analysis was to analyze the effect of ER on the short-term surgical outcomes of subsequent LG. The PubMed, EMBASE, and Cochrane Library databases were searched to find eligible studies published from inception to March 21, 2021. Short-term surgical outcomes were compared between the ER-LG group and the LG-only group. The registration ID of this current meta-analysis on PROSPERO is CRD42021238031. Nine studies involving 3611 patients were included in this meta-analysis. The LG-only group had a higher T stage (T1-T2: OR=2.42, 95% CI=1.09 to 5.34, P=0.03; T3-T4: OR=0.41, 95% CI=0.19 to 0.91, P=0.03) than the ER-LG group. The ER-LG group showed a shorter operation time than the LG-only group (MD=-5.98, 95% CI=-10.99 to -0.97, P=0.02). However, no difference was found in operation time after subgroup analysis of propensity score matching studies. No significant difference was found in intraoperative blood loss, time to first oral feeding, or postoperative hospital stay between the ER-LG group and the LG-only group. And no significance was found in overall complications (OR=1.16, 95% CI=0.89 to 1.50, P=0.27), complications of grade ≥ II (OR=1.11, 95% CI=0.71 to 1.73, P=0.64), complications of grade ≥ III b (OR=1.47, 95% CI=0.49 to 4.43, P=0.49) between the ER-LG group and the LG-only group. ER did not affect subsequent LG in terms of short-term outcomes, and the ER-LG group might have a shorter operation time than the LG-only group.


'Is this something I should be worried about?': A study of nurses' recontextualisation work when making clinical decisions based on patient reported outcome data.
As clinical care practices are becoming more digitalised, information about patients is increasingly being encoded as quantified data, and the processes of sorting data are often supported by algorithmic computations. One such practice becoming more prevalent across Western countries is the clinical use of Patient Reported Outcome (PRO) data. Drawing on ethnographic fieldwork carried out in a Danish setting among nurses managing PRO-based breast cancer follow-up, we examine how clinical decisions are made on the basis of PRO-data and what this requires from the nurses. By applying the concept of recontextualisation work as an analytical perspective, we shed light on the efforts of nurses when mobilising complementary information about patients in order to recontextualise the otherwise decontextualised data, thereby giving data practical value in clinical decision-making. Recontextualisation work, we show, is shaped by organisational structure, available resources, and nurses' professional capacity. Drawing analytical attention to the work of recontextualisation allows for a nuanced understanding of the efforts required to make data workable and hence what it takes to carry out clinical decisions in today's datafied healthcare system.


USP15 regulates p66Shc stability associated with Drp1 activation in liver ischemia/reperfusion.
Liver ischemia/reperfusion (I/R) injury is a major clinical concern of liver transplantation, which accounts for organ rejection and liver dysfunction. The adaptor protein p66Shc acts as a crucial redox enzyme and is implicated in liver I/R. Elevated p66Shc expression is associated with hepatocellular apoptosis in liver I/R, but the molecular mechanisms of p66Shc responsible for its aberrant expression and function remain unknown. In the present study, hepatocyte-specific p66Shc-knockdown mice exhibited clear inhibition in hepatocellular apoptosis and oxidative stress under liver I/R, while hepatocyte-specific p66Shc overexpression mice displayed the deteriorative impairment. Mechanistically, p66Shc-triggered mitochondrial fission and apoptosis in liver I/R by mediating ROS-driven Drp1 activation. Furthermore, a screening for p66Shc-interacting proteins identified ubiquitin-specific protease 15 (USP15) as a mediator critical for abnormal p66Shc expression. Specifically, USP15 interacted with the SH2 domain of p66Shc and maintained its stabilization by removing ubiquitin. In vivo, p66Shc knockdown abrogated USP15-driven hepatocellular apoptosis, whereas p66Shc overexpression counteracted the antiapoptotic effect of USP15 silencing in response to liver I/R. There was clinical evidence for the positive association between p66Shc and USP15 in patients undergoing liver transplantation. In summary, p66Shc contributes to mitochondrial fission and apoptosis associated with Drp1 activation, and abnormal p66Shc expression relies on the activity of USP15 deubiquitination under liver I/R. The current study sheds new light on the molecular mechanism of p66Shc, and identifies USP15 as a novel mediator of p66Shc to facilitate better therapeutics against liver I/R.


Catch-up growth in the first two years of life in Extremely Low Birth Weight (ELBW) infants is associated with lower body fat in young adolescence.
To investigate growth patterns and anthropometrics in former extremely low birth weight (ELBW, <1000 g) children and link these outcomes to neurocognition and body composition in childhood. ELBW children were examined at birth (n = 140), at 9 and 24 months (n≥96) and at approximately 11 years within the framework of the PREMATCH (PREMATurity as predictor children's of Cardiovascular and renal Health) case-control (n = 93-87) study. Regional growth charts were used to convert anthropometrics into Z-scores. Catch-up growth in the first two years of life was qualified as present if ΔZ-score >0.67 SDS. At 11 years, anthropometrics, neurocognitive performance, body composition, grip strength and puberty scores were assessed. ELBW neonates displayed extra-uterine growth restriction with mean Z-scores for height, weight and head circumference of -0.77, -0.93 and -0.46 at birth, -1.61, -1.67 and -0.72 at 9 months, -1.22, -1.61 and -0.84 at 24 months, and -0.42, -0.49 and -1.09 at 11 years. ELBW children performed consistently worse on neurocognitive testing with an average intelligence quotient equivalent at 11 years of 92.5 (SD 13.1). Catch-up growth was not associated with neurocognitive performance. Compared to controls, ELBW cases had lower grip strength (13.6 vs. 15.9 kg) and percentage lean body weight (75.1 vs. 80.5%), but higher body fat (24.6 vs. 19.2%) and advanced puberty scores at 11 years (all P≤0.025). Catch-up growth for weight and height in the first two years of life in cases was associated with a lower percentage body fat compared to cases without catch-up growth (16.8% catch-up growth for weight vs. 25.7%, P<0.001; 20.9% catch-up for height vs. 25.8%, P = 0.049). In young adolescence, former ELBW children still have difficulties to reach their target height. Compared to normal birth weight controls, ELBW adolescents show lower neurocognitive performance and grip strength and a higher percentage body fat, a potential risk factor for adverse health outcomes in adulthood. Our key finding is that catch-up growth in ELBW children in the first two years of life is associated with a lower percentage body fat and is therefore likely to be beneficial.


"How to" Course for Resident Reviewers: from the Resident and Fellow Education Committee of the Society for Surgery of the Alimentary Tract (SSAT).
The Resident and Fellow Education Committee of the Society for Surgery of the Alimentary Tract (SSAT) hosted a "How to" course for resident reviewers at the 2021 Annual Meeting at Digestive Disease Week. This panel drew from their extensive experience to help neophyte reviewers perform high quality, comprehensive peer reviews. Dr. Snyder kicked off the session with "Why Should I be a Resident Reviewer?" Dr. Talamini followed by "Defining the Review Process," while Dr. Keller presented "OK, You Are Ready to Review, Where to Start?" Dr. Pawlik ended the session with "How to Be an Excellent Reviewer." Residents are encouraged to apply the content from these sessions to volunteer as reviewers and develop critical skills to help further their academic surgery career.


Midwife-centred management: a qualitative study of midwifery group practice management and leadership in Australia.
Midwifery group practice (MGP) has consistently demonstrated optimal health and wellbeing outcomes for childbearing women and their babies. In this model, women can form a relationship with a known midwife, improving both maternal and midwife satisfaction. Yet the model is not widely implemented and sustained, resulting in limited opportunities for women to access it. Little attention has been paid to how MGP is managed and led and how this impacts the sustainability of the model. This study clarifies what constitutes optimal management and leadership and how this influences sustainability. This qualitative study forms part of a larger mixed methods study investigating the management of MGP in Australia. The interview findings presented in this study are part of phase one, where the findings informed a national survey. Nine interviews and one focus group were conducted with 23 MGP managers, clinical midwife consultants, and operational/strategic managers who led MGPs. Transcripts of the audio-recordings were analysed using inductive, reflexive, thematic analysis. Three themes were constructed, namely: The manager, the person, describing the ideal personal attributes of the MGP manager; midwifing the midwives, illustrating how the MGP manager supports, manages, and leads the group practice midwives; and gaining acceptance, explaining how the MGP manager can gain acceptance beyond group practice midwives. Participants described the need for MGP managers to display midwife-centred management. This requires the manager to have qualities that mirror what is generally accepted as requirements for good midwifery care namely: core beliefs in feminist values and woman-centred care; trust; inclusiveness; being an advocate; an ability to slow down or take time; an ability to form relationships; and exceptional communication skills. Since emotional labour is a large part of the role, it is also necessary for them to encourage and practice self-care. Managers need to practice in a way that is midwife-centred and mimics good midwifery care. To offset the emotional burden and improve sustainability, encouraging and promoting self-care practices might be of value.


Pathogenesis of the tauopathies.
Microtubule-associated protein tau is the most commonly misfolded protein in human neurodegenerative diseases, where it becomes hyperphosphorylated and filamentous. Mutations in MAPT, the tau gene, cause approximately 5% of cases of frontotemporal dementia. They are frequently accompanied by parkinsonism. The existence of MAPT mutations has established that dysfunction of tau protein is sufficient to cause neurodegeneration and dementia. However, most tauopathies are not inherited in a dominant manner. The hyperphosphorylated sites are similar between diseases, but filament morphologies and tau isoform compositions vary. This is consistent with the existence of multiple tau conformers and recent findings have provided experimental support for this concept.


Graphene Oxide Membranes for Tunable Ion Sieving in Acidic Radioactive Waste.
Graphene oxide (GO) membranes with unique nanolayer structure have demonstrated excellent separation capability based on their size-selective effect, but there are few reports on achieving ion-ion separation, because it is difficult to inhibit the swelling effect of GO nano sheets as well as to precisely control the interlayer spacing d to a specific value between the sizes of different metal ions. Here, selective separation of uranium from acidic radioactive waste containing multication is achieved through a precise dual-adjustment strategy on d. It is found that GO swelling is greatly restricted in highly acidic solution due to protonation effect. Then the interlayer spacing is further precisely reduced to below the diameter of uranyl ion by increasing the oxidation degree of GO. Sieving uranyl ions from other nuclide ions is successfully realized in pH =3-3 mol L-1 nitric acid solutions.


Use of continuous subcutaneous insulin infusion pump in patients with type 2 diabetes mellitus.
In patients with type 2 diabetes, the control of hyperglycemia is often difficult despite full doses of oral hypoglycemic agents and extremely large doses of insulin. These patients pose a major management problem. The authors therefore investigated whether insulin given as a subcutaneous continuous infusion of insulin (CSII) would result in an improvement in glucose homeostasis. Four patients with badly controlled type 2 diabetes, on treatment with extremely high doses of insulin and oral hypoglycemic agents, were started on CSII. All four patients had a marked improvement in plasma glucose concentrations with a corresponding fall in HbA1c levels. This improvement was associated with a marked fall in the insulin doses necessary to maintain adequate glucose homeostasis. Since HbA1c levels fell from levels that would be associated with diabetic complications to those at which complications are markedly reduced, we recommend that patients with type 2 diabetes uncontrolled on extremely high doses of insulin be given a trial of treatment with CSII.


COVID-19 and the selection problem in national cause-of-death statistics.
The World Health Organization has issued international instructions for certification and classification (coding) of the coronavirus disease (COVID-19) as cause of death. Central to these instructions is the selection of the underlying cause of death for a public health preventive purpose. This article focuses on two rules for this selection: (1) that a death due to COVID-19 should be counted independently of pre-existing conditions that are suspected of triggering a severe course of COVID-19 and (2) that COVID-19 should not be considered as due to anything else. The article argues that observance of the first rule may not always lead to an optimal selection from a preventive point of view and that in the future the ascertainment of an animal source of the coronavirus (SARS-CoV-2) would make it possible to reconceptualize 'COVID-19' and create a zoonotic classification code by means of which a factor of a greater preventive value could be selected than what is currently possible.


Beneficial effects of endophytic Pantoea ananatis with ability to promote rice growth under saline stress.
Soil salinization severely inhibits plant growth, leading to a low crop yield. The aim of the current study was to isolate endophytic bacteria with the ability to promote rice growth under saline conditions. We isolated eight salt-tolerant endophytic bacteria from rice roots. An isolated strain D1 was selected due to its ability to stimulate rice seed germination in the presence of NaCl, which was identified as Pantoea ananatis D1. It exhibited multiple plant growth-promoting traits including phosphate solubilization, production of indole-3-acetic acid, 1-aminocyclopropane-1-carboxylic acid (ACC) deaminase and siderophore. Inoculation of P. ananatis D1 obviously enhanced the rice root and shoot growth under normal and saline conditions. It also significantly increased the contents of chlorophyll, total soluble protein, and proline in salt-stressed rice seedlings. Moreover P. ananatis D1 could ameliorate the oxidative stress in rice induced by NaCl and Na2 CO3 treatment. The malondialdehyde content and various antioxidant enzyme activities were decreased by P. ananatis D1 inoculation in salt-affected rice. In addition, P. ananatis D1 showed a positive potential for limiting the Na+ accumulation and enhancing the K+ uptake, leading to an increase of 1·2-1·7 fold in K+ /Na+ ratio under saline environment. Pantoea ananatis D1 has the ability to improve the salt tolerance of rice seedlings. The application of plant growth-promoting bacteria (PGPB) is an eco-friendly strategy to improve plant tolerance towards abiotic stresses. We demonstrated that P. ananatis D1 could be used as an effective halotolerant PGPB to enhance rice growth in different salt-affected soils.


Evaluation of Drug-Drug Interaction Liability for Buprenorphine Extended-Release Monthly Injection Administered by Subcutaneous Route.
Buprenorphine extended-release (BUP-XR) formulation is a once-monthly subcutaneous injection for the treatment of opioid use disorder (OUD). Buprenorphine undergoes extensive cytochrome P450 (CYP) 3A4 metabolism, leading to potential drug-drug interactions (DDIs) as reported for sublingual buprenorphine. Sublingual buprenorphine is subject to first-pass extraction, as a significant proportion of the dose is swallowed. Because subcutaneous administration avoids first-pass extraction, the DDI with CYP3A4 inhibitors is expected to be less than the 2-fold increase reported for the sublingual route. The objective of this analysis was to predict the magnitude of DDI following coadministration of BUP-XR with a strong CYP3A4 inhibitor or inducer using physiologically based pharmacokinetic (PBPK) modeling. Models were developed and verified by comparing predicted and observed data for buprenorphine following intravenous and sublingual dosing. Comparison of predicted and observed pharmacokinetic (PK) profiles and PK parameters demonstrated acceptable predictive performance of the models (within 1.5-fold). Buprenorphine plasma concentrations following administration of a single dose of BUP-XR (300 mg) were simulated using a series of intravenous infusions. Daily coadministration of strong CYP3A4 inhibitors with BUP-XR predicted mild increases in buprenorphine exposures (AUC, 33%-44%; Cmax , 17-28%). Daily coadministration of a strong CYP3A4 inducer was also associated with mild decreases in buprenorphine AUC (28%) and Cmax (22%). In addition, the model predicted minimal increases in buprenorphine AUC (8%-11%) under clinical conditions of 2 weeks' treatment with CYP3A4 inhibitors administered after initiation of BUP-XR. In conclusion, the PBPK predictions indicate that coadministration of BUP-XR with strong CYP3A4 inhibitors or inducers would not result in clinically meaningful interactions.


Mitochondrial oxidative stress mediated Fe-induced ferroptosis via the NRF2-ARE pathway.
Ferroptosis is a regulated form of cell death induced by iron (Fe)-dependent lipid peroxidation. At present, the underlying molecular mechanisms remain elusive. Herein, we hypothesized that mitochondria and the NRF2 (transcription factor nuclear factor E2-related factor 2) are potential mediators of ferroptosis, considering their well-established involvement in the oxidative stress pathway. We found that a high iron diet increased hepatic iron content and promoted glutathione (GSH) depletion, lipid peroxidation and oxidative stress. Dietary iron overload also decreased mRNA and protein expression levels of glutathione peroxidase 4 (GPX4) and cystine-glutamate antiporter (SLC7A11), and increased mRNA and protein expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), which are all markers of ferroptosis. Consistent with ferroptosis, iron overload promoted lipid peroxidation and the generation of mitochondrial reactive oxygen species (ROS), and decreased the mitochondrial membrane potential (MMP). Pre-treatment with deferoxamine mesylate (DFO, an iron chelator) alleviated ROS generation and lipid peroxidation, indicating a causative link between iron overload and lipid peroxidation. Suppression of mitochondrial oxidative stress attenuated ferroptosis. Experiments with HEK293T cells revealed that Fe-induced ferroptosis involved direct inhibition of NRF2 binding to antioxidant response elements (AREs) within the promoters of the gpx4 and slc7a11 genes, which in turn induced transcriptional silencing. In conclusion, our study provided a direct link between mitochondrial oxidative stress and ferroptosis via the NRF2-ARE pathway.


Utilizing benthic foraminifera to explore the environmental condition of the Laizhou Bay (Bohai Sea, China).
Through the analysis of benthic foraminifera in the soft bottom sediments of the Laizhou Bay - Yellow River Delta system, this study characterized the foraminiferal biotopes and explored the possibility of obtaining an index of ecological quality comparable with other estuarine and coastal environments of the world. Five foraminiferal biotopes have been identified and their distribution patterns highlight the ecological stress from the marine-fluvial water mixing and pollution. The foraminiferal species were analyzed as a function of organic carbon gradients, and the main species were assigned to four ecological groups based on their sensitivity/tolerance towards an increasing stress gradient. Finally, the relative proportions of the species assigned to the four different ecological groups were used for the definition of a marine biotic index based on foraminifera, i.e. the Foram-AMBI, and thus the assessment of the ecological quality status of marine soft-bottom habitats.


FGF4 and FGF9 have synergistic effects on odontoblast differentiation.
The purpose of this study was to investigate whether fibroblast growth factor 4 (FGF4) and FGF9 are active in dentin differentiation. Dentin matrix protein 1 (Dmp1) -2A-Cre transgenic mice, which express the Cre-recombinase in Dmp1-expressing cells, were crossed with CAG-tdTomato mice as reporter mouse. The cell proliferation and tdTomato expressions were observed. The mesenchymal cell separated from neonatal molar tooth germ were cultured with or without FGF4, FGF9, and with or without their inhibitors ferulic acid and infigratinib (BGJ398) for 21 days. Their phenotypes were evaluated by cell count, flow cytometry, and real-time PCR. Immunohistochemistry for FGFR1, 2, and 3 expression and the expression of DMP1 were performed. FGF4 treatment of mesenchymal cells obtained promoted the expression of all odontoblast markers. FGF9 failed to enhance dentin sialophosphoprotein (Dspp) expression levels. Runt-related transcription factor 2 (Runx2) was upregulated until day 14 but was downregulated on day 21. Compared to Dmp1-negative cells, Dmp1-positive cells expressed higher levels of all odontoblast markers, except for Runx2. Simultaneous treatment with FGF4 and FGF9 had a synergistic effect on odontoblast differentiation, suggesting that they may play a role in odontoblast maturation.


Assessment of the association between colchicine therapy and serious adverse events.
As data that prompted a 2009 labeling change detailing contraindications, precautions, and dosing recommendations for the first branded colchicine product were limited to case reports of myotoxicity and blood dyscrasias ascribed to the drug, we sought to quantify the association of colchicine therapy with serious adverse outcomes in a cohort of insured patients. Case-control study. Kaiser Permanente Colorado electronic data warehouses and electronic medical records. Cases were patients with a creatine kinase (CK) level of at least 2000 U/L or who developed a clinically significant non-cancer-related blood dyscrasia (thrombocytopenia, neutropenia, leukopenia, aplastic anemia, or pancytopenia) between January 1, 2006, and June 30, 2009 (954 cases). Each case was matched to up to 10 controls by age, sex, and index date (date of the increased CK level or blood dyscrasia-supporting laboratory value). Controls were patients without elevated CK levels or blood dyscrasias who had a routine health maintenance examination during the same time period (index date was the date of their health maintenance examination [9007 controls]). The primary study outcome was colchicine exposure, defined as a colchicine prescription purchase in the 100 days before the index date. The likelihood of colchicine exposure was examined with conditional logistic regression. Cases experienced a higher rate of previous colchicine exposure compared with controls (0.6% vs 0.2%, odds ratio 3.9, 95% confidence interval 1.4-10.7). In addition, cases had higher hospitalization rates (14.9% vs 5.0%, p<0.001), higher mean chronic disease scores (2.5 vs 0.0, p<0.001), and were more likely to have been exposed to drugs that may increase the risk of adverse events due to an interaction with a CYP3A4 inhibitor drug (6.9% vs 2.3%, p<0.001). Patients with confirmed elevations in CK level and/or blood dyscrasias had a higher rate of previous colchicine exposure, although low overall, and greater hospitalization rates and exposure to drugs that may increase the risk of adverse events compared with controls. These findings support the 2009 United States Food and Drug Administration labeling for the first branded colchicine product, cautioning use in patients with liver impairment or renal dysfunction and/or those receiving concurrent drugs that may increase risk of adverse events.


Children's Resilience to Ongoing Border Attacks: The Role of Father, Mother, and Child Resources.
To understand children's resilience to ongoing violent border attacks (low PTSD symptoms and internalizing/externalizing behavior problems, and high sense of coherence-SOC), this study examined a multidimensional model of protective resources. This model comprised factors at the family level (fathers'/mothers' coping strategies and SOC) and at the individual level (children's coping strategies and attachments with father/mother). Participants were 251 Israeli father-mother-child triads living near the border with Gaza (children ages 9-12 years). Preliminary analyses indicated children's prevalence of clinical PTSD was 6%. SEM analyses revealed the theoretical model's high fit with empirical data, χ2(1) = .00, p = .99, CFI = 1, TLI = 1, SRMR = .00, RMSEA = .00 [90% CI (.00, .00)]. More significant paths emerged between fathers' coping resources and children's resilience measures than for mothers' coping resources. Results also pinpointed the significant role of children's parental attachments and coping strategies. Discussion focused on the unique value of father, mother, and child risk/protective factors for explaining well-adjusted functioning among children living in conflict areas.


Minute mosaics caused by early chromosome loss.
Two genetic operations have been combined in order to ascertain whether there are differential proliferation rates in the syncytial nuclei and the blastoderm cells prior to the formation of the imaginal disc anlagen. Early chromosome loss caused by the mutantca nd has been associated with the generation ofMinute (M/M +) genotypes in normal (M +/M +) zygotes or of non-Minute genotypes inMinute zygotes. The results indicate that there is no growth competition betweenMinute and non-Minute cells prior to the formation of the imaginal discs. Growth competition, however, leads later, during the proliferation phase of the discs, to the demarcation of compartment boundaries within imaginal discs.


Luteolin and apigenin derived glycosides from Alphonsea elliptica abrogate LPS-induced inflammatory responses in human plasma.
Numerous Alphonsea species including Alphonsea elliptica (mempisang) leaves and fruits are indigenously used in inflammatory conditions such as postpartum swelling and rheumatism in southeast Asian countries. In our previous in-vitro findings, A. elliptica methanol extract exhibited platelet-activating factor inhibition, suggesting the presence of phyto-constituents with anti-inflammatory potential. However, so far there is no literature available on the anti-inflammatory activity of this species. Henceforth, based on the above background and our previous laboratory findings, we hypothesize that phytoconstituents of A. elliptica could possess anti-inflammatory potential against inflammatory mediators including prostaglandin-E2 (PGE2), cyclooxegenase-2 (COX-2) and cytokines (IL-1β and IL-6). Vacuum and column chromatography techniques were employed for the isolation of phytoconstituents. The structure elucidation was carried out using HRESI-MS, 1H and 13C-NMR analysis and compared with the published literature. For cytotoxicity analysis, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed on peripheral blood mononuclear cells. In-vitro anti-inflammatory activities were evaluated against the levels of PGE2, COX-2, IL-1β and IL-6 in lipopolysaccharide (LPS)-induced human plasma using enzyme-linked immunosorbent assay and radioimmunoassay. Unprecedentedly, chromatographic purification of methanolic leaves extract afforded five flavones namely vitexin, isovitexin, orientin, isoorientin, schaftoside with three flavanols; kaempferol, myricetin and rutin from A elliptica. In cell viability analysis, isolates did not present cytotoxicity up to 50 μM. In anti-inflammatory evaluation, orientin and isoorientin exhibited strong (≥70%), while isovitexin and vitexin produced strong to moderate (50-69%) PGE2, COX-2, IL-1β and IL-6 inhibition at 25 and 50 μM. Isoorientin, orientin, isovitexin, and vitexin showed significant (p < 0.05) and concentration-dependent PGE2 inhibition with IC50 values (μM) of 11.40, 14.71, 17.70 and 20.58 against indomethacin (8.80). Furthermore, isoorientin, orientin, isovitexin, and vitexin produced significant concentration-dependent inhibition with IC50 values (μM) of COX-2: 7.13, 9.51, 12.81, 16.61; IL-1β 4.80, 6.20, 10.85, 14.51; IL-6: 4.01, 5.90, 11.51 and 14.88 as compared to dexamethasone: 5.29, 2.93, 3.72, respectively (p < 0.05). Conclusively, isolated phytoconstituents are reported for the first time from the A. elliptica. Moreover, isovitexin, vitexin orientin and isoorientin abrogated LPS-induced inflammatory responses in human plasma at non-cytotoxic concentrations.


Admittance values associated with the acoustic reflex and reflex decay.
Acoustic stapedial reflexes were elicited from 10 normal S's in each of three age groups. Susceptance and conductance values were measured for each subject in both the unreflexed and reflexed states and at 10-sec intervals during a continuous, reflex-sustaining stimulation with pure tones. Percentage of reflex decay over time was noted for each group and as a function of stimulus frequency and measurement mode. No significant age group differences were noted. Significant stimulus frequency and measurement mode differences were presented to represent "normal" reflex decay.


The effect of beta-blockade on myocardial remodelling in Chagas' cardiomyopathy.
Chagas' disease has spread throughout Latin America because of the high rate of migration among these countries. Approximately 30% of Chagas' patients will develop cardiomyopathy, and 10% of these will develop severe cardiac damage leading to heart failure. Beta-blockade improves symptoms and survival in heart failure patients; however, its efficacy has not been well established in Chagas' disease. We evaluated the role of carvedilol in cardiac remodeling and mortality in a Chagas' cardiomyopathy animal model. We studied Trypanosoma cruzi infection in 55 Syrian hamsters that were divided into three groups: control (15), infected (20), and infected + carvedilol (20). Animals underwent echocardiography, electrocardiography, and morphometry for collagen evaluation in ventricles stained with picrosirius red. The left ventricular diastolic diameter did not change between groups, although it was slightly larger in infected groups, as was left ventricular systolic diameter. Fractional shortening also did not change between groups, although it was slightly lower in infected groups. Collagen accumulation in the interstitial myocardial space was significantly higher in infected groups and was not attenuated by carvedilol. The same response was observed in the perivascular space. The survival curve showed significantly better survival in the control group compared with the infected groups; but no benefit of carvedilol was observed during the study. However, in the acute phase (up to 100 days of infection), carvedilol did reduce mortality. Carvedilol did not attenuate cardiac remodeling or mortality in this model of Chagas' cardiomyopathy. The treatment did improve survival in the acute phase of the disease.


Presentation of a new mutation in FMF and evaluating the frequency of distribution of the MEFV gene mutation in our region with clinical findings.
Familial Mediterranean Fever (FMF), which is an autosomal recessive disease characterized by recurrent self-limiting fever, peritonitis, pleuritis, arthritis and erysipelas-like erythemas, has been common among ethnic groups such as Turkish, Armenian, Arabic and Jewish. The clinical presentation is caused by mutations in the MEFV gene encoding the Pyrin protein. In this study, we aimed to present a new mutation that has not been previously defined from the mutations in the MEFV gene which is responsible for the genetic pathology of familial Mediterranean fever and to evaluate the frequency of distribution of the MEFV gene mutation among different ethnic groups living in our region. In present retrospective study, a total of 2639 clinically suspected FMF patients who were referred to Hatay Mustafa Kemal University Hospital between 2010 and 2017 were recorded. MEFV gene mutations were observed using DNA sequence analysis. MEFV mutations were found in 2079 of the 2639 patients (78.7%) Among these patients 184 (6.97%) were homozygous, while 1365 (51.72%) were heterozygous. The most frequently observed mutation was R202Q (1319, 19.55%) followed by E148Q (n = 476, 7.05%), M694V (n = 439, 6.51%), V726A (n = 146, 2.16%) and M680I (n = 135, 2%). In a case clinically diagnosed as FMF, a new mutation called S145G (p. Ser145Gly, c.433A > G) was identified in exon 2 of the MEFV gene. Besides, addition of a new pathogenic MEFV variant to the literature, the relationship between the FMF clinic and homozygous form of R202Q, which was previously considered as a polymorphism, was highlighted.


Life-sustaining treatment preferences: matches and mismatches between patients' preferences and clinicians' perceptions.
Better clinician understanding of patients' end-of-life treatment preferences has the potential for reducing unwanted treatment, decreasing health care costs, and improving end-of-life care. To investigate patient preferences for life-sustaining therapies, clinicians' accuracy in understanding those preferences, and predictors of patient preference and clinician error. This was an observational study of 196 male veterans with chronic obstructive pulmonary disease who participated in a randomized trial. Measures included patients' preferences for mechanical ventilation (MV) and cardiopulmonary resuscitation (CPR) if needed in their current state of health, and outpatient clinicians' beliefs about those preferences. Analyses were based on 54% of participants in the trial who had complete patient/clinician data on treatment preferences. Patients were more receptive to CPR than MV (76% vs. 61%; P<0.001). Preferences for both treatments were significantly associated with the importance patients assigned to avoiding life-sustaining therapies during the final week of life (MV: b=-0.11, P<0.001; CPR: b=-0.09, P=0.001). When responses were dichotomized (would/would not want treatment), clinicians' perceptions matched patient preferences in 75% of CPR cases and 61% of MV cases. Clinician errors increased as patients preferred less aggressive treatment (MV: b=-0.28, P<0.001; CPR: b=-0.32, P<0.001). Clinicians erred more often about patients' wishes when patients did not want treatment than when they wanted it. Treatment decisions based on clinicians' perceptions could result in costly and unwanted treatments. End-of-life care could benefit from increased clinician-patient discussion about end-of-life care, particularly if discussions included patient education about risks of treatment and allowed clinicians to form and maintain accurate impressions of patients' preferences.


A new microcolumn-type microchip for examining the expression of chimeric fusion genes using a nucleic acid sandwich hybridization technique.
We report a new type of microcolumn installed in a microchip. The architecture allows use of a nucleic acid sandwich hybridization technique to detect a messenger RNA (mRNA) chain as a target. Data are presented that demonstrate that the expression of a chimeric fusion gene can be detected. The microcolumn was filled with semi-transparent microbeads made of agarose gel that acted as carriers, allowing increased efficiency of the optical detection of fluorescence from the microcolumn. The hybrid between the target trapped on the microbeads and a probe DNA labeled with a fluorescent dye was detected by measuring the intensity of the fluorescence from the microcolumn directly. These results demonstrate an easy and simple method for determining the expression of chimeric fusion genes with no preamplification.


Clinicopathologic correlation of cancer stem cell markers CD44, CD24, VEGF and HIF-1α in ductal carcinoma in situ and invasive ductal carcinoma of breast: an immunohistochemistry-based pilot study.
CD24(-/low)CD44(+) cells have been identified as putative cancer stem cells (CSCs) in breast cancer. However, the expression of these markers, as well as their association with clinical parameters or tumor microenvironment of breast cancer, remains largely unknown. In the present study, we examined the expression of CD44, CD24, VEGF, and HIF-1α in human breast tumor tissues and assessed their clinicopathological correlations. We investigated tissue samples, including 117 cases of invasive ductal carcinoma (IDCa), 14 cases of ductal carcinoma in situ (DCIS), and 15 cases of intraductal hyperplasia (IDH) from breast tissues. The expression of CD44, CD24, HIF-1α, and VEGF was evaluated using immunohistochemical staining. CD24, CD44, HIF-1α, and VEGF were expressed in 49 (41.9%), 51 (43.6%), 32 (27.4%), and 97 cases (82.9%), respectively, in IDCa. CD24(-/low)CD44(+) cells were noted in 48 (41.3%) cases. The levels of CD24 and VEGF expression correlated positively with tumor malignancy (P<0.05). Meanwhile, the expression of CD24, CD44, and VEGF correlated significantly positively with increasing tumor grade (P<0.05). In addition, associations between CD44 and VEGF, CD24 and VEGF, HIF-1α and VEGF, CD24(-/low)CD44(+) and VEGF, CD24(-/low)CD44(+) and HIF-1α were also observed (P<0.05). The HIF-1α expression level was relatively higher in early stage breast cancer patients with CD24(-/low)CD44(+) cells. Taken together, our results suggest that CD24 and VEGF may play important roles in breast tumorigenesis and progression, while HIF-1α may play a role in the early stage of breast carcinogenesis.


Paramagnetic contrast agents in nuclear magnetic resonance medical imaging.
Relaxation time differences are the sources of most of the contrast observed in proton NMR images, not only among normal organs and tissues but between lesions and the adjacent tissue. Although these differences are often large, there are low-contrast situations in which it would be desirable to increase the visibility of an organ or region. The study of time-dependent phenomena would also be aided by the ability to change selected relaxation times deliberately. One way to achieve these goals is to administer substances that change proton relaxation times in tissues without causing significant toxic effects or other physiologic changes. Paramagnetic ions and molecules, those with unpaired electrons, may be useful for this purpose because the very large magnetic effects associated with such electrons can drastically decrease water proton relaxation times at concentrations of the order of 100 to 1000 microM, which may be reached in certain organs after doses of 10 to 100 microM/kg. The general characteristics of such paramagnetic substances are described, and specific animal experiments with manganous ion and its complexes, and with stable nitroxide free radicals and molecular oxygen, are reviewed. The paramagnetic contrast agents already studied are effective, and many more are potentially possible, but the most important questions to be answered are whether acute and chronic toxicity are low enough to permit research and diagnosis on humans.


Symptom improvement as prognostic factor for survival in cancer patients undergoing palliative care: a pilot study.
The Edmonton Symptom Assessment Scale (ESAS) is a validated tool for physical symptom assessment in palliative care practice which evaluates symptoms through a numeric scale from 0 to 10. The use of symptom improvement as a prognostic factor is controversial. To this purpose, a pilot study in advanced cancer patients now undergoing only palliative care was conducted. Patients were considered eligible if no longer able to receive any anticancer treatment; they were scheduled to undergo ESAS assessment at the hospitalization and hospital discharge time points. Symptoms' scores were divided into three severity classes: mild, moderate and severe. Differences across symptoms' classes between hospitalization and hospital discharge time points were analysed with the paired-data McNemar test, according to tumour types. ESAS assessment was administered to 68 patients with gastrointestinal (39 patients) and non-small cell lung cancer (29 patients); median age was 69 years; Karnofsky Performance Status was 50 in 27 (39.7%) patients and >50 in 41 (60.3%) patients. Palliative Prognostic Score was A for 26 (38.2%) patients, B for 37 (54.4%) patients and C for 5 (7.4%) patients. A statistically significant reduction of severe severity class rates was observed. Symptom improvement correlates with survival improvement: Palliative Prognostic Score (hazard ratio (HR) 2.95, 95% CI 1.35-6.41, p = 0.006) and anorexia (HR 3.21, 95% 1.33-7.72, p = 0.009) appear to be prognostic factors for survival at the multivariate analysis for gastrointestinal cancer patients; asthenia is the only significant variable (HR 5.11, 95% CI 1.86-14.03, p = 0.002) for non-small cell lung cancer patients. Symptom improvement according to ESAS after palliative care treatment represents an important prognostic for survival in patients no longer suitable to receive any anticancer active therapies.


Chromosome aberration measurements in mitotic and G2-PCC lymphocytes at the standard sampling time of 48 h underestimate the effectiveness of high-LET particles.
The relationship between heavy-ion-induced cell cycle delay and the time-course of aberrations in first-cycle metaphases or prematurely condensed G(2)-cells (G(2)-PCC) was investigated. Lymphocytes of the same donor were irradiated with X-rays or various charged particles (carbon, iron, xenon, and chromium) covering an LET range of 2-3,160 keV/μm. Chromosome aberrations were measured in samples collected at 48, 60, 72, and 84 h postirradiation. Linear-quadratic functions were fitted to the data, and the fit parameters α and β were determined. At any sampling time, α values derived from G(2)-cells were higher than those from metaphases. The α value derived from metaphase analysis at 48 h increased with LET, reached a maximum around 155 keV/μm, and decreased with a further rise in LET. At the later time-points, higher α values were estimated for particles with LET > 30 keV/μm. Estimates of α values from G(2)-cells showed a similar LET dependence, yet the time-dependent increase was less pronounced. Altogether, our data demonstrate that heavily damaged lymphocytes suffer a prolonged G(2)-arrest that is clearly LET dependent. For this very reason, the standard analysis of aberrations in metaphase cells 48 h postirradiation will considerably underestimate the effectiveness of high-LET radiation. Scoring of aberrations in G(2)-PCC at 48 h as suggested by several authors will result in higher aberration yields. However, when particles with a very high-LET value (LET > 150 keV/μm) are applied, still a fraction of multiple damaged cells escape detection by G(2)-analysis 48 h postirradiation.


Dynamic Systolic Changes in Tricuspid Regurgitation Vena Contracta Size and Proximal Isovelocity Surface Area in Hypoplastic Left Heart Syndrome: A Three-Dimensional Color Doppler Echocardiographic Study.
The aims of this study were to investigate the dynamic changes in the vena contracta (VC) and proximal isovelocity surface area (PISA) through systole in patients with hypoplastic left heart syndrome and tricuspid regurgitation and to identify the stage of systole (early, mid, or late) in which VC and PISA radius are optimal. Twenty-eight patients with hypoplastic left heart syndrome were prospectively studied using continuous two-dimensional (2D) and three-dimensional (3D) echocardiography. Two-dimensional VC width, 3D VC area, and PISA radii (2D and 3D) were measured frame by frame throughout systole. The maximal 2D VC width, 3D VC area, and PISA radii in the first, middle, and last thirds of systole were compared, and correlations were explored with 3D tricuspid annular areas, right atrial volumes, and right ventricular volumes. In all, 35 data sets that met inclusion criteria were analyzed. On frame-by-frame analysis, maximal 2D VC width and 3D VC area were found in the first third of systole in 17% and 20% of studies, in the second third in 34% and 31%, and in the final third in 49% and 49%. Similarly, the maximal 2D and 3D PISA radii were found in the first third of systole in 26% and 17% of studies, in the second third in 28% and 34%, and in the final third in 46% and 49%. In hypoplastic left heart syndrome, detailed temporal analysis of tricuspid regurgitation-associated VC and PISA by 2D and 3D echocardiography reveals no reliable pattern predicting when in systole these parameters peak. Frame-by-frame measurement is necessary for identification of maximal VC and PISA radius on 2D and 3D color Doppler echocardiography because the severity of tricuspid regurgitation could be underestimated because of temporal variability in VC and PISA.


The Comparative Effects of Dexamethasone, Nanocurcumin, and Coenzyme Q10 Against Lumbar Laminectomy-Induced Epidural Fibrosis in a Rat Model.
One of the major problems in neurosurgical procedures is fibrosis formation. Therefore, the prevention of fibrosis is an important issue in spinal cord injury that needs to be addressed. No approved therapy has yet been found, and epidural fibrosis (EF) is a huge treatment challenge. In this regard, new drugs that can effectively prevent EF are still being considered. Hence, this study aimed to investigate the effects of dexamethasone (DEX), nanocurcumin (Nano-CUR), and coenzyme Q10 (CoQ10) on the prevention of EF in a rat laminectomy model. Thirty-five Sprague-Dawley male rats were randomly divided into 5 groups: sham group, laminectomy group, laminectomy + DEX group, in which 0.5 ml DEX (8 mg/ml) was applied locally on the laminectomy area, laminectomy + Nano-CUR group, in which 100 mg/kg Nano-CUR was administered intraperitoneally once a day for 7 days, and laminectomy + CoQ10 group, in which 30 mg/kg CoQ10 was administered once daily intraperitoneally for 7 days. After 4 weeks, the vertebral columns were removed from L1 and L3 and prepared for histopathological assays. The local administration of DEX could not improve the histological parameters, and EF was induced by laminectomy after 4 weeks. On the other hand, Nano-CUR could ameliorate EF at the laminectomy site compared to the laminectomy group, but the difference was not statistically significant. CoQ10 significantly reduced EF (P < 0.05), collagen density (P < 0.01), and inflammation in the arachnoid layer (P < 0.01). Our findings showed that Nano-CUR and CoQ10 had the potential to be used for treatment of EF.


Temporal regulation of cytokine mRNA expression in equine recurrent airway obstruction.
Acute and chronic inflammation of the airway remains an important health problem for equids. "Heaves" or recurrent airway obstruction (RAO) remains one of the most commonly diagnosed conditions affecting the lung of older horses in Europe and the United States. The typical clinical signs of RAO include non-productive coughing, serous nasal discharge, labored expiratory effort, and flaring of the nostrils. Auscultation of the lungs of the affected horse often reveals abnormal respiratory sounds, described as crackles and wheezes, throughout the area of the lung field. These clinical signs occur secondary to an inflammatory response that results in bronchospasm, excessive mucus production and airway obstruction. This inflammatory response is characterized by the presence of excessive mucus and inflammatory cells, primarily neutrophils, in the small airways. Most evidence suggests that RAO is the result of a pulmonary hypersensitivity to inhaled antigens. Exposure of affected horses to hay dust, pollens, and mold spores leads to neutrophil accumulation in the lung and bronchospasm. The identification of allergen-specific IgE in bronchoalveolar lavage (BAL) fluid and sera of affected horses supports the involvement of a late phase, IgE-mediated, hypersensitivity reaction in the pathogenesis of equine RAO. The production of IgE antibodies is regulated by the cytokines IL-4 and IL-13. Using a quantitative PCR method we have reported that horses with RAO exhibit a modified Type 2 cytokine response characterized by the production of IL-4 and IL-13 mRNA, but not IL-5 mRNA in BAL cells. Interferon-gamma mRNA was also elevated, suggesting a mixed response. While these results are consistent with equine RAO being the result of an aberrant Type 2 cytokine response to inhaled allergens, others have failed to find any evidence of elevated Type 2 cytokine mRNA in BAL from horses with "heaves". It is likely that these disparate results could be the result of differences in the clinical stage of the affected animals or the timing of sample collection. Here, we report a diverse pattern of cytokine gene expression when sampling a group of affected horses over a period of time.


Assessing a training programme for primary care dental practitioners in endodontics of moderate complexity: Pilot data on skills enhancement and treatment outcomes.
To explore the impact of dedicated training to extend the skills of primary care practitioners on the quality of endodontic care, using clinical, radiographic and patient-related outcomes. The quality of endodontic treatment performed at the beginning and end of training to become dentists with extended skills (DES) in endodontics was assessed in vitro and in vivo from endo-training blocks and self-reported logbooks containing clinical notes and radiographs respectively. The quality of endodontic care delivered by DES post-training was measured using clinical and radiographic outcomes. Patient-related outcomes were assessed using a self-report questionnaire, including the Oral Health Impact Profile – Endodontic Outcome Measure (OHIP-EOM). Data on eight dentists were examined pre-and post-training, five of whom participated in further follow-up investigations on the quality of endodontic care delivered to their patients. Significant improvements in skills were seen for all domains in vitro (p <0.05), and for all domains of the clinical treatment process, and achieving the correct working length of the root filling as seen by radiography in vivo (p <0.05). The quality of the clinical process was maintained following training. Positive patient outcome (OHIP-EOM) scores were recorded (mean score of 34.72, SD = 10.74, n = 120 pre-treatment and 25.85, SD = 7.74, n = 47 representing reduced impact at follow-up). The majority of patients reported being satisfied, or very satisfied, with the service they received (72.5%, n = 98); would use the service again (68.1%, n = 92); and would recommend the service to friends and family (74.8%, n = 101). Findings suggest that training for dentists working in practice can be successful in enhancing skills and changing practice, with evidence of high patient satisfaction and good clinical and patient-related outcomes. Pilot results must be interpreted with caution and further research is required.


Angiotensin II (AII) induced hypertension chemotherapy (IHC) for unresectable gastric cancer: with reference to resection after down staging.
Angiotensin II induced hypertension chemotherapy (IHC) is a drug delivery system for augmentation of anti-cancer effects on the experimental basis of the functional difference of microcirculation between tumor and normal tissue. Blood flow in tumor tissue increased selectively when the blood pressure was elevated by the infusion of angiotensin II. Two randomized controlled trials (RCT) for advanced gastric cancer using AFM regimen; a combination of adriamycin (ADM), 5-fluorouracil (5-FU), and mitomycin (MMC), showed increased response rate by IHC (response rate: IHC/non-IHC; 42.9% vs 10.5% in RCT-1, and 31.3% vs 6.7% in RCT-2, respectively). Toxicities were not different statistically between groups. In phase II for stage IVB gastric cancer patients (the criteria according to the General Rules of the Gastric Cancer Study of Japanese Research Society for Gastric Cancer), 5 complete response (CR) and 10 partial response (PR) (58%) were observed out of 26 unresectable cases without prior chemotherapy. Moreover, 5 of 15 responders could received curative gastrectomy and obtained conclusive down staging (19%). Here we discuss the role of enhancement of drug delivery for cancer chemotherapy on the basis of a series of clinical and experimental evidences.


Simultaneous hydrodynamic cavitation and glow plasma discharge for the degradation of metronidazole in drinking water.
In this study, a novel hydrodynamic cavitation unit combined with a glow plasma discharge system (HC-GPD) was proposed for the degradation of pharmaceutical compounds in drinking water. Metronidazole (MNZ), a commonly used broad-spectrum antibiotic, was selected to demonstrate the potential of the proposed system. Cavitation bubbles generated by hydrodynamic cavitation (HC) can provide a pathway for charge conduction during glow plasma discharge (GPD). The synergistic effect between HC and GPD promotes the production of hydroxyl radicals, emission of UV light, and shock waves for MNZ degradation. Sonochemical dosimetry provided information on the enhanced formation of hydroxyl radicals during glow plasma discharge compared to hydrodynamic cavitation alone. Experimental results showed a MNZ degradation of 14% in 15 min for the HC alone (solution initially containing 300 × 10-6 mol L-1 MNZ). In experiments with the HC-GPD system, MNZ degradation of 90% in 15 min was detected. No significant differences were observed in MNZ degradation in acidic and alkaline solutions. MNZ degradation was also studied in the presence of inorganic anions. Experimental results showed that the system is suitable for the treatment of solutions with conductivity up to 1500 × 10-6 S cm-1. The results of sonochemical dosimetry showed the formation of oxidant species of 0.15 × 10-3 mol H2O2 L-1 in the HC system after 15 min. For the HC-GPD system, the concentration of oxidant species after 15 min reached 13 × 10-3 molH2O2L-1. Based on these results, the potential of combining HC and GPD systems for water treatment was demonstrated. The present work provided useful information on the synergistic effect between hydrodynamic cavitation and glow plasma discharge and their application for the degradation of antibiotics in drinking water.


Evidence that Swimming May Be Protective of Knee Osteoarthritis: Data from the Osteoarthritis Initiative.
To date, there have not been any epidemiologic studies that have evaluated the association between swimming over a lifetime and knee health. The study aimed to evaluate the relationship of a history of swimming with knee pain, radiographic knee OA (ROA), and symptomatic knee OA (SOA). Cross-sectional retrospective study. Four academic centers in the United States. Respondents to the historical physical activity survey within the Osteoarthritis Initiative with knee radiographs and symptom assessments. In this retrospective study nested within the Osteoarthritis Initiative, researchers performed logistic regression with the predictor being swimming over a lifetime and over particular age ranges. Person-based definitions of frequent knee pain, ROA, and SOA. A total of 2637 participants were included, with a mean age of 64.3 years (SD 8.9), body mass index of 28.4 kg/m2 (SD 4.9), and 44.2% male. Over a lifetime, the adjusted prevalence measures for frequent knee pain, ROA, and SOA for any versus no history of swimming were 36.4% (33.4% - 39.5%) v. 39.9% (37.4% - 42.5%), 54.3% (51.0% - 57.6%) v. 61.1% (58.4% - 63.7%), and 21.9% (19.4% - 24.7%) v. 27.0% (24.7% - 29.4%) respectively. This is the first epidemiologic study to indicate that swimming is potentially beneficial toward knee health, particularly when performed earlier in life (before age 35). Future prospective studies are needed to confirm these findings and to better scrutinize the associations in older age groups.


Predictors of functioning of patients with chronic obstructive pulmonary disease.
To determine the extent to which mood, symptoms, lung function, and social support of patients with chronic obstructive pulmonary disease (COPD) predicted their level of functioning over a 30-month period. Prospective, longitudinal. The homes of patients living in or adjacent to metropolitan Toronto. Seventy-one patients (48 men and 23 women) with COPD who had a forced expiratory volume in 1 second less than 50% of predicted (FEV1 < 50%) and who spoke English. They ranged in age from 43 to 81 years (mean 66.37 years). The patients' level of functioning at the final data collection visit, 30 months after the initial measure. At both data collection visits patients completed measures of mood (negative mood scales of the Profile of Mood States), symptoms (Bronchitis-Emphysema Symptom Checklist), social support (Personal Resource Questionnaire), and functioning (Sickness Impact Profile). Data were analyzed by use of multiple regression analysis. From measures taken at the initial visit (T1), the best predictors of patients' functioning at 30 months (T2) were their functioning at T1, symptoms, FEV1, and age. Together these accounted for 70% of the variance in the final functioning scores, with initial functioning scores accounting for 51% of the variance. The most prevalent symptoms were dyspnea and fatigue, and both were highly correlated with functioning scores 30 months later. In this study, symptoms, FEV1, and age are predictive of functioning in patients with COPD over a 30-month time frame. However, only 50% of the 143 patients recruited into the study completed it. Therefore caution needs to be exercised when the results are applied to other patients with COPD.


Membrane Transporters and Channels in Melanoma.
Recent research has revealed that ion channels and transporters can be important players in tumor development, progression, and therapy resistance in melanoma. For example, members of the ABC family were shown to support cancer stemness-like features in melanoma cells, while several members of the TRP channel family were reported to act as tumor suppressors.Also, many transporter proteins support tumor cell viability and thus suppress apoptosis induction by anticancer therapy. Due to the high number of ion channels and transporters and the resulting high complexity of the field, progress in understanding is often focused on single molecules and is in total rather slow. In this review, we aim at giving an overview about a broad subset of ion transporters, also illustrating some aspects of the field, which have not been addressed in detail in melanoma. In context with the other chapters in this special issue on "Transportome Malfunctions in the Cancer Spectrum," a comparison between melanoma and these tumors will be possible.


Control of B cell development by Ras-mediated activation of Raf.
Cell fate commitment in a variety of lineages requires signals conveyed via p21ras. To examine the role of p21ras in the development of B lymphocytes, we generated transgenic mice expressing a dominant-negative form of Ras in B lymphocyte progenitors, using a novel transcriptional element consisting of the Emu enhancer and the lck proximal promoter. Expression of dominant-negative Ras arrests B cell development at a very early stage, prior to formation of the pre-B cell receptor. Furthermore, an activated form of Raf expressed in the same experimental system could both drive the maturation of normal pro-B cells and rescue development of progenitors expressing dominant-negative Ras. Hence p21ras normally regulates early development of B lymphocytes by a mechanism that involves activation of the serine/threonine kinase Raf.


Pupillary dynamics reflect the impact of temporal expectation on detection strategy.
Everyday life's perceptual decision-making is informed by experience. In particular, temporal expectation can ease the detection of relevant events in noisy sensory streams. Here, we investigated if humans can extract hidden temporal cues from the occurrences of probabilistic targets and utilize them to inform target detection in a complex acoustic stream. To understand what neural mechanisms implement temporal expectation influence on decision-making, we used pupillometry as a proxy for underlying neuromodulatory activity. We found that participants' detection strategy was influenced by the hidden temporal context and correlated with sound-evoked pupil dilation. A model of urgency fitted on false alarms predicted detection reaction time. Altogether, these findings suggest that temporal expectation informs decision-making and could be implemented through neuromodulatory-mediated urgency signals.


The ethics of suicide research.
Good quality, ethically sound research is needed in order to better understand, appropriately respond to, and reduce the incidence of suicide. There is, however, a lack of clarity around the nature of ethical problems associated with suicide research and how to resolve them. This is a formidable challenge for ethics committee members in approving and monitoring research. To describe the views that members of health research ethics committee hold regarding ethical problems and ethical practice in research involving people who are, or who have, been suicidal. Ethics committee members were invited to complete an online survey addressing the risks, benefits, and ethical problems associated with suicide research. Findings were aggregated into themes using an inductive form of content analysis. Concerns of ethics committees centered on accessing the population, potential harm to participants or the researcher, researcher competency, maintaining confidentiality, providing support to participants, and responding sensitively to the needs of family. Ethical research involving suicidal people requires both procedures to protect participants, and consideration of ethics as an ongoing negotiated process. The findings of this research provide a snapshot of views held by a number of ethics committee members.


Fetal and maternal risks associated with intrauterine transfusion procedures.
Continuing follow-up observations and study of information as derived from a large cohort of fetal recipients of intrauterine transfusion (IUT) is utilized to provide estimates of maternal and fetal risks associated with the transfusion procedures, subsequent maternal complications of the pregnancy, and the health, intelligence, and behavior of the erythroblastotic recipient. The upper limit of risk of the procedure is estimated to be 7.2 per cent. Fourteen per cent of hydropic fetuses survived through the perinatal period as compared with 47 per cent of nonhydropic fetuses. One infant developed acute lymphocytic leukemia (ALL) at age 4 1/2 years. The IUT survivors showed a marked correlation among the frequencies of abnormalities in the three areas measured: physical, intellectual, and social maturity. Only about 50 per cent were considered normal in these parameters of health. Maternal complications were observed in only 2 per cent of the cases.


Stroke burden in Guinea: Results from the Conakry Ignace Deen Hospital stroke registry.
Sub-Saharan Africa has extremely high stroke prevalence and case fatality. Most Sub-Saharan African regions are uncharted in terms of stroke characteristics, epidemiology, and burden. We report here the results from the first stroke registry in Guinea.