Experimental Studies on the Crack Initiation and Propagation of Hydraulic Fracturing with Different Coal Structure Combinations.
Coal structure is one of the key geological factors that affects the effect of coal reservoir stimulation. Based on the geological spatial combination characteristics, thickness, and proportion of different coal structures, the coal reservoir is divided into different coal structure combination types. The hydraulic fracturing device is used to carry out indoor fracturing experiments and dissect the crack initiation and expansion characteristics with different coal structure combinations. The results show that the coal structure combination is of the binary type (undeformed coal + granulated coal or cataclastic coal + granulated coal), and the undeformed coal (cataclastic coal) can overcome the tensile strength and minimum principal stress when it is driven by the high-pressure fluid. The undeformed coal (cataclastic coal) ruptures and forms longitudinal cracks. The increasing proportion of granulated coal inhibits crack expansion and promotes the transverse deformation of coal. The interface contact point between the undeformed coal (cataclastic coal) and granulated coal easily fractures along the cross section of the specimen. When the coal structure combination is the triplex type (undeformed coal + granulated coal + cataclastic coal or cataclastic coal + granulated coal + cataclastic coal), the undeformed coal or cataclastic coal is transformed. The forming fractures in the undeformed coal (cataclastic coal) can cut through the soft coal when the thickness of the undeformed coal (cataclastic coal) is large and the thickness of granulated coal is thin. On the contrary, it is not easy to cut through. When the coal structure combination is granulated coal + cataclastic coal + granulated coal, the cataclastic coal fails under shear stress and forms the crack along the cross section of the coal sample. The granulated coal inhibits the crack expansion at both ends. The research results have an important indicative significance for further understanding the fracture initiation and propagation mechanism of hydraulic fracturing with complex coal structures in coal reservoirs.


Legionella pneumophila-induced PKCalpha-, MAPK-, and NF-kappaB-dependent COX-2 expression in human lung epithelium.
Legionella pneumophila causes community- and hospital-acquired pneumonia. Lung airway and alveolar epithelial cells comprise an important barrier against airborne pathogens. Cyclooxygenase (COX) and microsomal PGE(2) synthase-1 (mPGES-1)-derived prostaglandins like prostaglandin E(2) (PGE(2)) are considered as important regulators of lung function. Herein we tested the hypothesis that L. pneumophila induced COX-2 and mPGES-1-dependent PGE(2) production in pulmonary epithelial cells. Legionella induced the release of PGE(2) in primary human small airway epithelial cells and A549 cells. This was accompanied by an increased expression of COX-2 and mPGES-1 as well as an increased PLA(2) activity in infected cells. Deletion of the type IV secretion system Dot/Icm did not impair Legionella-related COX-2 expression or PGE(2) release in A549 cells. L. pneumophila induced the degradation of IkappaBalpha and activated NF-kappaB. Inhibition of IKK blocked L. pneumophila-induced PGE(2) release and COX-2 expression. We noted activation of p38 and p42/44 MAP kinase in Legionella-infected A549 cells. Moreover, membrane translocation and activation of PKCalpha was observed in infected cells. PKCalpha and p38 and p42/44 MAP kinase inhibitors reduced PGE(2) release and COX-2 expression. In summary, PKCalpha and p38 and p42/44 MAP kinase controlled COX-2 expression and subsequent PGE(2) release by Legionella-infected lung epithelial cells. These pathways may significantly contribute to the host response in Legionnaires' disease.


Effect of metronidazole on chronic periodontal disease in subjects using a topically applied chlorhexidine gel.
A double blind between subject comparison of the effect of metronidazole and placebo tablets was completed over 22 weeks in 45 subjects with chronic periodontal disease ranging in severity from moderate (PI = 2.0-3.9) to high (PI = 4.0-6.0). All subjects used a topically applied chlorhexidine gel for the first 10 weeks. Throughout the trial plaque, bleeding and calculus were assessed on the buccal, lingual, mesial and distal surfaces of teeth 16, 21, 24, 36, 41 and 44 and their supporting tissues. The pocket depths on the same 4 aspects of all teeth present were measured. The regime employed consisted of oral hygiene instruction (OHI) at the initial visit followed by scaling and further OHI at visits 1 and 2 weeks later. After the third visit 16 X 200 mg metronidazole or placebo tablets were issued with instructions to take 1 that evening and 3 per day at 5-h intervals for the next 5 days. 4 weeks later, scaling and OHI were carried out and the course of test or placebo tablets was repeated. The subjects returned for further scaling and OHI 4 weeks later and the chlorhexidine gel was withdrawn. Final assessments were made 12 weeks later. The results showed that metronidazole had no effect on plaque levels and gingival bleeding beyond the effect of OHI, scaling and chlorhexidine gel. On the other hand, significantly greater reductions in pocket depths were achieved with the use of metronidazole. A surprising and interesting finding was that these reductions were apparent only in the subjects with severe periodontal disease (PI = 4.0-6.0).


Demonstration of high coincidence of pituitary adenoma in patients with ruptured Rathke's cleft cyst: Results of a prospective study.
Repeated chronic inflammation, such as under circumstances of ruptured Rathke's cleft cyst (RCC), is known as the fundamental basis of various pathological changes including neoplastic change, therefore to examine accurate incidence of pituitary adenomas is important for the preventive medicine. As a prospective study, patients were initially screened by the symptoms such as periodic headache and dizziness together with the abnormal findings such as seller floor bone defect on 3D-CT. Those screened patients who showed abnormal basal pituitary hormone values were additionally examined by several loading test and 3T magnetic resonance imaging (MRI) by three-dimensional reconstructions of Flair cube images. The presence of pituitary adenomas was evaluated by composite 3T MRI and (11)C methionine MET positron-emission tomography imaging. Immunohistochemical studies were employed for surgical biopsy specimens to demonstrate hormone production. 308 cases of RCC were diagnosed by both radiologic and intraoperative findings. Pathological examination confirmed 111 pituitary adenomas in 106 patients with ruptured RCC, therefore the rate of coincidence was revealed 34%. In 78 patients with abnormalities of pituitary hormone secretion, MET uptake was observed in the pituitary gland and verified pituitary adenoma pathologically. In addition, 28 adenomas were verified without MET-PET study on pathological examination only, for a total of 106 cases. High coincidence (34%) of ruptured RCC and pituitary adenomas was demonstrated, which is a proof that ruptured RCC is contributed to a risk factor of pituitary adenoma.


[Attention deficit hyperactivity disorder (ADHD) in preschoolers: nature, assessment and treatment].
Attention deficit hyperactivity disorder (ADHD) is the most frequently diagnosed behaviour problem in school-age children. Although more and more preschool-age children are referred in clinical settings for typical ADHD symptoms, few studies have examined the nature, the assessment as well as the treatment of ADHD in this age group. This literature review addresses the nature, the assessment, and the treatment of ADHD during the preschool period. The main themes reviewed are: prevalence, symptomatology, etiology, comorbidity, consequences on normal development and adaptation of the child, evolution of symptoms from preschool to school period, difficulties related to diagnosis, assessment modalities, psychosocial treatment, and pharmacological treatment.


Metabolic and cardiac responses of cunner Tautogolabrus adspersus to seasonal and acute changes in temperature.
The cunner is a marine teleost that exhibits winter dormancy (i.e., becomes inactive and stops feeding) when seawater temperatures fall below 5°C. To examine whether this dormant state is also associated with active metabolic depression, the effect of season on routine metabolic rate (MR(rout)) was measured at five different times throughout the year: early spring (5°C), late spring (9°C), summer (14°C), late fall (5°C), and winter (0°C). In addition, cardiac function (cardiac output, heart rate, and stroke volume) was measured at the last three measurement time points, and the ability of fall- and winter-acclimated cunner to adjust MR(rout) and cardiac function when challenged with acute temperature changes was assessed. The cunner actively depressed MR(rout) between fall and winter as temperature fell from 5° to 0°C ([Formula: see text]). In addition, MR(rout) showed a substantial but smaller Q(10) (4.3) when the MR(rout) at 0°C (winter) was compared with the value recorded during the previous spring at ∼5°C. These seasonal changes were essentially mirrored by the response of MR(rout) to acute 5°C increases and decreases in temperature. Similar to MR(rout), cardiac output (Q) decreased dramatically as temperature fell from 5°C (fall) to 0°C (winter) in the seasonal study ([Formula: see text]) and increased substantially when temperature was acutely increased from 0° to 5°C ([Formula: see text]). However, when subjected to an acute temperature decrease (from 5° to 0°C), the Q(10) for Q was only approximately 2-3. These results show that (1) cunner actively depress their metabolism in the fall and winter and that this is associated with a large decrease in cardiac function and (2) there is a decoupling between Q and MR(rout) when 5°C seasonally acclimated cunner are exposed to an acute temperature decrease to 0°C.


Dementia and occupational exposure to magnetic fields.
The purpose of the present report was to assess whether occupational magnetic field exposure is a risk factor for dementia, in particular for Alzheimer's disease. Case-control analyses were applied to 77 dementia cases, 55 of whom had Alzheimer's disease, ascertained from the population-based Swedish twin register. Two reference groups were derived, with 228 and 238 persons, respectively. Occupations were linked to a job-exposure matrix based on magnetic field measurements. Primary occupation, last occupation before reference date, and the occupation with the highest magnetic field exposure during the subject's lifetime were evaluated. For primary occupation, all relative risk estimates were close to unity. For last occupation, at the exposure level > or = 0.2 microT, a relative risk was found for dementia estimated at 3.3 [95% confidence interval (95% CI) 1.3-8.6] and 3.8 (95% CI 1.4-10.2) for reference groups 1 and 2, respectively. The relative risk for Alzheimer's disease was estimated at 2.4 (95% CI 0.8-6.9) and 2.7 (95% CI 0.9-7.8), respectively. For the occupation with the highest magnetic field exposure, the relative risk estimates were close to unity for reference group 1 and slightly elevated for reference group 2. The relative risk estimates were greater for the subjects who were younger at onset (< or =75 years). These results only partially support previous findings, but they indicate that occupational magnetic field exposure may possibly influence the development of dementia.


[Monomycin distribution in the tissues of animals of various ages].
The distribution of monomycin (15 mg/kg intramuscularly) in the blood serum and organs of mature, old and young rats was studied in the agar diffusion test. Bact. pumelis was used as test microorganism. The good absorption of this antibiotic into blood was revealed and its accumulation in high concentrations in the kidneys of animals of all ages, that conditions to a certain degree the nephrotoxicity of the preparation. Its accumulation in the organs and release from them is quicker in young rats than in mature and old ones. According to monomycin concentration, the organs were distributed in the following descending order: kidneys-liver-lungs-spleen.


[Electroacupuncture plus Gastrodin Improves Learning-memory Ability Possibly by Up-regulating Expression of SIRT 1 and PGC-1 ɑ in Hippocampal CA 1 Region of Alzheimer's Disease Rats].
To observe the effect of electroacupuncture (EA) combined with Gastrodin on learning-memory ability and expression of silent information regulator 2 homologous protein 1(SIRT 1) and peroxisome proliferator activated receptor γ coactivator (PGC-1 ɑ) of hippocampal CA 1 region in Alzheimer's disease(AD) rats, so as to explore its mechanism under-lying improvement of AD. Sixty male SD rats were randomly divided into normal control (normal), sham operation (sham), model, EA, Gastrodin and EA+ Gastrodin groups (n=10 in each). The AD model was established by intraperitoneal injection of D-Galactose (120 mg•kg-1•d-1) combined with bilateral hippocampal injection of β amyloid 1-40(Aβ 1-40). EA was applied at "Baihui"(GV 20), "Dazhui"(GV 14) and "Zusanli"(ST 36) for 30 min, once daily for 4 weeks. For rats of the Gastro-din group and EA+ Gastrodin group, intraperitoneal injection of gastrodin(10 mg/kg) was conducted once daily for 4 weeks. Morris water maze tests were used to assess the rat's learning-memory ability. Nissl staining was used to assess the morphological changes of neurons in the hippocampal CA 1 area. The expression of SIRT 1 and PGC-1 ɑ of hippocampal CA 1 region was mea-sured by immunohistochemical staining. 1) Morris water maze tests showed that, compared with the normal and sham group, the escape latency was significantly prolonged (P<0.05), and the percentage of platform quadrant residence duration and the platform crossing times were considerably decreased in the model group (P<0.05). After the intervention, the escape latency was obviously shortened (P<0.05), and the percentage of platform quadrant residence duration and the platform crossing times were markedly increased in the EA, Gastrodin and EA+Gastrodin groups relevant to the model group (P<0.05). 2) Nissl staining showed that, in comparison with the normal group or sham group, the number of cells in the hippocampal CA 1 area was decreased and the arrangement was disorganized in the model group. The number of cells in CA 1 area was relatively higher in the 3 treatment groups than in the model group. 3) The expression levels of SIRT 1 and PGC-1 ɑ proteins in the hippocampal CA 1 area were significantly down-regulated in the model group than in the normal and sham groups (P<0.05). After the intervention, the expression levels of SIRT 1 and PGC-1 ɑ in the EA, Gastrodin and EA+Gastrodin groups were significantly up-regulated compared with the model group (P<0.05). The effects of EA+Gastrodin were significantly superior to those of simple EA and simple Gastrodin in shortening the escape latency, up-regulating the expression levels of SIRT 1 and PGC-1 ɑ as well as in increasing the percentage of platform quadrant residence time and platform crossing times (P<0.05). Both EA and Gastrodin can improve the learning-memory ability of AD rats, which may be related to their effects in up-regulating the expression of SIRT 1 and PGC-1 ɑ and reducing neuronal injury in the CA 1 region of hippocampus, suggesting a protective role of EA on hippocampal neurons. The effect of EA combined with Gastrodin is markedly better than that of EA and Gastrodin alone.


[Sensitivity of the isolated adipose tissue to insulin in obesity with presence or absence of diabetes mellitus].
The authors studied the sensitivity of the isolated adipose tissue to various insulin concentrations in healthy women and also in women suffering from adiposity with the normal and diabetic test for glucose tolerance. Adipose tissue sensitivity to insulin was studied by the influence of insulin to the intensity of incorporation of carbohydrate of labeled glucose into the common lipids of the adipose tissue in its incubation with various insulin concentrations. A marked reduction of the adipose tissue sensitivity to physiological concentrations of insulin was shown in patients with adiposity. The extent of insulin sensitivity fall was the same in such patients with normal glucose tolerance and in those suffering from latent diabetes. A conclusion was drawn that the mentioned reduction of adipose tissue sensitivity to insulin could serve as a significant factor leading to the development of diabetic disturbances in adiposity. Another factor playing an important role in the development of diabetic disturbances in adiposity was compensatory possibilities of beta-cells of the pancreas.


Removal of adenosine from the rabbit pulmonary circulation, in vivo and in vitro.
The contributions of pulmonary endothelial and blood cells to the removal of adenosine during a single passage through the rabbit pulmonary circulation were investigated. In the isolated, blood-free perfused rabbit lung in situ, single pass pulmonary removal of [3H]-adenosine injected into the pulmonary artery was accomplished by a low-affinity, saturable process yielding apparent Michaelis-Menten constants of Km = 498 +/- 36 microM and Vmax = 39 +/- 4 mumol/min per lung. Similar experiments in the intact, anesthetized animal, in vivo revealed a rapid, high-affinity removal of [3H]adenosine from plasma with apparent Michaelis-Menten constants of Km = 3.3 +/- 0.5 microM and Vmax = 6.5 +/- 2.4 mumol/min per lung. However, complete recovery of the injected adenosine was achieved upon lysing of cells from blood collected during a single transpulmonary passage of the substrate, indicating that blood cells were responsible for adenosine removal in vivo. The rate of disappearance of adenosine from plasma, observed by incubating the substrate with whole rabbit blood in vitro, was comparable to that found in vivo. We conclude that although, in the absence of circulating blood, rabbit lung is able to extract adenosine in vitro, this mechanism is of little significance in vivo where blood cells appear to be primarily responsible for such removal.


Synchrony effects in inhibitory control over thought and action.
Two experiments explore whether synchrony between peak circadian arousal periods and time of testing influences inhibitory efficiency for younger and older adults. Experiment 1 assesses inhibitory control over no-longer-relevant thoughts, and Experiment 2 assesses control over unwanted but strong responses, as well as performance on neuropsychological tasks that index frontal function. Inhibitory control is greatest at optimal times for both age groups and is generally greater for younger than for older adults. Performance on 2 neuropsychological measures (Stroop and Trails) also changes over the day, at least for older adults, and is correlated with inhibitory indexes, suggesting that for older adults changes in inhibition may be mediated by circadian variations in frontal functioning. By contrast, access to well-learned responses is not vulnerable to synchrony or age effects.


[A tribute to Germán Schneider, MD, first editor of Revista Médica de Chile].
Germán Schneider was born in 1820 in Magdeburg, Germany, and graduated as M.D. at the University of Bonn. In 1848, caught by the political and intellectual reformist movement in Europe, he was exiled in Paris. As part of a large group of German immigrants, he arrived in Valdivia, Chile, in 1851. Later on he moved to Santiago and in 1871 he was nominated Professor of Clinical Medicine at the University of Chile school of Medicine. An active participant in the academic activities organized by Sociedad Médica de Santiago (a scientific society that evolved into the chilean Society of Internal Medicine) he was the leader of a six-men team who founded Revista Médica de Chile, in 1872. As first Editor of this medical journal, he established the basis for its continuous success and devotion to medical progress and education. Dr. Schneider died in 1884, leaving several distinguished pupils who followed his path, and a medical journal that now stands as one of the oldest in the world.


Outcomes of patients with early calcific aortic valve disease detected by clinically indicated echocardiography.
Previous studies have demonstrated relatively slow rates of progression of early calcific aortic valve disease (CAVD), which encompasses aortic sclerosis (ASc) and mild aortic stenosis (AS). The potential evolution to clinically significant AS is unclear and we therefore examined the long-term outcomes of patients with ASc and mild AS detected at the time of clinically indicated echocardiography. Data from initial clinically indicated echocardiograms performed between 2010-2018 in patients aged ≥18 years were extracted and linked to nationally collected outcome data. Those with impaired right or left systolic ventricular function or other significant valve disease were excluded. A time to first event analysis was performed with a composite primary outcome of cardiovascular death and aortic valve intervention (AVI). Of the 13,313 patients, 8,973 had no CAVD, 3,436 had ASc, and 455 had mild AS. The remainder had moderate or worse stenosis. Over a median follow up period of 4.2 (IQR 1.8-6.7) years (and after adjustment for age and sex), those with ASc were at greater risk of the primary outcome (HR 2.9, 95% CI 2.1-4.0) and need for AVI (HR 26.8, 95% CI 9.1-79.1) compared to those with no CAVD. Clinical event rates accelerated after approximately five years in those with mild AS. Patients with ASc are >25 times more likely to require AVI than those with no CAVD and follow up echocardiography should be considered within 3-4 years in those with mild AS.


T-2 Toxin Caused Mice Testicular Inflammation Injury via ROS-Mediated NLRP3 Inflammasome Activation.
T-2 toxin treatment causes male reproduction system dysfunction, although the exact mechanism remains unclear. In this research, male Kunming mice and TM4 cells were treated with varying concentrations of the T-2 toxin for evaluating the adverse effect of T-2 toxin on male reproductive function. MCC950 or NAC was used to block NLRP3 inflammasome activation and eliminate reactive oxygen species (ROS) accumulation in the TM4 cell, respectively. The results showed that: (1) T-2 toxin caused testicular atrophy, destroyed the microstructure and ultrastructure of the testis, and caused sperm deformities; (2) T-2 toxin increased the content and gene expressions of TNF-α and IL-6 and decreased the IL-10 content and gene expression, causing testis and TM4 cell inflammatory injury; (3) T-2 toxin activated NLRP3 inflammasome in the testis and TM4 cells and caused ROS accumulation in the testis; (4) suppressing NLRP3 inflammasome activation using 20 nM MCC950 alleviated the TM4 cell inflammatory damage caused via the T-2 toxin; nevertheless, 20 nM MCC950 did not reduce ROS accumulation in TM4 cells; and (5) NAC relieved the inflammatory damage in TM4 cells by inhibiting NLRP3 inflammasome activation. Taken together, T-2 toxin caused testicular inflammation injury through ROS-mediated NLRP3 inflammasome activation, resulting in male reproductive dysfunction.


Adalimumab Therapy Improves Intestinal Dysbiosis in Crohn's Disease.
The response to treatment with biologic drugs, in patients with Crohn's disease, could be associated with changes in gut microbiota composition. The aim of our study was to analyse the modification of microbiota during adalimumab therapy in patients with Crohn's disease. We performed a prospective study in patients with Crohn's disease analysing gut microbiota before start of adalimumab therapy (T0) and after six months of therapy (T1). Among the 20 included patients, the phylum Proteobacteria fell from 15.7 ± 3.5% at T0 to 10.3 ± 3.4% at T1 (p = 0.038). Furthermore, the trend in relation to therapeutic success was analysed. Regarding bacterial phyla, Proteobacteria decreased in patients in whom therapeutic success was obtained, passing from a value of 15.8% (± 4.6%) to 6.8 ± 3.1% (p = 0.049), while in non-responder patients, percentages did not change (T0 = 15.6 ± 5.7%, T1 = 16.8 ± 7.6%, p = 0.890). Regarding the Lachnospiraceae family, in patients with normalization of C reactive protein six 6 months of adalimumab therapy, it increased from 16.6 ± 3.1% at T0 to 23.9 ± 2.6% at T1 (p = 0.049). In conclusion, in patients who respond to Adalimumab therapy by decreasing inflammation, there is a trend of intestinal eubiosis being restored.


Biochemistry and lectin binding properties of mammalian salivary mucous glycoproteins.
The molecules responsible for the highly viscous properties of mucus are secretory glycoproteins referred to as mucins. Salivary mucins are characterized by a high sugar to protein ratio and are of a broad range of molecular weight from 7 x 10(4) to millions. With a few exceptions, they contain up to 30% of hexosamine (galactosamine and glucosamine), 8-33% of sialic acid, trace to 15% of galactose or fucose and little or no mannose. The size of carbohydrate side chains of these glycoproteins ranges from one to about fifteen units of sugar. These carbohydrate side chains are usually O-glycosidically linked through N-acetylgalactosamine to a peptidyl serine or threonine. In some instances, ester sulfate groups, mainly on N-acetylglucosamine, are also a structural feature. In many of these glycoproteins, the saccharide sequence is the same as that which determines the specificity of blood groups. Carbohydrate sequence analysis shows that salivary mucins exhibit considerable polydispersity, great diversity and remarkable structural flexibility not only among animal species but also within the same mucin molecule. Based on their lectin-binding ability, they can be used for purification of lectins, and lectins coupled to resin may be useful for the isolation of mucin-type glycoproteins. The epithelial mucous secretions modulate oral microbial flora; many secretory components serve as lectin-receptors for the attachment of microbes. The judicious use of lectins with widely differing binding characteristics has already been valuable in the in situ localization of salivary glycoproteins, in elucidating structural details, recording sugar density within a given tissue section, and defining host-parasite interactions. It is hoped that their use, together with monoclonal antibody (158) and tissue culture techniques (159, 160) will further clarify the roles of individual secretory mucous glycoproteins in health and disease.


Long term liver preservation using artificial blood substitutes.
Twenty-four hour hypothermic perfusion preservation of the liver was aimed using an artificial blood substitutes. A canine liver was harvested and preserved using originally designed perfusates. In group 1, Perfluorotributylamine solution (Oxypherol solution) was used. In group 2, (Pyridoxylated hemoglobin)-(Polyoxyethylene) conjugate solution (Stabilized Hemoglobin, PHP-1). In group 3 and in group 4, modified Stabilized hemoglobin, PHP-3 and PHP-4 was used. After the preservation, each liver was transplanted orthotopically. Postoperative graft function was estimated the following parameter, such as bile excretion, consciousness level, activated clotting time, and survival rate. In group 1 and group 2, improvement of such factors were not fully observed. On the contrary, in group 3 and 4, complete recovery of the function was seen and in group 4, longer survival was obtained. PHP solution was considered suitable perfusate for liver preservation.


Relationship between cephalometric characteristics and obstructive sites in obstructive sleep apnea syndrome.
Patients with obstructive sleep apnea syndrome (OSAS) have characteristic dentofacial features, but the sites of obstruction differ greatly. The purpose of this study was to investigate the dentofacial characteristics of patients with OSAS with respect to the obstructive sites. The subjects consisted of 30 Japanese men with OSAS divided into 3 groups of 10 patients each. One group had obstruction at the retropalatal and retroglossal region (Rp + Rg group), a second group had obstruction at the retropalatal region (Rp group), and a third group had obstruction due to tonsillar hypertrophy (tonsillar hypertrophy group). To identify the Rp + Rg and Rp groups, dynamic magnetic resonance imaging (MRI) was used. To identify the tonsillar hypertrophy group, Mackenzie's classification, axial MRI, and the weight of the tonsils were used. A control group was composed of 10 Japanese men showing no symptoms suggestive of OSAS. Lateral cephalometric radiographs were obtained for all of the subjects, and analysis of variance was performed for the 46 cephalometric parameters. Among the many dentofacial characteristics of OSAS patients, the tendencies for retrognathia, micrognathia, and skeletal Class II were strongest in the Rp + Rg group and somewhat strong in the Rp group. The presence of a long soft palate was dominant in the Rp group, whereas the tendency for a long face was dominant in the tonsillar hypertrophy group. All of the groups shared the characteristic of having an inferior position of the hyoid bone. Based on the results of the current study, we conclude that many features of OSAS are specifically related to each obstructive type of OSAS.


Comparison of low-dose intravenous cyclophosphamide with oral mycophenolate mofetil in the treatment of lupus nephritis.
No previous study has compared mycophenolate mofetil (MMF) with low-dose cyclophosphamide (CYC) in the treatment of lupus nephritis (LN). To do so, we recruited patients with LN (class III, IV, or V) and randomized them to receive either low-dose CYC or oral MMF. Those with crescentic LN, a serum creatinine over 265 μmol/l, and neurological or pulmonary lupus were excluded. MMF was prescribed at daily doses of 1.5-3 g for 24 weeks, while CYC was administered as six fortnightly infusions of 500 mg each. All patients received three methylprednisolone injections, followed by oral corticosteroids. Maintenance therapy with azathioprine and low-dose corticosteroid was started at end of induction therapy. The primary end point was treatment response at 24 weeks, while secondary end points were complete remission, Systemic Lupus Erythematosus Disease Activity Index and adverse events. Of the 173 patients recruited, 100 were equally randomized to receive either CYC or MMF. Baseline characteristics were similar, except for higher 24 h proteinuria in the CYC group. At 24 weeks, 37 patients in each group achieved the primary end point. The complete remission rate was 50% in CYC and 54% in MMF group. Gastrointestinal symptoms were significantly more frequent in patients receiving MMF (52 vs. 4%). However, other adverse events were similar. Thus, low-dose intravenous CYC is comparable in safety and efficacy to oral MMF in the induction treatment of less severe LN.


[Complications after photocoagulation and cryotherapy (author's transl)].
A report of 3 cases is given. Following a photocoagulation because of a retinal tear a rapidly maturing cataract developed. The same occured in a patient after treatment with equatorial transconjunctival cryotherapy (according to Haut) because of dense vitreous turbidities. Though the vitreous cleared, 6 weeks after surgery a mature cataract had developed which had to be removed. In the third case a peripheral retinal hole was surrounded by dryo applications. 6 weeks later a severe proliferative macular detachment developed. Brief case reports and a discussion follow.


Stable and Active Oxidation Catalysis by Cooperative Lattice Oxygen Redox on SmMn2O5 Mullite Surface.
The correlation between lattice oxygen (O) binding energy and O oxidation activity imposes a fundamental limit in developing oxide catalysts, simultaneously meeting the stringent thermal stability and catalytic activity standards for complete oxidation reactions under harsh conditions. Typically, strong O binding indicates a stable surface structure, but low O oxidation activity, and vice versa. Using nitric oxide (NO) catalytic oxidation as a model reaction, we demonstrate that this conflicting correlation can be avoided by cooperative lattice oxygen redox on SmMn2O5 mullite oxides, leading to stable and active oxide surface structures. The strongly bound neighboring lattice oxygen pair cooperates in NO oxidation to form bridging nitrate (NO3-) intermediates, which can facilely transform into monodentate NO3- by a concerted rotation with simultaneous O2 adsorption onto the resulting oxygen vacancy. Subsequently, monodentate NO3- species decompose to NO2 to restore one of the lattice oxygen atoms that act as a reversible redox center, and the vacancy can easily activate O2 to replenish the consumed one. This discovery not only provides insights into the cooperative reaction mechanism but also aids the design of oxidation catalysts with the strong O binding region, offering strong activation of O2, high O activity, and high thermal stability in harsh conditions.


Cholecystokinin stimulates dopamine synthesis in synaptosomes by a cyclic AMP-dependent mechanism.
The effects of different fragments of cholecystokinin (CCK) on dopamine synthesis were studied in synaptosomal preparations from the striatum, substantia nigra, and frontal cortex. In striatal synaptosomes, dopamine synthesis rate measured by dopamine accumulation was 12.5% lower than that measured by 3,4-dihydroxyphenylalanine (DOPA) accumulation; however, K+-accelerated synthesis was the same for both methods. Synthesis rate was independent of exogenous tyrosine levels. In the three regions studied, the combined stimulatory effects of 8-Br-cyclic AMP and high K+ were additive. CCK-5, CCK-3, CCK-27-33, and CCK-8 (sulphated) enhanced synthesis, CCK-5 being the most potent fragment. The nonsulphated octapeptide had no effect. In all three regions, CCK-5 and high K+ had an additive effect on dopamine synthesis; CCK-5 and 8-Br-cyclic AMP together produced the same enhancement of synthesis as CCK-5 alone. CCK-5 produced similar dose-dependent increases in dopamine synthesis and cyclic AMP accumulation in striatal synaptosomes, and both effects were blocked by the CCK antagonist proglumide.


Protein O-mannosylation in animal development and physiology: from human disorders to Drosophila phenotypes.
Protein O-mannosylation has a profound effect on the development and physiology of mammalian organisms. Mutations in genes affecting O-mannosyl glycan biosynthesis result in congenital muscular dystrophies. The main pathological mechanism triggered by O-mannosylation defects is a compromised interaction of cells with the extracellular matrix due to abnormal glycosylation of alpha-dystroglycan. Hypoglycosylation of alpha-dystroglycan impairs its ligand-binding activity and results in muscle degeneration and failure of neuronal migration. Recent experiments revealed the existence of compensatory mechanisms that could ameliorate defects of O-mannosylation. However, these mechanisms remain poorly understood. O-mannosylation and dystroglycan pathway genes show remarkable evolutionary conservation in a wide range of metazoans. Mutations and downregulation of these genes in zebrafish and Drosophila result in muscle defects and degeneration, also causing neurological phenotypes, which suggests that O-mannosylation has similar functions in mammals and lower animals. Thus, future studies in genetically tractable model organisms, such as zebrafish and Drosophila, should help to reveal molecular and genetic mechanisms of mammalian O-mannosylation and its role in the regulation of dystroglycan function.


Transient ionized hypocalcemia and secondary hyperparathyroidism accompanying acute adrenal insufficiency.
To describe the hitherto unrecognized occurrence of transient ionized hypocalcemia with acute adrenal insufficiency and its therapy. We present three case reports with documented longitudinal laboratory findings. Transient ionized hypocalcemia of acute illness has been noted in children and adults and is associated with increased mortality. Precipitating illnesses include gram-positive and gram-negative sepsis and staphylococcal toxic shock syndrome. We encountered three patients with transient ionized hypocalcemia associated with acute adrenal insufficiency. Similar to severely ill, transiently hypocalcemic patients without adrenal insufficiency, one patient demonstrated 25-hydroxyvitamin D deficiency, a second had minimal magnesium deficiency, and a third had no identifiable underlying abnormality. All three patients exhibited a transient increase in levels of serum intact parathyroid hormone and 1,25-dihydroxyvitamin D in response to ionized hypocalcemia, indicative of temporary secondary hyperparathyroidism. Two of the three patients were treated solely with glucocorticoids and intravenous administration of fluids, whereas the third received minimal intramuscularly administered magnesium and antibiotics in addition. All ultimately demonstrated a return to normal of serum total and ionized calcium, parathyroid hormone, and 1,25-dihydroxyvitamin D with no further treatment, even though one patient remained deficient in 25-hydroxyvitamin D. On the basis of these cases, we conclude that acute adrenal insufficiency and its treatment must be added to the disorders associated with transient ionized hypocalcemia and that transient secondary hyperparathyroidism is characteristic of at least some of the patients.


Detergent-solubilized monomeric and dimeric cytochrome bc1 isolated from bovine heart.
Mitochondrial cytochrome bc1 complex, isolated from frozen bovine heart, was solubilized with five different "non-denaturing" detergents: dodecyl maltoside, octaethylene glycol monododecyl ether (C12E8), Triton X-100, Tween 20, and sodium cholate. The hydrodynamic properties of the solubilized complex III's were then investigated by sedimentation analysis. Complex III exists as a stable and monodisperse dimer when it is solubilized in low ionic strength buffer with a low concentration of any of the five detergents. At pH 7.8, 20 degrees C, the protein sediments as a homogeneous species with an s(obs) of about 14 S. The protein molecular weight of the 14S particle, after correction for bound detergent, is 465,000 +/- 30,000 as measured by sedimentation equilibrium analysis. The aggregation state and/or homogeneity of cytochrome bc1 is strongly dependent upon the concentration of the solubilizing detergent and ionic strength. The enzyme becomes a homogeneous, monomeric complex with a protein molecular weight of 235,000 +/- 20,000 and an s(obs) of 10-10.5 S after it is solubilized in high concentrations of Tween 20 (more than 5 mg/mg of protein) and sodium chloride (more than 0.5 M). However, a heterogeneous mixture of subcomplexes is produced upon solubilization of the complex with high concentrations of the other detergents and 0.5 M NaCl. Monomerization of cytochrome bc1 by Tween 20 and 0.5 M NaCl has no effect on either the spectral properties, the subunit composition, or the enzymatic activity and is reversible since the dimeric 14S particle is regenerated upon removal of the high concentration of salt.(ABSTRACT TRUNCATED AT 250 WORDS)


Generation and evaluation of a CYP2C9 heteroactivation pharmacophore.
Positive cooperativity (auto- and heteroactivation) of drug oxidation, a potential cause of drug interactions, is well established in vitro for cytochrome P450 (P450) 3A4 but to a much lesser extent for other drug-metabolizing P450 isoforms. Using a high throughput fluorescent-based CYP2C9 effector assay, we identified >30 heteroactivators from a set of 1504 structurally diverse compounds. Several potent heteroactivators of CYP2C9-mediated 7-methoxy-4-trifluoromethyl-coumarin metabolism are marketed drugs or endogenous compounds (amiodarone, niclosamide, liothyronine, meclofenemate, zafirlukast, estropipate, and dichlorphenamide, yielding 150% control reaction velocity at 0.04, 0.09, 0.5, 1, 1.2, 1.5, and 2.5 microM, respectively). Some heteroactivators are also known CYP2C9 substrates or inhibitors, suggesting potential multiple binding sites and substrate-dependent effects. v(150%), the concentration of effector giving 150% of control reaction velocity, was used as pharmacophore modeling parameter based on enzyme kinetic assumptions. The generated pharmacophore (training set: n = 36, v(150%) 0.04-150 microM) contains one hydrogen bond acceptor, one aromatic ring, and two hydrophobes. v(150%) values for 94% of the training set heteroactivators were predicted within 1 log unit for the residual (r [log observed v(150%)] versus [log predicted v(150%)] = 0.71; r2 0.50). The model also correctly identifies close to 70% of potent inhibitors (IC50 < 1 microM) as high-affinity CYP2C9 binders, suggesting that heteroactivators and inhibitors share some common structural CYP2C9 binding features, supporting the previously suggested hypothesis that CYP2C9 heteroactivators can bind within the active site.


Young age is an independent adverse prognostic factor in early stage breast cancer: a population-based study.
To compare the prognosis of young breast cancer patients with the older ones. Utilizing the Surveillance, Epidemiology, and End Results database, we identified 150,588 female breast cancer patients diagnosed during 2003-2014, including 6,668 patients younger than 35 years and 143,920 patients aged between 35 and 60 years. Kaplan- Meier analysis was performed to compare the prognosis of these two groups. Univariate and multivariate Cox proportional hazard models were utilized to identify independent prognostic factors and calculate the HR and 95% CI. Subgroup analysis was performed stratified according to the lymph node status and estrogen receptor (ER) status. The young patients presented with more aggressive clinicopathological characteristics, including larger tumor size (P<0.001), more lymph node metastasis (P<0.001), higher grade (grades III and IV, P<0.001), more ER/progesterone receptor absence (P<0.001), and more human epidermal growth factor receptor 2 overexpression (P<0.001). The patients younger than 35 years presented with inferior breast cancer-specific survival (BCSS) and overall survival (OS) (log-rank, P<0.001) in comparison with the older ones. In the multivariable Cox proportional hazard regression analysis, young age remained to be an independent adverse prognostic factor in operable breast cancer in terms of BCSS (HR, 1.200; 95% CI, 1.110-1.297; P<0.001) and OS (HR, 1.111; 95% CI, 1.032-1.196; P=0.005). In the subgroup analysis, young age remained a significant adverse prognostic factor in N0 (BCSS), N1, and ER-positive subgroups (P<0.05). Young age is an independent adverse prognostic factor in operable breast cancer. Young patients may receive more intensive treatment than older ones.


Exploring the correlation between genetic transcription and multi-temporal developmental autism spectrum disorder using resting-state functional magnetic resonance imaging.
The present investigation aimed to explore the neurodevelopmental trajectory of autism spectrum disorder (ASD) by identifying the changes in brain function and gene expression associated with the disorder. Previous studies have indicated that ASD is a highly inherited neurodevelopmental disorder of the brain that displays symptom heterogeneity across different developmental periods. However, the transcriptomic changes underlying these developmental differences remain largely unknown. To address this gap in knowledge, our study employed resting-state functional magnetic resonance imaging (rs-fMRI) data from a large sample of male participants across four representative age groups to stratify the abnormal changes in brain function associated with ASD. Partial least square regression (PLSr) was utilized to identify unique changes in gene expression in brain regions characterized by aberrant functioning in ASD. Our results revealed that ASD exhibits distinctive developmental trajectories in crucial brain regions such as the default mode network (DMN), temporal lobe, and prefrontal lobes during critical periods of neurodevelopment when compared to the control group. These changes were also associated with genes primarily located in synaptic tissues. The findings of this study suggest that the neurobiology of ASD is uniquely heterogeneous across different ages and may be accompanied by distinct molecular mechanisms related to gene expression.


Synergistic effects of temperature and humidity on the symptoms of COPD patients.
This panel study investigates how temperature, humidity, and their interaction affect chronic obstructive pulmonary disease (COPD) patients' self-reported symptoms. One hundred and six COPD patients from Shanghai, China, were enrolled, and age, smoking status, St. George Respiratory Questionnaire (SGRQ) score, and lung function index were recorded at baseline. The participants were asked to record their indoor temperature, humidity, and symptoms on diary cards between January 2011 and June 2012. Altogether, 82 patients finished the study. There was a significant interactive effect between temperature and humidity (p < 0.0001) on COPD patients. When the indoor humidity was low, moderate, and high, the indoor temperature ORs were 0.969 (95% CI 0.922 to 1.017), 0.977 (0.962 to 0.999), and 0.920 (95% CI 0.908 to 0.933), respectively. Low temperature was a risk factor for COPD patients, and high humidity enhanced its risk on COPD. The indoor temperature should be kept at least on average at 18.2 °C, while the humidity should be less than 70%. This study demonstrates that temperature and humidity were associated with COPD patients' symptoms, and high humidity would enhance the risk of COPD due to low temperature.


Compression of the common peroneal nerve by intramuscular ganglion from the superior tibio-fibular joint.
Eight patients had symptoms from ganglia arising from the superior tibio-fibular joint with physical signs that resembled the anterior tibial and peroneal compartment syndromes. Five ganglia were in the peroneus longus muscle in which they produced only an ill-defined firmness. Histologically the ganglia showed much cellular activity which must not be mistaken for malignant change.


The causal role of smoking in anxiety and depression: a Mendelian randomization analysis of the HUNT study.
Cigarette smoking is strongly associated with mental illness but the causal direction of the association is uncertain. We investigated the causal relationship between smoking and symptoms of anxiety and depression in the Norwegian HUNT study using the rs1051730 single nucleotide polymorphism (SNP) variant located in the nicotine acetylcholine receptor gene cluster on chromosome 15 as an instrumental variable for smoking phenotypes. Among smokers, this SNP is robustly associated with smoking quantity and nicotine dependence. Method In total, 53 601 participants were genotyped for the rs1051730 SNP and provided information on smoking habits and symptoms of anxiety and depression using the Hospital Anxiety and Depression Scale (HADS). Self-reported smoking was positively associated with the prevalence of both anxiety and depression, and the measured polymorphism was positively associated with being a current smoker and the number of cigarettes smoked in current smokers. In the sample as a whole, risk of anxiety increased with each affected T allele [odds ratio (OR) 1.06, 95% confidence interval (CI) 1.02-1.09, p = 0.002] but there was no association with depression (p = 0.31). However, we found no clear association of the polymorphism with either anxiety (OR 1.03, 95% CI 0.97-1.09, p = 0.34) or depression (OR 1.02, 95% CI 0.95-1.09, p = 0.62) among smokers. As there was no association of the smoking-related rs1051730 SNP with anxiety and depression among smokers, the results suggest that smoking is not a cause of anxiety and depression.


[The art of nursing management].
It is often said that management is a science as well as an art. Nursing managers have to master the science of management and make management an art, which is the goal of nursing leadership. The purpose of this paper was to integrate the views of Eastern and Western scholars and propose a combination of science and art in nursing management, to include the following components: the art of management and leadership; the art of to manage or not to manage, the art of leadership, and the art of delegation. The concept of "government by doing nothing that goes against nature," of Taoism, "Zen management," from Buddhism, and "situational leadership" have also been considered in this paper in the hope of providing guidance for nursing management.


A quantitative study of enteric endocrine cells in celiac sprue.
A quantitative morphological investigation of eight endocrine cell types in mucosal biopsies from adults with untreated celiac sprue was undertaken. The quantitative data expressed as cells per millimeter of epithelium most accurately reflected the changes seen in celiac disease, as it takes into account changes in mucosal thickness due to the absence of villi in celiac biopsies. The results showed significant increases in the number of cholecystokinin and enterochromaffin cells, a significant decrease in somatostatin, gastric inhibitory polypeptide and secretin cells, and no change in the motilin, gastrin, and glicentin cells. Significant changes in cell size (cross-sectional area) were also demonstrated in the somatostatin and gastrin cells which were smaller in the celiac biopsies.


Vision: the additivity law made to work for heterochromatic photometry with bipartite fields.
Additivity failures are common in heterochromatic photometry when the usual criterion of equal brightness is used. Using instead the criterion of a minimally distinct border between two precisely juxtaposed fields, we found that the additivity law holds.


Oesophageal stricture in a cat due to oral administration of tetracyclines.
A three-year-old, male neutered domestic shorthair cat was presented with dysphagia and regurgitation following treatment with oral doxycycline and oxytetracycline for Haemobartonella felis infection. Fluoroscopy confirmed the presence of multiple strictures along the entire length of the oesophagus. Balloon dilatation was performed successfully on two occasions and the symptoms resolved. To the authors' knowledge, this is the first report of oesophageal strictures associated with oral administration of tetracyclines in a cat in the UK.


Hemorrhage and epilepsy in cryptic cerebrovascular malformations.
A series of 15 angiographically cryptic, histologically proved, cerebrovascular malformations occurred. Nine patients were admitted to the hospital with evidence of recent neurological deterioration or onset of headache. Six patients had convulsions. Computed tomographic scan and surgical exploration disclosed a substantial cerebral hematoma in eight instances. The pathological diagnosis was arteriovenous malformation in 11 cases, cavernous angioma in three, and venous angioma in one. Histological evidence of previous microhemorrhage was present in the majority of the specimens, including the patients who had seizures. A change in neurological status or onset of seizures probably indicates recent hemorrhage in cryptic cerebrovascular malformations.


IFNT stimulates lysosomal function via type I IFN signaling pathway in pregnant bovine leukocytes.
Interferon tau (IFNT) stimulates lysosomal activation via the Janus-activated kinase in peripheral blood leukocytes during pregnancy recognition. IFNT-mediated lysosomal activation could serve as a novel marker for early pregnancy in cattle. IFNT is important in establishing pregnancy in ruminants. Secreted IFNT in the uterus induces the expression of an interferon-stimulated gene (ISG) in uterine tissues and peripheral blood leukocytes (PBLs). In our previous study, increased lysosome and lysosomal cathepsin (CTS) activity and mRNA expression were observed in PBLs of pregnant cows on day 18 of pregnancy. However, the mechanism of IFNT stimulation in PBLs is unclear. Here, we explored the IFNT-mediated lysosomal activation mechanisms in PBLs during early pregnancy in dairy cows. PBLs collected from the peripheral blood of Holstein cows on day 18 post artificial insemination, after confirmation of their pregnancy status, were used to detect the expression of lysosomal-associated membrane protein (LAMP) 1, 2, CTSB and CTSK. Expression of all genes was significantly higher in PBLs of pregnant cows than in nonpregnant cows. In vitro IFN-mediated stimulation of PBLs collected from cows that did not undergo AI significantly increased lysosomal acidification and expression of LAMP1 and 2, as well as the activities of CTSB and CTSK. Immunodetection analysis showed an increase in LAMP1 and CTSK levels in the PBLs of day 18 pregnant cows. JAK inhibitor significantly decreased lysosomal acidification, CTSK activity, LAMP1, 2, and CTSK expression in the presence of IFNT. These results suggest that IFNT regulates lysosomal function via a type 1IFN-mediated pathway in PBLs during pregnancy recognition.


[Multiple insecticide resistances and kdr mutation of Culex pipiens pallens in north-central Anhui Province].
To understand the status of resistance to multiple insecticides and the frequencies of kdr mutations in Culex pipiens pallens from north-central Anhui Province. From July to September, 2014, the C. pipiens pallens mosquito larvae were collected in Huaibei, Bengbu and Chuzhou cities of the north-central Anhui Province and reared to adults. The female adult mosquitoes at 3-5 days post emergence were tested for susceptibility to the four insecticides, namely 0.05% deltamethrin, 5% malathion, 0.1% bendiocarb and 4% DDT, by using the standard WHO resistance tube bioassay. The detection of the point mutations of the kdr gene at codon 1014 was conducted by PCR and DNA sequencing in the deltamethrin-resistant and -susceptible mosquitoes. High levels of resistance to all the four insecticides were found in all the three tested populations, although mosquito mortality varied among populations and test insecticides. Among the test insecticides, DDT showed lowest mortality with no significant difference (F = 1.027, P > 0.05) in all test populations, whereas significantly different mortalities were observed among populations for the remained three insecticides tested (deltamethrin, malathion, and bendiocarb) (F = 23.823, 33.955, 128.841; all P < 0.01). Two types of non-synonymous kdr mutation at codon position 1014 (L1014F and L1014S) were observed. A positive correlation between L1014F mutation frequencies and deltamethrin resistance levels were detected in the three mosquito populations (r2 = 0.718, P < 0.01). The observed high levels of resistance to multiple-insecticides coupled with the occurrence of medium to high kdr frequencies in populations of C. pipiens pallens could profoundly affect the mosquito vector control programme in China. The local health departments need to strengthen vector dynamic monitoring and implement rational resistance management strategies.


Predicting the crystallization potential of urine from cats and dogs with respect to calcium oxalate and magnesium ammonium phosphate (struvite).
The objective of this study was to validate two programs (SUPERSAT and EQUIL 2) for calculation of calcium oxalate (CaOx) and magnesium ammonium phosphate (struvite; MAP) relative supersaturation (RSS) in dog and cat urine. Healthy adult cats (n = 10) and dogs (n = 9) were fed standard diets for a 3-wk period. Urine was collected (24 h, dogs; 48 h, cats) and filtered, and the pH was measured. A 20-mL aliquot was titrated to pH 2 and frozen for analysis. Additional aliquots were incubated with 1 g seed crystals at 38 degrees C; CaOx for 24 h (cat) and 2, 6 and 9 d (dog); MAP for 48 h (dog) and 6 d (cat). Samples were analyzed for 10 substances. RSS was calculated using EQUIL 2 and SUPERSAT. CaOx RSS (SUPERSAT): dog urine was initially supersaturated, whereas cat urine was undersaturated with the diets used. Cat urine reached the solubility product (K(sp)), (RSS = 1) after 24-h incubation, whereas dog urine was still approaching K(sp) at 9 d. MAP RSS (SUPERSAT): urine from both species was undersaturated and increased toward K(sp) during incubation. Final RSS values were compared for both programs. SUPERSAT resulted in values close to 1 for both CaOx and MAP; EQUIL 2 gave similar values for CaOx RSS, although MAP RSS values were considerably higher than 1. In conclusion, EQUIL 2 and SUPERSAT both calculated reasonably accurate RSS values for CaOx, whereas only SUPERSAT provided an accurate measure of MAP RSS.


A minimal mechanosensing model predicts keratocyte evolution on flexible substrates.
A mathematical model is proposed for shape evolution and locomotion of fish epidermal keratocytes on elastic substrates. The model is based on mechanosensing concepts: cells apply contractile forces onto the elastic substrate, while cell shape evolution depends locally on the substrate stress generated by themselves or external mechanical stimuli acting on the substrate. We use the level set method to study the behaviour of the model numerically, and predict a number of distinct phenomena observed in experiments, such as (i) symmetry breaking from the stationary centrosymmetric to the well-known steadily propagating crescent shape, (ii) asymmetric bipedal oscillations and travelling waves in the lamellipodium leading edge, (iii) response to remote mechanical stress externally applied to the substrate (tensotaxis) and (iv) changing direction of motion towards an interface with a rigid substrate (durotaxis).


Hepatitis B vs. hepatitis C infection on viral hepatitis-associated hepatocellular carcinoma.
To determine clinical-pathologic variables in patients with a new diagnosis of hepatocellular carcinoma (HCC) and underlying hepatitis B vs. C infection. Patients presenting to a single urban hospital with a new diagnosis of HCC were entered into a clinical database. Variables including number and size of tumors, presence of metastases, serum alpha-Fetoprotein, hepatitis serologies, severity of hepatic dysfunction, and presence of cirrhosis were evaluated in 127 patients. Patients with hepatitis B (HBV) were more likely to develop HCC at a younger age than patients with hepatitis C (HCV) (HBV-26% under age 40, HCV-0% under age 40; p < 0.001), with greater serum alpha-Fetoprotein production (median level: HBV-1000 ng/ml vs. HCV-37 ng/ml; p = 0.002), with larger tumors (HBV-78% >5 cm, HCV-28% >5 cm; p < 0.001), in the absence of cirrhosis (HBV-40%, HCV-0%; p < 0.001), and a decreased eligibility for curative treatment (HBV-14%, HCV-34%; p < 0.05). Conversely, patients with HCV were more likely to develop HCC in association with multiple co-morbidities, cirrhosis, and older age. Significant clinical-pathologic differences exist among HCC patients with underlying HBV vs. HCV. These differences impact eligibility for potentially-curative therapy and prognosis.


A Systematic Literature Review on Traumatic Optic Neuropathy.
Traumatic optic neuropathy (TON) is an uncommon vision-threatening disorder that can be caused by ocular or head trauma and is categorized into direct and indirect TON. The overall incidence of TON is 0.7-2.5%, and indirect TON has a higher prevalence than direct TON. Detection of an afferent pupillary defect in the presence of an intact globe in a patient with ocular or head trauma with decreased visual acuity strongly suggests TON. However, afferent pupillary defects may be difficult to detect in patients who have received narcotics that cause pupillary constriction and in those with bilateral TON. Mechanical shearing of the optic nerve axons and contusion necrosis due to immediate ischemia from damage to the optic nerve microcirculation and apoptosis of neurons is a probable mechanism. The proper management of TON is controversial. High-dose corticosteroid therapy and decompression of the optic nerve provide no additional benefit over observation alone. Intravenous erythropoietin may be a safe and efficient treatment for patients with TON.


Clathrate hydrates in nature.
Scientific knowledge of natural clathrate hydrates has grown enormously over the past decade, with spectacular new findings of large exposures of complex hydrates on the sea floor, the development of new tools for examining the solid phase in situ, significant progress in modeling natural hydrate systems, and the discovery of exotic hydrates associated with sea floor venting of liquid CO2. Major unresolved questions remain about the role of hydrates in response to climate change today, and correlations between the hydrate reservoir of Earth and the stable isotopic evidence of massive hydrate dissociation in the geologic past. The examination of hydrates as a possible energy resource is proceeding apace for the subpermafrost accumulations in the Arctic, but serious questions remain about the viability of marine hydrates as an economic resource. New and energetic explorations by nations such as India and China are quickly uncovering large hydrate findings on their continental shelves.


Hemorrhagic shock secondary to spontaneous rupture of a non-secretory adrenal cortical tumour: A case report.
A 21-year-old female presented with left-sided loin pain and profound circulatory shock. After emergency laparotomy, angiography, embolisation and histological investigation, a diagnosis of spontaneous rupture of a benign non-secretory adrenal cortical tumour was made. To our knowledge, this is the only reported case of this diagnosis.


Does traditional birth attendant training increase use of antenatal care? A review of the evidence.
A combined narrative review and metanalytic review was conducted to summarize published and unpublished studies completed between 1970 and 2002 on the relationship between traditional birth attendant (TBA) training and increased use of professional antenatal care (ANC). Fifteen studies (n = 15) from 8 countries and 2 world regions were analyzed. There are, to varying degrees, positive associations between TBA training and TBA knowledge of the value and timing of ANC services, TBA behavior in offering advice or assistance to obtain ANC, and compliance and use of ANC services by women cared for by TBAs or living in areas served by TBAs. There is a serious lack of information about TBA training program characteristics. Although the findings cannot be causally attributed to TBA training, the results suggest that training may increase ANC attendance rates by about 38%. This magnitude of improvement could contribute to a reduction in maternal and perinatal mortality in areas where women have access to quality antenatal and emergency obstetric care. There is an urgent need to improve capacity for evaluation and research of the effect of TBA training programs and other factors that influence women's use of ANC services.


18 F-FDG-PET/MRI in patients with Graves' orbitopathy.
Currently, therapeutic management of patients with Graves' orbitopathy (GO) relies on clinical assessments and MRI. However, monitoring of inflammation remains difficult since external inflammatory signs do not necessarily represent the orbital disease activity. Therefore, we aimed to evaluate the diagnostic value of 18F-FDG-PET/MRI to assess the inflammation of GO patients. Enrolled patients with new onset of GO underwent ophthalmological examinations to evaluate the activity (CAS) and severity of GO (NOSPECS), as well as an 18F-FDG-PET/MRI (Siemens Biograph mMR) with dual time point imaging (immediately post-injection and 60 min p.i.). A subset of PET parameters including maximum standardized uptake value (SUVmax), metabolic target volume (MTV), and total lesion glycolysis (TLG) were obtained separately per eye and per extraocular eye muscle (EOM). EOM thickness was measured on the co-registered MRI. Of 14 enrolled patients, three showed mild, seven moderate-to-severe, and four sight-threatening GO. Patients with severe GO showed statistically significant higher TLG than patients with mild GO (p = 0.02) and higher MTV than patients with mild (p = 0.03) and moderate (p = 0.04) GO. Correlation between NOSPECS on one hand and MTV and TLG on the other was significant (R2 = 0.49-0.61). TLG and MTV derived from FDG-PET appear to be good discriminators for severe vs. mild-to-moderate GO and show a significant correlation with NOSPECS. As expected, PET parameters of individual eye muscles were not correlated with associated eye motility, since fibrosis, and not inflammation, is mainly responsible for restricted motility. In conclusion, 18F-FDG-PET/MRI can be used for assessment of GO inflammation.


Persistence of hepatitis C virus in peripheral blood mononuclear cells of sustained viral responders to pegylated interferon and ribavirin therapy.
The aim of this paper was to assess the persistence of hepatitis C virus (HCV) among patients successfully treated with peginterferon and ribavirin. The persistence of viral RNA was evaluated in the serum and peripheral blood mononuclear cells (PBMCs) of 25 chronic hepatitis C patients with sustained viral response to peginterferon and ribavirin treatment up to 56 months after the completion of therapy. Viral RNA was detected in the peripheral blood mononuclear cell cultures of five patients (20%), but none had detectable serum HCV RNA. At present, the clinical relevance of this finding is unclear. It is possible that viral persistence and, specifically, the presence of HCV RNA in PBMCs may lead to HCV reactivation under special circumstances, such as immunosuppression.


18F-EF5 PET Is Predictive of Response to Fractionated Radiotherapy in Preclinical Tumor Models.
We evaluated the relationship between pre-treatment positron emission tomography (PET) using the hypoxic tracer 18F-[2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3- pentafluoropropyl) acetamide] (18F-EF5) and the response of preclinical tumor models to a range of fractionated radiotherapies. Subcutaneous HT29, A549 and RKO tumors grown in nude mice were imaged using 18F-EF5 positron emission tomography (PET) in order to characterize the extent and heterogeneity of hypoxia in these systems. Based on these results, 80 A549 tumors were subsequently grown and imaged using 18F-EF5 PET, and then treated with one, two, or four fraction radiation treatments to a total dose of 10-40 Gy. Response was monitored by serial caliper measurements of tumor volume. Longitudinal post-treatment 18F-EF5 PET imaging was performed on a subset of tumors. Terminal histologic analysis was performed to validate 18F-EF5 PET measures of hypoxia. EF5-positive tumors responded more poorly to low dose single fraction irradiation relative to EF5-negative tumors, however both groups responded similarly to larger single fraction doses. Irradiated tumors exhibited reduced 18F-EF5 uptake one month after treatment compared to control tumors. These findings indicate that pre- treatment 18F-EF5 PET can predict the response of tumors to single fraction radiation treatment. However, increasing the number of fractions delivered abrogates the difference in response between tumors with high and low EF5 uptake pre-treatment, in agreement with traditional radiobiology.


Diagnosis and management of patients with reflux symptoms refractory to proton pump inhibitors.
Approximately a third of patients with suspected gastro-oesophageal reflux disease are resistant or partial responders to proton pump inhibitors (PPIs). Many of these patients do not have gastro-oesophageal reflux disease, but suffer from functional heartburn or dyspepsia. The potential mechanisms underlying failure of PPI treatment in patients with reflux-related symptoms include persistence of isolated or mixed acid, weakly acidic, bile or gas reflux, impaired oesophageal mucosal integrity, chemical or mechanical hypersensitivity to refluxates and psychological comorbidity. After thorough clinical evaluation and failure of empirical changes in PPI dose regime, diagnostic investigations include endoscopy and reflux monitoring with pH or pH-impedance monitoring. If symptoms are clearly related to persistent reflux, baclofen, antireflux surgery or pain modulators can be considered. If not, pain modulators are the only currently available therapy.


Study of single and multidigit activation in monkey somatosensory cortex using voltage-sensitive dye imaging.
Toward the goal of understanding cutaneous sensory integration during manual behavior, we used voltage-sensitive dye (VSD) imaging to study the organization and dynamics of anesthetized monkey primary somatosensory cortex (SI) in response to single and multidigit tactile stimulation. We find that in both macaque and squirrel monkey SI, VSD reveals clear focal digit topography consistent with previous electrophysiological and intrinsic signal imaging studies. VSD also reveals interactions in SI in response to multidigit stimulation. With a tactile funneling paradigm in areas 3b and 1 in squirrel monkeys, VSD reveals two-digit induction of subthreshhold influences, consistent with lateral intracortical inhibition. In response to tactile apparent motion stimuli, VSD reveals preferential response to motion stimuli over static tactile stimuli in both areas 1 and 3b. Comparison of the response at different digit locations to "toward digit" stimuli suggests the presence of direction-selective response in area 1; however, further study is needed. These exciting results indicate that VSD constitutes a powerful tool for studying somatosensory cortical processing in nonhuman primates and should be further developed for future somatosensory studies in awake behaving monkeys.


Effects of psychoeducational intervention for married patients with bipolar disorder and their spouses.
The relative benefit of adding a structured psychoeducational intervention to standard medication treatment for married patients with bipolar disorder and their spouses was assessed. Patients were randomly assigned to receive either medication management or medication management plus a marital intervention with their spouses for an 11-month period. Patients' symptoms, functioning, and adherence to their medication regimens were measured at study entry and at 11 months. Significant effects favoring the combined treatments were observed for overall patient functioning but not for symptom levels. The marital intervention was associated with improved medication adherence. Combined psychosocial and medication treatment does not affect patients' symptom levels beyond the effects of medication alone, but it does result in significant incremental gains in overall patient functioning.


Music and Sound in Time Processing of Children with ADHD.
ADHD involves cognitive and behavioral aspects with impairments in many environments of children and their families' lives. Music, with its playful, spontaneous, affective, motivational, temporal, and rhythmic dimensions can be of great help for studying the aspects of time processing in ADHD. In this article, we studied time processing with simple sounds and music in children with ADHD with the hypothesis that children with ADHD have a different performance when compared with children with normal development in tasks of time estimation and production. The main objective was to develop sound and musical tasks to evaluate and correlate the performance of children with ADHD, with and without methylphenidate, compared to a control group with typical development. The study involved 36 participants of age 6-14 years, recruited at NANI-UNIFESP/SP, subdivided into three groups with 12 children in each. Data was collected through a musical keyboard using Logic Audio Software 9.0 on the computer that recorded the participant's performance in the tasks. Tasks were divided into sections: spontaneous time production, time estimation with simple sounds, and time estimation with music. (1) performance of ADHD groups in temporal estimation of simple sounds in short time intervals (30 ms) were statistically lower than that of control group (p < 0.05); (2) in the task comparing musical excerpts of the same duration (7 s), ADHD groups considered the tracks longer when the musical notes had longer durations, while in the control group, the duration was related to the density of musical notes in the track. The positive average performance observed in the three groups in most tasks perhaps indicates the possibility that music can, in some way, positively modulate the symptoms of inattention in ADHD.


Non parasitic splenic cyst: a case report.
Primary splenic cyst is a rare entity and majority of the cases are classified as epithelial cysts. They are uncommon, comprising only about 10% of benign non-parasitic cysts. Most of the cysts are asymptomatic, and they are incidental findings during abdominal ultrasonography. We report a case of 20 years old male who presented with 1 year history of mild abdominal pain and left upper quadrant fullness. Ultrasound and computed tomography (CT) both were suggestive of splenic cyst. Serological tests were negative for parasitic infection. Splenectomy was done. Histopathological findings are consistent with splenic epithelial cyst.


The treatment of psychotic symptoms in Fahr's disease with lithium carbonate.
A 20-year-old man with Fahr's disease who presented with bilateral basal ganglia calcifications, idiopathic dementia, choreoathetotic movements, and kyphoscoliosis developed psychotic symptoms that were refractory to treatment with haloperidol and responded to treatment with lithium carbonate.


Histone Modifications, Modifiers and Readers in Melanoma Resistance to Targeted and Immune Therapy.
The treatment of melanoma has been revolutionized by new therapies targeting MAPK signaling or the immune system. Unfortunately these therapies are hindered by either primary resistance or the development of acquired resistance. Resistance mechanisms involving somatic mutations in genes associated with resistance have been identified in some cases of melanoma, however, the cause of resistance remains largely unexplained in other cases. The importance of epigenetic factors targeting histones and histone modifiers in driving the behavior of melanoma is only starting to be unraveled and provides significant opportunity to combat the problems of therapy resistance. There is also an increasing ability to target these epigenetic changes with new drugs that inhibit these modifications to either prevent or overcome resistance to both MAPK inhibitors and immunotherapy. This review focuses on changes in histones, histone reader proteins and histone positioning, which can mediate resistance to new therapeutics and that can be targeted for future therapies.


[Transposition of the great arteries. Its anatomical correction. Our initial experience].
Arterial switch correction of transposition of the great arteries has been performed without mortality on 8 children, 7 neonates and one 6 years old child, at our institution. One infant and the 6 year old child has previous pulmonary artery banding and modified Blalock-Taussig shunts. The coronary cuffs were anastomosed to the neo-aorta using the "trap-door" technique described by Mee and in seven the Lecompte manoeuvre was used. Postoperative management included treatment for persistent pulmonary hypertension and left ventricular dysfunction. All patients were discharged in satisfactory condition, and continue to do so at a maximum follow-up of ten months. These results encourage us to elect the arterial switch procedure as the primary treatment of transposition of the great arteries.


Multicompartment model of body composition assessment in Chinese-American adults.
Using hydrodensitometry, dual energy x-ray absorptiometry, and deuterium dilution techniques, multiple compartment body composition assessment was performed on 29 adult Chinese-American men (n = 11) and women (n = 18). The purpose of the investigation was to determine if significant differences exist in the estimation of percentage of body fat (%BF) and fat-free mass (FFM), based on 2-, 3-, and 4-compartment models of body composition. Height, weight, and the body mass index (BMI) for the men were 170 cm, 63 kg, and 22 kg/m2 ; for the women, values were 161 cm, 59 kg, and 23 kg/m2 , respectively. Estimated values for %BF from density alone and density adjusted for TBW were not significantly different for either the men or women (20.5% vs. 18.8%) and (28.2% vs. 27.4%). However, %BF estimated from the 4-compartment model of density, TBW and BMC resulted in significantly lower values for both groups, 17.5% for men and 26.8% for women. The lack of a significant difference in %BF between density only and density adjusted for TBW indicates that TBW was within the accepted constancy value associated with hydrodensitometry. When density was adjusted for variation in both TBW and BMC, a significant decline occurred in the estimate of %BF for men, but not for women. The average TBW to FFM ratio was 0.75., 0.74, and 0.73 when using FFM values from 2-, 3-, and 4-compartment models, respectively. The average BMC to FFM ratio from two-, three-, and four-compartment estimates of FFM were 0.054, 0.053, and 0.052 for the men and 0.060, 0.059, and 0.059 for the women. The results suggest that Chinese-American men and women have similar TBW/FFM ratios, but the BMC/FFM ratio is higher in women than men. Am. J. Hum. Biol. 9:21-27 © 1997 Wiley-Liss, Inc. This article is a US Government work and, as such, is in the public domain in the United States of America.


Enhanced chickenpox exanthema in vaccine injection site.
Exacerbation of viral exanthema has been described after different types of aggression. We report a case of enhanced chickenpox exanthema occurring in the vaccination site of an otherwise healthy boy. Specific local inflammatory modifications may explain the increased number of varicella skin lesions on the site of a previous vaccine-induced inflammation.


Phase I biomarker modulation study of atorvastatin in women at increased risk for breast cancer.
Selective estrogen receptor modulators (SERMs), tamoxifen, and raloxifene that reduce the risk of breast cancer are limited to only estrogen receptor-positive (ER(+)) breast cancer. In addition, patient acceptance of SERMs is low due to toxicity and intolerability. New agents with improved toxicity profile that reduce risk of ER-negative breast cancer are urgently needed. Observational studies show that statins can reduce breast cancer incidence and recurrence. The objective of this prospective short-term prevention study was to evaluate the effect of a lipophilic statin, atorvastatin, on biomarkers in breast tissue and serum of women at increased risk. Eligible participants included women with previous history of carcinoma in situ, or atypical hyperplasia, or 5 year breast cancer projected Gail risk >1.67 %, or lifetime breast cancer risk >20 % calculated by models including Claus, Tyrer-Cuzick, Boadicea, or BRCAPRO. Patients underwent baseline fine needle aspiration (FNA) of the breast, blood collection for biomarker analysis, and were randomized to either no treatment or atorvastatin at 10, 20, or 40 mg/day dose for 3 months. At 3 months, blood collection and breast FNA were repeated. Biomarkers included C-reactive protein (CRP), lipid profile, atorvastatin, and its metabolites, Ki-67, bcl-2, EGFR, and pEGFR. Baseline genotype for 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAR) was also measured. Among 60 patients evaluated, a significant reduction in serum CRP, cholesterol and low-density lipoprotein (LDL), and increase in atorvastatin metabolites in serum and breast FNAs was demonstrated. No changes were observed in other tissue biomarkers. This study shows that atorvastatin and its metabolites are detectable in breast samples and may lower serum CRP among women without hyperlipidemia.


Improving the sensitivity in chiral capillary electrophoresis.
CE is known for being one of the most powerful analytical techniques when performing enantioseparations due to its numerous advantages such as excellent separation efficiency and extremely low solvents and reagents consumption, all of them derived from the capillary small dimensions. Moreover, it is worth highlighting that unlike in chromatographic techniques, in CE the chiral selector is generally within the separation medium instead of being attached to the separation column which makes the method optimization a more versatile task. Despite its numerous advantages, when using UV-Vis detection, CE lacks of sensitivity detection due to its short optical path length derived from the narrow separation capillary. This issue can be overcome by means of different approaches, either by sample treatment procedures or by in-capillary preconcentration techniques or even by employing detection systems more sensitive than UV-Vis, such as LIF or MS. The present review assembles the latest contributions regarding improvements of sensitivity in chiral CE published from June 2013 until May 2015, which follows the works included in a previous review reported by Sánchez-Hernández et al. [Electrophoresis 2014, 35, 12-27].


Activity of disinfectants against vancomycin-resistant Enterococcus faecium.
Vancomycin-resistant enterococci (VRE) often contaminate the hospital environment. We examined the activity of commonly used disinfectants against eight strains of VRE, using a quantitative suspension test method. Isopropyl alcohol and sodium hypochlorite were highly effective. Hydrogen peroxide was ineffective for all strains. After 10 minutes of incubation (the manufactures' recommended time of exposure), three phenolic and three quaternary ammonium compounds also were highly effective. After 3 minutes of exposure, however, occasional failures did occur. With the exception of 3% hydrogen peroxide, most disinfectants appear to be active against VRE.


Pathogen richness and abundance predict patterns of adaptive major histocompatibility complex variation in insular amphibians.
The identification of the factors responsible for genetic variation and differentiation at adaptive loci can provide important insights into the evolutionary process and is crucial for the effective management of threatened species. We studied the impact of environmental viral richness and abundance on functional diversity and differentiation of the MHC class Ia locus in populations of the black-spotted pond frog (Pelophylax nigromaculatus), an IUCN-listed species, on 24 land-bridge islands of the Zhoushan Archipelago and three nearby mainland sites. We found a high proportion of private MHC alleles in mainland and insular populations, corresponding to 32 distinct functional supertypes, and strong positive selection on MHC antigen-binding sites in all populations. Viral pathogen diversity and abundance were reduced at island sites relative to the mainland, and islands housed distinctive viral communities. Standardized MHC diversity at island sites exceeded that found at neutral microsatellites, and the representation of key functional supertypes was positively correlated with the abundance of specific viruses in the environment (Frog virus 3 and Ambystoma tigrinum virus). These results indicate that pathogen-driven diversifying selection can play an important role in maintaining functionally important MHC variation following island isolation, highlighting the importance of considering functionally important genetic variation and host-pathogen associations in conservation planning and management.


Effects of sense of coherence on depressive symptoms after employment in the Japan Self-Defense Force among male young adults.
Objective The present study aimed to explore the effects of sense of coherence (SOC) on depressive symptoms after employment in the Japan Self-Defense Force among male young adults.Methods In April 2013, 953 new male members of the Japan Ground Self-Defense Force (JGSDF; age range: 18-24 years) participated in this study. Depressive symptoms were assessed using the 20-item version of the Center for Epidemiologic Studies Depression scale (CES-D), which defines a score of 16 or greater as indicating the presence of depressive symptoms. The SOC score was assessed using a 13-item version (SOC-13), in which a score of 59 or greater is as assigned to the high score group. A second survey was conducted two months later, in June of 2013. For the analysis, we selected participants without depressive symptoms at the baseline survey. The association between SOC scores at baseline and the onset of depressive symptoms was examined using a logistic regression analysis.Results The final analysis was conducted on data on 389 new male members of the JGSDF. The logistic regression analysis showed a significant reduction in the onset of depressive symptoms among the group with high SOC scores (odds ratios: 0.59, 95% confidence interval=0.35-0.98) as compared with that observed in the group with low SOC scores.Conclusions The present study clarified that SOC among male young adults has a buffering effect on the risk of developing depressive symptoms after employment in the Japan Self-Defense Force. Our results may be useful for improving the mental health of new employees.


Antimicrobial and hypoglycemic activities of novel N-Mannich bases derived from 5-(1-adamantyl)-4-substituted-1,2,4-triazoline-3-thiones.
The reaction of 5-(1-adamantyl)-4-ethyl or allyl-1,2,4-triazoline-3-thione with formaldehyde solution and various 1-substituted piperazines yielded the corresponding N-Mannich bases. The newly synthesized N-Mannich bases were tested for in vitro inhibitory activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Six compounds showed potent antibacterial activity against one or more of the tested microorganisms, while two compounds exhibited moderate activity against the tested Gram-positive bacteria. None of the newly synthesized compounds were proved to possess marked activity against Candida albicans. The oral hypoglycemic activity of six compounds was determined in streptozotocin (STZ)-induced diabetic rats. Four compounds produced significant strong dose-dependent reduction of serum glucose levels, compared to gliclazide at 10 mg/kg dose level (potency ratio > 75%).


Genistein Ameliorates Cyclophosphamide - Induced Hepatotoxicity by Modulation of Oxidative Stress and Inflammatory Mediators.
The present study investigated the protective effect of the phytoestrogen, genistein (GEN), against (CP)-induced acute hepatotoxicity in rats. Male adult rats were randomly assigned into five groups. Normal control group received the vehicles; CP group received a single dose of CP (200 mg/kg, i.p). The other three groups received subcutaneous GEN at doses of 0.5, 1 and 2 mg/kg/day, respectively, for 15 consecutive days prior CP injection. Sera and liver tissues were collected forty-eight hours after CP injection for assessment of liver function enzymes (ALT and AST) in rat sera, the hepatic oxidative/nitrosative biomarkers (GSH, MDA and NOx), hepatic interleukin-1β, and myeloperoxidase activity. Immunohistochemistry of cyclooxygenase-2 and histopathological examination of liver tissues were also conducted. The CP-induced acute liver damage was evidenced by elevated serum ALT and AST accompanied by increased hepatic oxidative stress and inflammatory biomarkers. Immunohistochemical outcomes revealed hepatic cyclooxygenase-2 expression in CP group with distortion of liver architecture. GEN-pretreatment significantly ameliorated the deterioration of liver function and exerted significant anti-oxidant and anti-inflammatory activity with a marked decline in hepatic cyclooxygenase-2 expression in a dose dependent-manner. The present study demonstrated that the antioxidant and anti-inflammatory activities of GEN might contribute to its protective effects against CP-induced liver damage.


Dilated, arrhythmogenic cardiomyopathy in emery-dreifuss muscular dystrophy due to the emerin splice-site mutation c.449 + 1G>A.
Cardiac involvement in X-linked Emery-Dreifuss muscular dystrophy (X-EDMD) usually includes arrhythmias but not dilative cardiomyopathy (dCMP). Here, we report an X-EDMD patient with severe dCMP and life-threatening ventricular arrhythmias associated with other phenotypic features unusual for X-EDMD. A 46-year-old patient with X-EDMD due to the known splice-site mutation c.449 + 1G>A in the emerin gene experienced palpitations for the first time at the age of 21 years, and a first syncope at the age of 23 years. He was started on phenprocoumon due to atrial fibrillation and systolic dysfunction. At the age of 28 years he received his first pacemaker. Echocardiography at the age of 36 years showed left ventricular dilatation, enlarged atria, myocardial thickening, 28% ejection fraction and diastolic dysfunction. dCMP was suspected. At the age of 38 years, a cardiac resynchronization therapy system was implanted, which was upgraded to an implantable cardioverter defibrillator (ICD) because of ventricular tachycardias (at the age of 42 years). During the following months, the ICD discharged 30 times due to ventricular tachycardias. In May 2013, he required recurrent cardio-pulmonary resuscitation because ventricular fibrillation occurred with no discharge of the ICD. He was listed for heart transplantation. He also had hypothyroidism, liver hemangiomas, thrombopenia, anemia and diverticulosis. X-EDMD may occur along with dCMP. An ICD may be ineffective for ventricular fibrillation in X-EDMD. X-EDMD may be associated with unusual, atypical phenotypic features.


Clinical predictors and recommendations for staging computed tomography scan among men with prostate cancer.
To identify clinical variables associated with a positive computed tomography (CT) scan and estimate the performance of imaging recommendations in patients from a diverse sample of urology practices. This study comprised 2380 men with newly diagnosed prostate cancer seen at 28 practices in the Michigan Urological Surgery Improvement Collaborative from March 2012 through September 2013. Data included age, prostate-specific antigen (PSA) level, Gleason score (GS), clinical T stage, total number of positive biopsy cores, whether or not the patient received a staging abdominal and/or pelvic CT scan, and CT scan result. We fit a multivariate logistic regression model to identify clinical variables associated with metastases detected by CT scan. We estimated the sensitivity and specificity of existing imaging recommendations. Among 643 men (27.4%) who underwent a staging CT scan, 62 men (9.6%) had a positive study. In the multivariate analysis, PSA, GS, and clinical T stage were independently associated with the occurrence of a positive CT scan (all P values <.05). The American Urological Association's Best Practice Statements' recommendations for imaging when PSA level >20 ng/mL or GS ≥ 8 or locally advanced cancer had a sensitivity of 87.3% and specificity of 82.6%. Compared with current practice, implementing this recommendation in the Michigan Urological Surgery Improvement Collaborative population was estimated to result in approximately 0.5% of positive study results being missed, and 26.1% of fewer study results overall. Successful implementation of CT imaging criterion of PSA level >20, GS ≥ 8, or clinical stage ≥ T3 would ensure that CT scans are performed for almost all men who would have positive study results while reducing the number of negative study results.


Using Human-Induced Pluripotent Stem Cell Derived Neurons on Microelectrode Arrays to Model Neurological Disease: A Review.
In situ physiological signals of in vitro neural disease models are essential for studying pathogenesis and drug screening. Currently, an increasing number of in vitro neural disease models are established using human-induced pluripotent stem cell (hiPSC) derived neurons (hiPSC-DNs) to overcome interspecific gene expression differences. Microelectrode arrays (MEAs) can be readily interfaced with two-dimensional (2D), and more recently, three-dimensional (3D) neural stem cell-derived in vitro models of the human brain to monitor their physiological activity in real time. Therefore, MEAs are emerging and useful tools to model neurological disorders and disease in vitro using human iPSCs. This is enabling a real-time window into neuronal signaling at the network scale from patient derived. This paper provides a comprehensive review of MEA's role in analyzing neural disease models established by hiPSC-DNs. It covers the significance of MEA fabrication, surface structure and modification schemes for hiPSC-DNs culturing and signal detection. Additionally, this review discusses advances in the development and use of MEA technology to study in vitro neural disease models, including epilepsy, autism spectrum developmental disorder (ASD), and others established using hiPSC-DNs. The paper also highlights the application of MEAs combined with hiPSC-DNs in detecting in vitro neurotoxic substances. Finally, the future development and outlook of multifunctional and integrated devices for in vitro medical diagnostics and treatment are discussed.


Socioeconomic status and health: do gradients differ within childhood and adolescence?
Socioeconomic status (SES) gradients may not be static across the lifespan, but instead may vary in strength across different life stages. This study examined the periods in childhood when SES and health relationships emerge and are strongest among US children. Data came from the National Health Interview Survey, 1994, a cross sectional, nationally representative sample of 33,911 US children ages 0-18. Parents were asked about family SES and child health status. Global health measures included overall ratings of child health, activity and school limitations. Acute conditions included childhood injuries and respiratory illnesses. For all global child health measures, lower family SES was associated with poorer child health in a gradient fashion (P < .001); these differences did not vary across age. For specific conditions, interaction effects of SES with age were found (P < .05). Interaction effects revealed that for injury and acute respiratory illness, expected SES gradients (lower SES with poorer outcomes) were evident during adolescence. In contrast, respiratory illness had a reverse SES gradient in early childhood. In sum, for global child health measures, associations of lower SES with poorer health throughout childhood suggest that factors that do not change with age (e.g., health care quality) may best explain overall health status. However, for acute conditions, the relationship between low SES and poor child health appears most consistently during adolescence. This suggests that normal development-related changes during adolescence, such as increasing peer group affiliation, may help explain these gradients. These patterns are important to understand for optimally timing interventions to reduce SES disparities in US children's health.


Initiation of strong prescription opioids in Australia: cohort characteristics and factors associated with the type of opioid initiated.
To describe the characteristics of Australians initiating strong opioids and examine the factors associated with the type of opioid initiated. Pharmaceutical Benefits Scheme dispensing records were extracted for a 10% sample of people who initiated a strong opioid treatment episode (buprenorphine, fentanyl, hydromorphone, morphine, oxycodone) between 29 September 2009 and 31 December 2013, as evidenced by the absence of a strong opioid dispensing for at least 90 days. The cohort was restricted to people with complete medicines ascertainment. Socio-demographic characteristics, previous dispensing histories and index opioid use were examined. Multinomial logistic regression was used to calculate adjusted relative risk ratios (aRRRs) and 95% confidence intervals (CIs) to determine the factors associated with the type of opioid medicine initiated, relative to oxycodone. The cohort consisted of 125 335 people: 58.3% were female and 63.7% were aged ≥65 years. The most commonly initiated strong opioid was oxycodone (72.8%), usually 5 mg immediate-release tablets (76.1%). Compared to people aged 18-44 years, those ≥85 years were 14.18 times as likely (95% CI 12.67-15.87) to initiate morphine than oxycodone. Compared to people without a cancer treatment history, those with a cancer treatment history were 2.34 times as likely (95% CI 2.11-2.60) to initiate morphine than oxycodone. The most commonly initiated strong opioid was oxycodone, usually at lower strengths. Those who initiated oxycodone were more likely to be younger with no previous cancer treatment history. As these are high-risk characteristics for potential harms, a judicious approach when initiating strong opioids for this group is necessary.


CDK9: A key player in cancer and other diseases.
Cyclin-Dependent Kinase 9 (CDK9) is part of a functional diverse group of enzymes responsible for cell cycle control and progression. It associates mainly with Cyclin T1 and forms the Positive Transcription Elongation Factor b (p-TEFb) complex responsible for regulation of transcription elongation and mRNA maturation. Recent studies have highlighted the importance of CDK9 in many relevant pathologic processes, like cancer, cardiovascular diseases, and viral replication. Herein we provide an overview of the different pathways in which CDK9 is directly and indirectly involved.


Carcinosarcoma of the stomach with alpha-fetoprotein-producing hepatoid adenocarcinoma: an unexpected combination of two rare subtypes of gastric cancer in one tumor.
Carcinosarcoma is a rare malignant neoplasm comprising both epithelial and mesenchymal components. Hepatoid adenocarcinoma (HAC) is another rare type of cancer. To date, there are only four reported cases of concurrent carcinosarcomas with HAC across all tumor types, all of which were observed in uterine tumors. Here, we report an unusual case of gastric carcinosarcoma associated with alpha-fetoprotein (AFP)-producing HAC in a 76-year-old woman. Upon admission, the patient had an elevated serum AFP concentration (448 µg/L), a necrotic polypoid tumor of the central gastric cardia revealed by endoscopy, and no evidence of distant metastasis indicated by computed tomography (CT). Owing to malignancy indicated by biopsy, the patient underwent proximal subtotal gastrectomy. The resected tumor was composed of both an HAC component and a sarcoma component, microscopically. The sample was positive for AFP, hepatocyte paraffin (Hep-Par) 1, glypican-3, SALL4, CDX2, cytokeratin (CK) (pan), CK18, desmin, and vimentin staining immunohistochemically. In summary, the tumor was diagnosed as carcinosarcoma of the stomach with AFP-producing HAC. To our knowledge, this is the first report of gastric carcinosarcoma with AFP-producing HAC in the English literature describing gastric tumors.