Isometric exercise has opposite effects on central pain mechanisms in fibromyalgia patients compared to normal controls.
Aerobic exercise has been shown to activate endogenous opioid and adrenergic systems and attenuate experimental pain in normal control subjects (NC). In contrast, fibromyalgia (FM) subjects' experimental pain ratings increase after aerobic exercise, suggestive of abnormal pain modulation. In order to determine whether central or peripheral mechanisms are predominantly involved in the abnormal pain modulation of FM patients, the effects of handgrip exercise on thermal (cutaneous) and mechanical (somatic) experimental pain was tested in local as well as remote body areas of FM and NC subjects. Supra-threshold thermal pain ratings and pressure pain thresholds over both forearms were obtained before and during 90 s of sustained 30% maximal voluntary contraction (MVC). This isometric exercise resulted in substantially decreased thermal pain ratings and increased mechanical thresholds in local as well as remote body areas in NC. Opposite effects were detected in FM patients. Thus, sustained local muscular contraction induced widespread pain inhibitory effects in NC. In contrast, the widespread hyperalgesic effects of exercise on FM patients clearly indicate altered central pain mechanisms. However, whether these exercise effects of FM patients result from abnormal descending inhibition or excessive activation of muscle nociceptive afferents needs to be addressed in future studies.


Isosorbide in treatment of infantile hydrocephalus.
This paper reports the experiences of the second clinical trial in the use of isosorbide in the treatment of 34 selected cases of infantile hydrocephalus of all types. Subject to careful biochemical monitoring of serum electrolyte, urea, and acid-base balance, treatment with 2 g/kg body weight 6-hourly is safe. Side effects are immediately eliminated by interrupting therapy. With lower dosage, prolonged maintenance therapy was possible, for as long as 11 months, without side effects and with need for much less frequent biochemical monitoring. Isosorbide effectively prevented the need for shunt therapy in 10 of 34 patients, including 3 infants with uncomplicated congenital hydrocephalus of moderate degree and infants whose hydrocephalus was associated with spina bifida and whose cerebral mantle was between 20 to 25 mm. In posthaemorrhagic and postmeningitic hydrocephalus valuable time was gained before shunt therapy until the infant and his CSF were fit for operation.


Substrate Channeling via a Transient Protein-Protein Complex: The case of D-Glyceraldehyde-3-Phosphate Dehydrogenase and L-Lactate Dehydrogenase.
Substrate channeling studies have frequently failed to provide conclusive results due to poor understanding of this subtle phenomenon. We analyzed the mechanism of NADH-channeling from D-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to L-lactate Dehydrogenase (LDH) using enzymes from different cells. Enzyme kinetics studies showed that LDH activity with free NADH and GAPDH-NADH complex always take place in parallel. The channeling is observed only in assays that mimic cytosolic conditions where free NADH concentration is negligible and the GAPDH-NADH complex is dominant. Molecular dynamics and protein-protein interaction studies showed that LDH and GAPDH can form a leaky channeling complex only at the limiting NADH concentrations. Surface calculations showed that positive electric field between the NAD(H) binding sites on LDH and GAPDH tetramers can merge in the LDH-GAPDH complex. NAD(H)-channeling within the LDH-GAPDH complex can be an extension of NAD(H)-channeling within each tetramer. In the case of a transient LDH-(GAPDH-NADH) complex, the relative contribution from the channeled and the diffusive paths depends on the overlap between the off-rates for the LDH-(GAPDH-NADH) complex and the GAPDH-NADH complex. Molecular evolution or metabolic engineering protocols can exploit substrate channeling for metabolic flux control by fine-tuning substrate-binding affinity for the key enzymes in the competing reaction paths.


[Obliteration of a coronary artery aneurysm with a PTFE-covered stent (stent graft)].
Coronary aneurysms are very rare: their frequency ranges between 1% and 2%. The most frequent associated disease in atherosclerosis, although they have also been described associated to: infections or connective tissue diseases, Kawasaki's disease, thoracic traumas and of congenital origin. Furthermore, they are sometimes related to coronary stenting (including drug-eluting stenting) and intracoronary brachytherapy. Their evolution is not well known and their most serious complications are: thrombosis, embolization and rupture. The literature review revealed that they can be treated safely with stent grafts.


Effects of Lithium Oxide Addition on Sintering Behavior and Electrical Conductivity of Ce0.8Gd0.2O1.9 Ceramics Prepared by Commercial Powders.
The densification behavior and electrical conductivity of Ce0.8Gd0.2O1.9 ceramics with lithium oxide concentrations ranging from 0 to 7 mol% were investigated. The sintered density was found to increase with increasing Li2O content up to 2 mol% and then to decrease somewhat upon further Li20 addition. Dense Ce0.8Gd0.2O1.9 ceramics with 97% of the theoretical density could be obtained by sintering the milled mixture with 2 mol% Li2O addition at 1250 degrees C for 5 h. The conductivity of the 2 mol% Li2O-added specimen showed a maximum value of 4.99 x 10(-3) Ω(-1) x cm(-1) at 700 degrees C. Pure Ce0.8Gd0.2O1.9 ceramics needed to be sintered at 1550 degrees C in order to obtain an equivalent theoretical density and conductivity. The addition of Li2O was found to promote the sintering properties and electrical conductivities of Gd2O3-doped CeO2.


An oxidized implant surface may improve bone-to-implant contact in pristine bone and bone defects treated with guided bone regeneration: an experimental study in dogs.
The aim of the present study was to histometrically evaluate bone healing in the absence of bone defects and in the presence of surgically created bone defects treated by guided bone regeneration at oxidized and turned implant surfaces. Three months after dental extractions, standardized buccal dehiscence defects (height: 5 mm; width: 4 mm) were surgically created following implant site preparation in the mandible of 10 dogs. Oxidized-surface implants (OSI) and turned-surface implants (TSI) were inserted bilaterally, and the bone defects were treated by guided bone regeneration. After 3 months of healing, the animals were sacrificed, blocks were dissected, and undecalcified sections were obtained and processed for histometric analysis. The percentage of bone-to-implant contact (BIC) and bone density (BD) was evaluated inside the threads on the buccal (regenerated bone) and lingual sides (pristine bone) of the implants. Data were evaluated using two-way analysis of variance (P <0.05). New bone formation could be observed in OSI and TSI in the region of the defect creation. The BIC values observed in OSI for pristine and regenerated bone were 57.03% +/- 21.86% and 40.86% +/- 22.73%, respectively. TSI showed lower values of BIC in pristine bone (37.39% +/- 23.33%) and regenerated bone (3.52% +/- 4.87%). The differences between OSI and TSI were statistically significant. BD evaluation showed no statistically significant differences between OSI and TSI in pristine and regenerated bone. The oxidized implant surface promoted a higher level of BIC than the turned implant surface at pristine and regenerated bone.


Painless erythema of the hands associated with non-Hodgkin's lymphoma in a lung transplant recipient.
Acral erythema limited to the fingers or the hands has been described in systemic disease. We report the case of a 17-year-old patient who had undergone lung transplantation for cystic fibrosis. Six weeks after transplantation, rapidly growing large-cell immunoblastic non-Hodgkin's lymphoma of the lungs and mediastinum was diagnosed. Sharply demarcated, painless, glovelike erythema was found on both hands. Therapy was reduction of immunosuppression and 12 cycles of extracorporeal photophoresis. After 4 months, lymphoma was in clinical and radiologic remission. Bilateral erythema of the hands also had disappeared. Acral erythema has been reported in association with chemotherapy, collagen vascular disease, infections as with HIV, hepatitis C virus, parvovirus B19, or cytomegalovirus. None of the described associations were detected in this case.


Skin, hair and nail changes in a case of citrullinemia with late manifestation.
We report the case of a 56-year-old woman with a history of episodes of vomiting and coma. Hyperammoniemia , hypouremia , hypercitrullinemia and the decreased arginino -succinic synthetase activity on skin fibroblast cultures permitted us to diagnose citrullinemia. We think that the skin changes, i.e. atrophy of the epidermis, thin and short collagen bundles, dystrophic elastic fibers, increased fundamental matrix, were due to the undernutrition state and were not specific. The dosage of the amino acids of the total skin showed a decreased hydroxylation of lysine in the insoluble fraction, and the presence of proline and hypdroxyproline in the soluble fraction. These metabolic changes were not specific and evidenced the disorganization and the lysis of the connective tissue due to the under-nutritional state. The nail changes, i.e. clubbed fingers and 'half-and-half nail' syndrome, were not specific either. The hair changes mentioned by other authors in newborns and young children, i.e. sparse and brittle blond hair, presence of transverse opaque bands ('irregularly banded hair'), were not present in our case. We only found changes in the cuticle and some trichorrhexis which were not specific of the disease either.


Sonographic Evaluation of Urolithiasis Formation with Positive Family History in the Population of Lahore.
The purpose of the research is to know the sonographic evaluation of urolithiasis formation with positive family history in population of Lahore because urolithiasis is a major problem in Pakistan. According to a survey in 1985-1987 the incidence rate reaches to 8.3/100,000 individuals in the Punjab. In Pakistan, urolithiasis is the sixth major cause of surgery. The study was conducted to rule out the role of positive family history in people suffering from urolithiasis. This was an observational cross-sectional study conducted at the Radiology department of the University of Lahore teaching hospital and Gilani Ultrasound center-Afro-Asian Institute, Lahore, Pakistan. A total of 125 patients were included in the study which were diagnosed with urolithiasis and individuals with any other abnormality were excluded from the study. The duration of the study was from January 2017 to April 2017. Data were tabulated and analyzed using SPSS version 24. The data were reported using descriptive and inferential statistics. The quantitative variable like age was assessed using mean standard deviation and standard errors. The qualitative variables like gender were reported using percentages and frequencies. Urolithiasis is commonly seen in the males (77 individuals out of 125) as compared to females (48 individuals out of 125) and mid pole of right kidney is the most common site of the renal stones deposition (13.6%), and the relationship of father is mostly seen as familial history (39.2%). It is concluded that positive family history is the major predisposing factor in urolithiasis and one of the cause in the development of stones in the urinary tract or in other words people who have a history of urolithiasis in blood relations have more tendency of stone formation in any part of their lives. Its positive aspect is that we can do a screening in blood relations, especially whose parents or family members diagnosed with stones and can do preventive measures for that. Moreover, its negative aspect is that there are several causes of the stone formation in the urinary tract.


Short- and Long-Term Outcomes of Simultaneous Hepatic Artery Resection and Reconstruction for Perihilar Cholangiocarcinoma.
Because surgical resection with simultaneous hepatic artery (HA) resection and reconstruction for perihilar cholangiocarcinoma (PHC) is technically demanding, the surgical indication for this challenging procedure is controversial. Thus, this study aimed to evaluate the efficacy of simultaneous HA resection and reconstruction for PHC. Between January 2002 and January 2018, 13 patients with PHC underwent surgical intervention with simultaneous resection and reconstruction of the HA at Yamaguchi University Hospital (Ube, Japan) and Osaka University Hospital (Suita, Japan). There were 2 cases (15.4%) of 90-day postoperative mortality. Nine patients (69.2%) developed major postoperative complications (Clavien-Dindo classification ≥IIIa). Curative resections (R0) were achieved in 8 cases (61.5%). The median survival time (MST) and 1- and 3-year survival rates after resection (including in-hospital deaths) were 20.9 months and 61.5 and 10.3%, respectively. The MST and 1- and 2-year survival rates of 8 patients who underwent R0 resection were significantly better than those of the other 5 patients (24.2 vs. 10.2 months, 75.0 vs. 40.0%, and 50.0 vs. 0.0%, respectively, p = 0.0228). Simultaneous HA resection and reconstruction is technically possible and may provide long-term survival in selected patients with locally advanced PHC.


Do intrauterine growth restriction and overweight at primary school age increase the risk of elevated body mass index in young adults?
Obesity is one of the rising public health problems characterized as a risk factor for many chronic diseases in adulthood. Early life events such as intrauterine growth restriction, as well as life style, are associated with an increased prevalence of this disease. The present study was performed to determine if intrauterine growth restriction interacts with overweight at primary school age to affect body mass index (BMI) in young adults. From June 1, 1978 to May 31, 1979, 6827 singleton liveborns from Ribeirão Preto, São Paulo State, Brazil, corresponding to 98% of all births at the 8 maternity hospitals, were examined and their mothers were interviewed. Samples from the initial cohort were examined again at primary school age (8 to 11 years of age) and at the time of military service (18 years of age). There were 519 male individuals with complete measurements taken in the three surveys. Intrauterine growth-restricted individuals had a BMI 0.68 kg/m(2) lower than that of individuals who were not restricted (95%CI = -1.34 to -0.03) and overweight at primary school age showed a positive and strong effect on BMI at 18 years of age (coefficient 5.03, 95%CI = 4.27 to 5.79). However, the increase in BMI was much higher--6.90 kg/m(2)--when the conscript had been born with intrauterine growth restriction and presented overweight at primary school age (95%CI = 4.55 to 9.26). These findings indicate that the effect of intrauterine growth restriction on BMI at 18 years of age is modified by later weight gain during school age.


German EstSmoke: estimating adult smoking-related costs and consequences of smoking cessation for Germany.
We compared predicted life-time health-care costs for current, never and ex-smokers in Germany under the current set of tobacco control polices. We compared these economic consequences of the current situation with an alternative in which Germany were to implement more comprehensive tobacco control policies consistent with the World Health Organization (WHO) Framework Convention for Tobacco Control (FCTC) guidelines. German EstSmoke, an adapted version of the UK EstSmoke simulation model, applies the Markov modelling approach. Transition probabilities for (re-)currence of smoking-related diseases were calculated from large German disease-specific registries and the German Health Update (GEDA 2010). Estimations of both health-care costs and effect sizes of smoking cessation policies were taken from recent German studies and discounted at 3.5%/year. Germany. German population of prevalent current, never and ex-smokers in 2009. Life-time cost and outcomes in current, never and ex-smokers. If tobacco control policies are not strengthened, the German smoking population will incur €41.56 billion life-time excess costs compared with never smokers. Implementing tobacco control policies consistent with WHO FCTC guidelines would reduce the difference of life-time costs between current smokers and ex-smokers by at least €1.7 billion. Modelling suggests that the life-time healthcare costs of people in Germany who smoke are substantially greater than those of people who have never smoked. However, more comprehensive tobacco control policies could reduce health-care expenditures for current smokers by at least 4%.


Expandable stents: unusual locations.
Expandable metallic prostheses have been used widely for malignant biliary stenoses and are being used increasingly for malignant dysphagia and esophago-airway fistulas. Potentially, such prostheses can be placed for gut neoplasms obstructing beyond the esophagus or gastric cardia. This series reports our experience with expandable metallic stents in the stomach, jejunum, and colon. All patients with expandable gastrointestinal stents (other than biliary tree or esophagus) were reviewed. Indications for stent placement, type and location of prosthesis, patient demographics, procedural problems, and data with regard to outcome were defined. Over a 6-yr period, expandable prostheses (Z stent, Esophacoil, and Ultraflex) were placed in nine patients with widespread malignancy (afferent loop obstruction, three; colon obstruction, three; gastric outlet obstruction, two; and esophagojejunal interposition stricture, one). There was one colon perforation as a consequence of dilation prior to placement of the prosthesis. Subsequent problems included migration (one), occlusion by food bolus (one), and tumor overgrowths/ingrowths (three) which were treated with laser. Median survival approximated 9 months. Expandable metallic prostheses have the potential to palliate malignant gastrointestinal stenoses that have traditionally been treated with surgical bypass or comfort care measures only.


Relationship between the critical points found by the electron localization function and atoms in molecules approaches in adducts with hydrogen bonds.
In this work, 11 adducts with hydrogen bonds were studied by using the B3LYP exchange-correlation functional of the Kohn-Sham approach and the Møller-Plesset second-order perturbation theory MP2. With both approaches, the geometry of each adduct was optimized with the aug-cc-pVTZ basis set. The binding energies of the considered systems, found by the MP2 method, range from 1.2 to 8.3 kcal/mol. By using the atoms in molecules (AIM) analysis and the electron localization function (ELF) we found that the critical points positions characteristic of hydrogen bonds obtained by AIM and ELF are very similar each other. Besides, we found a linear correlation between the critical points positions found by AIM and those obtained by ELF with the B3LYP method and also with the MP2 method. The slope of such a linear relationship was close to 1 and the y-intercept close to 0.


Static and kinetic friction force and surface roughness of different archwire-bracket sliding contacts.
The aim of this study was to determine the static and kinetic friction forces of the contact bracket-archwire with different dental material compositions in order to select those materials with lower resistance to sliding. We carried out sliding friction tests by means of a universal testing machine following an experimental procedure as described in ASTM D1894 standard. We determined the static and kinetic friction forces under dry and lubricating conditions using an artificial saliva solution at 36.5ºC. The bracket-archwire pairs studied were: stainless steel-stainless steel; stainless steel-glass fiber composite; stainless steel-Nitinol 60; sapphire-stainless steel; sapphire-glass fiber composite; and sapphire-Nitinol 60. The best performance is obtained for Nitinol 60 archwire sliding against a stainless steel bracket, both under dry and lubricated conditions. These results are in agreement with the low surface roughness of Nitinol 60 with respect to the glass fiber composite archwire. The results described here contribute to establishing selection criteria for materials for dental archwire-brackets.


Study on polyamide microcapsules containing oily liquids.
Oily liquids were microencapsulated within polyphthalamide membranes with dodecyl sulphonate sodium (DSS) as an emulsifier. The mean diameter and the distribution, as well as the zeta-potential, of the microcapsules were analysed. It was found that the mean diameter decreases with an increase in stirring speed and emulsifier concentration during the emulsification step. The addition of DSS to aqueous phase resulted in a decrease in zeta-potential of the microcapsules.


Twenty-four hour membrane oxygenation in dogs without anticoagulation.
Is systemic heparinization or heparin-bonded circuitry better than no anticoagulation during 24 hours of cardiopulmonary bypass? We compared blood pressure, coagulation state, oxygenator function, and scanning electron microscopic appearance of the circuits. There were three groups of five dogs each: Group I had no anticoagulants; Group II received systemic heparization; Group III perfusions utilized heparin-bonded circuits. Group I animals all survived, whereas 80 percent (four fifths) in Group II and 20 percent (one fifth) in Group III survived. Arterial pressures were better maintained in Group I as compared to Groups II and III. The coagulation parameters were similar in all groups. Oxygenator function was maintained at normal in all groups. No thrombi were present in any of the circuits following perfusion. The surfaces in Group I had less debris on them compared to Groups II and III. Animals that died had fibrin thrombi present in tissues examined histologically. Systemic heparinization had no advantage over no heparin in this study. The striking similarity of the coagulation state between Groups I and II and better preservation of the surfaces in Group I were unexpected. Heparin-bonded circuits were unsatisfactory when compared to no anticoagulation and systemic heparinization. Additional experiments with various species with and without anticoagulation must be done to determine the best guidlines for human cardiopulmonary bypass.


Physical Harm and Death in the Context of Coercive Measures in Psychiatric Patients: A Systematic Review.
Background: For centuries coercive measures in psychiatry have been means of averting acute danger. It has been known for almost as long that these measures can lead to harm or even death to those affected. Over the past two decades the topic has increasingly been the subject of scientific discussion and research. While the legal and ethical preconditions for coercive measures in psychiatry as well as epidemiological studies on their incidence and patients' subjective experiences have increasingly come into focus, research on possible adverse events has lagged behind. To our knowledge there is no systematic review on the harmful or even fatal physical adverse effects of coercive interventions in psychiatry. Methods: We searched the databases PubMed and CINAHL for primary literature with a search string based on the PICO framework including key words describing different psychiatric diagnoses, coercive measures, and harms. Results: In total, 67 eligible studies (mainly case reports and case series) of very heterogeneous quality were included. Two RCTs were found reporting position-dependent cardiac deterioration, but were, however, carried out with healthy people and were characterized by a small number of cases. Death was the most frequently reported harm: cardiac arrest by chest compression in 14 studies, cardiac arrest by strangulation in 9, and pulmonary embolism in 8 studies. Further harms were, among others, venous thromboembolism and injuries. Injuries during physical restraint were reported in 0.8-4% of cases. For other kinds of coercive interventions, there are no sufficient data. Venous thromboembolism occurred in a considerable percentage of cases during mechanical restraint, also under prophylaxis. The most commonly reported coercive measure was restraint, distinguishing in mechanical restraint (43 studies), physical restraint (22 studies), bedrails (eight studies), vest restraint (7 studies), and chair restraint (6 studies). Forced medication was explicitly mentioned only in two, but seems to have occurred in nine studies. Six studies included seclusion. Conclusion: Coercive measures can lead to physical harm or even death. However, there is a significant lack of data on the incidence of such adverse events related to coercive interventions. Though reported anecdotally, physical adverse events during seclusion appear to be highly underresearched.


Effect of bilateral oophorectomy on mammary tumor formation in BRCA1 mutant mice.
Germline mutations of breast cancer-associated gene 1 (BRCA1) predispose women to breast and ovarian cancer. It was recently shown that bilateral oophorectomy decreases breast cancer incidence in BRCA1 mutation carriers. To model human BRCA1 carriers, our laboratory has previously created mice with a conditional knockout of the full-length BRCA1 gene in the mammary epithelium combined with a heterozygous knockout of the p53 tumor suppressor gene. These mice developed ER-negative mammary tumors and were employed to determine the effects of oophorectomy on tumor formation. Individual knockout mice (BRCA1(Co/Co) MMTV-Crep53+/-), following two complete pregnancies, were either oophorectomized or sham treated. Mice were subsequently examined for the development of palpable mammary tumors until they were 12 months of age. Until 135 days post-oophorectomy (255 days of age), the tumor incidence was similar in both oophorectomized and intact mice, approximately 30%. After this time, the increase in tumor incidence was much lower in the oophorectomized mice, while tumor incidence increased in non-oophorectomized mice. The effects of oophorectomy on mammary development in both control and knockout mice were also examined. Oophorectomized mice with a conditional knockout of full-length BRCA1 in conjunction with a loss of one p53 allele exhibited glandular regression with a reduction in the number of mammary epithelial cells following oophorectomy. This study employed a model that may be relevant for testing agents useful against breast cancer in BRCA1 carriers and a subset of sporadic cancers. The data also show that oophorectomy, if performed significantly prior to the time that tumors arise, appears to be quite effective.


Patient-controlled analgesia in the management of postoperative pain.
Patient-controlled analgesia (PCA) is a delivery system with which patients self-administer predetermined doses of analgesic medication to relieve their pain. Since its introduction in the early 1980s, the daily management of postoperative pain has been extensively optimised. The use of PCA in hospitals has been increasing because of its proven advantages over conventional intramuscular injections. These include improved pain relief, greater patient satisfaction, less sedation and fewer postoperative complications. All PCA modes contain the following variables: initial loading dose, demand dose, lockout interval, background infusion rate and 1-hour or 4-hour limits. Morphine is the most studied and most commonly used intravenous drug for PCA. In spite of the fact that it is the 'first choice' for PCA, other opioids have been successfully used for this option. The most observed adverse effects of opioid-based PCA are nausea and vomiting, pruritus, respiratory depression, sedation, confusion and urinary retention. Although intravenous PCA is the most studied route of PCA, alternative routes have extensively been described in the literature. PCA by means of peridural catheters and peripheral nerve catheters are the most studied. Recently, transdermal PCA has been described. The use of peripheral or neuraxial nerve blocks is recommended to avoid the so called opioid tolerance observed with the intravenous administration of opioids. Numerous studies have shown the superiority of epidural PCA to intravenous PCA. The beneficial postoperative effects of epidural analgesia are more apparent for high-risk patients or those undergoing higher risk procedures. PCA with peripheral nerve catheters results in increased postoperative analgesia and satisfaction for surgery on upper and lower extremities. Serious complications occur rarely with these catheters. With the introduction of an Acute Pain Service, management of postoperative pain can be improved. This will also help to minimise adverse effects related to PCA and to avoid lethal mishaps.


Correlating Gene-specific DNA Methylation Changes with Expression and Transcriptional Activity of Astrocytic KCNJ10 (Kir4.1).
DNA methylation serves to regulate gene expression through the covalent attachment of a methyl group onto the C5 position of a cytosine in a cytosine-guanine dinucleotide. While DNA methylation provides long-lasting and stable changes in gene expression, patterns and levels of DNA methylation are also subject to change based on a variety of signals and stimuli. As such, DNA methylation functions as a powerful and dynamic regulator of gene expression. The study of neuroepigenetics has revealed a variety of physiological and pathological states that are associated with both global and gene-specific changes in DNA methylation. Specifically, striking correlations between changes in gene expression and DNA methylation exist in neuropsychiatric and neurodegenerative disorders, during synaptic plasticity, and following CNS injury. However, as the field of neuroepigenetics continues to expand its understanding of the role of DNA methylation in CNS physiology, delineating causal relationships in regards to changes in gene expression and DNA methylation are essential. Moreover, in regards to the larger field of neuroscience, the presence of vast region and cell-specific differences requires techniques that address these variances when studying the transcriptome, proteome, and epigenome. Here we describe FACS sorting of cortical astrocytes that allows for subsequent examination of a both RNA transcription and DNA methylation. Furthermore, we detail a technique to examine DNA methylation, methylation sensitive high resolution melt analysis (MS-HRMA) as well as a luciferase promoter assay. Through the use of these combined techniques one is able to not only explore correlative changes between DNA methylation and gene expression, but also directly assess if changes in the DNA methylation status of a given gene region are sufficient to affect transcriptional activity.


Molecular phylogeny of the mycorrhizal desert truffles (Terfezia and Tirmania), host specificity and edaphic tolerance.
Terfezia and Tirmania, so called desert truffles, are mycorrhizal fungi mostly endemic to arid and semi-arid areas of the Mediterranean Region, where they are associated with Helianthemum species. The aim of this work was to study the phylogenetic relationships in these pezizalean hypogeous fungi. The restriction fragment length polymorphism (RFLP) and DNA sequences of internal transcribed spacers (ITS) of the nuclear rDNA were studied for several morphological species, Terfezia arenaria, T. boudieri, T. claveryi, T. leptoderma, T. terfezioides (=Mattirolomyces terfezioides), Tirmania nivea and T. pinoyi. The sequences were analyzed with distance and parsimony methods. Phylogenetic analyses indicated a close genetic relationship between Tirmania and Terfezia. They may have arisen from a single evolutionary lineage of pezizalean fungi that developed the hypogeous habit as an adaptation to heat and drought in Mediterranean ecosystems. This analysis also supports the re-establishment of the genus Mattirolomyces. The genera Tirmania and Terfezia were monophyletic, and morphological species corresponded to phylogenetic species. The Tirmania clade comprises desert truffles with smooth spores and amyloid asci, which were found in deserts. The Terfezia clade grouped species found in semi-arid habitats having ornamented and spherical spores. These species are adapted to exploit different types of soil (either acid or basic soils) in association with specific hosts (either basophilous or acidophilous species). Although other factors might also play a role, host specialization and edaphic tolerances (fungus and/or host tolerances) might be the key in the species diversity of these genera.


[Comparison of HER2 gene status between primary breast cancer and synchronous axillary lymph node metastasis].
To investigate the discordant rate of HER2 gene status between primary breast cancer and synchronous axillary lymph node metastasis. One hundred and fifty cases of primary breast cancer with corresponding synchronous lymph node metastases were collected, including 50 cases of HER2 FISH positive, 50 cases of HER2 FISH negative and 50 cases of HER2 FISH equivocal primary tumors, at Peking Union Medical College Hospital between May 2012 and June 2015. The HER2 gene status in lymph node metastatic tumors was analyzed by FISH, and the discordance of HER2 gene status was identified between primary and metastatic tumors. The incidence of discordant HER2 gene status between primary breast cancer and synchronous lymph node metastasis was 20.67%(31/150). Forty-four FISH positive, 3 FISH equivocal and 3 FISH negative cases were found in the first group of 50 patients with HER2 positive results in primary tumor. Forty seven FISH negative, 3 FISH equivocal cases were discovered in the second group of 50 patients with HER2 negative results in primary tumor. Four FISH positive, 18 FISH negative and 28 equivocal cases were observed in the third group of 50 patients with HER2 equivocal results in primary tumor. The discordance of HER2 gene status between primary tumor and lymph node metastasis in the third group of patients was significantly higher than the other two groups (P<0.05). Significant discordance of HER2 gene status between the primary and lymph node metastatic tumors exists. Patients with lymph node metastasis, simultaneous testing of HER2 status may be performed in both primary breast tumor and its lymph node metastasis. HER2 status of nodal metastatic lesion may be more relevant for guiding anti-HER2 target therapy.


Cardiovascular implications of thiazolidinedione therapy.
The incidence of obesity and type 2 diabetes mellitus (DM2) in the United States has been increasing dramatically over the past 15 years, and is now at epidemic proportions. DM2 is the clinical manifestation of a long-term metabolic process that is initiated by cells' decreased sensitivity to the actions of insulin. Many outcome studies have identified DM2 as a strong and independent risk factor for the development of cardiovascular complications such as hypertension, arteriosclerosis, and heart failure. The goals of therapy in treating DM2 are to improve the long-term outlook for these patients. However, in selecting a therapeutic regimen for patients, clinicians should be aware that potentially severe adverse events may occur at a rate not previously identified in phase 3 studies. Certain therapies used to treat DM2, by effectively increasing the sensitivity of insulin, have also been reported to cause adverse effects, which can precipitate symptomatic heart failure. The purpose of this column is to discuss the therapeutic options available for treating patients with DM2, the potential pathophysiology of the adverse events of symptomatic heart failure, encouragement of use of the US Food and Drug Administration MedWatch program for reporting adverse events associated with medication therapy, and review of newer treatment guidelines for use of insulin-sensitizing agents in patients with chronic heart failure.


Local Competition Amplifies the Corrosive Effects of Inequality.
Inequality is widely believed to incite conflict, but the evidence is inconsistent. We argue that the spatial scale of competition-the extent to which individuals compete locally, with their interaction partners, or globally, with the entire population-can help settle the question. We built a mathematical model of the evolution of conflict under inequality and tested its predictions in an experimental game with 1,205 participants. We found that inequality increases conflict, destroys wealth, and engenders risk taking. Crucially, these effects are amplified by local competition. Thus, inequality is at its most damaging when it arises between close competitors. Indeed, at the extremes, the combined effects of inequality and the scale of competition are very large. More broadly, our findings suggest that disagreements in the literature may be the result of a mismatch between the scale at which inequality is measured and the scale at which conflict occurs.


Sequential somatostatin and gastrin releases in response to secretin in rat in vivo.
Secretin in known to inhibit gastric acid secretion. Exogenous secretin has also been shown to have a biphasic effect on acid secretion, being stimulatory then inhibitory. To explain this effect, we studied the timing of gastrin, somatostatin, and HCl releases in the gastric lumen in response to an i.v. bolus of secretin (360 pmol) or saline in conscious rats provided with a chronic double gastric fistula and having had or not antrectomy. After secretin but not saline, an immediate and transient increase in acid and gastrin secretions was first observed. After a 4 min lag, a dramatic increase in somatostatin secretion was then observed, together with a 90 percent inhibition of acid secretion and a return of gastrin release to basal level. Twenty min after secretin administration, a rebound increase in acid and gastrin outputs occurred, whereas somatostatin output returned to basal level. The secretin-induced somatostatin release was higher in rats with antrectomy than in those without antrectomy suggesting that the observed somatostatin output mostly originated from the fundus. This present study suggests that a bolus of secretin induced a gastrin release and thus could stimulate acid secretion. These pharmacological findings could provide an explanation for the so-called paradoxical secretin-induced stimulation of gastrin secretion in particular conditions.


Jejunal and ileal absorption in patients with chronic renal disease. Effect of 1alpha-hydroxycholecalciferol.
Calcium absorption in 30-cm segments of small intestine was measured by constant perfusion of test solutions containing different concentrations of calcium gluconate. In both the jejunum and ileum, calcium absorption rates increased progressively as luminal calcium concentration was increased stepwise between 1 and 20 mM. Although calcium transport was not saturable within these limits, unidirectional flux ratios of calcium (47Ca) suggest that calcium absorption is active in both the jejunum and ileum. Calcium absorption in patients with chronic renal disease was markedly depressed in both regions of the small intestine. This was due to decreased flux out of the lumen; flux in the reverse direction was normal. Flux ratios in the renal disease patients showed no evidence for active calcium transport. Treatment of these patients for 1 wk within 2 mug/day of 1alpha-hydroxycholecalciferol [1alpha-(OH)-D3] restored net calcium absorption and unidirectional calcium flux out of the lumen to normal values in the jejunum; in the ileum, 1alpha-(OH)-D3 increased calcium absorption 60-83% of normal at the various luminal calcium concentrations. 1alpha(OH)-D3 had no effect on unidirectional calcium flux into the lumen or on xylose and electrolyte absorption in either area of the small intestine.


The relationship between Alu I polymorphisms in the calcitonin receptor gene and fluorosis endemic to Chongqing, China.
This study explored the association between an Alu I polymorphism at position 1,377 of the calcitonin receptor (CTR) gene and endemic fluorosis. A case-control study of 321 participants was conducted in regions with high fluorosis rates (Wushan and Fengjie counties) and those without high fluorosis rates (Yubei Qu county; termed nonfluorosis areas) in Chongqing, China. The participants were divided into three groups: the fluorosis group (FG) from areas with high fluoride exposure (121), the nonfluorosis group (NFG) from areas with high fluoride exposure (130), and a control group (CG) from areas with no excessive fluoride exposure (70). An Alu I polymorphism in the CTR gene was genotyped using polymerase chain reaction-restriction fragment length polymorphism analysis. The genotype distributions within each group were as follows: CC 60.33% (73/121), CT 30.58% (37/121) and TT 9.09% (11/121) for the FG; CC 74.62% (97/130), CT 21.54% (28/130) and TT 3.85% (5/130) for the NFG, and CC 68.57% (48/70), CT 31.43% (22/70) and TT 0% (0/70) for the CG. Significant differences in Alu I genotypes were observed among the groups (χ(2) = 12.317, υ = 4, p = 0.015). Allele frequencies of CTR genotypes differed significantly among the groups (χ(2) = 8.859, υ = 2, p = 0.012): C 75.62% (183/242) and T 24.38% (59/242) for the FG, C 85.38% (222/260) and T 14.62% (38/260) for the NFG, and C 84.29% (118/140) and T 15.71% (22/140) for the CG. An association between fluorosis and the Alu I polymorphism in the CTR gene was observed in fluoride-exposed populations.


In vitro skin expansion: Wound healing assessment.
For treatments requiring split-thickness skin grafts, it is preferable to mesh the grafts. This reduces the amount of excised skin and covers more wound area. The mesh technique, however, destroys surface continuity, which results in scarring. Strain-based bioreactors, on the other hand, have successfully expanded split-thickness skin grafts in vitro within a 7-day period, increasing graft coverage. After in vitro expansion, the expanded skin grafts were tested in a porcine full-thickness excisional wound model. Expanded graft take rate was 100%. Volumetric, histologic, and mechanical assessments indicated that expanded grafts were comparable to unexpanded grafts (positive control). While there was considerable variation in expansion (31% to -3.1%), this technique has the potential to enhance the coverage area of skin grafts while reducing or eliminating scarring.


Biochemical biomarker responses of green-lipped mussel, Perna canaliculus, to acute and subchronic waterborne cadmium toxicity.
The biochemical responses of the green-lipped mussel, Perna canaliculus, to waterborne cadmium (Cd) were investigated in order to delineate toxic mechanisms, and the impacts of exposure dose and duration, of this important toxicant in a potential sentinel species. Mussels were exposed for either 96 h (acute: 0, 2000, 4000 μgL(-1) Cd) or for 28 d (subchronic: 0, 200, 2000 μgL(-1) Cd), and the digestive gland, gill and haemolymph were examined for impacts. Biochemical responses measured included those associated with metal detoxification (metallothionein-like protein; MTLP), oxidative stress (catalase, lipid peroxidation), cellular homeostasis (alkaline phosphatase, Na(+), K(+)-ATPase; NKA), and energy utilisation (glycogen, haemolymph protein). Following acute exposure, digestive gland glycogen and gill NKA activity were significantly altered by Cd exposure relative to levels in mussels exposed to Cd-free seawater. Subchronic Cd exposure resulted in a significant increase in MTLP levels in both the gill and the digestive gland. This increase was correlated strongly with the levels of Cd accumulation measured in these tissues (R=0.957 for gill, 0.964 for digestive gland). Catalase activity followed a similar pattern, although the correlation with tissue Cd accumulation was not as strong (R=0.907 for gill, 0.708 for digestive gland) as that for MTLP. Lipid peroxidation increased in the digestive gland at Days 7 and 14 at both subchronic Cd levels tested, but this effect had largely dissipated by Days 21 and 28 (with the exception of the 2,000 μgL(-1) group at Day 28). Alkaline phosphatase activity decreased significantly with Cd exposure in both tissues. This effect was observed at both tested concentrations in the gill, but only at the highest concentration for digestive gland. A decrease in digestive gland glycogen levels was observed in Cd-exposed mussels (Days 14 and 21 at 2,000 μgL(-1)), while haemolymph protein levels increased as a result of subchronic Cd exposure. These findings indicated that biochemical responses in Cd-exposed mussels were tissue-specific, dose- and time-dependent, with duration of exposure being the predominant effect. This study shows that biochemical changes in Cd-exposed green-lipped mussels can be linked to tissue metal accumulation and are consistent with previously reported physiological effects. It also suggests that green-lipped mussels are amenable to a multiple biomarker approach and may be of use as a bioindicator species for monitoring coastal metal pollution.


Cyclic adenosine monophosphate (cAMP) levels in predialysis patients with chronic renal failure.
We studied the changes in the urinary cAMP level in fifty-five predialysis patients (30 men and 25 women) with chronic renal failure (CRF). The excretion of cAMP in 20 patients with first-degree CRF (serum creatinine levels below 356.6 mmol/I) and 15 patients with second or third degree CRF (serum creatinine below 800 mmol/I) was compared with that of 20 age-matched controls using the original I-125 RIA (radioimmunoassay) kit of Incstar Corporation, USA. The urinary cAMP was within normal limits in first-degree CRF patients (mean +/- Sx = 2,617 +/- 268.2 nmol/l) whose serum calcium level was slightly decreased. When calculated per 100 ml of glomerular filtration rate, their urinary cAMP level was significantly elevated--101.17 +/- 0.39--as compared with that of the controls--2.5 +/- 0.2. The urinary cAMP excretion was significantly higher in second and third degree CRF patients--mean 3,755 +/- 435.2 nmol/l, p < 0.05. This increase correlated with hypocalcemia whereas the serum alkaline phosphatase levels remained normal. 20% of the patients with second or third degree CRF had normal urinary cAMP excretion. In our opinion, urinary cAMP levels can reliably be employed as a sensitive and specific indicator of the onset of mild secondary hyperparathyroidism in predialysis patients with CRF.


Lack of interference by the unnatural isomer of 5-formyltetrahydrofolate with the effects of the natural isomer in leucovorin preparations.
Leucovorin, a mixture of the natural (6S) and unnatural (6R) diastereomers of 5-formyltetrahydrofolate, is administered clinically to enhance the antitumor activity of 5-fluorouracil. Because the 6R isomer persists at high concentrations in plasma for prolonged periods after iv leucovorin administration (J Clin Oncol 4:685-696, 1986), we have examined it to ascertain whether the 6R isomer could interfere with the cellular effects of the 6S isomer. The 6R compound had a poorer uptake into human CCRF-CEM lymphoblastic cells than the 6S compound, but the 6R compound could competitively inhibit the uptake of the natural isomer as determined in defined buffers. However, the 6R compound failed to interfere with cell growth support and enhancement of 5-fluorouracil cytotoxicity by the 6S isomer in CCRF-CEM cells in tissue culture experiments at concentrations up to 1 mM. Thus, the unnatural isomer of 5-formyltetrahydrofolate present in leucovorin preparations seems unlikely to have clinically relevant consequences.


Regulation of the Structure of Zirconium-Based Porphyrinic Metal-Organic Framework as Highly Electrochemiluminescence Sensing Platform for Thrombin.
An electrochemiluminescence (ECL) sensor provides a sensitive and convenient method for early diagnosis of diseases; however, it is still a challenge to develop simple and sensitive sensing platforms based on efficient ECL signals and luminophore groups. Porphyrin-based metal-organic frameworks (MOFs) show great potential in ECL sensing; however, the mechanism and structure-activity relationship, as well as application, are rarely reported. Herein, hydrothermal reactions obtained porphyrin Zr-MOFs (PCN-222) with different specific surface areas, pore sizes, structures, and surface charge states by tuning the reaction time were developed, which served both as the ECL luminophore, coreaction promoter for S2O82-, and a connection in the ECL immunoassay. By progressively controlling the condition of the hydrothermal reaction, PCN-222 with large surface area-abundant micropores can be obtained, which has good conductivity and positively charged surfaces, obtaining excellent ECL performance. The ECL performance and the enhancement mechanism were investigated in detail. Using PCN-222-6h with the best ECL intensity as the immobilization matrix for the aptamer, a highly sensitive and selective assay for thrombin was developed. The decrease of the ECL signal was logarithmically linear with the concentration of thrombin in the range from 50 fg mL-1 to 100 pg mL-1 with a low detection limit of 2.48 fg/mL. This proposed strategy provides a brand new approach for tuning of the structures of MOFs as effective ECL signal probes, thus providing wider possibilities for effective ECL immunoassays in the detection of other biomarkers in diagnosis of diseases.


Development of analytically capable time-of-flight mass spectrometer with continuous ion introduction.
The present article describes the results and findings explored in the course of the development of the analytically capable prototype of continuous time-of-flight (CTOF) mass spectrometer. Currently marketed pulsed TOF (PTOF) instruments use ion introduction with a 10 ns or so pulse width, followed by a waiting period roughly 100 micros. Accordingly, the sample is under excitation in 10(-4) part of the total measuring time. This very low duty cycle severely limits the sensitivity of the PTOF method. A possible approach to deal with this problem is to use linear sinusoidal dual modulation technique (CTOF) as described in this article. This way the sensitivity of the method is increased, due to the 50% duty cycle of the excitation. All other types of TOF spectrometer use secondary electron multiplier (SEM) for detection, which unfortunately discriminates in amplification in favor of the lighter ions. This discrimination effect is especially undesirable in a mass spectrometric method, which targets high mass range. In CTOF method, SEM is replaced with Faraday cup detector, thus eliminating the mass discrimination effect. Omitting SEM is made possible by the high ion intensity and the very slow ion detection with some hundred hertz detection bandwidth. The electrometer electronics of the Faraday cup detector operates with amplification 10(10) V/A. The primary ion beam is highly monoenergetic due to the construction of the ion gun, which made possible to omit any electrostatic mirror configuration for bunching the ions. The measurement is controlled by a personal computer and the intelligent signal generator Type Tabor WW 2571, which uses the direct digital synthesis technique for making arbitrary wave forms. The data are collected by a Labjack interface board, and the fast Fourier transformation is performed by the software. Noble gas mixture has been used to test the analytical capabilities of the prototype setup. Measurement presented proves the results of the mathematical calculations as well as the future potentiality for use in chemical analysis of gaseous mixtures.


Pediatric Palliative Transport in Critically Ill Children: A Single Center's Experience and Parents' Perspectives.
The transfer of critically ill children from intensive care units (ICUs) to their homes for palliation is seldom described. We report our 10-year pediatric palliative transport experience and conducted a survey to gain parents' perspectives of their child's transport experience. Over the study period, eight patients were transported from our pediatric ICU to their homes or hospice facilities. There were no intratransport adverse events. Parents who participated in the survey responded positively to the transport experience. The availability of a dedicated critical care transport service allowed for palliative transfers to be performed safely. Facilitating transport to allow withdrawal of life support at home is an acceptable option to families as part of holistic end-of-life care.


Non-response bias in a sample survey on alcohol consumption.
In a non-response follow-up study, non-respondents of the original mailed questionnaire were approached again by house visits in order to compare their alcohol consumption with that of the respondents of the same mailed questionnaire. Differences in alcohol consumption between respondents and non-respondents were found. There is strong evidence for overrepresentation of non-response among abstainers, but weak evidence among frequent excessive drinkers.


Atenolol and chlorthalidone therapy for hypertension: a double-blind comparison.
In a randomized, double-blind, parallel-group study of 31 patients with mild to moderate hypertension, we compared a placebo regimen with a regimen of atenolol and chlorthalidone (Tenoretic). The study, which lasted seven weeks, began with a single-blind two-week placebo lead-in period, followed by a four-week double-blind treatment phase, and concluded with a one-week single-blind placebo washout period. Of 24 patients included in the analysis of efficacy, seven received one Tenoretic 50 tablet per day (atenolol, 50 mg; chlorthalidone, 25 mg), nine received one Tenoretic 100 tablet per day (atenolol, 100 mg; chlorthalidone, 25 mg), and eight received placebo. Supine systolic/diastolic blood pressure (mean +/- SD) decreased from 154 +/- 15.2/102 +/- 4.6 mm Hg during the baseline period to 128 +/- 8.5/85 +/- 4.0 mm Hg during treatment in the group receiving Tenoretic 100, from 153 +/- 12.6/104 +/- 5.4 mm Hg to 137 +/- 4.5/91 +/- 4.4 mm Hg in the group receiving Tenoretic 50, and from 150 +/- 11.9/101 +/- 1.6 mm Hg to 145 +/- 11.6/93 +/- 5.1 mm Hg in the group receiving placebo. Reductions in systolic and diastolic blood pressures in the active treatment groups were significantly greater than the pressure reductions in the group receiving placebo (P less than .05 to .1). The combination of atenolol and chlorthalidone was well tolerated, and in no case was treatment discontinued because of side effects. This study showed that one tablet per day of either Tenoretic 50 or Tenoretic 100 is effective and well tolerated in the treatment of mild to moderate hypertension.


Early priming with inactivated poliovirus vaccine (IPV) and intradermal fractional dose IPV administered by a microneedle device: A randomized controlled trial.
Inactivated poliovirus vaccine (IPV) introduction and phased oral poliovirus vaccine (OPV) cessation are essential for eradication of polio. Healthy 6-week old infants in Bangladesh were randomized to one of five study arms: receipt of trivalent OPV (tOPV) or bivalent OPV (bOPV) at ages 6, 10 and 14 weeks, intramuscular IPV or intradermal one-fifth fractional dose IPV (f-IPV) at ages 6 and 14 weeks, or f-IPV at ages 6 and 14 weeks with bOPV at age 10 weeks (f-IPV/bOPV). All participants received tOPV at age 18 weeks. Of 975 infants randomized, 95% (922) completed follow-up. Type 1 seroconversion after 3 doses at 6, 10 and 14 weeks was higher with bOPV compared with tOPV (99% vs 94%, p=0.019). Seroconversions to types 1 and 3 after 2 IPV doses at ages 6 and 14 weeks were no different than after 3 doses of tOPV or bOPV at ages 6, 10 and 14 weeks. A priming response, seroconversion 1 week after IPV at 14 weeks among those who did not seroconvert after IPV at 6 weeks, was observed against poliovirus types 1, 2 and 3 in 91%, 84% and 97%, respectively. Compared with IPV, f-IPV failed non-inferiority tests for seroconversion with 1 or 2 doses and priming after 1 dose. The findings demonstrate considerable priming with IPV at age 6 weeks, comparable immunogenicity of tOPV and bOPV, and inferior immunogenicity of one-fifth f-IPV compared with IPV. If IPV induced priming at age 6 weeks is similar to that at age 14 weeks, IPV could be administered at a younger age and possibly with a higher coverage.


A randomised phase II trial of the Polo-like kinase inhibitor BI 2536 in chemo-naïve patients with unresectable exocrine adenocarcinoma of the pancreas - a study within the Central European Society Anticancer Drug Research (CESAR) collaborative network.
BI 2536, a novel Polo-like kinase 1 inhibitor, was assessed in patients with unresectable advanced exocrine adenocarcinoma of the pancreas. The study employed a two-stage design. Randomised first-line patients received BI 2536 200 mg on day 1 (n=43) or 60 mg on days 1-3 (n=43) every 21 days. Recruitment of second-line patients was planned for a second stage dependent on an interim analysis demonstrating ≥ 2 responses in the first 18 evaluable patients following 12 weeks of treatment and/or tumour control ≥ 12 weeks in 5 patients per schedule. Primary end point was objective response rate (ORR). By independent review, ORR was 2.3% (all partial) and 24.4% had stable disease as confirmed best response. The second stage was not initiated. Median overall and progression-free survivals were 149 (95% confidence interval (CI), 91-307) and 46 days (95% CI, 44-56). Most common drug-related adverse events were neutropenia (37.2%), leukopenia (29.1%), fatigue (29.1%) and nausea (22.1%); most common grade 3/4-related events were neutropenia (36.0%), leukopenia (27.9%) and thrombocytopenia (8.1%). Given the low ORR and poor survival, further development of BI 2536 monotherapy is not warranted in this population.


[Effect of exogenous pulmonary surfactant on isolated lung injury induced by ischemia-reperfusion in rats].
To study the effect of exogenous pulmonary surfactant (PS) on the acute lung injury to ischemia-reperfusion injury. The model of ischemia-reperfusion was established. Thirty male Sprague-Dawley rats were randomly divided into control (n = 10), I/R (n = 10), and PS (n = 10) groups. the isolated rat lungs were reperfused for 4 hours. I/R group: the isolated rat lungs were reperfused for 2 hours after 2 hours ischemia. PS group: exogenous pulmonary surfactant (10 mg/100 g BW) were given to the ischemic lungs through bronchus 2 hours before reperfusion. Wet to dry lung weight ratio (W/D) and pulmonary artery pressure (PAP) were checked. Immunohistochemical technique was used to determine the immune reactivity of lung tissues to endothelia nitric oxide synthase (eNOS) and surfactant protein A (SP-A). The pulmonary changes were also observed by light and electronic microscopes. W/D and PAP in I/R group were significantly higher than in PS group (P < 0.01). The expression of eNOS and SP-A in I/R group were significantly lower than those in PS group (P < 0.05). PS can significantly protect lung injury induced by ischemia-reperfusion in the isolated rat lungs. This protective effect is associated with the mechanism that the exogenous PS may reduce SP-A loss in the ischemia-reperfusion and activate the up-regulation of eNOS.


Sevoflurane modulates the activity of glyceraldehyde 3-phosphate dehydrogenase.
The mechanism of inhalation anesthesia remains to be fully elucidated. While certain neuronal membrane proteins are considered sites of action, cytosolic proteins may also be targets. We hypothesize that inhaled anesthetics may act via glyceraldehyde 3-phosphate dehydrogenase (GAPDH), which has recently been shown to participate in neuronal inhibition. We examined the effects of sevoflurane, a halogenated ether anesthetic, on the catalytic and fluorescence properties of GAPDH. Initial rates of oxidoreductase activity decreased approximately 30% at saturating levels of sevoflurane. NADH-stimulated oxidoreductase activity (25 microM NADH; 0.8mM NAD+) increased with sevoflurane. Sevoflurane quenched tryptophan fluorescence emission and increased polarization. Additionally, sevoflurane increased the susceptibility of GAPDH to thermal denaturation suggesting an effect on conformation. Our findings warrant further research on sevoflurane's effect on GAPDH and indicate that this approach may lead to delineation of a novel contribution to the mechanism of anesthesia.


IgG subclasses against Helicobacter pylori isolates: an important tool for disease characterization.
Helicobacter pylori infects around 50% of the world's population and is associated with diverse pathologies. In the most severe cases, the bacterium causes peptic ulcers and gastric cancer. The interplay between H. pylori and the host's immune response may help to determine the specific outcome of the infection. To study the relationship between antibody subclasses and variation in immune recognition, we determined the immunoglobulin G1 and 2 (IgG1 and IgG2) titres of sera obtained from patients with different H. pylori-associated pathologies. IgG1 and IgG2 titres were determined by ELISA in 44 sera of patients with different H. pylori-associated diseases (peptic ulcer, bleeding peptic ulcers, gastric cancer and dyspepsia). Soluble proteins from lysates were obtained from 12 different clinical isolates from similar associated diseases. We found that soluble proteins from lysates of H. pylori strains (SPLHP) recognition patterns in these sera were highly variable. Overall, IgG2 titres were higher than the IgG1 titres in the infected patients. In particular, those with peptic ulcers showed marked elevation in IgG2/IgG1 ratios, while SPLHPs from dyspeptic patients resulted in high IgG1 titres. Our results reveal that correlation of antibody subclass titres with Th1/Th2 markers may aid pathology characterization and show a potential diagnosis that could be formally evaluated in other studies.


Solvable Markov random field model in color image restoration.
We propose a scheme for image restoration of full color images by means of a solvable probabilistic model in the red-green-blue space. A special case of our solvable probabilistic model is equivalent to a multicomponent Gaussian model in the statistical mechanics. Exact closed expressions of the evidence and the expectation value of intensity at each pixel in our solvable probabilistic model can be obtained by using multidimensional Gaussian integral formulas and a discrete Fourier transform. In the present paper, the degradation process is assumed to be an additive white Gaussian noise. Hyperparameters are determined so as to maximize the evidence that is expressed in terms of the partition function in our solvable probabilistic model. This work is a pioneering work for the Bayesian approach to the color image restoration by means of the statistical-mechanical technique.


Spiritual issues in the care of dying patients: ". . . it's okay between me and god".
Spiritual issues arise frequently in the care of dying patients, yet health care professionals may not recognize them, may not believe they have a duty to address these issues, and may not understand how best to respond to their patients' spiritual needs. The case of a patient with a strong religious belief in a miraculous cure of metastatic pancreatic cancer is used to explore how better understanding of this belief and more explicitly spiritual conversation with the patient by his treating team might have provided opportunities for an improved plan of care. This article distinguishes spirituality from religion; describes the salient spiritual needs of patients at the end of life as encompassing questions of meaning, value, and relationship; delineates the role physicians ought to play in ascertaining and responding to those needs; and discusses the particular issue of miracles, arguing that expectations of miraculous cure ought not preclude referral to hospice care.


Approach to peripheral neuropathy and neuronopathy.
Neuropathic disorders encompass those that affect the neuron's cell body or neuropathies, those affecting the peripheral process, or peripheral neuropathies. The peripheral neuropathies can be broadly subdivided into the myelinopathies and axonopathies. These conditions can be hereditary or acquired. Each of these disorders has distinct clinical features that enable neurologists to recognize the various patterns of presentation. Once a particular pattern is established, further laboratory studies including electrophysiologic testing, nerve biopsy, and blood and cerebrospinal fluid examination can be performed to confirm the clinical impression. Therapy is available in some to correct the underlying disease state or at least to improve symptoms.


Changes of upper thoracic curve and shoulder balance in thoracic adolescent idiopathic scoliosis treated by anterior selective thoracic fusion using VATS.
A retrospective radiographic analysis. To evaluate changes of upper thoracic curve and shoulder balance in thoracic adolescent idiopathic scoliosis patients treated by anterior selective thoracic fusion using video-assisted thoracoscopic surgery and to identify adequacy of earlier criteria of double thoracic (DT) curve for anterior correction. Although anterior and posterior scoliosis correction show many differences in correction mechanisms, fusion levels, loss of correction etc., the criteria of DT curve was applied without differences. There are no reports about these differences. Forty patients were followed for a minimum of 3 years (range, 3-8 y). The magnitude and flexibility of upper thoracic, lower thoracic, and the superior portion of the lower thoracic curve were measured using full length standing and side-bending radiographs before surgery, at 1 week postoperatively, and at last follow-up. The correction rate and loss of correction of these curves were calculated and preoperative and postoperative radiographic shoulder heights (RSHs) were measured. RSH was defined as balanced (shoulder height difference <10 mm), mildly imbalanced (10-20 mm), or moderately imbalanced (>20 mm). T1 tilt and coronal balance were also evaluated. Patients were divided into groups based on these factors and postoperative RSH was compared. Flexibility of the upper thoracic curve was 46% and magnitude of the upper thoracic curve was corrected spontaneously from 28.6±7.8 degrees to 17.9±7.0 degrees with a 37.4% correction rate that did not change during follow-up. On average, preoperative left shoulder was 6.3±10.5 mm lower than right shoulder and this changed to 10.4±11.8 mm and 6.0±8.2 mm higher than right shoulder at 1 week postoperatively and at last follow-up, respectively. The group with an upper thoracic curve of ≥30 degrees or a superior portion of the lower thoracic curve of ≥30 degrees preoperatively had a higher left shoulder postoperatively (P=0.016, 0.040). Of the 12 patients with a symmetric or higher left shoulder (≥0 mm) preoperatively, 9 patients had a balanced shoulder (-10-10 mm) and 3 patients showed mild shoulder imbalance (<20 mm) at last follow-up. Among patients who have DT curve, patients with mild left shoulder elevation (<20 mm) can be treated by anterior correction unless the magnitude of upper thoracic curve or superior portion of lower thoracic curve are ≥30 degrees. For anterior correction, criteria of DT curve might be applied less strictly.


B lymphocyte differentiation induced by lipopolysaccharide. I. Generation of cells synthesizing four major immunoglobulin classes.
Cultured cells from mouse thoracic duct, spleen, lymph node, Peyer's patches, and bone marrow gave rise to cells containing large amounts of cytoplasmic IgM, IgGl, and IgG2 when stimulated by bacterial lipopolysaccharide (LPS). Differntiation of IgA producers occurred in bone marrow only, and to a lesser extent than other classes. Significant IgM responses preceded development of cells containing other classes. The differentiation of IgG and IgA producers did not appear to depend on T cells, since cultures from nu/nu or thymectomized-irradiated, bone marrow-protected mice responded as well as normals. Cultures from mice rendered deficient in B cells by anti-mu treatment responded normally to T cell mitogens, but did not proliferate or give rise to immunoglobulin-secreting cells when stimulated with LPS. Bone marrow cultures gave relatively meager proliferative responses to LPS, but generated as many or more immunoglobulin-secreting cells as did other tissues.


Disentangling functions of online aggression: The Cyber-Aggression Typology Questionnaire (CATQ).
Aggression in online contexts has received much attention over the last decade, yet there is a need for measures identifying the proximal psychological drivers of cyber-aggressive behavior. The purpose of this study was to present data on the newly developed Cyber-Aggression Typology Questionnaire (CATQ) designed to distinguish between four distinct types of cyber-aggression on dimensions of motivational valence and self-control. A sample 314 undergraduate students participated in the study. The results confirmed the predicted four-factor structure providing evidence for distinct and independent impulsive-aversive, controlled-aversive, impulsive-appetitive, and controlled-appetitive cyber-aggression types. Further analyses with the Berlin Cyberbullying Questionnaire, Reactive Proactive Aggression Questionnaire, and the Behavior Inhibition and Activation Systems Scale provide support for convergent and divergent validity. Understanding the motivations facilitating cyber-aggressive behavior could aid researchers in the development of new prevention and intervention strategies that focus on individual differences in maladaptive proximal drivers of aggression. Aggr. Behav. 43:74-84, 2017. © 2016 Wiley Periodicals, Inc.


Interface-induced ordering of gas molecules confined in a small space.
The thermodynamic properties of gases have been understood primarily through phase diagrams of bulk gases. However, observations of gases confined in a nanometer space have posed a challenge to the principles of classical thermodynamics. Here, we investigated interfacial structures comprising either O2 or N2 between water and a hydrophobic solid surface by using advanced atomic force microscopy techniques. Ordered epitaxial layers and cap-shaped nanostructures were observed. In addition, pancake-shaped disordered layers that had grown on top of the epitaxial base layers were observed in oxygen-supersaturated water. We propose that hydrophobic solid surfaces provide low-chemical-potential sites at which gas molecules dissolved in water can be adsorbed. The structures are further stabilized by interfacial water. Here we show that gas molecules can agglomerate into a condensed form when confined in a sufficiently small space under ambient conditions. The crystalline solid surface may even induce a solid-gas state when the gas-substrate interaction is significantly stronger than the gas-gas interaction. The ordering and thermodynamic properties of the confined gases are determined primarily according to interfacial interactions.


[Infections in intensive care units].
Hospital acquired infections are one of the most serious problems of public health. The problem of hospital infections assumes greatest relevance especially for patients in intensive care units (ICU). In these patients both the incidence (about 40%) and the mortality rate (non infected patients 13%; infected patients 47%) of infections is particularly high. Low respiratory tract represents the most frequent localization of ICU infections (30-50%). The causal pathogens are represented in more than 50% of cases by Gram-negative bacilli provided with low virulence and normally present in patients and in the hospital environment. The pathogenesis of infections in ICU is multiform, deriving from the interplay of many factors: the impairment of organic defenses; the age of the patients, often at the upper or lower limits; the multi-pathology and severity of underlying disease; the side effects of medical therapy (immunodepression); the closeness of many patients in narrow wards, that allows the diffusion of infections; the presence in the hospital environment of many pathogens with poly-antibiotic resistance. The control and prophylaxis programs should include: interventions on ICU structure in order to optimize the building projects and maintain high standard quality; training programs for medical and nursing personnel; interventions on patient-related factors; surveillance protocols (events documentation and monitoring of intervention results).


A constitutively active form of the protein kinase p90Rsk1 is sufficient to trigger the G2/M transition in Xenopus oocytes.
The protein kinase p90(Rsk) has previously been implicated as a key target of the MAPK pathway during M phase of meiosis II in Xenopus oocytes. To determine whether Rsk is a mediator of MAPK for stimulation of the G(2)/M transition early in meiosis I, we sought to generate a form of Rsk that would be constitutively active in resting, G(2) phase oocytes. Initial studies revealed that an N-terminal truncation of 43 amino acids conferred enhanced specific activity on the enzyme in G(2) phase, and stability was highest if the C terminus was not truncated. The full-length enzyme is known to be activated by phosphorylation at five sites. Two of these sites and flanking residues were replaced with either aspartic or glutamic acid, and Tyr(699) was mutated to alanine. The resulting construct, termed fully activated (FA) Rsk, had constitutive activity in G(2) phase, with a specific activity equivalent to that of wild type Rsk in M phase. In eight independent experiments approximately 45% of oocytes expressing FA-Rsk underwent germinal vesicle breakdown (GVBD, the G(2)/M transition) in the absence of progesterone, and this effect could be observed even in the presence of the MAPK kinase inhibitor U0126. Moreover, the specific activity of FA-Rsk in vivo was unaffected by U0126. In oocytes that did not undergo GVBD with FA-Rsk expression, subsequent treatment with progesterone resulted in a very rapid rate of GVBD even in the presence of U0126 to inhibit the endogenous MAPK/Rsk pathway. These results indicate that Rsk is the mediator of MAPK effects for the G(2)/M transition in meiosis I and in a subpopulation of oocytes Rsk is sufficient to trigger the G(2)/M transition.


Gaps in asthma care of the oldest adults.
To assess the adequacy of asthma care reported by a group of older adults who were subsequently hospitalized for their asthma. Prospective cohort study. Fifteen managed care organizations in the United States. Adults with asthma, enrolled in managed care. Patient survey of demographics, asthma symptoms, health status, comorbid conditions, asthma treatment, asthma knowledge, and asthma self-management at baseline and 1 year later. Of 254 older adults, 38 (15.0%) reported being hospitalized for asthma at 1-year follow-up. Of these, 22.9% owned a peak flow meter (PFM). Of those with allergies, only about half (56.0%) had been told how to avoid allergens and had been referred for formal allergy testing. Adrenergic drug use was high in some patients. Nearly all (94.6%) used beta-agonist metered-dose inhalers (MDIs); 60.0% reported theophylline; 17.1% reported beta-agonist MDI overuse (>8 puffs per day); 10.5% reported beta-agonist MDI over-use and theophylline; and 13.2% reported both beta-agonist MDI over-use and oral beta-agonist use. Only 18.4% of respondents rated their overall asthma attack knowledge as excellent. Compared with nonhospitalized older adults, the hospitalized group reported care that was more consistent with guidelines, but also higher rates of potentially toxic combinations of adrenergic drugs. Compared with younger hospitalized adults, older hospitalized adults had clear deficiencies, including lower use of PFMs (55.3% vs 22.9%) and worse asthma self-management knowledge. There are many opportunities to improve both the pharmacologic and non-pharmacologic care of older adults with asthma. Overuse of and potentially toxic combinations of inhaled and oral sympathomimetics should probably be avoided. Older asthmatics may also benefit from increased specialty referral, PFM use, allergy testing, and asthma teaching.


Clinical characteristics and mutation spectrum of GLA in Korean patients with Fabry disease by a nationwide survey: Underdiagnosis of late-onset phenotype.
Fabry disease is a rare X-linked lysosomal storage disorder caused by an α-galactosidase A deficiency. The progressive accumulation of globotriaosylceramide (GL-3) results in life-threatening complications, including renal, cardiac, and cerebrovascular diseases. This study investigated the phenotypic and molecular spectra of GLA mutations in Korean patients with Fabry disease using a nationwide survey.This study included 94 patients from 46 independent pedigrees: 38 adult males, 46 symptomatic females, and 10 pediatric males. Each diagnosis was based on an enzyme assay and GLA gene mutation analysis.The mean age at presentation was 24 years (range, 5-65 years); however, the diagnoses were delayed by 21 ± 19 years after the onset of symptoms. Those patients with late-onset Fabry disease were diagnosed by family screening or milder symptoms at a later age. Forty different mutations were identified: 20 missense (50%), 10 nonsense (25%), 8 frameshift (20%), and 2 splice site (5%) mutations. Five of them were novel. IVS4+919G>A (c.936+919 G>A) was not detected among the 6505 alleles via newborn screening using dried blood spots. Enzyme replacement therapy (ERT) was performed in all the males and pediatric patients, whereas 75% of the symptomatic females underwent ERT for 4.2 ± 3.6 years.This study described the demographic data, wide clinical spectrum of phenotypes, and GLA mutation spectrum of Fabry disease in Korea. Most of the patients had classical Fabry disease, with a 4 times higher incidence than that of late-onset Fabry disease, indicating an underdiagnosis of mild, late-onset Fabry disease.


Discovery of selective small-molecule activators of a bacterial glycoside hydrolase.
Fragment-based approaches are used routinely to discover enzyme inhibitors as cellular tools and potential therapeutic agents. There have been few reports, however, of the discovery of small-molecule enzyme activators. Herein, we describe the discovery and characterization of small-molecule activators of a glycoside hydrolase (a bacterial O-GlcNAc hydrolase). A ligand-observed NMR screen of a library of commercially available fragments identified an enzyme activator which yielded an approximate 90 % increase in kcat /KM values (kcat =catalytic rate constant; KM =Michaelis constant). This compound binds to the enzyme in close proximity to the catalytic center. Evolution of the initial hits led to improved compounds that behave as nonessential activators effecting both KM and Vmax values (Vmax =maximum rate of reaction). The compounds appear to stabilize an active "closed" form of the enzyme. Such activators could offer an orthogonal alternative to enzyme inhibitors for perturbation of enzyme activity in vivo, and could also be used for glycoside hydrolase activation in many industrial processes.


Identification of a regulatory SNP in the retinol binding protein 4 gene associated with type 2 diabetes in Mongolia.
Increased levels of retinol binding protein 4 (RBP4) in serum is associated with insulin resistance. To examine this further, the genomic region of RBP4 was genetically surveyed in Mongolian people, who as a group are suffering from a recent rapid increase in diabetes. The RBP4 gene was screened by DHPLC system, and the PCR fragments which showed heteroduplex peaks in multiple samples were followed by direct sequencing to identify common polymorphisms in 48 Mongolian diabetic samples. Identified single nucleotide polymorphisms (SNPs) were genotyped in 511 control and 281 type 2 diabetes samples. The functions of SNPs in the regulatory region were assessed by reporter gene assay and electrophoretic mobility shift assay. Possible association between functional SNPs and serum RBP4 levels or metabolic parameters was statistically assessed. Nine SNPs were identified in the RBP4 gene. A case-control study revealed that the rare alleles of four SNPs were associated with increased risk of diabetes, even after Bonferroni correction (-803, G > A, P = 0.0054; +5169, C > T, P = 0.0025; +6969, G > C, P = 0.0015; +7542, T > del, P = 0.0015). The -803 G > A SNP influenced the transcription efficiency in a hepatocarcinoma cell line as well as the binding efficiency of hepatocyte nuclear factor 1 alpha to the motif. In addition, the -803 A allele was associated with increased serum RBP4 levels in diabetic patients. We have identified a functional SNP in the RBP4 gene associated with type 2 diabetes in Mongolian people.


Assessing Racial and Ethnic Differences in Cardiovascular Disease in U.S. Family Caregivers of Persons With Dementia: Analysis of Data from the 2015-2020 Behavioral Risk Factor Surveillance System.
The current study examined racial and ethnic differences in psychological, behavioral, and metabolic risk factors for cardiovascular disease (CVD) and CVD conditions among family caregivers (FCGs) of persons with dementia. We used the 2015-2020 Behavioral Risk Factor Surveillance System data. The sample included a total of 6,132 FCGs of persons with dementia. Compared to non-Hispanic White FCGs, non-Hispanic Black and non-Hispanic Asian FCGs were less likely to have depression. The Other racial/ethnic FCG group was more likely to currently smoke. Non-Hispanic Black FCGs were less likely to have exercised, more likely to be obese, and more likely to have been diagnosed with diabetes. No differences in CVD conditions (e.g., angina/coronary heart disease, stroke, myocardial infarction) were detected between racial/ethnic minority FCGs and non-Hispanic White FCGs. Future studies should investigate relationships between racial/ethnic minority-specific caregiving and CVD by including a larger, racially and ethnically diverse population of FCGs. [Research in Gerontological Nursing, 16(5), 241-249.].


[Comparison of the tuberculin skin test with the interferon-gamma test in the framework of a surroundings investigation in a prison].
After the occurrence of a multidrug-resistant tuberculosis in a prison of Lower Saxony (Germany), 223 contact persons (178 inmates, 45 staff members) were identified. To detect latent tuberculosis infections, all contact persons were tested with the tuberculin skin test (TST) and the interferon-gamma release assay (IGRA). An additional standardised questionnaire on anamnestic information and risk factors was completed by the participants. The statistical analysis included 149 male inmates with a mean age of 39 years. 61.1% of the inmates were born in Germany, 14.8% were born in the USSR or, respectively, its follow-up states. With the TST 29.5% of the inmates were tested positive, whereas with the IGRA the positive rate was 18.1%. For 7 inmates there was a positive IGRA despite a negative TST. The positive predictive value of TST with respect to IGRA was 45.5%, agreement was 79.2% (kappa=0.44). The agreement found in this study is comparable to studies within populations with lower incidence. Numerous investigations outside Europe indicate a high risk of tuberculosis infection among inmates.


Effects of fatty acids on inducing endoplasmic reticulum stress in bovine mammary epithelial cells.
Fatty acids play important roles in the regulation of endoplasmic reticulum (ER) stress-induced apoptosis in different cells. Currently, the effects of fatty acids on bovine mammary epithelial cells (MEC) remain unknown. Our study examined bovine MEC viability and measured unfolded protein response (UPR)-related gene and protein expressions following fatty acid treatments. To evaluate the role of fatty acids, we treated MAC-T cells (a line of MEC) with 100 to 400 μM of saturated (palmitic and stearic acid) and unsaturated (palmitoleic, oleic, linoleic, and linolenic acid) fatty acids and 1 to 5 mM of short- and medium-chain fatty acids (acetic, propionic, butyric, and octanoic acid). Thereafter, we determined UPR-related gene expression using quantitative real-time PCR. Palmitic acid stimulated expression of XBP1s, ATF4, ATF6A, and C/EBP homologous protein (CHOP). Stearic acid increased expression of XBP1s and CHOP and decreased expression of ATF4 and ATF6A. Results of Western blot analysis and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that palmitic and stearic acid reduced MAC-T cell viability and induced extreme ER stress by increasing the protein expression of ER stress markers, such as phospho-PKR-like endoplasmic reticulum kinase, phospho-eIF2α, cleaved CASP-3, and CHOP. Among unsaturated long-chain fatty acids, palmitoleic acid increased expression of ATF4 and ATF6A. Oleic acid increased expression of XBP1s, ATF4, and ATF6A. Linoleic and linolenic acids increased expression of XBP1s, ATF4, and ATF6A but decreased expression of XBP1s and ATF6A at the highest dose. Although palmitoleic, oleic, and linoleic acid decreased CHOP expression, only palmitoleic acid increased MAC-T cell viability. Therefore, unsaturated long-chain fatty acids did not induce severe ER stress. Acetic, propionic, and butyric acids decreased expression of ATF4, ATF6A, and CHOP and increased XBP1s expression. Although only octanoic acid increased ATF4 and ATF6A expressions, it lowered expression of XBP1s and CHOP. Although fatty acid treatment did not increase the levels of ER stress proteins, butyric and octanoic acids reduced cell viability, possibly because of early differentiation. These results suggest that saturated fatty acids play important roles in MEC viability by inducing severe ER stress compared with unsaturated fatty acids. In addition, acetic and propionic acids (short- and medium-chain fatty acids) reduced ER stress. Therefore, the present study reflects the new insight that serum fatty acid concentration plays an important role in maintaining the lactation physiology of dairy cows.


Systemic analysis of tyrosine kinase signaling reveals a common adaptive response program in a HER2-positive breast cancer.
Drug-induced compensatory signaling and subsequent rewiring of the signaling pathways that support cell proliferation and survival promote the development of acquired drug resistance in tumors. Here, we sought to analyze the adaptive kinase response in cancer cells after distinct treatment with agents targeting human epidermal growth factor receptor 2 (HER2), specifically those that induce either only temporary cell cycle arrest or, alternatively, apoptosis in HER2-overexpressing cancers. We compared trastuzumab, ARRY380, the combination thereof, and a biparatopic, HER2-targeted designed ankyrin repeat protein (DARPin; specifically, 6L1G) and quantified the phosphoproteome by isobaric tagging using tandem mass tag liquid chromatography/tandem mass spectrometry (TMT LC-MS/MS). We found a specific signature of persistently phosphorylated tyrosine peptides after the nonapoptotic treatments, which we used to distinguish between different treatment-induced cancer cell fates. Next, we analyzed the activation of serine/threonine and tyrosine kinases after treatment using a bait peptide chip array and predicted the corresponding active kinases. Through a combined system-wide analysis, we identified a common adaptive kinase response program that involved the activation of focal adhesion kinase 1 (FAK1), protein kinase C-δ (PRKCD), and Ephrin (EPH) family receptors. These findings reveal potential targets to prevent adaptive resistance to HER2-targeted therapies.


External humeral condylar fracture in children. A long-term review of 30 cases operated.
Follow-up ranging from 2 to 14 years (mean 6 years) was obtained for 30 fractures of the external humeral condyle in children aged from 2 to 11 years; the patients had been submitted to reduction-osteosynthesis. Twelve patients were at the end of the growth period when followed-up. All of the patients were classified as Lagrange and Rigault grades II and III. Synthesis always involved two or three Kirschner wires bent under the skin. There were 24 perfect results and 6 good ones. Valgus equal to less than 10 degrees was present in 2 cases. Deficit in flexion-extension, present in 4 cases, did not exceed 20 degrees overall. Another case showed "fish-tail" radiographic deformity (due to epiphysiodesis) which did not interfere with function. Despite the potential danger of the lesion, the authors believe that careful surgical treatment provides very satisfactory results.


Autologous Fat Grafting as a Novel Approach to Parastomal Soft-tissue Volume Deficiencies.
The aim of this study is to describe a novel approach to revise maladaptive soft-tissue contour around an ileostomy. A patient with permanent ileostomy suffered from significant defects in soft-tissue contour due to scarring and wound contraction. He underwent autologous fat grafting to achieve sealing of his stoma appliance and improve cosmesis. Due to numerous surgeries, the stoma appliance would not seal and required daily appliance changes. The patient received autologous fat grafting to augment the contour around stoma. A complete fitting of stoma was achieved. The patient is satisfied with stoma sealing and is changing his stoma appliance every 5-7 days without skin excoriation. Autologous fat transfer is an effective approach to treat a subset of stoma patients with complex subcutaneous defects.


[A study of ultrasonic scaler. The effect of the different frequencies of the ultrasonics in the experimental calculus removal and roughness of the metallic plate after scaling].
In an attempt to determine how the degree of the experimental calculus removal on the metallic plate and its roughness after scaling would be affected by ultrasonics under high or low frequency, quantitative measurement and morphological observation were made. The results obtained were as follows: 1. On the calculus removal, larger effect was obtained by high frequency unit than low frequency. 2. On the roughness of the metallic plate after scaling, larger defect was observed by high frequency unit than low frequency. 3. Scanning electron microscopically, strip like defects were observed under low frequency unit, while exfoliation of the metallic plate in addition to the strip like defects were observed under high frequency.


Prevalence of hyperuricaemia among adults from Ningxia Hui Autonomous Region, China: a cross-sectional study.
This study aimed to estimate the prevalence of hyperuricaemia (HUA) and investigate its risk factors in the general adult population of Ningxia Hui Autonomous Region (NHAR), China. Cross-sectional study. Survey of cardiovascular disorders and their related risk factors in NHAR, China. 10 803 permanent residents aged 18 and older. HUA was defined as serum uric acid levels >420 µmol/L for men and >360 µmol/L for women. The overall prevalence of HUA in NHAR adults was 19.81% (95% CI 19.06 to 20.57), with prevalence values of 24.91% (95% CI 23.70 to 26.14) in men and 15.58% (95% CI 14.66 to 16.53, p<0.001) in women. The prevalence of HUA was higher in urban residents than in rural residents (23.26% vs 17.02%, p<0.001). HUA prevalence was relatively high in individuals younger than 30 years for both men and women, then decreased with age, and began to increase at the age of 40 for women and 60 for men. Higher level of education, being overweight or obese, alcohol consumption, hypertension, diabetes, higher triglycerides, higher total cholesterol and poorer renal function were associated with an increased risk of HUA. HUA prevalence is high among adults in NHAR. Young adults under 30 years and women over 50 years were identified as populations at high risk for HUA. Further attention ought to be placed to promoting healthy diets and implementing early interventions to manage dyslipidaemia, obesity and blood glucose level, as well as advocating for moderation of alcohol consumption.


Examining the role of unmeasured confounding in mediation analysis with genetic and genomic applications.
In mediation analysis if unmeasured confounding is present, the estimates for the direct and mediated effects may be over or under estimated. Most methods for the sensitivity analysis of unmeasured confounding in mediation have focused on the mediator-outcome relationship. The Umediation R package enables the user to simulate unmeasured confounding of the exposure-mediator, exposure-outcome, and mediator-outcome relationships in order to see how the results of the mediation analysis would change in the presence of unmeasured confounding. We apply the Umediation package to the Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) study to examine the role of unmeasured confounding due to population stratification on the effect of a single nucleotide polymorphism (SNP) in the CHRNA5/3/B4 locus on pulmonary function decline as mediated by cigarette smoking. Umediation is a flexible R package that examines the role of unmeasured confounding in mediation analysis allowing for normally distributed or Bernoulli distributed exposures, outcomes, mediators, measured confounders, and unmeasured confounders. Umediation also accommodates multiple measured confounders, multiple unmeasured confounders, and allows for a mediator-exposure interaction on the outcome. Umediation is available as an R package at https://github.com/SharonLutz/Umediation A tutorial on how to install and use the Umediation package is available in the Additional file 1.


Fluorescent β-ketoenole AmyGreen dye for visualization of amyloid components of bacterial biofilms.
Green-emitting water-soluble amino-ketoenole dye AmyGreen is proposed as an efficient fluorescent stain for visualization of bacterial amyloids in biofilms and the detection of pathological amyloids in vitro. This dye is almost non-fluorescent in solution, displays strong green emission in the presence of amyloid fibril of proteins. AmyGreen is also weakly fluorescent in presence to biomolecules that are components of cells, extracellular matrix or medium: nucleic acids, polysaccharides, lipids, and proteins. Thus, the luminescence turn-on behavior of AmyGreen can be utilized for visualization of amyloid components of bacterial biofilm extracellular matrix. Herein we report the application of AmyGreen for fluorescent staining of a number of amyloid-contained bacteria biofilms produced by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bordetella avium, and Staphylococcus aureus. The effectiveness of AmyGreen was compared to traditional amyloid sensitive dye Thioflavine T. The main advantage of AmyGreen (concentration 10-5 M) is a higher sensitivity in the visualization of amyloid biofilm components over Thioflavine T (10-4 M) as it was revealed when staining E. coli and K. pneumoniae bacterial biofilms. Besides, AmyGreen displays lower cross-selectivity to nucleic acids as demonstrated both in in-solution experiments and upon staining of eukaryotic human mesenchymal stem cells used as amyloid-free negative control over amyloid-rich bacterial biofilms. The results point to a lower risk of false-positive response upon determination of amyloid components of bacterial biofilm using AmyGreen. Co-staining of biofilm by AmyGreen and cellulose sensitive dye Calcofluor White show difference in their staining patterns and localization, indicating separation of polysaccharide-rich and amyloid-rich regions of investigated biofilms. Thus, we suggest the new AmyGreen stain for visualization and differentiation of amyloid fibrils in bacterial biofilms to be used solely and in combination with other stains for confocal and fluorescence microscopy analysis.


Association of a woman's own birth weight with subsequent risk for gestational diabetes.
Several studies have reported links between reduced fetal growth and subsequent risk for type 2 diabetes among older adults, but the association between indices of fetal growth and gestational diabetes mellitus (GDM), a major complication of pregnancy and a strong predictor of type 2 diabetes, remains little explored. To test the hypothesis that a woman's own fetal growth is inversely related to her later risk for GDM. Case-control study of linked hospital discharge and vital record data from the New York State Department of Health. Healthy women who completed their first pregnancies in New York State between 1994 and 1998 and who were also born in New York State. Records from each woman's first pregnancy were linked to those from her own birth (1970-1985). Cases were 440 women with a record of GDM. Controls were 22 955 remaining women with no indication of GDM. A woman's own birth weight, alone and adjusted for gestational age. Birth weight showed a U-shaped relationship to a woman's risk of GDM in her first pregnancy, with the highest risks associated with low and high birth weights. Odds ratios (ORs) adjusted for gestational age were 2.16 (95% confidence interval [CI], 1.04-4.50) for birth weight of less than 2000 g and 1.53 (95% CI, 1.03-2.27) for a birth weight of 4000 g or more. Adjustment for potential confounding factors, particularly prepregnancy body mass index and maternal diabetes, increased the OR for low birth weight to 4.23 (95% CI, 1.55-11.51), but reduced the OR for high birth weight to 0.92 (95% CI, 0.54-1.57), leaving a strong inverse dose-response relationship between birth weight and risk of GDM (adjusted P for trend <.001). In this large population-based study, a woman's own birth weight was strongly and inversely related to her risk of GDM, suggesting that early life factors may be important in the etiology of this disorder.