Clostridium difficile colitis mimicking acute peritonitis.
Five patients receiving penicillin V potassium or a cephalosporin antibiotic for 18 hours to 22 days developed fever, marked leukocytosis, and signs and symptoms that suggested right-lower-quadrant peritoneal irritation. All underwent emergency laparotomy, at which dilatation and inflammation of the ascending colon were found. Only one of the patients had profuse diarrhea, and two patients had no diarrhea prior to laparotomy. Postoperatively, Clostridium difficile colitis was diagnosed by stool toxin assay and was confirmed in one case by proctosigmoidoscopic biopsy results. Antibiotic-associated colitis must be considered in any patient who develops peritoneal signs while or after receiving antibiotics. Over a two-year period, the "acute abdomen" presentation accounted for 5.2% of all patients with C difficile colitis at our institutions. Early proctosigmoidoscopy or stool examination for C difficile or its toxin may avoid unnecessary laparotomy in such patients.


Common variants on 9p21.3 are associated with brain arteriovenous malformations with accompanying arterial aneurysms.
To investigate whether previously reported 9p21.3 single nucleotide polymorphisms (SNPs) are associated with risk of brain arteriovenous malformations (BAVM), which often have accompanying arterial aneurysms. Common variants in the 9p21.3 locus have been reported to be associated with multiple cardiovascular phenotypes, including coronary artery disease and intracranial aneurysms (rs10757278 and rs1333040). We used data from 338 BAVM cases participating in the University of California, San Francisco (UCSF)-Kaiser Brain AVM Study Project and 504 healthy controls to evaluate genotypes for seven common SNPs (minor allele frequency>0.05) that were imputed using 1000 Genomes Phase 1 European data (R(2)>0.87). Association with BAVM was tested using logistic regression adjusting for age, sex and the top three principal components of ancestry. Subgroup analysis included 205 BAVM cases with aneurysm data: 74 BAVM with aneurysm versus 504 controls and 131 BAVM without aneurysm versus 504 controls. We observed suggestive association with BAVM and rs10757278-G (OR=1.23, 95% CI 0.99 to 1.53, p=0.064) and rs1333040-T (OR=1.27, 95% CI 1.01 to 1.58, p=0.04). For rs10757278-G, the association was stronger in BAVM cases with aneurysm (OR=1.52, 95% CI 1.03 to 2.22, p=0.032) than in BAVM without aneurysm (OR=0.98, 95% CI 0.72 to 1.34, p=0.91). Similar patterns of effects were observed for rs1333040 and for other SNPs in linkage disequilibrium (r(2)>0.8) with rs10757278. Common 9p21.3 variants showed similar effect sizes for association with BAVM as previously reported for aneurysmal disease. The association with BAVM appears to be explained by known associations with aneurysms, suggesting that BAVM-associated aneurysms share similar vascular pathology mechanisms with other aneurysm types.


A study of the hydration of the alkali metal ions in aqueous solution.
The hydration of the alkali metal ions in aqueous solution has been studied by large angle X-ray scattering (LAXS) and double difference infrared spectroscopy (DDIR). The structures of the dimethyl sulfoxide solvated alkali metal ions in solution have been determined to support the studies in aqueous solution. The results of the LAXS and DDIR measurements show that the sodium, potassium, rubidium and cesium ions all are weakly hydrated with only a single shell of water molecules. The smaller lithium ion is more strongly hydrated, most probably with a second hydration shell present. The influence of the rubidium and cesium ions on the water structure was found to be very weak, and it was not possible to quantify this effect in a reliable way due to insufficient separation of the O-D stretching bands of partially deuterated water bound to these metal ions and the O-D stretching bands of the bulk water. Aqueous solutions of sodium, potassium and cesium iodide and cesium and lithium hydroxide have been studied by LAXS and M-O bond distances have been determined fairly accurately except for lithium. However, the number of water molecules binding to the alkali metal ions is very difficult to determine from the LAXS measurements as the number of distances and the temperature factor are strongly correlated. A thorough analysis of M-O bond distances in solid alkali metal compounds with ligands binding through oxygen has been made from available structure databases. There is relatively strong correlation between M-O bond distances and coordination numbers also for the alkali metal ions even though the M-O interactions are weak and the number of complexes of potassium, rubidium and cesium with well-defined coordination geometry is very small. The mean M-O bond distance in the hydrated sodium, potassium, rubidium and cesium ions in aqueous solution have been determined to be 2.43(2), 2.81(1), 2.98(1) and 3.07(1) Å, which corresponds to six-, seven-, eight- and eight-coordination. These coordination numbers are supported by the linear relationship of the hydration enthalpies and the M-O bond distances. This correlation indicates that the hydrated lithium ion is four-coordinate in aqueous solution. New ionic radii are proposed for four- and six-coordinate lithium(I), 0.60 and 0.79 Å, respectively, as well as for five- and six-coordinate sodium(I), 1.02 and 1.07 Å, respectively. The ionic radii for six- and seven-coordinate K(+), 1.38 and 1.46 Å, respectively, and eight-coordinate Rb(+) and Cs(+), 1.64 and 1.73 Å, respectively, are confirmed from previous studies. The M-O bond distances in dimethyl sulfoxide solvated sodium, potassium, rubidium and cesium ions in solution are very similar to those observed in aqueous solution.


Imaging the translational dynamics of CF3 in liquid helium droplets.
The translational dynamics of CF3 in liquid helium have been investigated by photodissociating CF3I dissolved in helium droplets consisting of several thousands of atoms. The velocity distribution of CF3 fragments that have escaped from the droplets has been determined using ion imaging techniques and is found to be considerably shifted to lower speeds with respect to the photodissociation of gas phase CF3I. The fragments furthermore show a speed dependent angular distribution that is isotropic for the slowest and approaches the gas phase distribution for the faster fragments. These distributions point to a nonthermal escape process in which, at least for the speeds relevant for the present experiment, the kinetic energy and momentum transfer from the fragments to the solvent appears to be governed by binary collisions with the individual helium atoms.


Characterization of a cDNA encoding a cysteine-rich cell surface protein located in the flagellar pocket of the protozoan Trypanosoma brucei.
We have characterized a cDNA encoding a cysteine-rich, acidic integral membrane protein (CRAM) of the parasitic protozoa Trypanosoma brucei and Trypanosoma equiperdum. Unlike other membrane proteins of T. brucei, which are distributed throughout the cell surface, CRAM is concentrated in the flagellar pocket, an invagination of the cell surface of the trypanosome where endocytosis has been documented. Accordingly, CRAM also locates to vesicles located underneath the pocket, providing evidence of its internalization. CRAM has a predicted molecular mass of 130 kilodaltons and has a signal peptide, a transmembrane domain, and a 41-amino-acid cytoplasmic extension. A characteristic feature of CRAM is a large extracellular domain with a roughly 66-fold acidic, cysteine-rich 12-amino-acid repeat. CRAM is conserved among different protozoan species, including Trypanosoma cruzi, and CRAM has structural similarities with eucaryotic cell surface receptors. The most striking homology of CRAM is to the human low-density-lipoprotein receptor. We propose that CRAM functions as a cell surface receptor of different trypanosome species.


Wild-type isocitrate dehydrogenase under the spotlight in glioblastoma.
Brain tumors actively reprogram their cellular metabolism to survive and proliferate, thus offering potential therapeutic opportunities. Over the past decade, extensive research has been done on mutant IDH enzymes as markers of good prognosis in glioblastoma, a highly aggressive brain tumor in adults with dismal prognosis. Yet, 95% of glioblastoma are IDH wild-type. Here, we review current knowledge about IDH wild-type enzymes and their putative role in mechanisms driving tumor progression. After a brief overview on tumor metabolic adaptation, we present the diverse metabolic function of IDH enzymes and their roles in glioblastoma initiation, progression and response to treatments. Finally, we will discuss wild-type IDH targeting in primary glioblastoma.


The Influence of Crown-to-Implant Ratio on Short Implant Marginal Bone Loss.
There is a need for more studies evaluating the marginal bone loss (MBL) of rehabilitations in the posterior regions of extremely resorbed maxillae and mandibles supported by short-length dental implants with a high crown/implant ratio (C/I-R). The aim of this study was to evaluate the influence of the C/I-R in implants on MBL considering dental implants with 4 mm of width and 7 mm of length. This retrospective cohort study included 59 patients (mean age of 52.8 years) rehabilitated with at least one implant 4 mm in width and 7 mm in length, with an anodically oxidized surface and external connection on the premolar or molar positions, supporting a fixed prosthesis, and in function for a period of 36 months. Periapical radiographs at 36 months were used to calculate the C/I-R and MBL. The Spearman correlation coefficient was used to test the correlation between C/I-R and MBL. The level of significance was set at 5%. One hundred eighteen implants from 59 patients were evaluated. The mean ± SD MBL was 0.67 ± 0.63 mm. The C/I-R mean ± SD was 2.53 ± 0.79 mm. Thirty implants presented a C/I-R ≤ 2, while 88 implants had a C/I-R > 2. A weak nonsignificant inverse correlation (r = -0.081; P = .383, Spearman) was registered between C/I-R and MBL. Within the limitations of this study, it is possible to conclude that implant-supported fixed prostheses with C/I-R > 2 do not correlate positively with MBL.


Health care-associated infections - an overview.
Health care-associated infections (HCAIs) are infections that occur while receiving health care, developed in a hospital or other health care facility that first appear 48 hours or more after hospital admission, or within 30 days after having received health care. Multiple studies indicate that the common types of adverse events affecting hospitalized patients are adverse drug events, HCAIs, and surgical complications. The US Center for Disease Control and Prevention identifies that nearly 1.7 million hospitalized patients annually acquire HCAIs while being treated for other health issues and that more than 98,000 patients (one in 17) die due to these. Several studies suggest that simple infection-control procedures such as cleaning hands with an alcohol-based hand rub can help prevent HCAIs and save lives, reduce morbidity, and minimize health care costs. Routine educational interventions for health care professionals can help change their hand-washing practices to prevent the spread of infection. In support of this, the WHO has produced guidelines to promote hand-washing practices among member countries.


Anti-tumor monoclonal antibodies in conjunction with β-glucans: a novel anti-cancer immunotherapy.
Monoclonal antibodies (mAbs) have greatly advanced the field of anti-cancer immunotherapy and have made a major impact in clinical medicine. While more mAbs have been approved by the FDA and entered into the clinical therapeutic arena with indications to treat various solid tumors and hematologic malignancies, extensive efforts have also been made to make mAb therapy more effective. Combination therapy of anti-tumor mAbs with chemotherapeutic drugs has been widely used in the clinical patient care. In addition, many immune stimulating agents have been specifically studied for this very purpose. One compound in particular, β-glucan, has shown very promising and exciting results in pre-clinical animal models and early phase human clinical trials. β-Glucans are naturally occurring, abundant polysaccharides with different structures that can be extracted and purified from fungi, bacteria, oats and barley. The active components of yeast-derived β-glucan exert their unique immune stimulating functions by binding specifically to complement receptor 3 (CR3) via lectin-like domain (LLD) and activating CR3 to promote cellular cytotoxicity of iC3b-coated cancer cells. In addition, particulate yeast-derived β-glucan stimulates both innate and adaptive anti-tumor immune responses. This review covers the anti-cancer mechanisms of anti-tumor mAbs and β-glucans, the pre-clinical studies done with β-glucans in conjunction with anti-tumor mAbs in human carcinoma xenograft models, and the preliminary results of human clinical trials with different β-glucans, as well as those of phase I/II and III studies using the combination of yeast-derived soluble β-glucan and anti-tumor mAbs.


Management of patients with hormone receptor-positive breast cancer with visceral disease: challenges and treatment options.
Endocrine therapy is an important treatment option for women with hormone receptor-positive (HR+) advanced breast cancer (ABC), yet many tumors are either intrinsically resistant or develop resistance to these therapies. Treatment of patients with ABC presenting with visceral metastases, which is associated with a poor prognosis, is also problematic. There is an unmet need for effective treatments for this patient population. Although chemotherapy is commonly perceived to be more effective than endocrine therapy in managing visceral metastases, patients who are not in visceral crisis might benefit from endocrine therapy, avoiding chemotherapy-associated toxicities that might affect quality of life. To improve outcomes, several targeted therapies are being investigated in combination with endocrine therapy for patients with endocrine-resistant, HR+ ABC. Although available data have considered patients with HR+ ABC as a whole, there are promising data from a prespecified analysis of a Phase III study of everolimus (Afinitor(®)), a mammalian target of rapamycin (mTOR) inhibitor, in combination with exemestane (Aromasin(®)) in patients with visceral disease progressing after nonsteroidal aromatase inhibitor therapy. In this review, challenges and treatment options for management of HR+ ABC with visceral disease, including consideration of therapeutic approaches undergoing clinical investigation, will be assessed.


Legg-Calve-Perthes' disease associated with chronic myeloid leukaemia in a child: case report.
Chronic myeloid leukaemia was discovered in a female child aged 12 years, whose presenting signs and symptoms were those of Legg-Calve-Perthes' disease in the left hip. The chronic myeloid leukaemia responded dramatically to myeleran therapy, whilst the Legg-Calve-Perthes' disease was treated by bed rest in hospital followed by weight-relieving paten-ended calliper. A rare case of CML in a female child who has 'Legg-Calve-Perthes' disease of the left hip in association is described.


Impulsive traits and 5-HT2A receptor promoter polymorphism in alcohol dependents: possible association but no influence of personality disorders.
Impulsive behavior in alcoholics puts them at serious risk of severer course of disease and has been related to the serotonergic neurotransmission dysfunction. The aim of this study is to investigate the association between impulsive aggression in alcohol dependents with regard to the G-1438A polymorphism in the promoter region of the 5-HT2A receptor gene. Furthermore, we investigated the statistical interaction between 5-HT2A alleles, antisocial personality disorder (APD) and impulsive aggression in alcohol dependents. Alcohol dependents were investigated because these personality disorders and impulsive behavior are very frequent in alcohol dependence anf of clinical relevance. One hundred and thirty-five patients of German descent meeting DSM-IV criteria of alcohol dependence were recruited. Blood samples were taken from alcohol dependents to determine 5-HT2A promoter polymorphisms using PCR (polymerase chain reaction) of lymphocyte DNA. Impulsive aggression was assessed using a German version of the Barratt Impulsiveness Scale which was translated and backtranslated. Alcohol dependents were subdivided into low- or high-impulsivity groups using a median split of the Barratt score. APD and borderline personality disorder (BPD) were assessed using the SCID-II interview. The low-impulsivity group was slightly older and showed a later age at alcoholism onset than the highly impulsive group. Alcohol dependents with high impulsive traits showed a significant association with 5-HT2A 1438 A alleles. After excluding alcohol dependents with APD or BPD from the analysis, this association remained significant. Furthermore, no association between APD, BPD and 5-HT2A alleles was noted. Inpatient alcohol dependents showed a significant association between 5-HT2A A alleles and impulsive traits, independent of the presence of APD or BPD. No association was noted between personality disorders and the polymorphism. This is the first report about an association of 5-HT2A promoter polymorphism and impulsive behavior in alcohol dependents. This finding may refer only to impulsive traits and may be independent of personality disorders in this sample. These results have to be confirmed in larger samples and in healthy control subjects to determine whether this association is of general validity.


Deletions of Chromosome 7q Affect Nuclear Organization and HLXB9Gene Expression in Hematological Disorders.
The radial spatial positioning of individual gene loci within interphase nuclei has been associated with up- and downregulation of their expression. In cancer, the genome organization may become disturbed due to chromosomal abnormalities, such as translocations or deletions, resulting in the repositioning of genes and alteration of gene expression with oncogenic consequences. In this study, we analyzed the nuclear repositioning of HLXB9 (also called MNX1), mapping at 7q36.3, in patients with hematological disorders carrying interstitial deletions of 7q of various extents, with a distal breakpoint in 7q36. We observed that HLXB9 remains at the nuclear periphery, or is repositioned towards the nuclear interior, depending upon the compositional properties of the chromosomal regions involved in the rearrangement. For instance, a proximal breakpoint leading the guanine-cytosine (GC)-poor band 7q21 near 7q36 would bring HLXB9 to the nuclear periphery, whereas breakpoints that join the GC-rich band 7q22 to 7q36 would bring HLXB9 to the nuclear interior. This nuclear repositioning is associated with transcriptional changes, with HLXB9 in the nuclear interior becoming upregulated. Here we report an in cis rearrangement, involving one single chromosome altering gene behavior. Furthermore, we propose a mechanistic model for chromatin reorganization that affects gene expression via the influences of new chromatin neighborhoods.


Metabolic and Bariatric Surgery for Pediatric Patients With Severe Obesity.
Severe obesity affects the health and well-being of millions of children and adolescents in the United States and is widely considered to be an "epidemic within an epidemic" that poses a major public health crisis. Currently, few effective treatments for severe obesity exist. Metabolic and bariatric surgery are existing but underuse treatment options for pediatric patients with severe obesity. Roux-en-Y gastric bypass and vertical sleeve gastrectomy are the most commonly performed metabolic and bariatric procedures in the United States and have been shown to result in sustained short-, mid-, and long-term weight loss, with associated resolution of multiple obesity-related comorbid diseases. Substantial evidence supports the safety and effectiveness of surgical weight loss for children and adolescents, and robust best practice guidelines for these procedures exist.


[Electro-echocardiographic correlation in mitral valve prolapse].
The study was performed in 33 patients with echocardiographic diagnosis of mitral valve prolapse (PVM), without any other associated heart disease. A 19 derivations electrocardiogram (ECG) was performed a direct inscription 4 channel Samborns 150 machine at 25 and 50 mm/sec. The purpose of the study was determine the alterations in ventricular depolarization and repolarization, and to correlate them with valve prolapse, as well as with cavitary and parietal dimensions, as measured by M mode and/or two-dimensional echocardiography. Left ventricular hypertrophy detected by ECG agreed with the ECO test in 77%; the sensitivity was of 86% and specificity of 67.5%. Left ventricular hypertrophy detected by ECG was not related with the type of prolapse. Ventricular repolarization alteration was very frequent (84.8%). Association of this parameter with initial notch of R in a VF becomes important for diagnosis suspicion (p less than 0.01). When the abnormal repolarization affected the anterolateral wall, posterior valve prolapse was frequent; when the posteroinferior region was the affected one, the prolapse occurred more frequently in both valves. An important correlation (p less than 0.01) was found between left ventricular dilatation detected by ECO and the abnormal ventricular repolarization.


Physiological effects of fast oscillating magnetic field gradients.
To evaluate the physiological thresholds of neuromuscular stimulation relevant to very fast NMR imaging studies that use gradient switching at frequencies of 1-2 kHz and a maximum magnetic field of up to 10 mT, a series of studies were done with human volunteers using an experimental echo planar gradient coil set. The threshold for induction of localized and momentary sensations in the human back and abdomen for 10 subjects is 60 T/s for sinusoidally oscillating magnetic fields at 1.27 kHz. The threshold relates to an E field of 6 V/m and is shown to vary with number of oscillations and frequency in accord with theory. Using a simple model of E field induction, the threshold for stimulation of cardiac electrical events should be greater than 4 times this value.


The reliability of sensitive information provided by injecting drug users in a clinical setting: clinician-administered versus audio computer-assisted self-interviewing (ACASI).
Research with injecting drug users (IDUs) suggests greater willingness to report sensitive and stigmatised behaviour via audio computer-assisted self-interviewing (ACASI) methods than during face-to-face interviews (FFIs); however, previous studies were limited in verifying this within the same individuals at the same time point. This study examines the relative willingness of IDUs to report sensitive information via ACASI and during a face-to-face clinical assessment administered in health services for IDUs. During recruitment for a randomised controlled trial undertaken at two IDU-targeted health services, assessments were undertaken as per clinical protocols, followed by referral of eligible clients to the trial, in which baseline self-report data were collected via ACASI. Five questions about sensitive injecting and sexual risk behaviours were administered to participants during both clinical interviews and baseline research data collection. "Percentage agreement" determined the magnitude of concordance/discordance in responses across interview methods, while tests appropriate to data format assessed the statistical significance of this variation. Results for all five variables suggest that, relative to ACASI, FFI elicited responses that may be perceived as more socially desirable. Discordance was statistically significant for four of the five variables examined. Participants who reported a history of sex work were more likely to provide discordant responses to at least one socially sensitive item. In health services for IDUs, information collection via ACASI may elicit more reliable and valid responses than FFI. Adoption of a universal precautionary approach to complement individually tailored assessment of and advice regarding health risk behaviours for IDUs may address this issue.


[Immune efficacy of rabies virus glycoprotein expressed by baculovirus vector].
To construct a recombinant baculovirus expressing glycoprotein (GP) of RV SRV9 strain and test the immunological efficacy in mice, open reading frame of rabies virus GP gene of SRV9 strain was cloned into the shuttle vector Bacmid to construct the recombinant shuttle plasmid Bacmid-G and transfection was performed into S f9 cells with the recombinant shuttle plasmid. CPE appeared in cell cultures was identified by electronmicroscopy. Western-blot, IFA and immunity tests in mice were performed to identify the immunoreactivity and immunogenicity of the expression products. Our results showed a recombinant baculovirus expressing GP protein of rabies virus SRV9 was obtained. The expression products possessed a favorable immunogenicity and fall immunized mice could develop 100% protective level of anti-rabies neutralizing antibody. In conclusion, The SRV9 glycoprotein expressed by the recombinant baculovirus in this study had good immunogenicity and could induce anti-rabies neutralizing antibody, which laid the foundation of further development of rabies subunit vaccine.


Nicotine-induced upregulation of nicotinic receptors: underlying mechanisms and relevance to nicotine addiction.
A major hurdle in defining the molecular biology of nicotine addiction has been characterizing the different nicotinic acetylcholine receptor (nAChR) subtypes in the brain and how nicotine alters their function. Mounting evidence suggests that the addictive effects of nicotine, like other drugs of abuse, occur through interactions with its receptors in the mesolimbic dopamine system, particularly ventral tegmental area (VTA) neurons, where nicotinic receptors act to modulate the release of dopamine. The molecular identity of the nicotinic receptors responsible for drug seeking behavior, their cellular and subcellular location and the mechanisms by which these receptors initiate and maintain addiction are poorly defined. In this commentary, we review how nicotinic acetylcholine receptors (nAChRs) are upregulated by nicotine exposure, the potential posttranslational events that appear to cause it and how upregulation is linked to nicotine addiction.


Detection of hypotension during Caesarean section with continuous non-invasive arterial pressure device or intermittent oscillometric arterial pressure measurement.
The intensified use of spinal anaesthesia (SPA) for Caesarean section significantly contributed to a decreased maternal mortality and morbidity. Nevertheless, one of the major side-effects is hypotension after SPA with potential negative effects on the fetus. Owing to discontinuous oscillometric measurements (non-invasive arterial pressure, NIAP), hypotensive episodes may be missed. Recently, a continuous NIAP measurement device (CNAP) with acceptable agreement with the mean invasive AP was introduced. We hypothesized that CNAP detects hypotensive episodes more reliably compared with NIAP measurements. A total of 65 women undergoing Caesarean section under SPA were included in the study analysis. A total of 888 NIAP measurements obtained at 3 min cycles, starting from before SPA and continued until delivery, were analysed. When averaged over all cycles, the lowest systolic AP identified by CNAP in each cycle [105 mm Hg, (24.4)] was significantly lower (P<0.001) than the average of the individual corresponding single NIAP measurements [126 mm Hg (22.1)] and highest CNAP average [126 mm Hg (24.5)]. Hypotension (systolic AP <100 mm Hg) was detected in 39% of all cycles with CNAP and in 9% with NIAP. Hypotension was detected in 91% of the patients based on CNAP and in 55% based on NIAP. Fetal acidosis defined by an umbilical vein pH under 7.25 did not occur when the lowest systolic AP measured by CNAP was above 100 mm Hg. The CNAP device detected more hypotensive episodes after SPA and significantly lower AP compared with NIAP. AP monitoring based on CNAP may improve haemodynamic management in this patient population with potential benefit for the fetus.


Gender and Age Differences in Levels, Types and Locations of Physical Activity among Older Adults Living in Car-Dependent Neighborhoods.
A thorough understanding of gender differences in physical activity is critical to effective promotion of active living in older adults. To examine gender and age differences in levels, types and locations of physical activity. Cross-sectional observation. Car-dependent urban and rural neighborhoods in Worcester County, Massachusetts, USA. 111 men and 103 women aged 65 years and older. From 2012 to 2014, participants were queried on type, frequency and location of physical activity. Participants wore an accelerometer for 7 consecutive days. Compared to women, men had a higher mean daily step count (mean (SD) 4385 (2122) men vs. 3671(1723) women, p=0.008). Men reported higher frequencies of any physical activity and moderate-to-vigorous physical activity, and a lower frequency of physical activity inside the home. Mean daily step counts and frequency of physical activity outside the home decreased progressively with age for both men and women. Women had a sharper decline in frequencies of self-reported physical activity. Men had a significant decrease in utilitarian walking, which women did not (p=0.07). Among participants who reported participation in any physical activity (n=190), more women indicated exercising indoors more often (59% vs. 44%, p=0.04). The three most commonly cited locations for physical activity away from home for both genders were streets or sidewalks, shopping malls, and membership-only facilities (e.g., YMCA or YWCA). The most common types of physical activity, performed at least once in a typical month, with over 40% of both genders reporting, included light housework, brisk walking, leisurely walking, and stretching. Levels, types and location preferences of physical activity differed substantially by gender. Levels of physical activity decreased progressively with age, with greater decline among women. Consideration of these gender differences is necessary to improve the effectiveness of active living promotion programs among older adults.


Critical Appraisal of International Clinical Practice Guidelines in Kidney Transplantation Using the Appraisal of Guidelines for Research and Education II Tool: A Systematic Review.
Although clinical practice guidelines (CPGs) are used for the development of local protocols in kidney transplantation (Ktx), the quality of their methodology is variable. This systematic review aimed to critically appraise international CPGs in all aspects of Ktx using the Appraisal of Guidelines for Research and Evaluation II tool. Clinical Practice Guidelines in Ktx and donation published between 2010 and 2017 were identified from MEDLINE, Embase, National Guideline Clearinghouse, National Health Service and National Institute for Health and Care Excellence Evidence Searches, and the websites of transplant societies. Using Appraisal of Guidelines for Research and Evaluation II, 3 appraisers assessed the quality of CPGs. Interrater reliability was measured using the intraclass correlation coefficient (ICC). Searches identified 3168 records, and 115 CPGs were included. The highest scoring Appraisal of Guidelines for Research and Evaluation II domain was "scope and purpose" (80%; range, 30%-100%), followed by "clarity of presentation" (77%; range, 43%-98%), "editorial independence" (52%; range, 0%-94%), "rigor of development" (47%; range 6%-97%) and "stakeholder involvement" (41%; range, 11%-85%). The poorest scoring domain was "applicability" (31%; range, 3%-74%). Most CPGs were recommended for future use either with (63%) or without (18%) modifications. A small number (14%) were not recommended for future use or reviewers (5%) did not agree on recommending the CPG. The overall mean CPG quality score was 4 of 7 (range, 2-7). The mean ICC of 0.74 indicated substantial agreement between reviewers. The quality of international CPGs in Ktx was variable, and most CPGs lacked key aspects of methodological robustness and transparency. Improvements in methodology, patient involvement, and strategies for implementation are required.


Theoretical Purge Factor Determination as a Control Strategy for Potential Mutagenic Impurities in the Synthesis of Drug Substances.
Mutagenic impurities (MIs) are of serious concern for pharmaceutical industry, regulatory agencies and public health. The first guideline addressing the control of genotoxic impurities (GTIs) dates back to 2006. Since then there have been several updates and refinements, which eventually resulted in the guideline, published by the International Conference on Harmonisation (ICH) in June 2014. The ICH M7 guideline, compared to previous ones, offers greater flexibility in terms of control strategies for GTIs in drug substances. More specifically, it describes a control strategy that relies on process controls in lieu of analytical testing which is based on understanding the process chemistry and process parameters that impact the levels of GTIs. This principle is adopted in the theoretical purge factor determination tool proposed by Teasdale et al. Several case studies applying the proposed theoretical purge factor determination tool were published in recent years. The results confirm the tool's good predictability of the extent to which the impurity is removed by the process. Hopefully, this approach will soon be released as an in-silico tool, generally accepted by the regulatory agencies.


Effect of acute increases in serum triiodothyronine on TSH and prolactin responses to TRH, and estimates of pituitary stores of TSH and prolactin in normal subjects and in patients with primary hypothyroidism.
Previous investigators have shown that daily administration of TRH to normal individuals leads to diminishing TSH responses which were believed due to rising serum T3 with subsequent feedback inhibition of the pituitary. Patients with primary hypothyroidism were examined in the present study to test this hypothesis, since their T3 cannot increase after TRH. Bi-daily TRH (100 mug) was given to 4 patients for 3 consecutive days, and repeated on a 4th day following oral T3 (50 mug). TSH and PRL responses were unchanged during these 3days of serial TRH and were unaltered by T3 administration on the fouth day. In 5 other hypothyroid subjects studied before and during 3 consecutive days of T3 administration, TSH but not PRL responses to TRH appeared to decrease slowly but progressively. These observations led us to re-examine TRH responses in normal subjects given T3, since other workers had reported that 50 mug T3 completely abolished TSH response. Responses to TRH in 11 normals on a control day were compared to those observed 1 hour after oral T3. In spite of marked increases in serum T3, there was no significant difference between the mean TSH responses of the two studies.


Eugenol activates Ca(2+)-permeable currents in rat dorsal root ganglion cells.
Although little is known about the mechanism of action of eugenol, some related compounds have been compared with capsaicin derivatives in terms of the relationship between their chemical structure and activity. To elucidate whether eugenol and capsaicin act via a common mechanism at the neuronal membrane, we investigated the effects of eugenol on rat DRG neurons using the whole-cell patch-clamp technique. Eugenol (0.125-1 mmol/L) produced an inward current in a concentration-dependent manner. The reversal potential for this inward current was around 0 mV in PSS. In Na(+)-deficient solutions, the amplitude of the inward current was slightly reduced at negative holding potentials, whereas in Ca(2+)-free solution, it was markedly reduced at all holding potentials tested. The reversal potential was not changed by superfusion with either solution. Niflumic acid (100 mumol/L) produced a significant inhibition of the current without a change in the reversal potential. These results suggest that eugenol activates a Ca(2+)-permeable channel as well as a Cl- channel. The latter channel may have been activated by the increase in intracellular Ca2+ concentration caused by the activation of the Ca(2+)-permeable channel. Capsazepine (10 mumol/L) partially inhibited the eugenol-induced current and completely inhibited the capsaicin-induced current. Eugenol (1 mmol/L) produced an inward current even after occurrence of desensitization of the capsaicin-induced current had occurred. Our results suggest that eugenol activates a Ca(2+)-permeable ion channel in rat DRG neurons through two different mechanisms: a capsaicin receptor-mediated pathway and a pathway independent of the capsaicin-receptor.


Pivotal role of the renin-angiotensin system in Lyon hypertensive rats.
We assessed the role of the renin-angiotensin system (RAS) in Lyon genetically hypertensive (LH) and normotensive (LN) rats by measuring 1) kidney renin and prorenin contents; 2) effects of early, prolonged angiotensin-converting enzyme (ACE) inhibition on blood pressure (BP) and regional hemodynamics; and 3) acute and chronic responses to angiotensin II (ANG II) and norepinephrine (NE). At the adult age, LH rats differed from LN rats by elevated BP, left ventricle weight, and vascular resistances, especially in the kidneys, associated with lower kidney renin and prorenin contents. ACE inhibition (perindopril, 3 mg.kg-1.24 h-1 orally from 3 to 15 wk of age) suppressed the development of hypertension, cardiac hypertrophy, and the increase in renal vascular resistances. No specific hypersensitivity to ANG II could be disclosed in acute conditions. In perindopril-treated LH rats, a 4-wk infusion of ANG II (200 ng.kg-1.min-1) but not of NE (1,000 ng.kg-1.min-1) restored hypertension, mimicked the hemodynamic alterations seen in untreated LH rats, and produced a brief sodium retention. It is concluded that in LH rats, despite a low basal renin secretion, hypertension and hemodynamic abnormalities 1) are fully dependent on an active RAS and 2) may involve an enhanced sensitivity to the chronic effects of ANG II.


Worldwide burden of cervical cancer in 2008.
The knowledge that persistent human papillomavirus infection is the main cause of cervical cancer has resulted in the development of assays that detect nucleic acids of the virus and prophylactic vaccines. Up-to-date and reliable data are needed to assess impact of existing preventive measures and to define priorities for the future. Best estimates on cervical cancer incidence and mortality are presented using recently compiled data from cancer and mortality registries for the year 2008. There were an estimated 530,000 cases of cervical cancer and 275,000 deaths from the disease in 2008. It is the third most common female cancer ranking after breast (1.38 million cases) and colorectal cancer (0.57 million cases). The incidence of cervical cancer varies widely among countries with world age-standardised rates ranging from <1 to >50 per 100,000. Cervical cancer is the leading cause of cancer-related death among women in Eastern, Western and Middle Africa; Central America; South-Central Asia and Melanesia. The highest incidence rate is observed in Guinea, with ∼6.5% of women developing cervical cancer before the age of 75 years. India is the country with the highest disease frequency with 134,000 cases and 73 000 deaths. Cervical cancer, more than the other major cancers, affects women <45 years. In spite of effective screening methods, cervical cancer continues to be a major public health problem. New methodologies of cervical cancer prevention should be made available and accessible for women of all countries through well-organised programmes.


[Comparative histo- and cytospectrophotometric study of the DNA content in the nuclei of lung cancer cells].
Histo- and cytospectrophotometric examinations of the lung carcinoma (26 observations, operation material) established that such features as hetero- and polyploidy, a considerable increase in the average content of DNA and "index of DNA accumulation" progressed as long as the degree of tumour differentiation decreased. Differences between poorly differentiated forms of squamous cell carcinoma and adenocarcinoma were found (the latter had more octoploid and other polyploid cells, higher values of the "index of DNA accumulation" and a significantly higher average DNA content in the nuclei than in squamous cell carcinoma) as well as between small- and large-cell variants of undifferentiated cancer (the latter had more octoploid and other polyploid cells, higher "index of DNA accumulation" and significantly higher average DNA content in the nuclei than in undifferentiated small-cell carcinoma). The cytospectrophotometric method for DNA determination may be used as an auxilliary test for the determination of the histological form, the degree of differentiation of lung carcinoma prognosis, and choice of the method of treatment.


Retinopathy in tropical pancreatic diabetes.
In a study of the retinopathy profile of 40 patients with tropical pancreatic diabetes, a form of secondary diabetes seen in tropical countries, diabetic retinopathy was detected in 13 patients. Ten patients had background retinopathy and three patients had proliferative retinopathy requiring laser photocoagulation. In two patients, fibrous retinitis proliferans was present. Three patients had evidence of diabetic maculopathy. To our knowledge, this is the first report of severe and sight-threatening retinopathy occurring with secondary diabetes. Retinopathy in these forms of diabetes has hitherto been considered to be rare or, if present, only of a mild background type.


Genetic variants of PDGF signaling pathway genes predict cutaneous melanoma survival.
To investigate whether genetic variants of platelet-derived growth factor (PDGF) signaling pathway genes are associated with survival of cutaneous melanoma (CM) patients, we assessed associations of single-nucleotide polymorphisms in PDGF pathway with melanoma-specific survival in 858 CM patients of M.D. Anderson Cancer Center (MDACC). Additional data of 409 cases from Harvard University were also included for further analysis. We identified 13 SNPs in four genes (COL6A3, NCK2, COL5A1 and PRKCD) with a nominal P < 0.05 and false discovery rate (FDR) < 0.2 in MDACC dataset. Based on linkage disequilibrium, functional prediction and minor allele frequency, a representative SNP in each gene was selected. In the meta-analysis using MDACC and Harvard datasets, there were two SNPs associated with poor survival of CM patients: rs6707820 C>T in NCK2 (HR = 1.87, 95% CI = 1.35-2.59, Pmeta= 1.53E-5); and rs2306574 T>C in PRKCD (HR = 1.73, 95% CI = 1.33-2.24, Pmeta= 4.56E-6). Moreover, CM patients in MDACC with combined risk genotypes of these two loci had markedly poorer survival (HR = 2.47, 95% CI = 1.58-3.84, P < 0.001). Genetic variants of rs6707820 C>T in NCK2 and rs2306574 T>C in PRKCD of the PDGF signaling pathway may be biomarkers for melanoma survival.


Inversions of specific DNA segments in flagellar phase variation of Salmonella and inversion systems of bacteriophages P1 and Mu.
Prophages P1 and Mu produces a trans-acting factor possessing the din+ activity which catalyzes the inversion of the specific DNA segment responsible for flagellar phase variation of Salmonella, din mutants were isolated from PICMclr100 phage by selecting phages that did not suppress the yh2 mutation of Salmonella in prophage state. No inversion loop structure was detected among DNA forms arising after denaturation and rehybridization of DNAs extracted from the din mutants. The DNA fragment containing C region of P1 was cloned on a plasmid vector, pCR1. The resulting hybrid plasmid, pKK2, was shown to possess the din+ activity: the vh2 mutant of Salmonella harboring the plasmid changed the flagellar phase. From analysis of the plasmid by use of BamHI and Bgl II, the din gene specifying the din+ activity was located near or within the C region of P1. It is highly plausible that the din gene of P1 was also involved in the inversion of the C region. Similarly, the DNA fragment containing the G and beta segments of Mu was cloned on pCR1. The resulting hybrid plasmid, pII101, also possessed the din+ activity.


Understanding three-dimensional spatial relationship between the mouse second polar body and first cleavage plane with full-field optical coherence tomography.
The morphogenetic relationship between early patterning and polarity formation is of fundamental interest and remains a controversial issue in preimplantation embryonic development. We use a label-free three-dimensional (3-D) imaging technique of full-field optical coherence tomography (FF-OCT) successfully for the first time to study the dynamics of developmental processes in mouse preimplantation lives. Label-free 3-D subcellular time-lapse images are demonstrated to investigate 3-D spatial relationship between the second polar body (2PB) and the first cleavage plane. By using FF-OCT together with quantitative study, we show that only 25% of the predicted first cleavage planes, defined by the apposing plane of two pronuclei, pass through the 2PB. Also only 27% of the real cleavage planes pass through the 2PB. These results suggest that the 2PB is not a convincing spatial cue for the event of the first cleavage. Our studies demonstrate the feasibility of FF-OCT in providing new insights and potential breakthroughs to the controversial issues of early patterning and polarity in mammalian developmental biology.


Dilated cardiomyopathy in epidermolysis bullosa: a retrospective, multicenter study.
Dilated cardiomyopathy (DC) has been reported in severe epidermolysis bullosa (EB) subtypes. Poor nutritional status, low carnitine levels, selenium deficiency, chronic iron overload, drugs and viral etiology have been proposed as potential contributors. This was a retrospective, descriptive, multicenter study describing EB patients that developed DC, and determining potential pre-disposing risk factors. Fifteen patients were enrolled in the study; 11 of them were male subjects (73%). Eighty-seven per cent of the participants had dystrophic EB and 13% had junctional EB. Mean age at diagnosis of DC was 12.18 +/- 4.99 years. Chronic anemia was diagnosed in 13 of 15 patients (86.7%). Sixty per cent of patients had prior red blood cell transfusions. At diagnosis, selenium levels were low in 55% of the patients (n = 11) and total carnitine levels were low in 45% of the patients (n = 11). Systolic function was moderately impaired, with a mean shortening fraction of 19.38% (SD = 5.04, n = 8). After a mean follow-up period of 6.3 +/- 4.8 years, six patients were alive without being on any medications (40.0%), two were alive on medications (13.3%) and seven had died (46.7%). Limitations of the study was that it was a retrospective chart review with relatively small sample size. Retrospective chart review, relatively small sample size. This study substantiates the association between DC and EB. Currently, there is no single risk factor identified in EB patients that leads to DC. Further prospective studies are needed.


ZEB1 hypermethylation is associated with better prognosis in patients with colon cancer.
Colon cancer (CC) is a heterogeneous disease that is categorized into four Consensus Molecular Subtypes (CMS) according to gene expression. Patients with loco-regional CC (stages II/III) lack prognostic factors, making it essential to analyze new molecular markers that can delineate more aggressive tumors. Aberrant methylation of genes that are essential in crucial mechanisms such as epithelial mesenchymal transition (EMT) contributes to tumor progression in CC. We evaluate the presence of hyper- and hypomethylation in subrogate IHC markers used for CMS classification (CDX2, FRMD6, HTR2B, ZEB1) of 144 stage II/III patients and CC cell lines by pyrosequencing. ZEB1 expression was also studied in control and shRNA-silenced CC cell lines and in paired normal tissue/tumors by quantitative PCR. The pattern of ZEB1 staining was also analyzed in methylated/unmethylated tumors by immunohistochemistry. We describe for the first time the hypermethylation of ZEB1 gene and the hypomethylation of the FRMD6 gene in 32.6% and 50.9% of tumors, respectively. Additionally, we confirm the ZEB1 re-expression by epigenetic drugs in methylated cell lines. ZEB1 hypermethylation was more frequent in CMS1 patients and, more importantly, was a good prognostic factor related to disease-free survival (p = 0.015) and overall survival (p = 0.006) in our patient series, independently of other significant clinical parameters such as patient age, stage, lymph node involvement, and blood vessel and perineural invasion. Aberrant methylation is present in the subrogate genes used for CMS classification. Our results are the first evidence that ZEB1 is hypermethylated in CC and that this alteration is an independent factor of good prognosis.


Development and Functionalization of Visible-Light-Driven Water-Splitting Photocatalysts.
With global warming and the depletion of fossil resources, our fossil fuel-dependent society is expected to shift to one that instead uses hydrogen (H2) as a clean and renewable energy. To realize this, the photocatalytic water-splitting reaction, which produces H2 from water and solar energy through photocatalysis, has attracted much attention. However, for practical use, the functionality of water-splitting photocatalysts must be further improved to efficiently absorb visible (Vis) light, which accounts for the majority of sunlight. Considering the mechanism of water-splitting photocatalysis, researchers in the various fields must be employed in this type of study to achieve this. However, for researchers in fields other than catalytic chemistry, ceramic (semiconductor) materials chemistry, and electrochemistry to participate in this field, new reviews that summarize previous reports on water-splitting photocatalysis seem to be needed. Therefore, in this review, we summarize recent studies on the development and functionalization of Vis-light-driven water-splitting photocatalysts. Through this summary, we aim to share current technology and future challenges with readers in the various fields and help expedite the practical application of Vis-light-driven water-splitting photocatalysts.


Graphene-Contacted Ultrashort Channel Monolayer MoS2 Transistors.
2D semiconductors are promising channel materials for field-effect transistors (FETs) with potentially strong immunity to short-channel effects (SCEs). In this paper, a grain boundary widening technique is developed to fabricate graphene electrodes for contacting monolayer MoS2 . FETs with channel lengths scaling down to ≈4 nm can be realized reliably. These graphene-contacted ultrashort channel MoS2 FETs exhibit superior performances including the nearly Ohmic contacts and excellent immunity to SCEs. This work provides a facile route toward the fabrication of various 2D material-based devices for ultrascaled electronics.


[Alcohol, cardiovascular prevention and cancer].
It is well known that light to moderate drinking (10-25 g/day) has a protective effect on ischaemic heart disease. This effect seems independent of the type of alcoholic beverage. Recently, the International Agency for Research on Cancer (World Health Organization) stated that alcoholic beverages are carcinogenic for human (oral cavity, pharynx, larynx, oesophagus, colorectum, liver and breast). There is a dose-response relationship between alcohol and cancer in that the risk of cancer increases proportionally with alcohol consumption. Low doses of alcohol (10 g/day) are associated with an increased risk for oral cavity, pharynx, larynx, oesophagus and breast cancer. Therefore, a physically active lifestyle and a healthy diet are more effective in preventing ischaemic heart disease than a low level of alcohol consumption.


Immunohistochemical detection of DNA topoisomerase type II alpha and Ki-67 in adenoid cystic carcinoma and pleomorphic adenoma of the salivary gland.
Immunohistochemical detection of cell proliferation-associated antigens was investigated in 28 cases of adenoid cystic carcinoma (ACC) and 20 cases of pleomorphic adenoma (PA), using antibodies against DNA topoisomerase type II alpha (topo-II) (Ki-S1) and Ki-67 (MIB-1). The correlation of staining indices with clinicopathological data, histological features and prognosis was also studied. The topo-II value was significantly higher in ACC than in PA (P<0.0001), and highest in the solid growth pattern of ACC. In addition, significant relationships were found between topo-II values and clinical features such as local recurrence, surgical margins, and distant metastases. By log-rank test, the topo-II index was also correlated significantly with patient survival (P<0.01). The values of topo-II index paralleled those of Ki-67 index in ACC, and a correlation coefficient of 0.97 was obtained. Topo-II may be considered an additional marker for estimating the proliferating fraction of cells and for predicting the short-term prognosis for patients with salivary gland tumors.


Plastic surgeons' perceptions of the affordable care act: results of a national survey.
The Affordable Care Act (ACA) aims to expand coverage to the uninsured, improve quality, and contain costs. The goal of this study was to ascertain how plastic surgeons perceive the ACA. An electronic questionnaire was e-mailed to members of the American Society of Plastic Surgeons between May and June 2014. The survey was anonymous and voluntary and included questions to assess understanding and opinions of the ACA. The survey was sent to 3070 members of the American Society of Plastic Surgeons, and the response rate was 17%. Sixty-eight percent agree or strongly agree that they understand the basic concepts of the ACA. The majority of respondents disagree (38% strongly disagree, 31% disagree) with the notion that the ACA will positively affect their practice, and 51% agree with the statement, "I do not support the ACA, and I believe it did too much." Two thirds (66%) believe that the ACA deserves a grade of D or F. When answers were analyzed across demographics, 42% of respondents with "Academic" practice background identify with the statement, "I support the ACA but I think it needs more work," compared to 15% of those who selected "Solo Practice" (p <0.001). The ACA will affect all specialties, including plastic surgery. The results of this survey suggest that many plastic surgeons believe that they have a baseline understanding of current health-care reform. The majority of surveyed surgeons do not support the Act. It is imperative that plastic surgeons possess the knowledge of the ACA; its changes, both current and impending, will likely affect patient mix, coverage of procedures, and reimbursement.


In vivo fluorescence imaging for tissue diagnostics.
Non-invasive fluorescence imaging has the potential to provide in vivo diagnostic information for many clinical specialties. Techniques have been developed over the years for simple ocular observations following UV excitation to sophisticated spectroscopic imaging using advanced equipment. Much of the impetus for research on fluorescence imaging for tissue diagnostics has come from parallel developments in photodynamic therapy of malignant lesions with fluorescent photosensitizers. However, the fluorescence of endogenous molecules (tissue autofluorescence) also plays an important role in most applications. In this paper, the possibilities of imaging tissues using fluorescence spectroscopy as a mean of tissue characterization are discussed. The various imaging techniques for extracting diagnostic information suggested in the literature are reviewed. The development of exogenous fluorophores for this purpose is also presented. Finally, the present status of clinical evaluation and future directions are discussed.


Psychological problems in adolescents with diabetes.
For youth with type 1 diabetes (T1DM), the transition into adolescence is often associated with poorer adherence to treatment, deteriorating metabolic control, and increased risk for psychological disorders. The current article summarizes recent findings on psychological problems for adolescents with diabetes, including depression, eating disorders, fear of hypoglycemia, and problems specific to adolescents with T2DM. The impact of family functioning on adolescent adjustment and the importance of parent-child collaboration on treatment management is emphasized. By using the strategies described in this article, primary care providers have the potential to support adolescents with diabetes, while screening for problems that may be better treated by other professionals.


The relationship between membrane status and fertility of boar spermatozoa after flow cytometric sorting in the presence or absence of seminal plasma.
The motility, viability (percent live), capacitation status and in vitro fertility of boar spermatozoa were examined, after staining with Hoechst 33,342 and flow cytometric sorting in the absence or presence of seminal plasma. Viability was higher in unstained controls and when seminal plasma was present in the medium used to collect spermatozoa from the cell sorter than when seminal plasma was absent or in the staining extender only, but motility was highest when seminal plasma was included in the extender only, compared with the controls and other treatments. The proportions of capacitated spermatozoa were increased by sorting, but were lower when seminal plasma was present, rather than absent, from the staining extender and the collection medium. Compared with unstained controls, extension and staining without sorting only increased the proportion of capacitated spermatozoa after washing in preparation for in vitro fertilization. The percentages of polyspermic, penetrated and cleaved oocytes were lower when inseminated with unsorted (stained) than control (unstained) spermatozoa, regardless of the presence or absence of seminal plasma. These parameters were higher for sorted than for control spermatozoa in the absence of seminal plasma, but in its presence penetration and cleavage were substantially lower. The proportions of capacitated spermatozoa were lower when seminal plasma was present in the collection medium only than in the staining extender or when it was absent altogether, but the former treatment substantially reduced the proportions of polyspermic, penetrated and cleaved oocytes, and the proportion of blastocysts. These findings indicate that sperm capacitation associated with flow cytometric sorting can be reduced by the inclusion of seminal plasma in the collection medium, but this treatment reduces the ability of spermatozoa to fertilize oocytes in vitro under these conditions.


Allelic polymorphisms in apical membrane antigen-1 are responsible for evasion of antibody-mediated inhibition in Plasmodium falciparum.
Apical membrane antigen-1 (AMA-1) is a target of antibodies that inhibit invasion of Plasmodium falciparum into human erythrocytes and is a candidate for inclusion in a malaria vaccine. We have identified a line of P. falciparum (W2mef) less susceptible to anti-AMA1 antibodies raised to the protein from a heterologous parasite line (3D7). We have constructed transgenic P. falciparum expressing heterologous AMA-1 alleles. In vitro invasion assays show that these transgenic parasites differ from parental lines in susceptibility to inhibitory antibodies, providing direct evidence that sequence polymorphisms within AMA-1 are responsible for evasion of immune responses that inhibit parasite invasion. We also generated a parasite line that would express a chimeric AMA-1 protein, in which highly polymorphic residues within domain 1 were exchanged. Inhibition assays suggest that these residues are not sufficient for inhibition by invasion-blocking antibodies. This study is the first to use P. falciparum allelic exchange to examine the relationship between genetic diversity and susceptibility to protective antibodies. The findings have important implications for the development of an AMA-1-based malaria vaccine.


Cutting Edge: Bim is required for superantigen-mediated B cell death.
To impair B cell clonal regulation, the microbial virulence factor, protein A of Staphylococcus aureus, can interact with evolutionarily conserved BCR-binding sites to induce a form of Fas-independent activation-associated B cell death that results in selective immune tolerance. We now show that this in vivo death pathway is associated with induction of increased transcript and protein levels of Bim, a BH3-only proapoptotic Bcl-2 family protein, which is inhibited by excess B cell-activating factor. An absolute requirement for Bim was documented, since Bim-deficient B cells were protected from in vivo superantigen-induced death and instead underwent persistent massive supraclonal expansion without functional impairment. These studies characterize a BCR-dependent negative clonal selection pathway that has been co-opted by a common bacterial pathogen to induce selective defects in host immune defenses.


Long-term safety of stimulant medications used to treat children with ADHD.
Attention-deficit/hyperactivity disorder (ADHD) is a common mental health condition that affects children, adolescents, and adults. Because it is a chronic condition and typically requires effective treatment for several years or more, information on the benefits and risks of long-term pharmacotherapy for ADHD is vital to clinicians. This article reviews the emerging literature on the safety of long-term stimulant medications in ADHD-the most commonly prescribed medications for this condition. Common side effects, including cardiovascular effects, growth effects, and tics, are discussed, as well as treatment of children younger than age 6 and evidence of carcinogenic and reproductive effects.


Myceligenerans cantabricum sp. nov., a barotolerant actinobacterium isolated from a deep cold-water coral.
An actinobacterium strain (M-201(T)) was isolated from a deep-sea scleractinian coral (Fam. Caryophillidae) collected at 1500 m depth in the Avilés Canyon in the Cantabrian Sea, Asturias, Spain. Strain M-201(T) grew at pH 6.0-9.0 (optimum pH 7.0), between 4 and 37 °C (optimum 28 °C) and at salinities of 0.5-10.5% (w/v) NaCl (optimum 0.5-3.0%). The peptidoglycan contained the amino acids Lys, Ala, Thr, Glu and one unknown amino acid component, and belonged to type A4α, and the cell-wall sugars are glucose, mannose and galactose. The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, an unknown phosphoglycolipid and seven unknown glycolipids. The predominant menaquinones were MK-9(H4) and MK-9(H6). Major cellular fatty acids were anteiso-C(15 : 0), iso-C(15 : 0) and anteiso-C(17 : 0). The genomic DNA G+C content was 72.4 mol%. The chemotaxonomic properties supported the affiliation of strain M-201(T) to the genus Myceligenerans . Phylogenetic analysis based on 16S rRNA gene sequences revealed that the organism was most closely related to Myceligenerans crystallogenes CD12E2-27(T) (98.2% 16S rRNA gene sequence similarity). However, it had a relatively low DNA-DNA relatedness value with the above strain (48%). The isolate showed antibiotic activity against Escherichia coli , Micrococcus luteus ATCC 14452 and Saccharomyces cerevisiae var. carlsbergensis. To the best of our knowledge, this is the first report of antibiotic production in the genus Myceligenerans . The differences in phenotypic, metabolic, ecological and phylogenetic characteristics justify the proposal of a novel species of the genus Myceligenerans , Myceligenerans cantabricum sp. nov., with M-201(T) ( = CECT 8512(T) = DSM 28392(T)) as the type strain.


Use of sodium hyaluronate and synthetic amino acid precursors of collagen for the symptomatic treatment of mucositis in patients undergoing haematopoietic stem cell transplants.
Oral mucositis (OM) may occur in up to 100% of patients undergoing condition regimen to hematopoietic stem cell transplant (HSCT). From the patient's perspective, OM is one of the most debilitating side effects of transplantation. It is commonly thought that oral hygiene can modify the incidence and severity of oral mucositis, therefore professional oral health care (POHC) is recommended prior to conditioning regimen for HSCT. A new strategy for the treatment of OM is sodium hyaluronate (SH) combined with amino acid precursors of collagen (Aas) (Mucosamin®). SH is a mucoaderent polymer acting as a mechanical barrier and pain reliever. Furthermore, it allows prolonged contact of the product with the mucous membrane. In this study, a total of 68 adult patients due to undergo HSCT for allogenic and autologous transplant were enrolled at the Stem Cell Transplant Unit. The patients were divided into two groups. One group was treated with POHC before HSCT and applications of Mucosamin® during the recovery after transplantation. The second group served as controls, with the usual treatment of Clorexidine 0.20% adopted by the department. After HSCT the same clinician, an expert in oral medicine trained for the clinical trial, evaluated symptoms of the patients' mucositis of both groups every day. The treated patients developed less severe OM, therefore Mucosamin® seems to have a protective role against the more severe phases of mucositis. The maximum OM pain, measured with the VAS scale, was higher in patients who did not use Mucosamin®. In the treated group OM resolved sooner than in the control group.


[Analysis of autopsies in HIV infection].
The analysis of 321 necropsies made in Clinical Infections Hospital N 2 from 1991 to 2001 showed a significant increase in the number of deaths of HIV-infection beginning from 1996. The highest mortality (40%) was registered among males aged 25-34 years. The deceased had a wide spectrum of opportunistic diseases (infections and tumors). The deceased with AIDS most frequently had cytomegaloviral infections (19%), tuberculosis (14%), Kaposi's sarcoma (10%), bacterial pneumonias (8%), toxoplasmosis (7%). A late stage of AIDS was characterized by generalized opportunistic diseases, the presence of several severe infectious diseases and more frequent neoplasms.


Synthesis of nickel-iron hydrogenase in Cupriavidus metallidurans is controlled by metal-dependent silencing and un-silencing of genomic islands.
Cupriavidus metallidurans CH34 is able to grow autotrophically as a hydrogen-oxidizing bacterium and produces nickel-dependent hydrogenases, even under heterotrophic conditions. Loss of its two native plasmids resulted in inability of the resulting strain AE104 to synthesize the hydrogenases and to grow autotrophically in phosphate-poor, Tris-buffered mineral salts medium (TMM). Three of eleven previously identified catabolic genomic islands (CMGIs; Van Houdt et al., 2009), two of which harbor the genes for the membrane-bound (CMGI-2) and the soluble hydrogenase (CMGI-3), were silenced in strain AE104 when cultivated in phosphate-poor TMM, explaining its inability to produce hydrogenases. Production of the soluble hydrogenase from the aut region 1 of CMGI-3, and concomitant autotrophic growth, was recovered when the gene for the zinc importer ZupT was deleted in strain AE104. The transcriptome of the ΔzupT mutant exhibited two up-regulated gene regions compared to its parent strain AE104. Expression of the genes in the aut region 1 increased independently of the presence of added zinc. A second gene region was expressed only under metal starvation conditions. This region encoded a TonB-dependent outer membrane protein, a putative metal chaperone plus paralogs of essential zinc-dependent proteins, indicating the presence of a zinc allocation pathway in C. metallidurans. Thus, expression of the genes for the soluble hydrogenase and the Calvin cycle enzymes on aut region 1 of CMGI-3 of C. metallidurans is under global control and needs efficient ZupT-dependent zinc allocation for a regulatory role, which might be discrimination of nickel.


Current Status of Parkinsonism-Related Adverse Events and Associated Drugs in Korea.
The aim of the study was to explore the current status of drug-induced parkinsonism and drugs possibly related to drug-induced parkinsonism in Korea. We conducted a cross-sectional study using the Korea Adverse Event Reporting System database between July 1, 2010, and June 30, 2015. We identified all adverse event reports associated with parkinsonism. There were 1402 adverse event reports associated with parkinsonism. The number of adverse event reports has increased annually. Among the 1499 drugs associated with parkinsonism, the most common were metoclopramide (49.77%) and paliperidone (16.14%). The major therapeutic groups (the third level of the Anatomical Therapeutic Chemical code) were propulsives (53.87%) and antipsychotics (35.58%). The mean time of onset of parkinsonism was 34.9 days. However, the time of onset of parkinsonism varied by drug, for example, it was 4.6 days for metoclopramide and 37.2 days for paliperidone. Metoclopramide and antipsychotics were reported in most adverse event reports associated with parkinsonism in Korea.


Upregulation of occludin by cytolethal distending toxin facilitates Glaesserella parasuis adhesion to respiratory tract cells.
Virulent Glaesserella parasuis may engender systemic infection characterized by fibrinous polyserositis and pneumonia. G. parasuis causes systemic disease through upper respiratory tract infection, but the mechanism has not been fully characterized. Tight junction (TJ) proteins maintain the integrity and impermeability of the epithelial barriers. In this work, we applied the recombinant cytolethal distending toxin (CDT) holotoxin and cdt-deficient mutants to assess whether CDT interacted with TJ proteins of airway tract cells. Our results indicated that CDT induced the TJ occludin (OCLN) expression in newborn pig tracheal epithelial cells within the first 3 hours of bacterial infection, followed by a significant decrease. Overexpression of OCLN in target cells made them more susceptible to G. parasuis adhesion, whereas ablation of OCLN expression by CRISPR/Cas 9 gene editing technology in target cells decreased their susceptibility to bacterial adhesion. In addition, CDT treatment could upregulate the OCLN levels in the lung tissue of C57/BL6 mice. In summary, highly virulent G. parasuis strain SC1401 stimulated the tight junction expression, resulting in higher bacterial adhesion to respiratory tract cells, and this process is closely related to CDT. Our results may provide novel insights into G. parasuis infection and CDT-mediated pathogenesis.


Association between BACH2 expression and clinical prognosis in diffuse large B-cell lymphoma.
BACH2, a B cell-specific transcriptional repressor, plays a significant role in B cell maturation. Despite a number of previous studies, the clinicopathological significance of BACH2 expression in diffuse large B cell lymphoma (DLBCL) remains to be established. The present study was performed to validate the significance of BACH2 expression as a predictor of prognosis in DLBCL. A total of 94 DLBCL cases were included in the present study. All were diagnosed between 2008 and 2011, and thorough clinical and pathological investigations were possible, including immunohistochemical analysis of BACH2. Eighteen cases were selected by positive MYC gene alteration (MYC+ group) according to cytogenetic study. The remaining 76 cases were subclassified into germinal center B cell phenotype (GCB group, 38 cases) or non-GCB phenotype (non-GCB group, 38 cases). There were no significant differences between the two groups with regard to clinical characteristics and outcomes. In the GCB group, 21 cases were judged to have high BACH2 expression, with 19 cases in the non-GCB group. In cases with high BACH2 expression in GCB and non-GCB groups, the 3-year overall survival (OS) rate was significantly shorter than that with low expression (71.7% vs 91.3%, P = 0.0256). In the MYC+ group, 15 cases had high BACH2 expression levels. Although overall the MYC+ group showed short survival time (3-year OS 35.0%), 3 out of 4 cases with low BACH2 expression are alive without disease relapse at the time of publication of this paper. In conclusion, BACH2 expression level is a promising predictor of prognosis for DLBCL.


Liver glucose-6-phosphatase activity is not modulated by physiological intracellular Ca2+ concentrations.
1. In the presence of MgATP and increasing amounts of added Ca2+, isolated liver microsomal vesicles accumulate approx. 10 nmol of Ca2+/mg of protein and buffer ambient free Ca2+ at increasing concentrations (0.22-10.9 microM). Under these experimental conditions, microsomal glucose-6-phosphatase activity is unaffected by the concentration of extravesicular free Ca2+. 2. Different levels of intravesicular Ca2+ were obtained by treating microsomes with the Ca2+ ionophore A23187 and by stimulating active microsomal Ca2+ accumulation with Pi (3 mM). In both instances, microsomal glucose-6-phosphatase activity is unaffected by the level of intravesicular Ca2+.


Central nervous system toxicity following the administration of levobupivacaine for lumbar plexus block: A report of two cases.
Central nervous system and cardiac toxicity following the administration of local anesthetics is a recognized complication of regional anesthesia. Levobupivacaine, the pure S(-) enantiomer of bupivacaine, was developed to improve the cardiac safety profile of bupivacaine. We describe 2 cases of grand mal seizures following accidental intravascular injection of levobupivacaine. Two patients presenting for elective orthopedic surgery of the lower limb underwent blockade of the lumbar plexus via the posterior approach. Immediately after the administration of levobupivacaine 0.5% with epinephrine 2.5 microgram/mL, the patients developed grand mal seizures, despite negative aspiration for blood and no clinical signs of intravenous epinephrine administration. The seizures were successfully treated with sodium thiopental in addition to succinylcholine in 1 patient. Neither patient developed signs of cardiovascular toxicity. Both patients were treated preoperatively with beta-adrenergic antagonist medications, which may have masked the cardiovascular signs of the unintentional intravascular administration of levobupivacaine with epinephrine. Although levobupivacaine may have a safer cardiac toxicity profile than racemic bupivacaine, if adequate amounts of levobupivacaine reach the circulation, it will result in convulsions. Plasma concentrations sufficient to result in central nervous system toxicity did not produce manifestations of cardiac toxicity in these 2 patients.


Trade policy and obesity prevention: challenges and innovation in the Pacific Islands.
The Pacific Island countries experience some of the highest rates of obesity in the world in part due to substantial dietary changes that mirror changes in the food supply in the region. Economic and political ties, donor aid, and trade links are key drivers of the changing availability and accessibility of processed and imported foods. Pacific Island countries have been innovative in developing trade-related policy approaches to create a less obesogenic food environment. Taxation-based approaches that affect pricing in the region include increased import and excise tariffs on sugared beverages and other high-sugar products, monosodium glutamate, and palm oil and lowered tariffs on fruits and vegetables. Other approaches highlight some higher-fat products through labeling and controlling the supply of high-fat meats. The bans on high-fat turkey tails and mutton flaps highlight the politics, trade agreements and donor influences that can be significant barriers to the pursuit of policy options. Countries that are not signatories to trade agreements may have more policy space for innovative action. However, potential effectiveness and practicality require consideration. The health sector's active engagement in the negotiation of trade agreements is a key way to support healthier trade in the region.


Binary asteroids: evidence for their existence from lightcurves.
The lightcurves of the asteroids 49 Pales and 171 Ophelia bear a striking resemblance to those of eclipsing binary stars. This evidence suggests that these asteroids are binary objects. Asteroids belonging to the Themis dynamical family have unusual lightcurves, possibly due to satellite events; these unusual lightcurves suggest that multiple objects may be formed during the disruption of asteroids in collisional events.


Mental Health Problems Among Whistleblowers: A Comparative Study.
Whistleblowers play a very important and indispensable role in society and health care sector, but their act may elicit retaliation and other negative effects, which may impact their mental health. The main aim of the present comparative study is to assess to what extent whistleblowers ( N = 27) more often suffer from severe mental health problems than other population-based groups in the Netherlands, i.e., matched controls ( N = 135), cancer patients ( N = 130), persons with (partial) work disabilities ( N = 194), physically "healthy" persons ( N = 200), and general population ( N = 1026), using the 36-Item Short-Form Health Survey scales (for general mental health) and the Symptom Checklist-90-Revised scales (for specific mental health problems: depression, anxiety, agoraphobia, interpersonal sensitivity and distrust, and sleeping problems). Logistic regression analyses showed that the prevalence of general mental health problems was much higher than among matched controls and people with work disabilities but similar to cancer patient when controlling for demographics. About 85% suffered from severe to very severe anxiety, depression, interpersonal sensitivity and distrust, agoraphobia symptoms, and/or sleeping problems, and 48% reached clinical levels of these specific mental health problems. These specific mental health problems were much more prevalent than among the general population.


Replacement of refined sugar by natural sweeteners: focus on potential health benefits.
Refined sugar is a processed product containing 99% sucrose, which is obtained from sugarcane (70%) or sugar beet (30%). In modern societies, sugar continues to play a significant role in the diet, recognised not only for its flavour and special sweetening properties but also for its role in food preservation. On the other hand, a high consumption of refined sugar is associated with non-communicable diseases and many health issues such as a high risk of dental caries, overweight and neurodevelopmental disorders in children. Alternatives like unrefined sugars have generated a lot of interest as a healthy substitute due to their nutraceutical properties. This paper is aimed to review the beneficial effects of sugar derived from natural sources and highlight health problems that could be caused by refined processed sugar. Refined sugar is frequently used in variety of items including processed foods, soft drinks or ice creams although it is considered unhealthy due to its high salt and sugar content as well as added fats and artificial coloring. Natural sugars are preferred because they have a high nutritional value and a high concentration of healthy compounds, which offset the negative effects of refined sugar. Therefore, removing refined sugar or at least reducing its consumption should be promoted as a healthier option in food choices.


Laser capture microdissection after γ-glutamyl transferase histochemistry: an optimization for gene expression analysis.
γ-Glutamyl transferase (GGT) is useful as a marker in pathological conditions, including several types of cancer. We optimized the histochemical detection of GGT to assay the gene expression profiles of phenotype-specific cells selected by laser capture microdissection (LCM). For optimization, we used the livers of rats subjected to hepatocarcinogenesis. This model induced nodules of hepatocytes and tumors with GGT activity. To obtain sufficient high-quality RNA after histochemistry and LCM, we included an RNase inhibitor and air-dried the tissue sections. This optimization allowed the visualization of GGT activity in situ and a yield of 1.4 to 2.0 μg of total RNA from 15 to 18 mm² of microdissected tissue (20 µm thickness). The average RNA integrity number in GGT-positive tissue, determined by chip-capillary electrophoresis, was 6.9, and the 28S/18S ribosomal RNA (rRNA) ratio was 1.4. The RNAs were processed for the Rat Gene 1.0 ST Array (Affymetrix). Comparable quality control metrics, such as signal intensity and RNA degradation plots, were found between the LCM samples and non-LCM tissue. The increased expression of Ggt1 expected in GGT-positive tissue was confirmed by microarrays and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). This optimization provided a suitable method for whole-transcript analysis of GGT-positive tissue isolated using LCM.


[Pain and treatment of pain in patients with AIDS].
Published articles report that 50-97% of patients with AIDS experience pain. The aim of the study was to determine the incidence and characteristics of pain connected with AIDS, to register pain treatment and patients' evaluation of such treatment. Ninety-five patients with AIDS underwent a semistructured interview. The overall incidence of AIDS-related pain was found to be 74%. Fifty-two percent of the patients experienced pain every day or constantly to a degree described as "some or severe". Thirty-one percent of the patients had a pain duration of more than three months and 25% of the patients were never free from pain. Eleven percent received medical pain treatment on a steady hourly basis. Despite these results, the majority of the patients were satisfied with the treatment and only three percent stated that they were not satisfied. It is concluded that patients with AIDS have a higher incidence of pain, which appears to be undertreated. The reason for this undertreatment is multifactorial. The patients appear to be very reluctant to receive medical pain treatment.


Biomechanics of haemostasis and thrombosis in health and disease: from the macro- to molecular scale.
Although the processes of haemostasis and thrombosis have been studied extensively in the past several decades, much of the effort has been spent characterizing the biological and biochemical aspects of clotting. More recently, researchers have discovered that the function and physiology of blood cells and plasma proteins relevant in haematologic processes are mechanically, as well as biologically, regulated. This is not entirely surprising considering the extremely dynamic fluidic environment that these blood components exist in. Other cells in the body such as fibroblasts and endothelial cells have been found to biologically respond to their physical and mechanical environments, affecting aspects of cellular physiology as diverse as cytoskeletal architecture to gene expression to alterations of vital signalling pathways. In the circulation, blood cells and plasma proteins are constantly exposed to forces while they, in turn, also exert forces to regulate clot formation. These mechanical factors lead to biochemical and biomechanical changes on the macro- to molecular scale. Likewise, biochemical and biomechanical alterations in the microenvironment can ultimately impact the mechanical regulation of clot formation. The ways in which these factors all balance each other can be the difference between haemostasis and thrombosis. Here, we review how the biomechanics of blood cells intimately interact with the cellular and molecular biology to regulate haemostasis and thrombosis in the context of health and disease from the macro- to molecular scale. We will also show how these biomechanical forces in the context of haemostasis and thrombosis have been replicated or measured in vitro.


Methylprednisolone induces preferential and rapid differentiation of CD34+ cord blood precursors toward NK cells.
Previous studies showed that methylprednisolone (MePDN) down-regulates the surface expression of activating NK receptors and sharply inhibits the NK cytotoxicity both in vitro and in vivo. Since MePDN is administered to patients undergoing hemopoietic stem cell transplant to treat acute graft versus host disease (GvHD), we analyzed whether it could also inhibit the NK cell differentiation from CD34(+) hemopoietic cell precursors, thus interfering with the development of effector cells with anti-leukemic potential. We show that MePDN promotes the in vitro differentiation of CD161+CD56+/- immature NK cells by inducing a rapid expression of NKp46, NKG2D, DNAX-accessory molecule 1 (DNAM-1), leukocyte function-associated antigen-1 and NKG2A and an efficient cytolytic activity. This phenotypic and functional NK cell maturation occurred more rapidly than in parallel control cultures performed in the absence of MePDN. In addition, MePDN induced CD33+CD161-CD56- myeloid precursors to switch toward NK cells. It is also of note that immature NK cells when cultured in the absence (but not in the presence) of MePDN produced high amounts of IL-8. These data indicate that MePDN can accelerate the in vitro NK cell differentiation, thus revealing a dichotomous effect on immature versus mature NK cells; in addition, interference with the in vitro development of myeloid cells occurred. These effects should be further investigated in hemopoietic stem cell transplanted patients receiving steroids to treat GvHD.


Human immunodeficiency virus infection and kidney disease.
Since the introduction of highly active antiretroviral therapy (HAART) in 1996, mortality in patients with human immunodeficiency virus (HIV) infection has decreased markedly. As a result, morbidity from other chronic conditions such as kidney, liver and heart disease is increasing. This is in part as a natural consequence of ageing, and in part due to the higher risk of solid organ failure in these individuals. This higher risk is related to the co-morbidities associated with HIV infection and to the metabolic consequences of drug therapy. Kidney disease is an important cause of morbidity and mortality in patients with HIV infection and encompasses a range of clinical presentations including acute kidney injury, chronic kidney disease (CKD), and end-stage kidney disease. Black race is the most important predictor of kidney disease in HIV-infected persons due to both genetic and modifiable causes. HIVassociated nephropathy (HIVAN) is caused by viral infection of the renal epithelium and, although decreasing in incidence, remains the most common cause of CKD in HIV-infected persons. In addition to HIVAN, a wide spectrum of other histopathological presentations, many of which are immune complex-mediated, is increasingly recognised. Clinicians who treat these patients should be aware of the nephrotoxic potential of several commonly used medications, particularly antiviral agents, and also the need to dose-adjust medication in renal impairment. The increased life expectancy of patients with HIV and end-stage kidney disease has meant that kidney transplantation is increasingly an option. Results from carefully conducted prospective studies are promising, at least in the short term.


Successful Transcatheter Arterial Embolisation for a Traumatic Iliacus Hematoma: A Case Report.
A traumatic iliacus hematoma is rare and usually occurs in patients after a fall involving a lower back injury. Although the hematoma may compress the femoral nerve causing femoral nerve palsy, the gold standard treatment for this condition has not been established. Here we report transcatheter arterial embolisation as a useful treatment strategy for a traumatic iliacus hematoma.


Analysis of hydroxylated polybrominated diphenyl ethers in rat plasma by using ultra performance liquid chromatography-tandem mass spectrometry.
Ultra performance liquid chromatography (UPLC) provides improved resolution, speed and sensitivity compared to conventional high performance liquid chromatography (HPLC). In this study, a robust UPLC-ESI-MS/MS method was developed for the rapid determination of nine hydroxylated polybrominated diphenyl ethers (OH-PBDEs) in rat plasma. Under the optimized conditions, the OH-PBDE congeners were eluted within 7.0 min. The limits of quantification defined at the signal-to-noise ratio of 10 were 0.17-2.78 ng/mL in rat plasma. The method provided good linearity for the calibration curves with recoveries of 93.3-114.0% and repeatability with relative standard deviation (RSD) of 0.6-5.8% for intra-day and 3.2-10.4% for inter-day measurements. The developed method was applied for supporting the pharmacokinetics investigation of 6-OH-BDE-47 in two groups of Sprague-Dawley rats that received, respectively a single dose of 0.60 mg/kg (high dose) and 0.15 mg/kg (low dose) by intravenous injection. The results showed that plasma levels of 6-OH-BDE-47 declined bi-exponentially with elimination half-life of 71.7 and 85.6 min for lower and higher dose group, respectively. The obtained results of short elimination half-life suggested that 6-OH-BDE-47 might not accumulate significantly in rat.


Characterization of the Invasive, Multidrug Resistant Non-typhoidal Salmonella Strain D23580 in a Murine Model of Infection.
A distinct pathovar of Salmonella enterica serovar Typhimurium, ST313, has emerged in sub-Saharan Africa as a major cause of fatal bacteremia in young children and HIV-infected adults. D23580, a multidrug resistant clinical isolate of ST313, was previously shown to have undergone genome reduction in a manner that resembles that of the more human-restricted pathogen, Salmonella enterica serovar Typhi. It has since been shown through tissue distribution studies that D23580 is able to establish an invasive infection in chickens. However, it remains unclear whether ST313 can cause lethal disease in a non-human host following a natural course of infection. Herein we report that D23580 causes lethal and invasive disease in a murine model of infection following peroral challenge. The LD50 of D23580 in female BALB/c mice was 4.7 x 10(5) CFU. Tissue distribution studies performed 3 and 5 days post-infection confirmed that D23580 was able to more rapidly colonize the spleen, mesenteric lymph nodes and gall bladder in mice when compared to the well-characterized S. Typhimurium strain SL1344. D23580 exhibited enhanced resistance to acid stress relative to SL1344, which may lend towards increased capability to survive passage through the gastrointestinal tract as well as during its intracellular lifecycle. Interestingly, D23580 also displayed higher swimming motility relative to SL1344, S. Typhi strain Ty2, and the ST313 strain A130. Biochemical tests revealed that D23580 shares many similar metabolic features with SL1344, with several notable differences in the Voges-Proskauer and catalase tests, as well alterations in melibiose, and inositol utilization. These results represent the first full duration infection study using an ST313 strain following the entire natural course of disease progression, and serve as a benchmark for ongoing and future studies into the pathogenesis of D23580.


Record Resolution of Nanometal Surface Energy Transfer Optical Nanoruler Projects 3D Spatial Configuration of Aptamers on a Living Cell Membrane.
Decrypting the in situ three-dimensional spatial configuration of an aptamer is of considerable significance; however, suitable nanoscale resolution tools are lacking. Herein, we show that a new nanometal surface energy transfer (NSET) optical nanoruler has a record resolution, down to single-nucleobase levels. We labeled fluorophores on different T bases of XQ-2d, including 5', 3', 6T, 22T, 38T, and 52T positions. The NSET nanoruler in situ decrypted the base sequence-dependent distance projection on the nanogold surface, demonstrating that 5', 3', stem, and loop structures are symmetrical in three-dimensional spatial configuration. The orientation of the 5' and 3' stem was toward the antiCD71-binding site, whereas the loop was in the opposite direction at a considerable distance. Molecular docking simulation was performed to list all of the possible conformations; however, all base distance parameters projecting on the nanogold surface determined a single conformation of XQ-2d. The specific binding sites of XQ-2d were Lys477, Ser691, and Arg698 on the CD71 receptor.


Synergistic antimicrobial efficacy of mesoporous ZnO loaded with 4-(α-L-rhamnosyloxy)-benzyl isothiocyanate isolated from the Moringa oleifera seed.
The antimicrobial activities of isolated compounds from seed extracts of Moringa oleifera and synergistic antimicrobial efficacy through hybridized complex of organic-inorganic composite materials were studied. The two main components of the Moringa oleifera seed were isolated and determined to be niazimicin and 4-(α-L-rhamnosyloxy)-benzyl isothiocyanate (RBI). The antimicrobial activity of the separated compounds of the Moringa oleifera seed were tested in vitro against 3 bacterial species and 2 fungal species by the paper disc diffusion assay and broth dilution methods. Both compounds showed antimicrobial activity against tested species and RBI was more effective than niazimicin. The MIC of RBI on S. aureus, E. coli, P. aeruginosa, C. albicans, and A. niger was 0.005%, 0.1%, 0.5%, 0.5%, and 0.5%, respectively, while the MIC of niazimicin on S. aureus was 0.1%. Next, we investigated the combined antimicrobial action of mesoporous ZnO and RBI by incorporating the compound within the pore of mesoporous ZnO. The MIC of mesoporous ZnO with RBI on S. aureus, E. coli, P. aeruginosa, C. albicans, and A. niger was 0.001%, 0.01%, 0.5%, 0.1%, and 0.1%, respectively. A synergistic effect of RBI with mesoporous ZnO was shown. From these results, the mesoporous ZnO could act as a reservoir for RBI and mesoporous ZnO with RBI could be used for cosmetic preservatives.


Clinical Benefit Derived from Decitabine Therapy for Advanced Phases of Myeloproliferative Neoplasms.
Treatment options are limited for patients with advanced forms of myeloproliferative neoplasms (MPN) including blast-phase disease (MPN-BP). Decitabine has frequently been deployed but its efficacy and safety profile are not well described in this population. We retrospectively reviewed 42 patients treated with decitabine either alone or in combination with ruxolitinib at our institution: 16 with MPN-BP, 14 with MPN accelerated-phase (MPN-AP), and 12 with myelofibrosis with high-risk features (MF-HR). The median overall survival (OS) for the MPN-BP patients was 2.6 months, and for those who received ≥2 cycles of decitabine therapy, it was 6.7 months (3.8-29.8). MPN-BP patients with a poor performance status and who required hospitalization at the time of the initiation of decitabine had a dismal prognosis. After a median follow-up of 12.4 months for MPN-AP patients, and 38.7 months for MF-HR patients, the median OS was not reached for either cohort, with 1 and 2 patients alive at 60 months, respectively. The probability of spleen length reduction and transfusion independence within 12 months of initiating decitabine was 28.6 and 23.5%, respectively. The combination of decitabine and ruxolitinib appeared to improve overall survival versus single-agent decitabine (21 and 12.9 months, respectively). Decitabine, alone or in combination with ruxolitinib, appears to have clinical benefit for patients with advanced phases of MPN when initiated early in the disease course prior to the development of MPN-BP.


Protective effect of cinnamon against acetaminophen-mediated cellular damage and apoptosis in renal tissue.
Acetaminophen, APAP, is a common over-the-counter drug with antipyretic-analgesic action. When APAP is used in large doses, it causes hepatotoxicity and nephrotoxicity but safe at therapeutic doses. Cinnamon (Cinnamomum zeylanicum) is extensively used in folk medicine due to its high content of natural antioxidants. The current investigation was planned to study the possible ameliorative effect of cinnamon toward induced APAP-apoptosis and cellular damage in renal cells. Four groups (nine rats each) were used; negative control group administrated distilled water for 15 days; positive control APAP group administrated a single dose of APAP (1 g/kg) orally on the last day; APAP+Cin L (200 mg/kg) and APAP+Cin H (400 mg/kg) aqueous extract of cinnamon orally once a day for 15 days. An hour after the last dose of cinnamon, all rats in the third and fourth group were administrated a single dose of APAP (1 g/kg) orally. GC/MS analysis was performed to identify the plant used in the study. APAP markedly increased serum levels of creatinine, BUN, and glucose and decreased levels of albumin and total protein. In addition, APAP could also exert severe alteration in the kidney histopathology along with upregulation of caspase-3 and PCNA. However, pre-treatment with cinnamon ameliorated the APAP-induced cellular alterations and apoptosis, possibly through its high content of antioxidants.