Electronic spectroscopy of gemcitabine and derivatives for possible dual-action photodynamic therapy applications.
In this paper, we explore the molecular basis of combining photodynamic therapy (PDT), a light-triggered targeted anticancer therapy, with the traditional chemotherapeutic properties of the well-known cytotoxic agent gemcitabine. A photosensitizer prerequisite is significant absorption of biocompatible light in the visible/near IR range, ideally between 600 and 1000 nm. We use highly accurate multiconfigurational CASSCF/MS-CASPT2/MM and TD-DFT methodologies to determine the absorption properties of a series of gemcitabine derivatives with the goal of red-shifting the UV absorption band toward the visible region and facilitating triplet state population. The choice of the substitutions and, thus, the rational design is based on important biochemical criteria and on derivatives whose synthesis is reported in the literature. The modifications tackled in this paper consist of: (i) substitution of the oxygen atom at O2 position with heavier atoms (O → S and O → Se) to red shift the absorption band and increase the spin-orbit coupling, (ii) addition of a lipophilic chain at the N7 position to enhance transport into cancer cells and slow down gemcitabine metabolism, and (iii) attachment of aromatic systems at C5 position to enhance red shift further. Results indicate that the combination of these three chemical modifications markedly shifts the absorption spectrum toward the 500 nm region and beyond and drastically increases spin-orbit coupling values, two key PDT requirements. The obtained theoretical predictions encourage biological studies to further develop this anticancer approach.


Improving primary health care delivery in Bihar, India: Learning from piloting and statewide scale-up of Ananya.
In 2010, the Bill and Melinda Gates Foundation (BMGF) partnered with the Government of Bihar (GoB), India to launch the Ananya program to improve reproductive, maternal, newborn and child health and nutrition (RMNCHN) outcomes. The program sought to address supply- and demand-side barriers to the adoption, coverage, quality, equity and health impact of select RMNCHN interventions. Approaches included strengthening frontline worker service delivery; social and behavior change communications; layering of health, nutrition and sanitation into women's self-help groups (SHGs); and quality improvement in maternal and newborn care at primary health care facilities. Ananya program interventions were piloted in approximately 28 million population in eight innovation districts from 2011-2013, and then beginning in 2014, were scaled up by the GoB across the rest of the state's population of 104 million. A Bihar Technical Support Program provided techno-managerial support to governmental Health as well as Integrated Child Development Services, and the JEEViKA Technical Support Program supported health layering and scale-up of the GoB's SHG program. The level of support at the block level during statewide scale-up in 2014 onwards was approximately one-fourth that provided in the pilot phase of Ananya in 2011-2013. This paper - the first manuscript in an 11-manuscript and 2-viewpoint collection on Learning from Ananya: Lessons for primary health care performance improvement - seeks to provide a broad description of Ananya and subsequent statewide adaptation and scale-up, and capture the background and context, key objectives, interventions, delivery approaches and evaluation methods of this expansive program. Subsequent papers in this collection focus on specific intervention delivery platforms. For the analyses in this series, Stanford University held key informant interviews and worked with the technical support and evaluation grantees of the Ananya program, as well as leadership from the India Country Office of the BMGF, to analyse and synthesise data from multiple sources. Capturing lessons from the Ananya pilot program and statewide scale-up will assist program managers and policymakers to more effectively design and implement RMNCHN programs at scale through technical assistance to governments.


Catalase overexpression fails to attenuate allergic airways disease in the mouse.
Oxidative stress is a hallmark of asthma, and increased levels of oxidants are considered markers of the inflammatory process. Most studies to date addressing the role of oxidants in the etiology of asthma were based on the therapeutic administration of low m.w. antioxidants or antioxidant mimetic compounds. To directly address the function of endogenous hydrogen peroxide in the pathophysiology of allergic airway disease, we comparatively evaluated mice systemically overexpressing catalase, a major antioxidant enzyme that detoxifies hydrogen peroxide, and C57BL/6 strain matched controls in the OVA model of allergic airways disease. Catalase transgenic mice had 8-fold increases in catalase activity in lung tissue, and had lowered DCF oxidation in tracheal epithelial cells, compared with C57BL/6 controls. Despite these differences, both strains showed similar increases in OVA-specific IgE, IgG1, and IgG2a levels, comparable airway and tissue inflammation, and identical increases in procollagen 1 mRNA expression, following sensitization and challenge with OVA. Unexpectedly, mRNA expression of MUC5AC and CLCA3 genes were enhanced in catalase transgenic mice, compared with C57BL/6 mice subjected to Ag. Furthermore, when compared with control mice, catalase overexpression increased airway hyperresponsiveness to methacholine both in naive mice as well as in response to Ag. In contrast to the prevailing notion that hydrogen peroxide is positively associated with the etiology of allergic airways disease, the current findings suggest that endogenous hydrogen peroxide serves a role in suppressing both mucus production and airway hyperresponsiveness.


Cloning of a gene encoding a DNA polymerase-exonuclease of Streptococcus pneumoniae.
A procedure was developed for cloning and characterizing genes that encode proteins with nuclease activity in the Streptococcus pneumoniae [pLS1] host/vector system. Clones are screened for nuclease activity by a DNase colony assay and the nucleases that they produce are characterized by detection of enzyme activity after sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The method was used to clone the gene encoding a DNA polymerase (Pol)-exonuclease of S. pneumoniae. The activity of this enzyme, the predominant DNA Pol of S. pneumoniae, is tenfold greater in cells carrying the multicopy recombinant plasmid than in cells without the plasmid. The enzyme corresponds to a 100-kDa polypeptide, and its properties are similar to PolI of Escherichia coli. A restriction map of the pSM22 plasmid containing the pneumococcal polA gene was obtained. The gene was transferred into Bacillus subtilis and E. coli, and it was expressed in both species. Its direction of transcription was determined by placement of the gene in both orientations in an E. coli hyperexpression plasmid. In one of the orientations the pneumococcal PolI enzyme was produced at a level 50-fold greater than normally found in S. pneumoniae, and it comprised 5% of the total protein.


[Paraneoplastic neurologic syndromes: laboratory diagnostics and immunological aspects].
Paraneoplastic neurologic syndromes (PNS) and autoimmune encephalitis (AE) are rare neurological disorders, which have similar symptoms, but vary in outcome and treatment strategy. In our retrospective statistical study we evaluated the autoantibody test results of serum and CSF from 2362 patients with suspected PNS and 1034 patients with suspected AE. For autoantibody testing, immunoblot assay (PNS) and cell-based indirect immunofluorescence assay (AE) were used. Autoantibodies were present in 8% of patients with suspected PNS: anti-Yo > anti-Hu > anti-Ma2 > anti-CV2 > anti-titin > anti-Zic4 > anti-amphiphysin > anti-Ri > anti-GAD65 > anti-Sox1 > anti-recoverin. Mostly elderly women were affected. Autoantibodies were present in 5.8% of patients with suspected AE: anti-NMDAR (young women) > anti-LGI1 (middle-aged men) > anti-GABABR (elderly men) > anti-Caspr2 (adult men). Our results correspond to the data described in the literature. The number of patients with suspected PNS and AE shows an increasing tendency, where the autoantibody testing with modern laboratory diagnostic methods helps in the early introduction of the appropriate therapy.


Light-controlled tools.
Spatial and temporal control over chemical and biological processes plays a key role in life, where the whole is often much more than the sum of its parts. Quite trivially, the molecules of a cell do not form a living system if they are only arranged in a random fashion. If we want to understand these relationships and especially the problems arising from malfunction, tools are necessary that allow us to design sophisticated experiments that address these questions. Highly valuable in this respect are external triggers that enable us to precisely determine where, when, and to what extent a process is started or stopped. Light is an ideal external trigger: It is highly selective and if applied correctly also harmless. It can be generated and manipulated with well-established techniques, and many ways exist to apply light to living systems--from cells to higher organisms. This Review will focus on developments over the last six years and includes discussions on the underlying technologies as well as their applications.


Evidence for sub-haplogroup h5 of mitochondrial DNA as a risk factor for late onset Alzheimer's disease.
Alzheimer's Disease (AD) is the most common neurodegenerative disease and the leading cause of dementia among senile subjects. It has been proposed that AD can be caused by defects in mitochondrial oxidative phosphorylation. Given the fundamental contribution of the mitochondrial genome (mtDNA) for the respiratory chain, there have been a number of studies investigating the association between mtDNA inherited variants and multifactorial diseases, however no general consensus has been reached yet on the correlation between mtDNA haplogroups and AD. We applied for the first time a high resolution analysis (sequencing of displacement loop and restriction analysis of specific markers in the coding region of mtDNA) to investigate the possible association between mtDNA-inherited sequence variation and AD in 936 AD patients and 776 cognitively assessed normal controls from central and northern Italy. Among over 40 mtDNA sub-haplogroups analysed, we found that sub-haplogroup H5 is a risk factor for AD (OR=1.85, 95% CI:1.04-3.23) in particular for females (OR=2.19, 95% CI:1.06-4.51) and independently from the APOE genotype. Multivariate logistic regression revealed an interaction between H5 and age. When the whole sample is considered, the H5a subgroup of molecules, harboring the 4336 transition in the tRNAGln gene, already associated to AD in early studies, was about threefold more represented in AD patients than in controls (2.0% vs 0.8%; p=0.031), and it might account for the increased frequency of H5 in AD patients (4.2% vs 2.3%). The complete re-sequencing of the 56 mtDNAs belonging to H5 revealed that AD patients showed a trend towards a higher number (p=0.052) of sporadic mutations in tRNA and rRNA genes when compared with controls. Our results indicate that high resolution analysis of inherited mtDNA sequence variation can help in identifying both ancient polymorphisms defining sub-haplogroups and the accumulation of sporadic mutations associated with complex traits such as AD.


Implementation and quantitative evaluation of analytical methods for attenuation correction in SPECT: a phantom study.
Three differing exact methods of inverting the two-dimensional (2D) exponential Radon transform were implemented and evaluated quantitatively with a phantom study. The phantom had the shape of a pie-chart divided into six cavities, each 480 ml in volume and 10 cm in height, that were symmetrically positioned in a cylinder that was 20 cm in diameter and 10 cm in height. This phantom tests for linearity between true activity concentration and measured activity concentration, and it is denoted as a linearity phantom in the present study. Each cavity contained a different concentration of a homogeneous solution of 99mTc (74, 148, 222, 296, 370 and 444 kBq ml(-1)). Data acquisition was performed with two energy windows: a 20% photopeak energy window set symmetrically over the 140 keV of 99mTc and a secondary 5% energy window set over the 122 keV peak. We optimized a triple-energy window scatter correction method for a gamma camera-collimator system to obtain accurate scatter-corrected projections. A circular ROI 3 cm in diameter was identified over each cavity region, and count density (counts per pixel) was calculated. This value was converted to activity concentration (kBq ml(-1)) using a cross-calibration coefficient between SPECT counts and the gamma well counter. The relation between true activity (x) and measured activity concentration (y) was fitted to a line using the least-squares method. Regression lines were y = 0.63 + 1.0255x (R2 = 0.9987), y = -2.62 + 1.0278x (R2 = 0.9995), and y = 0.092 + 1.0241x (R2 = 0.9989) for the Bellini, Inouye and Metz-Pan methods respectively. In another phantom study using two different types of phantoms, contrast of a cold region in the two was 96% and 101% for all three methods. Combined optimized scatter correction and analytical attenuation correction methods achieve good accuracy in quantification of activity distribution with a uniform attenuating medium.


In vitro activation of specific helper and suppressor T cells by the type 2 antigen polyvinylpyrrolidone (PVP).
Although type 2 antigens, such as PVP, generally do not activate specific TH, previous studies have established that low doses of PVP (0.0025 microgram) can activate TH in vivo which provide help in primed B cells for PVP-specific IgG responses. Doses of PVP that are optimally immunogenic for IgM antibody production (0.25 to 25 micrograms) preferentially activate PVP-specific TS, which suppress IgG antibody production. In the studies reported here, TH and TS that regulate PVP-specific IgG antibody responses were activated in vitro by culturing normal spleen cells for 4 days with PVP. Induction of the TH and TS is dependent upon the amount of PVP in culture: 10(-4) micrograms PVP activates TH, whereas 10(-2) micrograms PVP preferentially activates TS. TH induced in vitro express Thy-1, L3T4, and I-A determinants and help provided by these TH is similar in magnitude to that provided by TH from mice primed with 0.0025 microgram PVP in vivo. TH can also be activated in vitro if donor mice are treated with Cy before culture of their spleen cells with 10(-2) micrograms PVP. Cy pretreatment prevents TS activation, and TH are then induced in these cultures. The presence of TS does not prevent activation of TH by 10(-2) micrograms PVP, because removal of TS by treatment of T cells with anti-Lyt-2 + complement at the end of culture uncovers TH activity. This TH activity is comparable with that of TH obtained after culture with 10(-4) micrograms PVP. The ability to activate PVP-specific TH and TS in vitro should allow determination of the mechanisms involved in activation of T cells by type 2 antigens and the mechanisms by which TS and TH interact with one another.


CAR-macrophage versus CAR-T for solid tumors: The race between a rising star and a superstar.
Adoptive cell therapy (ACT) has been demonstrated to be one of the most promising cancer immunotherapy strategies due to its active antitumor capabilities in vivo. Engineering T cells to overexpress chimeric antigen receptors (CARs), for example, has shown potent efficacy in the therapy of some hematologic malignancies. However, the efficacy of chimeric antigen receptor T cell (CAR-T) therapy against solid tumors is still limited due to the immunosuppressive tumor microenvironment (TME) of solid tumors, difficulty in infiltrating tumor sites, lack of tumor-specific antigens, antigen escape, and severe side effects. In contrast, macrophages expressing CARs (CAR-macrophages) have emerged as another promising candidate in immunotherapy, particularly for solid tumors. Now at its nascent stage (with only one clinical trial progressing), CAR-macrophage still shows inspiring potential advantages over CAR-T in treating solid tumors, including more abundant antitumor mechanisms and better infiltration into tumors. In this review, we discuss the relationships and differences between CAR-T and CAR-macrophage therapies in terms of their CAR structures, antitumor mechanisms, challenges faced in treating solid tumors, and insights gleaned from clinical trials and practice for solid tumors. We especially highlight the potential advantages of CAR-macrophage therapy over CAR-T for solid tumors. Understanding these relationships and differences provides new insight into possible optimization strategies of both these two therapies in solid tumor treatment.


The Role of Bystanders in the Prevention of Railway Suicides in New South Wales, Australia.
Background: Bystanders can play a key role in preventing railway suicides by taking direct action or by raising an alarm. Aims: The study investigated in this context: (1) the prevalence of preventative actions by bystanders; (2) the relationship, if any, between first-hand preventions by bystanders and the degree of ambiguity around the imminence of danger; and (3) the nature of first-hand preventions by bystanders. Method: Data were obtained from a security reporting database at Sydney Trains for 2011-2019 for accident and suicide-related incidents (N = 1,278). Results: In 635 cases of suicide prevention, bystanders were identified as first responders in 11% of cases and as raising the alarm in 11% of cases. Bystanders as first responders intervened proportionally more where the ambiguity of danger is low (jumping) compared with high (sitting, standing, wandering). Of the 69 cases of bystander preventions, 77% involved physical interaction (e.g., holding back) and 49% involved more than one bystander. Limitations: The data source could be biased because of incompleteness or nonstandard reporting. Conclusion: Rail policy-makers should consider education and support for bystanders and staff: for example, by making known the prevalence of helping, the importance of intervening, and what types of intervention are most helpful.


Problems, diseases and diagnoses: a personal view.
Diseases and diagnoses are familiar words in the veterinary vocabulary and we seldom give much thought as to how we use them; we are more concerned about the practical problems they imply. However, there are occasions when it is essential that we use familiar words and concepts in a way that leaves no doubt as to the logical implications of our statements. The growing interest in surveys, monitoring and the use of computerised systems for epidemiological purposes points to the need for this discipline. In order to air the matter this paper presents some personal opinions that were based on Scadding (1967) and subsequently moulded by experience when designing a computerised data bank.


cis-Acting site controlling bidirectional transcription at the growth-differentiation transition in Dictyostelium discoideum.
A pair of adjacent genes, impA and dia1, are divergently transcribed but expressed at different stages in the life cycle of Dictyostelium discoideum. The intervening 654-bp region carries cis-acting regions that are essential for transcription in both directions as well as repression of dia1 in growing cells. We have focused on a 112-bp region proximal to dia1 that is essential for bidirectional transcription. Analyses of a set of internal deletions showed that the sequence between positions 80 and 97 (TTTGAATTTTTTGAATTT) is critical and that bases outside this region are dispensable. Site-directed mutations within this critical region confirmed the importance of this sequence for transcription both to the right and to the left. However, insertions of either 6 or 24 Ts into the run of 6 Ts separating the repeated GAA sequence had little effect on the functioning of the site in either direction, suggesting that factors recognize the half-sites TTGAATT separately. Inversion of the bases between positions 80 and 97 greatly reduced expression in both directions, indicating that orientation is critical for expression of both the nearby impA gene and the distal dia1 gene, which is more than 500 bp away. Comparison of 38 mutant constructs with multiple random variations in the region indicated that transcription factors may bind to a range of related sequences and still retain function. All functional constructs directed transcription both leftward and rightward, while all nonfunctional constructs were impaired for transcription in both directions. It appears that the same transcription complex controls transcription of both impA and dia1.


Dinosaur extinction researcher guilty of research misconduct.
But Robert DePalma did not commit fraud in paper claiming asteroid hit in springtime, university report finds.


Composite Pheochromocytoma/Paraganglioma-Ganglioneuroma: A Clinicopathologic Study of Eight Cases with Analysis of Succinate Dehydrogenase.
Ganglioneuromas represent the most well-differentiated spectrum of neoplasia arising from the sympathetic nervous system, while neuroblastomas represent the most poorly differentiated counterpart, and ganglioneuroblastomas represent intermediate stages of differentiation. Small series of cases have documented the co-occurrence of ganglioneuroma with a pheochromocytoma (Pheo)/paraganglioma (PGL) component. We report the clinicopathologic features of eight such cases, diagnosed between 2003 and 2015 with a mean follow-up of 22 months (1-47), which were evaluated for syndrome associations, SDHB expression, and clinical outcome. Mutations of the succinate dehydrogenase (SDH) complex subunits (A, B, C, D, and SDHAF2) have been implicated in predicting metastatic behavior and in identifying possible paraganglioma syndromes. The proliferative index was calculated by manual quantification of Ki-67-positive cells at selected hot-spots using ImageJ (NIH). In our series, composite Pheo/PGL-ganglioneuromas predominantly involved the adrenal gland (Pheo 7, PGL 1). The cases had an equal gender distribution (males 4, females 4), with a mean age at diagnosis of 67 years (range 53 to 86 years), an average size of 5.2 cm (range 2 to 8.2 cm), an average weight of 49.3 g (7.8 to 144.7 g, n = 6), and the majority were functionally active (7 of 8, 88%). The mean Ki67 proliferation rate was 2% (range 0.3 to 3%), and all cases retained SDHB expression (8/8, 100%). No patient (0/8, 0%) developed metastatic disease on follow-up. One patient had a retroperitoneal composite PGL-ganglioneuroma in the setting of neurofibromatosis type 1. No recurrent disease or other associations were identified. In our study, composite Pheo/PGL-ganglioneuromas predominantly affected the adrenal gland in older patients, showed no loss of SDHB, and no disease recurrence was identified.


Abnormal beta-endorphin and beta-lipotropin responses to TRH and LRH administration in primary and secondary affective disorders.
Anomalous anterior pituitary hormone responses to acute administration of TRH and LRH have previously been observed in patients with primary affective disorders (PAD), with TRH eliciting GH, FSH and LH rises, and LRH eliciting GH and Prl rises. We examined whether the same unusual responses were present also for beta-endorphin (beta-EP) and beta-lipotropin (beta-LPH) in 15 PAD patients, in 9 patients with secondary affective disorders (SAD), and in 7 controls. TRH (500 micrograms iv) elicited rises of beta-EP plasma levels in 5 PAD and 2 SAD patients, and of beta-LPH in 4 PAD and 3 SAD patients. LRH (150 micrograms iv) elicited rises of plasma beta-EP levels in 2 PAD and 2 SAD patients, and of beta-LPH in 5 PAD and 2 SAD patients. No rises of beta-EP and beta-LPH plasma levels were observed in PAD patients after saline administration, nor in the controls after TRH, LRH or saline administration.


Microsoft Word macro for analysis of cytosine methylation by the bisulfite deamination reaction.
Cytosine methylation at CpG dinucleotides is an important control mechanism in development, differentiation, and neoplasia. Bisulfite genomic sequencing and its modifications have been developed to examine methylation at these CpG dinucleotides. To use these methods, one has to (i) manually convert the sequence to that produced by bisulfite conversion and PCR amplification, taking into account that cytosine residues at CpG dinucleotides may or may not be converted depending on their methylation status, (ii) identify relevant restriction sites that may be used for methylation analysis, and (iii) conduct similar steps with the other DNA strand since the two strands of DNA are no longer complementary after bisulfite conversion. To automate these steps, we have developed a macro that can be used with Microsoft Word. This macro (i) converts genomic sequence to modified sequence that would result after bisulfite treatment facilitating primer design for bisulfite genomic sequencing and methylation-sensitive PCR assay and (ii) identifies restriction sites that are preserved in bisulfite-converted and PCR-amplified product only if cytosine residues at relevant CpG dinucleotides are methylated (and thereby not converted to uracil) in the genomic DNA.


CO2-stimulated NaCl absorption in the mouse renal cortical thick ascending limb of Henle. Evidence for synchronous Na +/H+ and Cl-/HCO3- exchange in apical plasma membranes.
These experiments evaluated salt transport processes in isolated cortical thick limbs of Henle (cTALH) obtained from mouse kidney. When the external solutions consisted of Krebs-Ringer bicarbonate (KRB), pH 7.4, and a 95% O2-5% CO2 gas phase, the spontaneous transepithelial voltage (Ve, mV, lumen-to-bath) was approximately mV; the net rate of Cl- absorption (JnetCl) was approximately 3,600 pmols s-1 cm-2; the net rate of osmotic solute absorption Jnetosm was twice JnetCl; and the net rate of total CO2 transport (JnetCO2) was indistinguishable from zero. Thus, net Cl- absorption was accompanied by the net absorption of a monovalent cation, presumably Na+, and net HCO3- absorption was negligible. This salt transport process was stimulated by (CO2 + HCO3-): omission of CO2 from the gas phase and HCO3- from external solutions reduced JnetCl, Jnetosm, and Ve by 50%. Furthermore, 10(-4) M luminal furosemide abolished JnetCl and Ve entirely. The lipophilic carbonic anhydrase inhibitor ethoxzolamide (10(-4) M, either luminal or peritubular) inhibited (CO2 + HCO3-)-stimulated JnetCl, Jnetosm, and Ve by approximately 50%; however, when the combination (CO2 + HCO3-) was absent, ethoxzolamide had no detectable effect on salt transport. Ve was reduced or abolished entirely by omission of either Na+ or Cl- from external solutions, by peritubular K+ removal, by 10(-3) M peritubular ouabain, and by 10(-4) M luminal SITS. However, Ve was unaffected by 10(-3) M peritubular SITS, or by the hydrophilic carbonic anhydrase inhibitor acetazolamide (2.2 x 10(-4) M, lumen plus bath). We interpret these data to indicate that (CO2 + HCO3-)-stimulated NaCl absorption in the cTALH involved two synchronous apical membrane antiport processes: one exchanging luminal Na+ for cellular H+; and the other exchanging luminal Cl- for cellular HCO3- or OH-, operating in parallel with a (CO2+ HCO3-)-independent apical membrane NaCl cotransport mechanism.


The association of autoimmune thyroid disease (AITD) with psoriatic disease: a prospective cohort study, systematic review and meta-analysis.
Autoimmune thyroid disease (AITD) and psoriatic disease share auto-immunological components. Few studies have investigated the link between both, yielding inconclusive results. We assessed the association of AITD with psoriatic disease in a prospective cohort study and performed a systematic review and meta-analysis. 8214 participants of the Rotterdam Study (RS) with thyroid peroxidase antibodies (TPO-Abs), thyroid-stimulating hormone (TSH) and/or free thyroxine (FT4) measurements and information on psoriatic disease were included. We performed logistic and Cox regression analyses and a systematic literature search in several electronic databases on AITD and psoriatic disease. We pooled odds ratios (ORs) of included studies using the Mantel-Haenszel method, while adding RS data on prevalent psoriatic disease. Within the RS, we found no association between TPO-Ab positivity and psoriatic disease. There was a positive trend between TSH and prevalent psoriatic disease, and between FT4 and incident psoriatic disease, although not significant. Out of 1850 articles identified, seven were included in the systematic review and four in the meta-analysis. The risk of psoriatic disease (pooled OR) was 1.71 (confidence interval (CI): 1.27-2.31) for TPO-Ab positivity, 1.25 (CI: 1.14-1.37) for AITD and 1.34 (CI: 1.16-1.54) respectively, and 1.17 (CI: 1.03-1.32) for hypothyroidism and hyperthyroidism. Our meta-analysis suggests that TPO-Ab positivity, hypothyroidism and hyperthyroidism might be associated with prevalent psoriatic disease. However, there are only few studies with large heterogeneity regarding psoriatic disease definition and indication of publication bias. Additional prospective data are needed to assess the association of AITD with incident psoriatic disease.


Occupational therapy in mother and child health care centers.
This paper describes the results of an infant stimulation program that involved mothers and their infants registered at Mother and Child Health Care centers in Jerusalem. A questionnaire was used to evaluate the mothers' knowledge, attitudes, and practices regarding the developmental needs of their infants. A developmental assessment was used to evaluate the infants' reaching and grasping abilities at 4 months of age. The questionnaire was completed by 175 mothers in the program (the experimental group) and a control group of 124 mothers. The results showed that, despite demographic differences that were likely to positively affect the control group's scores, the experimental group's scores were significantly higher. The results of the developmental assessment administered to 107 infants in the experimental group and 74 infants in the control group also indicated that, on 4 out of 5 reaching and grasping items, the experimental group performed significantly better. This study emphasizes the value of structuring a developmental curriculum for newborn infants and their mothers within an occupational therapy program.


[The Nationwide Survey on Avoidance of Targeted Radionuclide Therapy in Patients with Limited Activities of Daily Living and Those Undergoing Hemodialysis].
Targeted radionuclide therapy with high-dose radioisotopes should be performed in isolation rooms. Patients can be released only after radioactivity remaining in their bodies becomes less than the limits determined by the release criteria in order to secure public protection. Patients are asked to stay in isolation rooms for a few days. Physicians often face difficulties to carry out therapy in patients with limited activities of daily living and those undergoing hemodialysis, and have to avoid therapy in such cases. The Japanese Society of Nuclear Medicine conducted a nationwide survey in order to find out the actual situation. The survey results should reflect future improvement of therapeutic environment in collaborating with related societies and administrative bodies.


Preterm birth-associated cost of early intervention services: an analysis by gestational age.
Characterizing the cost of preterm birth is important in assessing the impact of increasing prematurity rates and evaluating the cost-effectiveness of therapies to prevent preterm delivery. To assess early intervention costs that are associated with preterm births, we estimated the program cost of early intervention services for children who were born in Massachusetts, by gestational age at birth. Using the Pregnancy to Early Life Longitudinal Data Set, birth certificates for infants who were born in Massachusetts between July 1999 and June 2000 were linked to early intervention claims through 2003. We determined total program costs, in 2003 dollars, of early intervention and mean cost per surviving infant by gestational age. Costs by plurality, eligibility criteria, provider discipline, and annual costs for children's first 3 years also were examined. Overall, 14,033 of 76,901 surviving infants received early intervention services. Program costs totaled almost $66 million, with mean cost per surviving infant of $857. Mean cost per infant was highest for children who were 24 to 31 weeks' gestational age ($5393) and higher for infants who were 32 to 36 weeks' gestational age ($1578) compared with those who were born at term ($725). Cost per surviving infant generally decreased with increasing gestational age. Among children in early intervention, mean cost per child was higher for preterm infants than for term infants. At each gestational age, mean cost per surviving infant was higher for multiples than for singletons, and annual early intervention costs were higher for toddlers than for infants. Compared with their term counterparts, preterm infants incurred higher early intervention costs. This information along with data on birth trends will inform budget forecasting for early intervention programs. Costs that are associated with early childhood developmental services must be included when considering the long-term costs of prematurity.


Global income and production impacts of using GM crop technology 1996-2013.
This paper provides an economic assessment of the value of using genetically modified (GM) crop technology in agriculture at the farm level. It follows and updates earlier annual studies which examined economic impacts on yields, key costs of production, direct farm income and effects, and impacts on the production base of the 4 main crops of soybeans, corn, cotton and canola. The commercialisation of GM crops has continued to occur at a rapid rate since the mid 1990s, with important changes in both the overall level of adoption and impact occurring in 2013. This annual updated analysis shows that there continues to be very significant net economic benefits at the farm level amounting to $20.5 billion in 2013 and $133.4 billion for the 18 years period (in nominal terms). These economic gains have been divided roughly 50% each to farmers in developed and developing countries. About 70% of the gains have derived from yield and production gains with the remaining 30% coming from cost savings. The technology have also made important contributions to increasing global production levels of the 4 main crops, having added 138 million tonnes and 273 million tonnes respectively, to the global production of soybeans and maize since the introduction of the technology in the mid 1990s.


SOX2 is a cancer-specific regulator of tumour initiating potential in cutaneous squamous cell carcinoma.
Although the principles that balance stem cell self-renewal and differentiation in normal tissue homeostasis are beginning to emerge, it is still unclear whether cancer cells with tumour initiating potential are similarly governed, or whether they have acquired distinct mechanisms to sustain self-renewal and long-term tumour growth. Here we show that the transcription factor Sox2, which is not expressed in normal skin epithelium and is dispensable for epidermal homeostasis, marks tumour initiating cells (TICs) in cutaneous squamous cell carcinomas (SCCs). We demonstrate that Sox2 is required for SCC growth in mouse and human, where it enhances Nrp1/Vegf signalling to promote the expansion of TICs along the tumour-stroma interface. Our findings suggest that distinct transcriptional programmes govern self-renewal and long-term growth of TICs and normal skin epithelial stem and progenitor cells. These programmes present promising diagnostic markers and targets for cancer-specific therapies.


Position paper: dentistry and the dental industry summit on managed care.
A taskforce of dental professionals and industry leaders looked at the impact of dental benefit programs on America's oral health. When properly done, such benefits programs are positive; but precautions must be taken to ensure that underfunded programs and those which restrict choice are not allowed to erode dental health. Six possible courses of action are developed, centered around education, communication, and collaboration.


C. elegans mre-11 is required for meiotic recombination and DNA repair but is dispensable for the meiotic G(2) DNA damage checkpoint.
We investigated the roles of Caenorhabditis elegans MRE-11 in multiple cellular processes required to maintain genome integrity. Although yeast Mre11 is known to promote genome stability through several diverse pathways, inviability of vertebrate cells that lack Mre11 has hindered elucidation of the in vivo roles of this conserved protein in metazoan biology. Worms homozygous for an mre-11 null mutation are viable, allowing us to demonstrate in vivo requirements for MRE-11 in meiotic recombination and DNA repair. In mre-11 mutants, meiotic crossovers are not detected, and oocyte chromosomes lack chiasmata but appear otherwise intact. gamma-irradiation of mre-11 mutant germ cells during meiotic prophase eliminates progeny survivorship and induces chromosome fragmentation and other cytologically visible abnormalities, indicating a defect in repair of radiation-induced chromosome damage. Whereas mre-11 mutant germ cells are repair-deficient, they retain function of the meiotic G(2) DNA damage checkpoint that triggers germ cell apoptosis in response to ionizing radiation. Although mre-11/mre-11 animals derived from heterozygous parents are viable and produce many embryos, there is a marked drop both in the number and survivorship of embryos produced by succeeding generations. This progressive loss of fecundity and viability indicates that MRE-11 performs a function essential for maintaining reproductive capacity in the species.


Kinematic gait analysis of hind limb symmetry in dogs at the trot.
To describe intratrial differences in hind limb symmetry in healthy dogs at the trot, using noninvasive, computer-assisted, three-dimensional kinematic gait analysis. 8 clinically normal large-breed adult dogs. Dynamic flexion and extension angles and angular velocities were calculated for the coxofemoral, femorotibial, and tarsal joints of dogs at the trot. Temporal and distance variables were computed. Essential Fourier coefficients were used to determine mean flexion and extension curves for all joints and to compare differences in movement between right and left hind limbs. Variances attributable to limb, dog, and trial were determined. Each joint had a characteristic pattern of flexion and extension movement that was used to compare intratrial symmetry of hind limb gait. Significant differences were not detected in temporal or distance variables between the right and left hind limbs. Significant differences were not noted in essential Fourier coefficients used to characterize coxofemoral, femorotibial, and tarsal joint angles and angular velocities, with the exception of the cosine-0 coefficient for coxofemoral angular velocity. Variation in joint angle and angular velocity measurements were attributable to individual dog and trial. Variation attributable to limb was negligible. Intratrial evaluation of right-left hind limb symmetry, using kinematic gait analysis, indicated objectively that hind limb movement is symmetrical at the trot in healthy large-breed dogs. Documentation of hind limb symmetry at the trot will help provide a basis for direct comparison of both hind limbs in future studies evaluating gait and treatment of dogs with musculoskeletal disease.


mGluR5 antagonism attenuates methamphetamine reinforcement and prevents reinstatement of methamphetamine-seeking behavior in rats.
Addiction to methamphetamine is a significant public health problem, and there are currently no pharmacological agents that are approved for the treatment of addiction to this powerful psychostimulant. Chronic methamphetamine use leads to cognitive dysfunction as well as numerous psychiatric, neurological, and cardiovascular complications. There is a growing body of literature implicating an important role for glutamate neurotransmission in psychostimulant addiction. In the present study, we examined the effects of the selective type 5 metabotropic glutamate receptor (mGluR5) antagonist 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) on intravenous self-administration of methamphetamine and reinstatement of methamphetamine-seeking behavior. Adult male Sprague-Dawley rats were trained to respond for intravenous methamphetamine (0.1 or 0.2 mg/kg per infusion) or food pellets and were subsequently administered vehicle or MTEP (0.3-3 mg/kg) before drug or food self-administration on a fixed-ratio 1 (FR1) schedule of reinforcement or a progressive ratio (PR) schedule of reinforcement. We also examined the effects of vehicle or MTEP (0.3-3 mg/kg) on cue- and drug-induced reinstatement of methamphetamine-seeking behavior as well as cue-induced reinstatement of food-seeking behavior. Our results show that MTEP dose dependently reduced the reinforcing effects of methamphetamine under FR1 and PR schedules of reinforcement without altering overall responding for food. MTEP also dose dependently prevented cue- and drug-induced reinstatement of methamphetamine-seeking behavior, but did not alter cue-induced reinstatement of food-seeking behavior. Together, these results indicate that mGluR5 receptors mediate methamphetamine reinforcement and methamphetamine-seeking behavior, and that pharmacological inhibitors of mGluR5 receptor function may represent a novel class of potential therapeutic agents for the treatment of methamphetamine addiction.


Zonisamide for weight loss in obese adults: a randomized controlled trial.
Zonisamide is a marketed antiepileptic drug that has serotonergic and dopaminergic activity in addition to blockade of sodium and calcium channels. Weight loss was an adverse effect associated with zonisamide treatment in epilepsy clinical trials. To evaluate the efficacy of zonisamide for weight loss in obese adults. Sixteen-week randomized, double-blind, placebo-controlled trial with an optional single-blind extension of the same treatment for another 16 weeks, conducted at Duke University Medical Center from March 2001 to March 2002. Fifty-five (92%) women and 5 (8%) men (mean [SE] body mass index, 36.3 [0.5]; mean age, 37.0 (1.0) years). Patients were randomly assigned to receive zonisamide (n = 30) or placebo (n = 30). All participants were prescribed a balanced hypocaloric diet (500 kcal/d deficit) and compliance was monitored with self-rated food diaries. Zonisamide therapy was started at 100 mg/d orally, with gradual increase to 400 mg/d and further increase to 600 mg/d for patients losing less than 5% of body weight at the end of 12 weeks. Placebo dosing was identical. Change in body weight. Of the 60 randomized patients, 51 completed the 16-week acute phase. In an intent-to-treat analysis using the available data for all randomized participants with the last observation carried forward, the zonisamide group lost more body weight than the placebo group (mean [SE], 5.9 [0.8] kg [6.0% loss] vs 0.9 [0.4] kg [1.0% loss]; t = 5.5; P<.001) during the 16-week period. A longitudinal mixed-model regression for weight change controlling for age, race, sex, body mass index, and percent body fat estimated that zonisamide treatment over the 16-week study duration was associated with significantly greater weight loss than was placebo (t = 6.4; P<.001). Seventeen (57%) of 30 in the zonisamide group and 3 (10%) of 30 in the placebo group lost at least 5% of body weight (P<.001) by week 16. Of the 37 participants who entered the extension phase, 36 completed week 32. The zonisamide group (n = 19) had a mean weight loss of 9.2 kg (1.7 kg) (9.4% loss) at week 32 compared with 1.5 kg (0.7 kg) (1.8% loss) for the placebo group (n = 17) (t = 4.0; P<.001). Zonisamide was tolerated well, with few adverse effects. In this short-term, preliminary trial, zonisamide and hypocaloric diet resulted in more weight loss than placebo and hypocaloric diet in the treatment of obesity.


White cell and marrow imaging: subtracting uncertainty.
A subtraction method for assessments of dual-isotope indium-111 (In)-labelled white cell and Tc-nanocoll was proposed, and following a pilot study was introduced in routine service to improve the confidence of reporters. This technical note describes a simple technique to produce subtraction images from routinely acquired images to investigate and exclude post joint replacement infection. Labelled leucocytes (with In) show areas of increased white cell accumulation, whereas Tc-nanocoll images show bone marrow distribution. Images resulting from the subtraction protocol highlight any areas of white cell activity which is not concurrent with the marrow distribution indicative of infection. Fusion images produced from these images sets also assists in localization of white cell accumulation(s). Key to the success of this technique is the use of simultaneous acquisition of both white cell and marrow images; thus removing any issues with patient movement and/or repositioning. Reporting clinicians convey a clear preference for the inclusion of the subtracted and fused images at clinical review.


Evidence-based practice in healthcare: an exploratory cross-discipline comparison of enhancers and barriers.
In order to improve health outcomes, healthcare providers need to base practice on current evidence. The purpose of this qualitative study was to explore and compare the understanding and experiences with evidence-based practice (EBP) in three different disciplines. Researchers conducted individual interviews with psychiatrists, nurses, and dental hygienists. The majority of study participants demonstrated an understanding of EBP and were able to identify enhancers and barriers to implementing EBP. Using a grounded theory approach, several major themes acting as enhancers and barriers to EBP emerged and revealed both differences and similarities within and across the three health disciplines. While saturation was not attempted, this exploratory research is important in contributing to understanding the cultural practice milieu in relation to individual characteristics in implementing evidence into practice with the overall aim of improving healthcare delivery and outcomes.


The occupational safety and health in hospitals from the point of nurses.
Hospitals have many forms of danger due to many different working conditions. Hospital personnel also take risks whilst providing health care which may cause health problems to themselves. The research, related to health and safety of nurses and other staff was carried out in order to compare and determine the occupational health problems and evaluate the occupational safety precautions and applications of a private hospital accredited with JCI (Joint Commission International) and also a university hospital. The research took place amongst 162 nurses of a university hospital and 150 nurses of a private hospital, both in Istanbul, Turkey. The data was gathered between March and July 2007 using a survey consisting of 7 questions to find out the socio-demographic characteristics and 17 questions related to the occupational safety precautions and the occupational health problems of health personnel. According to the nurses, the safety applications and precautions of the private hospital were better than the university hospital. It was found out that the university hospital was poor at providing an ergonomic working environment and the private hospital was poor at planning the timetables of the nurses. In addition to this,--in both hospitals--sharp or pointed devices, blood/blood fluids and infected material were discovered to cause occupational diseases and other problems. In conclusion, the precautions and applications regarding occupational health and safety in the private hospital accredited with JCI were better than the university hospital.


First Line Androgen Deprivation Therapy vs. Chemotherapy for Patients With Androgen Receptor Positive Recurrent or Metastatic Salivary Gland Carcinoma-A Retrospective Study.
Objectives: There is a lack of effective therapy for recurrent or metastatic salivary gland carcinoma. Androgen deprivation therapy has demonstrated efficacy in cases of salivary duct carcinoma (SDC) and high-grade adenocarcinoma not otherwise specified (NOS) that express androgen receptor. Materials and Methods: We conducted a single institution retrospective cohort study examining patients treated for recurrent/metastatic SDC or high-grade adenocarcinoma NOS of the salivary gland. Survival analyses were performed to assess for efficacy of first-line androgen deprivation therapy (ADT) vs. first-line conventional cytotoxic chemotherapy. Efficacy of salvage ADT was also assessed. Results: Fifty-eight patients were reviewed. Thirty-five patients had recurrent/metastatic disease of which 28 had SDC (80%) and 7 had high-grade adenocarcinoma NOS (20%). Median overall survival for first-line ADT was 25 months compared to 25 months for first-line chemotherapy [RR 0.54 (0.23-1.28, p = 0.16)]. Patients treated with first-line ADT had a response rate of 45% (9/20) and patients treated with first-line chemotherapy had a response rate of 14% (2/14). Six patients received salvage ADT with 1 patient demonstrating complete response and 3 with stable disease as best response (clinical benefit rate 67%). Conclusion: Overall survival for first line ADT and first line cytotoxic chemotherapy was comparable but response rates to first-line ADT were higher than those with first-line chemotherapy. Salvage ADT is active in recurrent/metastatic salivary gland carcinoma.


Method of predicting splice sites based on signal interactions.
Predicting and proper ranking of canonical splice sites (SSs) is a challenging problem in bioinformatics and machine learning communities. Any progress in SSs recognition will lead to better understanding of splicing mechanism. We introduce several new approaches of combining a priori knowledge for improved SS detection. First, we design our new Bayesian SS sensor based on oligonucleotide counting. To further enhance prediction quality, we applied our new de novo motif detection tool MHMMotif to intronic ends and exons. We combine elements found with sensor information using Naive Bayesian Network, as implemented in our new tool SpliceScan. According to our tests, the Bayesian sensor outperforms the contemporary Maximum Entropy sensor for 5' SS detection. We report a number of putative Exonic (ESE) and Intronic (ISE) Splicing Enhancers found by MHMMotif tool. T-test statistics on mouse/rat intronic alignments indicates, that detected elements are on average more conserved as compared to other oligos, which supports our assumption of their functional importance. The tool has been shown to outperform the SpliceView, GeneSplicer, NNSplice, Genio and NetUTR tools for the test set of human genes. SpliceScan outperforms all contemporary ab initio gene structural prediction tools on the set of 5' UTR gene fragments. Designed methods have many attractive properties, compared to existing approaches. Bayesian sensor, MHMMotif program and SpliceScan tools are freely available on our web site. This article was reviewed by Manyuan Long, Arcady Mushegian and Mikhail Gelfand.


Hallmarks of gastrointestinal neuroendocrine tumours: implications for treatment.
In the past few years, there have been advances in the treatment of neuroendocrine tumours (NETs) and improvements in our understanding of NET biology. However, the benefits to patients have been relatively modest and much remains yet to be done. The 'Hallmarks of Cancer', as defined by Hanahan and Weinberg, provide a conceptual framework for understanding the aberrations that underlie tumourigenesis and to help identify potential targets for therapy. In this study, our objective is to review the major molecular characteristics of NETs, based on the recently modified 'Hallmarks of Cancer', and highlight areas that require further research.


Primary hemorrhagic intramedullary melanoma. Case report with emphasis on the difficult preoperative diagnosis.
Primary melanoma of the central nervous system (CNS) is rare and primary spinal melanoma (PSM) is even more unusual. Preoperative diagnosis of melanocytic lesion as a PSM is difficult, because of the heterogeneous magnetic resonance (MR) signal intensity, due to hemorrhagic foci and melanin deposits. We describe the case of a 68 year-old male with a MR showing at Th8-Th9 level a well-defined intramedullary lesion; for the characteristics of hemorrhagic signal on MR and its association with a presumptive brain cavernoma, a preoperative diagnosis of intramedullary cavernous angioma was suspected. Pathological examination revealed a melanoma, and for the absence of other localizations outside the spinal cord, a diagnosis of primary spinal melanoma was established. The growth of PSM is slower and survival is longer than in the most common spinal metastasis from skin melanoma. Patients who undergo surgical excision, alone or associated with additional treatments, often show a long survival. We report this case to underline the importance and difficulties concerning the preoperative diagnosis of a hemorrhagic intramedullary lesion.


Phylogenetic position of Bartonella vinsonii subsp. arupensis based on 16S rDNA and gltA gene sequences.
The nucleotide sequences of the genes encoding 16S rRNA and citrate synthase (gltA) from a recently described member of the genus Bartonella, Bartonella vinsonii subsp. arupensis, isolated from mice and from the blood of a patient suffering from bacteraemia, were determined and compared with sequences of the 16S rDNA and gltA genes of other members of the genus Bartonella in order to determine its relative phylogenetic position. B. vinsonii subsp. arupensis appeared to be closely related to B. vinsonii subsp. vinsonii, another rodent-associated taxon, and to B. vinsonii subsp. berkhoffii, which was described recently in dogs.


Structured water molecules in the binding site of bromodomains can be displaced by cosolvent.
Bromodomains are α-helical bundles of approximately 110 residues that recognize acetylated lysine side chains mainly on histone tails. Bromodomains are known to play an important role in cancer and inflammation, and as such, significant efforts are being made to identify small-molecule inhibitors of these epigenetic reader proteins. Here, explicit solvent molecular dynamics (MD) simulations of two bromodomains (BAZ2B and CREBBP) are used to analyze the water molecules that seem to be conserved at the bottom of the acetyl-lysine binding site in most crystal structures of bromodomains. The MD runs suggest that the occupancy of the structured water molecules is influenced by conformational transitions of the loop that connects helices Z and A. Additional simulations in the presence of 50 molecules of cosolvent (i.e., 440 mM of dimethylsulfoxide, methanol, or ethanol) indicate that some of the structured water molecules can be displaced transiently. The residence time in the acetyl-lysine binding site is calculated to be about 1 ns, 2-5 ns, and 10-30 ns for methanol, ethanol, and dimethylsulfoxide, respectively, while the affinity of the three cosolvents for BAZ2B and CREBBP is in the range of 50-500 mM. The results described have implications for ligand design, suggesting that only structured water molecules that do not exchange with cosolvent should be maintained in crystal structures used for docking campaigns, and that hydroxy substituents should be incorporated in the ligand so as to map the structured water molecules replaced by (m)ethanol.


25th anniversary article: Ion exchange in colloidal nanocrystals.
We review the progress in ion exchange in a variety of nanocrystal structures from the earliest accounts dating back over two decades ago to the present day. In recent years the number of groups using this method to form otherwise difficult or inaccessible nanoparticle shapes and morphologies has increased considerably and the field has experienced a resurgence of interest. Whilst most of the early work on cation exchange centered on II-VI materials, the methodology has been expanded to cover a far broader range of semiconductor nanocrystals including low toxicity I-III-VI materials and the much less facile III-V materials. The extent of exchange can be controlled leading to lightly doped nanoparticles, alloys, core-shells, segmented rods and dots-in-rods. Progress has been driven by a better understanding of the underlying principles of the exchange process - from thermodynamic factors (differences in cation solubilities); the interactions between ions and transfer agents (solvents, ligands, anions, co-dopants); ionic in-diffusion mechanisms and kinetics. More recent availability of very detailed electron microscopy coupled with image reconstruction techniques has been a valuable tool to investigate the resulting heterostructures and internal interfaces. We start by surveying the range of synthetic approaches most often used to carry out ion exchange, mainly focusing on cation replacement strategies, and then describe the rich variety of nanostructures these techniques can bring forth. We also describe some of the principles that are used to establish the relative ease of exchange and to systematically improve the process where the basic energetics are less favorable. To help further the understanding of the underlying fundamentals we have gathered together useful data from the literature on solubilities, cation and anion hardness, ligand and solvent Lewis acid or base strengths for a wide range of chemical species generally used. We offer a perspective on the outlook for the field in terms of the emerging applications and the ion exchange derived materials that will enable them.


Wild-type p53 controls the level of fibronectin expression in breast cancer cells.
Aberrant fibronectin (FN) expression is associated with poor prognosis, cell adhesion, and cell motility in a variety of cancer cells. In this study, we investigated the relationship between p53 and FN expression in breast cancer cells. Basal FN expression was significantly decreased by treatment with the p53 activator III, RITA, in MCF7 breast cancer cells with wild-type p53. In addition, overexpression of wild-type p53 markedly decreased the level of FN expression in p53-mutant breast cancer cells. To examine the mechanism underlying the relationship between p53 and FN expression, we treated MCF7 breast cancer cells with the tumor promoter TPA (12-O-tetradecanoylphorbol-13-acetate). Our results showed that basal FN expression was increased by TPA treatment in a time-dependent manner. In contrast, the level of p53 expression was decreased by TPA treatment. However, the expression of FN and p53 was not altered by TPA in p53-mutant breast cancer cells. Furthermore, the alterations in FN and p53 expression in response to TPA were prevented by a specific MEK inhibitor, UO126. Finally, we demonstrated that TPA triggers degradation of p53 through the proteasomal pathway in MCF7 cells. TPA-induced FN expression was decreased by the proteasome inhibitor MG132. Under the same condition, p53 protein expression, but not mRNA expression, was reversed by MG132. Taken together, our data demonstrate that the level of FN expression is associated with the status and expression of p53 in breast cancer cells.


Aged and induced-premature ovarian failure mouse models affect diestrus profile and ovarian features.
Sex hormones exert a wide influence on several systems of the human body, especially in women, who undergo intense changes in the trans and postmenopausal periods. Different experimental models are used to mimic these conditions; however, the impact on hormonal profile may be different. This study aimed to analyze and compare vaginal cytology of different post-estropausal mice models, along with their microscopical ovarian features. Forty-six C57BL/6J female mice with the ages of 4, 6 and 18 months at the beginning of the experiment, weighing about 25-28 grams, constituted five groups: NC-(negative control) animals with no treatment, OVX-SHAM-sham ovariectomized, OVX-ovariectomized, VCD-medicated with 160 mg/kg/day of 4-vinylcyclohexene diepoxide via IP for 20 consecutive days, and Aged-senescent mice under physiological estropause. Euthanasia was performed at different periods for the removal of the ovaries, and after diestrus was confirmed by vaginal cytology for 10 consecutive days. For daily vaginal cytology, morphological and histomorphometric microscopic analyzes were performed. Aged mice presented significant increased neutrophils when compared to VCD group, as well as increased cornified epithelial cells when compared to OVX mice, and also increased nucleated epithelial cells when compared to VCD and OVX. NC and OVX-SHAM ovaries presented innumerous follicles at different stages of development, while VCD showed marked follicular atresia, depleted of primordial or developing follicles and a predominance of interstitial cells. The ovaries of aged mice were predominantly constituted by corpus luteum degenerated into corpus albicans, with rare antral follicles. All analyzed models led to different permanent diestrus profiles caused by each model, as indicated by ovarian features. This should be carefully considered when choosing a post-estropausal experimental model, in order to better correlate this challenging phase of female's life with physiological/pathological conditions.


Fruit properties and genetic diversity of five ber (Ziziphus mauritiana Lamk) cultivars.
The present study was conducted on five ber (Ziziphus mauritiana Lamk) cultivars (Komethry, Pakstany, Um-sulaem, Toffahy and Peyuan) grown in Saudi Arabia during 2005 and 2006 seasons. The aim of the present study was to investigate fruit properties (fruit weight, length, diameter, shape, specific gravity, seed weight, pulp percentage, total soluble solids (TSS), acidity percentage, TSS/acid, vitamin C content total, reducing and non-reducing sugars). Peyuan cv. had the heaviest fruit weight, fruit volume and reducing sugar content however, it was the lowest in pulp percentage and non-reducing sugars among the five cultivars in both seasons. Toffahy cv. had highest fruit diameter and seed weight while, had lowest TSS %, vitamin C and total sugars values. Um-sulaem cv. had highest acidity percentage and vitamin C content and lowest fruit weight, length and TSS/acid. On the other hand, Pakstany cv. had highest percentage of both pulp percentage, TSS, total and non-reducing sugars. Finally, Komethry had the longest fruit. The molecular characterization and fingerprint identification of the ber cultivars was conducted using the ISSR (Inter-Simple Sequence Repeats) technique. The ISSR technique was able to uniquely characterize and differentiate between the five ber genotypes. Moreover, the genetic similarity tree showed that the cultivar Um-slaem is genetically distant from the other four cultivars and the two cultivars Pakstany and Komethry were genetically identical.


Mu transposon insertion sites and meiotic recombination events co-localize with epigenetic marks for open chromatin across the maize genome.
The Mu transposon system of maize is highly active, with each of the approximately 50-100 copies transposing on average once each generation. The approximately one dozen distinct Mu transposons contain highly similar approximately 215 bp terminal inverted repeats (TIRs) and generate 9-bp target site duplications (TSDs) upon insertion. Using a novel genome walking strategy that uses these conserved TIRs as primer binding sites, Mu insertion sites were amplified from Mu stocks and sequenced via 454 technology. 94% of approximately 965,000 reads carried Mu TIRs, demonstrating the specificity of this strategy. Among these TIRs, 21 novel Mu TIRs were discovered, revealing additional complexity of the Mu transposon system. The distribution of >40,000 non-redundant Mu insertion sites was strikingly non-uniform, such that rates increased in proportion to distance from the centromere. An identified putative Mu transposase binding consensus site does not explain this non-uniformity. An integrated genetic map containing more than 10,000 genetic markers was constructed and aligned to the sequence of the maize reference genome. Recombination rates (cM/Mb) are also strikingly non-uniform, with rates increasing in proportion to distance from the centromere. Mu insertion site frequencies are strongly correlated with recombination rates. Gene density does not fully explain the chromosomal distribution of Mu insertion and recombination sites, because pronounced preferences for the distal portion of chromosome are still observed even after accounting for gene density. The similarity of the distributions of Mu insertions and meiotic recombination sites suggests that common features, such as chromatin structure, are involved in site selection for both Mu insertion and meiotic recombination. The finding that Mu insertions and meiotic recombination sites both concentrate in genomic regions marked with epigenetic marks of open chromatin provides support for the hypothesis that open chromatin enhances rates of both Mu insertion and meiotic recombination.


Impact of a reduced water salinity on the composition of Vibrio spp. in recirculating aquaculture systems for Pacific white shrimp (Litopenaeus vannamei) and its possible risks for shrimp health and food safety.
Tropical shrimp, like Litopenaeus vannamei, in land-based recirculating aquaculture systems (RAS) are often kept at low water salinities to reduce costs for artificial sea salt and the amount of salty wastewater. Although these shrimp are tolerant against low salinities, innate immunity suppression and changes in the microbial composition in the water can occur. As especially Vibrio spp. are relevant for shrimp health, alterations in the species composition of the Vibrio community were analysed in water from six RAS, run at 15‰ or 30‰. Additionally, pathogenicity factors including pirA/B, VPI, toxR, toxS, vhh, vfh, tdh, trh, flagellin genes and T6SS1/2 of V. parahaemolyticus were analysed. The Vibrio composition differed significantly depending on water salinity. In RAS at 15‰, higher numbers of the potentially pathogenic species V. parahaemolyticus, V. owensii and V. campbellii were detected, and especially in V. parahaemolyticus, various pathogenicity factors were present. A reduced salinity may therefore pose a higher risk of disease outbreaks in shrimp RAS. Because some of the detected pathogenicity factors are relevant for human health, this might also affect food safety. In order to produce healthy shrimp as a safe food for human consumption, maintaining high water salinities seems to be recommendable.


Mechanistic significance of perepoxide trapping experiments, with epoxide detection, in 1Deltag dioxygen reactions with alkenes.
The reactions of (1)O(2) with alkenes can share open-chain diradicals or cyclic peroxiranes as common polar intermediates. The latter in particular has been postulated on the basis of trapping experiments, which exploit the capability of reducing agents (R) to extract an oxygen atom from the putative perepoxide, to generate an epoxide. This theoretical study illustrates that trapping experiments cannot distinguish between a peroxirane and an open-chain intermediate pathway, because an epoxide is the shared outcome of the attack by R.


The potential for adjuvant radiotherapy in choroidal melanoma.
Controversy exists regarding the efficacy of enucleation in the management of choroidal melanoma. The effect of any form of ocular therapy on the prevalence of choroidal melanoma metastases is unknown. In a number of other systemic tumors, preoperative irradiation may lessen the occurrence of widespread disease. This type of therapeutic approach might be useful in the management of high-risk choroidal melanoma. In preliminary studies using 2,000 rad of preenucleation irradiation in patients with choroidal melanoma who have a poor prognosis, we have not observed notable morbidity. There are a number of limitations to the use of this adjunct therapy in choroidal melanoma management; however, a prospective national randomized trial of preenucleation irradiation in patients with high-risk choroidal melanoma might allow us to indirectly determine the effect of enucleation on the prevalence of choroidal melanoma metastases as well as delineate the potential role of this type of adjunct therapy in ocular melanoma.


Contribution of reactive oxygen species to cartilage degradation in rheumatic diseases: molecular pathways, diagnosis and potential therapeutic strategies.
Inflammatory joint diseases are of considerable socio-economic significance. However, mechanisms of cartilage destruction are so far only poorly understood. This review is dedicated to reactive oxygen species (ROS) like superoxide anion radicals, hydrogen peroxide, singlet oxygen, hypochlorous acid, hydroxyl radicals and nitric oxide that are generated under inflammatory conditions and also to their potential contribution to cartilage degradation. First, the relevance of rheumatic diseases and potential mechanisms of cartilage degradation are discussed in this review, followed by the description of the chemical constituents and the molecular architecture of articular cartilage as well as the different cell types that play a role in inflammation and cartilage destruction. Methods of the assessment of cartilage degeneration are also shortly discussed. In the main chapter of this review the characteristics of individual ROS, their generation under in vivo conditions as well as their reactivities with individual cartilage components are discussed. Because of the low selectivity of ROS, useful "markers" of cartilage degradation allowing the differentiation of effects induced by individual ROS are also discussed. In the last chapter current therapeutic concepts of the treatment of rheumatic diseases are reviewed. The recently developed "anti-TNF-alpha" therapy that is primarily directed against neutrophilic granulocytes that are powerful sources of ROS and, therefore, important mediators of joint degeneration are emphasised.


Survey of library and information use by health-care students.
The study compares and contrasts the usage and views of three groups of health-care students (Pre-Project 2000, Project 2000 and BSc Occupational Therapy) on their library facilities. A literature review is included which underpins the importance of libraries for health-care students. Data was compiled from survey responses. The results demonstrate which libraries the students use, how often they use them, what they do in the libraries, and the stock used. They also show the level of student confidence and the services used. The implications of the study for future provision are considered.


ICE Afe 1, an actively excising genetic element from the biomining bacterium Acidithiobacillus ferrooxidans.
Integrative conjugative elements (ICEs) are self-transferred mobile genetic elements that contribute to horizontal gene transfer. An ICE (ICEAfe1) was identified in the genome of Acidithiobacillus ferrooxidans ATCC 23270. Excision of the element and expression of relevant genes under normal and DNA-damaging growth conditions was analyzed. Bioinformatic tools and DNA amplification methods were used to identify and to assess the excision and expression of genes related to the mobility of the element. Both basal and mitomycin C-inducible excision as well as expression and induction of the genes for integration/excision are demonstrated, suggesting that ICEAfe1 is an actively excising SOS-regulated mobile genetic element. The presence of a complete set of genes encoding self-transfer functions that are induced in response to DNA damage caused by mitomycin C additionally suggests that this element is capable of conjugative transfer to suitable recipient strains. Transfer of ICEAfe1 may provide selective advantages to other acidophiles in this ecological niche through dissemination of gene clusters expressing transfer RNAs, CRISPRs, and exopolysaccharide biosynthesis enzymes, probably by modification of translation efficiency, resistance to bacteriophage infection and biofilm formation, respectively. These data open novel avenues of research on conjugative transformation of biotechnologically relevant microorganisms recalcitrant to genetic manipulation.


Research needs, environmental concerns, and logistical considerations for incorporating livestock grazing into coastal upland habitat management.
Along the Gulf of Mexico (GoM) coast, natural resource managers continually struggle with managing coastal uplands due to front-end costs, prolonged maintenance, and habitat-specific ecological needs. Prescribed fire, mechanical removal, and chemical treatments are common habitat management techniques used to remove invasive species, clear understory, and achieve other management goals. However, rapid development and changing climate exacerbate the difficulty in using these techniques. A potential alternative or complementary technique is using livestock for habitat management (i.e., targeted or controlled grazing). In other regions of the world, using livestock for conservation or restoration of managed lands has shown to be a less intrusive and more financially viable alternative. To better understand the research needs, logistical, and environmental concerns related to using livestock for habitat management in the coastal uplands of the GoM, we developed and distributed a survey to three groups of land users, including natural resource managers, researchers, and livestock producers in the region. Survey results show that over 96% of respondents are interested in using livestock for habitat management, but less than 10% of respondents were aware of any information that could be used to inform grazing practices for coastal upland habitat management along the Gulf of Mexico coast. There were differences among surveyed groups, but generally small-sized cattle breeds and goats were identified as the livestock with the most potential for environmental benefit and ease of containment. General concerns and areas for further investigation were implementation (e.g., which livestock type to use and grazing intensity), logistical considerations (e.g., fencing and rotational frequency), impacts of grazing on water quality, wildlife, vegetation, and livestock nutrition. Survey respondents overwhelmingly (at least 75% of each group) indicated that livestock grazing ideally would not be a standalone management practice and should be used in conjunction with other habitat management techniques such as prescribed burns, mechanical clearing, or chemical treatments. The results of the survey could be used to develop applied research projects and guidance documents that directly address informational needs related to using livestock for habitat management of coastal uplands along the Gulf of Mexico coast.


[tctN-mutation causing taillessness in mice heterozygous for gene T].
Screening of wild male mice trapped in Turkmenistan (Middle Asia) revealed a mouse with a mutation causing strong increase in expressivity of T mutation (Brachyury). A novel mutation was designated tctN-t complex tail interaction Novosibirsk. Compound heterozygotes T/tctN have tailless of extremely short tailed phenotype. Homozygotes tctN/tctN were completely viable and fertile. It was shown that the novel mutation was closely linked to T locus. Further genetic analysis showed that the chromosome with tct had no properties of t haplotypes: no lethal factors or the factors influencing fertility and segregation of homologoues; there was no effect on recombination frequency in the proximal part of chromosome 17 in tctN/+mice. The problems of t haplotype evolution are discussed.


Differences in intracellular DNA ligation after microinjection and transfection.
An uninterrupted avian sarcoma viral genome terminated by viral long terminal repeat sequences was cloned into a pBR322 plasmid. After introduction into a cultured avian cell, transcription of either the circular plasmid molecule or one linearized within the pBR322 sequences could initiate and terminate at long terminal repeat sequences, yielding full-sized viral RNA. A plasmid DNA molecule linearized by cleavage within the viral pol gene, on the other hand, would have to undergo ligation to yield full-sized viral RNA. Microinjection of each of these three types of DNA into the nuclei of quail cells promoted the release of similar virus titers, indicating that the plasmid DNA cleaved within the viral pol gene had been efficiently and accurately ligated. When plasmid DNA was transfected into quail cells, circular and pBR322-cleaved molecules directed the synthesis of similar virus titers, indicating that they were similarly taken up and utilized by the cells. Compared with these results, plasmid DNA cleaved within the pol gene was reduced in activity over 95% after transfection. This reduction did not result from inefficient ligation but from the generation of mutations (of limited size) during ligation of the transfected molecules. Mutations were not observed after microinjection even into the cytoplasm. Consistent with these findings, transfected DNA termini were found to be joined regardless of their structure, whereas ligation after microinjection required that single-stranded protruding DNA termini be complementary.


Improved template preparation for PCR-based assays for detection of food-borne bacterial pathogens.
Shigella flexneri, Salmonella enterica serotype Typhimurium, and Listeria monocytogenes were applied to FTA filters, and the filters were used directly as templates to demonstrate their sensitivity and applicability in PCR-based detection assays. With pure cultures, the sensitivities of detection by FTA filter-based PCR were 30 to 50 and 200 CFU for the gram-negative enterics and Listeria, respectively. Different numbers of S. flexneri cells were used in controlled contamination experiments with several different foods (produce, beef, and apple cider). Aliquots from concentrated food washes subsequently spotted onto FTA filters and assayed by PCR gave consistently positive results and detection limits similar to those observed with pure-culture dilutions. This universal method for PCR template preparation from bacterial cells is rapid and highly sensitive and reduces interference from food-associated inhibitors of PCR. In addition, its broad applicability eliminates the need for multiple methods for analysis of food matrices.


Biochemical and biological effects of nonionic nucleic acid methylphosphonates.
Oligodeoxyribonucleoside methylphosphonates with base sequences complementary to the anticodon loop of tRNALys and to the -ACCA-OH amino acid accepting stem of tRNA were prepared by chemical synthesis. Oligodeoxyadenosine methylphosphonates form stable, triple-stranded complexes with both poly(U) and poly(dT). These analogues selectively inhibit cell-free aminoacylation of tRNALys (E. coli) but have no effect on aminoacylation of tRNALys (rabbit). The extent of inhibition is temperature dependent and parallels the ability of the oligomer to bind to poly(U), which suggests that inhibition occurs as a result of oligomer binding to the -UUUU- anticodon loop of tRNALys (E. coli). The failure of the oligodeoxyadenosine methylphosphonates to inhibit tRNALys (rabbit) amino-acylation suggests that there may be a difference between the structure of tRNALys or its interaction with aminoacyl synthetase in the Escherichia coli and rabbit systems. The oligodeoxyadenosine analogues also effectively inhibit polyphenylalanine synthesis in cell-free translation systems derived from both E. coli and rabbit reticulocytes. The extent of inhibition parallels the Tm values of the oligo(A) phosphonate-poly(U) complexes and suggests that the inhibition is a consequence of complex formation with the poly(U) message. Tritium-labeled oligodeoxyribonucleoside methylphosphonates with a chain length of up to nine nucleotidyl units are taken up intact by mammalian cells in culture. All the oligomer analogues tested inhibited, to various extents, colony formation by bacterial, hamster, and human tumor cells in culture.


Regulation of neuropeptide stoichiometry in neurosecretory cells.
Peptidergic neurons and neurosecretory cells often contain multiple peptides, where they may be present in characteristic ratios. In this article, we describe how a set of five colocalized and coreleased peptides, two adipokinetic hormones (AKH I and AKH II), and three dimeric peptides (APRP 1, 2, and 3) are synthesized by the neurosecretory cells of the corpora cardiaca of the locust Schistocerca gregaria. We show that the five peptides are produced from two prohormones called pro-AKH I, or A-chain, and pro-AKH II, or B-chain. The amino acid sequences as determined by direct protein sequencing are given for both. Prior to processing, the two prohormones form the three possible dimers by the oxidation of the single cysteine residues found in each. The dimers, not the prohormones, are the direct precursors of the peptides. The dimeric precursors are called P1 (A-A), P2 (A-B), and P3 (B-B). Processing results in the generation of the two AKH peptides and the three dimers called adipokinetic hormone precursor-related peptides, or APRPs. Throughout postembryonic development, we show that the ratios of the AKHs and APRPs change dramatically and systematically. We show that these changes can be explained by the differential regulation of the synthesis of the two prohormones and their random association into dimers that are then completely processed. Regulation of peptide stoichiometry may expand the potential information content of the signals generated by multipeptide-producing neurons.


Functional electrical stimulation controlled by artificial neural networks: pilot experiments with simple movements are promising for rehabilitation applications.
This study falls within the ambit of research on functional electrical stimulation for the design of rehabilitation training for spinal cord injured patients. In this context, a crucial issue is the control of the stimulation parameters in order to optimize the patterns of muscle activation and to increase the duration of the exercises. An adaptive control system (NEURADAPT) based on artificial neural networks (ANNs) was developed to control the knee joint in accordance with desired trajectories by stimulating quadriceps muscles. This strategy includes an inverse neural model of the stimulated limb in the feedforward line and a neural network trained on-line in the feedback loop. NEURADAPT was compared with a linear closed-loop proportional integrative derivative (PID) controller and with a model-based neural controller (NEUROPID). Experiments on two subjects (one healthy and one paraplegic) show the good performance of NEURADAPT, which is able to reduce the time lag introduced by the PID controller. In addition, control systems based on ANN techniques do not require complicated calibration procedures at the beginning of each experimental session. After the initial learning phase, the ANN, thanks to its generalization capacity, is able to cope with a certain range of variability of skeletal muscle properties.


Haematopoietic cytokines in the biology and treatment of acute myeloid leukaemia.
In acute myeloid leukaemia (AML), age has a definite effect on the biology of the disease and also determines the outcome of chemotherapy. AML cells constitutively express mRNA and produce several haematopoietic cytokines. The haematopoietic cytokines: SCF, IL-3, GM-CSF and G-CSF induce leukaemic colonies or activate DNA synthesis in about 80% of AML cases. Both M-CSF and thrombopoietin stimulated AML cell proliferation is seen in vitro in about 50% of cases. Both IL-6 and IL-11 showed little proliferative activity on primary AML cells. The combinations of these cytokines were synergistic in stimulating the proliferation of AML cells. On the other hand, the inhibitory haematopoietic cytokines: TNF-alpha, TGF-beta, IFN-gamma and IL-4 have shown multiple effects on AML blast cell proliferation. In several in vitro systems, haematopoietic cytokines have failed to induce maturation of AML blasts. Only in AML with t(8;21), G-CSF has induced granulocytic maturation of AML blasts in vitro. AML cells with chromosomal abnormalities involving the 21q22 region differentiate in vitro into eosinophils in the presence of IL-5. IL-6 and IFN-alpha have induced megakaryocytic differentiation of blast cells from acute megakaryoblastic leukemia (M7) patients. The haematopoietic cytokines: SCF, IL-3 and GMCSF have protected in vitro AML cells from chemotherapy-induced apoptosis. Many clinical studies have been recently reported evaluating the effect of the haematopoietic cytokines: GM-CSF, G-CSF, IL-3 and PIXY321 as adjuncts to the chemotherapy of AML patients. Most studies have shown these haematopoietic cytokines to be well-tolerated and effective in augmenting neutrophil recovery in elderly AML patients when given after chemotherapy. On the other hand, considerable number of studies using these cytokines before and during chemotherapy to recruit AML cells into cell cycle and thus make them more susceptible to chemotherapy have reaveled no benefit. Several clinical trials have shown promising results after the use of IL-2 either as remission induction therapy in refractory and/or relapsed AML patients or as post-remission consolidative immunotherapy. Haematopoietic cytokines administered after chemotherapy can shorten the duration of neutropenia and hospitalisation without a significant effect on treatment outcome. On the other hand, their use before and during chemotherapy has yielded no benefit, and instead have led to delay of platelet recovery and worse survival rate in some elderly AML patients.


Laryngeal electromyographic changes in postthyroidectomy patients with normal vocal cord mobility.
Thyroidectomy has been used for the treatment of thyroid disease for more than 100 years. In spite of the advancement of surgical techniques, there is still a risk of laryngeal nerve injury. The risk of partial or complete injury still depends on some surgical and disease-related factors. The aim of this study is to show the partial injury and to establish these risk factors via laryngeal electromyographic analysis (LEMG) in postthyroidectomy patients with normal vocal cord motion and mucosal anatomy. Patients who had undergone thyroid surgery were enrolled in this prospective study. LEMG analysis was performed to all patients with normal vocal cord mobility preoperatively and was repeated after the first and the third months of surgery. Thyroarytenoid (TA) and cricothyroid (CT) muscles were used to evaluate recurrent and external branch of superior laryngeal nerves, respectively. Four of the 32 patients had mild-to-moderate degrees of partial LEMG changes during preoperative LEMG analysis of TA and CT muscles on each side. After 3 months of surgery, there was a statistically significant worsening of LEMG findings in the right and left external branches of superior and left recurrent laryngeal nerves. Disease and surgery-related risk factors were analyzed. However, there was no significant relationship on the progression of LEMG findings according to these parameters. This is the first prospective study which supports the risk of progression of LEMG changes in patients with normal laryngoscopic examination after thyroid surgery. No reliable significant risk factor was found influencing the LEMG progression.


Predictors of Intensive Care Unit Stay After Pediatric Supraglottoplasty.
Supraglottoplasty is a common procedure performed without evidence-based postoperative management plans. Patients are routinely admitted to the intensive care unit (ICU) postoperatively, but this may not be necessary in all cases. To determine (1) whether routine admission to the ICU after supraglottoplasty is warranted in all patients who undergo this procedure and (2) which factors predict requirement for ICU-level care. Retrospective case series and analysis of immediate postoperative outcomes of all children aged 1 month to 18 years who underwent supraglottoplasty at 1 tertiary-care children's hospital from January 1, 2008, through January 31, 2014. Exclusion criteria included preoperative admission to the ICU, preoperative need for positive-pressure ventilation, history of major airway reconstruction, or any concomitant other major procedure. Supraglottoplasty. Need for ICU-level care as defined by need for intubation, positive-pressure ventilation, multiple doses of racemic epinephrine, or oxygen via nasal cannula at greater than 4 L/min within the first 24 hours. Of 223 patients identified, 25 (11.2%) met our criteria for ICU-level care. Nine patients required intubation. Twenty of the 25 patients met ICU criteria within 4 hours of surgery. Univariate analysis was performed on 38 risk factors. Risk factors for ICU requirement that remained statistically significant on multivariable analysis (P < .05) included surgical duration longer than 30 minutes (odds ratio [OR], 4.48 [95% CI, 1.51-13.19]; P = .007), nonwhite race (OR, 4.42 [95% CI, 1.54-12.66]; P = .006), and a preoperative diagnosis of gastroesophageal reflux disease (OR, 0.10 [95% CI, 0.09-0.36]; P < .001). Our study suggests that most children undergoing supraglottoplasty do not require ICU-level care postoperatively. Those who require ICU-level care are likely to be identified within the first 4 hours after surgery. Consideration for routine ICU admission should be given to those with longer surgical duration and those of nonwhite race.


A follow-up study to monitor adult height among Spanish children with growth hormone deficiency who received biosimilar human recombinant growth hormone (Omnitrope®) during a phase III clinical trial.
An initial Phase III clinical trial has evaluated the efficacy and safety of biosimilar recombinant human growth hormone (rhGH; Omnitrope(®), Sandoz) in Spanish children with growth hormone deficiency (GHD). At the end of the study, those patients still growing were offered to remain on treatment (as in usual clinical practice), and continued to be monitored. The aim of this study was to determine the adult height achieved by the Spanish children who participated in the initial Phase III clinical trial, and to evaluate the long-term safety of rhGH treatment. This study was a multicenter, observational, retrospective follow-up study of patients who participated in the Phase III clinical trial (70 patients recruited). Auxological parameters [including height, height velocity, and their associated height standard deviation scores (HSDS)] were obtained from 39 patients. Safety was assessed by recording any adverse events (AEs). In total, 27 men and 12 women provided auxological data. At the start of the follow-up study, the mean age of the patients was 12.5 ± 2.7 years, mean height was 144.8 ± 13.9 cm and mean HSDS was -1.16 ± 0.63. By the end of the follow-up period, mean height had increased to 163.1 ± 7.6 cm (n = 36; men 165.5 ± 7.8 cm, women 157.6 ± 3.2 cm) and mean HSDS also increased to -1.01 ± 0.59 (n = 36; men -1.07 ± 0.52, women -0.86 ± 0.72). In terms of safety, no treatment-related AEs were reported during the study. This cohort of Spanish patients with GHD showed a positive response to rhGH treatment, achieving adult height within the local normal ranges. In addition, rhGH treatment was well tolerated, with no new or additional safety concerns.


Forgiveness and vengeance: the mediating role of gratitude.
This study examined the mediating role of gratitude on the relationship between forgiveness and vengeance. Participants were 331 university students (185 women, 146 men; ages 17 to 24 years), who completed a questionnaire package that includes the Vengeance Scale, the Trait Forgiveness Scale, and the Gratitude Questionnaire-Six Item Form. Hierarchical regression analyses showed that gratitude partially mediated the relationship between forgiveness and vengeance. The significance and limitations of the results were discussed.


Avian Reticuloendotheliosis in Chickens - An Update on Disease Occurrence and Clinical Course.
Avian reticuloendotheliosis (RE) represents an important immunosuppressive disease of poultry. The occurrence of RE in both chickens and turkeys has an immunosuppressive effect and may lead to vaccination failures. Avian reticuloendotheliosis virus (REV) is widely distributed in different kinds of birds, causing subclinical infections. Another important issue adhering to this disease is contamination of vaccines against fowl pox (FP) and Marek's disease (MD) with REV. The capability of REV to integrate into the genome of other larger DNA viruses complicates its diagnosis and prevention. There are no efficient vaccines against RE nor treatment, which also complicates how to limit its impact on poultry farming. This paper reviews the current state of knowledge of this important immunosuppressive agent of poultry emphasising the importance of this problem in terms of diagnosis of RE.


Salt-responsive ERF1 regulates reactive oxygen species-dependent signaling during the initial response to salt stress in rice.
Early detection of salt stress is vital for plant survival and growth. Still, the molecular processes controlling early salt stress perception and signaling are not fully understood. Here, we identified salt-responsive ERF1 (SERF1), a rice (Oryza sativa) transcription factor (TF) gene that shows a root-specific induction upon salt and hydrogen peroxide (H2O2) treatment. Loss of SERF1 impairs the salt-inducible expression of genes encoding members of a mitogen-activated protein kinase (MAPK) cascade and salt tolerance-mediating TFs. Furthermore, we show that SERF1-dependent genes are H2O2 responsive and demonstrate that SERF1 binds to the promoters of MAPK kinase kinase6 (MAP3K6), MAPK5, dehydration-responsive element bindinG2A (DREB2A), and zinc finger protein179 (ZFP179) in vitro and in vivo. SERF1 also directly induces its own gene expression. In addition, SERF1 is a phosphorylation target of MAPK5, resulting in enhanced transcriptional activity of SERF1 toward its direct target genes. In agreement, plants deficient for SERF1 are more sensitive to salt stress compared with the wild type, while constitutive overexpression of SERF1 improves salinity tolerance. We propose that SERF1 amplifies the reactive oxygen species-activated MAPK cascade signal during the initial phase of salt stress and translates the salt-induced signal into an appropriate expressional response resulting in salt tolerance.


[Isolation of Rec mutants of Bacillus subtilis via insertional mutagenesis].
A number of mutants supersensitive to mytomycine C were isolated via insertion of Tn917 into Bacillus subtilis chromosome. Six Rec mutants with lower transformation frequency, though with nondisturbed capacity of DNA binding and uptake, were isolated. Two of these mutations are situated in those chromosomal sites where location of Rec genes had not yet been registered.


Sibling history of myocardial infarction or stroke and risk of cardiovascular disease in the elderly: the Cardiovascular Health Study.
To assess the relationship between sibling history of myocardial infarction (MI) or stroke with cardiovascular disease (CVD) and risk factors in older adults. Prospective cohort study of 5,888 older adults participating in the Cardiovascular Health Study (CHS). History of MI and stroke in siblings was obtained by self-report. Participants with positive sibling histories were compared to those with negative histories to determine if prevalent or incident disease (coronary heart disease [CHD], MI, stroke, angina), subclinical CVD (carotid wall thickness, left ventricular mass, hypertension, diabetes, ankle-brachial index), CVD risk factors differed between groups. More than 91% (n = 5,383) of CHS participants reported at least one sibling. Sibling history of MI was associated with increased disease prevalence (CHD, MI, angina) and incidence (CHD, angina). Sibling history of stroke was associated with increased disease prevalence (CHD, angina). Sibling history of either MI or stroke was associated with increased disease prevalence and incidence for CHD, MI and angina, more subclinical disease, and a higher CVD risk profile. Sibling history of MI and stroke were markers of higher CVD risk status even in older adults. Of clinical importance, participants with positive sibling history have numerous risk factors amenable to intervention.


The Adjustment Disorder--New Module 20 as a Screening Instrument: Cluster Analysis and Cut-off Values.
Adjustment disorder (AjD) is a transient mental health condition emerging after stressful life events. Its diagnostic criteria have recently been under revision which led to the development of the Adjustment Disorder--New Module 20 (ADNM-20) as a self-report assessment. To identify a threshold value for people at high risk for AjD. As part of a randomized controlled trial evaluating a self-help manual for burglary victims, the baseline data of all participants (n=80) were analyzed. Besides the ADNM-20, participants answered self-report questionnaires regarding the external variables post-traumatic stress disorder symptomatology, depression, anxiety, and stress levels. We used cluster analysis and ROC analysis to identify the most appropriate cut-off value. The cluster analysis identified three different subgroups. They differed in their level of AjD symptomatology from low to high symptom severity. The same pattern of impairment was found for the external variables. The ROC analysis testing the ADNM-20 sum scoreagainst the theory-based diagnostic algorithm, revealed an optimal cut-off score at 47.5 to distinguish between people at high risk for AjD and people at low risk. The ADNM-20 distinguishes between people with low, moderate, and high symptomatology. The recommendation for a cut-off score at 47.5 facilitates the use of the ADNM-20 in research and practice.