Primary cultured neurons devoid of cellular prion display lower responsiveness to staurosporine through the control of p53 at both transcriptional and post-transcriptional levels.
We assessed the contribution of the cellular prion protein (PrPc) in the control of neuronal apoptosis by examining cell death in both human cells and murine primary cultured neurons. We first confirmed our previous finding that staurosporine-induced caspase activation is increased by PrPc overexpression in HEK293 cells. We show here that this phenotype is fully dependent on p53 and that the control of p53 activity by PrPc occurs at both transcriptional and post-transcriptional levels in human cells. Of most interest, we demonstrate that neuronal endogenous PrPc also controls a p53-dependent pro-apoptotic phenotype. Thus, DNA fragmentation and TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling)-positive cells were lower in primary cultured neurons derived from Zrch-1 mice embryos in which PrPc has been abrogated than in wild-type neurons. PrPc knock-out neurons also displayed drastically diminished caspase-3-like activity and immunoreactivity together with reduced p53 expression and transcriptional activity, a phenotype complemented in part by PrPc transfection. Interestingly, p53 expression was also reduced in the brain of adult Prnp-/- mice. Neuronal PrPc likely controls p53 at a post-transcriptional level because the deletion of cellular prion protein is accompanied by a higher Mdm2-like immunoreactivity and reduced phosphorylated p38 MAPK expression. We therefore propose that the physiological function of endogenous cellular prion could be to regulate p53-dependent caspase-3-mediated neuronal cell death. This phenotype likely occurs through up-regulation of p53 promoter transactivation as well as downstream by controlling p53 stability via Mdm2 expression.


Apoptotic effects of proteasome and histone deacetylase inhibitors in prostate cancer cell lines.
Prostate cancer is one of the most common types of urological cancers. Despite the implementation of effective radiotherapy and chemotherapy methods, prostate cancer cells can still show resistance to treatment. In recent years, a combination of proteasome and histone deacetylase inhibitors has been used to treat various malignancies. In this study, we examined the cytotoxic and apoptotic effects of the proteasome inhibitor bortezomib (Velcade/PS-341) and histone deacetylase inhibitor trichostatin A (TSA), used either alone or in combination, on the human prostate LNCaP and PC3 cell lines. We investigated the cytotoxic activity of these inhibitors using a WST-1 assay, IkBα and caspase-3 mRNA levels by real-time polymerase chain reaction, and caspase-3 activity and activation of phosphorylated (p-IkBα) protein by Western blotting. Low-dose bortezomib and TSA synergistically induced apoptosis in both prostate cancer cell lines. Combination treatment with TSA with bortezomib effectively inactivated NFkB signaling, upregulated the predominant endogenous apoptotic factor caspase-3, and disrupted the NFkB pathway in the androgen-independent PC3 cell line. In contrast, androgen-dependent LNCaP cells showed upregulation of caspase-3 through a pathway other than NFkB. This study examined the possible clinical use of bortezomib and TSA, together with reduced doses of chemotherapeutic agents with high cytotoxicity, to determine their apoptotic effects on the NFkB pathway in prostate cancer cell lines. Therefore, combination bortezomib and TSA treatment may represent a novel therapeutic strategy for prostate cancer.


Hepatic sinusoidal cells in health and disease: update from the 14th International Symposium.
This review aims to give an update of the field of the hepatic sinusoid, supported by references to presentations given at the 14th International Symposium on Cells of the Hepatic Sinusoid (ISCHS2008), which was held in Tromsø, Norway, August 31-September 4, 2008. The subtitle of the symposium, 'Integrating basic and clinical hepatology', signified the inclusion of both basal and applied clinical results of importance in the field of liver sinusoidal physiology and pathophysiology. Of nearly 50 oral presentations, nine were invited tutorial lectures. The authors of the review have avoided writing a 'flat summary' of the presentations given at ISCHS2008, and instead focused on important novel information. The tutorial presentations have served as a particularly important basis in the preparation of this update. In this review, we have also included references to recent literature that may not have been covered by the ISCHS2008 programme. The sections of this review reflect the scientific programme of the symposium (http://www.ub.uit.no/munin/bitstream/10037/1654/1/book.pdf): 1. Liver sinusoidal endothelial cells. 2. Kupffer cells. 3. Hepatic stellate cells. 4. Immunology. 5. Tumor/metastasis. Symposium abstracts are referred to by a number preceded by the letter A.


Contribution of the mesolimbic dopamine system in mediating the effects of leptin and ghrelin on feeding.
Feeding behaviour is crucial for the survival of an organism and is regulated by different brain circuits. Among these circuits the mesolimbic dopamine (DA) system is implicated in the anticipation and motivation for food rewards. This system consists of the dopaminergic neurons in the ventral tegmental area (VTA), and their projections to different cortico-limbic structures such as the nucleus accumbens and medial prefrontal cortex. While the importance of this system in motivational drive for different rewards, including drugs of abuse, has been clearly established, its role in energy balance remains largely unexplored. Evidence suggests that peripheral hormones such as leptin and ghrelin are involved in the anticipation and motivation for food and this might be partially mediated through their effects on the VTA. Yet, it remains to be determined whether these effects are direct effects of ghrelin and leptin onto VTA DA neurons, and to what extent indirect effects through other brain areas contribute. Elucidation of the role of leptin and ghrelin signalling on VTA DA neurons in relation to disruptions of energy balance might provide important insights into the role of this neural circuit in obesity and anorexia nervosa.


A levels and intelligence as predictors of medical careers in UK doctors: 20 year prospective study.
To assess whether A level grades (achievement) and intelligence (ability) predict doctors' careers. Prospective cohort study with follow up after 20 years by postal questionnaire. A UK medical school in London. 511 doctors who had entered Westminster Medical School as clinical students between 1975 and 1982 were followed up in January 2002. Time taken to reach different career grades in hospital or general practice, postgraduate qualifications obtained (membership/fellowships, diplomas, higher academic degrees), number of research publications, and measures of stress and burnout related to A level grades and intelligence (result of AH5 intelligence test) at entry to clinical school. General health questionnaire, Maslach burnout inventory, and questionnaire on satisfaction with career at follow up. 47 (9%) doctors were no longer on the Medical Register. They had lower A level grades than those who were still on the register (P < 0.001). A levels also predicted performance in undergraduate training, performance in postregistration house officer posts, and time to achieve membership qualifications (Cox regression, P < 0.001; b=0.376, SE=0.098, exp(b)=1.457). Intelligence did not independently predict dropping off the register, career outcome, or other measures. A levels did not predict diploma or higher academic qualifications, research publications, or stress or burnout. Diplomas, higher academic degrees, and research publications did, however, significantly correlate with personality measures. Results of achievement tests, in this case A level grades, which are particularly used for selection of students in the United Kingdom, have long term predictive validity for undergraduate and postgraduate careers. In contrast, a test of ability or aptitude (AH5) was of little predictive validity for subsequent medical careers.


Effects of altered adipose tissue morphology on plasma insulin levels in the rat.
The usual covariates of adiposity--adipocyte size, total body fat, and food intake--were experimentally dissociated using three new models of altered adipose tissue morphology in the rat. It was thereby possible to test the hypothesis that plasma immunoreactive insulin level (IRI) is a function of mean adipocyte size. In two of the models, experimental and control rats differ substantially in total body fat but show no difference in mean adipocyte size. In these models, no difference in plasma IRI was found between experimental and control animals. In a third model, experimental and control rats differ in mean adipocyte size but not in total body fat or daily food intake. In this model, plasma IRI was found to differ between experimental and control rats. These observations demonstrate a close link between adipocyte size and plasma IRI and suggest that the hyperinsulinemia and peripheral insulin resistance of obesity are more likely due to adipocyte hypertrophy than to increases in total body fat or daily food intake.


On the solid state structure of 4-iodobenzoic acid.
The solid-state structure of 4-iodobenzoic acid has been confirmed by variable temperature X-ray diffraction, variable temperature solid-state NMR and differential scanning calorimetry. 4-iodobenzoic acid crystallizes in the space group P2(1)/n, and dimerizes in the solid state about a center of inversion. Using extensive X-ray crystallographic data collections, the placement of the carboxylate H atoms from the residual electron density in difference Fourier maps was determined. The position of the electron density associated with the proton is found to vary with temperature in that the population of the disordered sites changes with varying temperature. Determination of the crystal structure between the temperatures of 248 and 198 K was not possible due to a phase transition, an endothermic event occurring at 230.77 K. The phase transition is also indicated by a change in the relaxation time of the ring carbon atoms in the solid-state NMR data. Though the dominating force in the dimeric unit in the solid state is the presence of strong hydrogen bonds, there are also van der Waals forces present between the iodine atoms. In the layered structure, the iodine-iodine distance is within the van der Waals contact radii, an interaction which causes a deformation in the electron density of the iodine atoms.


Compound image segmentation of published biomedical figures.
Images convey essential information in biomedical publications. As such, there is a growing interest within the bio-curation and the bio-databases communities, to store images within publications as evidence for biomedical processes and for experimental results. However, many of the images in biomedical publications are compound images consisting of multiple panels, where each individual panel potentially conveys a different type of information. Segmenting such images into constituent panels is an essential first step toward utilizing images. In this article, we develop a new compound image segmentation system, FigSplit, which is based on Connected Component Analysis. To overcome shortcomings typically manifested by existing methods, we develop a quality assessment step for evaluating and modifying segmentations. Two methods are proposed to re-segment the images if the initial segmentation is inaccurate. Experimental results show the effectiveness of our method compared with other methods. The system is publicly available for use at: https://www.eecis.udel.edu/~compbio/FigSplit. The code is available upon request. firstname.lastname@example.com. Supplementary data are available online at Bioinformatics.


Clinical feasibility of monitoring m-THPC mediated photodynamic therapy by means of fluorescence differential path-length spectroscopy.
The objective quantitative monitoring of light, oxygen, and photosensitizer is challenging in clinical photodynamic therapy settings. We have previously developed fluorescence differential path-length spectroscopy (FDPS), a technique that utilizes reflectance spectroscopy to monitor microvascular oxygen saturation, blood volume fraction, and vessel diameter, and fluorescence spectroscopy to monitor photosensitizer concentration. In this paper the clinical feasibility of the technique is tested on eight healthy volunteers and on three patients undergoing PDT of oral cavity cancers. Model-based analysis of the measured spectra provide quantitative tissue parameters that are corrected for background tissue absorption, autofluorescence, and the transmission of the optical system; this method allows comparison of intra- and inter-subject parameters. The FDPS correctly estimated the absence of m-THPC in volunteers and detected photobleaching in the areas receiving treatment light in patients undergoing PDT treatment. This study demonstrates the feasibility of monitoring clinical photodynamic therapy treatments using optical spectroscopy.


Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder.
Patterns of daily human activity are controlled by an intrinsic circadian clock that promotes ∼24 hr rhythms in many behavioral and physiological processes. This system is altered in delayed sleep phase disorder (DSPD), a common form of insomnia in which sleep episodes are shifted to later times misaligned with the societal norm. Here, we report a hereditary form of DSPD associated with a dominant coding variation in the core circadian clock gene CRY1, which creates a transcriptional inhibitor with enhanced affinity for circadian activator proteins Clock and Bmal1. This gain-of-function CRY1 variant causes reduced expression of key transcriptional targets and lengthens the period of circadian molecular rhythms, providing a mechanistic link to DSPD symptoms. The allele has a frequency of up to 0.6%, and reverse phenotyping of unrelated families corroborates late and/or fragmented sleep patterns in carriers, suggesting that it affects sleep behavior in a sizeable portion of the human population.


Sequences related to HLA-DR alpha chain on human chromosome 6: restriction enzyme polymorphism detected with DC alpha chain probes.
Three sets of cosmid clones--containing the HLA-DR alpha chain gene and two additional related genes--were isolated from human genomic DNA libraries by using a cDNA probe for the HLA-DR alpha chain. Southern blot analysis using DNA from somatic cell hybrids indicated that all of the clones mapped to chromosome 6. Partial sequence analysis showed that the two additional related genes were highly homologous to each other, and to the HLA-DR alpha chain, in parts of the exon that encoded the alpha 2 domain but were more divergent in intron sequences. One of the genes corresponds to the HLA-DR-related DC series. DNA probes made from this gene revealed marked restriction enzyme polymorphism when hybridized to genomic DNA from HLA-DR typed homozygous cell lines. The patterns obtained from a number of homozygous and heterozygous cell lines correlated with the HLA-DR crossreactive serotypes and also indicated that there is a further sequence in the haploid human genome that is closely homologous with the DC alpha chain sequence. One family was studied and showed the expected HLA-DR-associated inheritance of restriction enzyme patterns. No polymorphism has yet been demonstrated in restriction enzyme fragments that include the other cloned sequence, which may correspond to the SB alpha chain gene or to a novel HLA-DR-related gene. These experiments indicate that there are at least three sequences in the human genome related, but not identical, to the HLA-DR alpha chain gene.


Two-step model for ultrafast interfacial electron transfer: limitations of Fermi's golden rule revealed by quantum dynamics simulations.
Interfacial electron transfer (IET) is one of the crucial steps in the light-harvesting process that occurs in various assemblies for solar energy conversion, such as dye-sensitized solar cells or dye-sensitized photoelectrosynthesis cells. Computational studies of IET in dye-semiconductor assemblies employ a variety of approaches, ranging from phenomenological models such as Fermi's golden rule to more complex methods relying on explicit solutions of the time-dependent Schrödinger equation. This work investigates IET in a model pyridine-TiO2 assembly, with the goals of assessing the validity of Fermi's golden rule for calculation of the IET rates, understanding the importance of conformational sampling in modeling the IET process, and establishing an approach to rapid computational screening of dye-sensitizers that undergo fast IET into the semiconductor. Our results suggest that IET is a two-step process, in which the electron is first transferred into the semiconductor surface states, followed by diffusion of the electron into the nanoparticle bulk states. Furthermore, while Fermi's golden rule and related approaches are appropriate for predicting the initial IET rate (i.e., the initial transfer of an electron from the dye into the semiconductor surface states), they are not reliable for prediction of the overall IET rate. The inclusion of conformational sampling at room temperature into the model offers a more complete picture of the IET process, leading to a distribution of IET rates with a median rate faster than the IET rate obtained for the fully-optimized structure at 0 K. Finally, the two most important criteria for determination of the initial IET rate are the percentage of electron density on the linker in the excited state as well as the number of semiconductor acceptor states available at the energy of the excited state. Both of these can be obtained from relatively simple electronic structure calculations at either ab initio or semiempirical levels of theory and can thus be used for rapid screening of dyes with the desired properties.


A Case of Bilateral Anesthesia Mumps after Cesarean Section under Spinal Anesthesia: A Rare Case and Literature Review.
A 30-year-old pregnant female presented to the emergency department with labor pain in her 39th week of pregnancy. Cesarean section under spinal anesthesia was the chosen route of delivery for this patient due to previous cesarean section in her first pregnancy. The delivery itself was uneventful but seven hours after the surgery, bilateral swelling of parotid glands were noted. Rehydration therapy and a single dose of hydrocortisone (100 mg IV route) were administered, and swellings were completely resolved on postoperative day 2. This is one of the rare cases of anesthesia mumps after spinal anesthesia, and we think rehydration therapy and the single dose corticosteroid may prove useful in these cases.


Connective Mourning: The Case of Mourning and Memorialization Practices on X.
This study offers a conceptual framework of connective mourning. The case of mourning and memorialization practices on X. The study demonstrates the crucially different memorialization, and mourning practices and the various resulting parasocial practices and dynamics that they enable. Using the mourning and memorialization of Queen Elizabeth II as a case study, the study point to an emerging practice where through high centrality and density of reciprocity, and low modularity, mourners on X stimulate commonality via decentralized and loose networks that allow for solidarity building during crisis such as mourning. On the Queen specifically, the study grouped those that posted about her death into four categories: the Grievers, the Lauders, the Accusers, and the Defenders. This study concludes that when collective mourning occurs, individuals have more reciprocal relationships on a dyadic level which decreases modularity of the network.


Irresponsible authorship and wasteful publication.
Fraud is a dramatic offense in scientific publishing but other offenses are more frequent and probably far more damaging. The most frequent lesser offenses are irresponsible authorship and wasteful publication. The authorship problems include listing of "authors" who made little or no contribution to the work reported and omitting of persons who made major contributions. Wasteful publication includes dividing the results in a single study into two or more papers ("salami science"); republishing the same material in successive papers (which need not have identical format and content); and blending data from one study with additional data to extract yet another paper that could not make its way on the second set of data alone ("meat extenders"). Wasteful publication may be the most frequent of these offenses and is probably the most damaging because of its economic implications for publishers, readers, libraries, and indexes.


Unusual Presentation of Lumbar Surgical Site Infection: A Case Study of Early Onset Pasteurella multocida Infection after Arthrodesis.
BACKGROUND Infection is a serious surgical complication that significantly increases morbidity rates and health care expenses. Most human Pasteurella multocida infections are soft-tissue infections caused by dog or cat bites. Pasteurella multocida (P. multocida) is present in the oral, nasopharyngeal, and upper respiratory tract microbiota among cats, dogs, and other domestic or wild animals. Here, we report a case of lumbar surgical site infection caused by this bacterium. CASE REPORT A 70-year-old diabetic and overweight woman had a Pasteurella multocida surgical site infection after lumbar arthrodesis carried out for lumbar stenosis associated with spondylolisthesis. The patient had been in contact with her cat and claimed to have simply slept with it in her bed. Multiple antibiotic therapies and 3 debridement-irrigations with change of spinal implants during the last revision were needed. CONCLUSIONS Infections caused by P. multocida are rare and most often occur as a result of animal scratches or bites, but can sometimes occur after simple contact with an animal. Surgical site infection of spinal arthrodesis due to Pasteurella multocida implies treatment difficulties. In case of Pasteurella multocida infection of lumbar spinal arthrodesis, even in the early period, implant removal seems to be useful to limit the appearance of biofilm more specific to this micro-organism.


Prediction of Hepatocellular Carcinoma Prognosis and Immune Cell Infiltration Using Gene Signature Associated with Inflammatory Response.
It has been demonstrated that the inflammatory response influences cancer development and can be used as a prognostic biomarker in various tumors. However, the relevance of genes associated with inflammatory responses in hepatocellular carcinoma (HCC) remains unknown. The Cancer Genome Atlas (TCGA) database was analyzed using weighted gene coexpression network analysis (WGCNA) and differential analysis to discover essential inflammatory response-related genes (IFRGs). Cox regression studies, both univariate and multivariate, were employed to develop a prognostic IFRGs signature. Additionally, Gene Set Enrichment Analysis (GSEA) was used to deduce the biological function of the IFRGs signature. Finally, we estimated immune cell infiltration using a single sample GSEA (ssGSEA) and x-cell. Our results revealed that, among the major HCC IFRGs, two (DNASE1L3 and KLKB1) were employed to create a predictive IFRG signature. The IFRG signature could correctly predict overall survival (O.S) as per Kaplan-Meier time-dependent roc curves analysis. It was also linked to pathological tumor stage and T stage and might be used as a prognostic predictor in HCC. GSEA analysis concluded that the IFRG signature might influence the immune response in HCC. Immunological cell infiltration and immune checkpoint molecule expression differed in the high-risk and low-risk groups. As a result of our findings, DNASILE may play a role in the tumor microenvironment. However, more research is necessary to confirm the role of DNASE1L3 and KLKB1.


Contributions of stratospheric water vapor to decadal changes in the rate of global warming.
Stratospheric water vapor concentrations decreased by about 10% after the year 2000. Here we show that this acted to slow the rate of increase in global surface temperature over 2000-2009 by about 25% compared to that which would have occurred due only to carbon dioxide and other greenhouse gases. More limited data suggest that stratospheric water vapor probably increased between 1980 and 2000, which would have enhanced the decadal rate of surface warming during the 1990s by about 30% as compared to estimates neglecting this change. These findings show that stratospheric water vapor is an important driver of decadal global surface climate change.


Comparative study of intravenous amiodarone and procainamide in the treatment of atrial fibrillation of recent onset.
The aim of the present study was to compare the safety and efficacy of amiodarone and procainamide in the acute cardiology setting. The study population consisted of 223 patients with symptomatic atrial fibrillation (AF). After administration of digoxin for ventricular rate control, all patients who failed to restore sinus rhythm (SR) were randomized into 2 groups: group A (113 patients) were administered 300 mg amiodarone intravenously over 30 min and, in case of failure to restore SR, amiodarone of 20 mg/kg/24 h was administered intravenously. Group B (110 patients) were intravenously administered a bolus dose of 1 gm procainamide, at an infusion rate 50/mg/min, and, in case of failure to restore SR, 2 mg/min for the next 24 h. The rate of cardioversion to SR was similar between amiodarone (81.4%) and procainamide (82.7%) (P=NS). Procainamide loading recorded faster cardioversion times than amiodarone loading (P=0.02), but there was no significant difference after that. Amiodarone caused a significant decrease on systolic blood pressure compared to procainamide for the first 18 h (P<0.001), and a significant decrease in the diastolic blood pressure for the first 6 h (P<0.001). Side-effects for either medication were sparse. The only real prognostic factor for successful cardioversion remains the size of left atrium. Both drugs were equally effective in restoring SR, though procainamide acts quicker in the loading phase. Both medications are safe and side effects develop only in the maintenance phase.


The absence of correlation between immunoregulatory T cells and induced lymphoproliferative response in treated B-chronic lymphocytic leukemia patients.
Many data suggest T cell functional impairment in B-cell chronic lymphocytic leukemia (B-CLL). The mechanism responsible for this phenomenon is still unresolved. In 88 B-CLL patients (RAI II-IV) the relationship between immunoregulatory T cells and PHA induced lymphoproliferative response (LPR) was analysed before and after the therapy. The number of peripheral blood CD3+, CD4+ and CD8+ T lymphocytes was determined by indirect immunofluorescence assay using monoclonal antibodies. LPR was estimated in whole blood culture method. The absolute number of CD3+, CD4+ and CD8+ cells in untreated CLL patients was much higher than in healthy controls (n = 26), but the percentages of these subpopulations, CD4/CD8 ratio and LPR to PHA were significantly (p < 0.00001) decreased. The chemotherapy induced a significant rise of CD3+ and CD4+ percentages (p < 0.006 < p < 0.022 respectively) in comparison to baseline levels, but their levels remained significantly (p < 0.00001) lower than the controls. The CD4/CD8 ratio was also elevated after the therapy (p < 0.048) but remained below the normal value as well. The absolute number of CD3+ and CD4+ T cells were normalized after treatment, while the CD8+ cells were still higher (p < 0.044) than controls. The increase of LPR has been registered after treatment, but it failed to reach the control values. We could not find any correlation between the number of immunoregulatory T cells and induced LPR (r = 0.07, for CD4+; r = 0.09 for CD8+ cells). These data indicate some profound lymphoid cell defect in CLL patients affecting CD8+ proliferation as well as LPR.


Genetically encoded photoswitching of actin assembly through the Cdc42-WASP-Arp2/3 complex pathway.
General methods to engineer genetically encoded, reversible, light-mediated control over protein function would be useful in many areas of biomedical research and technology. We describe a system that yields such photo-control over actin assembly. We fused the Rho family GTPase Cdc42 in its GDP-bound form to the photosensory domain of phytochrome B (PhyB) and fused the Cdc42 effector, the Wiskott-Aldrich Syndrome Protein (WASP), to the light-dependent PhyB-binding domain of phytochrome interacting factor 3 (Pif3). Upon red light illumination, the fusion proteins bind each other, activating WASP, and consequently stimulating actin assembly by the WASP target, the Arp2/3 complex. Binding and WASP activation are reversed by far-red illumination. Our approach, in which the biochemical specificity of the nucleotide switch in Cdc42 is overridden by the light-dependent PhyB-Pif3 interaction, should be generally applicable to other GTPase-effector pairs.


[Meconium evacuation to improve feeding tolerance in very low birth weight preterm infants (Emita Protocol)].
It has been reported that feeding tolerance in preterm infants is associated with an early passage of meconium. Prospective, randomized or historical control studies that stimulate meconium evacuation have reported varied results. This study was intented to evaluate the use of enemas to speed up meconium evacuation, facilitating feeding tolerance. A controlled multicenter randomized trial that evaluated the use of physiological saline enemas with glycerol (0.8 ml glycerol + 3 ml saline or 1 ml glycerol + 5 ml saline depending on babies weighing less or more than 800 g at birth, respectively) versus simulation. This procedure was performed in the first 96 hours of life in infants with birth weight between 500 and 1,250 g. Maternal (preterm delivery, clinical chorioamnionitis, gestational hypertension, administration of magnesium sulfate and prenatal corticosteroids, fetal Doppler altered, type of delivery, gender, weight and gestational age, assessment of Apgar and need for assisted ventilation and oxygenotherapy) and nutritional history (age when feeding volumes of 100 ml/kg/day and full enteral feeding were reached, age to remove meconium, number of days on parenteral nutrition, weight at 28 days, weekly volumes of breast milk and preterm formula) were described. No significant differences were obtained regarding the age to reach full enteral intake or 100 ml/kg/day were found among the 101 patients in the study. Also, no differences in the following secondary variables are observed: number of episodes of late sepsis with or without positive blood culture, hyperbilirubinemia, necrotizing enterocolitis and intraventricular hemorrhage. The routine use of saline enemas and glycerin in this study does not alter the enteral feeding tolerance in very low birth weight preterm infants.


Both BC-box motifs of adenovirus protein E4orf6 are required to efficiently assemble an E3 ligase complex that degrades p53.
Small DNA tumor viruses typically encode proteins that either inactivate or degrade p53. Human adenoviruses encode products, including E4orf6 and E1B55K, that do both. Each independently binds to p53 and inhibits its ability to activate gene expression; however, in combination they induce p53 degradation by the ubiquitin pathway. We have shown previously that p53 degradation relies on interactions of E4orf6 with the cellular proteins Cul5, Rbx1, and elongins B and C to form an E3 ligase similar to the SCF and VBC complexes. Here we show that, like other elongin BC-interacting proteins, including elongin A, von Hippel-Lindau protein, and Muf1, the interaction of E4orf6 is mediated by the BC-box motif; however, E4orf6 uniquely utilizes two BC-box motifs for degradation of p53 and another target, Mre11. In addition, our data suggest that the interaction of E1B55K with E4orf6 depends on the ability of E4orf6 to form the E3 ligase complex and that such complex formation may be required for all E4orf6-E1B55K functions.


Sympathetic postganglionic cholinergic fibres.
When the postganglionic fibres to the nictitating membrane are stimulated in a cat treated with reserpine, the membrane contracts. The contraction is increased after the injection of eserine and is abolished with atropine. Thus the fibres stimulated appear to be cholinergic. When the splenic nerve is stimulated in a cat treated with reserpine there is similar evidence of the presence of cholinergic fibres; the spleen dilates, the dilatation is greater in the presence of eserine and is abolished by atropine. The hypogastric nerves when stimulated cause inhibition of the uterus of the virgin cat. When the cat is treated with reserpine, stimulation then causes contraction which is increased in the presence of eserine and abolished by atropine. There is also evidence of cholinergic fibres in the postganglionic supply to the vessels of the rabbit's ear. From this and other evidence it is suggested that a form of adrenergic mechanism may exist such that cholinergic fibres in the postganglionic sympathetic supply liberate acetylcholine; this in turn liberates noradrenaline from a store around the sympathetic nerve ending.


A transcriptome-based resolution for a key taxonomic controversy in Cupressaceae.
Rapid evolutionary divergence and reticulate evolution may result in phylogenetic relationships that are difficult to resolve using small nucleotide sequence data sets. Next-generation sequencing methods can generate larger data sets that are better suited to solving these puzzles. One major and long-standing controversy in conifers concerns generic relationships within the subfamily Cupressoideae (105 species, approx. 1/6 of all conifers) of Cupressaceae, in particular the relationship between Juniperus, Cupressus and the Hesperocyparis-Callitropsis-Xanthocyparis (HCX) clade. Here we attempt to resolve this question using transcriptome-derived data. Transcriptome sequences of 20 species from Cupressoideae were collected. Using MarkerMiner, single-copy nuclear (SCN) genes were extracted. These were applied to estimate phylogenies based on concatenated data, species trees and a phylogenetic network. We further examined the effect of alternative backbone topologies on downstream analyses, including biogeographic inference and dating analysis. Based on the 73 SCN genes (>200 000 bp total alignment length) we considered, all tree-building methods lent strong support for the relationship (HCX, (Juniperus, Cupressus)); however, strongly supported conflicts among individual gene trees were also detected. Molecular dating suggests that these three lineages shared a most recent common ancestor approx. 60 million years ago (Mya), and that Juniperus and Cupressus diverged about 56 Mya. Ancestral area reconstructions (AARs) suggest an Asian origin for the entire clade, with subsequent dispersal to North America, Europe and Africa. Our analysis of SCN genes resolves a controversial phylogenetic relationship in the Cupressoideae, a major clade of conifers, and suggests that rapid evolutionary divergence and incomplete lineage sorting probably acted together as the source for conflicting phylogenetic inferences between gene trees and between our robust results and recently published studies. Our updated backbone topology has not substantially altered molecular dating estimates relative to previous studies; however, application of the latest AAR approaches has yielded a clearer picture of the biogeographic history of Cupressoideae.


Health related quality of life in men with prostate cancer.
Quality of life is of great concern to patients considering treatment options for prostate cancer. In the absence of clinical trial data clearly demonstrating that a particular treatment is superior to another for localized prostate cancer, in terms of cause specific survival, patients may value quality of life as much as quantity of life. The goal of this review is to familiarize the reader with the methodology of quality of life research and to review the recent literature on quality of life outcomes in prostate cancer. A structured MEDLINE review of literature on health related quality of life in prostate cancer for the years 1995 to 2001 was performed, and was augmented with highly relevant articles from additional selected journals. In the case of advanced or metastatic disease, where the goal of treatment is palliation and symptom-free survival, quality of life often becomes the primary desired outcome. In localized disease all treatments affect health related quality of life, although the impact of each therapy on sexual, urinary and bowel function is unique. Although a highly personal and subjective entity, health related quality of life can be assessed using rigorous and scientifically stringent methods from the field of psychometric test theory. A substantial amount of literature exists regarding the use of established and validated instruments for assessing the impact of prostate cancer and its treatment on health related quality of life. This information is of critical importance when counseling men with newly diagnosed prostate cancer regarding treatment choices and is also helpful in setting appropriate expectations for men with metastatic disease.


Endogenous xenotropic murine leukemia virus-related sequences map to chromosomal regions encoding mouse lymphocyte antigens.
DNAs of all inbred mouse strains contain multiple copies (18 to 28 copies per haploid mouse genome) of endogenous xenotropic murine leukemia virus-related sequences detectable by Southern analysis with a xenotropic murine leukemia virus env gene-specific probe. After PvuII digestion, we identified a subset of xenotropic murine leukemia virus-related sequences that are well resolved by agarose gel electrophoresis and can be mapped to specific chromosomes by using recombinant inbred mouse strains. Interestingly, three of six xenotropic proviral loci that we mapped were integrated near genes encoding mouse lymphocyte antigens (Ly-m22, chromosome 1; Ly-m6, chromosome 2; and Ly-m10, chromosome 19) and a fourth xenotropic proviral locus mapped near a gene on chromosome 4 that has a major influence on xenotropic virus cell surface antigen levels. These studies indicate that xenotropic proviral loci are located on many different mouse chromosomes and may be useful markers for molecularly cloning and characterizing regions of the mouse genome important in lymphocyte development.


Neoadjuvant Chemotherapy Based on Abraxane/Human Neutrophils Cytopharmaceuticals with Radiotherapy for Gastric Cancer.
Gastric cancer remains one of the most lethal cancers with high incidence and mortality worldwide. The majority of gastric cancer patients are those who have first been diagnosed in advanced stage, in which the standard chemo-radiotherapy produces limited benefit along with severe general toxicity, thus the demand for improved therapeutic efficacy and decreased side effects drives the development of novel therapeutic strategies. Here, a neoadjuvant chemotherapy based on Abraxane/human neutrophils (NEs) cytopharmaceuticals with radiotherapy is presented for effective cancer treatment. Human NEs, the most abundant white blood cells in peripheral blood, are developed to carry Abraxane, the commercial albumin-bound paclitaxel nanoparticle, to form cytopharmaceuticals (Abraxane/NEs) which have been confirmed to maintain the intrinsic functions of human NEs. The modest radiation is applied not only to exert tumor disruption, but also to increase the release of inflammatory factors which guide the NEs homing to the tumoral sites. These amplified inflammatory factors at tumor sites excessively activate Abraxane/NEs to form neutrophil extracellular traps, along with a burst release of Abraxane to induce superior tumor suppression. This adjuvant chemo-radiotherapy based on cytopharmaceuticals may provide new opportunities for advanced cancer treatment, which reveals the huge clinical potential of human neutrophils as drug delivery vectors.


Support for schizophrenia susceptibility locus on chromosome 2q detected in a Swedish isolate using a dense map of microsatellites and SNPs.
Extended pedigrees are not only very useful to identify disease genes for rare Mendelian conditions, but they may also help unravel the genetics of complex diseases such as schizophrenia. In this study we performed genome-wide multipoint non-parametric linkage (NPL) score calculations using 825 microsatellites and 5,366 single nucleotide polymorphisms (SNPs), respectively, and searched for haplotypes shared by affected individuals, in three multiplex families including 29 genotyped affected individuals which in total contains 49 relative pairs useful for linkage studies. The most consistent results for microsatellites and SNPs were observed on 2q12.3-q14.1 (NPL scores 2.0, empirical P-value 0.009). However, the overall highest NPL score was observed on chromosome 2q33.3 using SNPs (NPL score 2.2, empirical P-value 0.007). Other chromosomal regions were detected on 5q15-q22.1, with microsatellites (NPL scores 1.7, empirical P-value 0.021) and with SNPs (NPL scores 2.0, empirical P-value 0.010) and on 5q23.1 (NPL score 1.9, empirical P-value 0.012) and 8q24.1-q24.2 (NPL score 2.1, empirical P-value 0.009) when using SNPs. The analysis of extended pedigrees allowed the search for haplotypes inherited identical by decent (IBD) by affected individuals. In all regions with NPL score >1.9 we found haplotypes inherited IBD by multiple cases. However, no common haplotypes were found for affected individuals in all families. In conclusion our NPL results support earlier findings suggesting that 2q and possibly 5q and 8q contain susceptibility loci for schizophrenia. Haplotype sharing in families helped to delimit the detected regions that potentially are susceptibility loci for schizophrenia.


Hepatotrophic effects of FK506 in dogs.
Portacaval shunt (Eck fistula) in dogs causes hepatocyte atrophy and organelle disruption, as well as tripling of hepatocyte mitoses. After submitting dogs to this procedure, FK506 was infused into the tied-off left portal vein. The size, anatomic quality, and replication of hepatocytes were enhanced in the portion of liver infused with FK506, with a significant spillover effect in the noninfused portion. These hepatotrophic qualities of FK506 may explain part of FK506's efficacy for the treatment of chronic liver rejection. Also, the observations support a trial with this drug for the treatment of autoimmune liver diseases because, in addition to turning off the immunologic genesis of such disorders, repair and regeneration of the damaged liver may be augmented. Finally, these hepatrophic qualities are part of an emerging spectrum of biologic effects caused by drugs that may modulate the enzyme cis-trans peptidyl-prolyl isomerase (PPIase), the principal constituent of the cytosolic binding sites of FK506, repatomycin, cyclosporine, and presumably other immunosuppressive drugs as yet undiscovered.


Mortality pattern of isolated Indians in northwestern Ontario: a 10-year review.
The mortality experience of an isolated Indian population in the Sioux Lookout Zone of northwestern Ontario from 1972 through 1981 is reviewed and compared with that of the Canadian population. Standardized mortality ratios for major categories of causes computed showed excessive risks in most conditions. Notable exceptions included circulatory diseases and neoplasms. Injuries and poisonings accounted for more than one-third of deaths. The proportionate mortality and age-specific mortality rates were considerably higher in all age groups in the Sioux Lookout Zone than in the whole of Canada. Excessive risks were found in almost all categories of accidental and violent deaths except motor vehicle accidents and accidental falls. Local conditions that contributed to the pattern observed are discussed. More than 90 percent of deaths from accidents and violence occurred before the medical care system was involved, highlighting the need for primary preventive strategies in reducing mortality due to these causes. While the infant mortality rate declined, pneumonia, gastroenteritis, and meningitis still accounted for 28 percent of infant deaths in the decade. Even with sudden infant death syndrome excluded, about 25 percent of infant deaths still occurred at home. Some features of the pattern of mortality reported here are also observed in other North American Indian groups undergoing the stresses of social change.


History of laparoscopic surgery.
Laparoscopic surgery, whose development has been so impressive in the last decade, was initially introduced at the beginning of this century by Dimitri Ott, Georg Kelling and Hans Christian Jacobeus. Von Ott inspected the abdominal cavity of a pregnant women in 1901 and afterwards Georg Kelling performed a procedure, called "koelioscopie", closer to the definition of modern laparoscopy. In the same year Jacobeus published his first report of what he called "Laparothorakoskopie". In the following years several authors in Europe and in the United States performed laparoscopic procedures for diagnostic purposes. It was only with the introduction of the rod-lens optical system and of the cold light fiber-glass illumination that laparoscopy became more popular especially in the gynecologist departments. At this time laparoscopy in general surgery was mainly performed for the diagnosis of liver disorders and abdominal trauma, until the intuition of Lukichev in 1983 and Muhe in 1985 who performed their personal technique of laparoscopic cholecystectomy in humans. Their rudimental techniques did not receive the attention they probably deserved and increasing interest in laparoscopy among general surgeons developed only after the French gynecologist Mouret performed in 1987 the first acknowledged laparoscopic cholecystectomy by means of four trocars. Operative laparoscopy has advanced surprisingly in the last ten years. Several operative procedures have been performed by this new approach. After its tumultuous debut, laparoscopic surgery is now entering a phase of slower development and nowadays it is impossible to predict the immediate and long-term evolution of the technique.


Prevalence of cardiovascular disease and risk factors, quality of life, and health behaviors of cancer survivors and their spouses: findings from MEPS.
Few population-based studies have examined the prevalence of cardiovascular disease (CVD) and risk factors, quality of life (QOL), and health behaviors of cancer survivors and their spouses. This case-control study aimed to fill this gap using the data from a set of large-scale surveys of individuals and families across the USA. Data were obtained from the 2010-2015 Medical Expenditure Panel Survey (MEPS). Using one-to-many (1:5) propensity score matching, we identified cancer survivors (N = 1037) and noncancer-matched controls (N = 5185), as well as survivor spouses (N = 1038) and matched controls (N = 5190). We used weighted multivariable logistic and linear regressions to examine the categorical and numerical outcomes. Compared with noncancer controls, survivors have higher rates of stroke (p < .05), hypertension (p < .05), high cholesterol (p < .01), fair or poor health (p < .0001), and report self-reported worse physical QOL scores (PCS) (p < .0001). A higher percentage of survivors report receiving BP checks (p < .01), serum cholesterol assessments (p < .001), routine physical checkups (p < .01), blood stool tests (p < .05), colonoscopies (p < .0001), and flu vaccinations (p < .05). Survivor spouses, compared to their respective matched controls, reported higher rates of serum cholesterol testing (p < .001), routine physical checkups (p < .01), and flu vaccinations (p < .01). Compared to the general population, cancer survivors are at higher risk for CVD, report worse physical QOL, and, along with their spouses, more frequently receive certain preventive health care services. There is a need for intervention to more fully engage cancer survivors and spouses in lifestyle behavior change associated with decreased CVD and related risk factors and improved QOL.


Stocking impacts the expression of candidate genes and physiological condition in introgressed brook charr (Salvelinus fontinalis) populations.
Translocation of plants and animal populations between environments is one of the major forms of anthropogenic perturbation experienced by pristine populations, and consequently, human-mediated hybridization by stocking practices between wild and exogenous conspecifics is of increasing concern. In this study, we compared the expression of seven candidate genes involved in multifactorial traits and regulatory pathways for growth as a function of level of introgressive hybridization between wild and domestic brook charr to test the null hypothesis of no effect of introgression on wild fish. Our analyses revealed that the expression of two of the genes tested, cytochrome c oxidase VIIa and the growth hormone receptor isoform I, was positively correlated with the level of introgression. We also observed a positive relationship between the extent of introgression and physiological status quantified by the Fulton's condition index. The expression of other genes was influenced by other variables, including year of sampling (reflecting different thermal conditions), sampling method and lake of origin. This is the first demonstration in nature that introgression from stocked populations has an impact on the expression of genes playing a role in important biological functions that may be related with fitness in wild introgressed populations.


Gendered health institutions: examining the organization of health services and men's use of HIV testing in Malawi.
Men in sub-Saharan Africa are less likely to use HIV testing services than their female counterparts. Norms of masculinity are frequently cited as the main barrier to men's use of HIV testing services, but very little is known about how health institutions are organized to facilitate or impede men's care. We examined the organization of health institutions in Malawi, and implications for men's use of HIV testing services. A mixed methods ethnography was conducted in Malawi between October 2013 and September 2014. National Ministry of Health guidelines from 2012 to 2014 were analysed, counting the frequency of recommended preventative services by sex. In-depth interviews were conducted with 18 healthcare workers and 11 national key informants (29 total). Five rural health facilities participated in direct observation and 52 observational journals were completed to document the structure and implementation of HIV services within local facilities. All data were analysed using the theory of gendered organization. Findings were grouped into one of the three theoretical levels of organization: (1) organizational policy; (2) organizational practice; and (3) structure of gendered expectations. Health institutions were gendered across three levels. Organizational policy: National guidelines omitted young and adult men's health during reproductive years (176-433 recommended visits for women vs. 32 visits for men). Health education strategies focused on reproductive and child health services, with little education strategies targeting men. Organizational practice: HIV testing was primarily offered during reproductive and child health services and located near female-focused departments within health facilities. As these departments were women's spaces, others could easily tell that men were using HIV services. Structure of gendered expectations: Clients who successfully accessed HIV testing services were perceived as exemplifying characteristics that were traditionally considered feminine: compliance (obeying instructions without explanation); deference (respecting providers regardless of provider behaviour); and patience ("waiting like a woman"). Health institutions in Malawi were organized in ways that created substantial, multilevel barriers to men's HIV testing and reinforced perceptions of absent, difficult men. Future research should prioritize a gendered organization framework to understand and address the complex realities of men's constrained access to HIV services.


The Role of the Speaker, the Listener, and Their Joint Contributions During Communicative Interactions: A Tripartite View of Intelligibility in Individuals With Dysarthria.
Purpose We present a tripartite view of intelligibility in which the contributions of both the speaker and listener, as well as their joint effort during interaction, are considered. While considerable research has examined communicative interactions in situ, there is a critical gap in current knowledge on how speech intelligibility unfolds during such interactions. Here, we argue that research examining speech intelligibility in communicative interactions may provide important groundwork for advancement in clinical interventions for individuals with dysarthria. Method First, we describe the view and argue for its consideration as a powerful way of thinking about speech intelligibility. We then briefly situate the view in the relevant literature on speech intelligibility and existing theoretical frameworks. We then identify suitable methodological paradigms for studying joint contributions to intelligibility and, lastly, discuss the clinical application and potential impact of this tripartite view. Conclusions Speech communication occurs through interaction; however, in the laboratory and clinic, emphasis is usually placed on individual speakers and listeners. We have proposed that it is critical to consider how the joint contributions of speakers and listeners affect speech intelligibility in communicative interaction. This conceptualization is well aligned with the International Classification of Functioning, Disability and Health, and the findings from such an approach will allow us to better understand how to maximize available resources to enhance speech intelligibility.


Multiple chromosomal rearrangements in a spontaneously arising t(6;7) rat immunocytoma juxtapose c-myc and immunoglobulin heavy chain sequences.
Spontaneously arising immunocytomas in Lou/Wsl rats contain a consistent translocation between chromosomes 6 and 7. The c-myc gene has been localized to chromosome 7 and has been shown to be rearranged in the majority of the rat immunocytomas. We now report the cloning of the rearranged 11-kilobase EcoRI c-myc fragment from the IgE-secreting IR75 tumor. Sequence analysis revealed that the cytogenetically visible t(6;7) translocation must have involved several events in this tumor. One event has led to the juxtaposition of c-myc and the switch mu region, in a head-to-head orientation. The breakpoint is approximately 850 base pairs upstream from the proximal c-myc promoter on chromosome 7. This area is distinct from the more common mouse plasmacytoma- and Burkitt lymphoma-associated translocation breakpoints and also differs from the known murine retroviral insertion sites. A second rearrangement has led to the transposition of sequences upstream from the switch gamma 1 region to the c-myc-distant end of the switch mu region, tail-to-tail. This requires at least two events, including one inversion. In addition to showing that identical loci (c-myc, immunoglobulin) are juxtaposed via chromosomal translocations in three different tumors (Burkitt lymphoma, mouse plasmacytoma, and rat immunocytoma) in different species (human, mouse, and rat), the multiple rearrangements in IR75 and some other tumors emphasize the selective value of c-myc activation by an immunoglobulin locus in the tumorigenic process.


Recombinant human growth/differentiation factor 5 stimulates mesenchyme aggregation and chondrogenesis responsible for the skeletal development of limbs.
We have expressed and biologically characterized recombinant human growth/differentiation factor 5 (huGDF5). This protein is composed of a mature homodimer consisting of 15 kD subunits. Using recombinant expressed protein, we have demonstrated that huGDF5 in vitro stimulated mesenchyme aggregation and chondrogenesis in rat limb bud cells. In vivo, partially purified huGDF5 induced cartilage and bone formation in muscular tissues of rodents. However, in contrast to the effects of other BMPs, as for example BMP-2, the osteoblastic MC3T3-E1 cells did not respond to huGDF5 as measured by alkaline phosphatase activity. These results suggest that the action of GDF5 may be relatively specific for chondrogenesis during the entire process of the endochondral bone formation. GDF5 may control the morphogenesis of cartilaginous tissue, including joints, in the skeletal development of limbs.


Clinical, Bacteriological and Immunological Profile of 20 Patients with Dermatitis Cruris Pustulosa Et Atrophicans.
This study was carried out to determine whether an abnormality in polymorphonuclear leucocyte (PMN) function and/or a deficiency in immunoglobulins (IgG and IgM) and complement (C4 and C3) could be the underlying cause of chronicity in DCPA. Twenty adult males were studied. Penicillin resistant coagulase positive S. Aureus was isolated from the pus samples of all the patients. AU the strains were susceptible to chloramphenicol, cotrimoxazole anderythromycin. Patch and usage tests done with coconut and mustard oil were negative. The total and differential leucocyte counts in all the patients were within normal limits. In vitro PMN functions were estimated by measuring percentage phagocytosis and intra cellular killing capacity (ICK) using S. aureus as the test organism. Both these parameters were significantly raised before treatment (p.001) and returned to normal after treatment. Immunolobulin levels did not rise above normal which may suggest a depressed response to bacterial infection. Complement (C3) levels were significantly lower (p) than the controls.


From the discovery of helminths to the discovery of their carcinogenic potential.
Cancer involves a major aberration in the normal behaviour of cells, making them divide continuously, which interferes with the normal physiology of the body. The link between helminths and their cancer-inducing potential has been proposed in the last century. The exact pathway is still not clear but chronic inflammation in response to the deposited eggs, immune response against soluble egg antigens, and co-infection with a third party (a bacteria, a virus, or infection leading to a change in microbiome) seems to be the reasons for cancer induction. This review looks into the historical outlook on helminths along with their epidemiology, morphology, and life cycle. It then focuses on providing correlations between helminth infection and molecular mechanism of carcinogenesis by elaborating upon epidemiological, clinical, and surgical studies. While the cancer-inducing potential has been convincingly established only for a few helminths and studies point out towards possible cancer-inducing ability of the rest of the helminths elucidated in this work, however, more insights into the immunobiology of helminths as well as infected patients are required to conclusively comment upon this ability of the latter.


High-fluence and high-density treatment of perioral rhytides using a new, fractionated 2,790-nm ablative erbium-doped Yttrium Scandium Gallium Garnet Laser.
In this study, we evaluated the safety and efficacy of a novel 2,790-nm erbium-doped yttrium scandium gallium garnet (Er:YSGG) laser system for the treatment of facial photodamage and perioral wrinkles using a single-treatment, high-fluence, high-density protocol. Eleven female participants with Fitzpatrick skin types II to III and facial wrinkles underwent a single full-face fractional ablative treatment with a 2,790-nm Er:YSGG laser. Follow-up visits were completed at 1, 2, and 6 weeks 3 and 6 months. Quartile improvement scale (0-4) and Fitzpatrick wrinkle scores (1-9) were used for the assessments. Based on blinded photographic assessments, the mean difference in Fitzpatrick wrinkle scores for full face wrinkles was 1.5 ± 1.2 (a reduction from 6.6 to 5.1; paired t-test, p = .003). There was also a statistically significant mean reduction of 1.7 ± 1.3 in perioral wrinkle scores (from 6.7 to 5.0; p = .002). No serious adverse events were reported. A novel, fractionated, ablative 2,790-nm Er:YSGG laser can safely and effectively treat photodamage and perioral wrinkles in a single treatment using a high-fluence, high-density protocol. Cutera provided the equipment used in this study and funding to Dr. Goldberg.


The development of software to support multiple systematic review types: the Joanna Briggs Institute System for the Unified Management, Assessment and Review of Information (JBI SUMARI).
Systematic reviews play an important role in ensuring trustworthy recommendations in healthcare. However, systematic reviews can be laborious to undertake and as such software has been developed to assist in the conduct and reporting of systematic reviews. The Joanna Briggs Institute and its collaborating centres consist of thousands of researchers, academics and clinicians across the globe conducting systematic reviews of various types. To support them in their work, modern software and online tools are required. Our aim was to develop a software program to support systematic reviewers across the globe. A working party was formed with extensive consultation with members of the Joanna Briggs Collaboration focusing on ideal features of a software program to support systematic reviews. The new systematic review software was built using an agile methodology and designed to be a modern web application. The new systematic review software, the Joanna Briggs Institute System for the Unified Management, Assessment and Review of Information (JBI SUMARI), was successfully developed through an iterative process of development, feedback, testing and review. The software is now available (https://www.jbisumari.org/) and supports the entire systematic review process for different types of systematic reviews. An agile software development approach combined with wide consultation and user testing can facilitate systematic review software design and development. This new software can support systematic reviews and guideline developers to create systematic reviews for a diverse range of questions.


Effects of a novel differentiation factor on the development of catecholamine traits in noncatecholamine neurons from various regions of the rat brain: studies in tissue culture.
The muscle-derived differentiation factor called MDF initiated expression of the catecholamine (CA) enzyme tyrosine hydroxylase (TH) in non-CA neurons isolated from a variety of regions in the rat brain. Specifically, subpopulations of neurons from the striatum, collicular plate, and cerebellum were TH-immunoreactive after an overnight exposure to MDF in culture. The number of immunopositive cells was greatest in the striatum, where more than half of all plated neurons expressed the enzyme. In contrast, MDF had no effect on the central neurons of the hippocampus or on peripheral sensory neurons. In 3H-thymidine studies, only brain neurons that had already withdrawn from mitosis expressed TH. These cells remained open to the epigenetic influence of MDF only during a brief and defined critical period that appears to be timed intrinsically. Without daily replenishment of MDF, expression of the enzyme disappeared after several days in culture, suggesting that MDF was rapidly depleted or degraded in vitro. However, in the continued presence of MDF, TH expression was maintained indefinitely, thus producing a permanent alteration in phenotype. Moreover, a single exposure to MDF during the critical period was sufficient to render neurons permanently receptive to the molecule so that TH expression could be reinitiated many days later. It is postulated that a memory of this biochemical interaction was established in these neurons, making transmitter phenotypic plasticity possible at later stages.


Missed Opportunities and the Impact of the Pandemic.
Benjamin is a 9-month-old, former 36-week gestation infant who presented to the high-risk infant follow-up clinic with parental concern for developmental regression. His mother reported that Benjamin seemed to be developing typically, but over the past 2 months, he has lost the ability to visually track objects, is not as engaged with her as he once was, and now only rarely makes babbling sounds. His mother also reported episodes of intermittent "bursts" of stiffening of his extremities and brief staring spells. Benjamin's mother described him as a "good, quiet baby." She commented that he used to laugh and cry more frequently but has recently been "very peaceful and calm." Benjamin's mother recently relayed her concerns for developmental regression to his pediatrician during an audio-only telehealth visit. Benjamin was referred to a pediatric neurologist, and the consultation visit is pending.His mother is a 28-year-old single parent whose pregnancy was complicated by pre-eclampsia, gestational diabetes, and anxiety. Benjamin required admission to the neonatal intensive care unit because of initial feeding difficulties. After 1 week, Benjamin was discharged to home and was referred for early intervention services. Owing to the pandemic, there were delays with initiating intervention, but bimonthly virtual interaction with a representative from the infant development program was eventually provided.Benjamin's mother expressed significant concerns regarding the potential of exposing him to a pandemic-related illness because of bringing her son to in-person medical visits. In fact, because of her concerns, she attended only virtual well-child pediatric visits over the past 6 months. A thorough social history revealed that she is a former dance studio instructor. The studio closed and she lost her primary source of income because of the pandemic. As a result, she decided to not send Benjamin to child care and maintained isolation from extended family members.On physical examination, pertinent findings included poor truncal tone, lack of orientation toward sounds, and limited eye contact. The Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III) was administered, and the results indicated severe delays across all developmental areas, consistent with a diagnosis of global developmental delay.Benjamin's clinical presentation to the HRIF clinic and a history of developmental regression and intermittent body movements raised concerns for infantile spasms. He was transferred to the emergency department for evaluation and consideration for admission to the neurology service. An electroencephalogram confirmed epileptiform abnormalities consistent with infantile spasms, and he was immediately started on treatment.Impacts of the pandemic on the medical care of vulnerable/at-risk pediatric patients have included delayed receipt of early intervention services, parental fear regarding potential exposure to pandemic-related illness while seeking preventative care, increased use of virtual visit platforms for medical care and developmental intervention services, etc. What factors should be considered when providing support for these vulnerable/at-risk patients?


The effect of in-office vital bleaching and patient perception of the shade change.
This study aimed to evaluate the degree of colour change after an in-office vital tooth bleaching procedure with a 35% hydrogen peroxide gel using a spectrophotometer. The study also determined the patients' perceptions of the colour change and assessed the post operative sensitivity during the first week of the intervention. The maxillary teeth (from 15 to 25) of 22 patients comprising of 11 males and 11 females were bleached with a 35% hydrogen peroxide (HP) gel in a single visit treatment procedure (Yotuel Special, Biocosmetics Laboratories, Spain). Colour readings of the two maxillary central incisors were obtained using a spectrophotometer (CM-2600d Konica, Minolta) before and after the bleaching procedure. All the patients were requested to complete a form regarding post-operative tooth sensitivity and to record their perceptions toward the success of the bleaching treatment. The quantitative effect of the bleaching material on tooth colour showed an increase in the L* values and a decrease in the a* and b* values. The changes were significant (Wilcoxon Signed Rank Sum Test; p < 0.05) from baseline until one month, except for the b* values one month after the bleaching procedure which were only significant at p < or = 0.1. The median overall colour change (deltaE) between baseline and after the bleaching procedure was 3.56. The mean value of the patients' colour perception was found to be 2.14 immediately after bleaching on a 3 point visual analogue scale. A Spearman correlation test showed a positive relationship between the deltaE values immediately and one week after bleaching and a weak relationship one week and one month after the bleaching procedure. There was a significant consistency in the patients' colour perception data immediately and one week after the bleaching process and a weak relationship between the deltaE values and the patients' colour perception one month after bleaching. Ten out of the twenty two patients experienced tooth sensitivity on the first day, immediately after the bleaching procedure. However only five patients experienced sensitivity on the second day, four patients on the third day and only one patient experienced sensitivity on the fourth and the fifth days after bleaching which was described as mild. Yotuel Special 35% HP was able to bleach the patients' teeth with a perceptive colour change noticeable by the patients; however colour regression was evident quantitatively from the first week. Tooth sensitivity was a temporary side effect. The material cost is reasonable, it was easy to use and the procedure is not dependant on light activation. A single application of this product may not be sufficient to give patients the bright smile they desire. However it is important to monitor the rebound effect after this procedure. Patients may experience some tooth sensitivity after the use of this bleaching material but the sensitivity is of a transient nature.


Hepatocyte nuclear factor-4 regulates intestinal expression of the guanylin/heat-stable toxin receptor.
We have investigated the regulation of gene transcription in the intestine using the guanylyl cyclase C (GCC) gene as a model. GCC is expressed in crypts and villi in the small intestine and in crypts and surface epithelium of the colon. DNase I footprint, electrophoretic mobility shift assay (EMSA), transient transfection assays, and mutagenesis experiments demonstrated that GCC transcription is regulated by a critical hepatocyte nuclear factor-4 (HNF-4) binding site between bp -46 and -29 and that bp -38 to -36 were essential for binding. Binding of HNF-4 to the GCC promoter was confirmed by competition EMSA and by supershift EMSA. In Caco-2 and T84 cells, which express both GCC and HNF-4, the activity of GCC promoter and/or luciferase reporter plasmids containing 128 or 1973 bp of 5'-flanking sequence was dependent on the HNF-4 binding site in the proximal promoter. In COLO-DM cells, which express neither GCC nor HNF-4, cotransfection of GCC promoter/luciferase reporter plasmids with an HNF-4 expression vector resulted in 23-fold stimulation of the GCC promoter. Mutation of the HNF-4 binding site abolished this transactivation. Transfection of COLO-DM cells with the HNF-4 expression vector stimulated transcription of the endogenous GCC gene as well. These results indicate that HNF-4 is a key regulator of GCC expression in the intestine.


Molecular Mechanism Involved in the Pathogenesis of Early-Onset Epileptic Encephalopathy.
Recent studies have shown that neurologic inflammation may both precipitate and sustain seizures, suggesting that inflammation may be involved not only in epileptogenesis but also in determining the drug-resistant profile. Extensive literature data during these last years have identified a number of inflammatory markers involved in these processes of "neuroimmunoinflammation" in epilepsy, with key roles for pro-inflammatory cytokines such as: IL-6, IL-17 and IL-17 Receptor (IL-17R) axis, Tumor-Necrosis-Factor Alpha (TNF-α) and Transforming-Growth-Factor Beta (TGF-β), all responsible for the induction of processes of blood-brain barrier (BBB) disruption and inflammation of the Central Nervous System (CNS) itself. Nevertheless, many of these inflammatory biomarkers have also been implicated in the pathophysiologic process of other neurological diseases. Future studies will be needed to identify the disease-specific biomarkers in order to distinguish epilepsies from other neurological diseases, as well as recognize different epileptic semiology. In this context, biological markers of BBB disruption, as well as those reflecting its integrity, can be useful tools to determine the pathological process of a variety of neurological diseases. However; how these molecules may help in the diagnosis and prognostication of epileptic disorders remains yet to be determined. Herein, authors present an extensive literature review on the involvement of both, systemic and neuronal immune systems, in the early onset of epileptic encephalopathy.


ABCA1 and HDL3 are required to modulate smooth muscle cells phenotypic switch after cholesterol loading.
Cholesterol-loaded smooth muscle cells (SMCs) modify their phenotypic behavior becoming foam cells. To characterize the role of ABCA1 and HDL3 in this process, we evaluated HDL3 effects on cholesterol-induced phenotypic changes in SMCs expressing or not ABCA1. SMCs, isolated from the aortae of wild-type (WT) and Abca1 knock-out (KO) mice, were cholesterol-loaded using a "water-soluble cholesterol''. Cholesterol loading downregulates the expression of Acta2 and calponin (SMC markers), and increases the expression of Mac-2, CD11b and MHCII (inflammation-related genes and surface antigens) and Abca1, Abcg1. HDL3 normalizes SMC marker expression and reduces the expression of inflammation-related genes/proteins in WT cells, an effect not observed with free apoA-I. The effect of HDL3 is almost lost in Abca1 KO cells, as well as when Abca1 is silenced in WT SMC. HDL3 does not differently affect cholesterol downloading in WT or KO cells and stimulates phospholipids removal in WT cells. Similarly, the expression of myocardin and its modulators, such as miR-143/145, is reduced by cholesterol loading in WT and Abca1 KO SMCs; HDL3 normalizes their levels in WT cells but not in KO cells. On the contrary, cholesterol loading induces Klf4 expression while HDL3 restores Klf4 to basal levels in WT cells, but again this effect is not observed in KO cells. Our results indicate that HDL3, by interacting with ABCA1, modulates the miR143/145-myocardin axis and prevents the cholesterol-induced gene expression modification in SMCs regardless of its cholesterol unloading capacity.


An overview of racial disparities in preterm birth rates: caused by infection or inflammatory response?
Infection has been hypothesized to be one of the factors associated with spontaneous preterm birth (PTB) and with the racial disparity in rates of PTB between African American and Caucasian women. However, recent findings refute the generalizability of the role of infection and inflammation. African Americans have an increased incidence of PTB in the setting of intraamniotic infection, periodontal disease, and bacterial vaginosis compared to Caucasians. Herein we report variability in infection- and inflammation-related factors based on race/ethnicity. For African American women, an imbalance in the host proinflammatory response seems to contribute to infection-associated PTB, as evidenced by a greater presence of inflammatory mediators with limited or reduced presence of immune balancing factors. This may be attributed to differences in the genetic variants associated with PTB between African Americans and Caucasians. We argue that infection may not be a cause of racial disparity but in association with other risk factors such as stress, nutritional deficiency, and differences in genetic variations in PTB, pathways and their complex interactions may produce differential inflammatory responses that may contribute to racial disparity.


Sevoflurane stimulates MAP kinase signal transduction through the activation of PKC alpha and betaII in fetal rat cerebral cortex cultured neuron.
Protein kinase C (PKC) is a key enzyme that participates in various neuronal functions. PKC has also been identified as a target molecule for general anesthetic actions. Raf, mitogen-activated protein kinase (MEK) and extracellular signal-regulated kinase (ERK1/2) have been thought to be target effectors of PKC. In the present study, we attempted to evaluate the effect of sevoflurane on PKC/MAPK cascade signaling in cultured fetal rat cerebral -cortex neurons, prepared from embryonic day 18 fetuses. The effects of sevoflurane on the translocation of 7 PKC isoforms (alpha, betaI, betaII, gamma, delta, varepsilon and zeta) were observed by immunoblotting using isoform-selective antibodies to PKCs. The treatment of neurons with sevoflurane induced the translocation of PKC alpha and PKC betaII species from the cytosol to the membrane fraction, which indicated the activation of these PKC isoforms. In contrast, there was no clear change in the distribution of other PKC isoforms. We next examined whether the specific activation of PKC alpha and betaII by sevoflurane could stimulate the MAP kinase signaling pathway in cultured neurons. Raf phosphorylation was increased by the administration of 0.25 mM sevoflurane. The phosphorylation of Raf proteins reached a maximum at 5-10 min. Subsequently, the phosphorylation of MEK proteins was increased at 10-15 min after sevoflurane treatments. That of ERK proteins was induced at 15-60 min. Moreover, the phosphorylation of ERK induced by sevoflurane was significantly decreased by the treatment of PKC inhibitor (staurosporine) and MEK inhibitor (PD98059). On the other hand, the contents of total Raf, MEK and ERK proteins were relatively constant at all times examined. To examine the -localization of phosphorylated-ERK protein, immunohistochemical staining of sevoflurane-treated cultured neurons was performed. The phosphorylated-ERK proteins were markedly accumulated in both the cytosol of the cell body and the neurites in the neuronal cells with time after 0.25 mM sevoflurane-treatment. These results demonstrated that sevoflurane induced the phosphorylation of the MAP kinase cascade through the activation of the PKC alpha and PKC betaII species.


[Morphological study of the mechanisms of osteointegration of intraosseal titanium implants].
The present study was undertaken to work out a new material based on titanium-coated polytetrafluoroethylene, which would have the integration potential similar to that of titanium implants, which would make it possible to use it as a model to study osseointegration processes. Rat experiments compared titanium implants and a combined model of a titanium-nanocoated polytetrafluoroethylene. The present study has indicated that the new experimental model of the implant opens the door to in-depth investigations of a peri-implant bone regeneration area.


[William Harvey and the beginnings of modern medical science].
Modern medical science was born in the post-Renaissance age and began to consolidate towards the middle of the XVII century thanks to physicists, physiologists, and biologists, most of whom were direct or indirect pupils, of Galilei. The discovery of blood circulation by Harvey is now considered the only progress in physiology at the beginning of the XVII century, comparable to the current advances seen in physical sciences. The history of this achievement could be written from the view point of the progressive advance in knowledge. In his experiments, Harvey referred to the authentic, not the imaginary experiments, and put forward irrefutable quantitative arguments. We can therefore claim that his discovery of blood circulation was the first proper explanation of an organic process and the starting point leading to experimental physiology. Nevertheless, the second monograph of the English researcher, dealing with the generation of animals, published in 1651, has some passages that correspond to modern scientific reasoning yet in others he includes confused, vague and capricious assertions compatible with the prescientific era that the author was not able to escape completely. In conclusion, it seems justified to assert that modern medical science did not all rise suddenly, but was gradually structured starting from the middle of the XVII century following the path traced by William Harvey in light of Galilei's thought.


[The parenteral drug addict in the emergency service].
Clinical and epidemiological features of intravenous drug addicts (IVDA), who attended the emergency department between 1984 and 1988, were studied. The number of cases treated over these 4 years had increased three-fold (256 vs 724). The median age had increased by 3 years (p less than 0.01). The sex ratio had not changed. A third of the cases knew that they were HIV-seropositive in 1988. The main reason for consultation in 1984 was overdosage and in 1988 it was fever. The rate of admission was similar in both years (around 21%). There was a significant increase in admissions caused by respiratory diseases in 1988 (p less than 0.0001) and a significant decrease of admissions caused by overdosage (p less than 0.001).


Attendance at religious services and mortality in a national sample.
Research and theory increasingly suggest that attendance at religious services is protective against premature mortality. However, prior studies are limited and do not extensively explore potential explanations for the relationship, especially in terms of religious beliefs and behaviors associated with service attendance. This study estimates the impact of service attendance on mortality in a national probability sample and provides the most extensive empirical examination of potential explanations. Individuals who report attending religious services once a month or more (just over 50 percent of the population) have a 30-35 percent reduced risk of death over a 7.5 year follow-up period after adjusting for potential confounding factors. Consistent with prior research, 20-30 percent of this effect may be explained by better health behaviors (especially physical activity) among regular service attendees. Surprisingly, other religious beliefs and behaviors do not explain, and often tend to suppress, the association between service attendance and mortality.


Effects of isoflavone supplements vs. soy foods on blood concentrations of genistein and daidzein in adults.
The objective of this investigation was to examine the pharmacokinetics of isoflavone concentrations over a 24-h period among healthy adults consuming either soy foods or soy isoflavone tablets at different doses. This randomized, cross-over trial was conducted with 12 generally healthy adults. The three phases of the intervention included isoflavone tablets at (1) 144 mg/day or (2) 288 mg/day and (3) soy foods designed to provide a calculated 96 mg isoflavones/day (doses in aglycone equivalents). Doses were spread out over three meals per day. After 6 days on each study phase, plasma isoflavone concentrations were determined on the seventh day at 0, 4, 8, 10, 12 and 24 h. Average levels of total isoflavone concentrations at 8, 10 and 12 h were >4 micromol/L for the soy food phase and for the higher dose tablet phase. Genistein concentrations were higher overall in the soy food vs. both the lower and the higher dose supplement phases of the study (P<.05). When comparing plasma concentrations for the two doses of tablets, saturation appeared more evident for genistein than for daidzein at the higher dose level. In conclusion, we observed important differences in the pharmacokinetics of genistein and daidzein contrasting the sources and doses of isoflavones when administered three times daily, including a possible advantage for increasing serum concentrations of isoflavones from consuming soy foods relative to isoflavone supplements.


Small molecule inhibitors of α-synuclein oligomers identified by targeting early dopamine-mediated motor impairment in C. elegans.
Parkinson's disease is a disabling neurodegenerative movement disorder characterized by dopaminergic neuron loss induced by α-synuclein oligomers. There is an urgent need for disease-modifying therapies for Parkinson's disease, but drug discovery is challenged by lack of in vivo models that recapitulate early stages of neurodegeneration. Invertebrate organisms, such as the nematode worm Caenorhabditis elegans, provide in vivo models of human disease processes that can be instrumental for initial pharmacological studies. To identify early motor impairment of animals expressing α-synuclein in dopaminergic neurons, we first used a custom-built tracking microscope that captures locomotion of single C. elegans with high spatial and temporal resolution. Next, we devised a method for semi-automated and blinded quantification of motor impairment for a population of simultaneously recorded animals with multi-worm tracking and custom image processing. We then used genetic and pharmacological methods to define the features of early motor dysfunction of α-synuclein-expressing C. elegans. Finally, we applied the C. elegans model to a drug repurposing screen by combining it with an artificial intelligence platform and cell culture system to identify small molecules that inhibit α-synuclein oligomers. Screen hits were validated using in vitro and in vivo mammalian models. We found a previously undescribed motor phenotype in transgenic α-synuclein C. elegans that correlates with mutant or wild-type α-synuclein protein levels and results from dopaminergic neuron dysfunction, but precedes neuronal loss. Together with artificial intelligence-driven in silico and in vitro screening, this C. elegans model identified five compounds that reduced motor dysfunction induced by α-synuclein. Three of these compounds also decreased α-synuclein oligomers in mammalian neurons, including rifabutin which has not been previously investigated for Parkinson's disease. We found that treatment with rifabutin reduced nigrostriatal dopaminergic neurodegeneration due to α-synuclein in a rat model. We identified a C. elegans locomotor abnormality due to dopaminergic neuron dysfunction that models early α-synuclein-mediated neurodegeneration. Our innovative approach applying this in vivo model to a multi-step drug repurposing screen, with artificial intelligence-driven in silico and in vitro methods, resulted in the discovery of at least one drug that may be repurposed as a disease-modifying therapy for Parkinson's disease.


Phase Separation in Lipid Lamellae Result from Ceramide Conformations and Lateral Packing Structure.
Intercellular lipids in the stratum corneum protect the living body from invasion by allergens and pathogens, and also suppresses water evaporation within the body. It is important to understand how differences in the microstructure of intercellular lipids arise. This microstructure is affected by lipid composition. Studies using intercellular lipid models have reported the formation of two phases with different short lamellar periodicities. However, the details of the packing structure characteristics of the two phases observed in these intercellular lipid models are unclear. Our previous report revealed that different short periodicity phases coexist in the N-(α-hydroxyoctadecanoyl)-dihydrosphingosine (CER[ADS]), cholesterol (CHOL), and palmitic acid (PA) complex model. In this study, the characteristics of the packing structure of two phases with different short lamellar periodicities, which were observed in the intercellular lipid model (CER[ADS]/CHOL/PA) that we used previously, were adjusted for models with different lipid compositions. The characteristics of the packed and lamellar structures have been determined by temperature-scanning small-angle X-ray scattering and wide-angle X-ray diffraction measurements simultaneously. These differences in lamellar structure were thought to be caused by differences in ceramides (CER) conformation between the hairpin and the V-shape type. The lamellar structure of the V-shaped CER conformation has a low orthorhombic ratio. The above results suggest that an increase in the ratio of CER with the V-shaped structure causes the lamellar structure to have low orthorhombic ratio, thereby contributing to a decrease in the bilayer's barrier function.


Protein affinity chromatography with purified yeast DNA polymerase alpha detects proteins that bind to DNA polymerase.
We have overexpressed the POL1 gene of the yeast Saccharomyces cerevisiae and purified the resulting DNA polymerase alpha polypeptide in an apparently intact form. We attached the purified DNA polymerase covalently to an agarose matrix and used this matrix to chromatograph extracts prepared from yeast cells. At least six proteins bound to the yeast DNA polymerase alpha matrix that did not bind to a control matrix. We speculate that these proteins might be DNA polymerase alpha accessory proteins. Consistent with this interpretation, one of the binding proteins, which we have named POB1 (polymerase one binding), is required for normal chromosome transmission. Mutations in this gene cause increased chromosome loss and an abnormal cell morphology, phenotypes that also occur in the presence of mutations in the yeast alpha or delta polymerase genes. These results suggest that the interactions detected by polymerase affinity chromatography are biologically relevant and may help to illuminate the architecture of the eukaryotic DNA replication machinery.


Correlated States of 2D Electrons near the Landau Level Filling ν=1/7.
The ground state of two-dimensional electron systems (2DESs) at low Landau level filling factors (ν≲1/6) has long been a topic of interest and controversy in condensed matter. Following the recent breakthrough in the quality of ultrahigh-mobility GaAs 2DESs, we revisit this problem experimentally and investigate the impact of reduced disorder. In a GaAs 2DES sample with density n=6.1×10^{10}/cm^{2} and mobility μ=25×10^{6} cm^{2}/V s, we find a deep minimum in the longitudinal magnetoresistance (R_{xx}) at ν=1/7 when T≃104 mK. There is also a clear sign of a developing minimum in R_{xx} at ν=2/13. While insulating phases are still predominant when ν≲1/6, these minima strongly suggest the existence of fractional quantum Hall states at filling factors that comply with the Jain sequence ν=p/(2mp±1) even in the very low Landau level filling limit. The magnetic-field-dependent activation energies deduced from the relation R_{xx}∝e^{E_{A}/2kT} corroborate this view and imply the presence of pinned Wigner solid states when ν≠p/(2mp±1). Similar results are seen in another sample with a lower density, further generalizing our observations.


Comparison by contact lens cytology and clinical tests of three contact lens types.
To determine if hydrogel lens materials from different FDA groups have different effects on the human ocular surface. Contact lenses from Groups I and II, and Group IV were tested on 10 healthy adapted hydrogel contact lens wearers. For each comparison, the subject wore 2 new contact lenses for approximately 45 min. Lens movement was measured, and comfort evaluated using a subjective scale. After removal of the lenses, fluorescein staining and tear break-up time were measured. Cells were collected by contact lens cytology (CLC), and the size and number of cells harvested from each lens were determined. There were differences between lens groups in lens movement and comfort, but no differences in fluorescein staining or tear break-up time. CLC showed no differences in cell counts or cell size. There was no correlation between the results of CLC and the clinical tests for lens movement, lens comfort, tear break-up time, and fluorescein staining. With short durations of lens wear, differences in ionicity and water content have no effect upon the size and number of cells collected from a contact lens. This suggests that, in the short-term, the shedding of cells beneath a hydrogel lens is not affected by the choices of lens material.


Consensus on Postoperative Recommendations After Transsphenoidal Surgery.
Guidelines for patient behavior following transsphenoidal surgery do not exist. To gain generally recommendations, the German pituitary working group conducted a study among pituitary surgeons to elucidate their opinions and customs of patients' counselling. Questions concerning daily activities, exertion of sports and work life were addressed. It was asked to provide the postoperative time interval after which specific activities can be resumed both after a routine or an extended approach. Fourteen pituitary surgeons returned the completed questionnaire. Following routine operations, washing the hair was allowed within one week, blowing the nose after 3, flying on an airplane and driving a car after one, lifting heavy weights after 4, playing wind instruments after 6, use of CPAP (continuous positive airway pressure) device after 3, permit leisure sports after 2 to 4 weeks (except for scuba diving). Competitive sports can be resumed after 6 weeks. Occupation with mental demands was considered feasible after 2 weeks, with physical labor after 4 weeks. After extended transsphenoidal surgery, the recommended time interval was roughly twice as long compared to the routine approach. Driving a car was allowed within the first 4 weeks after surgery by some pituitary surgeons, while others allow driving only after 3 months analogous to the regulations after craniotomy. The risk of scuba diving was considered high. The data of our study and the literature, and expert opinions from related scientific fields resulted in a consensus on recommendations for patients' conduct to minimize risks after transsphenoidal surgery.


Therapeutic Potential of Antioxidants and Hybrid TEMPOL Derivatives in Ocular Neurodegenerative Diseases: A Glimpse into the Future.
Reactive oxygen species play a significant role in the pathogenesis of various ocular neurodegenerative diseases especially glaucoma, age-related macular degeneration (AMD), and ocular ischemic stroke. Increased oxidative stress and the accumulation of ROS have been implicated in the progression of these diseases. As a result, there has been growing interest in exploring potential therapeutic and prophylactic strategies involving exogenous antioxidants. In recent years, there have been significant advancements in the development of synthetic therapeutic antioxidants for targeting reactive oxygen species (ROS) in neurodegenerative diseases. One area of focus has been the development of hybrid TEMPOL derivatives. In the context of ocular diseases, the application of next-generation hybrid TEMPOL antioxidants may offer new avenues for neuroprotection. By targeting ROS and reducing oxidative stress in the retina and optic nerve, these compounds have the potential to preserve retinal ganglion cells and trabecular meshwork and protect against optic nerve damage, mitigating irreversible blindness associated with these diseases. This review seeks to highlight the potential impact of hybrid TEMPOL antioxidants and their derivatives on ocular neurodegenerative disorders.


Revisiting the Radiosynthesis of [18F]FPEB and Preliminary PET Imaging in a Mouse Model of Alzheimer's Disease.
[18F]FPEB is a positron emission tomography (PET) radiopharmaceutical used for imaging the abundance and distribution of mGluR5 in the central nervous system (CNS). Efficient radiolabeling of the aromatic ring of [18F]FPEB has been an ongoing challenge. Herein, five metal-free precursors for the radiofluorination of [18F]FPEB were compared, namely, a chloro-, nitro-, sulfonium salt, and two spirocyclic iodonium ylide (SCIDY) precursors bearing a cyclopentyl (SPI5) and a new adamantyl (SPIAd) auxiliary. The chloro- and nitro-precursors resulted in a low radiochemical yield (<10% RCY), whereas both SCIDY precursors and the sulfonium salt precursor produced [18F]FPEB in the highest RCYs of 25% and 36%, respectively. Preliminary PET/CT imaging studies with [18F]FPEB were conducted in a transgenic model of Alzheimer's Disease (AD) using B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J (APP/PS1) mice, and data were compared with age-matched wild-type (WT) B6C3F1/J control mice. In APP/PS1 mice, whole brain distribution at 5 min post-injection showed a slightly higher uptake (SUV = 4.8 ± 0.4) than in age-matched controls (SUV = 4.0 ± 0.2). Further studies to explore mGluR5 as an early biomarker for AD are underway.


Photobiomodulation effects of blue light on osteogenesis are induced by reactive oxygen species.
Blue light-mediated photobiomodulation (PBM) is a promising approach to promote osteogenesis. However, the underlying mechanisms of PBM in osteogenesis are poorly understood. In this study, a human osteosarcoma cell line (i.e., Saos-2 cells) was subjected to intermittent blue light exposure (2500 µM/m2/s, 70 mW/cm2, 4.2 J/cm2, once every 48 h) and the effects on Saos-2 cell viability, metabolic activity, differentiation, and mineralization were investigated. In addition, this study addressed a possible role of blue light induced cellular oxidative stress as a mechanism for enhanced osteoblast differentiation and mineralization. Results showed that Saos-2 cell viability and metabolic activity were maintained upon blue light exposure compared to unilluminated controls, indicating no negative effects. To the contrary, blue light exposure significantly increased (p < 0.05) alkaline phosphatase activity and Saos-2 cell mediated mineralization. High-performance liquid chromatography (HPLC) assay was used for measurement of reactive oxygen species (ROS) activity and showed a significant increase (p < 0.05) in superoxide (O2•-) and hydrogen peroxide (H2O2) formed after blue light exposure. Together, these results suggest that the beneficial effects of blue light-mediated PBM on osteogenesis may be induced by controlled release of ROS.