A microRNA expression signature for cervical cancer prognosis.
Invasive cervical cancer is a leading cause of cancer death in women worldwide, resulting in about 300,000 deaths each year. The clinical outcomes of cervical cancer vary significantly and are difficult to predict. Thus, a method to reliably predict disease outcome would be important for individualized therapy by identifying patients with high risk of treatment failures before therapy. In this study, we have identified a microRNA (miRNA)-based signature for the prediction of cervical cancer survival. miRNAs are a newly identified family of small noncoding RNAs that are extensively involved in human cancers. Using an established PCR-based miRNA assay to analyze 102 cervical cancer samples, we identified miR-200a and miR-9 as two miRNAs that could predict patient survival. A logistic regression model was developed based on these two miRNAs and the prognostic value of the model was subsequently validated with independent cervical cancers. Furthermore, functional studies were done to characterize the effect of miRNAs in cervical cancer cells. Our results suggest that both miR-200a and miR-9 could play important regulatory roles in cervical cancer control. In particular, miR-200a is likely to affect the metastatic potential of cervical cancer cells by coordinate suppression of multiple genes controlling cell motility.


Endoscopy-guided balloon dilation of benign anastomotic strictures after radical gastrectomy for gastric cancer.
The aim of this study was to evaluate the outcome of endoscopic dilation for benign anastomotic stricture after radical gastrectomy in gastric cancer patients. Gastric cancer patients who underwent endoscopic balloon dilation for benign anastomosis stricture after radical gastrectomy during a 6-year period were reviewed retrospectively. Twenty-one patients developed benign strictures at the site of anastomosis. The majority of strictures occurred within 1 year after surgery (95.2%). The median duration to stenosis after surgery was 1.70 months (range, 0.17 to 23.97 months). The success rate of the first endoscopic dilation was 61.9%. Between the restenosis group (n=8) and the no restenosis group (n=13), there were no significant differences in the body mass index (22.82 kg/m(2) vs 22.46 kg/m(2)), interval to symptom onset (73.9 days vs 109.3 days), interval to treatment (84.6 days vs 115.6 days), maximal balloon diameter (14.12 mm vs 15.62 mm), number of balloon dilation sessions (1.75 vs 1.31), location of gastric cancer or type of surgery. One patient required surgery because of stricture refractory to repeated dilation. Endoscopic dilation is a highly effective treatment for benign anastomotic strictures after radical gastrectomy for gastric cancer and should be considered a primary intervention prior to proceeding with surgical revision.


Cholera in Pregnancy: A Systematic Review and Meta-Analysis of Fetal, Neonatal, and Maternal Mortality.
Maternal infection with cholera may negatively affect pregnancy outcomes. The objective of this research is to systematically review the literature and determine the risk of fetal, neonatal and maternal death associated with cholera during pregnancy. Medline, Global Health Library, and Cochrane Library databases were searched using the key terms cholera and pregnancy for articles published in any language and at any time before August 2013 to quantitatively summarize estimates of fetal, maternal, and neonatal mortality. 95% confidence intervals (CIs) were calculated for each selected study. Random-effect non-linear logistic regression was used to calculate pooled rates and 95% CIs by time period. Studies from the recent period (1991-2013) were compared with studies from 1969-1990. Relative risk (RR) estimates and 95% CIs were obtained by comparing mortality of selected recent studies with published national normative data from the closest year. The meta-analysis included seven studies that together involved 737 pregnant women with cholera from six countries. The pooled fetal death rate for 4 studies during 1991-2013 was 7.9% (95% CIs 5.3-10.4), significantly lower than that of 3 studies from 1969-1990 (31.0%, 95% CIs 25.2-36.8). There was no difference in fetal death rate by trimester. The pooled neonatal death rate for 1991-2013 studies was 0.8% (95% CIs 0.0-1.6), and 6.4% (95% CIs 0.0-20.8) for 1969-1990. The pooled maternal death rate for 1991-2013 studies was 0.2% (95% CIs 0.0-0.7), and 5.0% (95% CIs 0.0-16.0) for 1969-1990. Compared with published national mortality estimates, the RR for fetal death of 5.8 (95% CIs 2.9-11.3) was calculated for Haiti (2013), 1.8 (95% CIs 0.3-10.4) for Senegal (2007), and 2.6 (95% CIs 0.5-14.9) for Peru (1991); there were no significant differences in the RR for neonatal or maternal death. Results are limited by the inconsistencies found across included studies but suggest that maternal cholera is associated with adverse pregnancy outcomes, particularly fetal death. These findings can inform a research agenda on cholera in pregnancy and guidance for the timely management of pregnant women with cholera.


Liquid marble clearance and restoration via gas bubble insertion and bursting.
There is hitherto a lack of a simple way to disrupt the coating of particles from liquid marbles in order to introduce additional reagents. Here, a 40 μL liquid marble, created on a superhydrophobic substrate with a 2 mm hole, forms an overhead and overhanging liquid component from which a single gas bubble of up to 28 μL volume could be introduced via the latter. This caused a localized clearing of the particle shell at the apical region of the overhead component because the particles could not be energetically sustained at the thin film region of the bubble. The subsequent dispensation of 5 μL of an external liquid directly onto the shell-free apex of the liquid marble allowed the coalescence of the two liquid bodies, bubble rupture, and restoration of complete particle shell encapsulation. The addition of the liquid via the overhanging component was alternatively found incapable of increasing the size of the overhead drop component. The localized bubble-actuated transient shell clearance at the apex of the liquid marble to allow the addition of reagents shown here portends new vistas for liquid marbles to be used in biomedical applications.


Childhood Facial Palsy: Etiologic Factors and Clinical Findings, an Observational Retrospective Study.
The purpose of this study was to determine the etiologic factors, clinical characteristics, seasonal distributions, family history, response to corticosteroid therapy, recurrence and residual paralysis rates, and factors affecting these in pediatric facial palsy. Patients aged <18 years diagnosed with acute peripheral facial palsy were included in the study. Demographic data and clinical findings were retrieved from patients' records. The study was completed with 113 patients. Causes were idiopathic in 74 (65.4%) cases. Complete healing was not achieved in 6 (5.3%) patients, and recurrence was observed in 11 (9.7%). None of the patients with residual paralysis used corticosteroid, but all the patients with recurrence had employed them. We determined that young age may have an adverse impact on complication development and that corticosteroid therapy may be useful in the healing process in idiopathic facial nerve palsy. In conclusion, age may have an adverse impact in idiopathic facial nerve palsy, whereas corticosteroid therapy has a positive effect.


Nanoarchaeal 16S rRNA gene sequences are widely dispersed in hyperthermophilic and mesophilic halophilic environments.
The Nanoarchaeota, proposed as the fourth sub-division of the Archaea in 2002, are known from a single isolate, Nanoarchaeum equitans, which exists in a symbiotic association with the hyperthermophilic Crenarchaeote, Ignicoccus. N. equitans fails to amplify with standard archaeal 16S PCR primers and can only be amplified using specifically designed primers. We have designed a new set of universal archaeal primers that amplify the 16S rRNA gene of all four archaeal sub-divisions, and present two new sets of Nanoarchaeota-specific primers based on all known nanoarchaeal 16S rRNA gene sequences. These primers can be used to detect N. equitans and have generated nanoarchaeal amplicons from community DNA extracted from Chinese, New Zealand, Chilean and Tibetan hydrothermal sites. Sequence analysis indicates that these environments harbour novel nanoarchaeal phylotypes, which, however, do not cluster into clear phylogeographical clades. Mesophilic hypersaline environments from Inner Mongolia and South Africa were analysed using the nanoarchaeal-specific primers and found to contain a number of nanoarchaeal phylotypes. These results suggest that nanoarchaeotes are not strictly hyperthermophilic organisms, are not restricted to hyperthermophilic hosts and may be found in a large range of environmental conditions.


Cytotoxic mechanisms in vitro against Epstein-Barr virus infected lymphoblastoid cell lines in rheumatoid arthritis.
Impaired regulation of latent infection with Epstein-Barr virus (EBV) may contribute to the pathogenesis of rheumatoid arthritis (RA) by allowing uncontrolled polyclonal B cell activation. The control of EBV infection in vitro is dependent on several cytotoxic lymphoid cell populations. The present report examines the suppression of early lymphoblastoid outgrowth by natural killer (NK) like cells and the ability to form cytotoxic T lymphocytes (CTLs) specific for EBV in vitro. The latter was measured by a regression assay of EBV induced lymphoblastoid transformation. In this assay the regression of B cell outgrowth at four and six weeks is due to the generation of CTLs specific for EBV. Patients with RA were defective in this ability to generate CTLs. Eight out of nine patients with RA had a geometric mean at the 50% regression end point equal to or greater than 20 X 10(5) cells/ml. In contrast, the geometric mean for all control donors was less than 4 X 10(5) cell/ml. NK activity was measured by a conventional 51Cr release assay with K562 targets. Patients with RA did not have significantly different activity from that of controls (RA patients, n = 4, 45.6 +/- 19.7% (means +/- SD) at 50:1, effector:target; normals, n = 5, 56.6 +/- 5.7%). No spontaneous NK activity was detected against allogeneic or autologous EBV infected B cell targets. When peripheral mononuclear cells from patients were incubated for six days with interleukin-2, lysis of EBV infected targets was seen. No difference in this activity was seen between RA and control studies. Overall, these studies show that patients with RA are defective in their ability to generate CTLs specific for EBV in vitro.


[Poly(U)-dependent interaction of yeast tRNA(Phe) and its fragments with Escherichia coli ribosomes. II. Localization of tRNA binding centers with a P-site].
Poli(U)-dependent binding of yeast tRNA(Phe) lacking the 3'-terminal CA or CCA residues, and fragments of tRNA prepared by splitting the tRNA(Phe) at the G18 or 7mG46 nucleotides, to the 70S ribosomal P-site was studied. Equilibrium binding constants and free energies of binding were measured. The contribution of C74 and C75 was estimated at 3.9 kJ/mol and 3.0 kJ/mol, respectively, at 10 mM Mg2+ and 30 degrees C. The free energies of the binding of the anticodon arm the tRNA lacking its CCA terminus, and the tRNA fragment containing bases N1-N45 were found to be nearly equal. These results indicate that only the anticodon arm and the CCA terminus take part in deacylated tRNA-P-site interaction.


Two dimensional nanoarrays of individual protein molecules.
Protein molecules on solid surfaces are essential to a number of applications, such as biosensors, biomaterials, and drug delivery. In most approaches for protein immobilization, inter-molecular distances on the solid surface are not controlled and this may lead to aggregation and crowding. Here, a simple approach to immobilize individual protein molecules in a well-ordered 2D array is shown, using nanopatterns obtained from a polystyrene-block-poly(2-hydroxyethyl methacrylate) (PS-b-PHEMA) diblock copolymer thin film. This water-stable and protein-resistant polymer film contains hexagonally ordered PS cylindrical domains in a PHEMA matrix. The PS domains are activated by incorporating alkyne-functionalized PS and immobilizing azide-tagged proteins specifically onto each PS domain using "Click" chemistry. The nanometer size of the PS domain dictates that each domain can accommodate no more than one protein molecule, as verified by atomic force microscopy imaging. Immunoassay shows that the amount of specifically bound antibody scales with the number density of individual protein molecules on the 2D nanoarrays.


Efficacy and cost-effectiveness of a therapist-assisted web-based intervention for depression and anxiety in patients with ischemic heart disease attending cardiac rehabilitation [eMindYourHeart trial]: a randomised controlled trial protocol.
One in five patients with ischaemic heart disease (IHD) develop comorbid depression or anxiety. Depression is associated with risk of non-adherence to cardiac rehabilitation (CR) and dropout, inadequate risk factor management, poor quality of life (QoL), increased healthcare costs and premature death. In 2020, IHD and depression are expected to be among the top contributors to the disease-burden worldwide. Hence, it is paramount to treat both the underlying somatic disease as well as depression and anxiety. eMindYourHeart will evaluate the efficacy and cost-effectiveness of a therapist-assisted eHealth intervention targeting depression and anxiety in patients with IHD, which may help fill this gap in clinical care. eMindYourHeart is a multi-center, two-armed, unblinded randomised controlled trial that will compare a therapist-assisted eHealth intervention to treatment as usual in 188 CR patients with IHD and comorbid depression or anxiety. The primary outcome of the trial is symptoms of depression, measured with the Hospital Anxiety and Depression Scale (HADS) at 3 months. Secondary outcomes evaluated at 3, 6, and 12 months include symptoms of depression and anxiety (HADS), perceived stress, health complaints, QoL (HeartQoL), trial dropout (number of patients dropped out in either arm at 3 months) and cost-effectiveness. To our knowledge, this is the first trial to evaluate both the efficacy and cost-effectiveness of a therapist-assisted eHealth intervention in patients with IHD and comorbid psychological distress as part of CR. Integrating screening for and treatment of depression and anxiety into standard CR may decrease dropout and facilitate better risk factor management, as it is presented as "one package" to patients, and they can access the eMindYourHeart program in their own time and at their own convenience. The trial holds a strong potential for improving the quality of care for an increasing population of patients with IHD and comorbid depression, anxiety or both, with likely benefits to patients, families, and society at large due to potential reductions in direct and indirect costs, if proven successful. Trial registration The trial was prospectively registered on https://clinicaltrials.gov/ct2/show/NCT04172974 on November 21, 2019 with registration number [NCT04172974].


Kinetics of nitrogenase of Klebsiella pneumoniae. Heterotropic interactions between magnesium-adenosine 5'-diphosphate and magnesium-adenosine 5'-triphosphate.
The effects of MgADP and MgATP on the kinetics of a pre-steady-state electron-transfer reaction and on the steady-state kinetics of H2 evulution for nitrogenase proteins of K. pneumoniae were studied. MgADP was a competitive inhibitor of MgATP in the MgATP-induced electron transfer from the Fe-protein to the Mo-Fe-protein. A dissociation constant K'i = 20 micron was determined for MgADP. The release of MgADP or a coupled conformation change in the Fe-protein of K.pneumoniae occurred with a rate comparable with that of electron transfer, k approximately 2 X 10(2)S-1. Neither homotropic nor heterotropic interactions involving MgATP and MgADP were observed for this reaction. Steady-state kinetic data for H2 evolution exhibited heterotropic effects between MgADP and MgATP. The data have been fitted to symmetry and sequential-type models involving conformation changes in two identical subunits. The data suggest that the enzyme can bind up to molecules of either MgATP or MgADP, but is unable to bind both nucleotides simultaneously. The control of H2 evolution by the MgATP/MgADP ratio is not at the level of electron transfer between the Fe- and Mo-Fe-proteins.


Twelve-month prevalence of and risk factors for suicide attempts in the World Health Organization World Mental Health Surveys.
Although suicide is a leading cause of death worldwide, clinicians and researchers lack a data-driven method to assess the risk of suicide attempts. This study reports the results of an analysis of a large cross-national epidemiologic survey database that estimates the 12-month prevalence of suicidal behaviors, identifies risk factors for suicide attempts, and combines these factors to create a risk index for 12-month suicide attempts separately for developed and developing countries. Data come from the World Health Organization (WHO) World Mental Health (WMH) Surveys (conducted 2001-2007), in which 108,705 adults from 21 countries were interviewed using the WHO Composite International Diagnostic Interview. The survey assessed suicidal behaviors and potential risk factors across multiple domains, including sociodemographic characteristics, parent psychopathology, childhood adversities, DSM-IV disorders, and history of suicidal behavior. Twelve-month prevalence estimates of suicide ideation, plans, and attempts are 2.0%, 0.6%, and 0.3%, respectively, for developed countries and 2.1%, 0.7%, and 0.4%, respectively, for developing countries. Risk factors for suicidal behaviors in both developed and developing countries include female sex, younger age, lower education and income, unmarried status, unemployment, parent psychopathology, childhood adversities, and presence of diverse 12-month DSM-IV mental disorders. Combining risk factors from multiple domains produced risk indices that accurately predicted 12-month suicide attempts in both developed and developing countries (area under the receiver operating characteristic curve = 0.74-0.80). Suicidal behaviors occur at similar rates in both developed and developing countries. Risk indices assessing multiple domains can predict suicide attempts with fairly good accuracy and may be useful in aiding clinicians in the prediction of these behaviors.


Correlation between serological and immunofluorescence results in the investigation of brucellosis in veterinary surgeons.
Four serological tests and three immunofluorescence tests for IgG, IgM, and IgA were compared for value in the investigation of brucellosis in veterinary surgeons. No one serological test stood out over the others, and the immunofluorescence tests did not appear to have advantages over the serological tests. If a laboratory is limited in time and resources then the saline agglutination or the complement fixation test would be reasonably satisfactory. The 2-mercaptoethanol test and the antihuman globulin (Coombs' test) have no advantages over the other two and could be dropped. Immunofluorescence tests are not recommended for routine testing of brucellosis sera. The results and these recommendations apply to the 'vet' sera tested; it is reasonable to suppose that what applies to 'vet' sera will also apply to sera of those who work with or are in repeated contact with cattle and who will have had previous experience of brucella antigen, that is, dairy farmers, herdsmen, or slaughter house employees.


Microgrids: A Model for Basic Microsurgery Skills Training.
Introduction: Microsurgery is a subspecialised field which requires high technical skill. Laboratory training offers good opportunity for novice surgeons to learn and repetitively practise their skills prior to hands-on clinical practice. Commonly, the training programme consists of models in a stepwise increase in fidelity: from latex sheet to anaesthetised rat. We introduce microgrids model as a daily warm up procedure in a 5-day basic microsurgery course. The purpose of this study is to evaluate the correlation between microgrids colouring under magnification with microsuturing proficiency among novice surgeons. Materials and Methods: Participants were required to fill in microgrids under magnification everyday during their 5-day training as a starter test. The number of completely filled in microgrids in 20 seconds was recorded. A simulated cut on latex sheet was sutured and the time taken to apply five sutures was recorded. The sutures were evaluated with modified Global Rating Scale (GRS). Data was analysed with SPSS. Results: There was a statistically significant correlation between the number of microgrids coloured and the time taken to apply five sutures (p<0.01). An increase in number of microgrids coloured was significantly associated with the increase in quality of the suturing technique (p< 0.01). During the 5-day basic microsurgery skills training for novice surgeons, microsuturing skill improvement correlated with microgrid colouring. Conclusion: Microgrids colouring reflected microsuturing proficiency. It is an inexpensive, readily available, and simple model of 'warm up' for hand dexterity. The microgrids model can function as a starter test for initial training and a quick screening measure to assess microsurgical skill.


A population-based model for priority setting across the care continuum and across modalities.
The Health-sector Wide (HsW) priority setting model is designed to shift the focus of priority setting away from 'program budgets'--that are typically defined by modality or disease-stage--and towards well-defined target populations with a particular disease/health problem. The key features of the HsW model are i) a disease/health problem framework, ii) a sequential approach to covering the entire health sector, iii) comprehensiveness of scope in identifying intervention options and iv) the use of objective evidence. The HsW model redefines the unit of analysis over which priorities are set to include all mutually exclusive and complementary interventions for the prevention and treatment of each disease/health problem under consideration. The HsW model is therefore incompatible with the fragmented approach to priority setting across multiple program budgets that currently characterises allocation in many health systems. The HsW model employs standard cost-utility analyses and decision-rules with the aim of maximising QALYs contingent upon the global budget constraint for the set of diseases/health problems under consideration. It is recognised that the objective function may include non-health arguments that would imply a departure from simple QALY maximisation and that political constraints frequently limit degrees of freedom. In addressing these broader considerations, the HsW model can be modified to maximise value-weighted QALYs contingent upon the global budget constraint and any political constraints bearing upon allocation decisions. The HsW model has been applied in several contexts, recently to osteoarthritis, that has demonstrated both its practical application and its capacity to derive clear evidenced-based policy recommendations. Comparisons with other approaches to priority setting, such as Programme Budgeting and Marginal Analysis (PBMA) and modality-based cost-effectiveness comparisons, as typified by Australia's Pharmaceutical Benefits Advisory Committee process for the listing of pharmaceuticals for government funding, demonstrate the value added by the HsW model notably in its greater likelihood of contributing to allocative efficiency.


Cellular mechanisms that underlie bleaching and background adaptation.
Experiments were performed on rod photoreceptors isolated from the eye of the larval tiger salamander to determine if the same or different mechanisms underlie the desensitization produced by dim background light (background adaptation) and that which persists in the steady state in darkness after a significant fraction of the photopigment is bleached (bleaching adaptation). We have examined adaptational effects after light that bleached between approximately 50% and 95% of the photopigment under conditions which preclude pigment regeneration. The steady-state desensitization, far greater than that predicted by quantum-catch loss, is relieved upon regeneration of the visual pigment with 11-cis retinal. We measured the spread of desensitization along the long axis of the rod after a local bright bleach at one end by comparing responses to dim local test flashes elicited in different regions of the outer segment, before and after bleaching. The space constant for this spread was less than 2.5 microns. We have previously measured the space constant for the longitudinal spread of desensitization during a local dim background in Ambystoma rods to be 7 microns. This is similar to a space constant of 6 microns measured under similar conditions in Bufo rods by Lamb et al. (1981. J. Physiol. 319:463-496). If calcium carries the signal for background desensitization, this difference in space constant for background and bleaching adaptation precludes it as the messenger for the steady component of bleaching adaptation. Experiments with isobutylmethyl xanthine (IBMX) also indicate that Ca2+ as well as c-GMP are unlikely regulators of bleaching desensitization, since elevation of cytosolic levels of both of these internal messengers by IBMX has little effect on sensitivity in bleach-adapted cells. All of our findings are consistent with the notion that bleaching adaptation is not mediated by a freely diffusible cytoplasmic messenger.


[A new pathogenetic approach and a method of erectile dysfunction treatment and prevention--modulated erectile oxygenation of penile cavernous tissue].
The analysis of sexual activity of 185 male Muscovites has revealed an age-related sharp progressive shortening of adequate and spontaneous erections. A novel, pathogenetically sound approach and a method of therapy and prevention of erectile dysfunction has been developed (RF patent N 2228754). The method, called "Modulated Erectile Oxygenation of Penile Cavernous Tissue" (MEOPCT), consists in erection activation by behavioral measures and/or erectogenic drugs which induce adequate, nocturnal spontaneous and/or artificial erections adequate in frequency and duration for providing such oxygenation of cavernous bodies that warrants maintenance of their normal structure and function. There is no continuous close correlation between sexual activity and erections, on the one side, and ejaculation and orgasm, on the other side. Application of MEOPCT in 43 patients demonstrated the method ability to improve erection and cavernous hemodynamics without negative side effects.


Psychomotor screening for USAF pilot candidates: selecting a valid criterion.
Subjects for this research were 153 prospective pilots who were tested on computerized versions of the Two Hand Coordination (2HC) and Complex Coordination (CC) psychomotor tests. Independent variables included five basic error scores associated with the two psychomotor tests. The criterion for pilot performance was conceptualized as a function of the number of flying hours required to graduate from Undergraduate Pilot Training (UPTFLY). Results of MANOVA and multiple regression analyses revealed that performance on the two psychomotor tests was significantly related to the criterion for pilot performance (UPTFLY). The multiple regression analysis resulted in 27.1% of the variability of UPTFLY being accounted for by psychomotor performance. When the data were reanalyzed using a pass/fail UPT criterion the variability accounted for remained high, suggesting an anomaly associated with sample selection. Undergraduate pilot training outcome (pass/fail) remains the most valid criterion for Undergraduate Pilot Training success.


Isothiocyanates as cancer chemopreventive agents: their biological activities and metabolism in rodents and humans.
Isothiocyanates (ITCs) are a group of naturally occurring compounds that occur as thioglucoside conjugates, termed glucosinolates, in plants and cruciferous vegetables such as watercress, Brussels sprouts, broccoli, cabbage, kai choi, kale, horseradish, radish and turnip. ITCs inhibit the development of tumors in many of the experimental models investigated, and are being investigated as possible chemopreventive agents for specific human cancers. The goal of this review is to provide a mechanistic understanding for the biological activities of ITCs and to relate the metabolism of ITCs to their action as chemopreventive agents. In vivo animal studies have been conducted to address issues of tissue disposition, pharmacokinetics, and metabolism of ITCs. Methods for analysis of ITCs and their metabolites in urine and plasma have been developed. The metabolism of several naturally occurring ITCs as constituents of foodstuffs or as drugs has also been investigated in human studies. Finally, based on recent epidemiological studies, the role of dietary consumption of vegetables containing ITCs in prevention of human cancers and human cancer susceptibility is discussed.


A randomized, open-label study of the safety and tolerability of fospropofol for patients requiring intubation and mechanical ventilation in the intensive care unit.
Current drugs for induction and maintenance of sedation in mechanically ventilated patients in the intensive care unit have limitations. Fospropofol, a prodrug of propofol, has not been studied as a sedative in the ICU setting. In this randomized, open-label pilot study, patients received 1 of 3 regimens with a goal of maintaining a Ramsay Sedation Score of 2 to 5: (1) fospropofol IV infusion with a bolus and increased infusion rate for agitation events (infusion/bolus); (2) fospropofol IV infusion with an increased infusion rate for agitation events (infusion only); or (3) propofol IV infusion with an increased infusion rate for agitation events. Sixty patients received study drug and were included in the safety and efficacy analyses. Because incidence rates for adverse events were similar between fospropofol groups, and because the study was not powered to determine significant differences between treatment groups for safety variables, adverse events for both fospropofol groups were combined. In the fospropofol groups, 28 out of 38 patients (74%) experienced treatment-emergent adverse events in comparison with 14 out of 22 patients (64%) in the propofol group. The most common treatment-emergent adverse events with fospropofol were procedural pain (21.1%) and nausea (13.2%). Two patients (1 each in the fospropofol infusion/bolus and the propofol groups) experienced hypotension during the study as a potential sedation-related adverse event. Mean plasma formate levels were not significantly different among groups. Patients in all 3 treatment groups maintained Ramsay Sedation Scores of 2 to 5 for >90% of the time they were sedated. This pilot study suggests that fospropofol, administered in either an infusion/bolus or infusion-only regimen, is tolerable and effective for short-term induction and maintenance of sedation in mechanically ventilated intensive care unit patients.


[A simple kinetic model of myocardium contraction: calcium-mechanics coupling].
A kinetic model of cardiac muscle contraction is suggested. It is based on our earlier simplified model of the kinetics of the actin-myosin interaction. We examined the kinetics of formation of calcium-troponin complexes that open the binding sites-on actin for myosin heads. The model also takes into account the cooperativity of this process and the influence of myosin heads on it. It was shown that with proper choice of its parameters the model appropriately describes the dependence of myocardium activation.on sarcomeres length that underlies the Frank-Starling law of the heart. The model fits both steady state experiments on myocardial specimens with permeable membrane and twitch contractions of intact cardiac muscle. It also describes well the myocardium load-dependent relaxation.


Phylogenetic analysis and possible function of bro-like genes, a multigene family widespread among large double-stranded DNA viruses of invertebrates and bacteria.
Baculovirus repeated open reading frame (bro) genes and their relatives constitute a multigene family, typically with multiple copies per genome, known to occur among certain insect dsDNA viruses and bacteriophages. Little is known about the evolutionary history and function of the proteins encoded by these genes. Here we have shown that bro and bro-like (bro-l) genes occur among viruses of two additional invertebrate viral families, Ascoviridae and Iridoviridae, and in prokaryotic class II transposons. Analysis of over 100 sequences showed that the N-terminal region, consisting of two subdomains, is the most conserved region and contains a DNA-binding motif that has been characterized previously. Phylogenetic analysis indicated that these proteins are distributed among eight groups, Groups 1-7 consisting of invertebrate virus proteins and Group 8 of proteins in bacteriophages and bacterial transposons. No bro genes were identified in databases of invertebrate or vertebrate genomes, vertebrate viruses and transposons, nor in prokaryotic genomes, except in prophages or transposons of the latter. The phylogenetic relationship between bro genes suggests that they have resulted from recombination of viral genomes that allowed the duplication and loss of genes, but also the acquisition of genes by horizontal transfer over evolutionary time. In addition, the maintenance and diversity of bro-l genes in different types of invertebrate dsDNA viruses, but not in vertebrate viruses, suggests that these proteins play an important role in invertebrate virus biology. Experiments with the unique orf2 bro gene of Autographa californica multicapsid nucleopolyhedrovirus showed that it is not required for replication, but may enhance replication during the occlusion phase of reproduction.


[The epidemiology of sudden cardiac arrest in prehospital care in the area of the silesian voivodeship].
Introduction: Sudden cardiac arrest (SCA) is a serious medical and social issue. The incidence of SCA varies depending on the location and the circumstances. The aim: A retrospective analysis of non-hospital SCA cases from an epidemiological perspective. The research involved the population monitored by the Voivodeship Rescue Service (VRS) in Katowice. Material and methods The analysis covered dispatch order forms and emergency medical procedure forms of the VRS in Katowice in 2016 (n = 249 872). The retrospective analysis involved cases of non-hospital SCA in adults (n = 1603). Quantitative parameters have been presented as average values with standard deviation. Non-metric variables have been described by means of structure indicators. A comparative analysis was conducted by means of the Student's T-test for the quantitative variables and the Pearson's chisquared test for the non-metric variables. The statistical significance adopted for the purpose of all analyses was 0.05. Results: There were 1005 men (62.7%), 566 women (35.3%) and 32 cases (2.0%) where gender identification was not reported. Female individuals were generally older than male individuals (p = 0.000). Patients' average age was 65.7 years. The SCA attack rate was 59.37/100 000. SCA cases were usually reported in domestic conditions (71.1%, p = 0.000). In a majority of cases, the incident was witnessed by a third person (about 70.0% of cases, p= 0.000). Most of the SCA cases were reported in the first quarter of the year whereas the lowest number of cases was noticed in the third quarter (28.4 % vs 22.5 %). SCA was most frequent during the day. Restoration of spontaneous circulation was reported in 33.4% of the cases. Conclusions: The incidence of SCA is occasional in the context of all analyzed emergency cases in the period under research. However, SCA cases are related with a high risk of failure. Acting according to the currently available knowledge will probably cause an increase of the restoration of spontaneous circulation (ROSC) rate.


Short regulatory DNA sequences to target brain endothelial cells for gene therapy.
Gene vectors targeting CNS endothelial cells allow to manipulate the blood-brain barrier and to correct genetic defects in the CNS. Because vectors based on the adeno-associated virus (AAV) have a limited capacity, it is essential that the DNA sequence controlling gene expression is short. In addition, it must be specific for endothelial cells to avoid off-target effects. To develop improved regulatory sequences with selectivity for brain endothelial cells, we tested the transcriptional activity of truncated promoters of eleven (brain) endothelial-specific genes in combination with short regulatory elements, i.e., the woodchuck post-transcriptional regulatory element (W), the CMV enhancer element (C), and a fragment of the first intron of the Tie2 gene (S), by transfecting brain endothelial cells of three species. Four combinations of regulatory elements and short promoters (Cdh5, Ocln, Slc2a1, and Slco1c1) progressed through this in-vitro pipeline displaying suitable activity. When tested in mice, the regulatory sequences C-Ocln-W and C-Slc2a1-S-W enabled a stronger and more specific gene expression in brain endothelial cells than the frequently used CAG promoter. In summary, the new regulatory elements efficiently control gene expression in brain endothelial cells and may help to specifically target the blood-brain barrier with gene therapy vectors.


Downregulation of GRHL2 inhibits the proliferation of colorectal cancer cells by targeting ZEB1.
Previous reports have associated GRHL2 with tumor progression. However, the biological role of GRHL2 in human colorectal cancer (CRC) has not been explored. We examined the expression of GRHL2 in 75 CRC samples, as well as the paired non-tumor tissues, by immunohistochemistry, qRT-PCR, and western blot analysis. The association between GRHL2 expression and various clinicopathological parameters including Ki-67, a marker of proliferative activity, was also evaluated. We performed lentivirus-mediated shRNA transfection to knock down GRHL2 gene expression in HT29 and HCT116 CRC cells. Cell proliferation was examined by the CCK-8 (Cell Counting Kit-8) assay, colony formation, and cell cycle assay in vitro. Tumorigenesis in vivo was assessed using a mouse xenograft model. Moreover, we transiently silenced ZEB1 expression in GRHL2-knockdown CRC cells using specific shRNA, and then examined the effects on GRHL2 and E-cadherin expression, as well as cell proliferation. Herein, we demonstrated that enhanced GRHL2 expression was detected in CRC, and correlated with higher levels of Ki-67 staining, larger tumor size, and advanced clinical stage. Knocking down GRHL2 in HT29 and HCT116 CRC cells significantly inhibited cell proliferation by decreasing the number of cells in S phase and increasing that in the G 0/G 1 phaseof the cell cycle. This resulted in inhibition of tumorigenesis in vivo, as well as increased expression of ZEB1. Furthermore, transient ZEB1 knockdown dramatically enhanced cell proliferation and increased GRHL2 and E-cadherin expression. Collectively, our study has identified ZEB1 as a target of GRHL2 and suggested a reciprocal GRHL2-ZEB1 repressive relationship, providing a novel mechanism through which proliferation may be modulated in CRC cells.


Fishing for gaps in science: a bibliographic analysis of Brazilian freshwater ichthyology from 1986 to 2005.
To investigate Brazilian freshwater ichthyology, from 1986 to 2005, a bibliometric analysis was conducted using abstracts downloaded from The Web of Science database searching for the keywords 'fish', 'pisces', 'teleostei' and the address field having the word 'Brazil'. The results of this study showed that Brazilian freshwater ichthyology publications have been increasing during the study period. This process is a consequence of a series of investments that the Brazilian Government has made. Furthermore, data analyses identified scientific areas where there was a lack of scientific knowledge (e.g. studies of species threatened with extinction and certain hydrologic basins). Research institutions from the north-east and northern region of Brazil had the lowest participation in scientific productivity, which was a reflection of their regions poorer economic situation. This study showed that scientific productivity in Brazilian ichthyology was a direct reflection of state investment in research. Furthermore, data in this study follow expected statistical probabilities, for example, fishes from the most diverse families were the most studied. Thus, the study shows that great progress has been made by Brazilian ichthyologists in the last 20 years; however, due to the mega diversity of fishes in Brazil, much remains to be done if many species are to become known to science and to be saved from extinction. This it seems will depend on continued and further investment by Brazilian Government funding agencies, as Brazilian ichthyologists have demonstrated their capacity to generate high quality information about their study species.


Emotional functioning in eating disorders: attentional bias, emotion recognition and emotion regulation.
Interpersonal processes, anxiety and emotion regulation difficulties form a key part of conceptual models of eating disorders (EDs), such as anorexia nervosa (AN) and bulimia nervosa (BN), but the experimental findings to support this are limited. The Reading the Mind in the Eyes task, the Difficulties in Emotion Regulation Scale (DERS) and a computerized pictorial (angry and neutral faces) Stroop task were administered to 190 women [50 with AN, 50 with BN and 90 healthy controls (HCs)]. Those with an ED showed attentional biases to faces in general (medium effect), but specifically to angry faces over neutral faces (large effect) compared to HCs. The ED group also reported significantly higher emotion regulation difficulties (large effect) than HCs. There was a small difference between the ED and HC groups for the emotion recognition task (small-medium effect), particularly in the restricting AN (RAN) group. Depression and attentional bias to faces significantly predicted emotion regulation difficulties in a regression model. The data provide support for conceptualizations of EDs that emphasize the role of emotional functioning in the development and maintenance of EDs. Further research will concentrate on exploring whether these findings are state or trait features of EDs.


Neurons in the posterior interposed nucleus of the cerebellum related to vergence and accommodation. I. Steady-state characteristics.
The present study used single-unit recording and electrical microstimulation techniques in alert, trained rhesus monkeys to examine the involvement of the posterior interposed nucleus (IP) of the cerebellum in vergence and accommodative eye movements. Neurons related to vergence and ocular accommodation were encountered within a circumscribed region of the IP and their activity during changes in viewing distance was characterized. The activity of these neurons increased with decreases in vergence angle and accommodation (the far-response) but none showed changes in activity during changes in conjugate eye position and we therefore term them "far-response neurons." Far-response neurons were found within a restricted region of the IP that extended approximately 1 mm rostrocaudally and mediolaterally and 2 mm dorsal to the fourth ventricle. Microstimulation of this far-response region of the IP with low currents (<30 microA) often elicited divergence and accommodation for far. The behavior of 37 IP far-response neurons was examined during normal binocular viewing, during monocular viewing (blur cue alone), and during binocular viewing with accommodation open-loop (disparity cue alone). The activity of all cells was modulated under all three conditions. However, the change in activity of some of these neurons was significantly different under these three viewing conditions. The behavior of 70 IP far-response neurons was compared during normal binocular viewing and during viewing in which the accommodative response was significantly dissociated from the vergence response. The data from these two conditions was pooled and multiple regression analyses for each neuron generated two coefficients expressing the activity of the neuron relative to the vergence and to accommodative response respectively. On the basis of these coefficients, the overall activity of the neurons were classified as follows: 34 positively correlated with divergence, 11 positively correlated with far accommodation, 14 positively correlated with divergence and far accommodation, 9 positively correlated with divergence and accommodation, and 2 positively correlated with convergence and far accommodation. The results of this study demonstrate the involvement of a specific region of the posterior interposed nucleus of the cerebellum in vergence and accommodation. IP far-response neurons are active for vergence and accommodation irrespective of whether or not these eye movements are elicited by blur or disparity cues. The data in the present study strongly suggest that this cerebellar region is a far-response region that is involved in vergence as well as accommodative eye movements.


Surgonomics. Money down the drains.
The importance of delivering cost-effective quality surgical care has increased with the introduction of new payment mechanisms designed to slow the rise in health care costs. We examined the reasons for the use of a commonly used surgical input--a drain--to determine surgeons' feelings about the importance of costs. Both resident and attending general surgeons felt that the cost of the input was not an important consideration in the decision-making process of choosing the input. We believe that these findings are applicable across the range of inputs (hospital days, laboratory tests, ancillary procedures) used by surgeons in their practices. Unless this changes in the future, surgeons will not be able to provide quality surgical care within economic constraints.


Computational screening of transition metal/p-block hybrid electrocatalysts for CO2 reduction.
Among all the pollutants in the atmosphere, CO2 has the highest impact on global warming, and with the rising levels of this pollutant, studies on developing various technologies to convert CO2 into carbon-neutral fuels and chemicals have become more valuable. In this work, we present a detailed computational study of electrochemical reduction of CO2 reaction (the CO2 RR) to methane and/or methanol over different transition metal-p block catalysts using density functional theory calculations. In addition to the catalyst structure, we studied reaction mechanisms using free energy diagrams that explain the product selectivity with respect to the competing hydrogen evolution reaction. Furthermore, we developed scaling relations between all the active C bound intermediate species with ΔG(CO*) and O bound species with ΔG(OH*) The limiting potential lines with ΔG(OH*) as the descriptor are much less negative compared to UL lines with ΔG(CO*) as the descriptor indicating that catalyst materials following pathways via OH- bound intermediate species require more negative potentials than CO*→ HCO* and CO2 → COOH* steps to convert into products. We developed thermodynamic volcano plots with two descriptors; the CO* and OH* binding free energies and determined the best catalyst material among the initially investigated catalyst materials expecting this plot will provide guidance to the future work on improving the activity of transition metal-p block catalysts for this important reduction reaction.


Turning off Bacillus cereus quorum sensing system with peptidic analogs.
We explored quenching of the PlcR-PapR quorum-sensing system in Bacillus cereus. We generated PapR7-peptidic derivatives that inhibit this system and thus the production of virulence factors, reflected by a loss in hemolytic activity, without affecting bacterial growth. To our knowledge, these peptides represent the first potent synthetic inhibitors of quorum-sensing in B. cereus.


Synthesis and Reactivity of N-Heterocyclic Carbene Coordinated Formal Germanimidoyl-Phosphinidenes.
Treatment of N-heterocyclic carbene (NHC) ligated germylidenylphosphinidene MsFluidtBu-GeP(NHCiPr) (where MsFluidtBu is a bulky hydrindacene substituent, and NHCiPr is 1,3-diisopropyl-4,5-dimethyl-imidazolin-2-ylidene) with mesityl azide and 4-tertbutylphenyl azide afforded NHC coordinated formal germanimidoyl-phosphinidenes, which represent the first compounds bearing both Ge═N double bond and phosphinidene functionalities. Studies of the chemical properties revealed that the reactions preferred to occur at the Ge═N double bond, which underwent [2 + 2] cycloadditions with CO2 and ethyl isocyanate, and coordinated with coinage metals through the nitrogen atom.


Characterization of mutants of Escherichia coli temperature-sensitive for ribonucleic acid regulation: an unusual phenotype associated with a phenylalanyl transfer ribonucleic acid synthetase mutant.
A mutant strain AA-522, temperature-sensitive for protein synthesis, was isolated from a stringent strain (CP-78) of Escherichia coli K-12. The mutant strain has a relaxed phenotype at the nonpermissive growth temperature. Protein synthesis stops completely at 42 C, whereas the rate of ribonucleic acid (RNA) synthesis is maintained at 20% of the 30 C rate. Sucrose-gradient centrifugation analysis of RNA-containing particles formed at 42 C indicated the presence of "relaxed particles." These particles possess 16S and 23S RNA and are precursors to normal 50S and 30S ribosomal subunits. A search for the temperature-sensitive protein responsible for the halt in protein synthesis implicated phenylalanyl transfer RNA (tRNA) synthetase. Essentially no enzyme activity is detected in vitro at 30 or 40 C. Analysis of phenylalanyl tRNA synthetase activity in revertants of strain AA-522 indicated the presence of intragenic suppressor mutations. Revertants of strain AA-522 analyzed for the relaxed response at 42 C were all stringent; strain AA-522 was stringent at 30 C. These data indicate that a single mutation in phenylalanyl tRNA synthetase is responsible for both a block in protein synthesis and the relaxed phenotype at 42 C.


Respiratory Difficulties in Children With Underlying Asthma During Immunotherapy for High-risk Neuroblastoma.
Treatment of high-risk neuroblastoma now includes antibody based antitumor immunotherapy as part of standard care. Although this therapy has resulted in dramatic improvements in survival, it is associated with significant side effects. Children with underlying respiratory issues, and in particular asthma, may be more susceptible to immunotherapy associated respiratory compromise and pulmonary complications. Early routine involvement of pulmonology care is warranted for these patients in an effort to allow maximal delivery of immunotherapy and minimize acute and long-term complications.


Up-regulation of the levels of expression and function of a constitutively active mutant of the hamster alpha1B-adrenoceptor by ligands that act as inverse agonists.
The alpha1-adrenergic agonist phenylephrine stimulated phospholipase D (PLD) activity in Rat 1 fibroblasts transfected to express either the wild-type hamster alpha1B-adrenoceptor or a constitutively active mutant (CAM) form of this receptor. The EC50 for agonist stimulation of PLD activity was substantially lower at the CAM receptor than at the wild-type receptor as previously noted for phenylephrine stimulation of phosphoinositidase C activity. Sustained treatment of cells expressing the CAM alpha1B-adrenoceptor with phentolamine resulted in a marked up-regulation in levels of this receptor with half-maximal effects produced within 24 h and with an EC50 of approx. 40 nM. Such an up-regulation could be produced with a range of other ligands generally viewed as alpha1-adrenoceptor antagonists but equivalent treatment of cells expressing the wild-type alpha1B-adrenoceptor was unable to mimic these effects. After sustained treatment of the CAM alpha1B-adrenoceptor expressing cells with phentolamine, basal PLD activity was increased and phenylephrine was now able to stimulate PLD activity to greater levels than in vehicle-treated CAM alpha1B-adrenoceptor-expressing cells. The EC50 for phenylephrine stimulation of PLD activity was not altered, however, by phentolamine pretreatment and the associated up-regulation of the receptor. After phentolamine-induced up-regulation of basal PLD activity, a range of alpha1-antagonists were shown to possess the characteristics of inverse agonists of the CAM alpha1B-adrenoceptor as they were able to substantially decrease the elevated basal PLD activity.


Sex differences in stroke epidemiology: a systematic review.
Epidemiological studies, mainly based on Western European surveys, have shown that stroke is more common in men than in women. In recent years, sex-specific data on stroke incidence, prevalence, subtypes, severity and case-fatality have become available from other parts of the world. The purpose of this article is to give a worldwide review on sex differences in stroke epidemiology. We searched PubMed, tables-of-contents, review articles, and reference lists for community-based studies including information on sex differences. In some areas, such as secular trends, ischemic subtypes and stroke severity, noncommunity-based studies were also reviewed. Male/female ratios were calculated. We found 98 articles that contained relevant sex-specific information, including 59 incidence studies from 19 countries and 5 continents. The mean age at first-ever stroke was 68.6 years among men, and 72.9 years among women. Male stroke incidence rate was 33% higher and stroke prevalence was 41% higher than the female, with large variations between age bands and between populations. The incidence rates of brain infarction and intracerebral hemorrhage were higher among men, whereas the rate of subarachnoidal hemorrhage was higher among women, although this difference was not statistically significant. Stroke tended to be more severe in women, with a 1-month case fatality of 24.7% compared with 19.7% for men. Worldwide, stroke is more common among men, but women are more severely ill. The mismatch between the sexes is larger than previously described.


Should sex-specific norms be used to assess attention-deficit/hyperactivity disorder or oppositional defiant disorder?
The authors investigated whether sex-specific norms should be used to assess symptoms of attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) in girls. It was hypothesized that (a) there would be a group of girls who exhibit ADHD or ODD symptoms using sex-specific norms but not using Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994) criteria; (b) these girls would be significantly impaired relative to typically developing girls. These hypotheses were examined using behavior ratings completed by mothers and teachers of 1,491 elementary school students. Results showed that there was a small group of girls who did not meet DSM-IV criteria for ADHD or ODD but who had elevated ADHD and ODD scores when sex-specific norms were used. The same was not true for boys. The girls identified with sex-specific norms were more impaired than other girls. These results suggest that there may be a small number of girls who have behaviors and impairment that are consistent with ADHD and ODD, but they are not currently being identified by DSM-IV criteria.


What do women want? Valuing women's preferences and estimating demand for alternative models of maternity care using a discrete choice experiment.
In many countries, there has been a considerable shift towards providing a more woman-centred maternity service, which affords greater consumer choice. Maternity service provision in Ireland is set to follow this trend with policymakers committed to improving maternal choice at hospital level. However, women's preferences for maternity care are unknown, as is the expected demand for new services. In this paper, we used a discrete choice experiment (DCE) to (1) investigate women's strengths of preference for different features of maternity care; (2) predict market uptake for consultant- and midwifery-led care, and a hybrid model of care called the Domiciliary In and Out of Hospital Care scheme; and (3) calculate the welfare change arising from the provision of these services. Women attending antenatal care across two teaching hospitals in Ireland were invited to participate in the study. Women's preferred model of care resembled the hybrid model of care, with considerably more women expected to utilise this service than either consultant- or midwifery-led care. The benefit of providing all three services proved considerably greater than the benefit of providing two or fewer services. From a priority setting perspective, pursuing all three models of care would generate a considerable welfare gain, although the cost-effectiveness of such an approach needs to be considered.


Dose monitoring for boron neutron capture therapy using a reactor-based epithermal neutron beam.
The aims of this study were (i) to determine the variation with time of the relevant beam parameters of a clinical reactor-based epithermal neutron beam for boron neutron capture therapy (BNCT) and (ii) to test a monitoring system for its applicability to monitor the dose delivered to the dose specification point in a patient treated with BNCT. For this purpose two fission chambers covered with Cd and two GM counters were positioned in the beam-shaping collimator assembly of the epithermal neutron beam. The monitor count rates were compared with in-phanton reference measurements of the thermal neutron fluence rate, the gamma-ray dose rate and the fast neutron dose rate, at a constant reactor power, over a period of 2 years. Differences in beam output, defined as the thermal neutron fluence rate at 2 cm depth in a phantom, of up to 15% were observed between various reactor cycles. A decrease in beam output of about 5% was observed in each reactor cycle. An unacceptable decrease of 50% in beam output due to malfunctioning of the beam filter assembly was detected. For safe and accurate treatment of patients, on-line monitoring of the beam is essential. Using the calibrated monitor system, the standard uncertainty in the total dose at depth due to variations with time of the beam output parameters has been reduced to a clinically acceptable value of 1% (one standard deviation).


[The LIFE Child study: A cohort study investigating child development in changing environmental conditions].
The LIFE Child study: A cohort study investigating child development in changing environmental conditions Objectives: The LIFE Child study investigates healthy child development from pregnancy to young adulthood and the development of lifestyle diseases. Methods: Since study initiation in 2011, 1068 pregnant women and 4658 children have been included in the study. Children are recruited until the age of 16 years. Follow-up visits take place once per year. Assessments include physical examinations, interviews, questionnaires, standardized tests, and biological samples including genetic analysis. Results: We found significant associations between socio-economic status and health behaviour, between the weight of mothers and their children and between excessive media use and psychological complaints. Further projects dealt with the creation of references curves and the evaluation of new research methods. Conclusions: The study provides important insights into the interplay between the living environment, behaviour and child health.


Development of Dose Volume Histogram Analysis Program and Its Clinical Implementation.
Dose volume histogram (DVH) is one of the methods for evaluating the feasibility of radiotherapy plans. It is difficult to thoroughly comprehend an evaluation of each plan at a glance and to give a concise presentation of the case at conference. In this study, we provide a useful program that will fulfill such a purpose on a clinical setting. We have revised our protocols of radiotherapy planning, developed the program using Visual Basic 2010, which could facilitate an evaluation of DVH, and used it for checking plans and presentation at case conference. Since our DVH analysis program shows a result of DVH in a simple way, such as "OK (Okay)" or "NG (No good)", we can promptly comprehend the results of each radiotherapy plan at ease. This program easily tells us accordance between plans and protocols. We found this program useful and worth spreading.


T lymphocyte-mediated protection against Pseudomonas aeruginosa infection in granulocytopenic mice.
BALB/c mice immunized with Pseudomonas aeruginosa immunotype 1 polysaccharide develop protective T cell immunity to bacterial challenge. In vitro, T cells from immunized mice kill P. aeruginosa by production of a bactericidal lymphokine. The present study demonstrates that adoptive transfer of T cells from immunized BALB/c mice to granulocytopenic mice resulted in 97% survival on challenge with P. aeruginosa, compared with 17% survival with adoptive transfer of T cells from nonimmune BALB/c mice. This protection is specifically elicited by reexposure to the original immunizing antigen; adoptive recipients cannot withstand challenge with immunotype 3 P. aeruginosa. However, the adoptive recipients do survive simultaneous infection with both P. aeruginosa immunotypes 1 and 3. Adoptive transfer of T cells from the congenic CB.20 mice, which are unable to kill P. aeruginosa in vitro, provides only 20% protection to granulocytopenic mice. These studies indicate that transfer of specific immune T lymphocytes can significantly enhance the resistance to P. aeruginosa infection in granulocytopenic mice.


Evaluation of peritoneal fluid lactate as a marker of intestinal ischaemia in equine colic.
The most common cause of death as a direct result of colic is acute circulatory failure secondary to intestinal ischaemia. Early and accurate recognition of ischaemic bowel is essential to decrease complications and increase survival. Blood to peritoneal lactate values have been evaluated as a prognostic indicator, but lactate values characterised by type of lesion have not been reported. Plasma and peritoneal lactate values are higher in horses with intestinal ischaemia secondary to a strangulating obstruction (ISSO). Venous blood and peritoneal fluid were collected sequentially from 20 clinically healthy horses and 189 horses admitted for colic during a one-year period. Blood gas, pH, electrolyte (K+, Na+, Ca++, Cl-), glucose and lactate values were determined for blood and peritoneal fluid samples; other values recorded for peritoneal fluid included gross appearance, total protein and nucleated cell count. Information regarding diagnosis, treatment and outcome was retrieved from the medical records. Peritoneal and plasma levels of lactate were lower in control compared to clinical cases. Horses with ISSO had a higher peritoneal lactate value (8.45 mmol/l) than those with nonstrangulating obstruction (2.09 mmo/l). Factors with the strongest correlations with the presence of ISSO were changes in the gross appearance of the peritoneal fluid and values of peritoneal fluid chloride, pH and log10 lactate. Analysis of peritoneal fluid gross appearance, pH, lactate and chloride can be used for diagnosis of ISSO. Peritoneal fluid lactate is a better predictor of ISSO than blood lactate and may aid in early detection of catastrophic peritoneal lesions such as intestinal strangulation and rupture.


Host-Pathogen Interactions and Chronic Lung Allograft Dysfunction.
Lung transplantation is now considered to be a therapeutic option for patients with advanced-stage lung diseases. Unfortunately, due to post-transplant complications, both infectious and noninfectious, it is only a treatment and not a cure. Infections (e.g., bacterial, viral, and fungal) in the immunosuppressed lung transplant recipient are a common cause of mortality post transplant. Infections have more recently been explored as factors contributing to the risk of chronic lung allograft dysfunction (CLAD). Each major class of infection-(1) bacterial (Staphylococcus aureus and Pseudomonas aeruginosa); (2) viral (cytomegalovirus and community-acquired respiratory viruses); and (3) fungal (Aspergillus)-has been associated with the development of CLAD. Mechanistically, the microbe seems to be interacting with the allograft cells, stimulating the induction of chemokines, which recruit recipient leukocytes to the graft. The recipient leukocyte interactions with the microbe further up-regulate chemokines, amplifying the influx of allograft-infiltrating mononuclear cells. These events can promote recipient leukocytes to interact with the allograft, triggering an alloresponse and graft dysfunction. Overall, interactions between the microbe-allograft-host immune system alters chemokine production, which, in part, plays a role in the pathobiology of CLAD and mortality due to CLAD.


Interpretation of melperone intoxication: post-mortem concentration distribution and interpretation of intoxication data.
Since melperone abuse with lethal intoxication is common, expert opinions based on therapeutical and lethal concentration ranges can be considered as important. Because there is a lack of information about fatalities caused by melperone mono-intoxications and data on tissue samples with concentration distribution, the aim of this work is the examination of lethal concentration ranges of melperone and drug quantification in different matrices. An LC-MS/MS method was applied for analyses performed in blood and tissue samples. Quantification based on standard addition and sample preparation on liquid-liquid extraction with 1-chlorobutane. An appropriate tissue homogenization was performed ahead of extraction with an IKA Ultra-Turrax-Tube-Drive®. A Luna 5 µm C18 (2) 100 Å, 150 × 2 mm analytical column was used for chromatographic separation and the elution was performed with two mobile phases consisted of A (H2O/methanol = 95/5, v/v) and B (H2O/methanol = 3/97, v/v) both with 10 mM ammonium acetate and 0.1% acetic acid. A multi-drug LC-MS/MS analytical method developed was applied successfully for melperone quantification in different post-mortem matrices. No analytical problems could be identified during method development and analyses of real samples. The melperone lethal concentration calculated in femoral blood of the drug mono-intoxication investigated was 10 mg/L. Melperone concentration distribution was presented for the first time. The lethal reference concentration of melperone in femoral blood of 17.1 mg/L pointed out in different reference lists should be used with caution. Instead, a lower lethal melperone concentration should be considered. The post-mortem concentration distribution of the drug presented could be helpful in the interpretation of cases where no blood samples are available.


Evolutionary Approaches to Combat Antibiotic Resistance: Opportunities and Challenges for Precision Medicine.
The rise of antimicrobial resistance (AMR) in bacterial pathogens is acknowledged by the WHO as a major global health crisis. It is estimated that in 2050 annually up to 10 million people will die from infections with drug resistant pathogens if no efficient countermeasures are implemented. Evolution of pathogens lies at the core of this crisis, which enables rapid adaptation to the selective pressures imposed by antimicrobial usage in both medical treatment and agriculture, consequently promoting the spread of resistance genes or alleles in bacterial populations. Approaches developed in the field of Evolutionary Medicine attempt to exploit evolutionary insight into these adaptive processes, with the aim to improve diagnostics and the sustainability of antimicrobial therapy. Here, we review the concept of evolutionary trade-offs in the development of AMR as well as new therapeutic approaches and their impact on host-microbiome-pathogen interactions. We further discuss the possible translation of evolution-informed treatments into clinical practice, considering both the rapid cure of the individual patients and the prevention of AMR.


Inhibition of bacterial binding to mouse macrophages by Pseudomonas alginate.
Alginate, an acetylated polymer of D-mannuronic and L-guluronic acid obtained from a mucoid strain of Pseudomonas aeruginosa was shown to inhibit the binding of an isogenic non-mucoid revertant to mouse peritoneal and pulmonary macrophages. Inhibition of bacterial binding by the alginate was also demonstrated in tests with other non-mucoid P. aeruginosa strains and a strain of Staphylococcus albus. Since the mucoid form of P. aeruginosa eventually predominates in chronic P. aeruginosa infection in patients with cystic fibrosis, it is postulated that the alginate's inhibition of binding gives mucoid forms a selective advantage over non-mucoid forms against macrophage defence mechanisms in the lung.


CT based three dimensional dose-volume evaluations for high-dose rate intracavitary brachytherapy for cervical cancer.
In this study, high risk clinical target volumes (HR-CTVs) according to GEC-ESTRO guideline were contoured retrospectively based on CT images taken at the time of high-dose rate intracavitary brachytherapy (HDR-ICBT) and correlation between clinical outcome and dose of HR-CTV were analyzed. Our study population consists of 51 patients with cervical cancer (Stages IB-IVA) treated with 50 Gy external beam radiotherapy (EBRT) using central shield combined with 2-5 times of 6 Gy HDR-ICBT with or without weekly cisplatin. Dose calculation was based on Manchester system and prescribed dose of 6 Gy were delivered for point A. CT images taken at the time of each HDR-ICBT were reviewed and HR-CTVs were contoured. Doses were converted to the equivalent dose in 2 Gy (EQD2) by applying the linear quadratic model (α/β = 10 Gy). Three-year overall survival, Progression-free survival, and local control rate was 82.4%, 85.3% and 91.7%, respectively. Median cumulative dose of HR-CTV D90 was 65.0 Gy (52.7-101.7 Gy). Median length from tandem to the most lateral edge of HR-CTV at the first ICBT was 29.2 mm (range, 18.0-51.9 mm). On univariate analysis, both LCR and PFS was significantly favorable in those patients D90 for HR-CTV was 60 Gy or greater (p = 0.001 and 0.03, respectively). PFS was significantly favorable in those patients maximum length from tandem to edge of HR-CTV at first ICBT was shorter than 3.5 cm (p = 0.042). Volume-dose showed a relationship to the clinical outcome in CT based brachytherapy for cervical carcinoma.


In vitro activity of essential oils of free and nanostructured Melaleuca alternifolia and of terpinen-4-ol on eggs and larvae of Haemonchus contortus.
Haemonchus contortus is one of the major gastrointestinal nematodes responsible for significant economic and production losses of sheep. Diseases caused by this species lack effective anthelmintic products, and the search for new compounds to replace synthetic anthelmintics has been extensive. The present investigation assesses the in vitro activity of the essential oil of melaleuca (Melaleuca alternifolia), both free (TTO) and nanostructured (nanoTTO), and terpinen-4-ol (terp-4-ol) on eggs and larvae of H. contortus. Tests of egg hatching (EHT) and inhibition of larval migration (LMIT) were used to assess the in vitro efficacy of TTO, nanoTTO and terp-4-ol. Using EHT, at a concentration of 3.5 mg/ml, 100% inhibition occurred using TTO and terp-4-ol, with LC50 values of 0.43 and 0.63 mg/ml, and LC90 values of 1.75 mg/ml and 3.12 mg/ml, respectively. NanoTTO had lower activity, with 82.6% inhibition at the same concentration. Using LMIT, TTO and nanoTTO had a similar activity with 88.0% and 84.8% inhibition, respectively, at a concentration of 56 mg/ml. Terp-4-ol had a greater effect on larvae, with 85.7% inhibition at a concentration of 56 mg/ml and 82.4% at 3.5 mg/ml, demonstrating high activity at the lowest concentration tested. Therefore, the results indicate that all substances tested showed ovicidal and larvicidal activity against H. contortus. TTO, terp-4-ol and, mainly, nanoTTO may be targeted in in vivo studies, besides being a promising line of research into the control and treatment of veterinary important helminths.


Sampling variability of transient elastography according to probe location.
Heterogeneity of fibrosis throughout the liver has been reported. However, the need for several measurements when using transient elastography was not thoroughly investigated. The aim was to find out whether measurement of liver stiffness varies according to the probe location. Six hundred and twenty-five consecutive patients with chronic liver diseases referred for transient elastography were enrolled. All patients underwent successive liver stiffness measurements at three different sites. Representative measurements were acquisitions with a success rate greater than 60% and an interquartile range lower than 30% of the median. The sample included 371 eligible patients with three representative measurements. Comparing the three successive measurements categorized to fibrosis stages F0-F4, 68.2% of patients had agreement between all three sites. Discordance of one stage was noted in 28.3% of the patients, in 7% for two stages, and in 1.4% for three stages.The κ for comparing the maximal versus the minimal results was 0.43. There was no significant difference in the characteristics of patients with discordance and patients without discordance including age, sex, waist circumference, BMI, and etiology of liver disease. The stage of fibrosis was associated with discordance between measurements (P<0.001), demonstrating low discordance rate in patients with stages F0-F1 or F4 and high discordance rate in patients with stages F2 and F3. Sampling variability according to probe location is seen in transient elastography in approximately 30% of patients. Therefore, it may be suggested to perform transient elastography from various sites to minimize the sample error.


Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence.
Nicotinamide adenine dinucleotide (NAD), the cell's hydrogen carrier for redox enzymes, is well known for its role in redox reactions. More recently, it has emerged as a signaling molecule. By modulating NAD+-sensing enzymes, NAD+ controls hundreds of key processes from energy metabolism to cell survival, rising and falling depending on food intake, exercise, and the time of day. NAD+ levels steadily decline with age, resulting in altered metabolism and increased disease susceptibility. Restoration of NAD+ levels in old or diseased animals can promote health and extend lifespan, prompting a search for safe and efficacious NAD-boosting molecules that hold the promise of increasing the body's resilience, not just to one disease, but to many, thereby extending healthy human lifespan.


The relationship between wine consumption and cardiovascular risk: from epidemiological evidence to biological plausibility.
Epidemiological studies have suggested that cardiovascular disease morbidity and mortality can be decreased by moderate alcohol consumption. Several recent studies have also separately assessed the relative risk associated with different types of alcoholic beverages. The evidence obtained strongly suggests, although does not prove, that there is a major beneficial effect from drinking a low-moderate amount of wine. A meta-analysis has recently been performed on 19 of these studies, selected on the basis of the availability of specific information on the relative risk associated with wine consumption. The results indicate a negative association of moderate (up to 300 ml per day) wine consumption with the risk of cardiovascular events. Although some cardioprotective effects of alcoholic beverages are probably due to ethanol-induced elevation of HDL cholesterol, lowering of fibrinogen plasma levels and, perhaps, of platelet aggregation, it is reasonable to speculate that the cardiovascular protective effects of wine, observed in French and in other populations, may be attributed in part to the antioxidant, vasorelaxant, and antithrombotic properties of its polyphenolic components.


ACE inhibition and ANG II receptor blockade improve glomerular size-selectivity in IgA nephropathy.
Protein trafficking across the glomerular capillary has a pathogenic role in subsequent renal damage. Despite evidence that angiotensin-converting enzyme (ACE) inhibitors improve glomerular size-selectivity, whether this effect is solely due to ANG II blocking or if other mediators also play a contributory role is not clear yet. We studied 20 proteinuric patients with IgA nephropathy, who received either enalapril (20 mg/day) or the ANG II receptor blocker irbesartan (100 mg/day) for 28 days in a randomized double-blind study. Measurements of blood pressure, renal hemodynamics, and fractional clearance of neutral dextran of graded sizes were performed before and after 28 days of treatment. Both enalapril and irbesartan significantly reduced blood pressure over baseline. This reduction reached the maximum effect 4-6 h after drug administration but did not last for the entire 24-h period. Despite transient antihypertensive effect, proteinuria was effectively reduced by both treatments to comparable extents. Neither enalapril nor irbesartan modified the sieving coefficients of small dextran molecules, but both effectively reduced transglomerular passage of large test macromolecules. Theoretical analysis of sieving coefficients showed that neither drug affected significantly the mean pore radius or the spread of the pore-size distribution, but both importantly and comparably reduced the importance of a nonselective shunt pathway. These data suggest that antagonism of ANG II is the key mechanism by which ACE inhibitors exert their beneficial effect on glomerular size-selective function and consequently on glomerular filtration and urinary output of plasma proteins.


Genetic diversity of ospC in a local population of Borrelia burgdorferi sensu stricto.
The outer surface protein, OspC, is highly variable in Borrelia burgdorferi sensu stricto, the agent of Lyme disease. We have shown that even within a single population OspC is highly variable. The variation of ospA and ospC in the 40 infected deer ticks collected from a single site on Shelter Island, New York, was determined using PCR-SSCP. There is very strong apparent linkage disequilibrium between ospA and ospC alleles, even though they are located on separate plasmids. Thirteen discernible SSCP mobility classes for ospC were identified and the DNA sequence for each was determined. These sequences, combined with 40 GenBank sequences, allow us to define 19 major ospC groups. Sequences within a major ospC group are, on average, <1% different from each other, while sequences between major ospC groups are, on average, approximately 20% different. The tick sample contains 11 major ospC groups, GenBank contains 16 groups, with 8 groups found in both samples. Thus, the ospC variation within a local population is almost as great as the variation of a similar-sized sample of the entire species. The Ewens-Watterson-Slatkin test of allele frequency showed significant deviation from the neutral expectation, indicating balancing selection for these major ospC groups. The variation represented by major ospC groups needs to be considered if the OspC protein is to be used as a serodiagnostic antigen or a vaccine.


Insulin sensitivity and sorbitol production of the normal rabbit corneal epithelium in vitro.
Insulin-depleted, normal rabbit corneal epithelium was incubated in vitro in tissue culture medium containing high concentrations of glucose (35 mM). These short-term incubations showed that the epithelium took up glucose equally whether or not insulin had been added to the medium, indicating that corneal epithelium is an insulin-insensitive tissue. Sorbitol accumulation showed that the normal corneal epithelium has a sorbitol pathway which can be activated in the presence of high intracellular glucose. The low level of sorbitol accumulation in these normal epithelia is probably not osmotically significant.


Parameters of the fermentation of soybean flour by Monascus purpureus or Aspergillus oryzae on the production of bioactive compounds and antioxidant activity.
The objective of this work was to evaluate the effects the solid-state fermentation parameters of defatted soybean flour (DSF) by Monascus purpureus or Aspergillus oryzae on the bioactive compounds. Central composite rotatable design, multi-response optimization, and Pearson's correlation were used. The fermentation parameters as initial pH (X1), DSF-to-water ratio (X2), and incubation temperature (X3) were taken as independent variables. The function responses were isoflavone content, total phenolic content (TPC), and antioxidant activity. All fermentation parameters affected the isoflavone content when fermented by Monascus purpureus, whereas the TPC or antioxidant activities remained almost unchanged. For the fermentation by Aspergillus oryzae, all the function responses were influenced by X2 and X3 and were independent of the X1. Estimated optimum conditions were found as x1 = 6.0, x2 = 1:1, and x3 = 30 °C for both fungi. Achieving suitable fermentation parameters is essential to increase bioactive compounds in the DSF that makes it promising for food industrial applications.


Pharmacokinetic characterization of tizanidine nasal spray, a novel intranasal delivery method for the treatment of skeletal muscle spasm.
The skeletal muscle relaxant tizanidine is approved by the US FDA and the European Medicines Agency for treating spasticity and is supplied as tablets for oral administration. However, tizanidine has a poor bioavailability, due to extensive first-pass metabolism. Therefore, the nasal route of administration, which bypasses portal circulation, may increase the bioavailability of tizanidine and, possibly, reduce the time to peak plasma concentration, thereby shorting the latency of therapeutic effect. The objective of this study was to evaluate the pharmacokinetic profile of tizanidine nasal spray and compare it to the profile of tizanidine oral tablets. This open-label, phase I study comprised two protocols: protocol 1, tizanidine HCl solution (32.73 mg/mL) intranasally at single doses of 2 and 4 mg versus 4 mg tizanidine oral tablets (randomized, three periods crossover, 12 healthy subjects); and protocol 2, tizanidine HCl solution (16.36 mg/mL) intranasally at a single dose of 1 mg vs. 4 mg tizanidine oral tablets (randomized, two periods crossover, 12 healthy subjects, one dropout). Tizanidine plasma concentrations were determined by liquid chromatography/mass spectrometry. There was a linear relationship between different dosages of intranasal formulation and the area under the concentration-time curve and maximum plasma concentration (C(max)). The relative bioavailability of the different dosages of intranasal formulation were 1.29, 1.93, and 4.23 for 1, 2, and 4 mg intranasal administration, respectively. Comparison of C(max) values gave the following ratios: 0.91, 1.39, and 2.73, for 1, 2, and 4 mg intranasal administration, respectively. The mean time to C(max) (t(max)) was 0.99, 0.43, and 0.63 h for 1, 2, and 4 mg intranasal administration, respectively, whereas it was 1.13 and 1.30 h for the two series of 4 mg tizanidine oral tablets. The bioavailability of the tizanidine intranasal formulation was higher than that of tizanidine oral tablets. The t(max) was also shorter with the intranasal formulation. No serious adverse events occurred throughout the study, such that the two formulations resulted equally well-tolerated. The intranasal formulation of tizanidine results are therefore worthy of subsequent clinical testing in phase II.


Selecting linear-score distributions for modelling milk-culture results.
The data for this cross-sectional retrospective study are from surveys of 65 dairy-cattle herds in central New York, USA sampled between February, 1993 and March, 1995. The objective was to identify probability distributions of logarithmically transformed somatic-cell counts (linear score) for use in a simulation model of mastitis and milk quality. Probability density functions were estimated using maximum-likelihood estimators for the linear score of individual-cow composite-milk samples culture negative and culture positive for the pathogens Streptococcus agalactiae, Streptococcus non-agalactiae, Staphylococcus aureus, and coagulase-negative staphylococci for the complete dataset and by bulk-tank somatic-cell count group (< 500,000, > or = 500,000 SCC/ml). Based on the rankings of three goodness-of-fit tests (Anderson-Darling, Kolmogorov-Smirnov and chi 2), the Weibull distribution (among the three top-ranking distributions for 14 out of 15 cases) may be used to model the individual-cow linear-score response by culture-result-specific bulk-tank somatic-cell count group. A beta distribution was among the three top-ranking distributions for nine out of 15 culture-result-specific bulk-tank somatic-cell count groups and has a logical relationship to linear score because it is defined on a fixed interval. On the other hand, the normal distribution had a poorer fit than the Weibull and at least two other distributions for all culture negative and coagulase-negative staphylococci samples. We do not assume that the underlying biological processes are fully explained by either Weibull or beta distribution--but modelling the linear score for the above culture results with these distributions provided an adequate fit to the survey data, reduced the need for two-sided truncation that open intervals needed, and had errors that did not appear to be systematically positive or negative.


UL5, a protein required for HSV DNA synthesis: genetic analysis, overexpression in Escherichia coli, and generation of polyclonal antibodies.
The mutations in two DNA-negative ts mutants of herpes simplex virus type 1 (HSV-1), tsK13 and tsM19, have been previously mapped to a 2.0-kb fragment (coordinates 0.095-0.108) at the left end of the genome (S. Weller, D. Aschman, W. Sacks, D. Coen, and P. Schaffer, 1983, Virology 130, 290-305). Sequence analysis of the HSV-1 genome has revealed the existence of two open reading frames, UL5 and UL6, within this fragment (D. McGeoch, M. Dalrymple, A. Dolan, D. McNab, L. Perry, P. Taylor, and M. Challberg, 1988, J. Virol. 62, 444-453). In this paper we report fine mapping and sequence analysis of the mutations in tsK13 and tsM19 which unambiguously localize the mutations to UL5, predicted to encode a 99-kDa polypeptide. The mutation in tsK13 was shown to result in a single amino acid substitution, Pro236 to Leu, whereas tsM19 contains two substitutions, Pro236 to Ser and Ala249 to Val. Thus, both mutants are altered in Pro236. Temperature-shift experiments indicated that the UL5 gene product is required continuously during viral DNA synthesis, suggesting a direct role for the 99K protein in viral DNA synthesis. The UL5 gene product was overexpressed in Escherichia coli and used to generate polyclonal antibodies which detected proteins in HSV-1-infected cell extracts from 4 hr postinfection. Although a faint band of the predicted size (99 kDa) was observed, the majority of the immunoreactive material migrated as smaller bands which represent either proteolytic degradation during extraction or post-translational proteolytic modification of the UL5 gene product. Indirect immunofluorescence staining revealed that the UL5 gene product localizes to the nucleus in two patterns: diffuse staining throughout the nucleus and in discrete globules which appear at the periphery of the nucleus. Sequence analysis of the UL5 gene predicts that the 99-kDa protein contains a consensus sequence for an ATP binding site. Possible roles of this protein in viral DNA synthesis are discussed.


Macrophage and polymorphonuclear leukocyte function in patients with Alzheimer disease.
Monocyte derived macrophages and polymorphonuclear leukocytes (PMNs) isolated from the peripheral blood of thirteen patients with Alzheimer disease were studied for their cytotoxic effects on a sensitive allogenic tumor target. PMN cells from 11 of the 13 patients with Alzheimer disease were able to kill the tumor cells. In addition, the macrophages from 12 of the 13 Alzheimer disease patients were cytotoxic towards the tumor targets. Four of these patients possessed a plasma inhibitory factor which was capable of suppressing macrophage mediated cytotoxicity. When the lymphocytes from these patients were studied for their ability to be stimulated with the specific antigen, streptokinase, to produce macrophage activating factor (MAF), only 5 of the 13 patients studied possessed lymphocytes which were capable of producing MAF. Thus, the only immunological defect in Alzheimer disease patients which was observed in this study was in the ability of the lymphocytes to synthesize MAF.


[Cerebral ischemia in young adults].
An overview is given over etiology and prognosis of cerebral ischemias until the age of 40. In a time period of 19 years, 168 patients were diagnosed with cerebral ischemia until the age of 40 (91 females, 77 males). The most frequent etiology is premature atherosclerosis in patients with vascular risk factors (up to 50%). Cardiogenic embolism is responsible for 1 to 34% of the cases: cardiac valve diseases and endocarditis being the most frequent sources. In 2 to 19% a vasculitis is diagnosed. While infectious arteritis is especially frequent in countries of the third world, immunovasculitides are common in Europe and the USA. Noninflammatory vasculopathies include spontaneous or traumatic dissection, fibromuscular dysplasia and vascular malformations. A migrainous stroke is especially frequent in female smokers with intake of oral contraceptives. During pregnancy both sinus thrombosis and arterial ischemia occur. Hematologic causes for ischemia are polycythemia, thrombocytosis and genetic diseases (sickle cell anemia, AT3-deficiency). Cerebral ischemia may occur in connection with the ingestion of ergot-derivates. The prognosis of cerebral ischemia in young adults is better than in older stroke-patients.


Nocturnal blood pressure fall on ambulatory monitoring in a large international database. The "Ad Hoc' Working Group.
A wide range of definitions is used to distinguish subjects in whom blood pressure (BP) falls at night (dippers) from their counterparts (nondippers). In an attempt to standardize the definition of nondipping, we determined the nocturnal BP fall and night-day BP ratio by 24-hour ambulatory monitoring in 4765 normotensive and 2555 hypertensive subjects from 10 to 99 years old. In all subjects combined, the systolic/diastolic nocturnal fall and corresponding ratio averaged (+/- SD) -16.7 +/- 11.0/ -13.6 +/- 8.1 mm Hg and 87.2 +/- 8.0%/83.1 +/- 9.6%, respectively. In normotensive subjects, the 95th percentiles were -0.3/-1.1 mm Hg for the nocturnal fall and 99.7%/98.3% for the night-day ratio. Both the fall and ratio showed a curvilinear correlation with age. The smallest fall and largest ratio were observed in older (> or = 70 years) subjects. A higher BP on conventional sphygmomanometry was associated with a larger systolic (partial r = .11) and diastolic (r = .12) nocturnal BP fall. The diastolic (r = .08) but not the systolic night-day ratio increased with higher conventional BP. The nocturnal BP fall was larger and the corresponding night-day ratio smaller in oscillometric (n = 5884) than in auscultatory (n = 1436) recordings, in males (n = 3730) than in females (n = 3590), and in Europe (n = 4556) than in the other continents (n = 2764). The distributions of the nocturnal BP fall and night-day ratio showed considerable overlap among normotensive and hypertensive subjects, but the overlap tended to be larger for the ratio than for the fall. Of all subjects, 3.2% had systolic and diastolic ratios of 100% or more. With adjustments applied for confounders, the probability of being a nondipper increased 2.8 times (95% confidence interval, 2.0-4.0) from 30 to 60 years and 5.7 times (4.4-7.4) from 60 to 80 years. The odds ratios were 1.0 (0.8-1.4) for males versus females. 1.6 (1.2-2.1) for subjects with definite hypertension versus normotensive subjects, 2.4 (1.2-4.7) for Asians (n = 2213, 96% Japanese) versus inhabitants of the other continents, and 2.4 (1.5-3.8) for subjects examined with auscultatory versus oscillometric devices. In conclusion, the mathematical definition of nondipping, ie, having a night-day ratio of 100% or more for systolic and diastolic BPs, closely approximated the 95th percentiles of the night-day ratio in normotensive subjects. The ratio depends less on BP level than the nocturnal BP fall and is therefore to be preferred in the definition of dipping status. Notwithstanding the present findings, the reproducibility of nondipping and its prognostic significance need further clarification.


Outcomes of enhanced recovery after surgery (ERAS) in gynecologic oncology - A systematic review and meta-analysis.
To assess the benefit of Enhanced Recovery After Surgery (ERAS) on length of stay (LOS), postoperative complications, 30-day readmission, and cost in gynecologic oncology. A systematic literature search was performed in MEDLINE, EMBASE, Cochrane Register of Controlled Trials, and Web of Science for all peer-reviewed cohort studies and controlled trials on ERAS involving gynecologic oncology patients. Abstracts, commentaries, non-controlled studies, and studies without specific data on gynecologic oncology patients were excluded. Meta-analysis was performed on the primary endpoint of LOS. Subgroup analyses were performed based on risk of bias of the studies included, number of ERAS elements, and ERAS compliance. Secondary endpoints were readmission rate, complications, and cost. A total of 31 studies (6703 patients) were included: 5 randomized controlled trials, and 26 cohort studies. Meta-analysis of 27 studies (6345 patients) demonstrated a decrease in LOS of 1.6 days (95% confidence interval, CI 1.2-2.1) with ERAS implementation. Meta-analysis of 21 studies (4974 patients) demonstrated a 32% reduction in complications (OR 0.68, 95% CI 0.55-0.83) and a 20% reduction in readmission (OR 0.80, 95% CI 0.64-0.99) for ERAS patients. There was no difference in 30-day postoperative mortality (OR 0.61, 95% CI 0.23-1.6) for ERAS patients compared to controls. No difference in the odds of complications or reduction in LOS was observed based on number of included ERAS elements or reported compliance with ERAS interventions. The mean cost savings for ERAS patients was $2129 USD (95% CI $712 - $3544). ERAS protocols decrease LOS, complications, and cost without increasing rates of readmission or mortality in gynecologic oncology surgery. This evidence supports implementation of ERAS as standard of care in gynecologic oncology.


Effects of short- and long-term neurostimulation (tDCS) on Alzheimer's disease patients: two randomized studies.
Non-invasive brain stimulation is an effective treatment for Alzheimer's disease. The purpose of the two studies presented here is to compare the short- and long-term effects of transcranial direct current stimulation (t-DCS) on two samples of advanced AD patients. In Study 1 26 patients were involved in a 10-day anodal vs. sham tDCS intervention stimulating the left frontotemporal cortex. A pre-post test assessment was run using two different neurocognitive tests and EEG data. The same protocol was used in Study 2, which involved 18 different patients who underwent the same intervention 10 days a month for 8 months. Results confirmed how the t-DCS intervention was effective both in the short- and the long-term to slow down the progression of AD on specific neurophysiological domains and, to a certain extent, on neurophysiological activity. Discussion tDCS appear to be effective and to affect differently neurocognitive and neurophysiological functions when comparing short and long-term outcomes. Conclusions Anodal-tDCS is an effective way to slow down the progression of Alzheimer's both in the short and long term. It can also affect the EEG patterns, but this requires a more protracted intervention.


In vivo quantification of leukocyte behavior in the retina during endotoxin-induced uveitis.
The interaction between leukocytes and vascular endothelial cells plays an important role in various inflammatory disorders. This study evaluated leukocyte behavior in the retina during endotoxin-induced uveitis (EIU) in vivo. EIU was induced in female Lewis rats by footpad injection of lipopolysaccharide (LPS). The time-course changes of retinal leukocyte behavior were followed at 1.5, 3, 4.5, 6, 12, 24, 48, 72, and 120 hours after LPS treatment using acridine orange digital fluorography, consisting of high-resolution images from a scanning laser ophthalmoscope and a fluorescent nuclear dye of acridine orange. Major retinal vessels were significantly dilated (P < 0.05) at 4.5 hours after LPS injection. The vasodilation, marked in veins, became maximum at 24 hours and subsided at 72 hours. Leukocytes were observed rolling along the walls of major veins at 4.5 hours. The number of rolling leukocytes gradually increased and reached a peak level of 33.8 +/- 3.4 cells/minute per major vein at 12 hours. Leukocyte rolling was still observed at 72 hours. No rolling of leukocytes was observed along the arterial walls throughout any experiments. The velocities of rolling leukocytes were determined at 6, 12, 24, and 48 hours. The leukocyte rolling velocity at 6 hours was significantly slower (33.3 +/- 2.8 microns/second, P < 0.05) than at the other three times (average, 46.6 microns/second). Cellular infiltration into the vitreous cavity was detected at 24 hours and reached its maximum at 48 hours. This study demonstrates that it is possible to evaluate EIU by investigating retinal leukocyte behavior and that vasodilation of major retinal vessels and leukocyte-endothelial interactions precede inflammatory cell emigration into the vitreous. This method may be useful to quantify the severity of inflammation in EIU.