Increasing incidence of melanoma after solid organ transplantation: a retrospective epidemiological study.
The risk of melanoma in organ transplant recipients (OTR) is increased compared with the general population. This retrospective study registered all cases of post-transplant melanoma in kidney, heart, lung, and liver transplant recipients followed in our specialized post-transplant Dermatology Clinic since 1991. The yearly prevalence of melanoma and skin carcinoma between 2000 and 2015 was computed and compared in this population. Based on another cohort of kidney transplant recipients grafted since 2005, adjusted age- and sex-standardized incidence ratio (SIR) was calculated using a renal transplantation registry. In our overall OTR cohort, between 1991 and 2000, five melanomas occurred in 1800 OTRs (0.28%), whereas between 1991 and 2015, 53 melanomas were diagnosed in 49 of 4510 OTR (1.09%), representing a 3.9-fold increase in prevalence after 2000. Remarkably, the prevalence of nonmelanoma skin cancers remained unchanged over this period. Two deaths related to melanoma were recorded with an overall follow-up of 62 months. In our cohort of 1102 renal transplant recipients, the SIR of melanoma was 4.52. Our data suggest that contrasting with nonmelanoma skin cancer, the risk of post-transplant melanoma has considerably increased over the last decade.


Differential expression of entactin-1/nidogen-1 and entactin-2/nidogen-2 in myogenic differentiation.
Here, we show that entactin-2 expression is strongly, but transiently, induced in myogenic differentiation. Treatment of C2C12 myoblasts with actinomycin D in parallel to the induction of differentiation could demonstrate that this is due to enhanced transcription of the entactin-2 gene. Furthermore, treatment with the translation inhibitor cycloheximide could show that entactin-2 is a primary response gene. As p38 MAP kinase is an important regulator of myogenic differentiation, we also analyzed the possibility that entactin-2 might be a target of this pathway. However, using various p38 MAPK inhibitors, we could not detect involvement of p38 in entactin-2 up-regulation. Most remarkably, expression of the entactin-2 homolog entactin-1 dramatically declined in myogenesis, suggesting different functions of the two entactins in this process. A similar effect was seen in primary myoblasts isolated from two different mouse strains. Expression of high levels of entactin-1 in myoblasts using a retroviral expression system led to a higher proliferation rate both in growth and in differentiation medium and to reduced expression of various myogenic differentiation markers after the induction of differentiation. Furthermore, decreased expression of the entactin-2 gene after treatment of the cells with ent-2-specific siRNA preparation led to reduced expression of the cell cycle inhibitor p21. These data suggest important and distinct functions of entactin-1 and -2 in myogenic differentiation.


Tenovin-1 Induces Senescence and Decreases Wound-Healing Activity in Cultured Rat Primary Astrocytes.
Brain aging induces neuropsychological changes, such as decreased memory capacity, language ability, and attention; and is also associated with neurodegenerative diseases. However, most of the studies on brain aging are focused on neurons, while senescence in astrocytes has received less attention. Astrocytes constitute the majority of cell types in the brain and perform various functions in the brain such as supporting brain structures, regulating blood-brain barrier permeability, transmitter uptake and regulation, and immunity modulation. Recent studies have shown that SIRT1 and SIRT2 play certain roles in cellular senescence in peripheral systems. Both SIRT1 and SIRT2 inhibitors delay tumor growth in vivo without significant general toxicity. In this study, we investigated the role of tenovin-1, an inhibitor of SIRT1 and SIRT2, on rat primary astrocytes where we observed senescence and other functional changes. Cellular senescence usually is characterized by irreversible cell cycle arrest and induces senescence- associated β-galactosidase (SA-β-gal) activity. Tenovin-1-treated astrocytes showed increased SA-β-gal-positive cell number, senescence-associated secretory phenotypes, including IL-6 and IL-1β, and cell cycle-related proteins like phospho-histone H3 and CDK2. Along with the molecular changes, tenovin-1 impaired the wound-healing activity of cultured primary astrocytes. These data suggest that tenovin-1 can induce cellular senescence in astrocytes possibly by inhibiting SIRT1 and SIRT2, which may play particular roles in brain aging and neurodegenerative conditions.


Professional practice of nurses and influences on moral sensitivity.
To understand the professional practice of nurses and their influence on the development of moral sensibility. A qualitative and descriptive study, conducted between November 2015 and February 2016 in the hospitalization units of the medical clinic of two large hospitals located in Belo Horizonte, Minas Gerais. 14 nurses participated. Data collection was done through interviews, guided by semi-structured scripts. The data were submitted to content analysis. Two categories emerged: Professional practice of the nurse: internal and external goods and Moral sensitivity and the interface with the professional practice of nurses. The development of the moral sensitivity of nurses is influenced by factors related to professional practice, such as interpersonal relations, ethical education and management activities. Final considerations: In the professional practice, moral sensibility is an integral part of the ethical decision-making process in services, being essential for quality care.


Clinical presentation and differential splicing of SRSF2, U2AF1 and SF3B1 mutations in patients with acute myeloid leukemia.
Previous studies demonstrated that splicing factor mutations are recurrent events in hematopoietic malignancies with both clinical and functional implications. However, their aberrant splicing patterns in acute myeloid leukemia remain largely unexplored. In this study, we characterized mutations in SRSF2, U2AF1, and SF3B1, the most commonly mutated splicing factors. In our clinical analysis of 2678 patients, splicing factor mutations showed inferior relapse-free and overall survival, however, these mutations did not represent independent prognostic markers. RNA-sequencing of 246 and independent validation in 177 patients revealed an isoform expression profile which is highly characteristic for each individual mutation, with several isoforms showing a strong dysregulation. By establishing a custom differential splice junction usage pipeline, we accurately detected aberrant splicing in splicing factor mutated samples. A large proportion of differentially used junctions were novel, including several junctions in leukemia-associated genes. In SRSF2(P95H) mutants, we further explored the possibility of a cascading effect through the dysregulation of the splicing pathway. Furthermore, we observed a validated impact on overall survival for two junctions overused in SRSF2(P95H) mutants. We conclude that splicing factor mutations do not represent independent prognostic markers. However, they do have genome-wide consequences on gene splicing leading to dysregulated isoform expression of several genes.


Reverse engineering gene regulatory networks by modular response analysis - a benchmark.
Gene regulatory networks control the cellular phenotype by changing the RNA and protein composition. Despite its importance, the gene regulatory network in higher organisms is only partly mapped out. Here, we investigate the potential of reverse engineering methods to unravel the structure of these networks. Particularly, we focus on modular response analysis (MRA), a method that can disentangle networks from perturbation data. We benchmark a version of MRA that was previously successfully applied to reconstruct a signalling-driven genetic network, termed MLMSMRA, to test cases mimicking various aspects of gene regulatory networks. We then investigate the performance in comparison with other MRA realisations and related methods. The benchmark shows that MRA has the potential to predict functional interactions, but also shows that successful application of MRA is restricted to small sparse networks and to data with a low signal-to-noise ratio.


Functionalization of the TMEM175 p.M393T variant as a risk factor for Parkinson disease.
Multiple genome-wide association studies (GWAS) in Parkinson disease (PD) have identified a signal at chromosome 4p16.3; however, the causal variant has not been established for this locus. Deep investigation of the region resulted in one identified variant, the rs34311866 missense SNP (p.M393T) in TMEM175, which is 20 orders of magnitude more significant than any other SNP in the region. Because TMEM175 is a lysosomal gene that has been shown to influence α-synuclein phosphorylation and autophagy, the p.M393T variant is an attractive candidate, and we have examined its effect on TMEM175 protein and PD-related biology. After knocking down each of the genes located under the GWAS peak via multiple shRNAs, only TMEM175 was found to consistently influence accumulation of phosphorylated α-synuclein (p-α-syn). Examination of the p.M393T variant showed effects on TMEM175 function that were intermediate between the wild-type (WT) and knockout phenotypes, with reduced regulation of lysosomal pH in response to starvation and minor changes in clearance of autophagy substrates, reduced lysosomal localization, and increased accumulation of p-α-syn. Finally, overexpression of WT TMEM175 protein reduced p-α-syn, while overexpression of the p.M393T variant resulted in no change in α-synuclein phosphorylation. These results suggest that the main signal in the chromosome 4p16.3 PD risk locus is driven by the TMEM175 p.M393T variant. Modulation of TMEM175 may impact α-synuclein biology and therefore may be a rational therapeutic strategy for PD.


Paradoxical thrombotic effects of aspirin: experimental study on 1000 animals.
Aspirin administration decreases the risk of vascular ischemic problems. However, aspirin withdrawal may temporarily increase this risk. Previous studies reported that high dilutions of aspirin might cause a pro-thrombotic effect. This paper studies the effect of the lower end of the aspirin dose-response curve, its possible mechanism and clinical implications. Wistar rats were distributed into 100 groups of 10 rats each. Aspirin was injected at 100 mg/kg, 1 mg/kg and at several different aspirin dilutions along with cyclooxygenase (COX) 1 (SC-560), COX 2 (NS-398) or both selective inhibitors simultaneously using a laser-induced thrombosis model. The higher doses of aspirin decreased thrombosis. An opposite trend was observed with the lowest doses. SC-560 produced an anti-thrombotic effect antagonized by the highest aspirin dilutions. NS-398 created a pro-thrombotic effect that was antagonized by aspirin at higher doses. Simultaneous inhibition of COX 1 and 2 produced changes similar to COX 1 inhibition. COX 2 inhibition induced a pro-thrombotic effect that was antagonized by aspirin at 1 mg/kg or 100 mg/kg. The administration of the lowest aspirin doses induced a pro-thrombotic effect stronger than the antithrombotic effect of COX 1 selective inhibition. The mechanism of this last pro-thrombotic effect is induced by residual aspirin and is independent of COX 1 inhibition. This study may explain the cause of the paradoxical thrombo-embolic complications observed after aspirin discontinuation, an effect of residual aspirin rather than a rebound effect, and highlights the importance of low doses of substances as a barely studied source of side-effects.


Sensitivity, Specificity, and Limitations of Optical Coherence Tomography Angiography in Diagnosis of Polypoidal Choroidal Vasculopathy.
To evaluate the sensitivity and specificity of optical coherence tomography angiography (OCTA) in differentiating polypoidal choroidal vasculopathy (PCV) from age-related macular degeneration (AMD). Fundus color photographs, spectral-domain optical coherence tomography, and fluorescein angiography (step 1) and OCTA (step 2) of 50 eyes that had PCV or AMD were presented to two ophthalmologists. The final diagnoses of PCV were masked. Sensitivity and specificity were calculated and compared to the 2-step approach (before and after OCTA) in detecting PCV. The limitations were also evaluated. Of the 50 eyes, 31 were PCV and 19 were non-PCV. The sensitivity increased from 69.5% to 90% after OCTA; however, there was no significant improvement in specificity after OCTA. 70.9% of the eyes with PCV had clear or obvious branching vascular nets (BVNs) in OCTA with high sensitivity (97.5%) after OCTA. Contrarily, 29.1% had insignificant BVNs with a low sensitivity (72.5%) after OCTA. 27% of the occult choroidal neovascularization (CNV) cases were overdiagnosed as PCV when OCTA was applied. OCTA based on clear BVNs at the choroidal level increased sensitivity of diagnosis of PCV by 20%. However, the false-positive rate also increased in occult CNV. Several limitations for a correct diagnosis of PCV were noted.


Component-Resolved Diagnosis for Endotyping Patients with Chronic Rhinosinusitis with Nasal Polyps.
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 inflammation-mediated disease of the nasal mucosa and paranasal sinuses that often coexists with asthma. The role of atopy in the development and severity of CRSwNP is still a controversial issue. The aim of our study was to propose a systematic allergy workup to identify atopic patients in the context of CRSwNP and to characterize their allergen sensitization profile (sources/molecules). Patients with a diagnosis of CRSwNP (n = 97) were studied in the otorhinolaryngologist and allergy settings. Demographic and clinical data were collected for each patient. Different allergen sensitization profiles (sources/molecules) were evaluated in atopic CRSwNP patients by using component-resolved diagnosis (CRD). In our cohort of patients, the CRSwNP was frequently diagnosed during adulthood with significant impact on health-related quality of life. Asthma and atopy were the most common comorbidities with a prevalence of asthma in the atopic group. In CRSwNP patients sensitized to grass pollens and/or to house dust mites, the CRD analysis revealed a prevalence of sensitization to species-specific allergens of Phleum pratense (Phl p1, Phl p2, and Phl p5) or Dermatophagoides pteronyssinus (Der p1 and Der p2) rather than to cross-reactive ones. To define the allergen sensitization profile in atopic CRSwNP patients by CRD, it may be useful to better characterize type 2 inflammation, thus providing a personalized endotype-driven treatment.


Phospholipid Bilayers: Stability and Encapsulation of Nanoparticles.
Nanoparticles are widely studied for their potential medical uses in diagnostics and therapeutics. The interface between a nanoparticle and its target has been a focus of research, both to guide the nanoparticle and to prevent it from deactivating. Given nature's frequent use of phospholipid vesicles as carriers, much attention has been paid to phospholipids as a vehicle for drug delivery. The physical chemistry of bilayer formation and nanoparticle encapsulation is complex, touching on fundamental properties of hydrophobicity. Understanding the design rules for particle synthesis and encapsulation is an active area of research. The aim of this review is to provide a perspective on what preparative guideposts have been empirically discovered and how these are related to theoretical understanding. In addition, we aim to summarize how modern theory is beginning to help guide the design of functional particles that can effectively cross biological membranes.


Variational principle for the Pareto power law.
A mechanism is proposed for the appearance of power-law distributions in various complex systems. It is shown that in a conservative mechanical system composed of subsystems with different numbers of degrees of freedom a robust power-law tail can appear in the equilibrium distribution of energy as a result of certain superpositions of the canonical equilibrium energy densities of the subsystems. The derivation only uses a variational principle based on the Boltzmann entropy, without assumptions outside the framework of canonical equilibrium statistical mechanics. Two examples are discussed, free diffusion on a complex network and a kinetic model of wealth exchange. The mechanism is illustrated in the general case through an exactly solvable mechanical model of a dimensionally heterogeneous system.


Calibrating the Adaptive Learning Rate to Improve Convergence of ADAM.
Adaptive gradient methods (AGMs) have become popular in optimizing the nonconvex problems in deep learning area. We revisit AGMs and identify that the adaptive learning rate (A-LR) used by AGMs varies significantly across the dimensions of the problem over epochs (i.e., anisotropic scale), which may lead to issues in convergence and generalization. All existing modified AGMs actually represent efforts in revising the A-LR. Theoretically, we provide a new way to analyze the convergence of AGMs and prove that the convergence rate of Adam also depends on its hyper-parameter є, which has been overlooked previously. Based on these two facts, we propose a new AGM by calibrating the A-LR with an activation (softplus) function, resulting in the Sadam and SAMSGrad methods. We further prove that these algorithms enjoy better convergence speed under nonconvex, non-strongly convex, and Polyak-Łojasiewicz conditions compared with Adam. Empirical studies support our observation of the anisotropic A-LR and show that the proposed methods outperform existing AGMs and generalize even better than S-Momentum in multiple deep learning tasks.


Dual-Branch Network with a Subtle Motion Detector for Microaction Recognition in Videos.
By involving only subtle motions of body parts, video-based microaction recognition is a very important but challenging problem. Most existing action recognition methods are developed for general actions, and the current state-of-the-art methods usually largely rely on high-layer features learned from convolutional neural networks (CNNs). High-layer CNN features usually contain more semantic information but less detailed information. However, detailed information can be important for microactions due to the motion subtleness of such actions. In this paper, we propose to more effectively learn midlayer CNN features for enhancing microaction recognition. More specifically, we develop a new dual-branch network for microaction recognition: one branch uses the high-layer CNN features for classification, and the second branch further explores the midlayer CNN features for classification. In the second branch, we introduce a novel subtle motion detector consisting of three modules: 1) a discriminative spatial-temporal feature learning module, which further learns the subtle motion features corresponding to the discriminative spatial-temporal regions, 2) a parallel multiplier attention module, which further refines the features learned in channels and spatial-temporal domains, and 3) an activation fusion module, which fuses the max and average activations from midlayer CNN features for classification. In the experiments, we build a new microaction video dataset, where the micromotions of interest are mixed with other larger general motions such as walking. Comprehensive experimental results verify that the proposed method yields new state-of-the-art performance in two microaction video datasets, while its performance on two generalaction video datasets is also very promising.


Tmem2 Deficiency Leads to Enamel Hypoplasia and Soft Enamel in Mouse.
Teeth consist of 3 mineralized tissues: enamel, dentin, and cementum. Tooth malformation, the most common craniofacial anomaly, arises from complex genetic and environmental factors affecting enamel structure, size, shape, and tooth eruption. Hyaluronic acid (HA), a primary extracellular matrix component, contributes to structural and physiological functions in periodontal tissue. Transmembrane protein 2 (TMEM2), a novel cell surface hyaluronidase, has been shown to play a critical role during embryogenesis. In this study, we demonstrate Tmem2 messenger RNA expression in inner enamel epithelium and presecretory, secretory, and mature ameloblasts. Tmem2 knock-in reporter mice reveal TMEM2 protein localization at the apical and basal ends of secretory ameloblasts. Micro-computed tomography analysis of epithelial-specific Tmem2 conditional knockout (Tmem2-CKO) mice shows a significant reduction in enamel layer thickness and severe enamel deficiency. Enamel matrix protein expression was remarkably downregulated in Tmem2-CKO mice. Scanning electron microscopy of enamel from Tmem2-CKO mice revealed an irregular enamel prism structure, while the microhardness and density of enamel were significantly reduced, indicating impaired ameloblast differentiation and enamel matrix mineralization. Histological evaluation indicated weak adhesion between cells and the basement membrane in Tmem2-CKO mice. The reduced and irregular expressions of vinculin and integrin β1 suggest that Tmem2 deficiency attenuated focal adhesion formation. In addition, abnormal HA accumulation in the ameloblast layer and weak claudin 1 immunoreactivity in Tmem2-CKO mice indicate impaired tight junction gate function. Irregular actin filament assembly was also observed at the apical and basal ends of secretory ameloblasts. Last, we demonstrated that Tmem2-deficient mHAT9d mouse ameloblasts exhibit defective adhesion to HA-containing substrates in vitro. Collectively, our data highlight the importance of TMEM2 in adhesion to HA-rich extracellular matrix, cell-to-cell adhesion, ameloblast differentiation, and enamel matrix mineralization.


The effects of high-velocity hamstring muscle training on injury prevention in football players.
Background: Explosive and fast body movements, sprints, jumps and quick changes of direction, which are characteristic of the football training, place considerable strain on the hamstring muscles. Due to the high occurrence of hamstring injuries, new preventive strategies are required that focus on high-velocity training. The purpose was to assess the effectiveness of high-velocity elastic-band training in reducing the occurrence of hamstring injuries in football players. Methods: Male football players from 15 teams (n = 319) playing in national competitions participated in this study. The players were involved in a 5-week exercise period in either the intervention group (INT) or the control group (CON), with a follow-up period of ∼4 months where hamstring injuries and exposure time were recorded. The INT group had two to three sessions per week of elastic-band training with low-load, high-velocity leg curls while lying prone; the CON group performed self-paced football-specific drills. Results: The incidence rate of hamstring injuries was 6.5% in the INT group (8 out of 123 players) and 9.2% in the CON group (18 out of 196 players). Although the INT group showed almost 1/3 reduction in hamstring injury incidence compared to the CON group, the difference was not statistically significant (p > 0.05). Moreover, no differences (p > 0.05, odds ratio [OR] = trivial-to-small) in distribution between the groups were found in hamstring injury characteristics (leg dominance and mechanism) except for the distribution of injuries that occurred during matches or training (p = 0.036; OR = 6.14, moderate). Conclusion: The program of high-velocity elastic-band training did not prove to be effective in preventing hamstring muscle injuries in football players despite displaying some positive indications that could be considering when creating injury prevention programs.


Outcomes after oesophageal perforation: a retrospective cohort study of patients with different aetiologies.
The mortality rate after oesophageal perforation is high despite advances in operative and non-operative techniques. In this study, we sought to identify risk factors for hospital mortality after oesophageal perforation treatment. We retrospectively examined patients treated for oesophageal perforation in a university teaching hospital in Hong Kong between January 1997 and December 2013. Their demographic and clinical characteristics, aetiology, management strategies, and outcomes were recorded and analysed. We identified a cohort of 43 patients treated for perforation of the oesophagus (28 men; median age, 66 years; age range, 30-98 years). Perforation was spontaneous in 22 (51.2%) patients (15 with Boerhaave's syndrome and seven with malignant perforation), iatrogenic in 15 (34.9%), and provoked by foreign body ingestion in six (14.0%). Of the patients, 14 (32.6%) had pre-existing oesophageal disease. Perforation occurred in the intrathoracic oesophagus in 30 (69.8%) patients. Emergent surgery was undertaken in 23 patients: 16 underwent primary repair, six surgical drainage or exclusion, and one oesophagectomy. Twenty patients were managed non-operatively, 13 of whom underwent stenting. Two stented patients subsequently required oesophagectomy. Four patients had clinical signs of leak after primary repair: two were treated conservatively and two required oesophagectomy. Overall, six (14.0%) patients required oesophagectomy, one of whom died. Nine other patients also died in hospital; the hospital mortality rate was 23.3%. Pre-existing pulmonary and hepatic disease, and perforation associated with malignancy were significantly associated with hospital mortality (P=0.03, <0.01, and <0.01, respectively). Most oesophageal perforations were spontaneous. Mortality was substantial despite modern therapies. Presence of pre-existing pulmonary disease, hepatic disease, and perforation associated with malignancy were significantly associated with hospital mortality. Salvage oesophagectomy was successful in selected patients.


Stochastic electromagnetic beams focused by a bifocal lens.
In this paper, we study the focusing of a stochastic electromagnetic beam by a bifocal lens. By taking the electromagnetic Gaussian Schell-model (EGSM) beam as an example, the changes in the spectral density, in the spectral degree of coherence, and in the spectral degree of polarization of the EGSM beam as the beam is focused by an unapertured bifocal lens are investigated. It is shown that the spectral density, the spectral degree of coherence, and the spectral degree of polarization of the focused electromagnetic EGSM beams depend upon the coherence lengths and focal lengths of the bifocal lens. The influence of the coherence lengths and the focal lengths on the focused spectral density, the spectral degree of coherence, and the spectral degree of polarization are investigated in great detail.


A comparison of lung function methods for assessing dose-response effects of salbutamol.
Pulmonary function methods which are able to detect small pharmacological effects may be useful for assessing the full dose-response curve of bronchodilatators. We compared the ability of impulse oscillometry (R5, R20, X5, RF), plethysmography (sGaw) and spirometry [forced expiratory volume in 1 s (FEV(1)), maximal mid expiratory flow rate (MMEF)] to measure the dose-response effects of salbutamol in 12 healthy subjects, 12 mild asthmatics (mean FEV(1) 96% predicted) and 12 moderate asthmatics (mean FEV(1) 63% predicted). The techniques were performed twice to assess variability. Then salbutamol 10, 20, 100, 200 and 800 microg was administered. The sensitivity of the methods were compared by determining the lowest dose that caused changes greater than variability. In healthy subjects significant changes (p < or = 0.05) were observed only in FEV(1) (4.1%) and MMEF (14.6%) at 100 microg and sGaw (25.6%) and R20 (8.3%) at 200 microg. In mild asthmatics significant changes were observed in sGaw (15.9%) at 10 microg, X5 (23%), RF (20.3%) and MMEF (15.7%) at 20 microg, R5 (13.9%) and R20 (9.4%) at 100 microg and FEV(1) (7.1%) at 200 microg. All measurements except R20 demonstrated significant changes at 10 micro g in moderate asthmatics. The most sensitive test for assessing bronchodilatation is different in healthy subjects and asthmatics, and varies with severity of airflow obstruction.


Density-dependent prophylactic immunity reconsidered in the light of host group living and social behavior.
According to the density-dependent hypothesis (DDP), hosts living at high densities suffer greater risk of disease and so invest more in immunity. Although there is much empirical support for this, especially from invertebrate systems, there are many exceptions, notably in social insects. We propose that (A) density is not always the most appropriate population parameter to use when considering the risks associated with disease and (B) behavioral defenses should be given a greater emphasis in considerations of a host's repertoire of immune defenses. We propose a complementary framework stressing the connectivity between and within populations as a starting point and emphasizing the costs represented by disease above the risk of disease per se. We consider the components of immune defense and propose that behaviors may represent lower-cost defenses than their physiological counterparts. As group-living and particularly social animals will have a greater behavioral repertoire, we conclude that with group living comes a greater capacity for behavioral immune defense, most particularly for social insects. This may escape our notice if we consider physiological parameters alone.


Hepatoprotection via the IL-6/Stat3 pathway.
Stat3 is a vital transcription factor that is activated downstream of the gp130 receptor, primarily via IL-6 signaling in adult liver. A new study demonstrates that Stat3 provides hepatoprotection against Fas-mediated apoptotic liver damage by two mechanisms: direct inactivation of caspases and reduction of reactive oxygen species.


[Subarachnoid anesthesia with Sprotte 24-G needle in ambulatory surgery].
In order to evaluate the possibility of using a selective subarachnoid anesthesia in ambulatory surgery we studied its feasibility with a Sprotte needle 24 G in 103 patients (range 15-67 years) undergoing a knee joint arthroscopy. The subarachnoid anesthesia was achieved with Sprotte needle 24 G with introducer with patient on lateral decubitus. Hyperbaric bupivacaine 1% (0.05 mg/cm height) was used in order to obtain a selective homolateral metameric anesthesia between L1 and S3. The numbers of attempts were 1.29 (range 1-4). We involved the homolateral determatomeres in 94% of our attempts, adding a weak anesthetic action on contralateral ones. In the remaining 6% of the patients the anesthesia was bilateral and extending in an overlying manner. Anesthesia was adequate for the time needed to perform all the surgical procedures. Nevertheless in 3 patients the tourniquet was painful. We registered systemic hypotension only in 2% of the patients (a reduced systolic pressure value > 30%). No cases of postdural puncture headache were registered. Non postural atypical headache was seem in 3.9% of the patients. Urinary retention necessitating catheterization was noted only in 3 cases. A weak backache was revealed in 8.8%. When interviewed after surgery, 98% of our patients fulfilled the technique. In spite of technical difficulties that the use of the Sprotte needle may present, the selective subarachnoid anesthesia may be a safe alternative to the other anesthetic procedures for ambulatory surgery of the legs.


Philopatric predisposition to predation-induced ecological traps: habitat-dependent mortality of breeding eiders.
Because population size is sensitive to changes in adult survival, adult survival may be buffered against environmental variability. Philopatry may be adaptive in changing environments, but it could also constrain breeding habitat selection under changing conditions such as shifting predation regimes. Habitat preference and quality could become decoupled in long-lived philopatric species that evolved in stable environments when suddenly faced by increased adult predation risk, as dispersal may be triggered by past reproductive failure. We evaluated whether the Baltic eider (Somateria m. mollissima) population may currently face a predation-induced ecological trap. Eiders are philopatric and nest on open and forested islands. We hypothesized that open-nesting females would be disproportionately affected by increased predation. We compared female annual survival in these two habitats in 1996-2010. We also tested for effects of time trends, winter severity (NAO), female body condition, and habitat-specific predation pressure on survival. Our results revealed the lowest survival recorded for this species (Φ = 0.720), and survival on open islands was significantly lower (Φ = 0.679) than on forested islands (Φ = 0.761). Nonetheless, only 0.7 % of females changed breeding habitat type despite ample availability of alternative islands, and breeding phenology in both habitats was similar. Female survival increased with body condition, while it was unrelated to winter climate and stable over time. Open islands had a higher predation pressure on incubating females. Breeding philopatry results in a predator-mediated ecological trap for open-nesting eiders. Our results contribute to explaining the drastic decline of the Baltic eider population.


Optima: a windows-based program for computer-aided optimization of controlled-release dosage forms.
The purpose of this work was to develop a computer program that assists optimization of controlled-release devices, both visually and mathematically, using response surface methodology (RSM). A Windows-based computer program, Optima, which interactively implemented a number of subroutines for the optimization procedure, was developed. Optima is an integrated, user-friendly, and graphically oriented program for pharmaceutical dosage form optimization. Central composite design is implemented in the program. First- and second-order models containing up to five variables can be fitted to the data. The user can also choose between linear and exponential individual desirability functions, and use them to construct an overall desirability function that combines all the response variables in a single response. The program can predict the optimum levels of experimental variables, with respect to individual responses and/or the overall desirability. Optima has been successfully used in the development of sustained-release AZT-loaded microspheres. During the optimization process, three experimental variables were investigated and four responses were measured. The experimental design was a central composite design that was generated by the program. The response values were used by the program to calculate the individual desirability functions, which were then combined into an overall desirability function. The individual responses as well as the overall desirability function were optimized by fitting to a second-order polynomial equation. The response surfaces were generated and optimum levels of the experimental variables were predicted. The observed responses of the optimized formulation were very close to those predicted by Optima. The program proved to be a very useful, integrated tool for optimization of the controlled-release microspheres.


Treatment of amyotrophic lateral sclerosis: lessons learned from many failures.
Amyotrophic lateral sclerosis (ALS) is one of the most complex neurodegenerative diseases, involving both cortical and spinal components of motor neuron circuitry and non-neuronal cells that support the motor neurons. There is no effective therapeutic for ALS, and compounds that have extended the lifespan of ALS mouse models have failed in clinical trials. This viewpoint discusses current information regarding the changing views about ALS and what the failures in clinical trials can teach us in the search for an effective treatment. Previous challenges and roadblocks in drug discovery for ALS are noted, and solutions to current limitations are discussed. Learning from the past and moving forward with a new mindset can translate into successful and effective treatment strategies in ALS and other related diseases.


Risk factors for tooth loss in an adult population: a radiographic study.
The aim of the present study was to estimate the incidence and identify risk factors for tooth loss during a 5-year period in a randomly selected Danish population. In 1997 and 2003, 473 randomly selected adults received a full-mouth radiographic examination. The total number of teeth was 12,444. For each tooth, the following information was recorded from the radiographs: marginal bone level, filling, crown, root canal post, root filling, apicectomy, periapical status and caries lesion. Unconditional and conditional logistic regression analyses were used to identify risk factors for tooth loss. During the study period, 107 teeth in 60 individuals were lost. On the individual level, reduced marginal bone level and apical periodontitis (AP) were highly associated with tooth loss. On the tooth level, a reduced marginal bone level, AP and apicectomy were strongly associated with tooth loss. Canines were not lost often, whereas tooth loss was more frequently observed in molars and premolars than in incisors. A reduced marginal bone level and AP were associated with tooth loss over time. Furthermore, there was a higher risk of tooth loss in the posterior regions than in the anterior region.


Cascade Synthesis of Benzimidazole-Linked Pyrroles via Copper Catalyzed Oxidative Cyclization and Ketonization.
A three-component cascade reaction of 2-aminobenzimidazole, aldehyde, and terminal alkyne has been explored for an efficient synthesis of benzimidazole-linked tetrasubstituted pyrroles. The reaction sequence involves the formation of propargylamine, insertion of a terminal alkyne, and a ring opening reaction followed by an intramolecular carbonylative cyclization under aerobic conditions. It represents a novel strategy to the construction of C═N, C═C, C═O bonds and a new five-membered 2-ketopyrrole ring. In this process, the reaction conditions are crucial and an attempt to elucidate the novel reaction pathway is well supported by X-ray crystallography.


The use of functional imaging in the diagnosis of carotid patch infection.
Carotid patch infection following carotid patch angioplasty is a rare but serious complication. Accurate diagnosis is vital yet currently ill-defined. We present the use of computed tomography positron emission tomography and leucocyte radioisotope scintigraphy and highlight their potential role in the diagnosis of equivocal carotid patch infection.


Third ventricular width by transcranial sonography is associated with cognitive impairment in Parkinson's disease.
One-fourth of Parkinson's disease (PD) patients suffer from cognitive impairment. However, few neuroimaging markers have been identified regarding cognitive impairment in PD. This study aimed to explore the association between third ventricular width by transcranial sonography (TCS) and cognitive decline in PD. Participants with PD were recruited from one medical center in China. Third ventricular width was assessed by TCS, and cognitive function was analyzed by the Mini-Mental State Examination (MMSE). Receiver operating characteristic (ROC) analysis and Cox model analysis were utilized to determine the diagnostic and predictive accuracy of third ventricular width by TCS for cognitive decline in PD patients. A total of 174 PD patients were recruited. Third ventricular width was negatively correlated with MMSE scores. ROC analysis suggested that the optimal cutoff point for third ventricular width in screening for cognitive impairment in PD was 4.75 mm (sensitivity 62.7%; specificity 75.6%). After 21.5 (18.0, 26.0) months of follow-up in PD patients without cognitive impairment, it was found that those with a third ventricular width greater than 4.75 mm exhibited a 7.975 times higher risk of developing cognitive impairment [hazard ratio = 7.975, 95% CI 1.609, 39.532, p = 0.011] compared with patients with a third ventricular width less than 4.75 mm. Third ventricular width based on TCS emerged as an independent predictor of developing cognitive impairment in PD patients.


Changes in osmotic and turgor pressure in response to sugar accumulation in barley source leaves.
Pressure-probe measurements and single-cell sampling and analysis techniques were used to determine the effect of photosynthetic production and accumulation of sugars on osmotic and turgor pressures of individual cells of barley ( Hordeum vulgare L.) source leaves. In control plants, the changes in osmotic pressure in individual cells during the photoperiod were different for mesophyll (increase of 276 mOsmol/kg), parenchymatous bundle sheath (PBS; increase of 100 mOsmol/kg) and epidermis (remains constant). There was also an increase in osmotic pressure at the tissue level. Cooling of roots and the shoot apical meristem restricted the export of sugars from leaves, and the resulting changes in osmotic and turgor pressure were monitored. In contrast to the control leaves, mesophyll, PBS, and epidermal cells showed a similar increase in osmotic pressure (up to 500 mOsmol/kg). Cooling also increased the turgor pressure in epidermal and (to a greater extent) PBS cells. The difference in turgor pressure between epidermal and PBS cells is consistent with the presence of a water potential gradient within the leaf, from the vascular bundles towards the leaf surface.


[Interaction of different types of epithelium in a mixed culture].
Interaction of several lines of epithelial cells was studied in a mixed culture: FBT (bovine fetal trachea), MDSK (dog kidney), IAR-2 (rat liver), MPTR (SV-40 transformed mouse kidney). During mixed cultivation epithelia cells of different types were capable to force out each other from the substrate to full elimination. This capacity correlated with the pattern of cell contacts with the substrate. It is supposed that epithelial cells can form lamellae at the lower surfaces competing for substrate. Those cells which have lamellae with continuous marginal focal contacts and numerous focal contacts eliminate the cells having lamellae with few focal contacts.


Topological Diversity in Electrochemically Active Core-Modified Expanded Porphyrinoids.
Thiophene-based expanded porphyrinoids undergo a transition from a planar conformation to a twisted conformation upon a systematic increase in the number of thiophene units. Octaphyrin, with 40π electrons, displayed temperature-dependent interconversion between planar and nonplanar conformations in the solution state, in contrast to the rigid planar conformation in the solid state. 60π-dodecaphyrin and 70π-tetradecaphyrin have the maximum number of π-electrons for 12- and 14-heterocycle porphyrinoids, respectively. Spectro-electrochemical measurements confirmed facile reversible two-electron oxidation and the unstable radical cation intermediate in these systems.


Neurological disorders after severe pneumonia are associated with translocation of endogenous bacteria from the lung to the brain.
Neurological disorders are a common feature in patients who recover from severe acute pneumonia. However, the underlying mechanisms remain poorly understood. Here, we show that the neurological syndromes after severe acute pneumonia are partly attributed to the translocation of endogenous bacteria from the lung to the brain during pneumonia. Using principal components analysis, similarities were found between the brain's flora species and those of the lungs, indicating that the bacteria detected in the brain may originate from the lungs. We also observed impairment of both the lung-blood and brain-blood barriers, allowing endogenous lung bacteria to invade the brain during pneumonia. An elevated microglia and astrocyte activation signature via bacterial infection-related pathways was observed, indicating a bacterial-induced disruption of brain homeostasis. Collectively, we identify endogenous lung bacteria that play a role in altering brain homeostasis, which provides insight into the mechanism of neurological syndromes after severe pneumonia.


Regulation of subunit synthesis of Escherichia coli RNA polymerase.
lambdacI857s7drif(d)18 phage is a defective, specialized transducing phage carrying the RNA polymerase mutation rif(d), a dominant rifampicin-resistant allele. This phage DNA directs in vitro synthesis of the beta subunit of RNA polymerase in a DNA-dependent protein-synthesizing system. Prophage induction in cells that are lysogenic for this phage increases the rate of beta-subunit synthesis in vivo by at most 2-fold. No increase in subunit synthesis above the haploid level is observed in cells diploid for the beta gene.


Effect of Isometric Exercise on QTc Interval.
The QTc interval is affected by heart rate, autonomic nervous system and diseases like diabetes. However, the affect of exercise which alters autonomic nervous system activity, on QTc is not clear. On the other hand, the incidence of sudden cardiac death increases many fold post exercise. These events may be better explained by studying the effect of exercise on QTc. This study was designed with an aim to record the QTc interval changes in response to isometric exercise in a group of normal individuals with or without parental history of diabetes mellitus. Also the QTc duration was correlated with the LF-HF ratio. Twenty nine, healthy medical students were subjected to isometric hand grip test for 5min. ECG was recorded pre-exercise and at various time intervals post-exercise. All data are expressed in mean ± SD. Intra group comparison was done using paired t-test and unpaired t-test was used for comparison among group I and group II subjects, and among males and females. The difference in the pre and post exercise QTc values both within and between groups was statistically significant with group I subjects recording lower values. The post exercise LF: HF values were significantly increased when compared to pre exercise values in both the groups. There was no correlation between LF: HF and QTc. A longer than normal QTc interval predisposes to arrhythmia. Exercise brings about detectable changes in the QTc interval after a period of isometric exercise in normal individuals which in high risk individuals may predispose to sudden cardiac death. In addition women may be more susceptible to post-exercise arrhythmia owing to a longer QTc even at rest.


The effect of cell debris within biologic scaffolds upon the macrophage response.
All biomaterials, including biologic scaffolds composed of extracellular matrix (ECM), elicit a host immune response when implanted. The type and intensity of this response depends in part upon the thoroughness of decellularization and removal of cell debris from the source tissue. Proinflammatory responses have been associated with negative downstream remodeling events including scar tissue formation, encapsulation, and seroma formation. The relative effects of specific cellular components upon the inflammatory response are not known. The objective of the present study was to determine the effect of different cell remnants that may be present in ECM scaffold materials upon the host innate immune response, both in vitro and in vivo. Collagen scaffolds were supplemented with one of three different concentrations of DNA, mitochondria, or cell membranes. Murine macrophages were exposed to the various supplemented scaffolds and the effect upon macrophage phenotype was evaluated. In vivo studies were performed using an abdominal wall defect model in the rat to evaluate the effect of the scaffolds upon the macrophage response. Murine macrophages exposed in vitro to scaffolds supplemented with DNA, mitochondria, and cell membranes showed increased expression of proinflammatory M1 marker iNOS and no expression of the proremodeling M2 marker Fizz1 regardless of supplementation concentration. A dose-dependent response was observed in the rat model for collagen scaffolds supplemented with cell remnants. DNA, mitochondria, and cell membrane remnants in collagen scaffolds promote a proinflammatory M1 macrophage phenotype in vivo and in vitro. These results reinforce the importance of a thorough decellularization process for ECM biologic scaffold materials. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2109-2118, 2017.


Photocatalyzed alkylative cyclization of 2-isocyanobiphenyls with unactivated alkyl iodides.
We herein report the first photocatalyzed radical cascade cyclization of 2-isocyanobiaryls with unactivated alkyl iodides. This simple protocol operates under mild reaction conditions and affords 6-alkyl phenanthridines in good yields. To elucidate the reaction mechanism, Stern-Volmer quenching studies were carried out and these studies revealed that the photocatalyst is not directly involved in a single electron transfer process with the alkyl iodide.


Mineral metabolism and mortality in patients with chronic kidney disease.
Chronic kidney disease is associated with profound alterations in mineral metabolism. A growing body of evidence, based largely on observational studies, indicates that patient mortality is associated with altered mineral metabolism. Evidence is reviewed concerning the association between mortality and high concentrations of serum phosphorus, calcium, calcium-phosphate product, and parathyroid hormone. In addition, mortality may be independently associated with dialysate calcium concentration, type of phosphate binder therapy, and use of vitamin D analogs. Practices related to management of altered mineral metabolism may prove to be a promising means of improving outcomes for patients with chronic kidney disease.


MiR-1204 promotes ovarian squamous cell carcinoma growth by increasing glucose uptake.
MiR-1204 has been recently identified as an oncogenic miRNA in breast cancer. Our study aims to investigate the role of miR-1204 in ovarian squamous cell carcinoma. Expression of miR-1204 and glucose transporter 1 in ovarian biopsies and plasma of both OC patients and healthy controls was detected by qRT-PCR. Correlations between patients' clinicopathological data were analyzed by Chi-square test. MiR-1204 overexpression OC cell lines were established. Expression of GLUT-1 protein was detected by western blot. Glucose uptake was measured by glucose uptake assay. Cell proliferation was detected by CCK-8 assay. We found that miR-1204 expression was significantly correlated with tumor size. Expression levels of miR-1204 and GLUT-1 were significantly high in OC patients. Expression levels of miR-1204 were positively correlated with expression levels of GLUT-1 in OC patients. MiR-1204 overexpression significantly promoted GLUT-1 expression, glucose uptake and cell proliferation. MiR-1204 may promote ovarian squamous cell carcinoma growth by increasing glucose uptake.


Localization of human chorionic gonadotropin beta subunit transcripts in ovarian cancer tissue.
Recent studies demonstrated that besides placenta and malignant trophoblastic tumors, hCG and especially its beta-subunit is secreted by a varieties of tumors of different origin. The aim of the present investigation was to determine the expression pattern of human chorionic gonadotropin gene in ovarian cancer tissue. The study included 8 patients with epithelial ovarian carcinoma. The expression and distribution of hCGbeta mRNA was assessed by in situ RT-PCR method. The semi-quantitative assessment was performed using computer image analysis. Transformation of the images into the pseudocolour scale showed a clear difference in fluorescence intensity among individual cancer cells. The intensity of ISRT-PCR products corresponding with expression level of hCGbeta demonstrated that its production by individual cancer cells is different. In all studied specimens of the ovarian carcinoma tissue, cancer cells characterized by the presence of active hCGbeta gene were found, whereas noncancerous tissue demonstrated lack of the gene expression. Thus, the study clearly shows that the expression of hCGbeta is the feature of ovarian cancer tissue.


Gas bubble emboli detected by transcranial Doppler sonography in patients with prosthetic heart valves: a preliminary report.
After observing spikes in the Doppler signal of cerebral arteries of patients with neurologic symptoms and prosthetic heart valves, we then studied two groups of patients with prosthetic heart valves: seven patients with neurologic symptoms and 65 asymptomatic patients. Using transcranial Doppler sonography of the middle cerebral artery, we found Doppler spikes in six symptomatic and 24 asymptomatic patients with mechanical heart valves. No spikes were found in one symptomatic and 21 asymptomatic patients with biological valves or in 20 asymptomatic patients with mechanical valves. We concluded that gas cavitation during the opening or closure of the valve, producing bubble emboli, is the most probable explanation for these Doppler spikes in patients with mechanical prosthetic heart valves.


Cerebral abnormalities in the Neu-Laxova syndrome.
Cerebral abnormalities are considered an obligatory manifestation of the Neu-Laxova syndrome and include lissencephaly, severe microcephaly, aplasia of the corpus callosum, hypoplasia of the cerebellum, and other pathological changes. We present data on 3 cases with central nervous system anomalies, two of which have not been described previously, and summarize the literature on the subject. The problem of distinguishing type III lissencephaly is discussed.


Adherence to diet recommendations and risk of abdominal aortic aneurysm in the Malmö Diet and Cancer Study.
The research examining the association between quality of diet and abdominal aortic aneurysm (AAA) is scarce. The aim of the present study was to explore the association between diet quality and development of AAA for middle-aged individuals in the Malmö Diet and Cancer Study (MDCS), a prospective cohort study with baseline data collection carried out between 1991 and 1996. At baseline, the study participants who were eligible for this study (n = 26133) documented their dietary habits in a food diary and questionnaire. Incident AAA cases during an average of 20.7 years of follow-up were identified by using registers. A diet quality index consisting of six components, saturated fat, polyunsaturated fat, fibre, sucrose, fruits and vegetables and fish and shellfish, was used to assess the diet quality. After adjusting for potential confounders, the diet quality index was not associated with incident AAA. However, a tendency of decreased risk was observed among individuals adhering to recommendations for fruit and vegetables compared with non-adherence. When comparing the risk of more extreme intake groups, high intakes of both fruits and vegetables were associated with decreased risk.


Responses to occupational hazards: exit and participation.
The authors developed and tested a model linking subjective risk perceptions to both turnover intentions and employees' willingness to participate in health and safety programs. On the basis of data from 130 employees of a manufacturing firm, the model was supported. Risk perceptions were predicted by employees' accident history and perceptions of others' commitment to health and safety. In turn, risk perceptions predicted both turnover intentions and willingness to participate. These effects emerged after controlling for monomethod bias.


How to interpret IGF-1 and growth hormone stimulation tests.
You are seeing an 11-year-old boy in a general paediatric clinic referred with short stature. His height is below the 0.4th centile. The mid-parental height is on 50th centile. Baseline investigations, including renal and liver function, coeliac screen and thyroid function tests are normal. You have a suspicion of growth hormone deficiency. Should you check an insulin-like growth factor-1 level or proceed with a growth hormone provocation test? The current paper will aim to give an overview of these tests and factors to consider when interpreting the results.


Why have studies of tailored anti-platelet therapy failed so far?
Published data linking clopidogrel non-responsiveness to adverse ischaemic events lead to the suggestion that the magnitude of platelet inhibition by clopidogrel can be monitored and individually adjusted. This has been tested in randomised clinical trials (ARCTIC, GRAVITAS and TRIGGER-PCI), but despite reducing platelet reactivity, a strategy of therapy adjustment based on platelet function monitoring did not reduce the incidence of cardiac ischaemic events. Several critical issues regarding the design of these trials, which might in part have led to negative results, are discussed in this article.


Have we made any progress? Including students with intellectual disabilities in regular education classrooms.
To what extent are students with intellectual disabilities included in regular education classrooms in the United States? Although inclusion is an accepted best practice in special education, little progress has been made in including students with intellectual and other developmental disabilities. Using historical and the most recent available federal data, I explored the percentage of students with intellectual disabilities who are fully included in regular education classrooms, both nationally and in individual states. States are rank ordered by the percentage of students who are included. Nationally, in 2002-2003, less than 11% of students with intellectual disabilities were fully included in regular education classrooms. Research, policy, and advocacy issues are addressed.


Improving recording of capacity to consent and explanation of medication side effects in a psychiatric service for people with learning disability: audit findings.
This study aimed to examine the practice of psychiatrists in a large learning disability service in recording capacity to consent to treatment and side effect discussion, and the impact of measures aimed at improving this. Three audit cycles were completed between 2007 and 2009, each examining 26 case notes selected at random. Information was gathered on recording of capacity and documentation of explanation of potential side effects. Changes in practice following the introduction of a rubber stamp in 2008, as a visual prompt for clinicians, were examined. Rates of recording of capacity rose from 30% in 2007 to 51% in 2009 (P = 0.000006). Capacity was more likely to have been recorded if the stamp was present (odds ratio 13.5, p < 0.0001). Recording of side effect discussion was consistently higher than that of capacity and showed little change between cycles. We conclude that the use of a rubber stamp in case notes was associated with improvements in the recording of capacity assessments.


Antiphospholipid syndrome and the brain in pediatric and adult patients.
The most common neurological manifestations of antiphospholipid syndrome (APS) in all age-groups include stroke and transient ischemic attacks due to arterial thromboses and cerebral ischemia. Antiphospholipid antibodies may cause additional non-criteria neurological impairments through vascular, neuroinflammatory and direct neuronal effects. Anti-aggregant or anticoagulant therapies are indicated for APS-related ischemic strokes. Treatment regimens for asymptomatic antibody-positive patients and those with refractory or recurrent disease remain controversial. There is scant literature on the epidemiology and therapy of neurological APS manifestations in pediatric patients. Assessments of modifiable cardiovascular and inherited thrombophilia risk factors are essential in patients with APS. There may be a role for novel neuroimaging modalities in quantifying APS-related microstructural brain damage. The clinical utility of statins, antimalarials, angiotensin-converting enzyme inhibitors, and thrombin inhibitors warrant further research.


The safety and effectiveness of HBV vaccination in patients with juvenile idiopathic arthritis controlled by treatment.
To evaluate the safety and effectiveness of hepatitis B virus (HBV) vaccination in patients with juvenile idiopathic arthritis (JIA) controlled by treatment. Among 49 patients with juvenile idiopathic arthritis (JIA) at the outpatient clinic of Kagoshima University Hospital, we enrolled 25 who were controlled by treatment. All children were unimmunized and were vaccinated against HBV according to the schedule. Their responses to the vaccine and vaccine adverse events were examined during their visits. Nineteen of the 25 patients with JIA controlled by treatment developed effective antibody responses (76%). All eight patients with JIA below 10 years of age achieved seroconversion. The seroconversion was not influenced by biologics. Five adverse events were observed (6.7%). The rate of all adverse events did not surpass that of a previous report, and all adverse events were immediately resolved. None of the patients with JIA experienced a flare-up or clinical deterioration related to the vaccination. HBV vaccination is safe and effective. Pediatric rheumatologists should consider HBV vaccination for unimmunized patients with JIA, because the response to HBV vaccine might be influenced by age, and children have a higher risk for potential HBV infection than adults.


CD36 inhibitors reduce postprandial hypertriglyceridemia and protect against diabetic dyslipidemia and atherosclerosis.
CD36 is recognized as a lipid and fatty acid receptor and plays an important role in the metabolic syndrome and associated cardiac events. The pleiotropic activity and the multiple molecular associations of this scavenger receptor with membrane associated molecules in different cells and tissues have however questioned its potential as a therapeutic target. The present study shows that it is possible to identify low molecular weight chemicals that can block the CD36 binding and uptake functions. These inhibitors were able to reduce arterial lipid deposition, fatty acid intestinal transit, plasma concentration of triglycerides and glucose, to improve insulin sensitivity, glucose tolerance and to reduce the plasma concentration of HbAc1 in different and independent rodent models. Correlation between the anti-CD36 activity of these inhibitors and the known pathophysiological activity of this scavenger receptor in the development of atherosclerosis and diabetes were observed at pharmacological doses. Thus, CD36 might represent an attractive therapeutic target.


Toxicity evaluation of antiglaucoma drugs using stratified human cultivated corneal epithelial sheets.
To investigate the toxicity profiles of seven antiglaucoma topical eye drops and benzalkonium chloride (BAC) using stratified cultivated human corneal epithelial cell sheets (HCES) in a serum-free culture system. A range of prostaglandin analogies and preservatives, including BAC, sofZia (SZ), sodium benzoate (SB), and polyquaternium-1 (PQ) were tested. The barrier function and cell viability were examined by a carboxyfluorescein permeability assay and WST-1 assay. Histological evaluation of the HCES was also performed after application of each solution. The carboxyfluorescein permeability assay had a higher sensitivity for the detection of toxicity of test solutions than the WST-1 assay or histological examination. Latanoprost BAC, latanoprost/timolol BAC, and 0.02% or higher concentration of BAC were the most toxic, followed by latanoprost SB, latanoprost preservative-free, BAC 0.002%, and travoprost/ latanoprost PQ. Travoprost SZ and tafluprost BAC (preserved with 0.001% BAC) was the least toxic in our experimental conditions. The carboxyfluorescein permeability assay using HCES in a serum-free system was the most useful for the quantification of toxicity of ophthalmic solutions. Among the regimens examined, a BAC concentration of 0.001% or lower or non-BAC preservative sofZia was suggested to be the least toxic to the ocular surface.


Effects of Nigella sativa seeds and certain species of fungi extracts on number and activation of dural mast cells in rats.
In this study, we aimed to investigate the effects of Nigella sativa seeds and certain species of fungi extracts on the number and degranulation states of dural mast cells in rats. Rats were fed ad libitum with normal tap water or tap water with extract of N. sativa seed, Ramaria condensata, Lactarius salmonicolor, Lactarius piperatus, and Tricholoma terreum for 3 days. Mast cells in dura mater were counted and evaluated in terms of granulation and degranulation states. Compound 48/80, a mast cell degranulating agent, and T. terreum significantly increased the percent of degranulated mast cells in dura mater, respectively (p < 0.01 and p < 0.05). Moreover, T. terreum causes a significant increase in the total number of mast cells (p < 0.05). N. sativa significantly inhibited mast cell degranulation induced by both the compound 48/80 and T. terreum (p < 0.05), and significantly decreased the mast cell numbers increased by T. terreum (p < 0.05). Our results suggested that T. terreum following ingestion can contribute to headaches like migraine via dural mast cell degranulation and N. sativa may be able to exert analgesic and anti-inflammatory effects by stabilizing dural mast cells. However, investigation is needed to determine the ingredients of N. sativa that may be responsible for these beneficial effects.


Inhibition of NF-κB activation improves insulin resistance of L6 cells.
To explore the role of NF-κB activation in the development of insulin resistance and investigate whether or not that the inhibition of NF-κB activation by PDTC will improve the insulin resistance of L6 cells exposed to H2O2. L6 cells were treated with H2O2, PDTC or both H2O2 and PDTC for 4 hours. The uptake of glucose with stimulation of insulin, the expression of P38-MAPK, p- P38-MAPK, NF-κBp65, p- NF-κBp65, IRS-1, IRS-2, p-IRS-2, PI3K, IκBα, p- IκBα, caspase-8 and GLUT4, the production of ROS, TNF-α, IL-6 and IL-1β as well as the apoptosis rate of L6 cells were determined and compared in L6 treated with H2O2 alone or both H2O2 and PDTC. Compared with the L6 cells treated with H2O2 alone, the L6 cells treated with both H2O2 and PDTC showed (1) significantly lower production of ROS, TNF-α, IL-6 and IL-1β; (2) significantly decreased expression of P38-MAPK, p- P38-MAPK and NF-κBp65, p- NF-κBp65, p- IκBα and caspase-8; (3) significantly lower rate of apoptosis; (4) significantly higher expression of IRS-2, p-IRS-2 (Tyr 612), PI3K and GLUT4; (5) significantly higher uptake of glucose with stimulation of insulin; (6) significantly increased expression of Bcl2 and decreased ratio of Bax to Bcl2. Based on the findings of the present study, inhibition of NF-κB activation by PDTC would improve the insulin resistance of L6 cells exposed to H2O2.


[Retinopathy of prematurity in the Murcia region of Spain. Incidence and severity].
To determine the incidence and severity of Retinopathy of Prematurity (ROP) in the Murcia region of Spain. This was a retrospective study of all infants born preterm in the Murcia region during 2004, who were screened for ROP. Our screening criteria were: Infants with a gestational age <or= 32 weeks (GA) or with a birth weight <or= 1500 g (BW). We evaluated sex, GA, BW, parity and ophthalmologic evaluation. We then performed a descriptive study and a statistical analysis. The study sample involved 115 infants with an average GA of 29.67 weeks and BW of 1325 g. The incidence of ROP and severe ROP was 32.1% and 15.6% respectively. The likelihood of the premature infant developing severe ROP was found to be 88.8% if it was born before 29 weeks GA or weighed less than 1000 g BW. Significant differences (p < 0.001), in terms of GA and BW between infants with and without ROP, were found. A third of the preterm infants screened for ROP in the Murcia region developed the disease, and the 50% of these required treatment. The current screening criteria used in our region are appropriate. If more restrictive criteria were used, some severe ROP cases would not be detected. In order to be able to modify the current guidelines for screening for ROP, further studies are required.


Anomalous aortic origin of a coronary artery: learning from the past to make advances in the future.
To review anomalous aortic origin of a coronary artery (AAOCA) anatomy, prevalence, mechanism and risk of ischemia, presentation, evaluation, management, and future directions. Although most anatomic variants of AAOCA are benign, a small number are associated with increased risk of sudden death. A complete evaluation, including the use of advanced noninvasive imaging and provocative testing should be performed on nearly every patient with AAOCA. On the basis of recent studies, the ischemic risk appears to be greatest with a left anomalous coronary artery but an anomalous right coronary artery is not benign. Other risk factors include: a left anomalous coronary with an intramural course, high take-off, or slit-like orifice, and a right anomalous coronary with a longer intramural course. Exercise restriction is rarely recommended. Management primarily consists of nonoperative care, or surgical repair in those who are symptomatic or who have high-risk variants. Surgery itself continues to evolve; however, it is not benign, with a higher than expected chance of morbidity. Advances have been made over the past decade regarding management of patients with AAOCA; however, the mechanism of ischemia and ability to predict risk is still incompletely understood. Management decisions should be based on anatomy, results of investigations, and shared decision-making with patients and their families. Surgery may be recommended for those at higher risk and should be done at centers experienced in AAOCA surgery. Future research should be collaborative in order to share experiences and insights to help advance our understanding of risk and ultimately to improve patient management.


The effect of antidepressant treatment on N-acetyl aspartate levels of medial frontal cortex in drug-free depressed patients.
The medial frontal cortex has been shown to modulate emotional behavior and stress responses, suggesting that the dysfunction of this region may be involved in the pathogenesis of depressive symptoms. The present study was performed to determine whether there was any effect of antidepressant treatment on the metabolite levels in the left medial frontal cortex as measured by proton magnetic resonance spectroscopy in depressed patients. Twenty patients diagnosed as having major depressive disorder according to DSM-IV and 18 healthy volunteer subjects were included in the study. Twelve of patients had their first episode and were drug-naïve. Other depressed patients were drug-free for at least 4 weeks. The severity of depression was assessed by HAM-D and Clinical Global Impression Scale-Severity (CGI-S). Single voxel, 8 cm(3), 1H MR spectra of left medial frontal cortex was acquired both before and following antidepressant treatment. The concentrations and ratios of N-acetyl aspartate (NAA), Creatine+Phosphocreatine (Cr+PCr) and Choline (Cho) were measured. Pretreatment NAA/Cr values of patients were lower than those of healthy controls, but this difference did not reach to statistically significant levels (t=1.83, df=36, p=0.07). However, antidepressant treatment had significant effect on NAA/Cr ratios (groupxtreatment interaction: F=9.93 df=1,36, p=0.03). After the treatment, NAA/Cr values of patients increased significantly compared to pretreatment values (t=3.32, df=19, p=0.004). No significant difference was observed between the post-treatment NAA/Cr values of patients and those of controls (t=1.64, df=36, p=0.19). Correlation analysis detected negative correlation between pretreatment CGI-S scores and NAA/Cr ratios (r=-0.51, p=0.02). This preliminary result suggests that there might be a possible defect in the neuronal integrity in the left medial frontal cortex (mainly left anterior cingulate cortex) of depressed patients. Antidepressant treatment with its neurotrophic effects might play a positive role in restoring the neuronal integrity. Further studies are needed to support these initial findings.


Hepatocellular carcinoma recurrence in hepatitis C virus-related cirrhosis treated with direct-acting antivirals: a case-control study.
Direct-acting antivirals (DAAs) therapy against hepatitis C viral (HCV) infection has markedly improved the sustained viral response. However, recent studies have suggested an unsuspected high rate of hepatocellular carcinoma (HCC) recurrence. A retrospective case-control study was carried out to investigate the impact of DAAs on tumor recurrence in patients with complete response to HCC treatment within our HCV-related cirrhosis cohort. Patients who received [group 1 (G1), n=22] or not [group 2 (G2), n=49] a DAAs therapy were matched 1 : 2 for age, sex, liver function, HCC stage, and treatment. Initial HCC were mostly Barcelona Clinic Liver Cancer stage A (95% G1, 94% G2). Sustained viral response with DAAs was achieved in 86% of patients. After a similar median overall follow-up time with similar radiologic surveillance after HCC treatment, 41% of patients developed radiologic tumor recurrence in G1 versus 35% of patients in G2 (P=0.7904). There was no significant difference in time to progression between the two groups [12 (9-16) months G1 vs. 14 (8-21) months G2, P=0.7688], or Barcelona Clinic Liver Cancer stage at recurrence. However, the interval between HCC treatment and antiviral therapy was significantly different among DAAs patients with recurrence and those without recurrence [7.0 (2.5-9.0) months vs. 36.0 (9.0-58.0) months, P=0.0235, respectively]. In our case-control study, HCV therapy with DAAs does not accelerate or prevent early HCC recurrence compared with untreated patients. The rate of recurrence, time to progression, and HCC pattern are similar. Early DAAs treatment (<12 months) after HCC cure should be discouraged considering the HCC recurrence rate during this period.


Pinacidil but not nicorandil opens ATP-sensitive K+ channels and protects against simulated ischemia in rabbit myocytes.
It has been proposed that ischemic preconditioning involves the regulation of ATP-sensitive potassium (K(ATP)) channels. The evidence is based largely on the ability of certain K(ATP) channel modulators to modify the protection in the various models of preconditioning. This study has investigated how two K(ATP) channel openers, pinacidil and nicorandil, affect both membrane currents and viability in isolated and ischemic rabbit cardiomyocytes. We used the whole-cell recording technique and in separate experiments viability was assessed by exposure to these drugs during ischemia. Pinacidil (50 micromol/l) increased K(ATP) current approximately four-fold in isolated cardiomyocytes. This increase reversed rapidly after treatment with the K(ATP) channel blocker glibenclamide (200 nmol/l). After simulated ischemia, pinacidil protected cardiomyocytes (the area under cell-death curve was 29.5 +/- 1.1% x h) which was significantly less than that in control (46.9 +/- 2.0% x h). The protection from pinacidil could be completely eliminated by pretreatment with 10 microM glibenclamide (46.9 +/- 2.0% x h). In contrast, nicorandil (1 mmol/l), which opens K(ATP) channels in some tissues, caused no detectable effect on the K(ATP) current. Similarly, nicorandil did not produce cardioprotection. These results indicate that pinacidil and nicorandil have very different effects on rabbit cardiomyocyte K(ATP) channels. Furthermore, because protection correlated with the ability of the agent to open the channel, they support a role for K(ATP) channels in preconditioning.


Medical ethics teaching. Report of a National Medical School Survey.
Medical ethics teaching was surveyed at American medical schools. Of 107 schools that responded, 97 indicated some kind of medical ethics teaching. This included, however, 19 schools where teaching was only by discussion of ethical issues in courses not primarily identified as ethics courses. Fifty-six institutions (up from 17 in 1972) reported that they conducted special conferences, lectures, or seminars on issues in medical ethics. Specific medical ethics electives were offered in 47 schools; some kind of required course existed at six institutions. The number of faculties with major commitments to medical ethics teaching increased approximately 50% (from 19 to 31). Several schools now have departments or interdepartmental teaching programs with formal structure and permanent staff.


Soft tissue reconstruction. Coverage of lower leg. Rotational flap.
The combined orthopedic and plastic surgical approach to the injured lower extremity has permitted successful salvage of otherwise severely injured limbs. Although numerous muscle and fascial flaps have been described for all regions of the leg between the knee and foot, specific treatment regimens have become popular based on the location of the wound. Refinements in flap surgery have permitted the approach discussed in this article to become standard in the care of patients with either chronic osteomyelitis or acutely injured limbs. This article delineates the muscle and fascial flaps that are used to reconstruct these defects.


Effects of endomorphin on substantia gelatinosa neurons in rat spinal cord slices.
1. Whole-cell patch recordings were made from substantia gelatinosa (SG) neurons in transverse lumbar spinal cord slices of 15- to 30-day-old rats. 2. Endomorphin 1 (EM-1) or EM-2 (<or=10 microM) hyperpolarized or induced an outward current in 26 of the 66 SG neurons. The I-V relationship showed that the peptide activates an inwardly rectifying K+ current. 3. EM-1 or EM-2 (0.3-10 microM) suppressed short-latency excitatory postsynaptic currents (EPSCs) and long-latency inhibitory postsynaptic currents (IPSCs) in nearly all SG neurons tested or short-latency IPSCs in six of the 10 SG neurons. [Met5] enkephalin or [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO) (1-10 microM) depressed EPSCs and IPSCs. EM-1 or EM-2 depressed synaptic responses without causing a significant change in holding currents or inward currents induced by glutamate. 4. Glutamate also evoked a short-latency outward current in five SG neurons or a biphasic current in two neurons; the outward current was blocked by tetrodotoxin (TTX, 0.3 microM) or bicuculline (10 microM). 5. EM-1 or DAMGO (1 or 5 microM) attenuated the glutamate-evoked outward or biphasic currents in four of the seven SG neurons. EM-1 (1 microm) reduced the frequency, but not the amplitude of miniature EPSCs or miniature IPSCs. 6.. Naloxone (1 microM) or the selective micro-opioid receptor antagonist beta-funaltrexamine (beta-FNA, 25 microM) antagonized the action of EM; EM-induced hyperpolarizations persisted in the presence of the kappa-opioid receptor antagonist (nor-binaltorphimine dihydrochloride, 1 microM) and/or sigma-opioid receptor antagonist (naltrindole hydrochloride, 1 microM). 7. It may be concluded that EM acting on micro-opioid receptors hyperpolarizes a population of SG neurons by activating an inwardly rectifying K+ current, and attenuates excitatory and inhibitory synaptic currents evoked in a population of SG neurons, probably by a presynaptic site of action.


[Frequency of adrenal hemorrhage in fatal forms of purpura fulminans in children. Etiopathogenic and therapeutic considerations].
Between 1971 and 1985, 43 children died of purpura fulminans in our intensive care unit: 11 had autopsy and adrenal haemorrhage was observed in 8 (73%). All these patients had an extensive purpura and a severe disseminated intravascular coagulation. Our series confirms the findings of previous studies: 69 autopsies showed 51 cases (74%) of macroscopic adrenal haemorrhage. Adrenal haemorrhage may be only one manifestation of multiple system organ failure consecutive to septic shock; however, its association with low plasma cortisol levels (as previously reported) suggests that glucocorticoid replacement therapy should be reconsidered in purpura fulminans.


Biological Involvement of MicroRNAs in Proliferative Vitreoretinopathy.
Even with a high surgical success rate for retinal detachment and proliferative vitreoretinopathy (PVR) supported by the robust improvement in vitrectomy surgery and its related devices, certain questions still remain for the pathogenesis and treatment of PVR. One of the important biological events in PVR is epithelial-mesenchymal transition (EMT) of the retinal pigment epithelial (RPE) cells. MicroRNAs are noncoding, small, single-strand RNAs that posttranscriptionally regulate gene expression and have essential roles in homeostasis and pathogenesis in many diseases. Recently, microRNAs also had a critical role in EMT in many tissues and cells. One main purpose of this brief review is to describe the knowledge obtained from microRNA research, especially concerning vitreoretinal diseases. In addition, the potential role of microRNAs in prevention of PVR by regulating EMT in RPE cells is described. Understanding microRNA involvement in PVR could be helpful for developing new biological markers or therapeutic targets and reducing the rate of visual disability due to PVR.


Spatially Defined Drug Targeting by in Situ Host-Guest Chemistry in a Living Animal.
Ensuring effective drug concentration specifically at sites of need, while limiting systemic side effects, remains a challenge in the discovery and use of new drug molecules. Carriers targeted through biological affinity (e.g., antibodies) afford a common means of drug localization, yet often deliver considerably less than 1% of an administered drug to a desired site in the body. We report on an alternative targeting paradigm using pendant guest motifs to direct molecules to sites distinguished by a hydrogel bearing a high density of a complementary cucurbituril supramolecular host. Host-guest affinity (K eq) of 1012 M-1 serves to spatially localize ∼4% of a model small molecule within hours of its administration in mice. These high-affinity interactions furthermore ensure long-lasting retention of the model compound at the site of interest, and the site can be serially targeted upon repeated dosing. This supramolecular homing axis extends the localization of small molecule payloads beyond injectable hydrogels, enabling targeting of modified biomaterials. This approach also has promising therapeutic utility, improving efficacy of a guest-modified chemotherapeutic agent in a tumor model.


Sampling for international normalized ratios in patients on hemodialysis with central venous catheters.
The primary objectives of this study were to evaluate the effect of varying heparin concentrations on International Normalized Ratio values and to assess the accuracy of these values deter mined through the arterial line of the dialysis circuit Twenty-two patients on hemodialysis with central venous catheters were studied After a peripheral venipuncture, timed samples from the arterial line of the hemodialysis circuit were obtained after dialysis was initiated and prior to initiating heparin. Assays for coagulation parameters were performed. There was no signifcant difference in any coagulation parameter measured from the arterial line samples compared to the venipuncture samples. Serial heparin dilutions in vitro demonstrated that residual amounts of heparin in the central venous catheter may falsely elevate International Normalized Ratio values. This study demonstrates that accurate International Normalized Ratio values in patients on hemodialysis with heparinized central venous catheters can be obtained ericiently and cost-effectively from the arterial line within 1 minute of dialysis initiation.


Sequencing the Biology of Entry: The Retroviral env Gene.
The surface envelope protein of any virus is major determinant of the host cell that is infected and as a result a major determinant of viral pathogenesis. Retroviruses have a single surface protein named Env. It is a trimer of heterodimers and is responsible for binding to the host cell receptor and mediating fusion between the viral and host membranes. In this review we will discuss the history of the discovery of the avian leukosis virus (ALV) and human immunodeficiency virus type 1 (HIV-1) Env proteins and their receptor specificity, comparing the many differences but having some similarities. Much of the progress in these fields has relied on viral genetics and genetic polymorphisms in the host population. A special feature of HIV-1 is that its persistent infection in its human host, to the point of depleting its favorite target cells, allows the virus to evolve new entry phenotypes to expand its host range into several new cell types. This variety of entry phenotypes has led to confusion in the field leading to the major form of entry phenotype of HIV-1 being overlooked until recently. Thus an important part of this story is the description and naming of the most abundant entry form of the virus: R5 T cell-tropic HIV-1.


Table 2 Fallacy in Descriptive Epidemiology: Bringing Machine Learning to the Table.
There is a lack of rigorous methodological development for descriptive epidemiology, where the goal is to describe and identify the most important associations with an outcome given a large set of potential predictors. This has often led to the Table 2 fallacy, where one presents the coefficient estimates for all covariates from a single multivariable regression model, which are often uninterpretable in a descriptive analysis. We argue that machine learning (ML) is a potential solution to this problem. We illustrate the power of ML with an example analysis identifying the most important predictors of alcohol abuse among sexual minority youth. The framework we propose for this analysis is as follows: (1) Identify a few ML methods for the analysis, (2) optimize the parameters using the whole data with a nested cross-validation approach, (3) rank the variables using variable importance scores, (4) present partial dependence plots (PDP) to illustrate the association between the important variables and the outcome, (5) and identify the strength of the interaction terms using the PDPs. We discuss the potential strengths and weaknesses of using ML methods for descriptive analysis and future directions for research. R codes to reproduce these analyses are provided, which we invite other researchers to use.


Association of Polymorphisms within HOX Transcript Antisense RNA (HOTAIR) with Type 2 Diabetes Mellitus and Laboratory Characteristics: A Preliminary Case-Control Study.
Type 2 diabetes mellitus (T2DM) is a complex heterogeneous disease resulting from the environment and genetic interactions. Lately, genetic association studies have shown that polymorphisms in long noncoding RNAs (lncRNAs) are associated with T2DM susceptibility. This preliminary study is aimed at investigating if HOX transcript antisense RNA (HOTAIR) polymorphisms contribute to T2DM development. Five hundred clinically diagnosed T2DM cases and 500 healthy controls were recruited from the southeast Iranian population. Genomic DNA was isolated from nucleated blood cells and genotyped for MspI (C/T) (rs920778) and AluI (A/G) (rs4759314) polymorphisms using the PCR-RFLP technique. For genotyping rs12826786 C/T and rs1899663 G/T variants, ARMS-PCR method was applied. Our findings indicated that HOTAIR rs920778 C/T, rs12826786 C/T, and rs4759314 A/G polymorphisms have a significant positive association with T2DM, while a negative association was observed between rs1899663 G/T T2DM susceptibility. Significant associations were also observed between rs920778 C/T and HDL-C as well as s4759314 A/G and both FBS and LDL-C in T2DM patients. Haplotype analysis indicated that the CGCG, CTTG, TGTA, and TTTG haplotypes of rs920778/rs1899663/rs12826786/rs4759314 significantly enhanced T2DM risk by 1.47, 1.96, 2.81, and 4.80 folds, respectively. No strong linkage disequilibrium was found between the four HOTAIR SNPs. We firstly reported that HOTAIR rs1899663 G/T, rs12826786 C/T, rs4759314 A/G, and rs920778 C/T polymorphisms might influence T2DM susceptibility by modulating different signaling pathways and could be regarded as potential prognostic markers in T2DM patients.


Efficacy and safety of donepezil over 3 years: an open-label, multicentre study in patients with Alzheimer's disease.
This 132-week, open-label extension study assessed the long-term efficacy and safety of donepezil in 579 patients with mild to moderate Alzheimer's disease (AD) who had previously participated in a 24-week double-blind study of 5 or 10 mg/day donepezil vs placebo. Patients enrolled in the present study had a 6-week single-blind placebo washout period followed by treatment with donepezil 5 mg/day for 6 weeks with an optional increase in dosage to 10 mg/day between weeks 6 and 32. After 6 weeks of open-label treatment with donepezil 5 mg/day, mean Alzheimer's Disease Assessment Scale -- cognitive subscale scores (ADAS-cog) improved by approximately two points, while after 12 weeks of open-label treatment (with a majority of patients receiving 10 mg/day), the mean ADAS-cog score was 1 point better than the score at the end of the placebo washout period. Scores then declined gradually over the remainder of the study. Mean changes in Clinical Dementia Rating-Sum of Boxes scores showed slight improvement over the first 12 weeks of open-label treatment and then slowly declined for the remainder of the study period. Donepezil was well tolerated over the entire 162-week study period. Overall, 85% of patients experienced at least one adverse event (AE). The most common included diarrhoea (12%), nausea (11%), infection (11%) and accidental injury (10%). Some patients discontinued the study due to AEs (15%). These results support the conclusion that donepezil is safe and effective for the long-term treatment of patients with mild to moderate AD.


Elevated Levels of Procalcitonin and Interleukin-6 are Linked with Postoperative Complications in Cardiac Surgery.
Cardiac surgery-associated acute kidney injury is a frequent and serious postoperative complication of cardiac surgery and is associated with an increased risk of morbidity, mortality, and length stay. In this study, we hypothesized that persistent elevation in inflammation in the first 48 h might be a powerful predictor of clinical outcome. Our aim was to elucidate the usefulness of interleukin-6 and procalcitonin postoperative levels in predicting mortality and renal complications in cardiac surgery patients. A total of 122 cardiac surgery patients were enrolled. Procalcitonin and interleukin-6 concentrations were measured on the second postoperative day, and their levels were evaluated versus a number of conditions and endpoints. Procalcitonin has a good predictive value for adverse renal outcome (p < 0.05). Interleukin-6 has a good predictive value for 30 days and overall mortality in cardiac surgery population (p < 0.05). We did not observe a significant difference in procalcitonin and interleukin-6 levels among patients with different types of surgery and different extracorporeal circulation time, but the levels of both the molecules increase significantly depending on number of transfusions received by patients (p < 0.01). We speculated that procalcitonin and interleukin-6 could be two effective biomarkers. There is a possibility of having a combined inflammatory multi-biomarker panel, with procalcitonin for predicting renal outcome and interleukin-6 for predicting mortality.


[REM-sleep behavior disorder and sleepwalking in a patient with Parkinson's disease and essential tremor].
REM-sleep behavior disorder (RBD), a form of parasomnia, is characterized by motor and/or speech activity during sleep corresponding to the dream content. RBD is currently considered as a marker of onset of neurodegenerative diseases (sinucleinopathies) and as a most specific early symptom of Parkinson's disease (PD). The authors describe a clinical case of a patient with the combination of essential tremor, initial signs of PD and RBD. A polysomnographic study has confirmed clinical signs of RBD and determined the disturbances of sleep architecture: the increase in falling asleep, number of awakenings, wakefulness during sleep, the absence of deep slow-wave sleep. The particular features of the patient were essential tremor and sleep walking.


Detecting changes in dynamic and complex acoustic environments.
Natural sounds such as wind or rain, are characterized by the statistical occurrence of their constituents. Despite their complexity, listeners readily detect changes in these contexts. We here address the neural basis of statistical decision-making using a combination of psychophysics, EEG and modelling. In a texture-based, change-detection paradigm, human performance and reaction times improved with longer pre-change exposure, consistent with improved estimation of baseline statistics. Change-locked and decision-related EEG responses were found in a centro-parietal scalp location, whose slope depended on change size, consistent with sensory evidence accumulation. The potential's amplitude scaled with the duration of pre-change exposure, suggesting a time-dependent decision threshold. Auditory cortex-related potentials showed no response to the change. A dual timescale, statistical estimation model accounted for subjects' performance. Furthermore, a decision-augmented auditory cortex model accounted for performance and reaction times, suggesting that the primary cortical representation requires little post-processing to enable change-detection in complex acoustic environments.


Does community care work? A model to evaluate the effectiveness of mental health services.
The aim of this paper is to evaluate the effectiveness of community Mental Health Departments in Lombardy (Italy), and analyse the eventual differences in outcome produced by different packages of care. The survey was conducted in 2000 on 4,712 patients treated in ten Mental Health Departments. Patients were assessed at least twice in a year with HoNOS (Health of the Nation Outcome Scales). Data on treatment packages were drawn from the regional mental health information system, which includes all outpatient and day-care contacts, as well as general hospital and inpatient admissions provided by Mental Health Departments. Multilevel growth models were used for outcomes statistical analysis, expressed in terms of change of the total HoNOS score. On the whole, Mental Health Departments were effective in reducing HoNOS scores. The main predictor of improvement was treatment, while length of care, gender and diagnosis were weaker predictors. After severity adjustment, some packages of care proved more effective than others. Appropriate statistical methods, comprehensive treatment descriptions and routine outcome assessment tools are needed to evaluate the effectiveness of community mental health services in clinical settings.


Performance Validity Classification Accuracy of Single-, Pairwise-, and Triple-Failure Models Using the Halstead-Reitan Neuropsychological Battery for Adults.
Embedded performance validity tests (PVTs) have been criticized for their poor specificity and sensitivity. Aggregated models of embedded PVTs have been proposed to improve their classification accuracy; however, limitations to aggregation-based improvement of PVTs have yet to be explored. The current study evaluated the classification accuracy of 3 types of models of embedded PVTs in the Halstead-Reitan Neuropsychological Battery for Adults (HRNB): a single-, a pairwise-, and a triple-failure model. In addition, this study evaluated the impact of aggregating between 1 and 6 embedded PVTs in each of these 3 types of models. Analyzing only the 2, 4, and 6 most discriminating embedded PVTs in the single-, pairwise-, and triple-failure models maximized classification accuracy, respectively. Comparisons across these models indicated that the single-failure model including only the two most discriminating embedded PVTs had the best classification accuracy; however, classification accuracy was only minimally improved in this model relative to analyzing just Reliable Digit Span. These results suggest that aggregation of embedded PVTs from the HRNB does not substantially improve their classification accuracy and that the benefits of aggregating PVTs may only emerge when the PVTs entered into the aggregated models have sufficient classification accuracy on their own.


Physiologically Based Pharmacokinetic Modeling in Pregnant Women Suggests Minor Decrease in Maternal Exposure to Olanzapine.
Pregnancy is accompanied by significant physiological changes that might affect the in vivo drug disposition. Olanzapine is prescribed to pregnant women with schizophrenia, while its pharmacokinetics during pregnancy remains unclear. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model of olanzapine in the pregnant population. With the contributions of each clearance pathway determined beforehand, a full PBPK model was developed and validated in the non-pregnant population. This model was then extrapolated to predict steady-state pharmacokinetics in the three trimesters of pregnancy by introducing gestation-related alterations. The model adequately simulated the reported time-concentration curves. The geometric mean fold error of Cmax and AUC was 1.14 and 1.09, respectively. The model predicted that under 10 mg daily dose, the systematic exposure of olanzapine had minor changes (less than 28%) throughout pregnancy. We proposed that the reduction in cytochrome P4501A2 activity is counteracted by the induction of other enzymes, especially glucuronyltransferase1A4. In conclusion, the PBPK model simulations suggest that, at least at the tested stages of pregnancy, dose adjustment of olanzapine can hardly be recommended for pregnant women if effective treatment was achieved before the onset of pregnancy and if fetal toxicity can be ruled out.