Simulating the spread of COVID-19 via a spatially-resolved susceptible-exposed-infected-recovered-deceased (SEIRD) model with heterogeneous diffusion.
We present an early version of a Susceptible-Exposed-Infected-Recovered-Deceased (SEIRD) mathematical model based on partial differential equations coupled with a heterogeneous diffusion model. The model describes the spatio-temporal spread of the COVID-19 pandemic, and aims to capture dynamics also based on human habits and geographical features. To test the model, we compare the outputs generated by a finite-element solver with measured data over the Italian region of Lombardy, which has been heavily impacted by this crisis between February and April 2020. Our results show a strong qualitative agreement between the simulated forecast of the spatio-temporal COVID-19 spread in Lombardy and epidemiological data collected at the municipality level. Additional simulations exploring alternative scenarios for the relaxation of lockdown restrictions suggest that reopening strategies should account for local population densities and the specific dynamics of the contagion. Thus, we argue that data-driven simulations of our model could ultimately inform health authorities to design effective pandemic-arresting measures and anticipate the geographical allocation of crucial medical resources.


Introduction The use and consumption of "products", such as cosmetic procedures and confectionery, is on a rise in the Danish population. However, it has never been evaluated if the same tendency can be observed among the providers of these products. In view of the upcoming Christmas, we decided to investigate this delicate matter. Methods This study was a survey-based cross-sectional study examining demographics, professional backgrounds, as well as frequency and preferences regarding confectionery and cosmetic procedures among confectioners and plastic surgeons. Results A total of 90 persons answered the questionnaire. Results showed that consumption of confectionery was high among both confectioners and plastic surgeons, and that the use of cosmetic procedures was higher among both confectioners and plastic surgeons than among the background population. Both groups preferred to know the person who provided "the product" within their respective area. Conclusion Most plastic surgeons do not need to know their confectioner but would like to know their cosmetic procedure provider. So, if you, as part of the department management, or simply as a well-meaning colleague, want to treat your staff/colleagues, you can safely order cake from a random confectioner but not cosmetic procedures from a random surgeon! Funding none. Trial registration not relevant.


Impact of rotational atherectomy on heavily calcified, unprotected left main disease.
There is little data on percutaneous coronary intervention (PCI) using rotational atherectomy (Rota) for severely calcified unprotected left main (ULM) lesions. Between January 2005 and August 2011, 64 consecutive patients who underwent drug-eluting stent implantation using Rota were retrospectively evaluated. Of these, 54.7% and 20.3% patients had diabetes and were undergoing hemodialysis (HD), respectively. The mean EuroSCORE and SYNTAX score was 5.6 and 35.4, respectively. Procedural success, defined as residual stenosis <30%, was achieved in 95.3% of patients without fatal complications. Periprocedural myocardial infarction occurred in 7.8% patients. At the 1-year follow up, cardiac death was observed in 6.3% of patients, and target lesion revascularization (TLR) and TLR in the main branch (TLR-MB) were required in 18.8% and 10.9% patients, respectively. Optimal stent expansion was achieved in the majority of 33 patients with available intravascular ultrasound (IVUS) data. However, 5 of 9 HD patients who underwent IVUS required TLR-MB despite optimal stent expansion. The rate of TLR-MB was significantly lower in the non-HD patients than in the HD patients (2.1% vs. 46.2%; P=0.003). PCI using Rota for calcified ULM lesions might guarantee high procedural success and a low complication rate. Although acceptable results were obtained at the 1-year follow up for non-HD patients, the rate of TLR-MB was considerably high for HD patients despite optimal stent expansion.


An abundant biliary metabolite derived from dietary omega-3 polyunsaturated fatty acids regulates triglycerides.
Omega-3 fatty acids from fish oil reduce triglyceride levels in mammals, yet the mechanisms underlying this effect have not been fully clarified, despite the clinical use of omega-3 ethyl esters to treat severe hypertriglyceridemia and reduce cardiovascular disease risk in humans. Here, we identified in bile a class of hypotriglyceridemic omega-3 fatty acid-derived N-acyl taurines (NATs) that, after dietary omega-3 fatty acid supplementation, increased to concentrations similar to those of steroidal bile acids. The biliary docosahexaenoic acid-containing (DHA-containing) NAT C22:6 NAT was increased in human and mouse plasma after dietary omega-3 fatty acid supplementation and potently inhibited intestinal triacylglycerol hydrolysis and lipid absorption. Supporting this observation, genetic elevation of endogenous NAT levels in mice impaired lipid absorption, whereas selective augmentation of C22:6 NAT levels protected against hypertriglyceridemia and fatty liver. When administered pharmacologically, C22:6 NAT accumulated in bile and reduced high-fat diet-induced, but not sucrose-induced, hepatic lipid accumulation in mice, suggesting that C22:6 NAT is a negative feedback mediator that limits excess intestinal lipid absorption. Thus, biliary omega-3 NATs may contribute to the hypotriglyceridemic mechanism of action of fish oil and could influence the design of more potent omega-3 fatty acid-based therapeutics.


Extracting Drug-Drug Interactions with Word and Character-Level Recurrent Neural Networks.
Drug-drug interactions (DDIs) are known to be responsible for nearly a third of all adverse drug reactions. Hence several current efforts focus on extracting signal from EMRs to prioritize DDIs that need further exploration. To this end, being able to extract explicit mentions of DDIs in free text narratives is an important task. In this paper, we explore recurrent neural network (RNN) architectures to detect and classify DDIs from unstructured text using the DDIExtraction dataset from the SemEval 2013 (task 9) shared task. Our methods are in line with those used in other recent deep learning efforts for relation extraction including DDI extraction. However, to our knowledge, we are the first to investigate the potential of character-level RNNs (Char-RNNs) for DDI extraction (and relation extraction in general). Furthermore, we explore a simple but effective model bootstrapping method to (a). build model averaging ensembles, (b). derive confidence intervals around mean micro-F scores (MMF), and (c). assess the average behavior of our methods. Without any rule based filtering of negative examples, a popular heuristic used by most earlier efforts, we achieve an MMF of 69.13. By adding simple replicable heuristics to filter negative instances we are able to achieve an MMF of 70.38. Furthermore, our best ensembles produce micro F-scores of 70.81 (without filtering) and 72.13 (with filtering), which are superior to metrics reported in published results. Although Char-RNNs turnout to be inferior to regular word based RNN models in overall comparisons, we find that ensembling models from both architectures results in nontrivial gains over simply using either alone, indicating that they complement each other.


Let's chat: developmental neural bases of social motivation during real-time peer interaction.
Humans are motivated to interact with each other, but the neural bases of social motivation have been predominantly examined in non-interactive contexts. Understanding real-world social motivation is of special importance during middle childhood (ages 8-12), a period when social skills improve, social networks grow, and social brain networks specialize. To assess interactive social motivation, the current study used a novel fMRI paradigm in which children believed they were chatting with a peer. The design targeted two phases of interaction: (1) Initiation, in which children engaged in a social bid via sharing a like or hobby, and (2) Reply, in which children received either an engaged ("Me too") or non-engaged ("I'm away") reply from the peer. On control trials, children were told that their answers were not shared and that they would receive either engaged ("Matched") or non-engaged ("Disconnected") replies from the computer. Results indicated that during Initiation and Reply, key components of reward circuitry (e.g., ventral striatum) were more active for the peer than the computer trials. In addition, during Reply, social cognitive regions were more activated by the peer, and this social cognitive specialization increased with age. Finally, the effect of engagement type on reward circuitry activation was larger for social than non-social trials, indicating developmental sensitivity to social contingency. These findings demonstrate that both reward and social cognitive brain systems support real-time social interaction in middle childhood. An interactive approach to understanding social reward has implications for clinical disorders, where social motivation is more affected in real-world contexts.


Multiple marker analysis in the avian optic tectum reveals three classes of neuroglia and carbonic anhydrase-containing neurons.
The distribution and biochemical diversity of neuroglial cells in the avian optic tectum were analyzed using immunohistochemical techniques. Polyclonal and monoclonal antibodies were employed to define the distributions and localizations of four proteins that are considered to be glial-specific in the mammalian central nervous system: glutamine synthetase, carbonic anhydrase-C, glial fibrillary acidic protein, and S-100 protein. The results showed the presence of at least three distinguishable populations of glia: glutamine synthetase/glial fibrillary acidic protein-positive fibrous astrocytes, glutamine synthetase/carbonic anhydrase-C-positive protoplasmic astrocytes, and S-100-positive oligodendroglia. In addition, a distinct population of neurons was observed that showed very intense immunostaining for the presence of carbonic anhydrase-C. The results suggest that the segregation of biochemical functions in the major categories of brain neuroglial cells (oligodendroglia and astroglia) varies significantly between vertebrate species. This observation raises the possibility of using comparative studies to refine our understanding of the roles that glial cells play in nervous tissue.


Cytotoxic and proliferative effect of tobacco products on Lewis lung adenocarcinoma cells and spleen lymphocytes.
The effect of tobacco products (TP) on the proliferation of lung adenocarcinoma cells (3LL) and mice spleen lymphocytes as well as on tumor growth and metastasis was analyzed. High concentrations of cigarette smoke condensate (CSC) or tobacco extract (TE) were cytotoxic for tumoral and lymphoid cells; in contrast smaller amounts of TP increased thymidine incorporation in both cell types. Lymphocytes were more susceptible to the toxic effect of TP than 3LL cells. When CSC or TE were mixed with 3LL cells and then inoculated into mice, they did not modify either the size of the local tumor induced by 3LL cells, or the number or appearance time of lung metastasis, although there was an increase in spleen weight.


[Palliative medicine in oncology].
The aim of Palliative Medicine is the study of the illness person and the preservation and defence of his dignity. It is not only not opposite to Curative Medicine but also complementary. It includes physical, psychological, social and spiritual factors. Palliative Medicine must be present from the diagnosis through the different evolutive stages of our patients. It is not only the care programs for terminally cancer patients. Surgery, radiotherapy and chemotherapy are used as specific palliation in some situations in order to improve quality of life, survival time or symptomatic control. Human dignity is based on the fact of being, apart from its circumstances or its abilities. When a patient tells us:--Doctor, I don't want to live. We should translate:--Doctor, I don't want to live ... this way. Then, we should wonder how are we taking care of this person. Good caring begins in a good information along the whole process. I summarize it, as progressive and bearable truth. The key to get an appropriate treatment of our patients is to combine the pharmacological, dietetic an physical treatment with a deep understanding of the human being that should inform the whole medical practise.


Source effects in SWIPE: shear-wave-assisted ultrasound imaging.
SWIPE is a novel method for ultrasonic image reconstruction that uses echo phase modulation induced by traveling shear waves to decipher lateral k-space image data. Our prior experimental work has demonstrated lateral resolution with SWIPE at higher than expected sidelobe levels. Here we examine the effect of the location of the mechanical excitation source used in SWIPE. Surface and internal sources were simulated using finite element modeling. The interaction of shear and surface (Rayleigh) waves was found to degrade the SWIPE point spread function when surface excitation was employed. Internal excitation was not negatively affected and yielded near-ideal results. Regions of ideal performance, simulated point spread functions, and phase non-linearity measurements for the two methods are presented. The results indicate that internal sources, e.g. acoustic radiation force, can be expected to yield high-quality SWIPE images.


A prospective examination of service use by abused and neglected children followed up into adulthood.
This study sought to determine whether abused and neglected children are more likely than those without childhood maltreatment to use health and social services as adults and whether psychiatric status mediates or moderates the relationship. A prospective cohort design was used. Individuals with documented cases of physical and sexual abuse and neglect (ages 0-10) and nonvictimized children matched on age, sex, and race-ethnicity were interviewed in adulthood (mean age 41 years). Past-year service use (general medical, mental health, substance abuse, and social) was assessed during 2003-2004 interviews (maltreated group, N=458; control group, N=349). Psychiatric status (posttraumatic stress disorder [PTSD], drug abuse, and major depressive disorder) was assessed during 1989-1995 (mean age 29) by structured interview. Individuals with histories of childhood abuse and neglect were significantly more likely than their control group counterparts to use mental health services (odds ratio [OR]=1.60, 95% confidence interval [CI]=1.04-2.45) and social services (OR=2.95, CI=2.19-3.97) in adulthood. Psychiatric status in young adulthood (PTSD and major depressive disorder) partially mediated the relationship between childhood maltreatment and use of mental health services, whereas major depression and drug abuse moderated the relationship between maltreatment and use of any services and general medical services. In adulthood, individuals with documented histories of childhood abuse and neglect are more likely than persons without such histories to use some types of services, and psychiatric status mediates and moderates these relationships. Findings have implications for the provision of services to persons with childhood abuse and neglect.


Genetic Inhibition of Receptor Interacting Protein Kinase-1 Reduces Cell Death and Improves Functional Outcome After Intracerebral Hemorrhage in Mice.
Recent studies using cultured cells and rodent intracerebral hemorrhage (ICH) models have implicated RIPK1 (receptor interacting protein kinase-1) as a driver of programmed necrosis and secondary injury based on use of chemical inhibitors. However, these inhibitors have off-target effects and cannot be used alone to prove a role for RIPK1. The aim of the current study was to examine the effect of genetic inhibition of the kinase domain of RIPK1 in a mouse ICH model. We subjected 2 lines of mice with RIPK1 point mutations of the kinase domain (K45A and D138N), rendering them kinase inactive, to autologous blood ICH and measured acute cell death and functional outcome. Compared with wild-type controls, RIPK1K45A/K45A and RIPK1D138N/D138N had significantly less cells with plasmalemma permeability, less acute neuronal cell death, less weight loss and more rapid weight gain to baseline, and improved performance in a Morris water maze paradigm after autologous blood ICH. In addition, mice systemically administered GSK'963, a potent, specific, brain penetrant small molecule RIPK1 inhibitor, had reduced acute neuronal death at 24 hours after ICH. The data show that the kinase domain of RIPK1 is a disease driver of ICH, mediating both acute cell death and functional outcome, and support development of RIPK1 inhibitors as therapeutic agents for human ICH.


Impact assessment of gilgel gibe hydroelectric dam on schitosomiasis: a cross sectional study in southwest ethiopia.
Intestinal schistosomiasis is prevalent in East Africa including Ethiopia. Constructed five years back, Gilgel Gibe dam is suspected to harbor the intermediate host for transmission of schistosomiasis. The objective of this study was to determine the prevalence of intestinal schistosomiasis and risk factors among school children. A comparative cross-sectional study was carried out in October 2008 in four Woredas bordering Gilgel Gibe dam, within 10 kilometers, and Bulbul, which is 30 Kms away from the dam. Children attending grades 1-8 in the schools located adjacent to the dam constituted the cases and those living in Bulbul constitute the controls. Using Epinfo version 6.0 for cross-sectional study, a sample size of 937 was determined. Sample size allocation was done 2:1 for cases and control. After interview, stool sample was collected and analyzed. Screening for the presence of intermediate host and physiochemical analyses of selected water bodies along the major water contact sites of the reservoir was also done Data were entered into computer and analyzed using SPSS for windows version 13.0.1. Out of 624 sampled cases and 312 controls, 585 and 270 participated in the study giving a response rate of 93.8% and 86.5%, respectively. Four hundred seventy four (81.0% of the cases and 203 (75.2%) controls use latrine regularly. On stool examination, 406 (47.5%) children, 295 (50.4%) cases and 111 (41.1%) controls) were positive to intestinal parasites but only two children, both from the control groups, were positive for Schistosoma mansoni. The three river water samples on which malacological survey was done had similar physicochemical characteristics in many ways except high conductivity, pH and percent of dissolved oxygen concentration (milligram per liter) at one site where uninfected Biomphilaria Pfeifferi was found The study revealed that schistosomiasis is not yet a problem at Gilgel-Gibe dam. But, continuous surveying is required as the intermediate host is prevalent, the water bodies are suitable for the intermediate host and cases of schistosomiasis are identified 30 kms away the dam, in control area.


Comparison of CAPD and CCPD in Children and their Limitations.
Soon after its introduction, continuous ambulatory peritoneal dialysis (CAPD) became the choice mode of dialysis treatment for small children. With the advent of automated machines, continuous cycling peritoneal dialysis (CCPD) is now finding more favor in many centers. Initial cost of CCPD is higher due to the need for automated machines, but puts much less strain on the family. However, there is evidence that biochemical control is better with CAPD. Growth and nutrition in both groups are found to be similar. CCPD may have advantages over CAPD with regard to infection, since the former has fewer disconnections. The same is also true with regard to hernias and leaks. Some patients still prefer CAPD, since it allows more freedom in life style compared to CCPD.


Anorexia nervosa, parental 'expressed emotion' and dropping out of treatment.
The number of dropouts from a long-term treatment study of patients with anorexia nervosa (AN) and bulimia nervosa (BN) was substantial. A variety of social, clinical, parental, and treatment factors were examined for their association with early termination of treatment by the patient or the family. Parents' expressed emotion' (EE) (particularly critical comments), BN, and the type of therapy offered (family or individual) were found to interact in some manner to result in dropping out. Some other aspects of parents' EE were also examined, including a comparison of scores in parental pairs; EE was found to be influenced by social class, and there were significant associations with the patient's symptomatology and social adjustment. There was a strong relationship between mothers' and fathers' scores in parental pairs.


Air pollution around schools is linked to poorer student health and academic performance.
Exposing children to environmental pollutants during important times of physiological development can lead to long-lasting health problems, dysfunction, and disease. The location of children's schools can increase their exposure. We examined the extent of air pollution from industrial sources around public schools in Michigan to find out whether air pollution jeopardizes children's health and academic success. We found that schools located in areas with the highest air pollution levels had the lowest attendance rates-a potential indicator of poor health-and the highest proportions of students who failed to meet state educational testing standards. Michigan and many other states currently do not require officials considering a site for a new school to analyze its environmental quality. Our results show that such requirements are needed. For schools already in existence, we recommend that their environmental quality should be investigated and improved if necessary.


Hemorrhagic periventricular leukomalacia: diagnosis by real time ultrasound and correlation with autopsy findings.
Hemorrhage into areas of periventricular leukomalacia may occur and range in size from microscopic to massive. Hitherto, the definitive diagnosis has been made only at autopsy. A case is described in which the diagnosis of hemorrhagic periventricular leukomalacia was made antemortem by real-time ultrasound scanning and confirmed at autopsy. Periventricular/intraventricular hemorrhage, a more common hemorrhagic lesion, may extend into periventricular with matter in a location ventral and medial to hemorrhagic periventricular leukomalacia. Real-time ultrasound scanning is a safe and reliable means of defining the topography of these two hemorrhagic lesions and, thereby, of suggesting the correct diagnosis.


Putative sex-specific human pheromones do not affect gender perception, attractiveness ratings or unfaithfulness judgements of opposite sex faces.
Debate continues over the existence of human sex pheromones. Two substances, androstadienone (AND) and estratetraenol (EST), were recently reported to signal male and female gender, respectively, potentially qualifying them as human sex pheromones. If AND and EST truly signal gender, then they should affect reproductively relevant behaviours such as mate perception. To test this hypothesis, heterosexual, Caucasian human participants completed two computer-based tasks twice, on two consecutive days, exposed to a control scent on one day and a putative pheromone (AND or EST) on the other. In the first task, 46 participants (24 male, 22 female) indicated the gender (male or female) of five gender-neutral facial morphs. Exposure to AND or EST had no effect on gender perception. In the second task, 94 participants (43 male, 51 female) rated photographs of opposite-sex faces for attractiveness and probable sexual unfaithfulness. Exposure to the putative pheromones had no effect on either attractiveness or unfaithfulness ratings. These results are consistent with those of other experimental studies and reviews that suggest AND and EST are unlikely to be human pheromones. The double-blind nature of the current study lends increased support to this conclusion. If human sex pheromones affect our judgements of gender, attractiveness or unfaithfulness from faces, they are unlikely to be AND or EST.


Atypical form of Alzheimer's disease with prominent posterior cortical atrophy: a review of lesion distribution and circuit disconnection in cortical visual pathways.
In recent years, the existence of visual variants of Alzheimer's disease characterized by atypical clinical presentation at onset has been increasingly recognized. In many of these cases post-mortem neuropathological assessment revealed that correlations could be established between clinical symptoms and the distribution of neurodegenerative lesions. We have analyzed a series of Alzheimer's disease patients presenting with prominent visual symptomatology as a cardinal sign of the disease. In these cases, a shift in the distribution of pathological lesions was observed such that the primary visual areas and certain visual association areas within the occipito-parieto-temporal junction and posterior cingulate cortex had very high densities of lesions, whereas the prefrontal cortex had fewer lesions than usually observed in Alzheimer's disease. Previous quantitative analyses have demonstrated that in Alzheimer's disease, primary sensory and motor cortical areas are less damaged than the multimodal association areas of the frontal and temporal lobes, as indicated by the laminar and regional distribution patterns of neurofibrillary tangles and senile plaques. The distribution of pathological lesions in the cerebral cortex of Alzheimer's disease cases with visual symptomatology revealed that specific visual association pathways were disrupted, whereas these particular connections are likely to be affected to a less severe degree in the more common form of Alzheimer's disease. These data suggest that in some cases with visual variants of Alzheimer's disease, the neurological symptomatology may be related to the loss of certain components of the cortical visual pathways, as reflected by the particular distribution of the neuropathological markers of the disease.


Portable ultrasound for difficult central venous access.
Central venous catheterization can be difficult and can cause serious complications. Ultrasound-guided venous access is increasingly used but reports concern only routine cases. We performed a prospective observational study in 'difficult' or 'failed' procedures to assess the usefulness of ultrasound guidance. We used the technique in 33 patients; 23 had previous failed attempts or had suffered complications from such attempts. Ultrasound provided an anatomical reason for failure in 16 patients. Ten other patients were expected to be difficult before catheterization. Ultrasound identified a suitable site for catheterization in all 33 patients. Real-time ultrasound was used to successfully catheterize 22 patients. In nine patients, a surface landmark technique was used, which failed in three patients. In these three patients, ultrasound guidance allowed successful cannulation. Ultrasound guidance is a useful technique to aid central venous access when difficulties or complications have been encountered or anticipated.


Caspase-1 mediates hyperlipidemia-weakened progenitor cell vessel repair.
Caspase-1 activation senses metabolic danger-associated molecular patterns (DAMPs) and mediates the initiation of inflammation in endothelial cells. Here, we examined whether the caspase-1 pathway is responsible for sensing hyperlipidemia as a DAMP in bone marrow (BM)-derived Stem cell antigen-1 positive (Sca-(1+)) stem/progenitor cells and weakening their angiogenic ability. Using biochemical methods, gene knockout, cell therapy and myocardial infarction (MI) models, we had the following findings: 1) Hyperlipidemia induces caspase-1 activity in mouse Sca-(1+) progenitor cells in vivo; 2) Caspase-1 contributes to hyperlipidemia-induced modulation of vascular cell death-related gene expression in vivo; 3) Injection of Sca-1+ progenitor cells from caspase-1(-/-) mice improves endothelial capillary density in heart and decreases cardiomyocyte death in a mouse model of MI; and 4) Caspase-1(-/-) Sca-(1+) progenitor cell therapy improves mouse cardiac function after MI. Our results provide insight on how hyperlipidemia activates caspase-1 in Sca-(1+) progenitor cells, which subsequently weakens Sca-(1+) progenitor cell repair of vasculature injury. These results demonstrate the therapeutic potential of caspase-1 inhibition in improving progenitor cell therapy for MI.


Risk Factor Analysis for Capsular Contracture, Malposition, and Late Seroma in Subjects Receiving Natrelle 410 Form-Stable Silicone Breast Implants.
Natrelle 410 silicone breast implants are approved in the United States for breast augmentation, reconstruction, and revision. In two ongoing, prospective, multicenter 10-year studies, 17,656 subjects received Natrelle 410 implants for augmentation (n = 5059), revision-augmentation (n = 2632), reconstruction (n = 7502), or revision-reconstruction (n = 2463). Capsular contracture, implant malposition, and late seroma were documented. Cox proportional hazards regression analyses evaluated potential associations between subject-, implant-, and surgery-related factors and these complications. Median follow-up was 4.1, 2.6, 2.1, and 2.3 years in the augmentation, revision-augmentation, reconstruction, and revision-reconstruction cohorts, respectively. Incidence of capsular contracture across cohorts ranged from 2.3 to 4.1 percent; malposition, 1.5 to 2.7 percent; and late seroma, 0.1 to 0.2 percent. Significant risk factors for capsular contracture were subglandular implant placement, periareolar incision site, and older device age in the augmentation cohort (p < 0.0001), older subject age in the revision-augmentation cohort (p < 0.0001), and higher body mass index (p = 0.0026) and no povidone-iodine pocket irrigation (p = 0.0006) in the reconstruction cohort. Significant risk factors for malposition were longer incision size in the augmentation cohort (p = 0.0003), capsulectomy at the time of implantation in the reconstruction cohort (p = 0.0028), and implantations performed in physicians' offices versus hospitals or standalone surgical facilities in both revision cohorts (p < 0.0001). The incidence of late seroma was too low to perform risk factor analysis. These data reaffirm the safety of Natrelle 410 implants. Knowledge of risk factors for capsular contracture and implant malposition offers guidance for reducing complications and optimizing outcomes. Risk, II.


Intersectional policy analysis of self-directed mental health care in Canada.
Recovery from mental illness is influenced by one's social location along multiple dimensions of identity, such as race, class, gender, age, and ability, and by how these social locations are expressed through structural and institutional barriers. This project was developed using an intersectional policy analysis framework designed to promote equity across identity locations-called the multistrand method-to examine the potential use of self-directed care financing approaches in the Canadian mental health system. A panel of 16 diverse stakeholders came together 4 times at structured 6-hr meetings to examine the evidence for self-directed care and explore its application in the Canadian context. Telephone interviews with evidence panel members were conducted to assess their perceptions of the group process and outcomes. Our analysis revealed ways that intersecting strand locations might differentially influence the degree of choice and recovery experienced by self-directed care participants. Individualized resource allocation, draining financial resources from ethnically specific services, unevenness in acceptance of the recovery orientation, and paucity of service options in different geographical regions were identified as contexts in which self-directed care policies could promote inequity. However, greater peer involvement in the model's implementation, use of indigenous community supports, purchase of material goods by economically disenfranchised persons, and access to services from ethnically diverse clinicians in the private sector were identified as equity-promoting model features. By couching their analysis at the level of unique socially-situated perspectives, the group developed detailed policy recommendations and insights into both the potential and limitations of self-directed care. The knowledge gained from our project can be used to develop uniquely Canadian self-directed care models tailored to promote recovery through empowerment and self-determination across intersecting identity strand locations. (PsycINFO Database Record


Tendon-Defect and muscle-unloaded models for relating a rotator cuff tear to glenohumeral stability.
Rotator cuff tear and glenohumeral instability are closely related. Any tear may disturb muscle force generation due to pain inhibition. In addition, a full-thickness tear may foster instability by removing a structural element constraining the joint. It was hypothesized that the loss of both dynamic force and static constraint with a rotator cuff tear will affect glenohumeral stability. In a tendon-defect model, dynamic and static elements of the joint were sacrificed. In a muscle-unloaded model, only the dynamic element was removed. The location and size of the defect were also investigated. The effect on instability of a small tendon defect was less than that of muscle unloading, implying that a patient with a small tear would have less instability than a patient with weak or nonfunctioning supraspinatus and infraspinatus muscles. On the other hand, with a larger tear the defect had a greater effect than muscle-unloading because sectioning of the glenohumeral and coracohumeral ligaments was included in the model. Clinically, such a defect in the front is critical for anterior stability because it might insult the important anterior capsule ligamentous complex. Orthopaedic surgeons should pay attention, therefore, to the effect of possible associated lesions of static constraints based on the size and location of the tear in addition to the dynamic stabilizer.


MECHANISMS IN ENDOCRINOLOGY: An update in the genetic aetiologies of combined pituitary hormone deficiency.
Over the last 5 years, new actors involved in the pathogenesis of combined pituitary hormone deficiency in humans have been reported: they included a member of the immunoglobulin superfamily glycoprotein and ciliary G protein-coupled receptors, as well as new transcription factors and signalling molecules. New modes of inheritance for alterations of genes encoding transcription factors have also been described. Finally, actors known to be involved in a very specific phenotype (hypogonadotroph hypogonadism for instance) have been identified in a wider range of phenotypes. These data thus suggest that new mechanisms could explain the low rate of aetiological identification in this heterogeneous group of diseases. Taking into account the fact that several reviews have been published in recent years on classical aetiologies of CPHD such as mutations of POU1F1 or PROP1, we focused the present overview on the data published in the last 5 years, to provide the reader with an updated review on this rapidly evolving field of knowledge.


X. Lamb and veal. Comprehensive evaluation of fatty acids in foods.
As a result of critical review of information on lipid composition of foods, representative values have been derived for the lipid and fatty acid contents of lamb and veal. Comprehensive tabulations of fatty acids in 100-gm. portions of raw and cooked retail cuts are given. The mean fatty acid profiles of the lean and adipose tissues which were used for computing the fatty acid values in the food tables are presented. The lean tissue lipid of lamb contains a significant amount of caprylic, arachidic, and arachidonic acids which are not present in the adipose tissue. A comparison of beef and veal shows that veal lipid is a richer source of polyunsaturated fatty acids. The new values presented here for fatty acids in lamb and veal should provide nutritionists and dietitians better means for evaluating diets.


[Resected lung cancer with production of CA19-9].
We report 2 cases of resected CA19-9 producing adenocarcinoma of the lung. Immunohistochemical studies of the specimens in 2 cases showed positive staining for CA19-9 in most of tumor cells. The serum CA19-9 levels decreased after operations and effective chemotherapy in these cases. But the serum CA19-9 levels increased with regrowth of tumors or with no therapeutic gain by chemotherapy. The serum CA19-9 level was useful to evaluate the therapeutic effect of surgery and chemotherapy, and may be effective in detecting the recurrence of lung cancer.


Efficacy of treatment and long-term follow-up of Batrachochytrium dendrobatidis PCR-positive anurans following itraconazole bath treatment.
All anuran specimens in the Wildlife Conservation Society's collections testing positive for Batrachochytrium dendrobatidis (Bd) were treated with itraconazole and then studied after treatment to assess the long-term effects of itraconazole and the drug's effectiveness in eliminating Bd carriers. Twenty-four individuals and eight colonies of 11 different species (75 total specimens) tested positive for Bd via polymerase chain reaction (PCR) on multicollection survey. All positive individuals and colonies were treated with a 0.01% itraconazole bath solution and retested for Bd via one of two PCR methodologies within 14 days of treatment completion, and all were negative for Bd. A total of 64 animals received secondary follow-up PCR testing at the time of death, 6-8 mo, or 12-15 mo post-treatment. Fourteen animals (14/64, 21.9%) were PCR positive for Bd on second follow-up. The highest percentage positive at second recheck were green-and-black poison dart frogs (Dendrobates auratus; 5/5 specimens, 100%), followed by red-eyed tree frogs (Agalychnis callidryas; 4/11, 36.4%), grey tree frogs (Hyla versicolor; 1/3, 33.3%), and green tree frogs (Hyla cinera; 3/11, 27.3%). Re-testing by PCR performed on 26/28 individuals that died during the study indicated 11/26 (42.3%) were positive (all via DNA extracted from formalin-fixed paraffin-embedded skin sections). However, there was no histologic evidence of chytridiomycosis in any of 27/28 individuals. The small number of deceased animals and effects of postmortem autolysis limited the ability to determine statistical trends in the pathology data, but none of the necropsied specimens showed evidence of itraconazole toxicity. Problems with itraconazole may be species dependent, and this report expands the list of species that can tolerate treatment. Although itraconazole is effective for clearance of most individuals infected with Bd, results of the study suggest that repeat itraconazole treatment and follow-up diagnostics may be required to ensure that subclinical infections are eliminated in amphibian collections.


Skewed sex ratios at birth and future marriage squeeze in China and India, 2005-2100.
I examine the potential impact of the anticipated future marriage squeeze on nuptiality patterns in China and India during the twenty-first century. I use population projections from 2005 to 2100 based on three different scenarios for the sex ratio at birth (SRB). To counteract the limitations of cross-sectional methods commonly used to assess the severity of marriage squeezes, I use a two-sex cohort-based procedure to simulate marriage patterns over the twenty-first century based on the female dominance model. I also examine two more-flexible marriage functions to illustrate the potential impact of changes in marriage schedules as a response to the marriage squeeze. Longitudinal indicators of marriage squeeze indicate that the number of prospective grooms in both countries will exceed that of prospective brides by more 50% for three decades in the most favorable scenario. Rates of male bachelorhood will not peak before 2050, and the squeeze conditions will be felt several decades thereafter, even among cohorts unaffected by adverse SRB. If the SRB is allowed to return to normalcy by 2020, the proportion of men unmarried at age 50 is expected to rise to 15% in China by 2055 and to 10% in India by 2065. India suffers from the additional impact of a delayed fertility transition on its age structures.


Critical action as a pathway to social mobility among marginalized youth.
Marginalized youth's development occurs in contexts rife with racialized, gendered, and socioeconomic social identity threats and barriers to social mobility. An emergent line of inquiry suggests critical action-a component of critical consciousness, defined as engaging in individual or collective social action to produce social change-may bolster career development for those experiencing marginalization. Yet, the specific mechanisms underlying critical action-career development associations are not well understood. Applying structural equation modeling (SEM) to 4 waves of longitudinal data from the Maryland Adolescent Development in Context Study (when participants were 17, 19, 21, and 29 years old), the authors explore the role of critical action for African American participants from lower-SES households (n = 261). The obtained model, which links critical action to career expectancies in adolescence and occupational attainment in adulthood, converges with earlier research linking critical consciousness to career development, social mobility pathways, and occupational attainment among marginalized youth. This study adds to previous literature by suggesting that critical action: (a) plays a significant role in fostering career expectancies in adolescence, particularly during high school, among marginalized youth; and (b) may promote the attainment of higher-status occupations in adulthood. Given the role of occupational attainment in social mobility and inclusion, these findings suggest an important mechanism by which social inequities may be narrowed. (PsycINFO Database Record


Identifying drug targets with thermal proteome profiling using IBT-16plex.
Thermal proteome profiling (TPP) has been widely used for the identification of drug targets for several years, and TMTpro-16plex has recently been evaluated for TPP of vehicle- and drug-treated samples in a single labeling process to reduce missing values and save instrument time. A novel isobaric labeling reagent, IBT-16plex, was developed with slightly better performance in protein identification and quantification than the commercially available TMTpro-16plex. In this study, we applied the newly developed IBT-16plex for target identification of methotrexate and panobinostat using TPP. The known targets of these two drugs were successfully identified with elevated melting temperatures, and some known off-targets and potential new off-targets were also identified. IBT-16plex can be a cost-effective replacement for TMTpro-16plex for TPP applications.


HLA-B27 and rheumatic diseases of childhood.
In childhood, the histocompatibility antigen HLA-B27 is associated with juvenile ankylosing spondylitis, Reiter's syndrome, and the sacroiliitis of juvenile psoriatic arthritis, and inflammatory bowel diseases. The low frequency of signs or symptoms of spine or sacroiliac joint disease at onset differentiate these disorders from their adult counterparts and make early diagnosis difficult. The presence of enthesitis and the absence of rheumatoid factor and antinuclear antibody suggests the diagnosis of one of the seronegative spondyloarthropathies. The mechanisms by which HLA-B27 positivity confers susceptibility to disease are uncertain. To date, no genetically determined differences in the HLA-B27 molecule, or in the T cell receptor which recognizes antigen in the context of HLA-B27, have been consistently shown to be associated with the presence of disease. There is no explanation for the onset of disease in childhood in some individuals.


Accurate or assumed: visual learning in children with ASD.
Children with autism spectrum disorder (ASD) are often described as visual learners. We tested this assumption in an experiment in which 25 children with ASD, 19 children with global developmental delay (GDD), and 17 typically developing (TD) children were presented a series of videos via an eye tracker in which an actor instructed them to manipulate objects in speech-only and speech + pictures conditions. We found no group differences in visual attention to the stimuli. The GDD and TD groups performed better when pictures were available, whereas the ASD group did not. Performance of children with ASD and GDD was positively correlated with visual attention and receptive language. We found no evidence of a prominent visual learning style in the ASD group.


Return to work after total hip and knee arthroplasty: a systematic review.
The aim of this study was to describe work status and time to return to work in patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA) and to determine which factors are associated with work status. A systematic search strategy in various databases through April 2013 was performed. All clinical studies concerning patients undergoing THA or TKA providing quantitative information on work status before and after surgery were eligible for inclusion. Extracted were study characteristics, data on work status and determinants of return to work. The methodological quality was evaluated in three quality aspects (selection bias, information bias and statistical analysis bias). Nineteen studies published between 1986 and 2013 were selected (4 on THA, 14 on TKA and 1 on THA and TKA). These studies included 3872 patients with THA and 649 patients with TKA. The proportions of patients returning to work ranged from 25 to 95% at 1-12 months after THA and from 71 to 83% at 3-6 months after TKA. The average time to return to work varied from 1.1 to 13.9 weeks after THA and from 8.0 to 12.0 weeks after TKA. Factors related to work status after THA and TKA included sociodemographic, health and job characteristics. Overall, the methodological quality of the studies was moderate to low. The majority of patients who are employed before THA and TKA return to work postoperatively. Comparisons of work status and the rate and speed of return to work between studies in THA and TKA are hampered by large variations in patient selection and measurement methods, underpinning the need for more standardization.


Pharmacokinetic compatibility of ginsenosides and Schisandra Lignans in Shengmai-san: from the perspective of p-glycoprotein.
Phytochemical-mediated alterations in P-glycoprotein (P-gp) activity may result in herb-drug interactions by altering drug pharmacokinetics. Shengmai-san, a traditional Chinese herbal medicine composed by Panax Ginseng, Ophiopogon Japonicus, and Schisandra Chinensis, is routinely being used for treating various coronary heart diseases. In our previous studies, Schisandra Lignans Extract (SLE) was proved as a strong P-gp inhibitor, and herein, the compatibility of Shengmai-san was studied by investigating the influence of SLE on the pharmacokinetics of the ginsenosides from the perspective of P-gp. Pharmacokinetic experiments were firstly performed based on in vitro uptake, efflux and transport experiments in Caco-2, LLC-PK1 wild-type and MDR1-overexpressing L-MDR1 cells. During the whole experiment, digoxin, a classical P-gp substrate, was used as a positive control drug to verify the cells used are the valid models. Meanwhile, the effects of SLE on the pharmacokinetics of ginsenosides were further investigated in rats after single-dose and multi-dose of SLE. The efflux ratios of ginsenoside Rb2, Rc, Rg2, Rg3, Rd and Rb1 were found more than 3.5 in L-MDR1 cells and can be decreased significantly by verapamil (a classical P-gp inhibitor). Contrarily, the efflux ratios of other ginsenosides (Rh1, F1, Re, and Rg1) were lower than 2.0 and not affected by verapamil. Then, the effects of SLE on the uptake and transport of ginsenosides were investigated, and SLE was found can significantly enhance the uptake and inhibit the efflux ratio of ginsenoside Rb2, Rc, Rg2, Rg3, Rd and Rb1 in Caco-2 and L-MDR1 cells. Besides, In vivo experiments showed that single-dose and multi-dose of SLE at 500 mg/kg could increase the area under the plasma concentration time curve of Rb2, Rc and Rd significantly without affecting terminal elimination half-time. In conclusion, SLE could enhance the exposure of ginsenosides Rb2, Rc, Rg2, Rg3, Rd and Rb1 significantly.


Involvement of GPX4 in irisin's protection against ischemia reperfusion-induced acute kidney injury.
Ischemia reperfusion (I/R)-induced acute kidney injury (AKI) is a common and serious condition. Irisin, an exercise-induced hormone, improves mitochondrial function and reduces reactive oxygen species (ROS) production. Glutathione peroxidase 4 (GPX4) is a key regulator of ferroptosis and its inactivation aggravates renal I/R injury by inducing ROS production. However, the effect of irisin on GPX4 and I/R-induced AKI is still unknown. To study this, male adult mice were subjected to renal I/R by occluding bilateral renal hilum for 30 min, which was followed by 24 hr reperfusion. Our results showed serum irisin levels were decreased in renal I/R mice. Irisin (250 μg/kg) treatment alleviated renal injury, downregulated inflammatory response, improved mitochondrial function, and reduced ER stress and oxidative stress after renal I/R, which were associated with upregulation of GPX4. Treated with RSL3 (a GPX4 inhibitor) abolished irisin's protective effect. Thus, irisin attenuates I/R-induced AKI through upregulating GPX4.


Noninvasive imaging of lipid nanoparticle-mediated systemic delivery of small-interfering RNA to the liver.
Mouse models with liver-specific expression of firefly luciferase were developed that enable a noninvasive and longitudinal assessment of small-interfering RNA (siRNA)-mediated gene silencing in hepatocytes of live animals via bioluminescence imaging. Using these models, a set of lipid nanoparticles (LNPs) with different compositions of cationic lipids, polyethylene glycol (PEG), and cholesterol, were tested for their abilities in delivering a luciferase siRNA to the liver via systemic administration. A dose-dependent luciferase knockdown by LNP/siRNA assemblies was measured by in vivo bioluminescence imaging, which correlated well with the results from parallel ex vivo analyses of luciferase mRNA and protein levels in the liver. RNA interference (RNAi)-mediated target silencing was further confirmed by the detection of RNAi-specific target mRNA cleavage. A single dose of LNP02L at 3 mg/kg (siRNA) caused 90% reduction of luciferase expression and the target repression lasted for at least 10 days. With identical components, LNPs containing 2% PEG are more potent than those with 5.4% PEG. Our results demonstrate that these liver-luciferase mouse models provide a powerful tool for a high-throughput evaluation of hepatic delivery platforms by noninvasive imaging and that the molar ratio of PEG lipid can affect the efficacy of LNPs in silencing liver targets via systemic administration.


Definition of a series of stages in the association of two herpesviral proteins with the cell nucleus.
We examined the kinetics and the nature of the association of two herpes simplex virus proteins, the major DNA-binding protein (ICP8) and the major capsid protein (ICP5), with the nuclei of infected cells. We defined a series of stages in the association of the ICP8 protein with the cell nucleus. (i) Immediately after synthesis, the protein was found in the cytoplasmic fraction but associated rapidly with the crude nuclear fraction. (ii) The initial association of ICP8 with the crude nuclear fraction was detergent sensitive but DNase resistant, and, thus, the protein was either bound to structures attached to the outside of the nucleus and had not penetrated the nuclear envelope or was loosely bound in the nucleus, (iii) At intermediate times, a low level of an intermediate form was observed in which the association of ICP8 with the nuclear fraction was resistant to both detergent and DNase treatment. The protein may be bound to the nuclear matrix at this stage. Inhibition of viral DNA synthesis caused the DNA-binding protein to accumulate in this form. (iv) At late times during the chase period, the association of ICP8 with the cell nucleus was resistant to detergent treatment but sensitive to DNase treatment. our results argue that at this stage ICP8 was bound to viral DNA. Thus, nuclear association of the DNA-binding protein did not require viral DNA replication. More important is the observation that there is a series of stages in the nuclear association of this protein, and, thus, there may be a succession of binding sites for this protein in the cell during its movement to its final site of action in the nucleus. The major capsid protein showed some similar stages of association with the cell nucleus but the initial association with the nucleus followed a lag period. Its early association with the crude nuclear fraction was also detergent sensitive but was resistant to detergent treatment at later times. Its association with the cell nucleus was almost completely resistant to DNase treatment at all times. Inhibition of viral DNA replication blocked the nuclear transport of this protein. Thus, these two viral proteins share some stages in nuclear transport, although their requirements for nuclear association are different.


Shaping of tumor and drug-resistant genomes by instability and selection.
Tumors with defects in mismatch repair (MMR) show fewer chromosomal changes by cytogenetic analyses than most solid tumors, suggesting that a greater proportion of the alterations required for malignancy occur in genes with nucleotide sequences susceptible to errors normally corrected by MMR. Here, we used genome-wide microarray comparative genomic hybridization to carry out a higher resolution evaluation of the effect of MMR competence on genomic alterations occurring in 20 cell lines and to determine if characteristic aberrations arise in MMR-proficient and -deficient HCT116 cells undergoing selection for methotrexate resistance. We observed different spectra of aberrations in MMR-proficient compared to -deficient cell lines, as well as among cell lines with different types of MMR-deficiency. We also observed different genetic routes to drug resistance. Resistant MMR-deficient cells most frequently displayed no copy number alterations (16/29 cell pools), whereas all MMR-proficient cells had unique abnormalities involving chromosome 5, including amplicons centered on the target gene, DHFR and/or a neighboring novel locus (7/13 pools). These observations support the concept that tumor genomes are shaped by selection for alterations that promote survival and growth advantage, as well as by the particular dysfunctions in genes responsible for maintenance of genetic integrity.


Cross-sectional association between plasma biomarkers and multimorbidity patterns in older adults.
Multimorbidity is the simultaneous presence of two or more chronic conditions. Metabolomics could identify biomarkers potentially related to multimorbidity. We aimed to identify groups of biomarkers and their association with different multimorbidity patterns. Cross-sectional analyses were conducted within the Seniors-ENRICA-2 cohort in Spain, with information from 700 individuals aged ≥65 years. Biological samples were analyzed using high-throughput proton nuclear magnetic resonance metabolomics. Biomarkers groups were identified with exploratory factor analysis, and multimorbidity was classified into three types: cardiometabolic, neuropsychiatric, and musculoskeletal. Logistic regression was used to estimate the association between biomarkers groups and multimorbidity patterns, after adjusting for potential confounders including sociodemographics, lifestyle, and body mass index. Three factors were identified: the "lipid metabolism" mainly reflected biomarkers related to lipid metabolism, such as very-low-density lipoprotein and low-density lipoprotein cholesterol; the "high-density lipoprotein cholesterol" mainly included high-density lipoprotein cholesterol subclasses and other lipids not included in the first factor; and the "amino acid/glycolysis/ketogenesis", composed of some amino acids, glycolysis-related metabolites and ketone bodies. Higher scores in the "lipid metabolism" factor were associated with a higher likelihood of cardiometabolic multimorbidity, odds ratio for tertile 3 vs. tertile 1 was 1.79 (95% confidence interval: 1.17-2.76). The "high-density lipoprotein cholesterol" factor was associated with lower odds of cardiometabolic multimorbidity [0.51 (0.32-0.82)], and the "amino acid/glycolysis/ketogenesis" factor was associated with more frequent cardiometabolic multimorbidity [1.85 (1.18-2.90)]. Different metabolomic biomarkers are associated with different multimorbidity patterns, therefore multiple biomarker measurements are needed for a complete picture of the molecular mechanisms of multimorbidity.


Rational design of biomimetic molecularly imprinted materials: theoretical and computational strategies for guiding nanoscale structured polymer development.
In principle, molecularly imprinted polymer science and technology provides a means for ready access to nano-structured polymeric materials of predetermined selectivity. The versatility of the technique has brought it to the attention of many working with the development of nanomaterials with biological or biomimetic properties for use as therapeutics or in medical devices. Nonetheless, the further evolution of the field necessitates the development of robust predictive tools capable of handling the complexity of molecular imprinting systems. The rapid growth in computer power and software over the past decade has opened new possibilities for simulating aspects of the complex molecular imprinting process. We present here a survey of the current status of the use of in silico-based approaches to aspects of molecular imprinting. Finally, we highlight areas where ongoing and future efforts should yield information critical to our understanding of the underlying mechanisms sufficient to permit the rational design of molecularly imprinted polymers.


Honeybee lifespan: the critical role of pre-foraging stage.
Assessing the various anthropogenic pressures imposed on honeybees requires characterizing the patterns and drivers of natural mortality. Using automated lifelong individual monitoring devices, we monitored worker bees in different geographical, seasonal and colony contexts creating a broad range of hive conditions. We measured their life-history traits and notably assessed whether lifespan is influenced by pre-foraging flight experience. Our results show that the age at the first flight and onset of foraging are critical factors that determine, to a large extent, lifespan. Most importantly, our results indicate that a large proportion (40%) of the bees die during pre-foraging stage, and for those surviving, the elapsed time and flight experience between the first flight and the onset of foraging is of paramount importance to maximize the number of days spent foraging. Once in the foraging stage, individuals experience a constant mortality risk of 9% and 36% per hour of foraging and per foraging day, respectively. In conclusion, the pre-foraging stage during which bees perform orientation flights is a critical driver of bee lifespan. We believe these data on the natural mortality risks in honeybee workers will help assess the impact of anthropogenic pressures on bees.


An in vitro method of alcoholic liver injury using precision-cut liver slices from rats.
Alcohol abuse results in liver injury, but investigations into the mechanism(s) for this injury have been hampered by the lack of appropriate in vitro culture models in which to conduct in depth and specific studies. In order to overcome these shortcomings, we have developed the use of precision-cut liver slices (PCLS) as an in vitro culture model in which to investigate how ethanol causes alcohol-induced liver injury. In these studies, it was shown that the PCLS retained excellent viability as determined by lactate dehydrogenase and adenosine triphosphate (ATP) levels over a 96-h period of incubation. More importantly, the major enzymes of ethanol detoxification; alcohol dehydrogenase, aldehyde dehydrogenase, and cytochrome P4502E1, remained active and PCLS readily metabolized ethanol and produced acetaldehyde. Within 24 h and continuing up to 96h the PCLS developed fatty livers and demonstrated an increase in the redox state. These PCLS secreted albumin, and albumin secretion was decreased by ethanol treatment. All of these impairments were reversed following the addition of 4-methylpyrazole, which is an inhibitor of ethanol metabolism. Therefore, this model system appears to mimic the ethanol-induced changes in the liver that have been previously reported in human and animal studies, and may be a useful model for the study of alcoholic liver disease.


Subtracting incoherent optical neuron model: analysis, experiment, and applications.
To fully use the advantages of optics in optical neural networks, an incoherent optical neuron (ION) model is proposed. The main purpose of this model is to provide for the requisite subtraction of signals without the phase sensitivity of a fully coherent system and without the cumbrance of photon-electron conversion and electronic subtraction. The ION model can subtract inhibitory from excitatory neuron inputs by using two device responses. Functionally it accommodates positive and negative weights, excitatory and inhibitory inputs, non-negative neuron outputs, and can be used in a variety of neural network models. This technique can implement conventional inner-product neuron units and Grossberg's mass action law neuron units. Some implementation considerations, such as the effect of nonlinearities on device response, noise, and fan-in/fan-out capability, are discussed and simulated by computer. An experimental demonstration of optical excitation and inhibition on a 2-D array of neuron units using a single Hughes liquid crystal light valve is also reported.


Meta-analysis of stereotactic hematoma removal and craniotomy hematoma removal in the treatment of hypertensive intracerebral hemorrhage in the elderly.
A large number of clinical studies suggested that surgery might be a better choice than conservative treatment for treating hypertensive intracerebral hemorrhage in the middle-aged and elderly. Stereotactic puncture can reduce the mass effect caused by hematoma, reduce the intervention of body homeostasis, reduce brain tissue damage, and improve the prognosis of patients with cerebral hemorrhage. This meta-analysis aims to evaluate the efficacy of stereotactic puncture and craniotomy in elderly patients with hypertensive intracerebral hemorrhage. A search strategy was designed to search in databases, including PubMed, Embase, Cochrane Central Register of Controlled Trials, CNKI, Wanfang database and relevant references. Literature on the efficacy and safety of different surgical methods for hypertensive cerebral hemorrhage in the middle-aged and elderly were retrieved. The search time was until August 17, 2022. Keywords included "hypertensive intracerebral hemorrhage," "stereotactic hematoma removal," "craniotomy." After the literature search, 2 researchers independently conducted literature screening, quality evaluation of included trials and data extraction. RevMan5.4 software was used to perform a Meta-analysis on the operation time, hospital stay, postoperative Glasgow Coma Scale (GCS) score, postoperative daily activity ability, postoperative complications and neurological prognosis scores included in the included studies. A total of 1988 samples were included in 9 studies. 1022 patients underwent stereotactic hematoma removal, and 968 patients underwent craniotomy hematoma removal. The orientation group had more advantages in the length of hospital stay, postoperative disability, pulmonary infection, intracranial infection and digestive tract ulcer, and the difference was statistically significant (P < .05). In addition, the length of stay (I²= 83%) of the included articles had good homogeneity (I²< 50%), and there was no significant difference between the 2 groups in operation time, postoperative GCS score, postoperative daily activity ability, and neurological prognosis score (P > .05). The meta-analysis indicate that compared to craniotomy for hematoma removal, stereotactic hematoma removal can reduce the postoperative disability rate, intracranial infection rate, lung infection rate, and digestive tract ulcer rate in middle-aged and elderly patients with hypertensive intracerebral hemorrhage.


Detection of hidden visual loss in multiple sclerosis. A comparison of pattern-reversal visual evoked potentials and contrast sensitivity.
The detection of hidden visual loss is important in establishing the diagnosis of multiple sclerosis, especially in patients who have neurologic symptoms of the disease. Both visual evoked potentials and contrast sensitivity have been used for this purpose. We compared the sensitivities of pattern-reversal visual evoked potentials and contrast sensitivity, measured with the Vistech VCTS 6500 chart, in detecting hidden visual loss in 18 patients with multiple sclerosis whose visual acuity was correctable to 20/20 (6/6) or better in the examined eye. Thirteen patients had delayed visual evoked potential latencies. An additional four patients had reduced P100 amplitudes without prolonged latencies. Nine patients had abnormal contrast sensitivity. The visual evoked potential was more sensitive than contrast sensitivity at detecting hidden visual loss in patients with multiple sclerosis (p less than 0.01).


Modeling the detailed kinetics of mitochondrial cytochrome c oxidase: Catalytic mechanism and nitric oxide inhibition.
Cytochrome c oxidase (CcO) catalyzes the exothermic reduction of O2 to H2O by using electrons from cytochrome c, and hence plays a crucial role in ATP production. Although details on the enzyme structure and redox centers involved in O2 reduction have been known, there still remains a considerable ambiguity on its mechanism of action, e.g., the number of sequential electrons donated to O2 in each catalytic step, the sites of protonation and proton pumping, and nitric oxide (NO) inhibition mechanism. In this work, we developed a thermodynamically constrained mechanistic mathematical model for the catalytic action of CcO based on available kinetic data. The model considers a minimal number of redox centers on CcO and couples electron transfer and proton pumping driven by proton motive force (PMF), and accounts for the inhibitory effects of NO on the reaction kinetics. The model is able to fit well all the available kinetic data under diverse experimental conditions with a physiologically realistic unique parameter set. The model predictions show that: 1) the apparent Km of O2 varies considerably and increases from fully reduced to fully oxidized cytochrome c depending on pH and the energy state of mitochondria, and 2) the intermediate enzyme states depend on pH and cytochrome c redox fraction and play a central role in coupling mitochondrial respiration to PMF. The developed CcO model can easily be integrated into existing mitochondrial bioenergetics models to understand the role of the enzyme in controlling oxidative phosphorylation in normal and disease conditions.


Ceramide synthase inhibitor fumonisin B1 inhibits apoptotic cell death in SCC17B human head and neck squamous carcinoma cells after Pc4 photosensitization.
The sphingolipid ceramide modulates stress-induced cell death and apoptosis. We have shown that ceramide generated via de novo sphingolipid biosynthesis is required to initiate apoptosis after photodynamic therapy (PDT). The objective of this study was to define the role of ceramide synthase (CERS) in PDT-induced cell death and apoptosis using fumonisin B1 (FB), a CERS inhibitor. We used the silicon phthalocyanine Pc4 for PDT, and SCC17B cells, as a clinically-relevant model of human head and neck squamous carcinoma. zVAD-fmk, a pan-caspase inhibitor, as well as FB, protected cells from death after PDT. In contrast, ABT199, an inhibitor of the anti-apoptotic protein Bcl2, enhanced cell killing after PDT. PDT-induced accumulation of ceramide in the endoplasmic reticulum and mitochondria was inhibited by FB. PDT-induced Bax translocation to the mitochondria and cytochrome c release were also inhibited by FB. These novel data suggest that PDT-induced cell death via apoptosis is CERS/ceramide-dependent.


Prior access to a sweet is more protective against cocaine self-administration in female rats than in male rats.
It is well established that female rats are more sensitive than male rats to the reinforcing effects of cocaine (Lynch, 2008 [42] for review). We hypothesized that greater preference for cocaine would support greater avoidance of a cocaine-paired taste cue in female vs. male rats. Moreover, at least in male rats, greater avoidance of the taste cue is associated with greater cocaine self-administration (Grigson and Twining, 2002 [3]). Thus, we anticipated that female rats would not only demonstrate greater avoidance of the drug-paired taste cue, but greater drug-taking as well. We tested these hypotheses by examining avoidance of a saccharin cue in male and female rats following several pairings with self-administered saline or cocaine (0.16, 0.33, or 0.66 mg/infusion). Contrary to expectations, the results showed that female rats exhibited less avoidance of the cocaine-associated saccharin cue than male rats and self-administered less, rather than more, cocaine, Thus, while female rats reportedly take more drug than male rats when the drug is presented in the absence of an alternative reward, they take less drug than male rats when the opportunity to self-administer cocaine is preceded by access to a palatable sweet. Females, then, may not simply be more sensitive to the rewarding properties of drug, but also to the reinforcing properties of natural rewards and this increase in sensitivity to sweets may serve to protect against drug-taking behavior.


An improved vaseline gap voltage clamp for skeletal muscle fibers.
A Vaseline gap potentiometric recording and voltage clamp method is developed for frog skeletal muscle fibers. The method is based on the Frankenhaeuser-Dodge voltage clamp for myelinated nerve with modifications to improve the frequency response, to compensate for external series resistance, and to compensate for the complex impedance of the current-passing pathway. Fragments of single muscle fibers are plucked from the semitendinosus muscle and mounted while depolarized by a solution like CsF. After Vaseline seals are formed between fluid pools, the fiber ends are cut once again, the central region is rinsed with Ringer solution, and the feedback amplifiers are turned on. Errors in the potential and current records are assessed by direct measurements with microelectrodes. The passive properties of the preparation are simulated by the "disk" equivalent circuit for the transverse tubular system and the derived parameters are similar to previous measurements with microelectrodes. Action potentials at 5 degrees C are long because of the absence of delayed rectification. Their shape is approximately simulated by solving the disk model with sodium permeability in the surface and tubular membranes. Voltage clamp currents consist primarily of capacity currents and sodium currents. The peak inward sodium current density at 5 degrees C is 3.7 mA/cm2. At 5 degrees C the sodium currents are smoothly graded with increasing depolarization and free of notches suggesting good control of the surface membrane. At higher temperatures a small, late extra inward current appears for small depolarizations that has the properties expected for excitation in the transverse tubular system. Comparison of recorded currents with simulations shows that while the transverse tubular system has regenerative sodium currents, they are too small to make important errors in the total current recorded at the surface under voltage clamp at low temperature. The tubules are definitely not under voltage clamp control.


The psychoanalytic impasse.
In the study of impediments to the success of psychoanalysis as a treatment method, the character structure of the analysand has received the most attention. Psychoanalysis has come to be used for the treatment of an ever-widening range of psychopathological states, and the analysts have become confronted with a greater incidence and variety of clinical situations which can develop into therapeutic obstacles. Whether the psychoanalytic impasse will become a therapeutic stepping-stone or an obstacle to treatment often depends upon the emotional response of the therapist and his resultant behavior. Accordingly, there has been a heightened interest in the study of countertransference. Some therapists equate the psychoanalytic treatment of patients with severe character deformations with "wild" analysis and therefore feel needless guilt and anxiety when they attemtp to treat patients who suffer from them; thus they increase the likelihood of their becoming therapeutic obstacles. We have considered the psychoanalytic impasse as an inevitable aspect of the analytic sequence and discussed countertransference reactions in this context. Technical complications resulting from adverse countertransference reactions are examined both in terms of the patient's provocations and responses in the analyst. Among the analyst's responses, three were emphasized: (1) helpless fellings which represent the patient's helplessness and vulnerability; (2) rage reactions; and (3) profound anxiety reactions. The patient's need to construct and environment similar to the early traumatic environment within the analysis can become a very difficult situation for a therapist. The resolution or at least understanding of these interactions becomes equivalent to the lifting of infantile amnesia, a step which has been considered the essence of psychoanalytic resolution. Thus, adverse reactions can become keys to the gaining of fundamental insights, permitting the analytic process to continue its inevitable course.


Heterocyclic boronic acids display sialic acid selective binding in a hypoxic tumor relevant acidic environment.
Boronic acids are well known for their ability to reversibly interact with the diol groups found in sugars and glycoproteins. However, they are generally indiscriminate in their binding. Herein we describe the discovery of a group of heterocyclic boronic acids demonstrating unusually high affinity and selectivity for sialic acids (SAs or N-acetylneuraminic acid), which are sugar residues that are intimately linked with tumor growth and cancer progression. Remarkably, these interactions strengthen under the weakly acidic pH conditions associated with a hypoxic tumoral microenvironment. In vitro competitive binding assays uncovered a significantly higher ability of 5-boronopicolinic acid, one of the derivatives identified in this work as a strong SA-binder, to interact with cell surface SA in comparison to a gold-standard structure, 3-propionamidophenylboronic acid, which has proven to be an efficient SA-binder in numerous reports. This structure also proved to be suitable for further chemical conjugation with a well-preserved SA-binding capability. These findings suggest an attractive alternative to other ongoing boronic acid based chemistry techniques aiming to achieve tumor-specific chemotherapies and diagnoses.


Quality-of-life and mortality in hemodialysis patients: roles of race and nutritional status.
Maintenance hemodialysis (MHD) patients often have protein-energy wasting, poor health-related quality of life (QoL), and high premature death rates, whereas African-American MHD patients have greater survival than non-African-American patients. We hypothesized that poor QoL scores and their nutritional correlates have a bearing on racial survival disparities of MHD patients. We examined associations between baseline self-administered SF36 questionnaire-derived QoL scores with nutritional markers by multivariate linear regression and with survival by Cox models and cubic splines in the 6-year cohort of 705 MHD patients, including 223 African Americans. Worse SF36 mental and physical health scores were associated with lower serum albumin and creatinine levels but higher total body fat percentage. Spline analyses confirmed mortality predictability of worse QoL, with an almost strictly linear association for mental health score in African Americans, although the race-QoL interaction was not statistically significant. In fully adjusted analyses, the mental health score showed a more robust and linear association with mortality than the physical health score in all MHD patients and both races: death hazard ratios for (95% confidence interval) each 10 unit lower mental health score were 1.12 (1.05-1.19) and 1.10 (1.03-1.18) for all and African American patients, respectively. MHD patients with higher percentage body fat or lower serum albumin or creatinine concentration perceive a poorer QoL. Poor mental health in all and poor physical health in non-African American patients correlate with mortality. Improving QoL by interventions that can improve the nutritional status without increasing body fat warrants clinical trials.


Rapid decline in FEV1 in grain handlers. Relation to level of dust exposure.
We have prospectively studied the respiratory health of a cohort of grain elevator workers in the Canadian west coast terminal elevators, beginning in 1975 and following them for 6 yr. We have used a "nested" case-control model to identify determinants of the worst trend in FEV1 over this period. The 10% of participants in this category had a mean decline of greater than 100 ml/yr. They were significantly more likely to have had a decline in FEV1 over a work week and to have nonspecific bronchial hyperreactivity. There was a significant relationship between the odds ratio of being a case and the mean level of dust exposure associated with the job and location at the work site; cases were associated with mean total dust levels greater than 5 mg/m3. We found no relationship between the odds ratio of being a case and a number of host factors, such as immediate skin reactivity to common allergens, history of asthma, bronchitis, or hay fever, or presence of respiratory symptoms. We conclude that exposure to grain dust at levels greater than 5 mg/m3 is associated with a serious adverse trend in FEV1.


CD4+CD25+ T cells in skin lesions of patients with cutaneous leishmaniasis exhibit phenotypic and functional characteristics of natural regulatory T cells.
Endogenous regulatory T (Treg) cells are involved in the control of infections, including Leishmania infection in mice. Leishmania viannia braziliensis is the main etiologic agent of cutaneous leishmaniasis (CL) in Brazil, and it is also responsible for the more severe mucocutaneous form. Here, we investigated the possible involvement of Treg cells in the control of the immune response in human skin lesions caused by L. viannia braziliensis infection. We show that functional Treg cells can be found in skin lesions of patients with CL. These cells express phenotypic markers of Treg cells--such as CD25, cytotoxic T lymphocyte-associated antigen 4, Foxp3, and glucocorticoid-induced tumor necrosis factor receptor--and are able to produce large amounts of interleukin-10 and transforming growth factor- beta . Furthermore, CD4+CD25+ T cells derived from the skin lesions of 4 of 6 patients with CL significantly suppressed in vitro the phytohemagglutinin-induced proliferative T cell responses of allogeneic peripheral-blood mononuclear cells (PBMCs) from healthy control subjects at a ratio of 1 Treg cell to 10 allogeneic PBMCs. These findings suggest that functional Treg cells accumulate at sites of Leishmania infection in humans and possibly contribute to the local control of effector T cell functions.


[Nurses' image perceived by academic and vocational high school teachers in Korea].
The purpose of this study was to identify nurses' image and its related factors to make nurses' image among academic and vocational high school teachers in Korea. Study samples were composed of 470 teachers who were from 12 high schools in G and J city located in southwestern part of Korea. Data were collected from August 26 to October 4, 2002. The internal consistency of the total scale was Cronbach's a =.940. In order to make nurses' image, 76.4% of respondents were influenced by the experience of their hospitalization in visiting hospitals. The mean score of nurses' image in general was 3.19+/-0.55; in four subcategories, 3.46+/-0.60 for professional image, 3.28+/-0.69 for traditional image, 2.93+/-0.70 for social image, and 2.91+/-0.64 for vision of nursing career. The mean score of nurses' image in general was more positive significantly in the 50's age group (F=6.43, p=.002) and in male groups (t=2.92, p=.002). On the basis of these findings, nursing professionals need to improve their working conditions, aspiration in job, and autonomy of nurses in their practice fields, monitor the mass media and other publishing materials continuously, and share the appropriate information on nursing profession to the school teachers and the public.


Efficient geometric integrators for nonadiabatic quantum dynamics. II. The diabatic representation.
Exact nonadiabatic quantum evolution preserves many geometric properties of the molecular Hilbert space. In the first paper of this series ["Paper I," S. Choi and J. Vaníček, J. Chem. Phys. 150, 204112 (2019)], we presented numerical integrators of arbitrary-order of accuracy that preserve these geometric properties exactly even in the adiabatic representation, in which the molecular Hamiltonian is not separable into kinetic and potential terms. Here, we focus on the separable Hamiltonian in diabatic representation, where the split-operator algorithm provides a popular alternative because it is explicit and easy to implement, while preserving most geometric invariants. Whereas the standard version has only second-order accuracy, we implemented, in an automated fashion, its recursive symmetric compositions, using the same schemes as in Paper I, and obtained integrators of arbitrary even order that still preserve the geometric properties exactly. Because the automatically generated splitting coefficients are redundant, we reduce the computational cost by pruning these coefficients and lower memory requirements by identifying unique coefficients. The order of convergence and preservation of geometric properties are justified analytically and confirmed numerically on a one-dimensional two-surface model of NaI and a three-dimensional three-surface model of pyrazine. As for efficiency, we find that to reach a convergence error of 10-10, a 600-fold speedup in the case of NaI and a 900-fold speedup in the case of pyrazine are obtained with the higher-order compositions instead of the second-order split-operator algorithm. The pyrazine results suggest that the efficiency gain survives in higher dimensions.


Evaluation of the combined application of ethanol-fixed and formaldehyde-fixed neutrophil substrates for identifying atypical perinuclear antineutrophil cytoplasmic antibodies in inflammatory bowel disease.
No clear guidelines for indirect immunofluorescence (IIF) detection and interpretation of antineutrophil cytoplasmic antibodies (ANCA) have been proposed for inflammatory bowel diseases (IBD). We evaluated the reliability of the combined use of ethanol- and formalin-fixed neutrophil substrates to identify atypical perinuclear ANCA (P-ANCA) by IIF under routine laboratory circumstances. A total of 204 IBD patients were assessed with four different fluorescent substrates in two distinct laboratories. Antibodies against myeloperoxidase, proteinase-3, and other specific granule proteins (elastase, lactoferrin, cathepsin G, lysozyme, and bactericidal permeability-increasing protein) were measured by an enzyme-linked immunosorbent assay. The combined application of ethanol- and formalin-fixed slides to detect atypical P-ANCA resulted in a lack of agreement between assays (kappa, < or =0.39) in the interassay study and moderate agreement in the interobserver study (kappa, 0.42). After atypical and typical P-ANCA patterns were combined, the consensus improved greatly. A total of 26.9% of patients were P-ANCA positive by at least two tests (44.3% of ulcerative colitis [UC] and 13.1% of Crohn's disease [CD] patients; P < 0.0001), while overall ANCA positivity was 22.5% to 34.8%. The combined application of ethanol-fixed and formaldehyde-fixed neutrophil substrates did not facilitate differentiation between P-ANCA and atypical P-ANCA, and the results were not consistent when substrates from different sources were used. Combining all P-ANCA ensures the highest sensitivity and specificity in differentiating UC from CD.


Sunscreen creams containing naringenin nanoparticles: Formulation development and in vitro and in vivo evaluations.
The aim of this study was to develop sunscreen creams containing polymeric nanoparticles (NPs) of naringenin for photoprotective and antioxidant effects. Polymeric NPs of naringenin were prepared and optimized. The NPs were incorporated into sunscreen creams and evaluated for in vitro and in vivo skin retention. The optimized naringenin NPs showed a size of 131.2 nm, zeta potential -25.4 mV, and entrapment efficiency 32.45%. The absence of drug-excipient interaction was confirmed by Fourier transform infrared spectroscopy and differential scanning calorimetry. X-Ray diffraction analysis demonstrated the amorphization of naringenin in nanoparticles. Transmission electron microscopy showed the sphericity of the NPs with the size of <200 nm. Cytotoxicity assessment in HaCaT cells indicated non-toxic nature of naringenin NPs. In vitro skin permeation studies demonstrated that higher amount of naringenin permeated at the end of 12 hours (Q12 hours = 184.03 ± 3.37 μg/cm2 ) and deposited in the skin (10.38 ± 0.48 μg/cm2 ) from NPs as compared to plain naringenin. Sunscreen creams (SC1-SC5) containing plain naringenin or NPs with/without nano-zinc oxide and nano-titanium dioxide were prepared and evaluated. Optimized cream (SC5) containing naringenin NPs showed highest SPF value and enhanced skin retention of naringenin in comparison with NPs in suspension form and other cream formulations. Optimized nanoparticulate sunscreen cream exhibited highest skin retention and negligible skin permeation of naringenin besides showing excellent SPF value.


Brigatinib: Novel ALK Inhibitor for Non-Small-Cell Lung Cancer.
We review here the pharmacology, pharmacokinetics, efficacy, safety, dosage and administration, potential drug-drug interactions and place in therapy of brigatinib for abnormal anaplastic lymphoma kinase (ALK) specific non-small-cell lung cancer (NSCLC). A literature search using PubMed was conducted using the terms brigatinib and ALK positive NSCLC from January 2013 to November 2018. All English-language articles evaluating brigatinib were analyzed for this review. Brigatinib was granted approval for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or are intolerant to crizotinib. It is administered at a dose of 90 mg orally once daily for the first 7 days then, if tolerated, increased to a dose of 180 mg orally once daily. Common adverse effects include nausea, fatigue, diarrhea, increased creatine phosphokinase levels, headache, dyspnea, and hypertension. Serious treatment-emergent adverse effects were pulmonary related. Relevance to Patient Care and Clinical Practice: This article discusses the clinical trials that led to the accelerated approval of brigatinib for its ability to overcome crizotinib-resistant mutations and for its increased central nervous system penetration properties. Brigatinib was granted accelerated approval for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or are intolerant to crizotinib. In a subset of NSCLC patients, brigatinib increases survival for approximately 1 year; however, side effects were detected.


Long-Term Quality of Life Outcomes Following Nissen Versus Toupet Fundoplication in Patients with Gastroesophageal Reflux Disease.
Laparoscopic fundoplication is the gold standard treatment for gastroesophageal reflux disease (GERD) refractory to medical management. Although many studies have compared Nissen fundoplication (NF) to Toupet fundoplication (TF), it is unclear which operation provides the best long-term reflux control. The objective of this study was to evaluate long-term quality-of-life (QoL) outcomes after NF versus TF. Clinical data from our single academic institutional foregut database were used to identify patients who underwent NF or TF (June 2010 to May 2016). Postoperative QoL was assessed through telephone at 1, 3, or 5 years postsurgery, using GERD-health related quality of life (GERD-HRQL), Gastroparesis Cardinal Symptom Index (GCSI), and Eckardt Dysphagia scores. Proton pump inhibitor (PPI) use and satisfaction with surgery were also obtained. Trends in outcomes over time were analyzed by logistic regression or Cochran-Armitage trend test. Our cohort included 155 TF and 161 NF patients. TF patients reported baseline dysphagia at higher rates (42.6% versus 19.9%; P < .001) and had worse preoperative esophageal dysmotility than NF patients. There were no significant differences in GERD-HRQL or GCSI scores between TF and NF patients at any time point postoperatively. Long-term satisfaction was equivalent between TF and NF patients 5 years postoperatively (70.0% versus 77.4%; P = .67). NF patients had higher Eckardt dysphagia scores 1 year after surgery compared to TF patients, but this difference was not present at 3 or 5 years postoperatively. Over time, PPI use increased and there was a trend toward increased GERD-HRQL scores in the TF group. Both TF and NF provide excellent long-term satisfaction for patients with GERD. NF and TF patients reported similar postoperative QoL scores. Our finding of increasing PPI use and a trend toward worsening GERD scores following TF warrants additional investigation regarding the long-term durability of TF.


[The use of xymedon for wound healing stimulation and prevention of suppuration of surgical wounds].
Xymedon, a new preparation of the pyrimidine series, was studied in experiment and in the clinic. Experiments showed that on the 5th postoperative day the tensile strength of the scar was greater by 57% and the elasticity strength was greater by 21.5% in animals given Xymedon that in the control animals; the tensile strength was 42.4% greater than in animals given methyluracil. Oral administration of Xymedon in the postoperative period in 92 patients with various forms of acute appendicitis allowed earlier removal of the sutures and reduction of the number of wound complications from 13.8 to 3.3%, as a result of which the patients were discharged from the clinic within a shorter period. The authors recommend Xymedon as a stimulator of reparative processes in the wound and for the prevention of postoperative wound suppuration in emergency abdominal surgery.


Toll-like receptors at the maternal-fetal interface in normal pregnancy and pregnancy complications.
Toll-like receptors (TLRs) form the major family of pattern recognition receptors (PRRs) that are involved in innate immunity. Innate immune responses against microorganisms at the maternal-fetal interface may have a significant impact on the success of pregnancy, as intrauterine infections have been shown to be strongly associated with certain complications of pregnancy. At the maternal-fetal interface, TLRs are expressed not only in the immune cells but also in non-immune cells such as trophoblasts and decidual cells; moreover, their expression patterns vary according to the stage of pregnancy. Here, we will update potential functions of TLRs in these cells, their recognition and response to microorganisms, and their involvement in the innate immunity. The impact of TLR-mediated innate immune response will be discussed via animal model studies, as well as clinical observations.


Xanthohumol inhibits growth and vascularization of developing endometriotic lesions.
Xanthohumol is a prenylated flavonoid isolated from hops, which is known to act as a pleiotropic cancer chemopreventive agent owing to its anti-proliferative, anti-inflammatory and anti-angiogenic properties. In the present study, we analyzed, for the first time, whether this dietary compound may also be used for the treatment of endometriosis. Peritoneal and mesenteric endometriotic lesions were surgically induced in BALB/c mice by uterine tissue transplantation into the abdominal cavity. The animals were treated daily with 100 µM xanthohumol (n= 8) or vehicle (control, n= 8) via the drinking water, starting 3 days before tissue transplantations. Lesion growth, cyst formation and vascularization were subsequently analyzed by means of high-resolution ultrasound imaging (at Day 0 and then once per week for 28 days), caliper measurements, western blotting, histology and immunohistochemistry over 4 weeks. In the treatment and control groups, uterine grafts developed typical endometriotic lesions with cyst-like dilated glands surrounded by a vascularized endometrial stroma. However, xanthohumol efficiently decreased the size of these lesions at Day 28, independent of their localization within the peritoneal cavity, compared with control (peritoneal: P =0.041; mesenteric: P =0.038). This was associated with a reduced level of phosphoinositide 3-kinase protein. Moreover, vascularization of xanthohumol-treated lesions was suppressed, as indicated by a significantly lower microvessel density at Day 28 when compared with vehicle-treated controls (peritoneal: P =0.026; mesenteric: P =0.004). Additional analyses revealed that treatment with xanthohumol did not affect the histomorphology, proliferation and vascularization of the uterine horns and ovaries. Taken together, these experimental findings suggest that xanthohumol inhibits the development of endometriotic lesions in mice without inducing serious side effects in the reproductive organs. Thus, xanthohumol represents a promising dietary phytochemical that, after further testing, may be considered for the use in the selective treatment of endometriotic lesions.


Altered innate defenses in the neonatal gastrointestinal tract in response to colonization by neuropathogenic Escherichia coli.
Two-day-old (P2), but not 9-day-old (P9), rat pups are susceptible to systemic infection following gastrointestinal colonization by Escherichia coli K1. Age dependency reflects the capacity of colonizing K1 to translocate from gastrointestinal (GI) tract to blood. A complex GI microbiota developed by P2, showed little variation over P2 to P9, and did not prevent stable K1 colonization. Substantial developmental expression was observed over P2 to P9, including upregulation of genes encoding components of the small intestinal (α-defensins Defa24 and Defa-rs1) and colonic (trefoil factor Tff2) mucus barrier. K1 colonization modulated expression of these peptides: developmental expression of Tff2 was dysregulated in P2 tissues and was accompanied by a decrease in mucin Muc2. Conversely, α-defensin genes were upregulated in P9 tissues. We propose that incomplete development of the mucus barrier during early neonatal life and the capacity of colonizing K1 to interfere with mucus barrier maturation provide opportunities for neuropathogen translocation into the bloodstream.


The inhibitory effect of nebulized albuterol on the early and late asthmatic reactions and increase in airway responsiveness provoked by inhaled allergen in asthma.
It is widely held that inhaled beta 2-adrenoceptor agonists inhibit the early asthmatic response (EAR) but not the late response (LAR) or attendant increase in bronchial responsiveness. In this study of 10 atopic asthmatic subjects, we have investigated the effects of a high dose of nebulized albuterol (2.5 mg) on the allergen-provoked EAR, LAR, and increase in histamine responsiveness. In a randomized blinded fashion, study subjects inhaled the following combinations: albuterol followed 10 min later by allergen, placebo followed by allergen, albuterol followed by saline (albuterol, placebo, and control study periods, respectively). Airway caliber was measured as FEV1 and followed at regular intervals for 7.5 h postallergen. Bronchial responsiveness to histamine was measured and recorded as the PC20 value before and at 1.5, 3.5, 5.5, and 7.5 h after allergen or control challenge. During the placebo study period, allergen challenge caused mean 29.6 +/- 6.4 and 24.4 +/- 6.4% falls in FEV1 at 20 min and 7.5 h, respectively (both p less than 0.05), and a progressive decrease in PC20 amounting to a geometric mean of 1.9 doubling dilutions at 7.5 h (p less than 0.05). Albuterol followed by allergen resulted in a 13.1 +/- 2.2% increase in FEV1 prior to allergen followed by abolition of the EAR and inhibition of the LAR with only a 9.2 +/- 3.5% fall in FEV1 at 7.5 h, significantly different from that of placebo at 7.5 h (p = 0.048). Similarly, PC20 histamine fell by only 0.64 doubling dilutions at 7.5 h, not significantly different from baseline values but different from placebo values (p = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)