Isolation, purification, and characterization of a collagen-associated serpin, caspin, produced by murine colon adenocarcinoma cells.
A 45-kDa serpin secreted by a murine colon adenocarcinoma cell line, colon26, was isolated, purified, and characterized. It was found to bind specifically to type I collagen with high affinity and to type III collagen with lower affinity. Immunohistochemical studies of murine embryonic tissues showed a specific distribution of this collagen-associated serpin, named caspin, in relation to the formation of bone, cartilage, teeth, and basement membrane. The expression of caspin in high and low lung metastatic subclones of colon26 cell lines was inversely correlated with their metastatic capacity: low lung metastatic cells secreted higher amounts of caspin than their high lung metastatic counterparts. Caspin also demonstrated high homology with human pigment epithelium-derived factor/early population doubling level cDNA-1, which reportedly induces neuronal differentiation of human retinoblastoma cells and is expressed in association with G0 growth arrest. These findings suggest that caspin/pigment epithelium-derived factor/early population doubling level cDNA-1 is a novel factor that might play a crucial role in embryogenesis and tumor metastasis through binding to the extracellular matrix.


B(1)(+)/actual flip angle and reception sensitivity mapping methods: simulation and comparison.
Knowledge of the spatial distribution of transmission field B(1)(+) and reception sensitivity maps is important in high-field (≥3 T) human magnetic resonance (MR) imaging for several reasons: these include post-acquisition correction of intensity inhomogeneities, which may affect the quality of images; modeling and design of radiofrequency (RF) coils and pulses; validating theoretical models for electromagnetic field calculations; testing the compatibility with MR environment of biomedical implants. Moreover, inhomogeneities in the RF field are an essential source of error for quantitative MR spectroscopy. Recent studies have also shown that B(1)(+) and reception sensitivity maps can be used for direct calculation of tissue electrical parameters and for estimating the local specific absorption rate (SAR) in vivo. Several B(1)(+) mapping techniques have been introduced in the past few years based on actual flip angle (FA) mapping, but, to date, none has emerged as a standard. For reception sensitivity calculation, the signal intensity equation can be used where the nominal FA distribution must be replaced with the actual FA distribution calculated by one of the B(1)(+) mapping techniques. This study introduces a quantitative comparison between two known methods for B(1)(+)/actual FA and reception sensitivity mapping: the double-angle method (DAM) and the fitting (FIT) method. Experimental data obtained using DAM and FIT methods are also compared with numerical simulation results.


Regenerable Nickel-Functionalized Activated Carbon Cathodes Enhanced by Metal Adsorption to Improve Hydrogen Production in Microbial Electrolysis Cells.
While nickel is a good alternative to platinum as a catalyst for the hydrogen evolution reaction, it is desirable to reduce the amount of nickel needed for cathodes in microbial electrolysis cells (MECs). Activated carbon (AC) was investigated as a cathode base structure for Ni as it is inexpensive and an excellent adsorbent for Ni, and it has a high specific surface area. AC nickel-functionalized electrodes (AC-Ni) were prepared by incorporating Ni salts into AC by adsorption, followed by cathode fabrication using a phase inversion process using a poly(vinylidene fluoride) (PVDF) binder. The AC-Ni cathodes had significantly higher (∼50%) hydrogen production rates than controls (plain AC) in smaller MECs (static flow conditions) over 30 days of operation, with no performance decrease over time. In larger MECs with catholyte recirculation, the AC-Ni cathode produced a slightly higher hydrogen production rate (1.1 ± 0.1 L-H2/Lreactor/day) than MECs with Ni foam (1.0 ± 0.1 L-H2/Lreactor/day). Ni dissolution tests showed that negligible amounts of Ni were lost into the electrolyte at pHs of 7 or 12, and the catalytic activity was restored by simple readsorption using a Ni salt solution when Ni was partially removed by an acid wash.


Head trauma and Parkinson's disease: results from an Italian case-control study.
We evaluated the possible association between head trauma and Parkinson's disease (PD). The FRAGAMP (Fattori di Rischio Ambientali e Genetici Associati alla Malattia di Parkinson) study is a large Italian multicenter case-control study carried out to evaluate the possible role of environmental and genetic factors in PD. Cases and controls were enrolled from six movement disorders centers located in the Central-Southern Italy. A standardized questionnaire was administered to record demographic, epidemiological, and clinical data. Positive history of head trauma was considered only if the head trauma preceded the onset of PD. All cases and controls underwent a standard neurological examination. Adjusted ORs and 95% CI were estimated using multivariate analysis (logistic regression). Four hundred ninety-two PD patients (292 men and 200 women) and 459 controls (160 men and 299 women) were enrolled in the study. A positive history for head trauma was reported by 106 (21.5%) PD patients and by 62 (13.5%) healthy controls. Multivariate analysis (OR adjusted by age, sex, family history, coffee smoking, and alcohol consumption) showed a significant positive association between PD and head trauma with an adjusted OR of 1.50 (95%CI 1.04-2.17; p value 0.03). In agreement with literature data, our study supports the positive association between head trauma and PD.


Fine structure, physiology and biochemistry of arthrospore germination in Streptomyces antibioticus.
During germination, Streptomyces antibioticus arthrospores passed through stages: darkening, swelling and germ tube emergence. The first stage, darkening, whose main features were a decrease in absorbance and a loss of refractility, only required exogenous divalent cations (Ca2+, Mg2+ or Fe2+) and energy that can be obtained from the spore reserves. This stage was blocked by agents that inhibit ATP formation but not by antibiotics that inhibit macromolecular synthesis. The second stage, swelling, needed an exogenous carbon source and was not blocked by mitomycin C. In this stage, the spores exhibited the highest cytochrome oxidase and catalase activities and respiratory quotient. The last stage, germ tube emergence, required additional carbon and nitrogen sources. Ammonium compounds were superior to nitrate. Dry weight remained constant during the stages of darkening and swelling, with a rapid increase from the moment of germ tube emergence. Optimum pH and temperature for germination were 8.0 and 45 degrees C, respectively. Heat treatment (55 degrees C for 10 min) had no effect on germination. The fine structure of the spore underwent important changes during germination. The wall of the swollen spore became stratified and the inner layer was continuous with the germ tube wall. Macromolecular synthesis occurred in the sequence RNA, protein and then DNA. Rifampicin, streptomycin and mitomycin C prevented synthesis when added at the start of incubation. The same effect was obtained if the addition was made during germination, except with mitomycin C which inhibited DNA, but not RNA and protein synthesis.


Observation of abruptly autofocusing waves.
We report on the experimental observation of abruptly autofocusing waves. This interesting family of wave packets has been realized by using a radially symmetric Airy intensity distribution. As demonstrated in our experiments, these waves can exhibit unusual features, such as the ability to autofocus by following a parabolic trajectory toward their focus.


The Effects of Cardiotrophin-1 on Early Synaptic Mitochondrial Dysfunction and Synaptic Pathology in APPswe/PS1dE9 Mice.
The coexistence of neuronal mitochondrial pathology and synaptic dysfunction is an early pathological feature of Alzheimer's disease (AD). Cardiotrophin-1 (CT-1) has been shown to exhibit impressive neuroprotective effects. Previous studies have shown positive effects of CT-1 on brain glucose metabolism and cognition in APPswe/PS1dE9 transgenic mice; however, little is known about the effects of CT-1 on early synaptic mitochondrial dysfunction and resultant synaptic pathology in the brain. In this study, 4-month-old transgenic mice with brain tissue-specific CT-1 expression were used alone or in combination with APPswe/PS1dE9 transgenic mice to evaluate the effect of CT-1 on synaptic mitochondrial dysfunction and resultant synaptic pathology, and cryptic memory deficits in the APPswe/PS1dE9 transgenic mice. The potential mechanism of action of CT-1 was also examined. Young CT-1×APPswe/PS1dE9 transgenic mice exhibited improvements in long-term learning and memory ability and ameliorations of synaptic mitochondrial/synaptic impairments compared to young APPswe/PS1dE9 transgenic mice. Moreover, CT-1 upregulated the expression of AMPAR and increased AMP-activated protein kinase (AMPK) activity in the hippocampus of APPswe/PS1dE9 transgenic mice. However, AMPK inhibition through shRNA knockdown of AMPKα blocked the neuroprotective effects of CT-1 on the expression of AMPAR and mitochondrial/synaptic dysfunction in Aβ-treated mouse neurons. These results suggest that CT-1 may be a potent candidate for the early prevention and treatment of AD.


Computational medicinal chemistry applications to target Asian-prevalent strain of hepatitis C virus.
Hepatitis C Virus (HCV), affecting millions of people worldwide, is the leading cause of liver disorder, cirrhosis, and hepatocellular carcinoma. HCV is genetically diverse having eight genotypes and several subtypes predominant in different regions of the globe. The HCV NS3/4A protease is a primary therapeutic target for HCV with various FDA-approved antivirals and several clinical developments. However, available protease inhibitors (PIs) have lower potency against HCV genotype 3 (GT3), prevalent in South Asia. In this study, the incumbent computational tools were utilized to understand and explore interactions of the HCV GT3 receptor with the potential inhibitors after the virtual screening of one million compounds retrieved from the ZINC database. The molecular dynamics, pharmacological studies, and experimental studies uncovered the potential PIs as ZINC000224449889, ZINC000224374291, and ZINC000224374456 and the derivative of ZINC000224374456 from the ZINC library. The study revealed that these top-hit compounds exhibited good binding and better pharmacokinetics properties that might be considered the most promising compound against HCV GT3 protease. Viability test, on primary healthy Human Gingival Fibroblasts (HGFs) and cancerous AGS cell line, was also carried out to assess their safety profile after administration. In addition, Surface Plasmon Resonance (SPR) was also performed for the determination of affinity and kinetics of synthesized compounds with target proteins.


Integrated analyzer and classifier of glottographic signals.
Electroglottography (EGG) and photoglottography (PGG) are two plausible methods to study voice production for monitoring the patterns of laryngeal vibrations. It has been suggested that measures such as open quotient and speed quotient calculated from glottographic signals can provide useful information regarding pathological phonation. In this paper, an integrated analyzer and classifier of glottographic signals was implemented. The system makes it possible to calculate the measures from digitized EGG and PGG signals automatically in order to examine vocal fold abnormality. The system developed several techniques to extract features from glottographic signals and proposed a statistical classification method that can possibly aid the diagnosis process. To check the reliability of the system, a training set and a test set of glottographic signals from normal people and patients with recurrent/superior laryngeal paralysis were analyzed and classified by the system. The results showed that the system is a useful tool for quantitative study of phonatory pathophysiology and can be used by the examiner who is interested in the clinical examination of glottographic signals. Moreover, glottographic techniques may have some clinical applications in the quantitative documentation of phonatory function in patients with voice disorders but requires further evaluation before clinical application.


[Lipid peroxidation as an indicator of the adaptive capacity of patients with chronic bronchitis during sanatorium and health resort treatment with a change in climate and geography].
Lipid peroxidation (LPO) in the blood plasma and erythrocytes was studied in 99 inhabitants of the southern part of West Siberia suffering from chronic bronchitis, of them 64 with obstructive bronchitis. They were sent for treatment to the contrast climatic zone (Yalta, the Crimea), and LPO was examined before the trip and after return in the course of a month (three times). LPO activity at a later stage as compared to the initial one was raised in the patients with signs of disadaptation (54 patients). The time course of LPO up to the initial level was over up to the 12th day after return in the patients with moderate symptoms of disadaptation in the warm season and up to the 30th day in the cold period. LPO activity in the patients with pronounced symptoms of disadaptation was more noticeable, the time course of the indicators up to the initial level was more delayed, particularly in erythrocytes and in the cold season. Thus LPO activity in chronic bronchitis in terms of its expression and period depends on patients' adaptogenicity to contrast change of climatic geographic zones after therapy in a sanatorium.


Platelet inhibition and endothelial cell adhesion on elastin-like polypeptide surface modified materials.
Platelet adhesion and activation are important early markers of biomaterial blood compatibility, while surfaces that promote enhanced endothelial cell adhesion and eNOS expression are strategic targets for long term vascular graft applications. Materials surface modified with fluorinated surface modifiers, containing peptides inspired from elastin cross-linking domains, have been used for the cross-linking of elastin-like polypeptide 4 (ELP4) macromolecules onto polyurethane surfaces. In the present study, ELP4 modified polyurethanes were evaluated in vitro to assess platelet adhesion, microparticle formation and bulk platelet activation following blood-material interactions. Reduced platelet adhesion and bulk platelet activation were observed following contact between reconstituted human blood and the ELP4 materials, relative to the uncoated base polyurethane controls. ELP4 modified materials also promoted endothelial cell adhesion and retention over a period of one week and showed that the endothelial cells exhibited an organized actin cytoskeleton and enhanced endothelial nitric oxide synthase (eNOS) expression relative to the control surfaces. These results indicate that polyurethane elastomers modified with ELP4 covalently bound to fluorinated surface modifiers provide a promising approach for endowing synthetic elastomers with both reduced blood platelet activation properties and enhanced endothelial cell adhesion for potential use in vascular graft applications.


Anthropometric measures and risk of cancers of the upper digestive and respiratory tract.
Data from a case-control study on the upper digestive and respiratory tract cancers were analyzed to investigate the relationship with anthropometric measures. The data set included 538 oropharyngeal, 410 esophageal, and 388 laryngeal cancer cases and 2,102 controls in hospital for acute nonneoplastic diseases, unrelated to tobacco or alcohol use, recruited in the same catchment areas as the cases. Lower body weight appeared to be an indicator of oropharyngeal and esophageal cancer and, more moderately, of laryngeal cancer. The multivariate odds ratio (OR) for oropharyngeal cancer was 5.0 for subjects in the lowest compared with the highest quartile of weight. The corresponding ORs were 6.2 for esophageal and 2.2 for laryngeal cancer. When quartiles of body mass index (BMI) were considered, the ORs in the lowest quartile were 4.0 for oropharyngeal, 6.3 for esophageal, and 2.4 for laryngeal cancer. Subjects in the lowest quartile of height had ORs of 2.0 for oropharyngeal, 1.6 for esophageal, and 1.4 for laryngeal cancer. When all the upper digestive and respiratory tract neoplasms were considered together, the OR for subjects with lower BMI who were also current smokers compared with never-smokers with higher BMI was 11.4. The OR was 5.0 for those consuming six or more drinks/day and with low BMI. Although the nature of the association needs to be clarified, these data suggest that leanness may be involved in the process of upper digestive and respiratory tract carcinogenesis.


Performance and feeding behaviour of two biotypes of the black currant-lettuce aphid, Nasonovia ribisnigri, on resistant and susceptible Lactuca sativa near-isogenic lines.
The black currant-lettuce aphid, Nasonovia ribisnigri, is an important pest of cultivated lettuce, Lactuca sativa. Since 1982, the control of this aphid on lettuce is largely based on host plant resistance, conferred by the Nr gene, introgressed from Lactuca virosa. The resistance mechanism remains to be identified. N. ribisnigri populations virulent on the Nr-based resistance in lettuce have emerged in several locations in Europe since 2007. The objective of this study was to investigate the resistance mechanism mediated by the Nr gene in lettuce by detailed studies of aphid feeding behaviour and performance. Both avirulent (Nr:0) and virulent (Nr:1)biotypes of N. ribisnigri were studied on five resistant and two susceptible near isogenic lines (NILs). In addition, survival and colony development were quantified.Nr:0 aphids showed a strong decrease in sieve element ingestion and took longer to accept a sieve element on resistant NILs compared with susceptible NILs, and no aphids survived on the resistant NIL. Nr:1 aphids fed and performed equally well on the resistant and susceptible NILs. The resistance mechanism against Nr:0 aphids encoded by the Nr gene seems to be located in the phloem, although we also observed differences in feeding behaviour during the pathway phase to the phloem. Nr:1 aphids were highly virulent to the resistance conferred by the Nr gene. The consequences of the appearance of Nr:1 aphids for control of N. ribisnigri are discussed.


Trajectory of intensive treat-to-target disease modifying drug regimen in an observational study of an early rheumatoid arthritis cohort.
Studies of early rheumatoid arthritis (RA) cohorts have analysed treatment response and prognostic factors at fixed time points. However, in treat-to-target protocols, therapeutic decision-making is dynamic and responsive to disease activity over time. To determine when a minimal residual disease response target should be expected, our primary objective was to identify the time-dependent therapeutic response to combination disease modifying antirheumatic drugs (DMARDs) for 12 months. Our secondary objective determined factors affecting this response trajectory. Observational cohort. Treat-to-target early RA clinic in Australian tertiary referral hospital. We enrolled consecutive patients attending an early arthritis clinic with symptom duration less than 12 months, who were diagnosed with RA for the first time between 2004 and 2008. 101 met these eligibility criteria and data were available at baseline through 12 months. intensive DMARDs according to a treat-to-target protocol. We measured disease activity scores (DAS) at each visit, then analysed therapeutic response and associated factors in a time-dependent fashion over 12 months. The median DAS4vESR of 4.46 at baseline decreased 12 weeks later by 24%, while the proportion with DAS4v ≤ 2.6 increased (p<0.01). DAS4v continued to decrease over 52 weeks. DAS4v reduction of at least -0.45 at 4 weeks was predictive of DAS4v at 28 and 52 weeks. Female gender, current smoking, primary education and an interaction between baseline weight and C reactive protein (CRP) negatively impacted DAS4v reduction over 4 and 52 weeks. Time-varying effects of blood pressure, neutrophils, erythrocyte sedimentation rate and CRP also significantly influenced DAS4v over 52 weeks. Time-dependent data suggest that the largest reduction of DAS4v to combination DMARDs occurs in the first month of therapy, and this predicts subsequent response. Variables known to impact long-term treatment response in RA also impacted early DAS4v response to combination DMARDs.


EEG in WNV Neuroinvasive Disease.
Neuroinvasive West Nile virus (WNV) is rare, occurring in less than 1% of those infected, and may manifest as meningitis, encephalitis, and/or acute flaccid paralysis. Patients may present initially with nonspecific symptoms including fevers. Although rare, neuroinvasive WNV is associated with significant morbidity and mortality. The mainstay of treatment is supportive care. Electroencephalography (EEG) allows for identification of nonconvulsive status epilepticus and other epileptiform and nonepileptiform patterns suggestive of underlying cognitive dysfunction. Our aim was to describe specific EEG patterns observed in WNV neuroinvasive disease. A retrospective chart review was conducted. West Nile virus was confirmed with serum and/or cerebrospinal fluid markers. Patients with a history of abnormal EEG were excluded. Electroencephalography reports were classified into categories based on the presence of epileptiform activity, focal slowing, generalized periodic discharges with triphasic morphology, and frontally predominant generalized rhythmic delta activity. In our cohort of 34 patients, 60% of focal EEG abnormalities were anterior-predominant, seen as epileptiform discharges, focal slowing, or frontally predominant generalized rhythmic delta activity. Nonepileptiform EEG patterns included nonspecific slowing and generalized periodic discharges with triphasic morphology. Two patients had electrographic seizures, one arising from the frontocentral head region. EEGs are important in the evaluation of WNV infection to rule out seizures or alternative causes of encephalopathy, and because of the risk of nonconvulsive seizures or status epilepticus in encephalitis. Although an anterior predominance of EEG abnormalities was seen in our cohort, this most likely is more correlative to encephalopathy than WNV itself. Although a specific correlative EEG pattern may not accompany all cases of WNV neuroinvasive disease, WNV should be considered as a possible etiology in patients presenting with an encephalitic or meningitic syndrome in the presence of abnormal EEG findings including encephalopathic patterns, particularly those with anterior predominant EEG changes.


XPG Asp1104His, XRCC2 Rs3218536 A/G and RAD51 135G/C Gene Polymorphisms and Colorectal Cancer Risk: A Meta-Analysis
Background: DNA repair mechanisms are crucial for sustaining DNA integrity and preventing carcinogenesis. The xeroderma pigmentosum group G (XPG), X-ray repair cross complementing group 2 (XRCC2) and RAD51 are candidate genes for DNA repair pathways. Methods: We performed a meta-analysis of 26 studies that assessed the impact of XPG Asp1104His, XRCC2 rs3218536 A/G and RAD51 135G/C polymorphisms on colorectal cancer (CRC) risk. This study included 10288 CRC patients and 11885 controls, and odds ratio (OR) with its 95% confidence interval (CI) were used to calculate the strength of association. Results: The results of overall meta-analysis suggested an association between the XPG Asp1104His polymorphism and CRC susceptibility in allele (OR=1.06; 95% CI=1.01-1.12) and heterozygote model (OR=1.16; 95%CI=1.02-1.31). In the subgroup analysis based on ethnicity and source of control, we found significantly increased CRC cancer risk in Asians (OR=1.12, 95%CI=1.04-1.21) and in hospital-based (OR=1.22, 95%CI=1.08-1.38) populations. Moreover, the RAD51 135 G/C polymorphism increased the risk of CRC in total using allele (OR=1.21) and recessive models (OR=1.62). However, XRCC2 rs3218536 A/G was not associated with the risk of CRC in total or in subgroups. Conclusions: According to the results of our meta-analysis, the XPG Asp1104His and RAD51 135 G/C polymorphisms might influence colorectal cancer risk.


[Non-specific hemosorption: current state and prospects].
Results of experimental and clinical evaluation of the method of nonspecific hemosorption obtained in the Laboratory of Clinical Immunology and Republican Centre for Application of Extracorporeal Therapies, Research Institute of Physical and Clinical Medicine, since 1985 are presented. Analysis of these and literature data on the efficiency of hemosorption in non-toxicological practice allows for the conclusion of socio-medical and economic feasibility of more extensive application of the method.


[Carotenoid retinopathy. I. Morphologic and functional findings].
Thirty patients who had undergone long-term treatment with carotenoids (max. 14 years and 336 g of carotenoids) were examined. Ophthalmoscopy revealed retinal crystals in 20 patients. The retinal crystals were usually located around the macula, forming a ring, and in one case they were even found in the macula itself. No deterioration of visual acuity or visual field defects were found, but there was a markedly dose-dependent prolongation of the duration of dark adaptation.


Development and application of an index of social function.
Brief indexes of social function were constructed in a project to develop a health index questionnaire designed to measure the social, emotional, and physical function of free-living populations. The social function items have been found to be generally applicable, capable of application by lay interviewers, and acceptable to interviewees. Initial evaluations to form composite scores for social function items have demonstrated their validity against concurrent assessments of a health professional. These social function indexes have been successfully applied in two randomized trials of innovative primary care services. The criteria for inclusion of items in the social function index questionnaire, the generation of the instrument, and the evaluation of questionnaire responses for their validity are summarized here.


Stereologic study of the hypothalamic infundibular nucleus in young and older women.
Aging in women is associated with dramatic changes in neuronal morphology and neuropeptide gene expression in the medial basal hypothalamus. There is hypertrophy of neurons expressing substance P and neurokinin B gene transcripts in the infundibular (arcuate) nucleus, accompanied by increased tachykinin gene expression. In addition, gonadotropin-releasing hormone (GnRH) gene expression is increased in a separate subpopulation of neurons within the medial basal hypothalamus. In contrast, the number of neurons expressing proopiomelanocortin (POMC) mRNA in the infundibular nucleus of older women is decreased. To determine whether neuronal degeneration contributes to these phenomena, unbiased stereologic methods were used to compare the total number of infundibular neurons between groups of young (premenopausal) and older (postmenopausal) women. There was no significant difference in the total number of infundibular neurons between young (520,000 +/- 42,000 neurons, mean +/- SEM) and older women (505,000 +/- 51,000 neurons, mean +/- SEM). The mean volume of neuronal somata, however, was increased by 40% in the older women (young, 1,860 +/- 180 microm(3) vs. older, 2,610 +/- 230 microm(3), mean +/- SEM, P < 0.05). These data demonstrate that neuronal hypertrophy in older women is not accompanied by degeneration of the infundibular nucleus. We conclude that the loss of menstrual cyclicity in middle-aged women cannot be explained by loss of neurons within the hypothalamic control center for reproduction.


[Indications of surgical treatment of spontaneous pneumothorax (analysis of 35 cases)].
The experiences in surgical treatment of 35 cases of spontaneous pneumothorax were reported. In 34 cases bullae or blebs were found during the operation. The operation is simple (inducing pleural adhesion by smearing pleura with iodine after local resection of bullae and blebs and with good results. No relapse occurred during 1-13 years followup. We suggest that operation should be considered for treating spontaneous pneumothorax in such cases including failure of medical management, relapse within a short time and more than two relapses. Most of the patients with impaired lung function and bilateral pneumothorax can be treated surgically as well.


[A case report: an EML4-ALK positive lung adenocarcinoma diagnosed with lymphoma previously].
In recent years, with the deepening of the research of molecular biology, targeted therapy has become one of the trend of lung cancer treatment. The individualized treatment of lung cancer is attached great importance at present. Echinoderm microtubule associated protein like 4 anaplastic lymphoma kinase (EML4-ALK) as a new biological marker is a hot topic in the field of lung cancer treatment. Meanwhile, with the improvement of anticancer treatment and survival, the incidence of multiple primary carcinomas (MPC) has become increasingly. But the report that malignant lymphoma complicated with lung adenocarcinoma harboring EML4-ALK fusion gene in one individual is rare. Here, we report an EML4-ALK positive non-small cell lung cancer (NSCLC) in a patient previously diagnosed with T cell lymphoma and review literature on metachronous lung cancer complicating with lymphoma.


Effects of nutrition and alcohol consumption on bone loss.
It is well established that excessive consumption of high-fat diets results in obesity. However, the consequences of obesity on skeletal development, maturation, and remodeling have been the subject of controversy. New studies suggest that the response of the growing skeleton to mechanical loading is impaired and trabecular bone mass is decreased in obesity and after high-fat feeding. At least in part, this occurs as a direct result of inhibited Wnt signaling and activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) pathways in mesenchymal stem cells by fatty acids. Similar effects on Wnt and PPAR-γ signaling occur after chronic alcohol consumption as the result of oxidative stress and result in inhibited bone formation accompanied by increased bone marrow adiposity. Alcohol-induced oxidative stress as the result of increased NADPH-oxidase activity in bone cells also results in enhanced RANKL-RANK signaling to increase osteoclastogenesis. In contrast, consumption of fruits and legumes such as blueberries and soy increase bone formation. New data suggest that Wnt and bone morphogenetic protein signaling pathways are the molecular targets for bone anabolic factors derived from the diet.


Comparative risk assessment of carcinogens in alcoholic beverages using the margin of exposure approach.
Alcoholic beverages have been classified as carcinogenic to humans. As alcoholic beverages are multicomponent mixtures containing several carcinogenic compounds, a quantitative approach is necessary to compare the risks. Fifteen known and suspected human carcinogens (acetaldehyde, acrylamide, aflatoxins, arsenic, benzene, cadmium, ethanol, ethyl carbamate, formaldehyde, furan, lead, 4-methylimidazole, N-nitrosodimethylamine, ochratoxin A and safrole) occurring in alcoholic beverages were identified based on monograph reviews by the International Agency for Research on Cancer. The margin of exposure (MOE) approach was used for comparative risk assessment. MOE compares a toxicological threshold with the exposure. MOEs above 10,000 are judged as low priority for risk management action. MOEs were calculated for different drinking scenarios (low risk and heavy drinking) and different levels of contamination for four beverage groups (beer, wine, spirits and unrecorded alcohol). The lowest MOEs were found for ethanol (3.1 for low risk and 0.8 for heavy drinking). Inorganic lead and arsenic have average MOEs between 10 and 300, followed by acetaldehyde, cadmium and ethyl carbamate between 1,000 and 10,000. All other compounds had average MOEs above 10,000 independent of beverage type. Ethanol was identified as the most important carcinogen in alcoholic beverages, with clear dose response. Some other compounds (lead, arsenic, ethyl carbamate, acetaldehyde) may pose risks below thresholds normally tolerated for food contaminants, but from a cost-effectiveness point of view, the focus should be on reducing alcohol consumption in general rather than on mitigative measures for some contaminants that contribute only to a limited extent (if at all) to the total health risk.


Glyphosate-based herbicide induces long-lasting impairment in neuronal and glial differentiation.
Glyphosate-based herbicides (GBH) are among the most sold pesticides in the world. There are several formulations based on the active ingredient glyphosate (GLY) used along with other chemicals to improve the absorption and penetration in plants. The final composition of commercial GBH may modify GLY toxicological profile, potentially enhancing its neurotoxic properties. The developing nervous system is particularly susceptible to insults occurring during the early phases of development, and exposure to chemicals in this period may lead to persistent impairments on neurogenesis and differentiation. The aim of this study was to evaluate the long-lasting effects of a sub-cytotoxic concentration, 2.5 parts per million of GBH and GLY, on the differentiation of human neuroepithelial stem cells (NES) derived from induced pluripotent stem cells (iPSC). We treated NES cells with each compound and evaluated the effects on key cellular processes, such as proliferation and differentiation in daughter cells never directly exposed to the toxicants. We found that GBH induced a more immature neuronal profile associated to increased PAX6, NESTIN and DCX expression, and a shift in the differentiation process toward glial cell fate at the expense of mature neurons, as shown by an increase in the glial markers GFAP, GLT1, GLAST and a decrease in MAP2. Such alterations were associated to dysregulation of key genes critically involved in neurogenesis, including PAX6, HES1, HES5, and DDK1. Altogether, the data indicate that subtoxic concentrations of GBH, but not of GLY, induce long-lasting impairments on the differentiation potential of NES cells.


Selectin Binding Sites Are Involved in Cell Adhesive Properties of Head and Neck Squamous Cell Carcinoma.
The formation of distant metastases often determines the fate of patients with head and neck squamous cell carcinoma (HNSCC). The expression of cell adhesion molecules (CAMs) and their ligands of the leukocyte adhesion cascade has been associated with metastatic competence in several malignant entities. In this study, human HNSCC cell lines were analyzed in vitro and in a spontaneous metastatic xenograft model. Immunohistochemical analyses of several CAMs were performed on xenograft tumors and tissue microarrays (TMA) from 453 patients with head and neck squamous cell carcinomas with full histo-pathological and clinical follow-up data. UTSCC 24A and 24B cells bind to E-selectin in vitro, show E-selectin dependent binding to human umbilical vein endothelial cells (HUVECs), and express sLeX. All HNSCC cells engrafted into severe combined immunodeficient (SCID) mice, and UTSCC 24A cells formed sporadically spontaneous lung metastases. The expression of CAMs varied between the cell lines, but a correlation between tumor growth and metastatic potential did not exist. None of the CAMS or their ligands could be identified to be of prognostic relevance in the TMA study. The in vitro results indicate that E-selectin and sLeX are involved in the adhesion of HNSCC cells to endothelium. However, specific prognostic markers chosen from the leukocyte adhesion cascade for HNSCC were not identified.


Portacaval shunt in the treatment of primary Budd-Chiari syndrome.
We have performed a side-to-side portacaval shunt as the treatment of choice in six cases of primary Budd-Chiari syndrome. All the patients (three men and three women, mean age 33 years) had marked hepatomegaly and massive ascites. Four patients had endoscopically proved esophageal varices with no episodes of bleeding. Preoperative angiographic studies, caval pressure measurement, laparoscopy, liver biopsy specimens, liver scanning, and liver function tests confirmed the diagnosis. A possible etiologic factor was evident in only two cases. A plain side-to-side portacaval shunt was performed in four patients, while two required the interposition of a graft. One patient died after surgery of hepatorenal syndrome. Four of the surviving patients are free of ascites and doing well at 29, 27, 25, and 6 months. The remaining patient subsequently developed cirrhosis and died 76 months after surgery. None of the patients who survived developed encephalopathy. Shunt patency was confirmed endoscopically by variceal decompression in the four patients with esophageal varices. We believe the side-to-side portacaval shunt is a reliable and effective procedure for the definitive management of primary budd-Chiari syndrome.


[What prosthodontic therapy should we select for periodontally compromised patients? Part 1: Review of the literature focusing on implant therapy for periodontally compromised patients].
From a large number of experimental and clinical studies, it has been suggested that dental implant therapy has good prognosis for totally and partially edentulous patients. However, it is unclear whether we can use the implants for periodontally compromised patients. The aim of the present study was is to consider scientific evidence on implant treatment for periodontitis-susceptible subjects with partially edentulous dentate. Clinical studies that documented survival rates or success rates of implant therapy for periodontally compromised patients were selected and reviewed. Most of the 22 reports that were reviewed suggested good survival or success rate of implant therapy in short-term or medium-term clinical results. Although there were only a few long-term follow up studies, it was indicated that individuals who had susceptibility to periodontal disease can be treated successfully with the implants. In all reports, treatment for infection was done before implants installation, and the importance of regular maintenance after the installation has been emphasized. From this literature review, it was advocated that periodontally compromised patients could be treated successfully with the implants. However, implant therapy should be reconsidered if oral infection cannot be satisfactorily controlled.


Amplification-mutagenesis--how growth under selection contributes to the origin of genetic diversity and explains the phenomenon of adaptive mutation.
The behavior of a particular bacterial genetic system has been interpreted as evidence that selective stress induces general mutagenesis or even preferentially directs mutations to sites that improve growth (adaptive mutation). It has been proposed that changes in mutability are a programmed response to stress in non-growing cells. In contrast, the amplification-mutagenesis model suggests that stress has no direct effect on the mutation rate and that mutations arise in cells growing under strong selection. In this model, stress serves only as a selective pressure that favors cells with multiple copies of a growth-limiting gene. Mutations are made more probable because more target copies are added to the selection plate-more cells with more mutational targets per cell. The amplification-mutagenesis process involves standard genetic events and therefore should apply to all biological systems. Idiosyncrasies of the particular system described here accelerate this process, allowing an evolutionary series of events to be completed in only a few days.


Sweat Gland Tumors Arising on Acral Sites: A Molecular Survey.
Recurrent oncogenic drivers have been identified in a variety of sweat gland tumors. Recently, integration of human papillomavirus type 42 (HPV42) has been reported in digital papillary adenocarcinoma (DPA). The main objectives of the present study were (i) to provide an overview of the prevalence of previously identified oncogenic drivers in acral sweat gland tumors and (ii) to genetically characterize tumors in which no recurrent genetic alteration has been identified yet. Cases of acral sweat gland tumors were identified from the database of the French network CARADERM. After histologic review, the presence of previously identified genetic alterations was investigated in the entire cohort (n=79) using a combination of immunohistochemistry and targeted DNA and RNA sequencing. Tumor entities with no recurrent genetic alterations were submitted to whole-transcriptome sequencing. CRTC1::MAML2 fusion was identified in cases of hidradenoma and hidradenocarcinoma (n=9/12 and n=9/12). A p.V600E mutation of BRAF was observed in all cases of tubular adenoma (n=4). YAP1:MAML2 and YAP1::NUTM1 fusions were observed in poroid tumors (n=15/25). ETV6::NTRK3 and TRPS1::PLAG1 fusion transcripts were identified in secretory carcinoma (n=1/1) and cutaneous mixed tumors (n=3/4), respectively. The HPV42 genome was detected in most cases of DPA (n=10/11) and in 1 adnexal adenocarcinoma not otherwise specified. Finally, whole-transcriptome analysis revealed BRD3::NUTM1 or NSD3::NUTM1 fusions in 2 cases of NUT adnexal carcinoma and NCOA4::RET and CCDC6::RET fusion transcripts in 2 cystadenoma/hidrocystoma-like tumors. Our study confirms distinctive cytogenetic abnormalities in a wide number of acral adnexal neoplasms and supports the use of molecular analysis as a valuable aid in the diagnosis of these rare and often difficult to diagnose group of neoplasms.


Higher dosage nicotine patches increase one-year smoking cessation rates: results from the European CEASE trial. Collaborative European Anti-Smoking Evaluation. European Respiratory Society.
The Collaborative European Anti-Smoking Evaluation (CEASE) was a European multicentre, randomized, double-blind placebo controlled smoking cessation study. The objectives were to determine whether higher dosage and longer duration of nicotine patch therapy would increase the success rate. Thirty-six chest clinics enrolled a total of 3,575 smokers. Subjects were allocated to one of five treatment arms: placebo and either standard or higher dose nicotine patches (15 mg and 25 mg daily) each given for 8 or 22 weeks with adjunctive moderately intensive support. The 12 month sustained success rates were: 25 mg patch for 22 weeks (L-25), 15.4%; 25 mg patch for 8 weeks (S-25), 15.9%; 15 mg patch for 22 weeks (L-15), 13.7%; 15 mg patch for 8 weeks (S-15), 11.7%; and placebo (P-0) 9.9% (placebo versus 15 mg, p<0.05; 25 mg versus 15 mg, p<0.03; 25 mg versus placebo, p<0.001, Chi-squared test). There was no significant difference in success rate between the two active treatment durations. Of the first week abstainers (n=1,698), 25.1% achieved success at 12 months as opposed to first week smokers, 2.7% of 1,877 subjects (p< 0.001). In summary, a higher than standard dose of nicotine patch was associated with an increase in the long-term success in smoking cessation but continuation of treatment beyond 8-12 weeks did not increase the success rates.


Conceptualizing autonomy in the context of chronic physical illness: relating philosophical theories to social scientific perspectives.
The aim of this article is to conceptualize autonomy in the context of chronic physical illness. To this end, we compare and contrast a selection of contemporary philosophical theories of autonomy with social scientific perspectives on chronic illness, particularly models of disability and symbolic interactionism. The philosophical theories mainly depart from a positive conceptualization of autonomy, which involves actively shaping one's life and identifying with fundamental values. This conceptualization is preferred over a negative conceptualization, which defines autonomy as non-interference, for its compatibility with social models of disability and with the assumption that people are interdependent. Interference may disable, but also enable people with a chronic illness to shape their lives. What matters is that people can realize what they want to realize. We suggest that, in the context of chronic physical illness, autonomy might be conceptualized as correspondence between what people want their lives to be like and what their lives are actually like. Disturbed autonomy might be restored either by expanding opportunities to arrange life or by adjusting how one wants life to be arranged. The grounds for the latter approach might be questioned, first, if people have not adjusted what they want carefully, and second, if reorganization of the material and social environment would have made it unnecessary to adjust one's arrangement of life.


Paradoxical dynamic interaction of heart period and vagal activity on atrioventricular conduction in the dog.
The dynamic interaction of simultaneously changing heart period and single vagal stimuli on atrioventricular conduction (AV interval) was quantified by subtracting the vagally induced responses of the paced heart preparation from those of the unpaced heart preparation. This difference was significantly greater (P less than 0.05) than the AV responses to changes in heart period (delta A) alone without vagal stimulation (using the identical delta AA recorded from the unpaced heart in the same preparation, but with a crushed sinoatrial node). That is, for a given increase in AA interval, the AV conduction time was considerably less when the change in AA was associated with increased vagal activity than in the absence of any vagal activity. Data from some dogs in which a complete AV block was produced for both paced and unpaced hearts suggested that one mechanism of the paradoxical response was located in AV nodal tissue. Data from other dogs, in which two surface atrial recording sites were used, indicated that shifts of pacemaker site and atrial activation patterns also are an important mechanism of the paradoxical response. The relative contribution of these two mechanisms is not fixed, but can vary considerably from animal to animal.


Increased adhesiveness of isolated monocytes to endothelium is prevented by vitamin C intake in smokers.
To explore pathophysiological mechanisms of cigarette smoking involved in atherogenesis, we compared adhesiveness of isolated blood monocytes with endothelium and plasma levels of the aqueous phase antioxidant vitamin C in nonsmokers and smokers before and after supplementation, using a novel monocyte adhesion assay with fixed human endothelial cells. Monocyte adhesion to unstimulated human umbilical vein endothelial cells ranged from 0.17% to 0.51% in the nonsmoker group (0.37+/-0.09%, mean +/-SD, n=13). In smokers with a 1 to 2 packs per day consumption, monocyte adhesion was increased to 0.71+/-0.17% (mean +/-SD, n=10, P<.001), ranging from 0.46% to 0.99%. Increased adhesiveness was mediated by the integrin CD11b/CD18, as shown by inhibition with a monoclonal antibody to CD11b but not associated with altered CD11b surface expression. Plasma vitamin C levels were reduced in smokers (48.2+/-14.1 micromol/L) versus nonsmokers (67.7+/-17.6 micromol/L; P<.025), while no significant differences were found in retinol, vitamin E, or beta-carotene levels. This confirms that the radical scavenger vitamin C reacts sensitively to oxidative stress induced by cigarette smoke in human plasma. Consistently, dietary supplementation with vitamin C (2 g per day) for 10 days raised plasma levels to 82.6+/-11.0 micromol/L (n=10, P<.001) in smokers and decreased monocyte adhesion to values found in nonsmokers (0.38+/-0.18%, P<.001). In contrast, vitamin C intake did not affect monocyte adhesiveness in nonsmokers (0.37+/-0.14%, n=6) despite increasing plasma levels to 82.9+/-11.8 micromol/L. Our data show that cigarette smoking increases CD11b-dependent monocyte adhesiveness in humans. Restoring reduced plasma vitamin C concentrations in smokers by oral supplementation decreased monocyte adhesion to values found in nonsmokers.


Cytotoxicity of Cheese and Cheddar Cheese food flavorings on Allim cepa L root meristems.
Despite their great importance for the food industry, flavorings, in general, raise a number of questions regarding their cytotoxicity, mutagenicity and carcinogenicity, since, in the literature, there are few studies found evaluating the toxicity on the systemic and cellular level, of these chemical compounds. The root meristems of Allium cepa (onion) are widely used for the assessment of toxicity of chemical compounds of interest. Thus, this study aimed to evaluate, in A. cepa meristematic cells, individually and in combination at the cellular level, the toxicity of synthetic Cheese and Cheddar Cheese food flavorings, identical to the natural, at doses of 1.0 and 2.0 mL, at exposure times of 24 and 48 hours. In combination we used 0.5 mL of Cheese flavor associated with 0.5 mL of Cheddar flavor; and 1.0 mL of Cheese flavor associated with 1.0 mL of Cheddar flavor, at exposure times of 24 and 48 hours. For these evaluations, we used groups of five onion bulbs, which were first embedded in distilled water and then transferred to their respective doses. The root tips were collected and fixed in acetic acid (3:1) for 24 hours. The slides were prepared by crushing and were stained with 2% acetic orcein. Cells were analyzed throughout the cell cycle, totaling 5,000 for each control and exposure time. The mitotic indices calculated and cellular aberrations observed were subjected to statistical analysis using the chi-square test (p <0.05). No chromosomal abnormalities nor those of mitotic spindle were observed for the treatments performed. The results, both individually and in combination, showed that the flavorings under study significantly reduced the cell division rate of the test system cells used. Therefore, under the conditions studied, the two flavorings were cytotoxic.


Community-Engaged Lifestyle Medicine as a Framework for Health Equity: Principles for Lifestyle Medicine in Low-Resource Settings.
Lifestyle risk factors, including tobacco and alcohol use, poor nutrition, and inactivity, comprise the leading actual causes of death and disproportionately affect diverse, lower-income and vulnerable populations. Fundamentally influenced by social determinants of health (including poverty, social linkages, food access, and built environment), these "unhealthy lifestyle" exposures perpetuate and sustain disparities in health outcomes, stealing years of healthy and productive life for minority, vulnerable groups. The authors call for implementation of a health equity framework within lifestyle medicine (LM). Community-engaged lifestyle medicine (CELM) is an evidence-based, participatory framework capable of addressing health disparities through LM, targeting health equity in addition to better health. CELM was developed in 2015 by the University of Texas Rio Grande Valley (UTRGV) Preventive Medicine Residency program to address lifestyle-related health disparities within marginalized border communities. The framework includes the following evidence-based principles: community engagement, cultural competency, and application of multilevel and intersectoral approaches. The rationale for each of these components and the growth of CELM within the American College of Lifestyle Medicine is described. Finally, illustrative examples are provided for how CELM can be instituted at micro and macro levels by LM practitioners.


Testosterone suppresses hepatic inflammation by the downregulation of IL-17, CXCL-9, and CXCL-10 in a mouse model of experimental acute cholangitis.
Autoimmune liver diseases predominantly affect women. In this study, we aimed to elucidate how sex affects autoimmune hepatic inflammation. Acute experimental cholangitis was induced by adoptive transfer of OVA-specific CD8(+) T cells into mice, which express the cognate Ag on cholangiocytes. In contrast to previous mouse models of cholangitis, this model displayed a strong sexual dimorphism: female mice developed marked cholangitis, whereas male mice were resistant to cholangitis induction. The recruitment of endogenous CD4(+) T cells, but not transferred CD8(+) T cells into female livers was strongly increased. These cells expressed higher amounts of the proinflammatory cytokine IL-17, which was at least in part responsible for the liver inflammation observed. The recruitment of endogenous CD4(+) T cells was associated with increased expression of the chemokines CXCL-9 and CXCL-10 in female livers. The sex-specific factor responsible for the observed differences was found to be testosterone: male mice could be rendered susceptible to liver inflammation by castration, and testosterone treatment was sufficient to completely suppress liver inflammation in female mice. Accordingly, testosterone treatment of female mice significantly reduced the expression of IL-17A, CXCL-9, and CXCL-10 within the liver. Serum testosterone levels of untreated mice negatively correlated with the IL-17, CXCL-9, and CXCL-10 expression in the liver, further supporting a role for testosterone in hepatic immune homeostasis. In conclusion, testosterone was found to be the major determinant of the observed sexual dimorphism. Further study into the role of testosterone for liver inflammation could lead to novel treatment targets in human autoimmune liver diseases.


QTc interval prolongation predicts postoperative mortality in heart failure patients undergoing surgical revascularization.
QTc interval prolongation is associated with increased mortality rates in patients with advanced heart failure. We investigated the predictive value of prolonged QTc interval in 567 patients with heart failure who were undergoing coronary artery bypass graft surgery The patients were in New York Heart Association class III or IV, with left ventricular ejection fractions of 0.40 or less. Before surgery, the QT interval duration was measured in leads II and V4 of the standard electrocardiogram and corrected by use of the Bazett formula. The QTc interval was prolonged (>440 msec) in 243 patients (43%) and normal in 324 (57%). The 2 study groups--prolonged QTc versus normal QTc--did not differ in terms of age (62 +/- 11 years vs 64 +/- 10 years, P=0.65), sex (80% male vs 76% male, P=0.31), ejection fraction (0.29 +/- 0.08 vs 0.29 +/- 0.09, P=0.72), hypertension (82% vs 78%, P=0.34), or diabetes (11% vs 7%, P=0.10). Within 1 month after coronary artery bypass grafting, 22 of 243 patients (9.1%) in the prolonged QTc group died, compared with 5 of 324 in the normal QTc group (1.5%) (P=0.0001). QTc interval prolongation was the only independent predictor of postoperative mortality on multivariate analysis (P=0.002). We conclude that patients with heart failure and preoperative QTc interval prolongation have increased mortality rates after coronary artery bypass grafting.


Appropriate NH4 +/NO3 - Ratio Triggers Plant Growth and Nutrient Uptake of Flowering Chinese Cabbage by Optimizing the pH Value of Nutrient Solution.
Compared with sole nitrogen (N), the nutrition mixture of ammonium (NH4 +) and nitrate (NO3 -) is known to better improve crop yield and quality. However, the mechanism underlying this improvement remains unclear. In the present study, we analyzed the changes in nutrient solution composition, content of different N forms in plant tissues and exudates, and expression of plasma membrane (PM) H+-ATPase genes (HAs) under different NH4 +/NO3 - ratios (0/100, 10/90, 25/75, 50/50 as control, T1, T2, and T3) in flowering Chinese cabbage. We observed that compared with the control, T1 and T2 increased the economical yield of flowering Chinese cabbage by 1.26- and 1.54-fold, respectively, whereas T3 significantly reduced plant yield. Compared with the control, T1-T3 significantly reduced the NO3 - content and increased the NH4 +, amino acid, and soluble protein contents of flowering Chinese cabbage to varying extents. T2 significantly increased the N use efficiency (NUE), whereas T3 significantly decreased it to only being 70.25% of that of the control. Owing to the difference in N absorption and utilization among seedlings, the pH value of the nutrient solution differed under different NH4 +/NO3 - ratios. At harvest, the pH value of T2 was 5.8; in the control and T1, it was approximately 8.0, and in T3 it was only 3.6. We speculated that appropriate NH4 +/NO3 - ratios may improve N absorption and assimilation and thus promote the growth of flowering Chinese cabbage, owing to the suitable pH value. On the contrary, addition of excessive NH4 + may induce rhizosphere acidification and ammonia toxicity, causing plant growth inhibition. We further analyzed the transcription of PM H+-ATPase genes (HAs). HA1 and HA7 transcription in roots was significantly down-regulated by the addition of the mixture of NH4 + and NO3 -, whereas the transcription of HA2, HA9 in roots and HA7, HA8, and HA10 in leaves was sharply up-regulated by the addition of the mixture; the transcription of HA3 was mainly enhanced by the highest ratio of NH4 +/NO3 -. Our results provide valuable information about the effects of treatments with different NH4 +/NO3 - ratios on plant growth and N uptake and utilization.


Quantification of β-aminopropionitrile, an inhibitor of lysyl oxidase activity, in plasma and tumor of mice by liquid chromatography tandem mass spectrometry.
Lysyl oxidase enzymes are reported to be involved in patho-physiological process such as tumorigenesis. β-Aminopropionitrile (BAPN) is an irreversible inhibitor of lysyl oxidase activity, suggesting a potentially useful therapeutic of interest in oncology. This paper describes the first assay concerning the quantification of BAPN by mass spectrometry. A high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) assay was developed for the quantification of BAPN in plasma and tumor of mice. This method combines dansyl chloride (Dns) derivatization and extraction using a solid-phase extraction Oasis Max column. Deuterated BAPN was used as internal standard (IS). Separation was achieved using an C₁₈ column HypersylGold, (ThermoElectron), 3.0 µm (100 × 2.1 mm i.d.). Gradient elution with water containing 0.1% acetic acid (A) and acetonitrile containing 0.1% acetic acid (B) was applied. Detection was performed with an electrospray ionization interface operating in negative ion mode. Selected reaction monitoring was used with ion transitions m/z 302 → 249 for BAPN-Dns and m/z 306 → 250 for the IS. The method was fully validated in plasma and was linear and sensitive in the range of 10-500 ng/mL. The lower limit of quantification in plasma was 2.5 ng/mL. This validated assay was successfully applied to a kinetic study of BAPN in mouse plasma and demonstrates that BAPN reaches the tumoral tissue.


Initiation of Behavioral Response to Antidepressants by Cholecystokinin Neurons of the Dentate Gyrus.
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used class of antidepressant drugs, but the cellular and molecular mechanisms by which their therapeutic action is initiated are poorly understood. Here we show that serotonin 5-HT1B receptors in cholecystokinin (CCK) inhibitory interneurons of the mammalian dentate gyrus (DG) initiate the therapeutic response to antidepressants. In these neurons, 5-HT1B receptors are expressed presynaptically, and their activation inhibits GABA release. Inhibition of GABA release from CCK neurons disinhibits parvalbumin (PV) interneurons and, as a consequence, reduces the neuronal activity of the granule cells. Finally, inhibition of CCK neurons mimics the antidepressant behavioral effects of SSRIs, suggesting that these cells may represent a novel cellular target for the development of fast-acting antidepressant drugs.


Clinical presentation of symptomatic acetabular dysplasia in skeletally mature patients.
Acetabular dysplasia is recognized as a cause of early degenerative hip osteoarthritis. The purpose of this study was to prospectively determine the early clinical presentation of symptomatic acetabular dysplasia in skeletally mature patients. Fifty-seven consecutive skeletally mature patients with a total of sixty-five symptomatic hips were diagnosed with symptomatic acetabular dysplasia on the basis of the history, physical examination, and radiographs. These fifty-seven patients were enrolled in this study and were followed prospectively for a minimum of twenty-four months postoperatively. The study group included forty-one female patients (72%) and sixteen male patients (28%) with a mean age of twenty-four years. All were treated with a periacetabular osteotomy and were followed for a minimum of twenty-four months. The initial presentation was insidious in 97% of the hips, and the majority (77%) of the hips were associated with moderate-to-severe pain on a daily basis. Pain was most commonly localized to the groin (72%) and/or the lateral aspect of the hip (66%). Activity-related hip pain was common (88%), and activity restriction frequently diminished hip pain (in 75% of the cases). On examination, thirty-one hips (48%) were associated with a limp; twenty-five (38%), with a positive Trendelenburg sign; and sixty-three (97%), with a positive impingement sign. The mean time from the onset of symptoms to the diagnosis of hip dysplasia was 61.5 months. The mean number of health-care providers seen prior to the definitive diagnosis was 3.3. The mean Harris hip score improved from 66.4 points preoperatively to 91.7 points at a mean of 29.2 months after the periacetabular osteotomy. The diagnosis of symptomatic acetabular dysplasia is commonly delayed, and procedures other than a pelvic reconstructive osteotomy are frequently recommended. The diagnosis of developmental dysplasia of the hip should be suspected and investigated when a skeletally mature, young, active patient has a predominant complaint of insidious activity-related groin pain and/or lateral hip pain. Prognostic Level IV. See Instructions to Authors for a complete description of levels of evidence.


Synthesis and characterization of various photosensitive copper(II) complexes with 5-(1-methylhydrazinyl)-1H-tetrazole as ligand and perchlorate, nitrate, dinitramide, and chloride as anions.
The preparation of 5-(1-methylhydrazinyl)-1H-tetrazole monohydrate (1⋅H2O) and various copper(II) complexes with perchlorate (2 and 3), nitrate (4, 5, and 6), dinitramide (7), and chloride (8) is described. The coordination compounds (monomers, dimers, and polymers) were characterized through infrared spectroscopy and elemental analysis. Further, the structures of 2 and 4-8 were determined by single-crystal X-ray diffraction. Compound 1 can act as a bidentate ligand in its neutral form (HMHT) and as a μ2- or μ3-bridging ligand in its deprotonated form (MHT). The energetic properties of the synthesized complexes, such as their sensitivities toward impact and friction, were determined, and laser ignition tests were performed. New information about the laser initiation process and the role of the anion in the initiation criterion was obtained. The perchlorate complexes 2 (T(decomp)=217 °C) and 3 (T(decomp)=206 °C) are potential primary explosives.


Biogenesis of mitchondria. Phospholipid synthesis in vitro by yeast mitochondrial and microsomal fractions.
The ability in vitro of yeast mitochondrial and microsomal fractions to synthesize lipid de novo was measured. The major phospholipids synthesized from sn-[2-(3)H]glycerol 3-phosphate by the two microsomal fractions were phosphatidylserine, phosphatidylinositol and phosphatidic acid. The mitochondrial fraction, which had a higher specific activity for total glycerolipid synthesis, synthesized phosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine and phosphatidic acid, together with smaller amounts of neutral lipids and diphosphatidylglycerol. Phosphatidylcholine synthesis from both S-adenosyl[Me-(14)C]methionine and CDP-[Me-(14)C]choline appeared to be localized in the microsomal fraction.


Meiotic spindle assembly in Drosophila females: behavior of nonexchange chromosomes and the effects of mutations in the nod kinesin-like protein.
Mature Drosophila oocytes are arrested in metaphase of the first meiotic division. We have examined microtubule and chromatin reorganization as the meiosis I spindle assembles on maturation using indirect immunofluorescence and laser scanning confocal microscopy. The results suggest that chromatin captures or nucleates microtubules, and that these subsequently form a highly tapered spindle in which the majority of microtubules do not terminate at the poles. Nonexchange homologs separate from each other and move toward opposite poles during spindle assembly. By the time of metaphase arrest, these chromosomes are positioned on opposite half spindles, between the metaphase plate and the spindle poles, with the large nonexchange X chromosomes always closer to the metaphase plate than the smaller nonexchange fourth chromosomes. Nonexchange homologs are therefore oriented on the spindle in the absence of a direct physical linkage, and the spindle position of these chromosomes appears to be determined by size. Loss-of-function mutations at the nod locus, which encodes a kinesin-like protein, cause meiotic loss and nondisjunction of nonexchange chromosomes, but have little or no effect on exchange chromosome segregation. In oocytes lacking functional nod protein, most of the nonexchange chromosomes are ejected from the main chromosomal mass shortly after the nuclear envelope breaks down and microtubules interact with the chromatin. In addition, the nonexchange chromosomes that are associated with spindles in nod/nod oocytes show excessive poleward migration. Based on these observations, and the structural similarity of the nod protein and kinesin, we propose that nonexchange chromosomes are maintained on the half spindle by opposing poleward and anti-poleward forces, and that the nod protein provides the anti-poleward force.


Two CheW coupling proteins are essential in a chemosensory pathway of Borrelia burgdorferi.
In the model organism Escherichia coli, the coupling protein CheW, which bridges the chemoreceptors and histidine kinase CheA, is essential for chemotaxis. Unlike the situation in E. coli, Borrelia burgdorferi, the causative agent of Lyme disease, has three cheW homologues (cheW(1) , cheW(2) and cheW(3) ). Here, a comprehensive approach is utilized to investigate the roles of the three cheWs in chemotaxis of B. burgdorferi. First, genetic studies indicated that both the cheW(1) and cheW(3) genes are essential for chemotaxis, as the mutants had altered swimming behaviours and were non-chemotactic. Second, immunofluorescence and cryo-electron tomography studies suggested that both CheW(1) and CheW(3) are involved in the assembly of chemoreceptor arrays at the cell poles. In contrast to cheW(1) and cheW(3) , cheW(2) is dispensable for chemotaxis and assembly of the chemoreceptor arrays. Finally, immunoprecipitation studies demonstrated that the three CheWs interact with different CheAs: CheW(1) and CheW(3) interact with CheA(2) whereas CheW(2) binds to CheA(1) . Collectively, our results indicate that CheW(1) and CheW(3) are incorporated into one chemosensory pathway that is essential for B. burgdorferi chemotaxis. Although many bacteria have more than one homologue of CheW, to our knowledge, this report provides the first experimental evidence that two CheW proteins coexist in one chemosensory pathway and that both are essential for chemotaxis.


Postnatal changes in sialylation of glycoproteins in rat liver.
Glycoproteins containing N-linked oligosaccharides were prepared from plasma and liver microsomes of rats aged 0-5 weeks, and galactose and sialic acid content were determined. The sialic acid/galactose ratios in plasma membrane N-glycans remained at about 1 throughout the postnatal period, suggesting that most of the galactose residues are sialylated. In the same way, it was suggested that most of the galactose residues of microsomal N-glycans were sialylated at 0, 4 and 5 weeks of age, but that the degree of sialylation was lower at the other ages, with a minimum at 2 weeks. When the activities of sialyltransferase and galactosyltransferase in liver Golgi membranes were determined, age-dependent changes were found, not only in the specific activities of the enzymes, but also in the Golgi membrane content per g of liver. The activity of galactosyltransferase per g of liver increased immediately after birth, whereas that of sialyltransferase remained at a low level for 2 weeks and then increased to a constant level at 4 weeks. It is probable that this delayed increase in the activity of sialyltransferase results in the decreased sialylation of microsomal N-glycans at 1, 2 and 3 weeks. Sialyltransferase was solubilized from the liver microsomes of rats aged 2, 3 and 4 weeks and characterized. Phosphocellulose column chromatography separated the activity into two subfractions, designated transferase I and transferase II in the order of elution. The increase in total sialyltransferase activity during this period was caused mainly by an increase in transferase I. Rechromatography of each transferase from 3-week-old rats after neuraminidase treatment showed that transferase I but not transferase II contained sialic acid residue(s) and that desialylated transferase I was eluted in a similar way as transferase II. Although the apparent Km value for CMP-N-acetylneuraminic acid and the heat stability of transferase I were different from those of transferase II, the difference was abolished by treating transferase I with neuraminidase, suggesting that transferase II may be a desialylated form of transferase I. These changes in the sialylation of membrane glycoproteins, including sialyltransferase, may be related to the control of liver growth during postnatal development.


Membrane-bound IgE receptor complexes fused with rat basophilic leukemia cells mediate degranulation.
The high affinity receptor for IgE on rat basophilic leukemia (RBL) cells mediates antigen-triggered cellular degranulation. Polyethylene glycol-induced membrane fusion methods were used to introduce exogenous IgE receptors into living RBL cells, and these were tested for normal activities. In cell-cell fusion experiments, RBL cells with fluorescein-labeled rat IgE bound to receptors and containing [5-1,2-3H(N)]hydroxytryptamine binoxalate ([3H]5HT) in their secretory granules were fused to cells with receptors occupied by rhodamine-labeled anti-dinitrophenyl mouse IgE. The fused cells showed a uniform surface distribution of both types of IgE, which could be patched independently by anti-IgE or dinitrophenylated bovine gamma globulin (DNP16BGG). [3H]5HT release could be triggered specifically by DNP16BGG. In vesicle-cell fusion experiments, plasma membrane vesicles, with receptors occupied by fluorescein- and 125I-labeled anti-DNP mouse IgE, were fused to RBL cells containing [3H]5HT. The cells showed substantial associated fluorescein fluorescence and 125I counts, and [3H]5HT release could be triggered specifically by DNP16BGG. These experiments indicate that IgE receptors can be dissociated from their natural cellular interactions and retain the ability to reassociate with another cell's components to deliver the transmembrane signal for degranulation.


Height loss predicts subsequent hip fracture in men and women of the Framingham Study.
Although height is a risk factor for osteoporotic fracture, current risk assessments do not consider height loss. Height loss may be a simple measurement that clinicians could use to predict fracture or need for further testing. The objective was to examine height loss and subsequent hip fracture, evaluating both long-term adult height loss and recent height loss. Prospective cohort of 3081 adults from the Framingham Heart Study. Height was measured biennially since 1948, and cohort followed for hip fracture through 2005. Adult height loss from middle-age years across 24 years and recent height loss in elderly years were considered. Cox proportional hazard regression was used to estimate association between height loss and risk of hip fracture. Of 1297 men and 1784 women, mean baseline age was 66 years (SD = 7.8). Average height loss for men was 1.06 inches (0.76), and for women was 1.12 inches (0.84). A total of 11% of men and 15% of women lost ≥2 inches of height. Mean follow-up was 17 years, during which 71 men and 278 women had incident hip fractures. For each 1-inch of height loss, hazard ratio (HR) = 1.4 in men [95% confidence interval (CI): 1.00, 1.99], and 1.04 in women (95% CI: 0.88, 1.23). Men and women who lost ≥2 inches of height had increased fracture risk (compared with 0 to <2 inches) of borderline significance: men HR = 1.8, 95% CI: 0.86, 3.61; women HR = 1.3, 95% CI: 0.90, 1.76. Recent height loss in elders significantly increased the risk of hip fracture, 54% in men and 21% in women (95% CI: 1.14, 2.09; 1.03, 1.42, respectively). Adult height loss predicted hip fracture risk in men in our study. Recent height loss in elderly men and women predicted risk of hip fracture.


Pattern of expression of HtrA1 during mouse development.
The human HtrA family of proteases consists of four members: HtrA1, HtrA2, HtrA3, and HtrA4. In humans the four HtrA homologues appear to be involved in several important functions such as cell growth, apoptosis, and inflammatory reactions, and they control cell fate via regulated protein metabolism. In previous studies it was shown that the expression of HtrA1 was ubiquitous in normal adult human tissues. Here we examined the expression of HtrA1 protein and its corresponding mRNA during mouse embryogenesis using Northern blotting hybridization, RT-PCR, and immunohistochemical staining analyses. Our results indicate that HtrA1 is expressed in a variety of tissues in mouse embryos. Furthermore, this expression is regulated in a spatial and temporal manner. Relatively low levels of HtrA1 mRNA are detected in embryos at the beginning of organogenesis (E8), and the levels of expression increase during late organogenesis (E14-E19). Our results show that HtrA1 was expressed during embryonic development in specific areas where signaling by TGFbeta family proteins plays important regulatory roles. The expression of HtrA1, documented both at mRNA and protein levels by RT-PCR and immunohistochemistry in the developing nervous system, is consistent with a possible role of this protein both in dividing and postmitotic neurons, possibly via its documented inhibitory effects on TGFbeta proteins. An exhaustive knowledge of the different cell- and tissue-specific patterns of expression of HtrA1 in normal mouse embryos is essential for a critical evaluation of the exact role played by this protein during development.


Post-Acute Care in China: Development, Challenges, and Path Forward.
To evaluate the evolution and challenges of China's post-acute care (PAC) system over the past 20 years and suggest actionable policy recommendations for its improvement. A retrospective review of policies and initiatives aimed at PAC system development, analyzed alongside unsolved challenges in light of global PAC practices, informed by literature reviews and collaborative discussion. PAC in China involves diverse settings such as general hospitals, inpatient rehabilitation centers, skilled nursing facilities, community health centers, and homes. The patients are mainly those discharged from acute hospitals with functional impairment and in need of continuous care. An extensive search of government policy documents, statistical sources, peer-reviewed studies, and the gray literature. The research team conducted literature reviews and discussions regularly to shape the findings. China has strengthened its PAC system through improved rehabilitation and nursing infrastructure, establishment of tiered rehabilitation networks, and adoption of innovative payment methods. However, challenges persist, including a lack of clinical consensus, resource constraints in PAC facilities and among professionals, the need for integrated care coordination, and the unification of PAC assessment tools and payment mechanisms. Although China has made substantial progress in its PAC system over 2 decades, continued efforts are needed to address its lingering challenges. Elevating awareness of PAC's significance and instituting policy adjustments targeting these challenges are essential for the system's optimization.


Intraperitoneal administration of salicylate dose-dependently prevents stress-induced ulcer formation in rats.
Stress has an important role in the induction of gastroduodenal injury. It was reported that oxygen free radicals played a role in the pathogenesis of this injury. Although some other antioxidant compounds and calcium channel blockers were examined in ulcer models, salicylate has not been tested for its gastroprotective effect in ulcer models by now. In the present study, intraperitoneal administration of 10, 25 and 50 mg/kg of salicylate dose-dependently prevented ulcer formation in obligatory immobilization model in rats. This protective effect of salicylate was found more potent than that of ranitidine for all doses tested. As expected, peroral (by gavage) administration of salicylate at 50 mg/kg exacerbated the ulcer score, in comparison with the control.


Hydrocortisone valerate. Double-blind comparison with two other topical steroids.
Hydrocortisone valerate cream (0.2 percent) was evaluated in three controlled clinical trials involving a total of sixty-eight patients with atopic dermatitis. This new nonfluorinated steroid was found to be as effective as the fluorinated beta-methasone valerate cream (0.1 percent) and significantly more effective than hydrocortisone cream (0.1 percent) and the placebo cream base. All studies were double-blind, paired comparisons, utilizing application of the medications three times a day for up to four weeks or until clearing occurred.


Chromosome 9p21 in ischemic stroke: population structure and meta-analysis.
Sequence variants on chromosome 9p21.3 are implicated in coronary artery disease and myocardial infarction, but studies in ischemic stroke have produced inconsistent results. We investigated whether these conflicting findings were due to false-positive studies confounded by population stratification or false-negative studies that failed to account for effects specific to certain stroke subtypes. After assessing for population stratification at 9p21.3 using genomewide data, we meta-analyzed 8 ischemic stroke studies. This analysis focused on 2 single nucleotide polymorphisms, rs1537378 and rs10757278, because these variants are in strong linkage disequilibrium with most single nucleotide polymorphisms analyzed in prior studies of the region. Principal component analysis of the genomewide data showed no evidence of population stratification at that locus. Meta-analysis confirmed that both rs1537378 and rs10757278 are risk factors for ischemic stroke (ORs, 1.09 [P=0.0014] and 1.11 [P=0.001], respectively). Subtype analysis revealed a substantial increase in the effect of each single nucleotide polymorphism for risk of large artery stroke, achieving an effect size similar to that seen in coronary artery disease/myocardial infarction. Variants on 9p21.3 are associated with ischemic stroke, and restriction of analysis to large artery stroke increases effect size toward that observed in prior association studies of coronary artery disease/myocardial infarction. Previous inconsistent findings are best explained by this subtype specificity rather than any unmeasured confounding by population stratification.


Surface functionalization of PLGA nanoparticles by non-covalent insertion of a homo-bifunctional spacer for active targeting in cancer therapy.
This work reports the surface functionalization of polymeric PLGA nanoparticles by non-covalent insertion of a homo-bifunctional chemical crosslinker, bis(sulfosuccinimidyl) suberate (BS3) for targeted cancer therapy. We dissolved BS3 in aqueous solution of PVA during formulation of nanoparticles by a modified solid/oil/water emulsion solvent evaporation method. The non-covalent insertion of BS3 was confirmed by Fourier transform infrared (FTIR) spectroscopy. Curcumin and annexin A2 were used as a model drug and a cell specific target, respectively. Nanoparticles were characterized for particle size, zeta potential and surface morphology. The qualitative assessment of antibody attachment was performed by transmission electron microscopy (TEM) as well as confocal microscopy. The optimized formulation showed antibody attachment of 86%. However, antibody attachment was abolished upon blocking the functional groups of BS3. The availability of functional antibodies was evaluated by the presence of a light chain fraction after gel electrophoresis. We further evaluated the in vitro release kinetics of curcumin from antibody coated and uncoated nanoparticles. The release of curcumin is enhanced upon antibody attachment and followed an anomalous release pattern. We also observed that the cellular uptake of nanoparticles was significantly higher in annexin A2 positive cells than in negative cells. Therefore, these results demonstrate the potential use of this method for functionalization as well as to deliver chemotherapeutic agents for treating cancer.


Application of forensic toxicology to the problem of domestic violence.
The role of the forensic toxicologist in helping to determine causes of death or in aiding in the resolution of "driving under the influence" or similar cases is well known and clearly understood. Less clearly defined is the position of the forensic toxicologist vis-à-vis other socially significant problems. However, as the 21st century approaches, it is worth considering how forensic toxicology can help in unraveling some of these problems. The problem of violence between intimates--that is, domestic violence--is a social problem in which it has been long felt that alcohol has played a part. Until now, though, no carefully controlled toxicological studies have been conducted to substantiate this or to determine whether other drug use is associated with domestic violence. At the San Francisco Medical Examiner's Office, toxicological data from both the victim and the suspect in 20 cases of domestic violence that ended in homicide have been gathered. It was found that alcohol or other drugs or a combination of these factors was invariably present in the suspect, the victim, or both. The implications of these results and how they can be used to develop a toxicological strategy to help reduce the most serious consequences of domestic violence are presented.


How to define an abdominal aortic aneurysm--influence on epidemiology and clinical practice.
Abdominal aortic aneurysm (AAA) is a dilatation of the abdominal aorta. There is, however, no general agreement on how to define an AAA. The lack of a uniform definition may have consequences on epidemiology and clinical practice. Several proposed definitions of an AAA exist, all based on the diameter of the abdominal aorta. Age, gender, and body size are all associated with the aortic diameter, and may therefore also be of importance when evaluating the aortic diameter. The precision of the measurement and the awareness of imaging shortcomings are also important. In order to demonstrate a true widening of the aorta the relation to adjacent aortic segments must be assessed. To demonstrate an expansion of a potential aneurysm, a follow-up period with repeated assessments is required. Thus, a fixed diameter does not serve as a proper definition of an aneurysm, but rather as a cut-off level for further assessment and/or follow-up.


Brain-computer interface robotics for hand rehabilitation after stroke: a systematic review.
Hand rehabilitation is core to helping stroke survivors regain activities of daily living. Recent studies have suggested that the use of electroencephalography-based brain-computer interfaces (BCI) can promote this process. Here, we report the first systematic examination of the literature on the use of BCI-robot systems for the rehabilitation of fine motor skills associated with hand movement and profile these systems from a technical and clinical perspective. A search for January 2010-October 2019 articles using Ovid MEDLINE, Embase, PEDro, PsycINFO, IEEE Xplore and Cochrane Library databases was performed. The selection criteria included BCI-hand robotic systems for rehabilitation at different stages of development involving tests on healthy participants or people who have had a stroke. Data fields include those related to study design, participant characteristics, technical specifications of the system, and clinical outcome measures. 30 studies were identified as eligible for qualitative review and among these, 11 studies involved testing a BCI-hand robot on chronic and subacute stroke patients. Statistically significant improvements in motor assessment scores relative to controls were observed for three BCI-hand robot interventions. The degree of robot control for the majority of studies was limited to triggering the device to perform grasping or pinching movements using motor imagery. Most employed a combination of kinaesthetic and visual response via the robotic device and display screen, respectively, to match feedback to motor imagery. 19 out of 30 studies on BCI-robotic systems for hand rehabilitation report systems at prototype or pre-clinical stages of development. We identified large heterogeneity in reporting and emphasise the need to develop a standard protocol for assessing technical and clinical outcomes so that the necessary evidence base on efficiency and efficacy can be developed.


Psoriasis: characteristics, psychosocial effects and treatment options.
Psoriasis is a complex chronic non-infectious inflammatory skin disease with a variety of different presentations. The classic presentation is of well-defined red plaques with silver scale. The characteristic scale makes the disorder highly visible and intrusive on the patient's lifestyle. The visible nature of the disease ensures that psoriasis has both physical and psychosocial effects. In normal skin, epidermal cell reproduction and proliferation takes 28 days. In psoriasis this process is considerably accelerated to approximately 4 days, resulting in the deposit of immature cells on the skin. While the exact cause of this process is unknown, certain environmental and genetic factors are known to be triggers. Disease management depends on disease severity, psychosocial effects and the patient's lifestyle. To effectively treat this disease the nurse must be skilled in psoriasis management, and in patient education and motivation. This article reviews the characteristics, aetiology, psychosocial effects and treatment strategies of psoriasis.


[Reflections on stress and burnout and their relationship with nursing].
This bibliographic review aimed to differentiate between stress and Burnout and to establish their relationship with nursing work to support the understanding of psychical suffering at work. The study was based on the analysis and interpretation of articles, thesis and dissertations produced between 1990 and 2001. Although there is a consensus among the individuals on the existence of stress and burnout, there are several controversies surrounding these terms. These theories were created in the context of capitalist production increase. Stress refers to a personal tiring that interferes in the life of the person but not necessarily in his/her relationship with the work. Burnout is a syndrome involving negative attitudes and behaviors towards users, clients, organization and work. It is a gradual process of subjective experiences that result in practical and emotional problems to workers and organizations. Nursing work facilitates stress and burnout and causes suffering and illness among workers.


Effects of the ACA on Health Care Coverage for Adults With Substance Use Disorders.
The authors assessed changes in health care coverage in nationally representative samples of low- and middle-income adults with and without substance use disorders following the 2014 Affordable Care Act marketplace launch and Medicaid expansion. Data from the 2012-2018 (N=407,985) National Survey on Drug Use and Health identified low- and middle-income nonelderly adults with alcohol, marijuana, cocaine, or heroin use disorders. A sociodemographically adjusted difference-in-differences analysis assessed the trends in Medicaid and individually purchased private insurance between adults with and without substance use disorders. Between 2012-2013 and 2015-2016, the percentages without health insurance significantly declined for adults with substance use disorders (from 27.8% to 18.7%) and for those without these disorders (from 22.6% to 14.6%). These trends were related to gains in Medicaid and in individually purchased private insurance but not to gains in employer-based private insurance coverage. Between 2015-2016 and 2017-2018, however, the percentages without health insurance among adults with substance use disorders (18.7% to 18.4%) and without these disorders (14.7% to 14.7%) was little changed. With insurance gains having stalled and the downturn of the U.S. economy, there is renewed urgency to extend health care coverage to middle- and low-income adults with substance use disorders that meets their substance use and general health needs.


Postoperative headache after surgery for vestibular schwannoma.
Postoperative headache was studied among 251 patients who underwent operation for vestibular schwannoma. A questionnaire based on the McGill Pain Questionnaire and the Finnish Pain Questionnaire was sent to the patients. Twenty-one expressions describing postoperative headache were extracted with a factor analysis. The pain intensity was expressed on a visual analog scale, and the risk factors for postoperative headache were evaluated. Immediately after the operation, 154 subjects reported headache. Eighty-nine of the patients had had headache before operation, whereas 65 patients experienced headache only after operation. An average of 8.9 years after surgery, 93 patients still reported headache. Headache was a major problem for 27 subjects; 18 of the 27 had suffered from headache before operation. A retrosigmoidal approach, postoperative gait problems, preoperative headache, and small tumor size predicted postoperative problems with headache. When headache is present before operation, it tends to continue after operation, and if headache continues for 1 year, it usually persists without being reduced.


Ocular findings in pediatric deaths under 2 years of age (1994-2004).
Our purpose is to highlight novel ocular findings of 102 forensic pediatric cases under 2 years of age who die suddenly. Forensic information, grossing, and microscopic eye protocol was followed. The most common diagnosis was Sudden Infant Death Syndrome (SIDS) (57/102). Novel cytoid bodies were present in the retina of 72/102 cases and they were located predominantly 90% (65/72) at the anterior part of the retina (p < 0.001). Of the SIDS cases, 85% (47/57) showed the presence of cytoid bodies, and among all diagnosis, SIDS was the most associated with cytoid bodies (p = 0.003). A second observation was extramedullary hematopoiesis (EMH) identified in 35/102 cases and 22 of the 57 SIDS cases. The most frequent EMH location was the choroids (29/35). This study is the first to demonstrate the presence of cytoid bodies and extramedullary hematopoiesis in the retinas of SIDS cases and children who die suddenly from other causes.


The role of thrombin in central nervous system activity and stroke.
Thrombin is a key factor of hemostasis, mediating the conversion of fibrinogen into fibrin. Along with prothrombin, of which thrombin is the active derivative, it has been found locally expressed in the central nervous system. This article aims to describe the role of thrombin in the normal functioning of the central nervous system and stroke. In this mini-review, the specialized databases Medscape, PubMed, and Web of Science, from the years 2003-2018, were used to find relevant documents by using MeSH terms: "thrombin" and "stroke". Prothrombin and thrombin influence neural development, protection and regeneration, thrombin being a relatively strong regulating factor of brain function. However, high levels of thrombin are detrimental to neuronal health, and cause atherosclerotic plaque development and instability - a leading cause of cerebral infarction. In stroke, thrombin promotes direct cellular toxicity, vascular disruption, oxidative stress and inflammatory response. There is a direct correlation between thrombin activity in the affected brain hemisphere and the infarction volume. Direct acting thrombin inhibitors, like dabigatran, significantly decrease the risk of ischemic stroke. Further studies on the correlation between thrombin levels, generation and activity and the risk and recurrence of ischemic cerebral stroke should give new insight on this association, resulting in an optimized practical therapeutic approach.


Thyroid hormone regulation of perch ovarian 3beta-hydroxysteroid dehydrogenase/delta5-delta4-isomerase activity: involvement of a 52-kDa protein.
Ovarian follicles were collected from perch belonging to the prespawning (vitellogenic) stage and incubated in vitro for 5 h in the absence (control) and presence of 3, 5, 3'-triiodothyronine (T3). Addition of increasing concentrations of T3 from 12.5 to 100 ng/ml caused a linear increase of 3beta-hydroxysteroid dehydrogenase/delta5-delta4-isomerase (3 beta-HSD) activity to 50 ng and then it leveled off indicating a saturation of enzyme activity with 50 ng T3. T3 stimulation of 3beta-HSD activity could be blocked by cycloheximide indicating the involvement of T3-induced protein (TIP) isolated and purified earlier from this laboratory. Addition of fish TIP purified from perch ovarian follicle (fTIP) or rat granulosa cell TIP to ovarian follicular incubation at a dose of 5 microg/ml significantly increased (P < 0.01) 3beta-HSD activity. To observe whether TIP acts directly on the enzyme or not, 3beta-HSD from perch ovarian follicle was purified to homogeneity by the following steps: (i) Sephadex G 75 gel filtration, (ii) DEAE-Sephacel chromatography, and (iii) NAD-affinity column chromatography. Purified 3beta-HSD gave a clear single band on an SDS gel and its molecular weight is 45 kDa. Addition of fTIP to an assay mixture containing purified 3beta-HSD resulted in a fourfold increase of the enzyme activity. fTIP alone did not show enzyme activity when incubated with the radiolabeled substrate. Addition of T3 (50 ng) to the 3beta-HSD assay mixture had no effect on the enzyme activity. Determination of Vmax and Km of the purified enzyme in the absence (control) and presence of fTIP demonstrated a considerable increase of 3beta-HSD affinity and rate of enzyme reaction.


Differential impairment of individuated finger movements in humans after damage to the motor cortex or the corticospinal tract.
The purpose of this study was to quantify the long-term loss of independent finger movements in humans with lesions relatively restricted to motor cortex or corticospinal tract. We questioned whether damage to the motor cortex or corticospinal tract would permanently affect the ability to move each finger to the same degree or would affect some fingers more than others. People with pure motor hemiparesis due to ischemic cerebrovascular accident were used as our experimental sample. Pure motor hemiparetic and control subjects were tested for their ability to make cyclic flexion/extension movements of each finger independently. We recorded their finger joint motion using an instrumented glove. The fingers of control subjects and of the unaffected hands (ipsilateral to the lesion) of hemiparetic subjects moved relatively independently. The fingers of the affected hands (contralateral to the lesion) of hemiparetic subjects were differentially impaired in their ability to make independent finger movements. The independence of the thumb was normal; the independence of the index finger was slightly impaired, while the independence of the middle, ring, and little fingers was substantially impaired. The differential long-term effects of motor cortical or corticospinal damage on finger independence may result from rehabilitative training emphasizing tasks requiring independent thumb and index movements, and from a greater ability of the spared components of the neuromuscular system to control the thumb independently compared with the other four fingers.


Fixation Strategies for Periprosthetic Fractures With Stable Implants.
The fixation of periprosthetic fractures remains challenging and controversial. It is important to achieve consensus opinions regarding the management of stable periprosthetic fractures with internal fixation. Key strategies to optimize surgical decision making and fixation and manage complications following these difficult injuries are addressed.


Effects of pantothenic acid on testicular function in male rats.
Pantothenic acid (PaA) is a water-soluble vitamin required to sustain various physiological functions in animals. The physiological roles of PaA on testicular function, in particular, testicular endocrinology and sperm mortility, were investigated in rats. Male rats at 3 weeks of age were fed a PaA-free diet or a 0.0016% PaA diet (control) for 7 weeks. Total body weight, as well as the weights of the liver, kidney, pituitary, testis, epididymis, seminal vesicle and prostate; sperm motility; and the plasma concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone and corticosterone were measured in rats at 10 weeks of age. Body weight gain decreased from 5 weeks of age in rats fed the PaA-free diet compared with the control. The relative weights of the testes were significantly higher in the PaA-deficient group compared with the control group. Several parameters of sperm motility were significantly reduced in the PaA-deficient group compared with the control group. In addition, the plasma concentrations of testosterone and corticosterone were significantly lower in the PaA-deficient group compared with the control group, whereas the plasma concentrations of FSH and LH showed no change. These results clearly demonstrate that PaA is an essential factor in testicular endocrinology and sperm motility in male rats.