Systemic injection of TNF-alpha attenuates fever due to IL-1 beta and LPS in rats.
The effect of tumor necrosis factor-alpha (TNF-alpha) on the febrile response to interleukin-1 beta (IL-1 beta) was investigated in rats. While both of these substances are capable of causing fever when injected into rats, an earlier study showed that the injection of antiserum against TNF-alpha enhanced endotoxin [lipopolysaccharide (LPS)] fever, suggesting that physiological levels of circulating TNF may act to limit the magnitude of fever. In the present study, the intraperitoneal injection of 1 microgram/kg of TNF-alpha significantly attenuated the fever due to the intraperitoneal injection of 10 micrograms/kg of IL-1 beta. Higher doses of TNF-alpha (10 and 50 micrograms/kg injected ip) slightly lowered the febrile response to this dose of IL-1 beta, but these changes were not significant. None of these doses of TNF-alpha alone significantly altered body temperature. The injection of 1 microgram/kg of TNF-alpha also significantly lowered the febrile response to the intraperitoneal injection of 10 micrograms/kg of LPS. The febrile responses to the preoptic area (POA) or intraperitoneal injection of IL-1 beta were not changed when a nonpyrogenic dose of TNF-alpha was simultaneously injected into the POA. Further studies are needed, however, before we can conclude that TNF does not act in the central nervous system to control the febrile response. These data support the hypothesis that nonpyrogenic levels of TNF act in the systemic circulation to suppress the development of fever.


microRNAs, Gap Junctional Intercellular Communication and Mesenchymal Stem Cells in Breast Cancer Metastasis.
The failed outcome of autologous bone marrow transplantation for breast cancer opens the field for investigations. This is particularly important because the bone marrow could be a major source of cancer cells during tertiary metastasis. This review discusses subsets of breast cancer cells, including those that enter the bone marrow at an early period of disease development, perhaps prior to clinical detection. This population of cells evades chemotherapeutic damage even at high doses. An understanding of this population might be crucial for the success of bone marrow transplants for metastatic breast cancer and for the eradication of cancer cells in bone marrow. In vivo and in vitro studies have demonstrated gap junctional intercellular communication (GJIC) between bone marrow stroma and breast cancer cells. This review discusses GJIC in cancer metastasis, facilitating roles of mesenchymal stem cells (MSCs). In addition, the review addresses potential roles for miRNAs, including those already linked to cancer biology. The literature on MSCs is growing and their links to metastasis are beginning to be significant leads for the development of new drug targets for breast cancer. In summary, this review discusses interactions among GJIC, miRNAs and MSCs as future consideration for the development of cancer therapies.


B-cell production and differentiation in adult rats.
The B-cell development in a group of rats was suppressed for the first 45 days of life by serial administration of rabbit anti-rat IgM and IgD antibody. Total or near total suppression of B lymphopoiesis was achieved. At 45 days, suppression was stopped by injection of IgM and IgD rat paraproteins. The sequence of B-cell and plasma cell development following suppression was assessed by immunohistological analysis of spleen lymph nodes and small intestinal lamina propria. The main findings are listed below. Complete reconstitution of B-cell numbers occurs within 8 days, at which stage germinal centres are also present. B lymphopoiesis in the red pulp of the spleen differs from that reported for bone marrow. Cells develop expressing surface sIgM and sIgM with IgA, but not sIgD. sIgD-positive cells first appear in splenic follicles 2 days after stopping suppression, but their appearance in lymph nodes is delayed until after 3 days. At this stage, sIgD-positive cells become apparent in the splenic red pulp. IgM plasma cells appear from day 4. IgA plasma cells in the gut appear in small numbers at day 6, and gradually increase to normal numbers by day 14. sIgG2c expression in the splenic marginal zone did not approach normal levels, even 2 weeks after suppression was stopped.


The Yeast Resource Center Public Data Repository.
The Yeast Resource Center Public Data Repository (YRC PDR) serves as a single point of access for the experimental data produced from many collaborations typically studying Saccharomyces cerevisiae (baker's yeast). The experimental data include large amounts of mass spectrometry results from protein co-purification experiments, yeast two-hybrid interaction experiments, fluorescence microscopy images and protein structure predictions. All of the data are accessible via searching by gene or protein name, and are available on the Web at http://www.yeastrc.org/pdr/.


Current treatment of vestibular, ocular motor disorders and nystagmus.
Vertigo and dizziness are among the most common complaints with a lifetime prevalence of about 30%. The various forms of vestibular disorders can be treated with pharmacological therapy, physical therapy, psychotherapeutic measures or, rarely, surgery. In this review, the current pharmacological treatment options for peripheral and central vestibular, cerebellar and ocular motor disorders will be described. They are as follows for peripheral vestibular disorders. In vestibular neuritis recovery of the peripheral vestibular function can be improved by treatment with oral corticosteroids. In Menière's disease a recent study showed long-term high-dose treatment with betahistine has a significant effect on the frequency of the attacks. The use of aminopyridines introduced a new therapeutic principle in the treatment of downbeat and upbeat nystagmus and episodic ataxia type 2 (EA 2). These potassium channel blockers presumably increase the activity and excitability of cerebellar Purkinje cells, thereby augmenting the inhibitory influence of these cells on vestibular and cerebellar nuclei. A few studies showed that baclofen improves periodic alternating nystagmus, and gabapentin and memantine, pendular nystagmus. However, many other eye movement disorders such as ocular flutter opsoclonus, central positioning, or see-saw nystagmus are still difficult to treat. Although progress has been made in the treatment of vestibular neuritis, downbeat and upbeat nystagmus, as well as EA 2, state-of-the-art trials must still be performed on many vestibular and ocular motor disorders, namely Menière's disease, bilateral vestibular failure, vestibular paroxysmia, vestibular migraine, and many forms of central eye movement disorders.


Production and ultrastructure of lysozyme and ethylenediaminetetraacetate-lysozyme spheroplasts of Escherichia coli.
Spheroplast production by lysozyme and ethylenediaminetetraacetate (EDTA) was examined as a means of obtaining osmotically sensitive cells for studies of enzyme localization. Physiologically young cells plasmolyzed with 0.5 m sucrose in 0.01 m tris(hydroxymethyl)aminomethane (Tris) buffer (pH 7, 8, or 9) were quantitatively converted to plasmolyzed osmotically sensitive rods after lysozyme treatment. Although such cells were osmotically sensitive, a 1:1 dilution in Tris buffer was necessary for conversion of rods into spheroplasts. Addition of EDTA resulted in a rapid conversion of the plasmolyzed spheroplasts into spherical structures devoid of a plasmolysis vacuole. These structures, which we call EDTA-lysozyme spheroplasts, contained a number of attached membranes. We believe that this conversion results from a weakening of the outer trilaminar component of the cell wall by EDTA, resulting in the collapse of the plasmolysis vacuole. Dilution of sucrose below 0.15 m also resulted in the collapse of the plasmolysis vacuole. Both the lysozyme spheroplasts and the EDTA-lysozyme spheroplasts were osmotically sensitive. Thin sections of the EDTA-lysozyme spheroplasts demonstrated that the outer trilaminar component of the cell wall was broken, exposing large areas of the cytoplasmic membrane to the environment.


Morphological features of gut ontogeny in the parasitic mite Varroa jacobsoni.
The study was focused on the morphological features of the gut through all of its developmental stages in both male and female V. jacobsoni from the drone brood. Histochemical methods were used. Along with histophysiological similarities, there are morphological differences in the gut structure in male and female. Gut development in this parasite's ontogeny is characterized by both morphological conservatism and substantial functional flexibility.


The microbiology of impetigo in indigenous children: associations between Streptococcus pyogenes, Staphylococcus aureus, scabies, and nasal carriage.
Impetigo is caused by both Streptococcus pyogenes and Staphylococcus aureus; the relative contributions of each have been reported to fluctuate with time and region. While S. aureus is reportedly on the increase in most industrialised settings, S. pyogenes is still thought to drive impetigo in endemic, tropical regions. However, few studies have utilised high quality microbiological culture methods to confirm this assumption. We report the prevalence and antimicrobial resistance of impetigo pathogens recovered in a randomised, controlled trial of impetigo treatment conducted in remote Indigenous communities of northern Australia. Each child had one or two sores, and the anterior nares, swabbed. All swabs were transported in skim milk tryptone glucose glycogen broth and frozen at -70°C, until plated on horse blood agar. S. aureus and S. pyogenes were confirmed with latex agglutination. From 508 children, we collected 872 swabs of sores and 504 swabs from the anterior nares prior to commencement of antibiotic therapy. S. pyogenes and S. aureus were identified together in 503/872 (58%) of sores; with an additional 207/872 (24%) sores having S. pyogenes and 81/872 (9%) S. aureus, in isolation. Skin sore swabs taken during episodes with a concurrent diagnosis of scabies were more likely to culture S. pyogenes (OR 2.2, 95% CI 1.1 - 4.4, p = 0.03). Eighteen percent of children had nasal carriage of skin pathogens. There was no association between the presence of S. aureus in the nose and skin. Methicillin-resistance was detected in 15% of children who cultured S. aureus from either a sore or their nose. There was no association found between the severity of impetigo and the detection of a skin pathogen. S. pyogenes remains the principal pathogen in tropical impetigo; the relatively high contribution of S. aureus as a co-pathogen has also been confirmed. Children with scabies were more likely to have S. pyogenes detected. While clearance of S. pyogenes is the key determinant of treatment efficacy, co-infection with S. aureus warrants consideration of treatment options that are effective against both pathogens where impetigo is severe and prevalent. This trial is registered; ACTRN12609000858291 .


Dietary cholesterol provided by eggs and plasma lipoproteins in healthy populations.
Extensive research has not clearly established a link between egg consumption and risk for coronary heart disease. The effects of egg intake on plasma lipids and low-density lipoprotein (LDL) atherogenicity in healthy populations need to be addressed. The lack of connection between heart disease and egg intake could partially be explained by the fact that dietary cholesterol increases the concentrations of both circulating LDL and high-density lipoprotein (HDL) cholesterol in those individuals who experience an increase in plasma cholesterol following egg consumption (hyperresponders). It is also important to note that 70% of the population experiences a mild increase or no alterations in plasma cholesterol concentrations when challenged with high amounts of dietary cholesterol (hyporesponders). Egg intake has been shown to promote the formation of large LDL, in addition to shifting individuals from the LDL pattern B to pattern A, which is less atherogenic. Eggs are also good sources of antioxidants known to protect the eye; therefore, increased plasma concentrations of lutein and zeaxanthin in individuals consuming eggs are also of interest, especially in those populations susceptible to developing macular degeneration and eye cataracts. For these reasons, dietary recommendations aimed at restricting egg consumption should not be generalized to include all individuals. We need to acknowledge that diverse healthy populations experience no risk in developing coronary heart disease by increasing their intake of cholesterol but, in contrast, they may have multiple beneficial effects by the inclusion of eggs in their regular diet.


MID1 and MID2 are required for Xenopus neural tube closure through the regulation of microtubule organization.
Closure of the neural tube requires both the change and maintenance of cell shape. The change occurs mainly through two coordinated morphogenetic events: cell elongation and apical constriction. How cytoskeletal elements, including microtubules, are regulated in this process in vivo is largely unknown. Here, we show that neural tube closure in Xenopus depends on orthologs of two proteins: MID1, which is responsible for Opitz G/BBB syndrome in humans, and its paralog MID2. Depletion of the Xenopus MIDs (xMIDs) by morpholino-mediated knockdown disrupted epithelial morphology in the neural plate, leading to neural tube defects. In the xMID-depleted neural plate, the normal epithelial organization was perturbed without affecting neural fate. Furthermore, the xMID knockdown destabilized and caused the disorganization of microtubules, which are normally apicobasally polarized, accounting for the abnormal phenotypes. We also found that the xMIDs and their interacting protein Mig12 were coordinately required for microtubule stabilization during remodeling of the neural plate. Finally, we showed that the xMIDs are required for the formation of multiple epithelial organs. We propose that similar MID-governed mechanisms underlie the normal morphogenesis of epithelial tissues and organs, including the tissues affected in patients with Opitz G/BBB syndrome.


Water quality of stormwater generated from an airport in a cold climate, function of an infiltration pond, and sampling strategy with limited resources.
Monitoring pollutants in stormwater discharge in cold climates is challenging. An environmental survey was performed by sampling the stormwater from Luleå Airport, Northern Sweden, during the period 2010-2013, when urea was used as a main component of aircraft deicing/anti-icing fluids (ADAFs). The stormwater collected from the runway was led through an oil trap to an infiltration pond to store excess water during precipitation periods and enhance infiltration and water treatment. Due to insufficient capacity, an emergency spillway was established and equipped with a flow meter and an automatic sampler. This study proposes a program for effective monitoring of pollutant discharge with a minimum number of sampling occasions when use of automatic samplers is not possible. The results showed that 90% of nitrogen discharge occurs during late autumn before the water pipes freeze and during snow melting, regardless of the precipitation during the remaining months when the pollutant discharge was negligible. The concentrations of other constituents in the discharge were generally low compared to guideline values. The best data quality was obtained using flow controlled sampling. Intensive time-controlled sampling during late autumn (few weeks) and snow melting (2 weeks) would be sufficient for necessary information. The flow meters installed at the rectangular notch appeared to be difficult to calibrate and gave contradictory results. Overall, the spillway was dry, as water infiltrated into the pond, and stagnant water close to the edge might be registered as flow. Water level monitoring revealed that the infiltration capacity gradually decreased with time.


Gene knockout of the alpha6 subunit of the gamma-aminobutyric acid type A receptor: lack of effect on responses to ethanol, pentobarbital, and general anesthetics.
The alpha6 subunit of the gamma-aminobutyric acid type A receptor (GABA(A)-R) has been implicated in mediating the intoxicating effects of ethanol and the motor ataxic effects of general anesthetics. To test this hypothesis, we used gene targeting in embryonic stem cells to create mice lacking a functional alpha6 gene. Homozygous mice are viable and fertile and have grossly normal cerebellar cytoarchitecture. Northern blot and reverse transcriptase-polymerase chain reaction analyses demonstrated that the targeting event disrupted production of functional alpha6 mRNA. Autoradiography of histological sections of adult brains demonstrated that diazepam-insensitive binding of [3H]Ro15-4513 to the cerebellar granule cell layer of wild-type mice was completely absent in homozygous mice. Cerebellar GABA(A)-R density was unchanged in the mutant mice; however, the apparent affinity for muscimol was markedly reduced. Sleep time response to injection of ethanol after pretreatment with vehicle or Ro15-4513 did not differ between genotypes. Sleep time response to injection of pentobarbital and loss of righting reflex and response to tail clamp stimulus in mice anesthetized with volatile anesthetics also did not differ between genotypes. Thus, the alpha6 subunit of the GABA(A)-R is not required for normal development, viability, and fertility and does not seem to be a critical or unique component of the neuronal pathway mediating the hypnotic effect of ethanol and its antagonism by Ro15-4513 in mice. Similarly, the alpha6 subunit does not seem to be involved in the behavioral responses to general anesthetics or pentobarbital.


Non-invasive detection of pulmonary pathogens in ventilator-circuit filters by PCR.
Ventilator associated pneumonia is a common and costly complication in critically ill and injured surgical patients. The diagnosis of pneumonia remains problematic and non-specific. Using clinical criteria, a diagnosis of pneumonia is typically not made until an infection is well established. Semi-quantitative cultures of endotracheal aspirate and broncho-alveolar lavage are employed to improve the accuracy of diagnosis but are invasive and require time for culture results to become available. We report data that show that an inexpensive, rapid and non-invasive alternative may exist. In particular we show that: 1). Bio-aerosols evolved in the breath of ventilated patients and captured in the hygroscopic condenser humidifier filter of the ventilator circuit contain pathogenic micro-organisms. 2). The number (CFU/ml) and identity (Genus, species) of the pathogens in the aerosol samples can rapidly and inexpensively be determined by PCR. 3). Data from a convenience sample of filters correlate with clinical findings from standard microbiological methods such as broncho-alveolar lavage. The evaluation of the bacterial load evolved in exhaled breath by PCR is amenable to repeated sampling. Since increasing bacterial burden is believed to correlate with the establishment of infection, the use of quantitative PCR may provide a method to rapidly, inexpensively, and effectively detect and diagnose the early onset of pneumonia and identify pathogens involved.


Clinical results of TRAM flap delay by selective embolization of the deep inferior epigastric arteries.
Preoperative selective embolization of the deep inferior epigastric arteries constitutes a new technique in TRAM flap delay. Whereas surgical ligation of these vessels has proved to be an effective delay procedure in experimental and clinical settings, it requires an additional operative step under general anesthesia. Despite the introduction of the free TRAM leading to improved flap perfusion, this microsurgical technique is not always available because of the requirements of specialized equipment and staff, longer operating hours, and subsequently higher expenses. The search for a minimally invasive, easy, and inexpensive technique to improve perfusion of the pedicled TRAM flap led us to selective embolization of the deep inferior epigastric arteries by an angiographic procedure. After 4 years of experience with this technique, we now present the first clinical results. Breast reconstruction by a delayed pedicled TRAM flap was performed in 40 patients with a mean age of 48.4 years (range, 31 to 66 years). The mean interval between embolization and surgery was 3.6 months. Postoperative data concerning flap survival and complications were available for all patients. Embolization of the deep inferior epigastric arteries was performed bilaterally in 35 patients (87.5 percent) and unilaterally in 5 patients (12.5 percent). Radiotherapy had been applied in 21 patients (52.5 percent) before surgery. Postoperative flap complications consisted of partial necrosis in three (7.5 percent), fat necrosis in one (2.5 percent), impaired wound healing in five (12.5 percent), and postoperative bleeding in two patients (5 percent). Abdominal wound healing complications occurred in six patients (15 percent), abdominal wall weakness in eight (20 percent), and hernia formation in four (10 percent). Surgical corrections were performed at the breast (TRAM flap) in 22 patients (55 percent) and at the abdomen (donor site) in 9 (22.5 percent). Preoperative selective embolization of the deep inferior epigastric arteries constitutes an alternative delay procedure for the pedicled TRAM flap. It is superior to the conventional procedure without delay, offers several advantages compared with surgical ligation of these vessels, and represents an alternative to the free TRAM flap in selected cases.


Does prenatal sonography affect intellectual performance?
Little is known about potential risks of ultrasound during pregnancy. The developing brain is susceptible to environmental influences, and prenatal ultrasound has been reported to affect cognitive abilities in animals. To assess a possible association between prenatal ultrasound and intellectual performance, we studied men born in Sweden from 1973 to 1978 who enrolled for military service from 1991 to 1996. Intellectual scores (mean +/- standard deviation = 5 +/- 2) were measured by a test battery at enrollment, and subnormal performance was defined as a score of 3 or less. We estimated differences in mean intellectual score between ultrasound-exposed and ultrasound-unexposed using linear regression, and we calculated relative risks of subnormal performance using logistic regression analysis. There were 7999 eligible men born in a hospital (Malmo) that included ultrasound scanning in standard antenatal care (exposed) and 197,829 men born in hospitals without ultrasound scanning programs (unexposed). We found lower intellectual performance scores (mean difference = -0.16; 95% confidence interval = -0.21 to -0.11) and an increased risk of subnormal performance (odds ratio = 1.28; CI = 1.18 to 1.38) among ultrasound-exposed compared with unexposed. However, men born in Malmo before scanning was introduced also had lower scores, and the decrease in test scores after the introduction of ultrasound was small. Moreover, we found no differences in intellectual performance within pairs of brothers as a result of ultrasound exposure. This study failed to demonstrate a clear association between ultrasound scanning and intellectual performance.


Phase diagrams of the Ziff-Gulari-Barshad model on random networks.
In this study, we revisited the Ziff-Gulari-Barshad (ZGB) model in order to study the behavior of its phase diagram when two well-known random networks play the role of the catalytic surfaces: the random geometric graph and the Erdös-Rényi network. The connectivity and, therefore, the average number of neighbors of the nodes of these networks can vary according to their control parameters, the neighborhood radius α, and the linking probability p, respectively. In addition, the catalytic reactions of the ZGB model are governed by the parameter y, the adsorption rate of carbon monoxide molecules on the catalytic surface. So, to study the phase diagrams of the model on both random networks, we carried out extensive steady-state Monte Carlo simulations in the space parameters (y, α) and (y, p) and showed that the continuous phase transition is greatly affected by the topological features of the networks while the discontinuous one remains present in the diagram throughout the interval of study.


Computerized photocolorimetric analysis of the effects of intraarticular betamethasone on the proteoglycan concentration of leporine knee cartilage matrix: influence of the number of intraarticular injections.
To study the effects of repeated injections of betamethasone on proteoglycan concentration in the articular cartilage of normal knees of Californian rabbits of both sexes. Eighty animals were randomly divided into eight groups of ten animals each. Three control groups (saline solution injected or not) and five study groups - therapeutical doses, repeated or not, of betamethasone injected into the right knee of each animal at weekly intervals. After eight days from the last injection, sections of articular cartilage from tibial plateaus collected from weight-bearing surfaces were stained with hematoxylin and eosin for light microscopy analysis and with safranin O for the proteoglycan content assay. The staining intensity of safranin O was quantified by histomorphometry using an Olympus BX 50 microscope and a microcomputer with the Image Pro-plus 4.5O software. Animals receiving one, two and four betamethasone injections showed no differences when compared to normal controls. Animals receiving six and eight injections had a significant decrease in safranin O staining intensity (p < 0.05) as compared to the control groups and the other study groups. A decrease in the concentration of articular cartilage proteoglycans dependent on repeated betamethasone injection was effectively demonstrated.


Evidence of Oligoclonal Bands Does Not Exclude Non-Inflammatory Neurological Diseases.
Cerebrospinal fluid analysis is an essential part of the diagnostic workup in various neurological disorders. Evidence of an intrathecal immunoglobulin synthesis, as demonstrated by Reiber's diagram or the more sensitive oligoclonal bands (OCB), are typical for neuroinflammatory diseases, and normally not expected in non-inflammatory neurological diseases. Therefore, patients with non-inflammatory neurological diseases are often used in control groups in studies investigating autoimmune diseases of the central nervous system. However, data about the frequency of intrathecal immunoglobulin synthesis in non-inflammatory neurological disease are scarce. The cerebrospinal fluid (CSF) records of a total of 3622 patients were screened and 2114 patients included with presumably non-inflammatory neurological diseases like dementia, idiopathic peripheral neuropathy, motoneuron disease, stroke, and epileptic seizures. Evidence of an intrathecal immunoglobulin synthesis can be found with low frequency also in non-inflammatory neurological diseases. A much higher rate of patients showed intrathecal immunoglobulin synthesis as demonstrated by OCB than by Reiber's diagram. In patients with disorders of the peripheral nervous system the frequency of OCB was much lower than in patients presenting with central nervous system manifestations. Evidence of an intrathecal immunoglobulin synthesis should not automatically lead to exclusion of non-inflammatory neurological diseases but should rather prompt the way to investigate for the origin of the intrathecal immunoglobulin synthesis.


B-vitamins and body composition: integrating observational and experimental evidence from the B-PROOF study.
Higher folate and vitamin-B12 have been linked to lower risk of overweight. However, whether this is a causal effect of these B-vitamins on obesity risk remains unclear and evidence in older individuals is scarce. This study aimed to assess the role of B-vitamin supplementation and levels on body composition in older individuals. A double-blind, randomized controlled trial in 2919 participants aged ≥ 65 years with elevated homocysteine levels. The intervention comprised a 2-year supplementation with a combination of folic acid (400 µg) and vitamin B12 (500 µg), or with placebo. Serum folate, vitamin-B12, active vitamin-B12 (HoloTC), methylmalonic acid (MMA), and anthropometrics were measured at baseline and after 2 years of follow-up. Dietary intake of folate and vitamin-B12 was measured at baseline in a subsample (n = 603) using a validated food-frequency questionnaire. Fat mass index (FMI) and fat-free mass index (FFMI) were assessed with Dual Energy X-ray absorptiometry (DXA). Cross-sectional analyses showed that a 1 nmol/L higher serum folate was associated with a 0.021 kg/m2 lower BMI (95% CI - 0.039; - 0.004). Higher HoloTC (per pmol/L log-transformed) was associated with a 0.955 kg/m2 higher FMI (95% CI 0.262; 1.647), and higher MMA (per μgmol/L) was associated with a 1.108 kg/m2 lower FMI (95% CI - 1.899; - 0.316). However, random allocation of B-vitamins did not have a significant effect on changes in BMI, FMI or FFMI during 2 years of intervention. Although observational data suggested that folate and vitamin B12 status are associated with body composition, random allocation of a supplement with both B-vitamins combined versus placebo did not confirm an effect on BMI or body composition.


Long-term effects of carbon containing engineered nanomaterials and asbestos in the lung: one year postexposure comparisons.
The hallmark geometric feature of single-walled carbon nanotubes (SWCNT) and carbon nanofibers (CNF), high length to width ratio, makes them similar to a hazardous agent, asbestos. Very limited data are available concerning long-term effects of pulmonary exposure to SWCNT or CNF. Here, we compared inflammatory, fibrogenic, and genotoxic effects of CNF, SWCNT, or asbestos in mice 1 yr after pharyngeal aspiration. In addition, we compared pulmonary responses to SWCNT by bolus dosing through pharyngeal aspiration and inhalation 5 h/day for 4 days, to evaluate the effect of dose rate. The aspiration studies showed that these particles can be visualized in the lung at 1 yr postexposure, whereas some translocate to lymphatics. All these particles induced chronic bronchopneumonia and lymphadenitis, accompanied by pulmonary fibrosis. CNF and asbestos were found to promote the greatest degree of inflammation, followed by SWCNT, whereas SWCNT were the most fibrogenic of these three particles. Furthermore, SWCNT induced cytogenetic alterations seen as micronuclei formation and nuclear protrusions in vivo. Importantly, inhalation exposure to SWCNT showed significantly greater inflammatory, fibrotic, and genotoxic effects than bolus pharyngeal aspiration. Finally, SWCNT and CNF, but not asbestos exposures, increased the incidence of K-ras oncogene mutations in the lung. No increased lung tumor incidence occurred after 1 yr postexposure to SWCNT, CNF, and asbestos. Overall, our data suggest that long-term pulmonary toxicity of SWCNT, CNF, and asbestos is defined, not only by their chemical composition, but also by the specific surface area and type of exposure.


Cilostazol attenuates indices of liver damage induced by thioacetamide in albino rats through regulating inflammatory cytokines and apoptotic biomarkers.
Even though cilostazol was assessed before in several models of atherosclerosis, so far its full systematic effect as a natural anti-inflammatory and anti-apoptotic mediator in the protection of liver damage and complication has not been fully clarified, which is the target of this study. For that purpose, we examined the protective effect of cilostazol (10 and 5mg/kg, p.o. b.wt.) in an acute hepatic injury model by orally injecting it for 3 weeks prior to a single dose of TAA (300mg/kg, i.p) injection. Ursodeoxycholic acid was used as a standard drug (50mg/kg, p.o. b.wt.). After injection of thioacetamide by 48hr, rats were sacrificed. On the serum biochemical level, cilostazol ameliorated the thioacetamide consequence, where it presented a significant enhancement in the liver enzymes activities [Aspartate aminotransferase (AST) & Alanine aminotransferase (ALT)]. On the other hand, at the tissue level (Liver), it revealed a significant improvement in pro-inflammatory cytokines [Tumor necrosis factor alpha (TNF-α), Interleukin 1 beta (IL-1β), Nuclear factor kappa B (NF-κB), NF-κB (P65/P50 nucleus translocation), caspase-3, cleaved caspase-3 & C-reactive protein (CRP)], redox level [Reduced glutathione (GSH) & Malondialdehyde (MDA)], histopathological findings, Reverse transcription polymerase chain reaction (RT-PCR) analysis (expression of TNF-α and NF-κB mRNA levels), and immunohistochemical reaction (caspase-3 & TNF-α). Obviously, the high dose of cilostazol (10mg/kg, p.o. b.wt.) displayed a more pronounced effect than its lower one and nearly equal to ursodeoxycholic acid in the most of the parameters. These results give a new awareness into the hopeful molecular mechanisms by which cilostazol attenuates several factors participated in the progression of liver damage.


Obliteration of processus vaginalis: aberrations in the regulatory mechanism result in an inguinal hernia, hydrocele or undescended testis.
The testis is descended through the processus vaginalis via propulsive force generated by the muscles derived from the gubernaculum. After propelling the testis, the smooth muscle should undergo programmed cell death for obliteration of the processus vaginalis. Achievement of programmed cell death mandates a transient decrease in sympathetic, but an increase in parasympathetic, tonuses. Since the sympathetic tonus is androgen-dependent, the decrease in androgen levels during the third trimester appears to be responsible for the process. Alterations in timing, intensity or duration of the decrease in sympathetic tonus under the control of the central nervous system give rise to hernia, hydrocele or abnormal testis localizations. The persistence of decrease causes undescended, retracted, or ascended testis. Absence or inadequacy of the decrease in sympathetic tonus results in rescue of more smooth muscle, thus inhibiting the obliteration. Inadequacy in the intensity or duration rescues less smooth muscle and gives rise to a hydrocele. Persistence of signals towards inducing programmed cell death contributes to decrease in fertility, and provides a basis for epididymo-vasal anomalies. The reduction in the central regulatory mechanism that involves catecholaminergic activity explains the blunting of luteinizing hormone (LH) response to gonadotropin-releasing hormone (GnRH). The explained mechanism precisely defines the role of all factors, and links all of the associations related to the process of descent.


A nodal gamma/delta T-cell lymphoma with an association of Epstein-Barr virus.
The postthymic gamma/delta T-cell lymphoma is rare, and most occur as extranodal tumors, e.g., in hepatosplenic or cutaneous forms. We here report an unusual nodal case that initially presented as a T-zone lymphoma. The neoplasm recurred as systemic lymphadenopathy 25 months after complete remission with terminal high-grade transformation. Phenotypic analysis showed CD1-, CD2+, CD3+, CD4-, CD5-, CD7+, CD8+, CD10-, CD16-, CD19-, CD20-, CD21-, CD25-, CD56-, CD57-, T-cell receptor (TCR) alpha/beta antigens negative, TCR gamma/delta antigens positive, and an HLA-DR+ phenotype. Cytogenetic studies showed clonal chromosomal translocations involving chromosomes 1, 5, 6, 8, 15, and X in eight of 15 cells; t(X;5;1)(q13;q13;p22) and t(6;15;8)(p22;q26;q13). Genotypic analysis showed the same clone, characterized by the TCR gamma-chain gene rearrangement pattern, to be present in both initial and recurrent tumors. The lymphoma cells were also demonstrated to express the latent membrane protein-1 by immunohistochemistry and EBV-encoded small RNAs by in situ hybridization. Southern blot analysis using the probe of the terminal repeat demonstrated incorporation of multiple copies of EBV in the recurrent tumor. However, the initial lesion, which contained a smaller number of EBV-positive cells, showed no such evidence of clonal proliferation. These data suggest that EBV may be associated with high-grade transformation, although its exact role in lymphomagenesis remains uncertain. The present study also adds to our understanding of the clinicopathologic spectrum of gamma/delta T-cell neoplasia.


Resolved Psychosis after Liver Transplantation in a Patient with Wilson's Disease.
A psychiatric involvement is frequently present in Wilson's disease. Psychiatric symptoms are sometimes the first and only manifestation of Wilson's disease. More often a psychiatric involvement is present beside a neurologic or hepatic disease.We describe the case of a 18 years-old male patient who shows a clinic and laboratoristic pattern of cirrhosis and an history of subchronic hallucinatory psychosis, behavioral symptoms and mood disturbances with depressed mood. He hadn't familiar history of liver or psychiatric disease. Laboratory and imaging tests confirmed the diagnosis of Wilson's disease with psichiatric involvement. After liver transplantation copper metabolism and liver function normalised and we noticed no recurrency of the psichiatric illness. Very few cases of psychiatric improvement after orthotopic liver transplantation (OLT) has been described until now.


Reusing models of actors and services in smart homecare to improve sustainability.
Industrial countries are faced with a growing elderly population. Homecare systems with assistive smart house technology enable elderly to live independently at home. Development of such smart home care systems is complex and expensive and there is no common reference model that can facilitate service reuse. This paper proposes reusable actor and service models based on a model-driven development process where end user organizations and domain healthcare experts from four European countries have been involved. The models, specified using UML can be reused actively as assets in the system design and development process and can reduce development costs, and improve interoperability and sustainability of systems. The models are being evaluated in the European IST project MPOWER.


Atypical speech production of multisyllabic words and phrases by children with developmental dyslexia.
The prevalent "core phonological deficit" model of dyslexia proposes that the reading and spelling difficulties characterizing affected children stem from prior developmental difficulties in processing speech sound structure, for example, perceiving and identifying syllable stress patterns, syllables, rhymes and phonemes. Yet spoken word production appears normal. This suggests an unexpected disconnect between speech input and speech output processes. Here we investigated the output side of this disconnect from a speech rhythm perspective by measuring the speech amplitude envelope (AE) of multisyllabic spoken phrases. The speech AE contains crucial information regarding stress patterns, speech rate, tonal contrasts and intonational information. We created a novel computerized speech copying task in which participants copied aloud familiar spoken targets like "Aladdin." Seventy-five children with and without dyslexia were tested, some of whom were also receiving an oral intervention designed to enhance multi-syllabic processing. Similarity of the child's productions to the target AE was computed using correlation and mutual information metrics. Similarity of pitch contour, another acoustic cue to speech rhythm, was used for control analyses. Children with dyslexia were significantly worse at producing the multi-syllabic targets as indexed by both similarity metrics for computing the AE. However, children with dyslexia were not different from control children in producing pitch contours. Accordingly, the spoken production of multisyllabic phrases by children with dyslexia is atypical regarding the AE. Children with dyslexia may not appear to listeners to exhibit speech production difficulties because their pitch contours are intact. RESEARCH HIGHLIGHTS: Speech production of syllable stress patterns is atypical in children with dyslexia. Children with dyslexia are significantly worse at producing the amplitude envelope of multi-syllabic targets compared to both age-matched and reading-level-matched control children. No group differences were found for pitch contour production between children with dyslexia and age-matched control children. It may be difficult to detect speech output problems in dyslexia as pitch contours are relatively accurate.


A trial-based economic evaluation of 2 nurse-led disease management programs in heart failure.
Although previously conducted meta-analyses suggest that nurse-led disease management programs in heart failure (HF) can improve patient outcomes, uncertainty regarding the cost-effectiveness of such programs remains. To compare the relative merits of 2 variants of a nurse-led disease management program (basic or intensive support by a nurse specialized in the management of patients with HF) against care as usual (routine follow-up by a cardiologist), a trial-based economic evaluation was conducted alongside the COACH study. In terms of costs per life-year, basic support was found to dominate care as usual, whereas the incremental cost-effectiveness ratio between intensive support and basic support was found to be equal to €532,762 per life-year; in terms of costs per quality-adjusted life-year (QALY), basic support was found to dominate both care as usual and intensive support. An assessment of the uncertainty surrounding these findings showed that, at a threshold value of €20,000 per life-year/€20,000 per QALY, basic support was found to have a probability of 69/62% of being optimal against 17/30% and 14/8% for care as usual and intensive support, respectively. The results of our subgroup analysis suggest that a stratified approach based on offering basic support to patients with mild to moderate HF and intensive support to patients with severe HF would be optimal if the willingness-to-pay threshold exceeds €45,345 per life-year/€59,289 per QALY. Although the differences in costs and effects among the 3 study groups were not statistically significant, from a decision-making perspective, basic support still had a relatively large probability of generating the highest health outcomes at the lowest costs. Our results also substantiated that a stratified approach based on offering basic support to patients with mild to moderate HF and intensive support to patients with severe HF could further improve health outcomes at slightly higher costs.


Maternal perinatal undernutrition modifies lactose and serotranferrin in milk: relevance to the programming of metabolic diseases?
A close link between intrauterine growth restriction and development of chronic adult diseases such as obesity, diabetes, and hypertension has been established both in humans and animals. Modification of growth velocity during the early postnatal period (i.e., lactation) may also sensitize to the development of metabolic syndrome in adulthood. This suggests that milk composition may have long-lasting programming/deprogramming metabolic effects in the offspring. We therefore assess the effects of maternal perinatal denutrition on breast milk composition in a food-restricted 50% (FR50) rat model. Monosaccharides and fatty acids were characterized by gas chromatography, and proteins were profiled by surface-enhanced laser desorption/ionization-time-of-flight analysis in milk samples from FR50 and control rat dams. Milk analysis of FR50 rats demonstrated that maternal undernutrition decreases lactose concentration and modulates lipid profile at postnatal day 10 by increasing the unsaturated fatty acids/saturated fatty acids and diminishes serotransferrin levels at postnatal day 21. Our data indicate that maternal perinatal undernutrition modifies milk composition both quantitatively and qualitatively. These modifications by maternal nutrition open new perspectives to identify molecules that could be used in artificial milk to protect from the subsequent development of metabolic diseases.


Beta2-adrenoceptor-mediated prejunctional facilitation and postjunctional inhibition of sympathetic neuroeffector transmission in the guinea pig vas deferens.
This study examines the role of prejunctional and postjunctional beta-adrenoceptors in the modulation of sympathetic cotransmission in the guinea pig vas deferens. The prejunctional involvement of beta-adrenoceptors was evaluated by testing the effects of several agonists and antagonists on the nerve stimulation-evoked overflow of ATP and norepinephrine (NE) from the "in vitro" vas deferens. The nonsubtype-selective beta-adrenoceptor agonist isoproterenol and the beta2-subtype-selective agonist clenbuterol increased, to a similar degree, the overflow of ATP and NE, while the beta1-subtype-selective agonist xamoterol and the beta3-subtype-selective agonist BRL 37 344 had no effect. Pretreatment with ICI 118, 551, a beta2-subtype-selective antagonist, abolished the facilitation of cotransmitter release by isoproterenol and clenbuterol, while the beta1-subtype-selective antagonist atenolol had no effect. Activation of beta-adrenoceptors by either isoproterenol or clenbuterol, but not by xamoterol and BRL 37 344, reduced the amplitude of contractions evoked by exogenously applied ATP. Pretreatment with propranolol or ICI 118, 551, but not atenolol, prevented these inhibitory effects. Isoproterenol in lower concentrations produced dose-dependent reduction of the purinergic but not the adrenergic phase of nerve stimulation-induced contraction of the guinea pig vas deferens. When applied in concentrations greater than 1 microM, isoproterenol, but not clenbuterol, actually produced a concentration-dependent facilitation of contractions evoked by both nerve stimulation and exogenously applied ATP. Antagonists of alpha-adrenoceptors blocked these facilitatory effects. Together, these results demonstrate that beta2-adrenoceptors can influence sympathetic neuroeffector transmission both prejunctionally, where they facilitate equally well the release of sympathetic cotransmitters and postjunctionally, where they inhibit smooth muscle contractions evoked by ATP.


Pituitary apoplexy: a rare cause of middle cerebral artery infarction.
Pituitary apoplexy is a well-known complication of a pituitary adenoma. However, an ischaemic event caused by pituitary apoplexy is rare. We reported a case of pituitary apoplexy with middle cerebral artery infarction in a 44-year old man who presented with a sudden onset of altered sensorium. Vasospasm is the most likely underlying cause of the infarction in this case secondary to transdiaphragmatic rupture of the sella tumour into the subarachnoid space.


Not all fairness is created equal: A study of employee attributions of supervisor justice motives.
A large body of research demonstrates that employee perceptions of fair treatment matter. The overwhelming focus of these investigations has been on how employees react to whether or not they perceive their supervisor behaved in a fair manner. We contend, however, that employees not only question and react to whether they are treated fairly, but also to why they believe their supervisor acted fairly in the first place. To do so, we consider how employee attributions of supervisor motives for fair treatment influence the cognitive and affective mechanisms by which fair treatment influences employee reactions to fairness. Drawing from the justice actor model, we focus on both cognitive (establishing fairness, identity maintenance, and effecting compliance) and affective (positive affect) motives underlying supervisors' fair treatment. Relying on theory and research on motive attribution and leader affect, we develop predictions for how employees' perceptions of these motives as a result of short-term exchanges over time influence supervisor-directed citizenship behavior through both cognitive (trust in the supervisor) and affective (positive affect) mechanisms. Our experience sampling study of 613 weekly fair events (from 171 employees) largely supported our predictions, demonstrating that attribution of supervisor motives is a meaningful component of an employee's justice experience. (PsycINFO Database Record (c) 2020 APA, all rights reserved).


[Ethical problems in extreme prematurity].
I examine the question whether it is always morally obligatory to sustain the life of a premature infant and come to the conclusion that this is not the case. Touching on questions concerning the value of life, I argue that it is not always in a premature infant's best interests to have its life sustained. I sharply distinguish my patient-centered perspective from that of the Nazis. Finally, I raise the question of how a premature infant should be treated when the decision has been made to allow it to die.


Differential GABAB-receptor-mediated effects in perisomatic- and dendrite-targeting parvalbumin interneurons.
Inhibitory parvalbumin-containing interneurons (PVIs) control neuronal discharge and support the generation of theta- and gamma-frequency oscillations in cortical networks. Fast GABAergic input onto PVIs is crucial for their synchronization and oscillatory entrainment, but the role of metabotropic GABA(B) receptors (GABA(B)Rs) in mediating slow presynaptic and postsynaptic inhibition remains unknown. In this study, we have combined high-resolution immunoelectron microscopy, whole-cell patch-clamp recording, and computational modeling to investigate the subcellular distribution and effects of GABA(B)Rs and their postsynaptic effector Kir3 channels in rat hippocampal PVIs. Pre-embedding immunogold labeling revealed that the receptors and channels localize at high levels to the extrasynaptic membrane of parvalbumin-immunoreactive dendrites. Immunoreactivity for GABA(B)Rs was also present at lower levels on PVI axon terminals. Whole-cell recordings further showed that synaptically released GABA in response to extracellular stimulation evokes large GABA(B)R-mediated slow IPSCs in perisomatic-targeting (PT) PVIs, but only small or no currents in dendrite-targeting (DT) PVIs. In contrast, paired recordings demonstrated that GABA(B)R activation results in presynaptic inhibition at the output synapses of both PT and DT PVIs, but more strongly in the latter. Finally, computational analysis indicated that GABA(B) IPSCs can phasically modulate the discharge of PT interneurons at theta frequencies. In summary, our results show that GABA(B)Rs differentially mediate slow presynaptic and postsynaptic inhibition in PVIs and can contribute to the dynamic modulation of their activity during oscillations. Furthermore, these data provide evidence for a compartment-specific molecular divergence of hippocampal PVI subtypes, suggesting that activation of GABA(B)Rs may shift the balance between perisomatic and dendritic inhibition.


Chronic nonsteroidal anti-inflammatory drug (NSAID) use suppresses multiple CpG islands hyper methylation (CIHM) of tumor suppressor genes in the human gastric mucosa.
There have been reports showing a protective role of nonsteroidal anti-inflammatory drugs (NSAIDs) against gastrointestinal cancers. CpG island hyper methylation (CIHM) of tumor suppressor genes is a major event in carcinogenesis. We investigated the CIHM status of non-cancerous gastric mucosa in chronic NSAID users and non-users and assessed the effect of NSAIDs on CIHM. Gastric mucosa samples were obtained from 51 chronic NSAID users and 180 non-users. CIHM of p14(ARF), p16(INK4a), death-associated protein kinase (DAP-kinase), and E-cadherin (CDH1) genes were determined by methylation-specific PCR. CIHM high was defined as two or more CpG islands methylated. CIHM of p14, p16, CDH1, and CIHM high were lower in chronic NSAID users than in non-users (p14: non-users vs users = 32.2%vs 9.8%, P = 0.003; p16: non-users vs users = 35.0%vs 15.7%, P = 0.02; CDH1: non-users vs users = 36.1%vs 9.8%, P = 0.0009; CIHM high: non-users vs users = 44.4%vs 17.6%, P = 0.0009). NSAID use was also associated with decreased number of CIHM by anova (R = -0.32, P < 0.0001). Multivariate logistic regression analysis with adjustment for sex, age, Helicobacter pylori infection, and NSAID use revealed that NSAID use was inversely correlated with all four CIHM and CIHM high as an independent factor (p14: odds ratio [OR] = 0.17, 95% confidence interval [CI] = 0.06-0.48; p16: OR = 0.32, 95% CI = 0.14-0.75; DAP-kinase: OR = 0.45, 95% CI = 0.22-0.92; CDH1: OR = 0.18, 95% CI = 0.06-0.48; CIHM high: OR = 0.21, 95% CI = 0.09-0.49). No association was found between CIHM status and the duration or dose of NSAIDs. Chronic NSAID use suppresses CIHM in human gastric mucosa. NSAIDs may have a suppressive role against methylation-related gastric carcinogenesis.


Sexual transmission of Toxoplasma gondii in sheep.
Male sheep of reproductive age were distributed into three groups: GI, a sheep inoculated (oral) with 2.0×10(5) oocysts of the P strain of Toxoplasma gondii; GII, a sheep infected (subcutaneous) with 1.0×10(6) tachyzoites of the RH strain of T. gondii; and GIII, a sheep kept as a control (not infected). After the inoculation of the males, 12 breeding ewes, which were not pregnant and which were serologically negative for reproductive diseases (particularly toxoplasmosis), were distributed into three groups, synchronized, and subsequently exposed to natural mating with previously inoculated males. The distribution was as follows: five ewes that underwent natural mating with the GI male, five ewes that were exposed to natural mating with the GII male, and two ewes that were mated with the non-infected male (control). Serum samples of all the ewes were collected on days -30, -14, -7, -1, and 0 (days before natural mating) and on days 1, 3, 5, 7, 11, 14, and weekly until birth; the presence of serum antibodies against T. gondii was assessed by IFAT. Using a bioassay and PCR, T. gondii was isolated from the semen of the infected reproducing sheep before mating. Following natural mating, 5 of the 12 females displayed antibodies specific for T. gondii; of these animals, two of the ewes underwent natural mating with the male inoculated with oocysts (GI) and three with the male infected with tachyzoites (GII). One of the females that displayed antibodies specific to this coccidian and that underwent natural mating with the GII sheep had a macerated fetus on the 70th day following coverage. Using a bioassay after the birth, it was possible to isolate T. gondii from samples of the "pool" of tissues from the five females that seroconverted after natural mating and from their respective lambs. Using PCR, the DNA of T. gondii was isolated from the "pool" of tissues from one and two females exposed to natural mating with the reproductive males infected with the oocysts and tachyzoites, respectively. Using this technique, it was also possible to diagnose the presence of the parasite in the "pool" of tissues from the lambs of one female that underwent natural mating with the male sheep infected with oocysts. These results demonstrated the sexual transmission of T. gondii in the sheep species with consequent vertical transmission to their lambs.


The study of clinical profile and outcome of patients with snakebite in a rural community.
Snakebite remains an underrated cause of accidental death in modern India, primarily in rural India, where people fail to reach out to modern medicine and fall victim to the handful of quacks using traditional healing methods. If promptly diagnosed and treated based on various clinical determinants like mode of presentation, time of medical intervention, recognition of the species, and analysis of a series of reliably identified bites, the treatment outcome would be more promising. We aimed to study snakebite patients' clinical profile and treatment outcome in a rural tertiary care setup. This is a retrospective study in which the data evaluated from an epidemiological viewpoint; gender and age of the snake bite victim, time when bitten, interval between the bite and medical consultation, pattern of toxicity, and response to anti-snake venom (ASV). Of a total of 200 patients bitten by a snake, 121 were males, with 77% adults. In nearly all cases, the type of snake was unknown; however, most of the bites were poisonous, showing one or the other type of toxicity. One hundred seventy-one patients survived the snake bite, and 29 succumbed. When Logistic regression was done with Death/discharge as the dependent variable and "Time to bite and reaching hospital, Age, Sex, number of ASV given, Ventilation needed or not, pack cell volume (PCV) numbers, Fresh Frozen Plasma (FFP) numbers, Dialysis and presence or absence of toxicity" as the independent variables, the model developed did not account for any respectable amount of variation in the outcome. The only variable found to be predicting the outcome significantly was FFP. It is often difficult to identify the type of snake, and thus polyvalent antisnake venom remains the only available treatment resource. Readily available treatment resources, timely intervention, appropriate referral, and close ICU will alleviate mortality.


Evaluation of Very Integrated Program: Health Promotion for Patients With Alcohol and Drug Addiction-A Randomized Trial.
Compared to the general population, patients with alcohol and drug addiction have an increased risk of additional hazardous lifestyles and suffer from more chronic diseases, adding to their already significantly higher morbidity and mortality. The objective of this study was to test the efficacy of the Very Integrated Program (VIP) on treatment and health outcomes for patients diagnosed with alcohol and drug addiction. Parallel randomized clinical trial with intervention as add-on to addiction care as usual. A total of 322 patients aged 18 years or older were identified, and the study requirements were fulfilled by 219 patients, 7 of whom participated in a pilot. The intervention was a 6-week intensive, tailored, educational program that included motivational interviewing, a smoking cessation program, dietary and physical activity counseling, and patient education. The main outcome measures were substance-free days, time to relapse, and treatment adherence assessed after 6 weeks and 12 months. Secondary outcomes were lifestyle factors, symptoms of comorbidity, and quality of life. Missing data were imputed conservatively by using data closest to the follow-up date and baseline values in patients with no follow-up. The 212 patients (intervention, n = 113; control, n = 99) were randomized, and 202 had complete data for primary outcomes. After 6 weeks, there were no significant differences between the groups regarding primary or secondary outcomes. At the 12-month follow-up, the patients in the control group had significantly more total substance-free days (139 days; ranging 0 to 365 vs. 265; 0 to 366, p = 0.021)-specifically among the patients with drug addiction-and higher physical and mental quality of life (45 vs. 58, p = 0.049 and 54 vs. 66, p = 0.037), but not in the per-protocol analysis (60 vs. 46, p = 0.52 and 70 vs. 66, p = 0.74). The sensitivity analyses did not support significant differences between the groups. Overall, adding VIP intervention did not improve outcome of the alcohol or drug addiction care or the lifestyle compared to the addiction care alone. This patient group is still in need of effective programs, and new intervention research is required to develop that.


Tarantula huwentoxin-IV inhibits neuronal sodium channels by binding to receptor site 4 and trapping the domain ii voltage sensor in the closed configuration.
Peptide toxins with high affinity, divergent pharmacological functions, and isoform-specific selectivity are powerful tools for investigating the structure-function relationships of voltage-gated sodium channels (VGSCs). Although a number of interesting inhibitors have been reported from tarantula venoms, little is known about the mechanism for their interaction with VGSCs. We show that huwentoxin-IV (HWTX-IV), a 35-residue peptide from tarantula Ornithoctonus huwena venom, preferentially inhibits neuronal VGSC subtypes rNav1.2, rNav1.3, and hNav1.7 compared with muscle subtypes rNav1.4 and hNav1.5. Of the five VGSCs examined, hNav1.7 was most sensitive to HWTX-IV (IC(50) approximately 26 nM). Following application of 1 microm HWTX-IV, hNav1.7 currents could only be elicited with extreme depolarizations (>+100 mV). Recovery of hNav1.7 channels from HWTX-IV inhibition could be induced by extreme depolarizations or moderate depolarizations lasting several minutes. Site-directed mutagenesis analysis indicated that the toxin docked at neurotoxin receptor site 4 located at the extracellular S3-S4 linker of domain II. Mutations E818Q and D816N in hNav1.7 decreased toxin affinity for hNav1.7 by approximately 300-fold, whereas the reverse mutations in rNav1.4 (N655D/Q657E) and the corresponding mutations in hNav1.5 (R812D/S814E) greatly increased the sensitivity of the muscle VGSCs to HWTX-IV. Our data identify a novel mechanism for sodium channel inhibition by tarantula toxins involving binding to neurotoxin receptor site 4. In contrast to scorpion beta-toxins that trap the IIS4 voltage sensor in an outward configuration, we propose that HWTX-IV traps the voltage sensor of domain II in the inward, closed configuration.


The Effect of Root Exudate 7,4'-Dihydroxyflavone and Naringenin on Soil Bacterial Community Structure.
Our goal was to investigate how root exudate flavonoids influence the soil bacterial community structure and to identify members of the community that change their relative abundance in response to flavonoid exudation. Using a model system that approximates flavonoid exudation of Medicago sativa roots, we treated a soil with 7,4'-dihydroxyflavone and naringenin in two separate experiments using three different rates: medium (equivalent to the exudation rate of 7,4'-dihydroxyflavone from M. sativa seedlings), high (10× the medium rate), and low (0.1× the medium rate). Controls received no flavonoid. Soil samples were subjected to ATP assays and 16S rRNA gene amplicon sequencing. The flavonoid treatments caused no significant change in the soil ATP content. With the high 7,4'-dihydroxyflavone treatment rate, operational taxonomic units (OTUs) classified as Acidobacteria subdivision 4 increased in relative abundance compared with the control samples, whereas OTUs classified as Gaiellales, Nocardioidaceae, and Thermomonosporaceae were more prevalent in the control. The naringenin treatments did not cause significant changes in the soil bacterial community structure. Our results suggest that the root exudate flavonoid 7,4'-dihydroxyflavone can interact with a diverse range of soil bacteria and may have other functions in the rhizosphere in addition to nod gene induction in legume-rhizobia symbiosis.


Antiplatelet Treatment in Stroke: New Insights.
Stroke is a feared vascular event among healthy people and those with cardiovascular disease, and holds a leading position as a cause of disability and death worldwide. Antiplatelet therapy is central in the management of patients with ischemic nonembolic stroke and transient ischemic attacks. In this narrative review, we provide an overview and update of evidence regarding antiplatelet treatment in the primary and secondary prevention of stroke. Aspirin, clopidogrel and aspirin plus dipyridamole are the mainstays of antiplatelet treatment post-stroke, while promising agents include triflusal, cilostazol and ticagrelor. Available data are in favor of dual antiplatelet treatment in the early treatment of atherosclerotic large vessel disease. Long-term dual antiplatelet treatment should be individualized keeping in mind the higher rates of bleeding complications. Treatment with an antiplatelet agent is recommended to reduce recurrent stroke and death in patients with a non-cardioembolic ischemic stroke or transient ischemic attack. Moreover, clinicians should carefully assess the pros and cons in each case and individualize the need for prolonged dual antiplatelet therapy.


Emticiciafontis sp. nov., isolated from a freshwater pond.
A bacterial strain, designated IMCC1731T, was isolated from an eutrophic freshwater pond and characterized using a polyphasic taxonomic approach. Cellular growth occurred at pH 6-9 (optimum, pH 8.0), at 10-30 °C (optimum, 25 °C) and with 0-1 % (w/v) NaCl (optimum, 0 %). Phylogenetic analyses based on 16S rRNA gene sequences indicated that strain IMCC1731T belonged to the genus Emticicia in the family Cytophagaceae and was most closely related to Emticicia ginsengisoli Gsoil 085T (98.1 %) followed by Emticicia paludis HMF3850T (95.0 %), Emticicia oligotrophica DSM 17448T (94.7 %), Emticicia aquatica HMF2925T (94.4 %) and Emticicia sediminis JBR12T (94.0 %). The DNA-DNA relatedness between strain IMCC1731T and E. ginsengisoli Gsoil 085T was 47±4 %. The DNA G+C content of strain IMCC1731T was 37.7 mol%. The predominant cellular fatty acids were summed feature 3 (C16 : 1ω6c and/or C16 : 1ω7c) and iso-C15 : 0. Based on the physiological and chemotaxonomic characteristics, DNA-DNA relatedness and 16S rRNA gene phylogeny, stain IMCC1731T is considered to represent a novel species of the genus Emticicia, for which the name Emticicia fontis sp. nov. is proposed. The type strain is IMCC1731T (=KCTC 52248T=JCM 31373T).


Probing Far-Infrared Surface Phonon Polaritons in Semiconductor Nanostructures at Nanoscale.
Phonon polaritons hold potential prospects of nanophotonic applications at the mid- and far-infrared wavelengths. However, their experimental investigation in the far-infrared range has long been a technical challenge due to the lack of suitable light sources and detectors. To obviate these difficulties, here we use an electron probe with sub-10 meV energy resolution and subnanometer spatial resolution to study far-infrared surface phonon polaritons (∼50-70 meV) in ZnO nanostructures. We observe ultraslow propagation and interference fringes of propagating surface phonon polaritons and obtain their dispersion relation through measurements in the coordinate space. By mapping localized modes in nanowires and flakes, we reveal their localized nature and investigate geometry and size effects. Associated with simulation, we show that surface phonon polariton behaviors can be well described by the local continuum dielectric model. Our work paves the way for spatial-resolved investigation of surface phonon polaritons by electron probes and forwards polaritonics in the far-infrared range.


Distinct Shifts in Microbiota Composition during Drosophila Aging Impair Intestinal Function and Drive Mortality.
Alterations in the composition of the intestinal microbiota have been correlated with aging and measures of frailty in the elderly. However, the relationships between microbial dynamics, age-related changes in intestinal physiology, and organismal health remain poorly understood. Here, we show that dysbiosis of the intestinal microbiota, characterized by an expansion of the Gammaproteobacteria, is tightly linked to age-onset intestinal barrier dysfunction in Drosophila. Indeed, alterations in the microbiota precede and predict the onset of intestinal barrier dysfunction in aged flies. Changes in microbial composition occurring prior to intestinal barrier dysfunction contribute to changes in excretory function and immune gene activation in the aging intestine. In addition, we show that a distinct shift in microbiota composition follows intestinal barrier dysfunction, leading to systemic immune activation and organismal death. Our results indicate that alterations in microbiota dynamics could contribute to and also predict varying rates of health decline during aging in mammals.


Robotic suture of a large caval injury caused by endo-GIA stapler malfunction during laparoscopic wedge resection of liver segments VII and VIII en-bloc with the right hepatic vein.
Primary endo-GIA stapler malfunction occurred during robotic wedge resection of liver segments VII and VIII en-bloc with the right hepatic vein, in an obese woman diagnosed with single liver metastasis from a previous carcinoid tumour. Haemorrhage was soon controlled by clamping the vena cava below the injury using two wristed forceps angled at 90 degrees . With the two instruments locked in the holding position the ensuing operative strategy was discussed between surgeon and anaesthesia teams. Using the third robotic arm the caval injury was repaired laparoscopically with interrupted polypropylene sutures. The patient was transfused with two units of packed red blood cells, recovered uneventfully, and was discharged on post-operative day five. We conclude that even the most advanced technologies can fail and that surgeons should be fully aware of the consequences of these malfunctions and be prepared for repair. From this point of view, the da Vinci surgical system seems to have some advantages over classical laparoscopic methods including the ability to lock the wristed instruments in the holding position, the use of three arms by the same operating surgeon, and the extreme facilitation of intracorporeal suturing and knot-tying in deep and narrow spaces, extremely difficult if not impossible with conventional laparoscopic instruments.


Previous breastfeeding experience and duration of any and exclusive breastfeeding among multiparous mothers.
High breastfeeding attrition rates have been attributed to a number of factors, but the effect of previous breastfeeding experience on subsequent breastfeeding duration has not been adequately investigated. In this study, 559 multiparous mothers were recruited and followed prospectively for 12 months or until the infant was weaned. When compared with having previously breastfed for > 3 months, no previous breastfeeding experience (HR 3.24 [95% CI 2.37-4.42]) or a breastfeeding duration of ≤ 3 months (HR 2.56; 95% CI 2.05?3.20) substantially increased the risk of early weaning. Similarly, participants who had not exclusively breastfed (HR 1.82 [95% CI 1.46?2.26]) or who had exclusively breastfed for ≤ 2 months (HR 1.65 [95% CI 1.29?2.10]) were more likely to stop exclusive breastfeeding when compared with those who had exclusively breastfed for > 2 months. More than 40 percent of the participants who had previously breastfed for > 3 months had shorter current breastfeeding durations. The median decreases in any and exclusive breastfeeding for this group were 16.4 weeks and 13.1 weeks, respectively. Multiparous women with no previous breastfeeding experience and those with a short duration of previous breastfeeding should be provided with greater support to promote a longer duration of breastfeeding. Multiparous women with a longer duration of breastfeeding should be strongly encouraged to meet or exceed this duration with their current infant.


Telomerase reverse transcriptase expression protects transformed human cells against DNA-damaging agents, and increases tolerance to chromosomal instability.
Reactivation of telomerase reverse transcriptase (TERT) expression is found in more than 85% of human cancers. The remaining cancers rely on the alternative lengthening of telomeres (ALT), a recombination-based mechanism for telomere-length maintenance. Prevalence of TERT reactivation over the ALT mechanism was linked to secondary TERT function unrelated to telomere length maintenance. To characterize this non-canonical function, we created a panel of ALT cells with recombinant expression of TERT and TERT variants: TERT-positive ALT cells showed higher tolerance to genotoxic insults compared with their TERT-negative counterparts. We identified telomere synthesis-defective TERT variants that bestowed similar genotoxic stress tolerance, indicating that telomere synthesis activity is dispensable for this survival phenotype. TERT expression improved the kinetics of double-strand chromosome break repair and reduced DNA damage-related nuclear division abnormalities, a phenotype associated with ALT tumors. Despite this reduction in cytological abnormalities, surviving TERT-positive ALT cells were found to have gross chromosomal instabilities. We sorted TERT-positive cells with cytogenetic changes and followed their growth. We found that the chromosome-number changes persisted, and TERT-positive ALT cells surviving genotoxic events propagated through subsequent generations with new chromosome numbers. Our data confirm that telomerase expression protects against double-strand DNA (dsDNA)-damaging events, and show that this protective function is uncoupled from its role in telomere synthesis. TERT expression promotes oncogene-transformed cell growth by reducing the inhibitory effects of cell-intrinsic (telomere attrition) and cell-extrinsic (chemical- or metabolism-induced genotoxic stress) challenges. These data provide the impetus to develop new therapeutic interventions for telomerase-positive cancers through simultaneous targeting of multiple telomerase activities.


CXCR4/CXCL12 signaling impacts enamel progenitor cell proliferation and motility in the dental stem cell niche.
Dental stem cells are located at the proximal ends of rodent incisors. These stem cells reside in the dental epithelial stem cell niche, termed the apical bud. We focused on identifying critical features of a chemotactic signal in the niche. Here, we report that CXCR4/CXCL12 signaling impacts enamel progenitor cell proliferation and motility in dental stem cell niche cells. We report cells in the apical bud express CXCR4 mRNA at high levels while expression is restricted in the basal epithelium (BE) and transit-amplifying (TA) cell regions. Furthermore, the CXCL12 ligand is present in mesenchymal cells adjacent to the apical bud. We then performed gain- and loss-of-function analyses to better elucidate the role of CXCR4 and CXCL12. CXCR4-deficient mice contain epithelial cell aggregates, while cell proliferation in mutant incisors was also significantly reduced. We demonstrate in vitro that dental epithelial cells migrate toward sources of CXCL12, whereas knocking down CXCR4 impaired motility and resulted in formation of dense cell colonies. These results suggest that CXCR4 expression may be critical for activation of enamel progenitor cell division and that CXCR4/CXCL12 signaling may control movement of epithelial progenitors from the dental stem cell niche.


Relationship Between COVID-19 Threat Beliefs and Individual Differences in Demographics, Personality, and Related Beliefs.
Individual differences in demographics, personality, and other related beliefs are associated with coronavirus disease 2019 (COVID-19) threat beliefs. However, the relative contributions of these different types of individual differences to COVID-19 threat beliefs are not known. In this study, a total of 1,700 participants in Croatia (68% female; age 18-86 years) completed a survey that included questions about COVID-19 risks, questions about related beliefs including vaccination beliefs, trust in the health system, trust in scientists, and trust in the political system, the HEXACO 60 personality inventory, as well as demographic questions about gender, age, chronic diseases, and region. We used hierarchical regression analyses to examine the proportion of variance explained by demographics, personality, and other related beliefs. All three types of individual differences explained a part of the variance of COVID-19 threat beliefs, with related beliefs explaining the largest part. Personality facets explained a slightly larger amount of variance than personality factors. These results have implications for communication about COVID-19.


Elimination of polarized light scattered by surface roughness or bulk heterogeneity.
An interferential technique is described to eliminate polarized scattering from optical substrates and coatings. Conditions of annulment are respectively given for surface roughness and for bulk heterogeneity, at each direction of space. At low-level scattering, the method offers a complete discrimination of surface and bulk effects, whatever the micro-structural parameters. Arbitrary scattering levels can be treated in a similar way, but require the knowledge of microstructure.


Heptaphylline induces apoptosis in human colon adenocarcinoma cells through bid and Akt/NF-κB (p65) pathways.
Heptaphylline derivatives are carbazoles in Clausena harmandiana, a medicinal plant that is utilized for headache, stomach ache, and other treatments of illness. The present study examined the effects of heptaphylline and 7-methoxyheptaphylline on apoptosis of human colon adenocarcinoma cells (HT-29 cell line). Quantification of cell viability was performed using cell proliferation assay (MTT assay) and of protein expression through immunoblotting. The results showed that only heptaphylline, but not 7-methoxyheptaphylline, significantly significantly activated cleaved of caspase-3 and poly (ADP-ribose) polymerase (PARP-1) which resulted in HT-29 cell death. We found that heptaphylline activated BH3 interacting-domain death agonist (Bid) and Bak, proapoptotic proteins. In contrast, it suppressed X-linked inhibitor-of-apoptosis protein (XIAP), Bcl-xL and survivin, inhibitors of apoptosis. In addition, heptaphylline inhibited activation of NF-κB/p65 (rel), a regulator of apoptotic regulating proteins by suppressing the activation of Akt and IKKα, upstream regulators of p65. The findings suggested that heptaphylline induces apoptosis in human colon adenocarcinoma cells .


Affective temperaments and psychopathological dimensions of personality in bipolar and cyclothymic patients.
The aims of the study were: (1) to study possible associations between temperament, personality dimensions, and psychopathological variables in a clinical sample of euthymic patients with bipolar disorder (BD) and cyclothymia; and (2) to assess how Cloninger's temperament and personality dimensions were associated with affective temperaments. Participants, consisting of 60 patients with BD (type I or II) and cyclothymia in the euthymic phase, completed Akiskal's Temperament Evaluation of Memphis, Pisa, Paris, and San Diego-Autoquestionnaire (TEMPS-A), and Cloninger's Temperament and Character Inventory-revised version (TCI-R). The diagnostic groups differed in past hospitalization, for age at onset of the disorder, and on two affective temperaments: the TEMPS-A Hyperthymia, and the TEMPS-A Irritability. There were six significant associations between affective temperaments and Cloninger's personality dimensions, ranging from 0.26 to 0.54. The measures of Akiskal and of Cloninger tap common behavioral features in patients with bipolar disorder and cyclothymia, yet the differences indicate that the two measures are not redundant. BD and cyclothymic patients differed significantly in temperament and personality, differences that may have important implications for treatment.


Light scattering by periodic rough surfaces: equivalent jump conditions.
We present an interface model based on two-scale homogenization to predict the coherent scattering of light by a periodic rough interface between air and a dielectric. Contrary to previous approaches where the roughnesses are replaced by a layer filled with an equivalent medium, our modeling yields effective jump conditions applying across the region containing the roughnesses. The validity of the model is inspected by comparison with direct numerics and with experimental measurements on an air/silicium rough interface near the Brewster angle. It is shown that the interface model reproduces accurately the shift in the Brewster phenomenon without any adjustable parameter, which is of practical importance in retrieval methods to get thickness or filling fraction with reliable physical values.


[Hemodynamic effects of etomidate in cardiac surgery during induction of anesthesia].
For comparison of the induction effects of domestic etomidate on hemodynamics with gamma-OH, each group of thirty patients undergoing either repair of ASD or MVR was randomly selected. Certain hemodynamic parameters involving CI, SI, IC, MAP, HR and SVR (cardiac index, stroke volume index, index of contractility, mean artery pressure, heart rate and systemic vascular resistance) were followed throughout the course of induction. The results showed that HR decreased in gamma-OH 2 minutes after intravenous injection (P less than 0.05) but not in etomidate. MAP and SVR decreased 5 minutes after the administration of drugs (P less than 0.05), while the others showed no significant changes. We conclude that etomidate is superior to gamma-OH in patients for cardiac operations during induction.


Complex I function is defective in complex IV-deficient Caenorhabditis elegans.
Cytochrome c oxidase (COX) is hypothesized to be an important regulator of oxidative phosphorylation. However, no animal phenotypes have been described due to genetic defects in nuclear-encoded subunits of COX. We knocked down predicted homologues of COX IV and COX Va in the nematode Caenorhabditis elegans. Animals treated with W09C5.8 (COX IV) or Y37D8A.14 (COX Va) RNA interference had shortened lifespans and severe defects in mitochondrial respiratory chain function. Amount and activity of complex IV, as well as supercomplexes that included complex IV, were decreased in COX-deficient worms. The formation of supercomplex I:III was not dependent on COX. We found that COX deficiencies decreased intrinsic complex I enzymatic activity, as well as complex I-III enzymatic activity. However, overall amounts of complex I were not decreased in these animals. Surprisingly, intrinsic complex I enzymatic activity is dependent on the presence of complex IV, despite no overall decrease in the amount of complex I. Presumably the association of complex I with complex IV within the supercomplex I:III:IV enhances electron flow through complex I. Our results indicate that reduction of a single subunit within the electron transport chain can affect multiple enzymatic steps of electron transfer, including movement within a different protein complex. Patients presenting with multiple defects of electron transport may, in fact, harbor a single genetic defect.


Involvement of calpains in Ca2+-induced disruption of excitation-contraction coupling in mammalian skeletal muscle fibers.
In skeletal muscle fibers, the coupling between excitation of the surface membrane and the release of Ca(2+) from the sarcoplasmic reticulum is irreversibly disrupted if cytoplasmic Ca(2+) concentration ([Ca(2+)]) is raised to micromolar levels for a prolonged period. This excitation-contraction (EC) uncoupling may contribute to muscle weakness after some types of exercise and in certain muscle diseases and has been linked to structural alteration of the triad junctions, but its molecular basis is unclear. Both mu-calpain, a ubiquitous Ca(2+)-activated protease, and muscle-specific calpain-3 become autolytically activated at micromolar Ca(2+) and have been suggested to be responsible for the uncoupling. This study used controlled Ca(2+) exposure in mechanically skinned fibers from extensor digitorum longus muscle to show that EC uncoupling still occurs in muscle fibers of calpain-3-deficient mice, with a Ca(2+) dependence indistinguishable from that in normal mice and rats. Western blotting of muscle fibers that had been partially EC uncoupled by exposure to an intermediate Ca(2+) level ( approximately 5 microM Ca(2+) for 3 min, no ATP) showed the presence of autolytic activation of a proportion of the mu-calpain present, but with little or no activation of calpain-3. Homogenates of normal and calpain-3-deficient muscles exposed to micromolar Ca(2+) displayed similar levels of diffusible proteolytic activity, as gauged by the rate of decline of passive force in stretched, skinned muscle fibers. Exogenously added mu-calpain, preactivated by elevated [Ca(2+)] and applied in the presence of 1 microM Ca(2+), disrupted EC coupling in a manner similar to raised [Ca(2+)]. We conclude that calpain-3 is not responsible for Ca(2+)-induced disruption of EC coupling, but that mu-calpain is a plausible candidate.


Danon disease as a cause of concentric left ventricular hypertrophy in patients who underwent endomyocardial biopsy.
Danon disease is an X-linked dominant disorder; concentric left ventricular hypertrophy (LVH) is one of its manifestations. In this study, we investigated the prevalence of Danon disease in patients with concentric LVH who underwent endomyocardial biopsy (EMB). A total of 50 patients with concentric LVH underwent EMB from January 2008 to December 2010. Cardiac amyloidosis was diagnosed in 14 patients; genetic analysis of lysosome-associated membrane protein 2 (LAMP2) was done in the remaining 36 patients. Three novel LAMP2 frameshift mutations were found. They were c.808_809 insG in exon 6, c.320_321 insCATC in exon 3, and c.257_258delCC in exon 3, leading to a premature stop codon on cDNA analysis. The prevalence of Danon disease was seen in 6% (3 of 50) of unselected concentric LVH patients who underwent EMB, or 8% (3 of 36) after excluding cardiac amyloidosis through EMB. All the three patients were male teenagers with a mean age of 15 ± 1 years, and had mild mental retardation, two of the three with Wolff-Parkinson-White (WPW) syndrome and markedly increased left ventricular voltage. All the three patients had increased serum hepatic enzymes and creatine kinase (CK) concentrations. There was no death or cardiovascular hospitalization during 20 ± 15 months of follow-up. Danon disease may account for a number of patients with concentric LVH who underwent EMB. Danon disease should be suspected in the male teenager with concentric LVH, especially with elevated serum hepatic enzymes and CK concentrations, and/or WPW syndrome with markedly increased voltage of the left ventricle. Genetic analysis of LAMP2 can help make the diagnosis.


Detecting Regions of Maximal Divergence for Spatio-Temporal Anomaly Detection.
Automatic detection of anomalies in space- and time-varying measurements is an important tool in several fields, e.g., fraud detection, climate analysis, or healthcare monitoring. We present an algorithm for detecting anomalous regions in multivariate spatio-temporal time-series, which allows for spotting the interesting parts in large amounts of data, including video and text data. In opposition to existing techniques for detecting isolated anomalous data points, we propose the "Maximally Divergent Intervals" (MDI) framework for unsupervised detection of coherent spatial regions and time intervals characterized by a high Kullback-Leibler divergence compared with all other data given. In this regard, we define an unbiased Kullback-Leibler divergence that allows for ranking regions of different size and show how to enable the algorithm to run on large-scale data sets in reasonable time using an interval proposal technique. Experiments on both synthetic and real data from various domains, such as climate analysis, video surveillance, and text forensics, demonstrate that our method is widely applicable and a valuable tool for finding interesting events in different types of data.


Comparison between dietary assessment methods and biomarkers in estimating dietary (poly)phenol intake.
Background: although widely used, there is limited understanding of the suitability of different dietary assessment tools to estimate (poly)phenol intake. This study aims to compare the agreement between a food frequency questionnaire (FFQ) and a 7-day food diary (7DD) in assessing (poly)phenol intake and explore their associations with the urinary and plasma (poly)phenol metabolites. Methods: healthy free-living participants aged 18-80 years (n = 413) completed a 7DD and an FFQ (EPIC-Norfolk) and provided a 24 h urine and a fasting plasma sample. A comprehensive in-house (poly)phenol database was used to estimate (poly)phenol intake. The phenolic metabolite levels were analysed using a validated LC-MS method. The agreement between dietary assessment methods and biomarkers were evaluated by intraclass correlation coefficients (ICC), weighted kappa, quartile classification, Bland-Altman plots and correlations. Results: the total (poly)phenol intake estimated from FFQ was higher than from 7DD (median 1463 and 1042 mg d-1, respectively). The agreement between FFQ and 7DD were moderate (ICC 0.51-0.59) for total (poly)phenols, flavan-3-ols, total phenolic acids, hydroxycinnamic acids and alkylmethoxyphenols, and were poor for all the other classes and subclasses (ICC 0.00-0.48). Positive correlations with total urine phenolic metabolites were found in FFQ estimated anthocyanins, dihydroflavonols, total lignans, tyrosols, alkylmethoxyphenols, total phenolic acids, and total stilbenes and the 7DD estimated theaflavins and thearubigins (all FDR adjusted p values < 0.1). No significant correlations were found between total plasma phenolic metabolites and (poly)phenol intake. Conclusion: agreements between dietary assessment tools were moderate for the major classes of (poly)phenols, while agreements between (poly)phenol intake and biomarkers were poor. Future research using biomarker approaches to increase the accuracy of estimating (poly)phenol exposure in larger populations is needed.


Increased tau protein level in postmortem cerebrospinal fluid.
Microtubule-associated protein tau has been reported to be significantly increased in cerebrospinal fluid (CSF) of the patients with Alzheimer's disease (AD), which suggests that it is possibly a biological marker for the diagnosis of AD. The underlying mechanism of the increased tau level in CSF, however, is not known. In this study, the tau levels were compared between antemortem and postmortem CSF. The postmortem tau levels in CSF were significantly increased in all groups including AD, neurological control, and nondemented control. A striking elevation of CSF tau was observed during the postmortem change with the nondemented subjects. These findings may offer some insight into the understanding of the mechanism of the increased tau level in CSF with AD and other related disorders.


Effect of heparin-superoxide dismutase on γ-radiation induced DNA damage in vitro and in vivo.
The effects of heparin-superoxide dismutase (SOD) conjugate (heparin-SOD) on γ-radiation induced DNA damage in vivo and in vitro were evaluated. Plasmid pcDNA3.0 solution was mixed with heparin-SOD, SOD, and a mixture of heparin and SOD (heparin + SOD), respectively, and irradiated with (60)Co at a dosage of 120 Gy. DNA injury was analyzed using agarose gel electrophoresis. The results showed that the degree of injury of pcDNA3.0 mixed with heparin-SOD, SOD, or heparin + SOD was less than that of untreated pcDNA3.0, and among them the degree of injury of pcDNA3.0 mixed with heparin-SOD was the least. It also showed that the protective effect increased with an increase of heparin-SOD concentration. The effects of SOD and heparin-SOD on the DNA damage and tumor inhibition rate of (60)Co γ-radiation exposure on tumor-bearing mice were also studied. Agarose gel electrophoresis showed that, when different SOD samples were administered before irradiation, the thymus DNA injuries of heparin-SOD, SOD, or heparin + SOD groups were more serious than that of the control group, and the DNA injuries of heparin-SOD or heparin + SOD groups were the most serious, which contradicted the above in vitro experiments. However, when heparin-SOD was administered post irradiation, it showed a repairing effect on the injured DNA.


The quality of life of patients suffering from schizophrenia--a comparison with healthy controls.
In the past, the first goal of schizophrenia treatment was to reduce psychotic symptoms, mainly positive symptoms. Recently, as a result of an emphasis on patient needs, the concept of quality of life (QoL) has been brought into the treatment. The goal has therefore changed from the alleviation of symptoms to improvement of the patient's satisfaction with social activities. Self-evaluations by people with schizophrenia were previously thought to lack reliability because of the presence of psychopathological symptoms and poor awareness of the disease. Recently the importance of evaluating the satisfaction of patients themselves, however, has been recognized in schizophrenia. Studies on this field showed us, that QoL data from patients with chronic mental illness were reliable and concluded that subjective QoL evaluation was applicable to such patients. The purpose of the present study was to compare the QoL in patients suffering from schizophrenia in clinical remission with healthy controls and examine the extent of the effects of subjective cognitive functioning on QoL in these patients. Data were obtained using the quality of life questionnaire (Quality of Life Enjoyment and Satisfaction--Q-LES-Q), and subjective questionnaire for cognitive dysfunction (Cognitive Failures Questionnaire--CFQ) for 40 schizophrenia patients in clinical remission and 40 healthy controls. Cognitive function correlates negatively with subjective QoL in patients with schizophrenia.


Flux balance analysis for ethylene formation in genetically engineered Saccharomyces cerevisiae.
Biosynthesis of ethylene (ethene) is mainly performed by plants and some bacteria and fungi, via two distinct metabolic routes. Plants use two steps, starting with S-adenosylmethionine, while the ethylene-forming microbes perform an oxygen dependent reaction using 2-oxoglutarate and arginine. Introduction of these systems into Saccharomyces cerevisiae was studied in silico. The reactions were added to a metabolic network of yeast and flux over the two networks was optimised for maximal ethylene formation. The maximal ethylene yields obtained for the two systems were similar in the range of 7-8 mol ethylene/10 mol glucose. The microbial metabolic network was used for testing different strategies to increase the ethylene formation. It was suggested that supplementation of exogenous proline, using a solely NAD-coupled glutamate dehydrogenase, and using glutamate as the nitrogen source, could increase the ethylene formation. Comparison of these in silico results with published experimental data for yeast expressing the microbial system confirmed an increased ethylene formation when changing nitrogen source from ammonium to glutamate. The theoretical analysis methods indicated a much higher maximal yield per glucose for ethylene than was experimentally observed. However, such high ethylene yields could only be obtained with a concomitant very high respiration (per glucose). Accordingly, when ethylene production was optimised under the additional constraint of restricted respiratory capacity (i.e. limited to experimentally measured values) the theoretical maximal ethylene yield was much lower at 0.2/10 mol glucose, and closer to the experimentally observed values.


Telomere length analysis from minimally-invasively collected samples: Methods development and meta-analysis of the validity of different sampling techniques: American Journal of Human Biology.
Telomeres are the protective caps of chromosomes. They shorten with cell replication, age, and possibly environmental stimuli (eg, infection and stress). Short telomere length (TL) predicts subsequent worse health. Although venous whole blood (VWB) is most commonly used for TL measurement, other, more minimally invasive, sampling techniques are becoming increasingly common due to their field-friendliness, allowing for feasible measurement in low-resource contexts. We conducted statistical validation work for measuring TL in dried blood spots (DBS) and incorporated our results into a meta-analysis evaluating minimally invasive sampling techniques to measure TL. We isolated DNA extracts from DBS using a modified extraction protocol and tested how they endured different shipping conditions and long-term cryostorage. We then included our in-house DBS TL validation statistics (correlation values with VWB TL and age) in a series of meta-analyses of results from 24 other studies that published similar associations for values between TL measured in DBS, saliva, and buccal cells. Our modified DBS extraction technique produced DNA yields that were roughly twice as large as previously recorded. Partially extracted DBS DNA was stable for 7 days at room temperature, and still provided reliable TL measurements, as determined by external validation statistics. In our meta-analysis, DBS TL had the highest external validity, followed by saliva, and then buccal cells-possibly reflecting similarities/differences in cellular composition vs VWB. DBS DNA is the best proxy for VWB from the three minimally-invasively specimen types evaluated and can be used to expand TL research to diverse settings and populations.


[A new injectable delayed-action neuroleptic with sedative and antipsychotic action: cis-(Z)-clopenthixol decanoate. Clinical trials].
70 psychiatric patients were treated with a depot preparation of cis (Z) clopenthixol decanoate, a new sedative and anti-psychotic neuroleptic. The mean dosage interval was two weeks, an amount of drug from 50 to 1000 mg for each I.M. injection. Significant improvements were obtained on thinking disturbance, hostile-suspiciousness and anxious-depression symptoms groups. Thus, paranoid schizophrenia seems the best indication of cis (Z) clopenthixol decanoate. Side effects (parkinsonism, weight increase) were of low intensity, and no depression was observed. This new long-acting depot neuroleptic may be used not only in hospitalized chronic schizophrenic patients, but also in outpatients as maintenance treatment: excellent results were obtained in such patients with a very low (less than 200 mg) fortnightly dosage. Advantages and indications of cis (Z) clopenthixol decanoate are discussed.