Liver Transplantation for Acute Liver Failure Due to Yellow Phosphorus Poisoning - A Comprehensive Review.
Yellow phosphorus or metal phosphide (YP-MP) rodenticide poisoning has been a known cause of acute liver failure (ALF) in many countries of Asia and North and South America over the last decade. It is a highly toxic compound and is a well-known cause of intentional or accidental poisoning in both adults and children. In lower doses, it causes gastrointestinal symptoms and mild hepatic injury, and patients may spontaneously recover. In higher doses, hepatic necrosis and fatty infiltration may cause significant injury and may even lead to ALF, characterized by hepatic encephalopathy, coagulopathy, and lactic acidosis. Cardiotoxicity, rhabdomyolysis, and neutropenia are other well-documented complications. If untreated, it may lead to multi-organ dysfunction and death. Plasmapheresis and continuous renal replacement therapy (CRRT) have been used with limited success in patients who do not recover spontaneously. However, patients who develop ALF often need liver transplantation (LT). Liver transplantation has been successfully performed in ALF due to YP-MP poisoning in several countries, with good results in both adult and pediatric patients. Separate criteria for LT are important to ensure early and rapid listing of critical patients on the waiting list. The success rates of LT for ALF due to YP-MP rodenticide poisoning are very promising, provided there are no contra-indications to transplant. Plasma exchange, CRRT, or cytosorb can be used as a bridge to transplant in selected patients. In the long term, only with an increase in public awareness and sale restrictions can we prevent the intentional and accidental poisoning caused by this easily available, highly toxic compound.


Novel Cathelicidins from Pigeon Highlights Evolutionary Convergence in Avain Cathelicidins and Functions in Modulation of Innate Immunity.
Cathelicidins are short cationic host defense peptides and play a central role in host innate immune system. Here we identified two novel cathelicidins, Cl-CATH2 and 3, from Columba livia. Evolutionary analysis of avian cathelicidins via phylogenetic tree and Ka/Ks calculations supported the positive selection that prompted evolution of CATH2 to CATH1 and 3, which originate from common ancestor and could belong to one superfamily. Cl-CATH2 and 3 both adopt amphipathic α-helical comformations identified by circular dichroism and the 3D structures built by Rosetta. Cl-CATH2 of CATH2 family with the most expression abundance in bird, exhibited relatively weak antimicrobial activity, but acted instead on the innate immune response without showing undesirable toxicities. In macrophages primed by LPS, Cl-CATH2 significantly down-regulated the gene and protein expressions of inducible nitric oxide synthase and pro-inflammatory cytokines while enhancing the anti-inflammatory cytokine, acting through MAPK and NF-κB signaling pathways. Molecular docking shows for the first time that cathelicidin binds to the opening region of LPS-binding pocket on myeloid differentiation factor 2 (MD-2) of toll-like receptor (TLR)4-MD-2 complex, which in turn inhibits the TLR4 pathway. Our results, therefore, provide new insight into the mechanism underlying the blockade of TLR4 signaling by cathelicidins.


Changes in soil physical and chemical properties in long term improved natural and traditional agroforestry management systems of cacao genotypes in Peruvian Amazon.
Growing cacao (Theobroma cacao L.) in an agroforestry system generates a productive use of the land, preserves the best conditions for physical, chemical and biological properties of tropical soils, and plays an important role in improving cacao production and fertility of degraded tropical soils. The aim of this study was to evaluate the impact of two long term agroforestry systems of cacao management on soil physical and chemical properties in an area originally inhabited by 30 years old native secondary forest (SF). The two agroforestry systems adapted were: improved natural agroforestry system (INAS) where trees without economic value were selectively removed to provide 50% shade and improved traditional agroforestry system (ITAS) where all native trees were cut and burnt in the location. For evaluation of the changes of soil physical and chemical properties with time due to the imposed cacao management systems, plots of 10 cacao genotypes (ICS95, UF613, CCN51, ICT1112, ICT1026, ICT2162, ICT2171, ICT2142, H35, U30) and one plot with a spontaneous hybrid were selected. Soil samples were taken at 0-20, 20-40 and 40-60 cm depths before the installation of the management systems (2004), and then followed at two years intervals. Bulk density, porosity, field capacity and wilting point varied significantly during the years of assessment in the different soil depths and under the systems assessed. Soil pH, CEC, exchangeable Mg and sum of the bases were higher in the INAS than the ITAS. In both systems, SOM, Ext. P, K and Fe, exch. K, Mg and Al+H decreased with years of cultivation; these changes were more evident in the 0-20 cm soil depth. Overall improvement of SOM and soil nutrient status was much higher in the ITAS than INAS. The levels of physical and chemical properties of soil under cacao genotypes showed a marked difference in both systems.


Derivation of chondrogenically-committed cells from human embryonic cells for cartilage tissue regeneration.
Heterogeneous and uncontrolled differentiation of human embryonic stem cells (hESCs) in embryoid bodies (EBs) limits the potential use of hESCs for cell-based therapies. More efficient strategies are needed for the commitment and differentiation of hESCs to produce a homogeneous population of specific cell types for tissue regeneration applications. We report here that significant chondrocytic commitment of feeder-free cultured human embryonic stem cells (FF-hESCs), as determined by gene expression and immunostaining analysis, was induced by co-culture with primary chondrocytes. Furthermore, a dynamic expression profile of chondrocyte-specific genes was observed during monolayer expansion of the chondrogenically-committed cells. Chondrogenically-committed cells synergistically responded to transforming growth factor-beta1 (TGF-beta1) and beta1-integrin activating antibody by increasing tissue mass in pellet culture. In addition, when encapsulated in hydrogels, these cells formed cartilage tissue both in vitro and in vivo. In contrast, the absence of chondrocyte co-culture did not result in an expandable cell population from FF-hESCs. The direct chondrocytic commitment of FF-hESCs can be induced by morphogenetic factors from chondrocytes without EB formation and homogenous cartilage tissue can be formed in vitro and in vivo.


A Dual Immunological Raman-Enabled Crosschecking Test (DIRECT) for Detection of Bacteria in Low Moisture Food.
Among the physical, chemical and biological hazards that could arise with respect to food safety, bacterial contamination has been one of the main concerns in recent years. Bacterial contamination in low moisture foods (LMFs) was an emerging threat which used to draw less attention as LMFs were considered at low risk of such a hazard. Bacteria can survive in low moisture environments and cause foodborne diseases once they enter the digestive system. Common detection methods such as ELISA and PCR are not well suited to LMFs, as most of them operate under aqueous environments. In this study, a Dual Immunological Raman-Enabled Crosschecking Test (DIRECT) was developed for LMFs using a nano-scaled surface enhanced Raman scattering (SERS) biosensor platform and multivariate discriminant analysis with a portable Raman spectrometer. It could provide a limit of detection (LOD) of 102 CFU/g of bacteria in model LMFs, with a detection time of 30-45 min. It has the potential to become a quick screening method for on-site bacteria detection for LMFs to identify food safety risks in real time.


Monogalactosyldiacylglycerol deficiency in Arabidopsis affects pigment composition in the prolamellar body and impairs thylakoid membrane energization and photoprotection in leaves.
Monogalactosyldiacylglycerol (MGDG) is the major lipid constituent of chloroplast membranes and has been proposed to act directly in several important plastidic processes, particularly during photosynthesis. In this study, the effect of MGDG deficiency, as observed in the monogalactosyldiacylglycerol synthase1-1 (mgd1-1) mutant, on chloroplast protein targeting, phototransformation of pigments, and photosynthetic light reactions was analyzed. The targeting of plastid proteins into or across the envelope, or into the thylakoid membrane, was not different from wild-type in the mgd1 mutant, suggesting that the residual amount of MGDG in mgd1 was sufficient to maintain functional targeting mechanisms. In dark-grown plants, the ratio of bound protochlorophyllide (Pchlide, F656) to free Pchlide (F631) was increased in mgd1 compared to the wild type. Increased levels of the photoconvertible pigment-protein complex (F656), which is photoprotective and suppresses photooxidative damage caused by an excess of free Pchlide, may be an adaptive response to the mgd1 mutation. Leaves of mgd1 suffered from a massively impaired capacity for thermal dissipation of excess light due to an inefficient operation of the xanthophyll cycle; the mutant contained less zeaxanthin and more violaxanthin than wild type after 60 min of high-light exposure and suffered from increased photosystem II photoinhibition. This is attributable to an increased conductivity of the thylakoid membrane at high light intensities, so that the proton motive force is reduced and the thylakoid lumen is less acidic than in wild type. Thus, the pH-dependent activation of the violaxanthin de-epoxidase and of the PsbS protein is impaired.


Effect of Dimerization on the Dynamics of Neurotransmitter:Sodium Symporters.
Dimerization is a common feature among the members of the neurotransmitter:sodium symporter (NSS) family of membrane proteins. Yet, the effect of dimerization on the mechanism of action of NSS members is not fully understood. In this study, we examined the collective dynamics of two members of the family, leucine transporter (LeuT) and dopamine transporter (DAT), to assess the significance of dimerization in modulating the functional motions of the monomers. We used to this aim the anisotropic network model (ANM), an efficient and robust method for modeling the intrinsic motions of proteins and their complexes. Transporters belonging to the NSS family are known to alternate between outward-facing (OF) and inward-facing (IF) states, which enables the uptake and release of their substrate (neurotransmitter) respectively, as the substrate is transported from the exterior to the interior of the cell. In both LeuT and DAT, dimerization is found to alter the collective motions intrinsically accessible to the individual monomers in favor of the functional transitions (OF ↔ IF), suggesting that dimerization may play a role in facilitating transport.


Buoyant ascent rate profiles for the MK10 and MK11 submarine escape and immersion equipment.
Since the U.S. Navy transitioned from the MK10 to the MK11 submarine escape and immersion equipment (SEIE), there has been an increase in the incident rate of pulmonary barotrauma during submarine escape training. This study compares the ascent rate profiles of the MK10 and MK11 SEIE to determine if ascent rate differences between the escape suits are associated with increased pulmonary barotraumas. Buoyant ascent rates of the MK10 and MK11 SEIE were compared using weighted manikins equivalent to the 1st, 50th, and 99th percentile body weight of a submariner. Human ascents using the MK11 (n=126) were compared to human ascents in the same trainer wearing the MK10 (n=124). Manikin mean ascent times were faster for the MK10 than the MK11 (5.19 seconds vs 5.28 seconds, p ≺ 0.05). Terminal velocity (Vt) was affected by manikin weight (p ≺ 0.001). Human trials confirmed the manikin results. The average mean ascent velocity for the MK10 group was 0.155 meters/ second faster than the MK11 group's mean ascent velocity (p ≺ 0.001). Mean ascent velocity was inversely correlated with all anthropometrics for the MK10 group (p ≺ 0.01). Neither height nor body mass index showed a significant association with mean ascent velocity for the MK11 group. The Vt of buoyant ascents is significantly affected by body weight. As the mean ascent rate of the MK11 is slower than that of the MK10, ascent rate profile differences between the suits do not appear to explain the recent increase in pulmonary barotrauma incident rates during escape training.


The glycointeractome of serogroup B Neisseria meningitidis strain MC58.
Neisseria meningitidis express numerous virulence factors that enable it to interact with diverse microenvironments within the host, during both asymptomatic nasopharyngeal colonization and invasive disease. Many of these interactions involve bacterial or host glycans. In order to characterise the meningococcal glycointeractome, glycan arrays representative of structures found on human cells, were used as a screening tool to investigate host glycans bound by N. meningitidis. Arrays probed with fluorescently labelled wild-type MC58 revealed binding to 223 glycans, including blood group antigens, mucins, gangliosides and glycosaminoglycans. Mutant strains lacking surface components, including capsule, lipooligosaccharide (LOS), Opc and pili, were investigated to identify the factors responsible for glycan binding. Surface plasmon resonance and isothermal calorimetry were used to confirm binding and determine affinities between surface components and host glycans. We observed that the L3 LOS immunotype (whole cells and purified LOS) bound 26 structures, while L8 only bound 5 structures. We further demonstrated a direct glycan-glycan interaction between purified L3 LOS and Thomsen-Friedenreich (TF) antigen, with a KD of 13 nM. This is the highest affinity glycan-glycan interaction reported to date. These findings highlight the diverse glycointeractions that may occur during different stages of meningococcal disease, which could be exploited for development of novel preventative and therapeutic strategies.


Retrograde nerve growth factor signaling abnormalities in familial dysautonomia.
Familial dysautonomia (FD) is the most prevalent form of hereditary sensory and autonomic neuropathy (HSAN). In FD, a germline mutation in the Elp1 gene leads to Elp1 protein decrease that causes sympathetic neuron death and sympathetic nervous system dysfunction (dysautonomia). Elp1 is best known as a scaffolding protein within the nuclear hetero-hexameric transcriptional Elongator protein complex, but how it functions in sympathetic neuron survival is very poorly understood. Here, we identified a cytoplasmic function for Elp1 in sympathetic neurons that was essential for retrograde nerve growth factor (NGF) signaling and neuron target tissue innervation and survival. Elp1 was found to bind to internalized TrkA receptors in an NGF-dependent manner, where it was essential for maintaining TrkA receptor phosphorylation (activation) by regulating PTPN6 (Shp1) phosphatase activity within the signaling complex. In the absence of Elp1, Shp1 was hyperactivated, leading to premature TrkA receptor dephosphorylation, which resulted in retrograde signaling failure and neuron death. Inhibiting Shp1 phosphatase activity in the absence of Elp1 rescued NGF-dependent retrograde signaling, and in an animal model of FD it rescued abnormal sympathetic target tissue innervation. These results suggest that regulation of retrograde NGF signaling in sympathetic neurons by Elp1 may explain sympathetic neuron loss and physiologic dysautonomia in patients with FD.


Echocardiography in Percutaneous Left Atrial Appendage Occlusion and Related Complications.
Atrial fibrillation (AF) is a devastating disease with a large global prevalence. The left atrial appendage (LAA) is a major source of thrombi in patients with AF. Echocardiography plays an important role in identifying LAA thrombi and has become an invaluable imaging tool in planning for LAA occlusion (LAAO) in patients intolerant to anticoagulation. This review article will discuss the role of echocardiography in selecting patients for LAAO, intraprocedural monitoring, and identifying procedure-related complications.


How important is permanency planning for children? Considerations for pediatricians involved in child protection.
"Permanency planning" refers to maximizing stability in living situations for children in the care of child protection agencies. This issue concerns pediatricians who may be involved in assessing and providing care for these children. In North America, permanency planning is widely advocated if not always effectively implemented. The concept, however, is still controversial from the perspective of protecting parents' interests. This paper examines the principles and evidence underlying the concept of permanency planning in order to ascertain whether emphasizing it remains justified in terms of children's emotional health and development. Three related bodies of literature are reviewed: requirements for healthy child development, conditions that create risk for children, and outcomes for children in care. The findings suggest that permanency planning is vitally important for children and is not only justified, but should be given major emphasis. The implications for pediatricians are discussed.


A carbon nanotube toxicity paradigm driven by mast cells and the IL-₃₃/ST₂ axis.
Concern about the use of nanomaterials has increased significantly in recent years due to potentially hazardous impacts on human health. Mast cells are critical for innate and adaptive immune responses, often modulating allergic and pathogenic conditions. Mast cells are well known to act in response to danger signals through a variety of receptors and pathways including IL-33 and the IL-1-like receptor ST2. Here, the involvement of mast cells and the IL-33/ST2 axis in pulmonary and cardiovascular responses to multi-walled carbon nanotube (MWCNT) exposure are examined. Toxicological effects of MWCNTs are observed only in mice with a sufficient population of mast cells and are not observed when mast cells are absent or incapable of responding to IL-33. Our findings establish for the first time that mast cells and the IL-33/ST2 axis orchestrates adverse pulmonary and cardiovascular responses to an engineered nanomaterial, giving insight into a previously unknown mechanism of toxicity. This novel mechanism of toxicity could be used for assessing the safety of engineered nanomaterials and provides a realistic therapeutic target for potential nanoparticle induced toxicities.


Evaluating the impact on physical inactivity of Together an Active Future, a partnership approach to physical activity promotion. A difference-in-differences study.
Low physical activity is one of the leading causes of ill health in the UK and an important determinant of health inequalities. Little is known about the effectiveness of community-wide interventions to increase physical activity and whether effects differ by demographic groups, including area deprivation and ethnicity. 6 relatively disadvantaged local authority areas in Lancashire, UK, between 2016 and 2021. We conducted a doubly robust difference-in-differences study using a large nationally representative repeated cross-sectional survey to investigate the impact of Together an Active Future (TAAF), an intervention aiming to reduce physical inactivity through a programme of creative engagement, partnership building, training and communication. The primary outcome was physical inactivity (the percentage of the population engaging in less than 30 min physical activity of at least moderate intensity per week). While inactivity increased during the pandemic, it increased to a lesser extent in the intervention population. TAAF was associated with 2.63 percentage point lower level of physical inactivity (95% CI 0.80 to 4.45) in the intervention group relative to the control group. Subgroup analysis found no evidence of differences in effect between groups defined by deprivation, ethnicity, disability, gender or age. The study suggests that a programme of creative engagement, partnership building, training and communication can help reduce physical inactivity, potentially mitigating some of the effect of pandemic restrictions. Further monitoring is required to understand the impact of this intervention outside of the pandemic context.


Kick effect of enzymes causes filament compression.
We investigate the influence of enzymes on the structure and dynamics of a filament by dissipative particle dynamics simulations. Enzyme exerts a kick force on the filament monomer. We pay particular attention to two factors: the magnitude of kick force and enzyme concentration. Large kick force as well as high enzyme concentration prefers a remarkable compression of the filament reminiscent of the effective depletion interaction owing to an effective increase in enzyme size and the reduction of solvent quality. Additionally, the kick effect gives rise to an increase of enzyme density from the center-of-mass of the filament to its periphery. Moreover, the increase of enzyme concentration and kick force also causes a decrease in relaxation time. Our finding is helpful to understand the role of catalytic force in chemo-mechano-biological function and the filament behavior under chemical reaction via kick-induced change of solvent quality.


Association between cigarette smoking and the vaginal microbiota: a pilot study.
Smoking has been identified in observational studies as a risk factor for bacterial vaginosis (BV), a condition defined in part by decimation of Lactobacillus spp. The anti-estrogenic effect of smoking and trace amounts of benzo[a]pyrene diol epoxide (BPDE) may predispose women to BV. BPDE increases bacteriophage induction in Lactobacillus spp. and is found in the vaginal secretions of smokers. We compared the vaginal microbiota between smokers and non-smokers and followed microbiota changes in a smoking cessation pilot study. In 2010-2011, 20 smokers and 20 non-smokers were recruited to a cross-sectional study (Phase A) and 9 smokers were enrolled and followed for a 12-week smoking cessation program (Phase B). Phase B included weekly behavioral counseling and nicotine patches to encourage smoking cessation. In both phases, participants self-collected mid-vaginal swabs (daily, Phase B) and completed behavioral surveys. Vaginal bacterial composition was characterized by pyrosequencing of barcoded 16S rRNA genes (V1-V3 regions). Vaginal smears were assigned Nugent Gram stain scores. Smoking status was evaluated (weekly, Phase B) using the semi-quantitative NicAlert® saliva cotinine test and carbon monoxide (CO) exhalation. In phase A, there was a significant trend for increasing saliva cotinine and CO exhalation with elevated Nugent scores (P value <0.005). Vaginal microbiota clustered into three community state types (CSTs); two dominated by Lactobacillus (L. iners, L. crispatus), and one lacking significant numbers of Lactobacillus spp. and characterized by anaerobes (termed CST-IV). Women who were observed in the low-Lactobacillus CST-IV state were 25-fold more likely to be smokers than those dominated by L. crispatus (aOR: 25.61, 95 % CI: 1.03-636.61). Four women completed Phase B. One of three who entered smoking cessation with high Nugent scores demonstrated a switch from CST-IV to a L.iners-dominated profile with a concomitant drop in Nugent scores which coincided with completion of nicotine patches. The other two women fluctuated between CST-IV and L. iners-dominated CSTs. The fourth woman had low Nugent scores with L. crispatus-dominated CSTs throughout. Smokers had a lower proportion of vaginal Lactobacillus spp. compared to non-smokers. Smoking cessation should be investigated as an adjunct to reducing recurrent BV. Larger studies are needed to confirm these findings.


Predictors of myocardial damage prior to hospital admission among patients with acute chest pain or other symptoms raising a suspicion of acute coronary syndrome.
To evaluate factors which, prior to hospital admission, predict the development of acute coronary syndrome or acute myocardial infarction among patients who call for an ambulance due to suspected acute coronary syndrome. Prospective observational study. All the patients who called for an ambulance due to suspected acute coronary syndrome in South Hospital's catchment area in Stockholm and in the Municipality of Göteborg between January and November 2000, were included. On arrival of the ambulance crew, a blood sample was drawn for bedside analysis of serum myoglobin, creatine kinase (CK)MB and troponin-I. A 12-lead electrocardiogram (ECG) was simultaneously recorded. In all, 538 patients took part in the survey. Their mean age was 69 years and 58% were men. In all, 307 patients (57.3%) had acute coronary syndrome and 158 (29.5%) had acute myocardial infarction. Independent predictors of the development of acute coronary syndrome were a history of myocardial infarction (P=0.006), angina pectoris (P=0.005) or hypertension (P=0.017), ECG changes with ST elevation (P<0.0001), ST depression (P<0.0001) or T-wave inversion (P=0.012) and the elevation of CKMB (P=0.005). Predictors of acute myocardial infarction were being a man (P=0.011), ECG changes with ST elevation (P<0.0001) or ST depression (P<0.0001), the elevation of CKMB (P<0.0001) and a short interval between the onset of symptoms and blood sampling (P=0.010). Among patients transported by ambulance due to suspected acute coronary syndrome, predictors of myocardial damage can be defined prior to hospital admission on the basis of previous history, sex, ECG changes, the elevation of biochemical markers and the interval from the onset of symptoms until the ambulance reaches the patient.


A 3D electrical impedance tomography (EIT) system for breast cancer detection.
A medical device which allows imaging of the distribution of conductivity in 3D in regions below the skin surface has been developed and tested. Its purpose is to enable early detection and preliminary diagnosis of breast tumours. Design of the measuring system and software are described. Results of clinical evaluation of the system are presented. EIT images of healthy and cancerous breasts are presented and discussed. The system is able to visualize various states of the breast and it may be possible to apply it to breast cancer detection.


Incomplete inhibition of platelet aggregation and glycoprotein IIb-IIIa receptor blockade by abciximab: importance of internal pool of glycoprotein IIb-IIIa receptors.
Resting platelets contain a substantial internal pool of GPIIb-IIIa complexes that is exposed on the surface of activated platelets. Whether the exposure of internal GPIIb-IIIa complexes on the activated platelet surface affects therapy with GPIIb-IIIa antagonists is poorly understood. We addressed this issue in thirteen patients who underwent elective coronary stenting and received abciximab. Platelet aggregation, surface expression of GPIIb-IIIa and P-selectin, receptor blockade of GPIIb-IIIa, and platelet release in response to ADP and thrombin-receptor activating peptide (TRAP) were determined ex vivo by Lumi-aggregometry and flow cytometry before, during and after abciximab administration. We found that inhibition of aggregation and GPIIb-IIIa blockade of ADP-stimulated platelets was almost complete during abciximab administration. In contrast, when TRAP was used to stimulate platelets ex vivo aggregation was only partially inhibited, most likely due to release of internal pool of unblocked GPIIb-IIIa complexes. Using electron microscopy we found that 7E3-occupied GPIIb-IIIa complexes are internalized into the surface connected system (SCS) and the alpha-granules of washed platelets which was associated with a reduced degranulation of the alpha-granula membrane protein P-selectin. We conclude, that despite internalization of abciximab into the internal pool of GPIIb-IIIa, upon strong platelet activation with thrombin a significant amount of unblocked internal GPIIb-IIIa can be exposed on the platelet surface and mediate platelet aggregation. Incomplete blockade of the internal GPIIb-IIIa pool may limit clinical efficacy of abciximab.


Insight into protein S-nitrosylation in Chlamydomonas reinhardtii.
Protein S-nitrosylation, a post-translational modification (PTM) consisting of the covalent binding of nitric oxide (NO) to a cysteine thiol moiety, plays a major role in cell signaling and is recognized to be involved in numerous physiological processes and diseases in mammals. The importance of nitrosylation in photosynthetic eukaryotes has been less studied. The aim of this study was to expand our knowledge on protein nitrosylation by performing a large-scale proteomic analysis of proteins undergoing nitrosylation in vivo in Chlamydomonas reinhardtii cells under nitrosative stress. Using two complementary proteomic approaches, 492 nitrosylated proteins were identified. They participate in a wide range of biological processes and pathways, including photosynthesis, carbohydrate metabolism, amino acid metabolism, translation, protein folding or degradation, cell motility, and stress. Several proteins were confirmed in vitro by western blot, site-directed mutagenesis and activity measurements. Moreover, 392 sites of nitrosylation were also identified. These results strongly suggest that S-nitrosylation could constitute a major mechanism of regulation in C. reinhardtii under nitrosative stress conditions. This study constitutes the largest proteomic analysis of protein nitrosylation reported to date. The identification of 381 previously unrecognized targets of nitrosylation further extends our knowledge on the importance of this PTM in photosynthetic eukaryotes. The data have been deposited to the ProteomeXchange repository with identifier PXD000569.


[Efficacy and safety of use of likoprofit in patients with chronic prostatitis and prostatic adenoma].
The article summarizes the results of the clinical trials on application of likoprofit in patients with a chronic prostatitis and prostate adenoma, which were conducted by the Russian urologists for the last 8 years. Application of likoprofit in patients after TURP contributes to significantly earlier and effective restoration of microcirculation, which decreases the risk of development of postoperative complications and accelerates rehabilitation of patients. Studies in which likoprofit was applied in patients with a chronic prostatitis and prostate adenoma, proved that likoprofit also has antiedematous effect, improves the urination act, improves ejaculate parameters, positively impacts on sexual function, and has a high safety profile.


Draft Genome Sequence and Annotation of the Phytopathogenic Ralstonia pickettii (Previously Burkholderia glumae) Strain ICMP-8657.
Strain ICMP-8657 was formerly taxonomically classified as Burkholderia glumae and reported to be the producer of an antibacterial pyrazole derivative. Here, we report the draft genome sequence of ICMP-8657, which failed to demonstrate the biosynthetic capacity to produce the stated antibacterial compound, leading to its taxonomic reclassification as Ralstonia pickettii ICMP-8657.


Brucellosis in Colombia: Current Status and Challenges in the Control of an Endemic Disease.
Brucellosis is a zoonosis of nearly worldwide distribution. The disease is considered to be endemic in most of the developing countries with a substantial impact on both human and animal health as well as on the economy. The aim of this scoping review is to provide an overview of the brucellosis status in Colombia and the factors associated with its persistence, to highlight the strengths and gaps of the adopted countermeasures and to supply evidence to policy-makers on the best approaches to mitigate the disease burden. Due to the presence of brucellosis in several susceptible production livestock systems scattered throughout the country, a plan for its control, prevention and eradication was established almost 20 years ago. However, despite extensive efforts, brucellosis prevalence has fluctuated over the years without any trend of decreasing. The restricted budget allocated for brucellosis control is a limiting factor for the success of the program. For instance, the absence of indemnities for farmers results in infected animals remaining on farms which potentially increases the risk of disease spread. Likewise, disease surveillance is restricted to Brucella abortus and excludes other Brucella species of importance, such as B. melitensis and B. suis. The countermeasures are mostly focused on cattle and only a few actions are in place for the management of brucellosis in other livestock species. In humans, cases of brucellosis are annually diagnosed, although the disease remains highly underreported. High impact educational and training programs are required to address the disease in a comprehensive manner, including vulnerable groups, such as traditional smallholders and low-productivity regions, as well as other stakeholders, such as healthcare and veterinary authorities. Important financial investments based on sustained cooperation between governmental institutions, industry, and farmers are important for developing affordable and effective strategies to control the disease.


The incidence of health financing in South Africa: findings from a recent data set.
There is an international call for countries to ensure universal health coverage. This call has been embraced in South Africa (SA) in the form of a National Health Insurance (NHI). This is expected to be financed through general tax revenue with the possibility of additional earmarked taxes including a surcharge on personal income and/or a payroll tax for employers. Currently, health services are financed in SA through allocations from general tax revenue, direct out-of-pocket payments, and contributions to medical scheme. This paper uses the most recent data set to assess the progressivity of each health financing mechanism and overall financing system in SA. Applying standard and innovative methodologies for assessing progressivity, the study finds that general taxes and medical scheme contributions remain progressive, and direct out-of-pocket payments and indirect taxes are regressive. However, private health insurance contributions, across only the insured, are regressive. The policy implications of these findings are discussed in the context of the NHI.


EDHF and gap junctions: important regulators of vascular tone within the microcirculation.
Arterioles within the microcirculation control organ blood flow and represent the main peripheral resistance within the circulation. However, larger vessels with a diameter of more than 150 microm are mostly used to study vascular behavior. Although arterioles have features in common with these conducting vessels, they exhibit distinct properties and the contribution of different pathways to constriction or relaxation varies with vessel size. This is especially the case for endothelium-dependent relaxations, which occur in response to mechanical stimuli (e.g. blood flow) and agonists. Autacoids released from the endothelium include nitric oxide, prostaglandins and an endothelium-derived hyperpolarizing factor (EDHF). Whereas nitric oxide is dominant in larger vessels, the importance of EDHF increases with decreasing vessel size. Its chemical nature is still a matter of debate and different substances have been identified to act as an EDHF in different vascular beds, e.g. epoxyeicosanoids, potassium ions, anandamide, hydrogen peroxide or C-type natriuretic peptide. Despite this heterogeneity of proposed factors it is unclear if such a factor indeed exists in all vessels since the hyperpolarization of vascular smooth muscle has been proposed to be induced by simple current transfer from the adjacent endothelium. For this to occur the cells need to be electrically coupled and this requirement is fulfilled by gap junctions which are composed of connexins forming intercellular channels. Aside from myoendothelial coupling gap junctions also interconnect endothelial cells thus creating a functional unit, which efficiently synchronizes cellular behavior within the arteriolar tree of the microcirculation.


Neural activity related to drug craving in cocaine addiction.
Crack cocaine dependence and addiction is typically associated with frequent and intense drug wanting or craving triggered by internal or environmental cues associated with past drug use. Water O 15 positron emission tomography (PET) studies were used to localize alterations in synaptic activity related to cue-induced drug craving in 8 crack cocaine-dependent African American men. In a novel approach, script-guided imagery of autobiographical memories were used as individualized cues to internally generate a cocaine craving state and 2 control (ie, anger and neutral episodic memory recall) states during PET image acquisition. The mental imagery of personalized drug use and anger-related scripts was associated with self-ratings of robust drug craving or anger, and comparable alterations in heart rate. Compared with the neutral imagery control condition, imagery-induced drug craving was associated with bilateral (right hemisphere amygdala activation greater than left) activation of the amygdala, the left insula and anterior cingulate gyrus, and the right subcallosal gyrus and nucleus accumbens area. Compared with the anger control condition, internally generated drug craving was associated with bilateral activation of the insula and subcallosal cortex, left hippocampus, and anterior cingulate cortex and brainstem. A brain-wide pixel-by-pixel search indicated significant positive and negative correlations between imagery-induced cocaine craving and regional cerebral blood flow (rCBF) in distributed sites. The collected findings suggest the craving-related activation of a network of limbic, paralimbic, and striatal brain regions, including structures involved in stimulus-reward association (amygdala), incentive motivation (subcallosal gyrus/nucleus accumbens), and anticipation (anterior cingulate cortex).


Pathways and determinants of early spontaneous vegetation succession in degraded lowland of South China.
Continuous and prolonged human disturbances have caused severe degradation of a large portion of lowland in South China, and how to restore such degraded ecosystems becomes an increasing concern. The process and mechanisms of spontaneous succession, which plays an important role in vegetation restoration, have not been adequately examined. To identify the pathways of early spontaneous vegetation succession, 41 plots representing plant communities abandoned over different times were established and investigated. The communities and indicator species of the vegetation were classified by analyzing the important values of plant species using multivariate analyses. The results indicated that the plant species could be classified into nine plant communities representing six succession stages. The pathway and species composition also changed in the process of succession. We also measured 13 environmental variables of microtopography, soil structure and soil nutrition in each plot to examine the driving forces of succession and the vegetation-environment relationships. Our results showed that the environmental variables changed in diverse directions, and that soil bulk density, soil water capacity and soil acidity were the most important factors.


Detection of the G>C SNP and rare mutations in the 28-bp repeat of TYMS using gel-based capillary electrophoresis.
Polymorphisms in the 5' regulatory region of the thymidylate synthase gene (TYMS) have been shown to modulate thymidylate synthase expression and are associated with resistance to fluoropyrimidine-based therapies. These polymorphisms include a two repeat (2R) or three repeat (3R) of a 28-bp sequence and a G>C SNP in the second repeat of the 3R allele (TSER*3 G>C). Genotyping methods for the TYMS 5'-UTR polymorphisms have typically involved visualizing PCR and RFLP products on agarose gels. This article describes the use of a robust capillary electrophoresis assay for TYMS 5'-UTR genotyping. As part of pharmacogenetic studies, we performed TYMS genotyping for the 5'-UTR polymorphisms in 314 colorectal cancer patients. A gel-based capillary electrophoresis method, employing a high-resolution gel cartridge on a QIAxcel(®) system, was developed to detect PCR products and RFLP fragment sizes. The high resolution of the capillary electrophoresis technique allowed identification of a 6-bp insertion in the second repeat of the 3R allele in three patients. The frequency of the insertion allele was 0.4% in Caucasians and 1.3% in African-Americans. We also found 3.3% of Caucasian patients were heterozygous for a G>C SNP in the first repeat of the 2R allele, but this allele was not observed in the African-American patients. We describe a robust RFLP genotyping technique that employs size discrimination by capillary electrophoresis to genotype the TYMS TSER*3 G>C SNP. The technique also allows identification of a 6-bp insertion in the 3R allele, and we report the allelic frequencies for two uncommon TSER alleles.


(18)F-FDG-PET/CT and (18)F-NaF-PET/CT in men with castrate-resistant prostate cancer.
To evaluate (18)F-labeled-fluorodeoxyglucose ((18)F-FDG-) and (18)F-labeled-sodium fluoride ((18)F-NaF-) positron emission tomography/computed tomography (PET/CT) as biomarkers in metastatic castrate-resistant prostate cancer (mCRPC). Nine men (53-75 years) in a phase 1 trial of abiraterone and cabozantinib had (18)F-FDG-PET/CT, (18)F-NaF-PET/CT and standard imaging ((99m)Tc-labeled-methylene-diphosphonate ((99m)Tc-MDP) bone scan and abdominal/pelvic CT) at baseline and after 8 weeks of therapy. Baseline disease was classified as widespread (18)F-FDG-avid, oligometastatic (18)F-FDG-avid (1 site), or non-(18)F-FDG-avid. Metabolic response was classified using European Organisation for Research and Treatment of Cancer (EORTC) criteria. Treatment response using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, Prostate Cancer Working Group 2 (PCWG2) guidelines and days on trial (DOT) were recorded. All men were followed for 1 year or until progression. Four men had (18)F-FDG-avid disease: two with widespread (DOT 53 and 76) and two with oligometastatic disease (DOT 231 and still on trial after 742+ days). Five men had non-(18)F-FDG-avid disease; three remained stable or improved (2 still on trial while one discontinued for non-oncologic reasons; DOT 225-563+), and 2 progressed (DOT 285 and 532). Despite the small sample size, Kaplan-Meier analysis showed a significant difference in progression free survival (PFS) between men with widespread (18)F-FDG-avid, oligometastatic (18)F-FDG-avid and non-(18)F-FDG-avid disease (p < 0.01). All men had (18)F-NaF-avid disease. Neither (18)F-NaF-avid disease extent nor intensity was predictive of treatment response. (18)F-FDG-PET/CT may be superior to (18)F-NaF-PET/CT and standard imaging in men with mCRPC on abiraterone and cabozantinib. (18)F-FDG-PET/CT may have potential to stratify men into 3 groups (widespread vs. oligometastatic (18)F-FDG-avid vs. non-(18)F-FDG-avid mCRPC) to tailor therapy. Further evaluation is warranted.


Morphology of transplacentally induced nervous system tumors in rats: some aspects of this model in neurooncology.
The morphology of 1136 single tumors of the nervous system induced by transplacental action of alkylating and related substances is analyzed. Tumors of the central nervous system are considered to yield the most representative model for the different stages of gliomas in humans. This and derived standardized models therefore are appropriate for studying open questions, especially as regards the treatment of human brain tumors.


Distributed Adaptive Neural Control for Stochastic Nonlinear Multiagent Systems.
In this paper, a consensus tracking problem of nonlinear multiagent systems is investigated under a directed communication topology. All the followers are modeled by stochastic nonlinear systems in nonstrict feedback form, where nonlinearities and stochastic disturbance terms are totally unknown. Based on the structural characteristic of neural networks (in Lemma 4), a novel distributed adaptive neural control scheme is put forward. The raised control method not only effectively handles unknown nonlinearities in nonstrict feedback systems, but also copes with the interactions among agents and coupling terms. Based on the stochastic Lyapunov functional method, it is indicated that all the signals of the closed-loop system are bounded in probability and all followers' outputs are convergent to a neighborhood of the output of leader. At last, the efficiency of the control method is testified by a numerical example.


Chronic kidney disease and risk of death from infection.
Infection, bacteremia and sepsis are major sources of morbidity and mortality in patients with end-stage renal disease. This study sought to determine the association between predialysis chronic kidney disease (CKD) and infection-related mortality. We analyzed participants in the Third National Health and Nutrition Examination Survey (NHANES III). The study included adults ≥45- years-old without end-stage renal disease. Estimated glomerular filtration rate (eGFR) was categorized as ≥60, 45-59.9 and <45 ml/min per 1.73 m(2), and urinary albumin-to-creatinine ratio (ACR) as <30, 30-299.9 and ≥300 mg/g. The study identified infection-related mortality, including septicemia, respiratory, abdominal and gastrointestinal, cardiac, kidney and genitourinary, neurologic, and other infections over a median of 13 years using the National Death Index. Of 7,400 participants included in the study, 206 died from infections. Compared to individuals with eGFR ≥60 ml/min per 1.73 m(2), infection-related mortality was higher for those with lower eGFR [adjusted HR = 1.36 (95% CI: 0.81, 2.30) and 2.36 (1.04, 5.38) for eGFR of 45-59.9 and <45 ml/min per 1.73 m(2), respectively; p trend = 0.06]. Compared to individuals with ACR <30 mg/g, infection-related mortality was higher for ACR levels of 30-299 and ≥300 mg/g [adjusted HR = 1.68 (95% CI: 0.97, 2.92) and 2.84 (0.92, 8.74), p trend = 0.02]. Reduced eGFR and albuminuria are associated with increased risk for infection-related mortality. Efforts are needed to reduce its incidence and mitigate the effects of infections among individuals with CKD.


Phase-coexisting patterns, horizontal segregation, and controlled convection in vertically vibrated binary granular mixtures.
We report patterns consisting of coexistence of synchronous and asynchronous states [for example, a granular gas co-existing with (i) bouncing bed, (ii) undulatory subharmonic waves, and (iii) Leidenfrost-like states] in experiments on vertically vibrated binary granular mixtures in a Hele-Shaw cell. Most experiments have been carried out with equimolar binary mixtures of glass and steel balls of same diameter by varying the total layer height (F) for a range of shaking acceleration (Γ). All patterns as well as the related phase diagram in the (Γ,F) plane have been reproduced via molecular dynamics simulations of the same system. The segregation of heavier and lighter particles along the horizontal direction is shown to be the progenitor of such phase-coexisting patterns as confirmed in both experiment and simulation. At strong shaking we uncover a partial convection state in which a pair of convection rolls is found to coexist with a Leidenfrost-like state. The crucial role of the relative number density of two species on controlling the buoyancy-driven granular convection is demonstrated. The onset of horizontal segregation can be explained in terms of an anisotropic diffusion tensor.


Neural representations of cryo-EM maps and a graph-based interpretation.
Advances in imagery at atomic and near-atomic resolution, such as cryogenic electron microscopy (cryo-EM), have led to an influx of high resolution images of proteins and other macromolecular structures to data banks worldwide. Producing a protein structure from the discrete voxel grid data of cryo-EM maps involves interpolation into the continuous spatial domain. We present a novel data format called the neural cryo-EM map, which is formed from a set of neural networks that accurately parameterize cryo-EM maps and provide native, spatially continuous data for density and gradient. As a case study of this data format, we create graph-based interpretations of high resolution experimental cryo-EM maps. Normalized cryo-EM map values interpolated using the non-linear neural cryo-EM format are more accurate, consistently scoring less than 0.01 mean absolute error, than a conventional tri-linear interpolation, which scores up to 0.12 mean absolute error. Our graph-based interpretations of 115 experimental cryo-EM maps from 1.15 to 4.0 Å resolution provide high coverage of the underlying amino acid residue locations, while accuracy of nodes is correlated with resolution. The nodes of graphs created from atomic resolution maps (higher than 1.6 Å) provide greater than 99% residue coverage as well as 85% full atomic coverage with a mean of 0.19 Å root mean squared deviation. Other graphs have a mean 84% residue coverage with less specificity of the nodes due to experimental noise and differences of density context at lower resolutions. The fully continuous and differentiable nature of the neural cryo-EM map enables the adaptation of the voxel data to alternative data formats, such as a graph that characterizes the atomic locations of the underlying protein or macromolecular structure. Graphs created from atomic resolution maps are superior in finding atom locations and may serve as input to predictive residue classification and structure segmentation methods. This work may be generalized to transform any 3D grid-based data format into non-linear, continuous, and differentiable format for downstream geometric deep learning applications.


Chemotherapy after nivolumab for advanced gastric cancer (REVIVE): a prospective observational study.
Nivolumab therapy is a standard-of-care treatment for heavily pretreated patients with advanced gastric cancer (AGC). Previous studies have reported improvement in the objective response rate to chemotherapy after nivolumab therapy for other types of cancer. This study evaluated the efficacy and safety of chemotherapy after nivolumab therapy in AGC. We conducted a prospective, multicenter, observational study in pretreated patients with nivolumab-refractory or -intolerant AGC. Patients received irinotecan, oxaliplatin-containing regimens, or trifluridine/tipiracil. The primary endpoint was overall survival. A total of 199 patients were included (median age: 69 years; male: 70%; female: 30%). Median overall survival and progression-free survival were 7.5 months [95% confidence interval (CI): 6.7-9.7 months] and 2.9 months (95% CI: 2.2-3.5 months), respectively. Objective response and disease control rates were 16.8% (95% CI: 11.6% to 23.6%) and 18.9% (95% CI: 38.9% to 54.6%), respectively. A prognostic index using alkaline phosphatase and the Glasgow Prognostic Score was generated to classify patients into three risk groups (good, moderate, and poor). The hazard ratios of the moderate and poor groups to the good group were 1.88 (95% CI: 1.22-2.92) and 3.29 (95% CI: 1.92-5.63), respectively. At the initiation of chemotherapy, 42 patients had experienced immune-related adverse events due to prior nivolumab therapy. The most common grade 3-4 adverse events were neutropenia (7.5%), anemia (8.0%), and anorexia (7.5%). The administration of cytotoxic chemotherapy after nivolumab therapy may give rise to a synergistic antitumor effect in AGC. Further investigation is warranted to confirm these findings.


Caring for Premature Life and Death: The Relational Dynamics of Detachment in a NICU.
Drawing on fieldwork in a neonatal intensive care unit (NICU) in Chiang Mai during 2010 and 2012, I examine neonatal care as a contingent entanglement of technological and ethical relationships with vulnerable others. Along the continuum of universal antenatal and delivery care, neonatal medicine becomes a normative part of reproductive health care in Chiang Mai. As the NICU opens its door to sick newborns whose belonging to kinship and the nation-state is uncertain, neonatal care requires deliberate practices to incorporate them into life-sustaining connections. By tracing medical staff's effort to be accountable to their fragile patients, I show that withdrawing of intensive care is relational work that requires affective involvement and distancing through commensality, prosthetic extensions, and karmic network. This specific mode of care, which is premised on the combination of unconditional openness and careful detachment, offers insight into a possible enactment of hospitality within biomedical institutions.


Changes in seizure threshold over the course of electroconvulsive therapy affect therapeutic response and are detected by ictal EEG ratings.
Therapeutic effectiveness of electroconvulsive therapy is influenced by the degree to which the stimulus intensity exceeds the seizure threshold. However, the threshold rises variably over the treatment course, confounding maintenance of desired relative stimulus intensity. In 47 depressed patients, decreases in relative stimulus intensity between treatments 1 and 6 were associated with diminished therapeutic response at treatment 6 for unilateral (UL) ECT. A multivariate model including manual ratings of ictal EEG data predicted whether seizure threshold rose with 82% accuracy. The same EEG variables were also significantly related to therapeutic response. Thus, decreases in relative stimulus intensity over the ECT course affect the therapeutic potency of UL ECT. Further, ictal EEG indices have considerable potential for predicting such stimulus intensity changes and their effect on therapeutic outcome.


Immunohistochemical study of opioid receptors after chronic morphine treatment in rats.
Previously, we have used the biochemical receptor binding method to investigate whether down-regulation of the opioid receptor is a mechanism for morphine tolerance, and we were led to a negative conclusion. In the current study, we further used immunohistochemistry to reinvestigate this issue. Male Sprague-Dawley rats (250-300 g) were chronically treated with morphine s.c. for 2, 4 or 6 days, using an escalating dosage paradigm (5-45 mg), which resulted in a 1.8 to 4.0-fold increase in AD50. Rat brains were removed, frozen, coronally sectioned (14 microm) and processed for mu- or delta-opioid receptor immunohistochemistry using the Avidin-Biotin Complex (ABC) method. No significant decrease in mu-opioid receptor (MOR) immunodensity was found in most of the brain regions, which were enriched with MOR after chronic treatment with morphine except for the anteroventral thalamic nucleus in the ventrolateral part (AVVL). No significant change in delta-opioid receptor (DOR) immunodensity after chronic treatment with morphine was found either. Therefore, our conclusion is that down regulation of opioid receptors may not be an important mechanism for morphine tolerance.


Cutaneous metastasis from small cell lung carcinoma. Case report.
We report a rare case of cutaneous metastatic small cell lung carcinoma of the upper lip in a 73-year-old man, which was excised and the defect repaired with a single advancement flap from the cheek. The prognosis of such lesions is poor, and the incidence of other metastases elsewhere is high. The aim of treatment was to give him optimal quality of life for the short time left. The patient died of his primary disease four months later.


The effects of basic fitness parameters on the implementation of specific military activities.
The aim of this study was to determine whether basic fitness parameters have the impact on the specific military activity such as walking 18 km with 25 kg of load. The members of Croatian Armed Forces (30 soldiers) were tested before the beginning of the training program. The study has included variables for the assessment of muscular endurance: push-ups in 2 minutes, sit-ups in 2 minutes, maximum number of pull-ups before dropping from the bar, bench press with 70% of body weight-max number of repetitions, max number of squats for 60 seconds, then the variables for the assessment of aerobic capacity: the 3200m run and relative oxygen uptake using the direct method of measurement on a treadmill as well as the variable for the assessment of body fat (body fat %). As the criterion variable, it was used the 18 km walking with 25 kg of load. The results of the regression analysis have shown statistically significant relation of predictor variables with the criterion variable. The two variables, 3200m run and RVO2 had a significant Beta coefficient. Based on the obtained results it could be concluded that great cardio-respiratory endurance has a much larger impact on the walking length of 18 km with a load of 25 kg than other fitness parameters.


Policy search with rare significant events: Choosing the right partner to cooperate with.
This paper focuses on a class of reinforcement learning problems where significant events are rare and limited to a single positive reward per episode. A typical example is that of an agent who has to choose a partner to cooperate with, while a large number of partners are simply not interested in cooperating, regardless of what the agent has to offer. We address this problem in a continuous state and action space with two different kinds of search methods: a gradient policy search method and a direct policy search method using an evolution strategy. We show that when significant events are rare, gradient information is also scarce, making it difficult for policy gradient search methods to find an optimal policy, with or without a deep neural architecture. On the other hand, we show that direct policy search methods are invariant to the rarity of significant events, which is yet another confirmation of the unique role evolutionary algorithms has to play as a reinforcement learning method.


ECT for prolonged catatonia.
Electroconvulsive therapy (ECT) is highly effective for acute catatonia but its use in prolonged catatonia is not well established. We report three cases of prolonged catatonia with medical complications or comorbidities treated by ECT. Case reports. A 24 year-old woman developed fever and autonomic instability after parenteral neuroleptics. Catatonia and autonomic signs persisted for 14 weeks. After minimal improvement from lorazepam, 15 bilateral ECTs led to resolution. A 26-year-old woman with a history of lupus erythematosus, complicated by lupus cerebritis with lesions in the cortex and basal ganglia and a communicating hydrocephalus, was catatonic for 9 weeks. Lorazepam produced marginal improvement. A series of 14 bilateral ECTs led to improved mobility, speech, and interaction, but the response was less robust than Case 1. A 40-year-old man with mental retardation and intermittent psychosis developed severe neuroleptic malignant syndrome and remained catatonic for 4 months. After lorazepam produced minimal improvement, his catatonia resolved with 20 bilateral ECTs. ECT may improve prolonged catatonia with complex medical comorbidities, but may require many treatment sessions. Gross cerebral pathology may predict a less robust response. As for acute catatonia, ECT may resolve prolonged catatonia after benzodiazepines have failed.


Proximity to death and participation in the long-term care market.
The extent to which increasing longevity increases per capita demand for long-term care depends on the degree to which utilization is concentrated at the end of life. We estimate the marginal effect of proximity to death, measured by being within 2 years of death, on the probabilities of nursing home and formal home care use, and we determine whether this effect differs by availability of informal care--i.e. marital status and co-residence with an adult child. The analysis uses a sample of elderly aged 70+ from the 1993-2002 Health and Retirement Study. Simultaneous probit models address the joint decisions to use long-term care and co-reside with an adult child. Overall, proximity to death significantly increases the probability of nursing home use by 50.0% and of formal home care use by 12.4%. Availability of informal support significantly reduces the effect of proximity to death. Among married elderly, proximity to death has no effect on institutionalization. In conclusion, proximity to death is one of the main drivers of long-term care use, but changes in sources of informal support, such as an increase in the proportion of married elderly, may lessen its importance in shaping the demand for long-term care.


Decreased Amount of Supporting Alveolar Bone at Single-Rooted Premolars Is Under Estimated by 2D Examinations.
The purpose of this study was to relate the proportions of bone-supported root length of a 2D view into the amount of a 3D bone-attached root surface area (BA-RSA) by using a dental laser scanner examination. White-light 3D scanning technology was used to probe 36 maxillary and 35 mandibular single-rooted premolars. The bone-supported height (BSH) and BA-RSA at designated levels (95-25%) were compared using statistical t tests. The 100% BSH and BA-RSA of the maxillary/mandibular premolars were 12.6 ± 1.60 mm/13.45 ± 1.47 mm (p < 0.05) and 220.78 ± 35.31 mm2/199.51 ± 26.33 mm2 (p < 0.01), respectively. Approximately 79-80%, 59-60%, and 35-36% premolars 2D BSH remained in comparison to 75%, 50%, and 25% 3D BA-RSA preservation, respectively. However, corresponding to a 75%, 50%, and 25% 2D BSH reserve, premolars retained 67-68%, 39-41%, and 15-17% 3D BA-RSA, respectively. When taking 1.0 mm connective tissue attachment into account, 60% 3D BA-RSA and 50% 2D BSH loss were noted at the 5.1-5.4 mm clinical attachment level. Assigning a periodontal prognosis and determining the severity of periodontitis for premolars with alveolar bone loss based on 3D's or 2D's measurement is inconsistent.


Alcohol: a missed opportunity. A survey of all accident and emergency departments in England.
To determine the extent to which the recommendations of the alcohol harm reduction strategy for England and the Choosing Health white paper for the provision of screening and brief interventions for hazardous and harmful drinkers have been adopted by accident and emergency departments. Telephone/postal survey of all 191 Type 1 departments in England. The survey was part of a larger study investigating the impact of the changes in the licensing act (2004) on alcohol-related attendances. 4 departments use formal screening tools and 24 ask general questions about consumption (98.9% response rate). Blood alcohol levels were measured as required by 100 departments. No departments routinely measure blood alcohol, and 84 departments never assess blood alcohol levels. Alcohol-related attendances were formally recorded by 131 departments. Access to an alcohol health worker or a clinical nurse specialist was reported by 32 departments. Although departments may be willing to address hazardous alcohol consumption, the low numbers of departments utilising formal screening tools suggests that patients who may benefit from help or advice remain undetected.


A novel synthetic cannabinoid derivative inhibits inflammatory liver damage via negative cytokine regulation.
The therapeutic potential of cannabinoids has been described previously for several inflammatory diseases, but the molecular mechanisms underlying the anti-inflammatory properties of cannabinoids are not well understood. In this study, we investigated the mechanism of action of a novel synthetic cannabinoid, [(+)(6aS,10aS)-6,6-Dimethyl-3-(1,1-dimethylheptyl)-1-hydroxy-9-(1H-imidazol-2-ylsulfanylmethyl]-6a,7,10,10a-tetrahydro-6H-dibenzo[b,d]pyran (PRS-211,092) that has no psychotropic effects but exhibits immunomodulatory properties. Treatment with PRS-211,092 significantly decreased Concanavalin A-induced liver injury in mice that was accompanied by: 1) promotion of early gene expression of interleukin (IL)-6 and IL-10 that play a protective role in this model; 2) induction of early gene expression of the suppressors of cytokine signaling (SOCS-1 and 3), followed by 3) inhibition of several pro-inflammatory mediators, including IL-2, monocyte chemoattractant protein-1 (MCP-1), IL-1beta, interferon-gamma, and tumor necrosis factor alpha. Based on these results, we propose a mechanism by which PRS-211,092 stimulates the expression of IL-6, IL-10 and the SOCS proteins that, in turn, negatively regulates the expression of pro-inflammatory cytokines. Negative regulation by PRS-211,092 was further demonstrated in cultured T cells, where it inhibited IL-2 production and nuclear factor of activated T cells activity. These findings suggest that this cannabinoid derivative is an immunomodulator that could be developed as a potential drug for hepatitis as well as for other short- or long-term inflammatory diseases.


Surgical treatment of Candida endocarditis.
Case reports from a group of 15 patients with Candida endocarditis seen and treated at the Los Angeles-University of Southern California Medical Center between 1960 and 1974, together with a survey of other reported cases, serve to re-emphasize the importance of early diagnosis of this disease and lead to certain conclusions regarding its treatment. With medical or surgical treatment alone, the mortality for Candida endocarditis is 82 per cent. With surgery and medical treatment combined, the mortality is 20 percent. It is important to institute medical treatment as soon as diagnosis of Candida endocarditis is made and surgery must be performed as soon as possible, preferably within 24 to 48 hours or, at most, a few days after the patient has left the hospital. Close observation of the patient after discharge is important.


[Reaction of the brain receptor system to the effect of low intensity microwaves].
We have found that two important brain synaptic receptor systems are very sensitive to the influence of low intensity microwaves. Both the excitatory glutamatergic and the inhibitory GABAergic are affected by microwave exposure. Power densities higher 50 microW/cm2 caused changes in the binding properties of these receptors to agonists. Low frequence modulation of microwaves was essential for these effects. Statistically significant effects on mean value of binding were observed at 16 Hz modulation. Exposure to microwave radiation changes the binding of agonists to glutamate and GABA receptors in different ways. An increase was observed for glutamate and a decrease for GABA. We suppose that the effect of microwaves is related to the stress reactions of the organism.


Some physiologically meaningful features obtained from the vectorcardiography.
The nature of the information provided by the vectorcardiograph (VCG) is described, and the use of Fourier descriptors in VCG classification is discussed. The Fourier transform relation of the VCG loop, cardiac axis determination from Fourier descriptors, and PVC screening using Fourier descriptors are considered. To demonstrate the usefulness of the features discussed as a feature set for the classification process, two different data sets from the MIT/BIH database are serially analysed. The use of Fourier descriptors in 2-D template matching is also discussed.


Key-string algorithm--novel approach to computational analysis of repetitive sequences in human centromeric DNA.
To use a novel computational approach, Key-string Algorithm (KSA), for the identification and analysis of arbitrarily large repetitive sequences and higher-order repeats (HORs) in noncoding DNA. This approach is based on the use of key string that plays a role of an arbitrarily constructed "computer enzyme". A cluster of novel KSA-related methods was introduced and developed on the basis of a combination of computations on a very modest scale, by eye inspection and graphical display of results of analysis. Sequence analysis software was developed, containing seven programs for KSA-related analyses. This approach was demonstrated in the case study of alpha satellites and HORs in the human genetic sequence AC017075.8 (193277 bp) from the centromeric region of human chromosome 7. The KSA segmentation method was applied by using DCCGTTT, GTA, and TTTC key strings. Fifty-five copies of 2734-bp 16mer HORs were identified and investigated, and a start-string TTTTTTAAAAA was identified. The HOR-matrix was constructed and employed for graphical display of mutations. KSA identification of HORs in AC017075.8 was compared with that of RepeatMasker and Tandem Repeat Finder, which identified alpha monomers in AC017075.8, but not the HORs. On the basis of KSA study, the centromere folding was described as an effect of HORs and super-HORs (3 x 2734 bp) in AC017075.8. The following novel computational KSA-based methods, easy-to-use and intended for computational "pedestrians", were demonstrated: color-HOR diagram, KSA-divergence method, 171-bp subsequence-convergence diagram, and total frequency distribution of the key-string subsequence lengths. The results were supplemented by Fast Fourier Transform, employing a novel mapping of symbolic genomic sequence into a numerical sequence. The KSA approach offers a simple and robust framework for a wide range of investigations of large repetitive sequences and HORs, involving a very modest scope of computations that can be carried out by using a PC. As the KSA method is HOR-oriented, the identification of HORs is even easier than the identification of underlying alpha monomer itself. This approach provides an easy identification of point mutations, insertions, and deletions, with respect to consensus. This may be useful in a wide range of investigations and applied in forensic medicine, medical diagnosis of malignant diseases, biological evolution, and paleontology.


2013 statement on human papillomavirus [corrected] test utilization.
This statement from the Cytopathology Education and Technology Consortium summarizes appropriate and inappropriate uses of human papillomavirus testing in cervical cancer screening based on guidelines from the American Society for Colposcopy and Cervical Pathology and the American Cancer Society. © 2014 S. Karger AG, Basel.


Lead and PCB's in canvasback ducks: relationship between enzyme levels and residues in blood.
Blood samples were taken for two successive years from canvasback ducks trapped in the Chesapeake Bay. The first winter (1972-1973) five plasma enzymes known to respond to organochlorine poisoning were examined. Abnormal enzyme elevations suggested that 20% of the population sampled (23/115 ducks) might contain organochlorine contaminants, but no residue analyses were performed. The second winter (1974) two of the same enzymes, aspartate aminotransferase and lactate dehydrogenase, and a third enzyme known to be specifically inhibited by lead, delta-aminolevulinic acid dehydratase, were assayed in 95 blood samples. Blood residues of organochlorine compounds and of lead were determined in representative samples, and the correlations between residue levels and enzyme changes were examined. The enzyme bioassays in 1974 indicated that lead was a more prevalent environmental contaminant than organochlorine compounds in canvasback ducks; 17% of the blood samples had less than one-half of the normal delta-aminole vulinic acid dehydratase activity, but only 11% exhibited abnormal aspartate aminotransferase or lactate dehydrogenase activities. These findings were confirmed by residue analyses that demonstrated lead concentrations four times higher than background levels, but only relatively low organochlorine concentrations. There was a highly significant inverse correlation between delta-aminolevulinic acid dehydratase activity and blood lead concentrations (P less than 0.01), and a weaker but significant correlation between plasma aspartate aminotransferase activity and blood PCB concentrations (P less than 0.05). It was apparent that delta-aminolevulinic acid dehydratase activity in the blood provided a sensitive and precise estimate of lead contamination in waterfowl. In canvasback ducks 200 ppb of lead in the blood caused a 75% decrease in delta aminolevulinic acid dehydratase activity, a magnitude of enzyme inhibition that disturbs heme synthesis and is regarded as detrimental in humans.


Methane Emissions from Non-producing Oil and Gas Wells and the Potential Role of Seismic Activity: A Case Study in Northeast British Columbia, Canada.
Increasing seismic activity due to fluid injections for oil and gas production may be contributing to leakage along non-producing oil and gas wells and emitting methane, a potent greenhouse gas. However, the extent to which nearby seismicity may drive or exacerbate methane emissions and cause well integrity issues is unknown. Therefore, we analyze field evaluations at 448 non-producing oil and gas wells in Northeast British Columbia (NEBC) and geospatially analyze oil and gas well and fluid injection data alongside locations of 3515 earthquakes from 2001 to 2021 and 130 faults. Through analysis of ground and helicopter-based field evaluations of non-producing wells in NEBC, we show that methane emission rates of non-producing wells average at 8301 mg/h/well but vary by 10 orders of magnitude. We find that higher methane emission rates (milligrams of methane/h/well) are observed at wells with larger flowing pressures at the wellhead during completion (kPa) and with shorter distances (m) to earthquakes, particularly at plugged wells. These results imply that seismicity may increase the likelihood of non-producing well integrity issues and methane leakage, thereby also exacerbating groundwater contamination and environmental degradation risks.


Toward selectivity control of a heme peptide electrode by modification with a phase-transition polymer.
Reduction currents for H2O2 at a heme peptide (HP)-modified electrodes are suppressed by inhibitors, such as imidazole derivatives. Although this inhibition effect allows determinations of the total inhibition ability of imidazole derivatives, it has no selectivity. In this study the selectivity control of HP-modified electrodes for imidazole derivatives was performed utilizing the thermoresponsive phase transition of poly(N-isopropylacrylamide), which was chemically immobilized on HP-modified electrodes. The inhibition ratios for imidazole derivatives appeared to be small at temperatures below the lower critical solution temperature (LCST), and to be large above the LCST. This change was ascribed to a steric hindrance caused by a phase transition of the polymer. On the other hand, the inhibition ratio for histamine, which has a larger molecular size relative to imidazole, was not significantly changed by the phase transition. Thus, the selectivity of the HP-modified electrode was found to be controllable using an immobilized phase-transition polymer.


[The choice of intermediate molluscan host by the miracidium of Schistosoma bovis].
When the usual intermediate hosts (B. truncatus and P. metidjensis) and several other species of Molluscs are together exposed to the miracidia of S. bovis, we demonstrate that about 75% of the miracidia penetrate B. truncatus and P. metidjensis, while 25% penetrate the Pulmonates (B. glabrata, B. straminea and H. duryi) and no miracidium penetrates the Prosobranches (M. tuberculata, M. cornuarietis). When the miracidia penetrate the non-vector Molluscs, it takes less than 24 hours for them to get encapsulated, except for B. straminea, in which the reaction takes 24 to 48 hours.


[Clinical tests of a new corticoid for topical use: Nerisona].
Diflucortolone valerate 0.1% (Nerisona), a new topical corticoid, was clinically investigated in ointment form in 51 patients suffering from neither weeping nor very dry allergic and inflammatory skin diseases. The results obtained were good, improvement being observed in 92.1% of the treated cases. The cosmetic properties of the preparation were excellent. No local or systemic side effects were observed.


The secretory IgA system of the gut.
Most commonly, humoral immunity manifested in the gastrointestinal tract of mammals is due to the presence of secretory IgA antibodies. Antibody specificities have been detected in the secretory IgA of gut secretions to a wide range of naturally occurring viral and bacterial components and to test antigens such as chemically modified proteins. Much of the IgA found in gut secretions is synthesized and secreted locally by the abundant plasma cells of the lamina propria. Development of methods for establishing local protective immunity in the gut requires knowledge of the origins of these plasma cells and of the whereabouts of their precursors when they are susceptible to antigen-driven proliferation and/or maturation. The Peyer's patches have been shown to contain a population of B lymphocytes especially rich in precursors for IgA plasma cells and in cells which can repopulate gut lamina propria with such IgA plasma cells. The Peyer's patches also appear to 'sample' gut antigens, in that small amounts of antigens are passed intact through their dome epithelial cells. Recent experiments bearing on the origins, differentiation and maturation, antigen sensitivity, migration and lodging of precursors for gut IgA plasma cells are discussed. We use the following three systems: (1) congenic transfer of cells from different murine lymphoid cell sources or mixtures of these (CB20 leads to BALB/c or BALB/c leads to CB20) and the use of allo-antisera to IgA allotypic determinants to assess their potential to impart an adoptive IgA antibody response to the recipient and to repopulate its histocompatible lamina propria with IgA plasma cells; (2) clonal precursor analysis (the method of Klinman) both to enumerate antigen-sensitive cells in different tissues of mice and to evaluate their potential to generate plasma cells making particular isotypes and idiotypes of antibodies; (3) use of pairs of Thiry-Vella loops in rabbits, each member either bearing or lacking a Peyer's patch, and quantitation of antibodies of each isotype and of total secretory IgA to assess the response of each loop with the time after local immunization. The results from all three systems provide strong evidence for the importance of Peyer's patches in supplying cells responsible for local humoral immunity and suggest both a differentiative pathway for IgA precursors and their whereabouts when antigen may cause the expansion of a population of specific cells.


Experiencing depression: women's perspectives in recovery.
Depression, as perceived by 10 women, is presented in this descriptive study. Guided by symbolic interactionism and feminist theory this qualitative study used semistructured interviews, self-report measures, observations and participant self-reflective journals to elicit women's views on depression and its affect on, and meaning in, their lives. The theme of loss of self was the central feature in their experiences that characterized depression and, in turn, affected their efforts in recovery and healing. Six other themes reflected their experiences in living with depression including: the transformed self, wanting and monitoring, the self as healer, revealing vs, concealing, acceptance and belonging, and making sense of depression--meaning and understanding.


Remotely Assessing Fraction of Photosynthetically Active Radiation (FPAR) for Wheat Canopies Based on Hyperspectral Vegetation Indexes.
Fraction of photosynthetically active radiation (FPAR), as an important index for evaluating yields and biomass production, is key to providing the guidance for crop management. However, the shortage of good hyperspectral data can frequently result in the hindrance of accurate and reliable FPAR assessment, especially for wheat. In the present research, aiming at developing a strategy for accurate FPAR assessment, the relationships between wheat canopy FPAR and vegetation indexes derived from concurrent ground-measured hyperspectral data were explored. FPAR revealed the most strongly correlation with normalized difference index (NDI), and scaled difference index (N*). Both NDI and N* revealed the increase as the increase of FPAR; however, NDI value presented the stagnation as FPAR value beyond 0.70. On the other hand, N* showed a decreasing tendency when FPAR value was higher than 0.70. This special relationship between FPAR and vegetation index could be employed to establish a piecewise FPAR assessment model with NDI as a regression variable during FPAR value lower than 0.70, or N* as the regression variable during FPAR value higher than 0.70. The model revealed higher assessment accuracy up to 16% when compared with FPAR assessment models based on a single vegetation index. In summary, it is feasible to apply NDI and N* for accomplishing wheat canopy FPAR assessment, and establish an FPAR assessment model to overcome the limitations from vegetation index saturation under the condition with high FPAR value.


Effect of erdosteine on the rate and duration of COPD exacerbations: the RESTORE study.
Oxidative stress contributes to chronic obstructive pulmonary disease (COPD) exacerbations and antioxidants can decrease exacerbation rates, although we lack data about the effect of such drugs on exacerbation duration.The RESTORE (Reducing Exacerbations and Symptoms by Treatment with ORal Erdosteine in COPD) study was a prospective randomised, double-blind, placebo-controlled study, enrolling patients aged 40-80 years with Global Initiative for Chronic Obstructive Lung Disease stage II/III. Patients received erdosteine 300 mg twice daily or placebo added to usual COPD therapy for 12 months. The primary outcome was the number of acute exacerbations during the study.In the pre-specified intention-to-treat population of 445 patients (74% male; mean age 64.8 years, forced expiratory volume in 1 s 51.8% predicted) erdosteine reduced the exacerbation rate by 19.4% (0.91 versus 1.13 exacerbations·patient-1·year-1 for erdosteine and placebo, respectively; p=0.01), due to an effect on mild events; the reduction in the rate of mild exacerbations was 57.1% (0.23 versus 0.54 exacerbations·patient-1·year-1 for erdosteine and placebo, respectively; p=0.002). No significant difference was observed in the rate of moderate and severe exacerbations (0.68 versus 0.59 exacerbations·patient-1·year-1 for erdosteine and placebo, respectively; p=0.054) despite a trend in favour of the comparison group. Erdosteine decreased the exacerbation duration irrespective of event severity by 24.6% (9.55 versus 12.63 days for erdosteine and placebo, respectively; p=0.023). Erdosteine significantly improved subject and physician subjective severity scores (p=0.022 and p=0.048, respectively), and reduced the use of reliever medication (p<0.001), but did not affect the St George's Respiratory Questionnaire score or the time to first exacerbation.In patients with COPD, erdosteine can reduce both the rate and duration of exacerbations. The percentage of patients with adverse events was similar in both the placebo and erdosteine treatment groups.


A neuronal model of predictive coding accounting for the mismatch negativity.
The mismatch negativity (MMN) is thought to index the activation of specialized neural networks for active prediction and deviance detection. However, a detailed neuronal model of the neurobiological mechanisms underlying the MMN is still lacking, and its computational foundations remain debated. We propose here a detailed neuronal model of auditory cortex, based on predictive coding, that accounts for the critical features of MMN. The model is entirely composed of spiking excitatory and inhibitory neurons interconnected in a layered cortical architecture with distinct input, predictive, and prediction error units. A spike-timing dependent learning rule, relying upon NMDA receptor synaptic transmission, allows the network to adjust its internal predictions and use a memory of the recent past inputs to anticipate on future stimuli based on transition statistics. We demonstrate that this simple architecture can account for the major empirical properties of the MMN. These include a frequency-dependent response to rare deviants, a response to unexpected repeats in alternating sequences (ABABAA…), a lack of consideration of the global sequence context, a response to sound omission, and a sensitivity of the MMN to NMDA receptor antagonists. Novel predictions are presented, and a new magnetoencephalography experiment in healthy human subjects is presented that validates our key hypothesis: the MMN results from active cortical prediction rather than passive synaptic habituation.


A hydrogen sulfide-releasing cyclooxygenase inhibitor markedly accelerates recovery from experimental spinal cord injury.
Spinal cord trauma causes loss of motor function that is in part due to the ensuing inflammatory response. Hydrogen sulfide (H2S) is a potent, endogenous anti-inflammatory and neuroprotective substance that has been explored for use in the design of novel nonsteroidal anti-inflammatory drugs. In the current study, we evaluated the potential beneficial effects of ATB-346 [2-(6-methoxynapthalen- 2-yl)-propionic acid 4-thiocarbamoyl-phenyl ester], an H2S-releasing derivative of naproxen, in a murine model of spinal cord injury (SCI). SCI was induced in mice by spinal cord compression, produced through the application of vascular clips to the dura via a T5 to T8 laminectomy. ATB-346, naproxen (both at 30 μmol/kg), or vehicle was orally administered to the mice 1 and 6 h after SCI and once daily thereafter for 10 d. Motor function [Basso Mouse Scale (BMS) of locomotion] improved gradually in the mice treated with naproxen. However, those treated with ATB-346 exhibited a significantly more rapid and sustained recovery of motor function, achieving greater than double the increase in locomotion score of the naproxen group by the 10th day of treatment. ATB-346 also significantly reduced the severity of inflammation (proinflammatory cytokines, apoptosis of neural tissue, and nitrosative stress) that characterized the secondary effects of SCI. Again, the effects of ATB-346 were superior to those of naproxen for several parameters. These results showed marked beneficial effects of an H2S-releasing derivative of naproxen in an animal model of SCI, significantly enhancing recovery of motor function, possibly by reducing the secondary inflammation and tissue injury that characterizes this model. The combination of inhibition of cyclooxygenase and delivery of H2S may offer a promising alternative to existing therapies for traumatic injury.


Antigen-specific and -nonspecific mitogenic signals in the activation of human T cell clones.
We have directly compared the signals required for: induction of the [Ca+2]i response, expression of Tac antigen, and proliferation in antigen-specific human T cell clones. We have previously shown that antigen-specific activation of cloned T cells under conditions leading to proliferation is accompanied by a rapid increase in [Ca+2]i. Cloned T cells showed increased [Ca+2]i, enhanced Tac expression, and proliferated in response to specific antigen in the presence of viable, genetically appropriate antigen-presenting cells. Paraformaldehyde fixation of antigen-presenting cells after "pulsing" with antigen prevented proliferation, but did not affect MHC-restricted [Ca+2]i or Tac responses. Treatment of cloned T cells with monoclonal anti-T3 antibody also increased [Ca+2]i and Tac expression but did not induce proliferation. Proliferation was restored by viable autologous or allogenic APC or exogenous IL 2, but not by IL 1. In contrast to resting T cells, T cell clones were insensitive to the mitogenic effects of lectins or of ionophores and phorbol esters. These results suggest that activation of antigen-specific T cells requires the sequential action of at least two signals. The first is MHC restricted and is mediated by interaction of antigen + MHC class II products with the T cell receptor (T3-Ti) complex. This leads to Tac expression and increased [Ca+2]i, but is not sufficient for proliferation. This signal can be bypassed by anti-T3 monoclonal antibodies. Proliferation requires a second, nonantigen-specific, non-MHC-restricted antigen-presenting cell signal, which cannot be replaced by IL 1 in our system. This signal can be bypassed, however, by the addition of exogenous IL 2 to cells that have received the first signal and express Tac, suggesting that it is required for IL 2 synthesis and secretion. T cell clones therefore provide a useful model for studying antigen-dependent and -independent events in cell activation.


Notch suppresses angiogenesis and progression of hepatic metastases.
The Notch pathway plays multiple key roles in tumorigenesis, and its signaling components have therefore aroused great interest as targets for emerging therapies. Here, we show that inhibition of Notch, using a soluble receptor Notch1 decoy, unexpectedly caused a remarkable increase in liver metastases from neuroblastoma and breast cancer cells. Increased liver metastases were also seen after treatment with the γ-secretase inhibitor PF-03084014. Transgenic mice with heterozygous loss of Notch1 demonstrated a marked increase in hepatic metastases, indicating that Notch1 signaling acts as metastatic suppressor in the liver microenvironment. Inhibition of DLL1/4 with ligand-specific Notch1 decoys increased sprouting of sinusoidal endothelial cells into micrometastases, thereby supporting early metastatic angiogenic growth. Inhibition of tumor-derived JAG1 signaling activated hepatic stellate cells, increasing their recruitment to vasculature of micrometastases, thereby supporting progression to macrometastases. These results demonstrate that inhibition of Notch causes pathologic activation of liver stromal cells, promoting angiogenesis and growth of hepatic metastases. Our findings have potentially serious implications for Notch inhibition therapy.


Naturally acquired hepatitis A antibodies after haematopoetic stem cell transplantation.
Haematopoietic stem cell transplant (HSCT) recipients lose immune memory of exposure to infectious agents and vaccines accumulated throughout their lifetime and therefore need to be revaccinated. We aimed to evaluate the influence of different factors on hepatitis A virus (HAV) immunity in both child and adult HSCT recipients living in an intermediate endemic region, Turkey. Eighty patients (age range 2·5-57 years) who had HAV serology prior to HSCT were evaluated. The prevalence of HAV seropositivity was 85% (n=68) before HSCT. There was no history of HAV vaccination before HSCT in children and HAV vaccine was not available in Turkey 10 years ago, so it was assumed that all seropositive patients reflected natural immunity. After the exclusion of six patients with autologous HSCT, the remaining 62 seropositive and allogeneic patients were included in this retrospective study. The duration of HAV seropositivity was estimated using the Kaplan-Meier method, log-rank analysis and Cox regression models. Estimated mean time to loss of HAV seropositivity was 48·6 months after transplantation. Patients who were older (⩾18 years) at transplantation and who had older (⩾18 years) donors became seronegative later (P<0·05). Cox backward-stepwise regression confirmed that older age of recipient at transplantation was the only significant parameter for HAV seropositivity (P<0·05). HAV-inactivated vaccine might be recommended later to older HSCT recipients in intermediate endemic regions.


Zika virus infection as a cause of congenital brain abnormalities and Guillain-Barré syndrome: From systematic review to living systematic review.
Background. The Zika virus (ZIKV) outbreak in the Americas has caused international concern due to neurological sequelae linked to the infection, such as microcephaly and Guillain-Barré syndrome (GBS). The World Health Organization stated that there is "sufficient evidence to conclude that Zika virus is a cause of congenital abnormalities and is a trigger of GBS". This conclusion was based on a systematic review of the evidence published until 30.05.2016. Since then, the body of evidence has grown substantially, leading to this update of that systematic review with new evidence published from 30.05.2016 - 18.01.2017, update 1. Methods. We review evidence on the causal link between ZIKV infection and adverse congenital outcomes and the causal link between ZIKV infection and GBS or immune-mediated thrombocytopaenia purpura. We also describe the transition of the review into a living systematic review, a review that is continually updated. Results. Between 30.05.2016 and 18.01.2017, we identified 2413 publications, of which 101 publications were included. The evidence added in this update confirms the conclusion of a causal association between ZIKV and adverse congenital outcomes. New findings expand the evidence base in the dimensions of biological plausibility, strength of association, animal experiments and specificity. For GBS, the body of evidence has grown during the search period for update 1, but only for dimensions that were already populated in the previous version. There is still a limited understanding of the biological pathways that potentially cause the occurrence of autoimmune disease following ZIKV infection. Conclusions. This systematic review confirms previous conclusions that ZIKV is a cause of congenital abnormalities, including microcephaly, and is a trigger of GBS. The transition to living systematic review techniques and methodology provides a proof of concept for the use of these methods to synthesise evidence about an emerging pathogen such as ZIKV.


Clinical correlates of social adjustment in patients with obsessive-compulsive disorder.
Patients with obsessive-compulsive disorder (OCD) frequently show poor social adjustment, which has been associated with OCD severity. Little is known about the effects that age at symptom onset, specific OCD symptoms, and psychiatric comorbidities have on social adjustment. The objective of this study was to investigate the clinical correlates of social functioning in OCD patients. Cross-sectional study involving 815 adults with a primary DSM-IV diagnosis of OCD participating in the Brazilian Research Consortium on Obsessive-Compulsive Spectrum Disorders. Patients were assessed with the Social Adjustment Scale, the Medical Outcomes Study 36-item Short-Form Health Survey, the Yale-Brown Obsessive-Compulsive Scale, the Dimensional Yale-Brown Obsessive-Compulsive Scale, and the Structured Clinical Interview for DSM-IV Axis I Disorders. Clinical correlates of social adjustment were assessed with generalized linear models with gamma distribution. Poor overall social functioning was associated with greater OCD severity (p = 0.02); hoarding symptoms (p = 0.004); sexual/religious obsessions (p = 0.005); current major depressive disorder (p = 0.004); current post-traumatic stress disorder (p = 0.002); and current eating disorders (p = 0.02). Poor social adjustment was also associated with impaired quality of life. Patients with OCD have poor social functioning in domains related to personal relationships and professional performance. Hoarding symptoms and sexual/religious obsessions seem to have the strongest negative effects on social functioning. Early age at OCD symptom onset seems to be associated with professional and academic underachievement and impairment within the family unit, whereas current psychiatric comorbidity worsen overall social functioning. In comparison with quality of life, social adjustment measures seem to provide a more comprehensive overview of the OCD-related burden.


Quality, not quantity: the role of natural products and chemical proteomics in modern drug discovery.
Chemical genetics and reverse chemical genetics parallel classical genetics but target genes at the protein level and have proven useful in recent years for screening combinatorial libraries for compounds of biological interest. However, the performance of combinatorial chemistry in filling pharmaceutical pipelines has been lower than anticipated and the tide may be turning back to Nature in the search for new drug candidates. Even though diversity oriented synthesis is now producing molecules that are natural product-like in terms of size and complexity, these molecules have not evolved to interact with biomolecules. Natural products, on the other hand, have evolved to interact with biomolecules, which is why so many can be found in pharmacopoeias. However, the cellular targets and modes of action of these fascinating compounds are seldom known, hindering the drug development process. This review focuses on the emergence of chemical proteomics and reverse chemical proteomics as tools for the discovery of cellular receptors for natural products, thereby generating protein/ligand pairs that will prove useful in identifying new drug targets and new biologically active small molecule scaffolds. Such a system-wide approach to identifying new drugable targets and their small molecule ligands will help unblock the pharmaceutical product pipelines by speeding the process of target and lead identification.