Prospective, observational study of pain and analgesic prescribing in medical oncology outpatients with breast, colorectal, lung, or prostate cancer.
Pain is prevalent among patients with cancer, yet pain management patterns in outpatient oncology are poorly understood. A total of 3,123 ambulatory patients with invasive cancer of the breast, prostate, colon/rectum, or lung were enrolled onto this prospective study regardless of phase of care or stage of disease. At initial assessment and 4 to 5 weeks later, patients completed a 25-item measure of pain, functional interference, and other symptoms. Providers recorded analgesic prescribing. The pain management index was calculated to assess treatment adequacy. Of the 3,023 patients we identified to be at risk for pain, 2,026 (67%) reported having pain or requiring analgesics at initial assessment; of these 2,026 patients, 670 (33%) were receiving inadequate analgesic prescribing. We found no difference in treatment adequacy between the initial and follow-up visits. Multivariable analysis revealed that the odds of a non-Hispanic white patient having inadequate pain treatment were approximately half those of a minority patient after adjusting for other explanatory variables (odds ratio, 0.51; 95% CI, 0.37 to 0.70; P = .002). Other significant predictors of inadequate pain treatment were having a good performance status, being treated at a minority treatment site, and having nonadvanced disease without concurrent treatment. Most outpatients with common solid tumors must confront issues related to pain and the use of analgesics. There is significant disparity in pain treatment adequacy, with the odds of undertreatment twice as high for minority patients. These findings persist over 1 month of follow-up, highlighting the complexity of these problems.


The global health burden of infection-associated cancers in the year 2002.
Several infectious agents are considered to be causes of cancer in humans. The fraction of the different types of cancer, and of all cancers worldwide and in different regions, has been estimated using several methods; primarily by reviewing the evidence for the strength of the association (relative risk) and the prevalence of infection in different world areas. The estimated total of infection-attributable cancer in the year 2002 is 1.9 million cases, or 17.8% of the global cancer burden. The principal agents are the bacterium Helicobacter pylori (5.5% of all cancer), the human papilloma viruses (5.2%), the hepatitis B and C viruses (4.9%), Epstein-Barr virus (1%), human immunodeficiency virus (HIV) together with the human herpes virus 8 (0.9%). Relatively less important causes of cancer are the schistosomes (0.1%), human T-cell lymphotropic virus type I (0.03%) and the liver flukes (0.02%). There would be 26.3% fewer cancers in developing countries (1.5 million cases per year) and 7.7% in developed countries (390,000 cases) if these infectious diseases were prevented. The attributable fraction at the specific sites varies from 100% of cervix cancers attributable to the papilloma viruses to a tiny proportion (0.4%) of liver cancers (worldwide) caused by liver flukes.


Environmental exposures and respiratory morbidity among very low birth weight infants at 1 year of life.
Preterm infants have a substantially increased risk of developing respiratory illnesses. The goal of this study was to consider the impact of modifiable postnatal exposures on respiratory morbidity among a cohort of very low birth weight (VLBW) infants. (1) Assess the rates of respiratory morbidity and exposure to indoor respiratory triggers in a population of VLBW infants at 1 year; (2) determine the association between exposures and respiratory morbidity. We enrolled 124 VLBW infants into a prospective cohort study. Parents were called at 1 year to assess respiratory outcomes and environmental exposures. We used bivariate and multivariate analyses to assess the relationship between environmental exposures and acute care for respiratory illnesses. At 1 year, 9% of infants had physician-diagnosed asthma, 47% required >or=1 acute visit and 11% required hospitalisation for respiratory illness. The majority of infants (82%) were exposed to at least one indoor respiratory trigger. Infants living with a smoker (61% vs 40%) and infants exposed to pests (62% vs 39%) were more likely than unexposed infants to require acute care for respiratory problems. In a multivariate regression controlling for demographics, birth weight, bronchopulmonary dysplasia, and family history of asthma or allergies, both living with a smoker (OR 2.62; CI 1.09 to 6.29) and exposure to pests (OR 4.41; CI 1.22 to 15.94) were independently associated with the need for acute care for respiratory illnesses. In this sample, respiratory morbidity and exposure to triggers were common. VLBW infants may benefit from interventions that decrease exposure to respiratory triggers.


Longer-term use of electronic cigarettes when provided as a stop smoking aid: Systematic review with meta-analyses.
Moderate certainty evidence supports use of nicotine electronic cigarettes to quit smoking combustible cigarettes. However, there is less certainty regarding how long people continue to use e-cigarettes after smoking cessation attempts. We set out to synthesise data on the proportion of people still using e-cigarettes or other study products at 6 months or longer in studies of e-cigarettes for smoking cessation. We updated Cochrane searches (November 2021). For the first time, we meta-analysed prevalence of continued e-cigarette use among individuals allocated to e-cigarette conditions, and among those individuals who had successfully quit smoking. We updated meta-analyses comparing proportions continuing product use among individuals allocated to use nicotine e-cigarettes and other treatments. We included 19 studies (n = 7787). The pooled prevalence of continued e-cigarette use at 6 months or longer was 54% (95% CI: 46% to 61%, I2 86%, N = 1482) in participants assigned to e-cigarette conditions. Of participants who had quit combustible cigarettes overall 70% were still using e-cigarettes at six months or longer (95% CI: 53% to 82%, I2 73%, N = 215). Heterogeneity in direction of effect precluded meta-analysis comparing long-term use of nicotine e-cigarettes with NRT. More people were using nicotine e-cigarettes at longest follow-up compared to non-nicotine e-cigarettes, but CIs included no difference (risk ratio 1.15, 95% CI: 0.94 to 1.41, n = 601). The levels of continued e-cigarette use observed may reflect the success of e-cigarettes as a quitting tool. Further research is needed to establish drivers of variation in and implications of continued use of e-cigarettes.


Thiopurine monotherapy is effective in ulcerative colitis but significantly less so in Crohn's disease: long-term outcomes for 11 928 patients in the UK inflammatory bowel disease bioresource.
Thiopurines are widely used as maintenance therapy in inflammatory bowel disease (IBD) but the evidence base for their use is sparse and their role increasingly questioned. Using the largest series reported to date, we assessed the long-term effectiveness of thiopurines in ulcerative colitis (UC) and Crohn's disease (CD), including their impact on need for surgery. Outcomes were assessed in 11 928 patients (4968 UC, 6960 CD) in the UK IBD BioResource initiated on thiopurine monotherapy with the intention of maintaining medically induced remission. Effectiveness was assessed retrospectively using patient-level data and a definition that required avoidance of escalation to biological therapy or surgery while on thiopurines. Analyses included overall effectiveness, time-to-event analysis for treatment escalation and comparison of surgery rates in patients tolerant or intolerant of thiopurines. Using 68 132 patient-years of exposure, thiopurine monotherapy appeared effective for the duration of treatment in 2617/4968 (52.7%) patients with UC compared with 2378/6960 (34.2%) patients with CD (p<0.0001). This difference was corroborated in a multivariable analysis: after adjusting for variables including treatment era, thiopurine monotherapy was less effective in CD than UC (OR 0.47, 95% CI 0.43 to 0.51, p<0.0001). Thiopurine intolerance was associated with increased risk of surgery in UC (HR 2.44, p<0.0001); with a more modest impact on need for surgery in CD (HR=1.23, p=0.0015). Thiopurine monotherapy is an effective long-term treatment for UC but significantly less effective in CD.


Metagenomic analyses of novel viruses and plasmids from a cultured environmental sample of hyperthermophilic neutrophiles.
Two novel viral genomes and four plasmids were assembled from an environmental sample collected from a hot spring at Yellowstone National Park, USA, and maintained anaerobically in a bioreactor at 85°C and pH 6. The double-stranded DNA viral genomes are linear (22.7 kb) and circular (17.7 kb), and derive apparently from archaeal viruses HAV1 and HAV2. Genomic DNA was obtained from samples enriched in filamentous and tadpole-shaped virus-like particles respectively. They yielded few significant matches in public sequence databases reinforcing, further, the wide diversity of archaeal viruses. Several variants of HAV1 exhibit major genomic alterations, presumed to arise from viral adaptation to different hosts. They include insertions up to 350 bp, deletions up to 1.5 kb, and genes with extensively altered sequences. Some result from recombination events occurring at low complexity direct repeats distributed along the genome. In addition, a 33.8 kb archaeal plasmid pHA1 was characterized, encoding a possible conjugative apparatus, as well as three cryptic plasmids of thermophilic bacterial origin, pHB1 of 2.1 kb and two closely related variants pHB2a and pHB2b, of 5.2 and 4.8 kb respectively. Strategies are considered for assembling genomes of smaller genetic elements from complex environmental samples, and for establishing possible host identities on the basis of sequence similarity to host CRISPR immune systems.


Cytochrome oxidase immunohistochemistry in rat brain and dorsal root ganglia: visualization of enzyme in neuronal perikarya and in parvalbumin-positive neurons.
Histochemical detection of cytochrome oxidase activity has been widely used to deduce patterns of neuronal electrical activity in the CNS. Here we investigated the utility of cytochrome oxidase localization by immunohistochemistry and compared immunostaining with histochemical staining patterns in dorsal root ganglia of the rat. In addition, a limited survey of cytochrome oxidase immunostaining density within what are thought to be highly active parvalbumin-immunoreactive neurons was conducted. The immunohistochemical approach produced granular cytoplasmic immunolabelling in neuronal cell bodies and allowed identification of individual labelled cells in all brain regions including those within dense immunoreactive networks of neuropil. Neuronal somata exhibited a wide range of staining densities which were particularly evident in the hippocampus and dorsal root ganglia. The distribution of neurons intensely immunoreactive for cytochrome oxidase within various structures was consistent with previous histochemical descriptions of enzyme activity. Densitometric measurements of immunohistochemical reaction product in individual neurons of hippocampus, substantia nigra, cerebellum and dorsal root ganglia showed that the rate of product deposition was linear with time under conditions chosen for comparisons of staining density. Quantitative analysis of cytochrome oxidase immunohistochemical and histochemical staining densities within the same cells in adjacent sections of dorsal root ganglion gave a correlation coefficient of r = 0.75 (P less than 0.001). In sections processed immunohistochemically for both cytochrome oxidase and parvalbumin, most but not all parvalbumin-containing cells displayed dense cytochrome oxidase immunolabelling. Conversely, many examples were found of neurons that were densely stained for cytochrome oxidase, but lacked parvalbumin. Immunohistochemistry for cytochrome oxidase reveals the enzyme in neuronal cell bodies with a clarity not usually seen with the histochemical method. Combination of this immunohistochemical approach with simultaneous immunolabelling of other neuronal markers, as shown here in the case of parvalbumin, is expected to assist the elucidation of patterns of activity in neurochemically identified cell types and anatomically defined neural systems.


Anaphase-promoting complex/cyclosome participates in the acute response to protein-damaging stress.
The ubiquitin E3 ligase anaphase-promoting complex/cyclosome (APC/C) drives degradation of cell cycle regulators in cycling cells by associating with the coactivators Cdc20 and Cdh1. Although a plethora of APC/C substrates have been identified, only a few transcriptional regulators are described as direct targets of APC/C-dependent ubiquitination. Here we show that APC/C, through substrate recognition by both Cdc20 and Cdh1, mediates ubiquitination and degradation of heat shock factor 2 (HSF2), a transcription factor that binds to the Hsp70 promoter. The interaction between HSF2 and the APC/C subunit Cdc27 and coactivator Cdc20 is enhanced by moderate heat stress, and the degradation of HSF2 is induced during the acute phase of the heat shock response, leading to clearance of HSF2 from the Hsp70 promoter. Remarkably, Cdc20 and the proteasome 20S core α2 subunit are recruited to the Hsp70 promoter in a heat shock-inducible manner. Moreover, the heat shock-induced expression of Hsp70 is increased when Cdc20 is silenced by a specific small interfering RNA (siRNA). Our results provide the first evidence for participation of APC/C in the acute response to protein-damaging stress.


Experience-driven plasticity of visual cortex limited by myelin and Nogo receptor.
Monocular deprivation normally alters ocular dominance in the visual cortex only during a postnatal critical period (20 to 32 days postnatal in mice). We find that mutations in the Nogo-66 receptor (NgR) affect cessation of ocular dominance plasticity. In NgR-/- mice, plasticity during the critical period is normal, but it continues abnormally such that ocular dominance at 45 or 120 days postnatal is subject to the same plasticity as at juvenile ages. Thus, physiological NgR signaling from myelin-derived Nogo, MAG, and OMgp consolidates the neural circuitry established during experience-dependent plasticity. After pathological trauma, similar NgR signaling limits functional recovery and axonal regeneration.


An update on ocular involvement in mucopolysaccharidoses.
The purpose of this review is to provide an update on ocular manifestations of mucopolysaccharidoses (MPS), to highlight diagnostic pitfalls in the evaluation of affected patients, and to briefly review etiopathogenesis, systemic manifestations, and therapeutic interventions in MPS. Advances in hematopoietic stem cell transplantation and enzyme replacement therapy for MPS have led to decreased morbidity and increased life-span of patients. Besides other causes, visual impairment because of corneal opacification, retinal degeneration, and optic atrophy remains a common cause of disability in MPS. The application of a standard ophthalmic evaluation protocol may serve as an important diagnostic and disease monitoring tool in patients. Diagnostic delays are not uncommon in patients with MPS. Given the early ocular involvement in MPS, ophthalmologists play a crucial role in early detection and follow-up of patients with MPS. Ophthalmic evaluation can be impeded by corneal opacification and patient cooperation. Altered corneal biomechanics confound intraocular pressure measurements. Recently developed therapies have made early detection increasingly important. Accurate diagnosis of specific MPS subtypes is of paramount importance for initiating appropriate therapy. Combined with advances in supportive care of ocular and systemic manifestations, the prognosis for patients with MPS has vastly improved.


Following the Assembly of Iron Oxide Nanocubes by Video Microscopy and Quartz Crystal Microbalance with Dissipation Monitoring.
We have studied the growth of ordered arrays by evaporation-induced self-assembly of iron oxide nanocubes with edge lengths of 6.8 and 10.1 nm using video microscopy (VM) and quartz crystal microbalance with dissipation monitoring (QCM-D). Ex situ electron diffraction of the ordered arrays demonstrates that the crystal axes of the nanocubes are coaligned and confirms that the ordered arrays are mesocrystals. Time-resolved video microscopy shows that growth of the highly ordered arrays at slow solvent evaporation is controlled by particle diffusion and can be described by a simple growth model. The growth of each mesocrystal depends only on the number of nanoparticles within the accessible region irrespective of the relative time of formation. The mass of the dried mesocrystals estimated from the analysis of the bandwidth-shift-to-frequency-shift ratio correlates well with the total mass of the oleate-coated nanoparticles in the deposited dispersion drop.


High Heels Increase Women's Attractiveness.
Research has found that the appearance of women's apparel helps increase their attractiveness as rated by men and that men care more about physical features in potential opposite-sex mates. However, the effect of sartorial appearance has received little interest from scientists. In a series of studies, the length of women's shoe heels was examined. A woman confederate wearing black shoes with 0, 5, or 9 cm heels asked men for help in various circumstances. In Study 1, she asked men to respond to a short survey on gender equality. In Study 2, the confederate asked men and women to participate in a survey on local food habit consumption. In Study 3, men and women in the street were observed while walking in back of the female confederate who dropped a glove apparently unaware of her loss. It was found that men's helping behavior increased as soon as heel length increased. However, heel length had no effect on women's helping behavior. It was also found that men spontaneously approached women more quickly when they wore high-heeled shoes (Study 4). Change in gait, foot-size judgment, and misattribution of sexiness and sexual intent were used as possible explanations.


Variability in reference point microindentation and recommendations for testing cortical bone: maximum load, sample orientation, mode of use, sample preparation and measurement spacing.
Reference Point Indentation (RPI) is a novel microindentation tool that has emerging clinical potential for the assessment of fracture risk as well as use as a laboratory tool for straight-forward mechanical characterisation of bone. Despite increasing use of the tool, little research is available to advise the set-up of testing protocols or optimisation of testing parameters. Here we consider five such parameters: maximum load, sample orientation, mode of use, sample preparation and measurement spacing, to investigate how they affect the Indentation Distance Increase (IDI), the most published measurement parameter associated with the RPI device. The RPI tool was applied to bovine bone; indenting in the proximal midshaft of five femora and human bone; indenting five femoral heads and five femoral neck samples. Based on the findings of these studies we recommend the following as the best practice. (1) Repeat measurements should be utilised to reduce the coefficient of variation (e.g. 8-15 repeats to achieve a 5-10% error, however the 3-5 measurements used here gives a 15-20% error). (2) IDI is dependent on maximum load (r=0.45 on the periosteal surface and r=0.94 on the machined surface, p<0.05), mode of use (i.e. comparing the device held freehand compared to fixed in its stand, p=0.04) and surface preparation (p=0.004) so these should be kept consistent throughout testing. Though sample orientation appears to have minimal influence on IDI (p>0.05), care should also be taken in combining measurements from different orientations. (3) The coefficient of variation is higher (p=0.04) when holding the device freehand, so it should ideally be kept supported in its stand. (4) Removing the periosteum (p=0.04) and machining the surface of the bone (p=0.08) reduces the coefficient of variation, so should be performed where practical. (5) There is a hyperbolic relationship between thickness and IDI (p<0.001) with a sample thickness 10 fold greater than the maximum indentation depth recommended, to ensure a representative measurement. (6) Measurement spacing does not appear to influence the IDI (p>0.05), so it can be as low as 500 µm. By following these recommendations, RPI users can minimise the potential confounding effects associated with the variables investigated here and reduce the coefficient of variation, hence achieving more consistent testing. This optimisation of the technique enhances both the clinical and laboratory potential of the tool.


Stabilization of a metastable state of Torpedo californica acetylcholinesterase by chemical chaperones.
Chemical modification of Torpedo californica acetylcholinesterase by the natural thiosulfinate allicin produces an inactive enzyme through reaction with the buried cysteine Cys 231. Optical spectroscopy shows that the modified enzyme is "native-like," and inactivation can be reversed by exposure to reduced glutathione. The allicin-modified enzyme is, however, metastable, and is converted spontaneously and irreversibly, at room temperature, with t(1/2) approximately 100 min, to a stable, partially unfolded state with the physicochemical characteristics of a molten globule. Osmolytes, including trimethylamine-N-oxide, glycerol, and sucrose, and the divalent cations, Ca(2+), Mg(2+), and Mn(2+) can prevent this transition of the native-like state for >24 h at room temperature. Trimethylamine-N-oxide and Mg(2+) can also stabilize the native enzyme, with only slight inactivation being observed over several hours at 39 degrees C, whereas in their absence it is totally inactivated within 5 min. The stabilizing effects of the osmolytes can be explained by their differential interaction with the native and native-like states, resulting in a shift of equilibrium toward the native state. The stabilizing effects of the divalent cations can be ascribed to direct stabilization of the native state, as supported by differential scanning calorimetry.


Space-time clustering of glioma cannot be attributed to specific histological subgroups.
We previously showed that infectious exposures may be involved in the aetiology of adult glioma, by analysing for space-time clustering using population-based data from the South of the Netherlands. Here we extended these analyses and describe in detail the space-time clustering patterns in glioma subgroups, gender and age-categories. Knox tests for space-time interactions between cases were applied with fixed thresholds of close in space, <5 km, and close in time, <1 year apart. We used the spatial coordinates of the addresses at diagnosis in the analyses. Tests were repeated replacing geographical distance with distance to the Nth nearest neighbour. N was chosen such that the mean distance was 5 km. Data were also analysed by a second order procedure based on K-functions. There was only statistically significant space-time clustering for oligodendroglioma. Clustering was present for adults aged 30-54 years and was more pronounced among males. Given the low prior probability of an infectious aetiology for this specific subgroup, these results should probably be interpreted as false-positive. We conclude that space-time clustering of glioma cannot be attributed to a specific glioma subgroup. The observed clustering in our previous study is therefore probably an overall effect within and between glioma subgroups.


Selective stimulation by cinnamaldehyde of progesterone secretion in human adrenal cells.
Cinnamon bark has been used to treat menstrual pain and infertility. While several pharmacological studies have suggested anti-inflammatory properties, the mechanisms by which the herb exerts its various activities have not been well understood. Recent reports suggest menstrual distress is related to higher estradiol levels, higher estradiol/progesterone ratios. Cinnamaldehyde, a major active constituent of Cinnamomum cassia has been shown to stimulate cathecholamine release from adrenal glands. The objective of the present study is to examine whether cinnamaldehyde stimulates secretion of progesterone and other steroid hormones in human adrenal cells. Human adrenal cells, H295R were exposed for 24h in a serum-free medium to various concentrations of cinnamaldehyde. Steroid hormones in the cultured medium were measured by a highly sensitive LC-electrospray ionization-tandem mass spectrometry. Exposure to cinnamaldehyde increased progesterone release in a dose-dependent manner. Testosterone and dehydroepiandrosterone concentrations decreased in the presence of cinnamaldehyde. The release of cortisol or estradiol was not affected by treatment with cinnamaldehyde. cAMP in the cultured medium was increased from 0.06+/-0.0007pmol/ml to 0.12+/-0.0028pmol/ml by exposure to cinnamaldehyde. The addition of isobutylmehtylxanthine, a phosphodiesterase inhibitor, caused a doubling of the amount of cAMP up to 0.397+/-0.036pmol/ml in the presence of cinnamaldehyde. These data suggest that cinnamaldehyde selectively induced progesterone production and inhibited production of testosterone and dehydroepiandrosterone in human adrenal cells.


Analysis of spatial lamellar distribution from adaptive-optics second harmonic generation corneal images.
The spatial organization of stromal collagen of ex-vivo corneas has been quantified in adaptive-optics second harmonic generation (SHG) images by means of an optimized Fourier transform (FT) based analysis. At a particular depth location, adjacent lamellae often present similar orientations and run parallel to the corneal surface. However this pattern might be combined with interweaved collagen bundles leading to crosshatched structures with different orientations. The procedure here reported provides us with both principal and crosshatched angles. This is also able to automatically distinguish a random distribution from a cross-shaped one, since it uses the ratio of the axes lengths of the best-fitted ellipse of the FT data as an auxiliary parameter. The technique has successfully been applied to SHG images of healthy corneas (both stroma and Bowman's layer) of different species and to corneas undergoing cross-linking treatment.


Conformational order in aggregates of conjugated polymers.
With the abundant variety and increasing chemical complexity of conjugated polymers proliferating the field of organic semiconductors, it has become increasingly important to correlate the polymer molecular structure with its mesoscale conformational and morphological attributes. For instance, it is unknown which combinations of chemical moieties and periodicities predictably produce mesoscale ordering. Interestingly, not all ordered morphologies result in efficient devices. In this work we have parametrized accurate classical force-fields and used these to compute the conformational and aggregation characteristics of single strands of common conjugated polymers. Molecular dynamics trajectories are shown to reproduce experimentally observed polymeric ordering, concluding that efficient organic photovoltaic devices span a range of polymer conformational classes, and suggesting that the solution-phase morphologies have far-reaching effects. Encouragingly, these simulations indicate that despite the wide-range of conformational classes present in successful devices, local molecular ordering, and not long-range crystallinity, appears to be the necessary requirement for efficient devices. Finally, we examine what makes a "good" solvent for conjugated polymers, concluding that dispersive π-electron solvent-polymer interactions, and not the electrostatic potential of the backbone interacting with the solvent, are what primarily determine a polymer's solubility in a particular solvent, and consequently its morphological characteristics.


Effects of low versus high frequencies of repetitive transcranial magnetic stimulation on cognitive function and cortical excitability in Alzheimer's dementia.
The aim of the study was to compare the long-term efficacy of high versus low frequency repetitive transcranial magnetic stimulation (rTMS), applied bilaterally over the dorsolateral prefrontal cortex (DLPFC), on cognitive function and cortical excitability of patients with Alzheimer's disease (AD). Forty-five AD patients were randomly classified into three groups. The first two groups received real rTMS over the DLPFC (20 and 1 Hz, respectively) while the third group received sham stimulation. All patients received one session daily for five consecutive days. In each session, rTMS was applied first over the right DLPFC, immediately followed by rTMS over the left DLPFC. Mini Mental State Examination (MMSE), Instrumental Daily Living Activity (IADL) scale and the Geriatric Depression Scale (GDS) were assessed before, after the last (fifth) session, and then followed up at 1 and 3 months. Neurophysiological evaluations included resting and active motor threshold (rMT and aMT), and the duration of transcallosal inhibition (TI) before and after the end of the treatment sessions. At base line assessment there were no significant differences between groups in any of the rating scales. The high frequency rTMS group improved significantly more than the low frequency and sham groups in all rating scales (MMSE, IADL, and GDS) and at all time points after treatment. Measures of cortical excitability immediately after the last treatment session showed that treatment with 20 Hz rTMS reduced TI duration. These results confirm that five daily sessions of high frequency rTMS over the left and then the right DLPFC improves cognitive function in patients with mild to moderate degree of AD. This improvement was maintained for 3 months. High frequency rTMS may be a useful addition to therapy for the treatment of AD.


Therapists' techniques in the treatment of adolescent depression.
When comparing the relative effectiveness of different psychological treatment approaches using clinical trials, it is essential to establish fidelity to each manualized therapy, and differentiation between the treatment arms. Yet few psychological therapy trials include details about the assessment of treatment integrity and little is known about the specific techniques used by therapists, or to what degree these techniques are shared or distinct across different therapeutic approaches. The aims of this study were: to establish the fidelity of two established psychological therapies - cognitive-behaviour therapy (CBT) and short-term psychoanalytic psychotherapy (STPP) - in the treatment of adolescent depression; and to examine whether they were delivered with adherence to their respective treatment modalities, and if they could be differentiated from each other and from a reference treatment (a brief psychosocial intervention; BPI). The study also aimed to identify shared and distinct techniques used within and across the three treatments. Audio-tapes (N=230) of therapy sessions, collected as part of a trial, were blind double-rated using the Comparative Psychotherapy Process Scale (CPPS), which includes subscales for cognitive-behavioural and psychodynamic-interpersonal techniques. The treatments were delivered with reasonable fidelity and there was clear differentiation in the use of cognitive-behavioural and psychodynamic-interpersonal techniques between CBT and STPP, and between these two established psychological therapies and BPI. An item-level analysis identified techniques used across all three treatments, techniques that were shared between BPI and CBT, and techniques that were unique to CBT and STPP.


Immunomodulation with pomalidomide at early lymphocyte recovery after induction chemotherapy in newly diagnosed AML and high-risk MDS.
An immunosuppressive microenvironment promoting leukemia cell immune escape plays an important role in the pathogenesis of AML. Through its interaction with cereblon, a substrate receptor for the E3 ubiquitin ligase complex, pomalidomide leads to selective ubiquitination of transcription factors Aiolos and Ikaros thereby promoting immune modulation. In this phase I trial, 51 newly diagnosed non-favorable risk AML and high-risk MDS patients were enrolled and treated with AcDVP16 (cytarabine 667 mg/m2/day IV continuous infusion days 1-3, daunorubicin 45 mg/m2 IV days 1-3, etoposide 400 mg/m2 IV days 8-10) induction therapy followed by dose- and duration-escalation pomalidomide beginning at early lymphocyte recovery. Forty-three patients (AML: n = 39, MDS: n = 4) received pomalidomide. The maximum tolerated dose of pomalidomide was 4 mg for 21 consecutive days. The overall complete remission (CR + CRi) rate, median overall survival, and disease-free survival were 75%, 27.1 and 20.6 months, respectively. Subset analyses revealed 86% CR/CRi rate in AML patients with unfavorable-risk karyotype treated with pomalidomide. Pomalidomide significantly decreased Aiolos expression in both CD4+ and CD8+ peripheral blood and bone marrow T cells, promoted T cell differentiation, proliferation, and heightened their cytokine production. Finally, pomalidomide induced distinct gene expression changes in immune function-related ontologies in CD4+ and CD8+ T cells.


Mortality in patients with epilepsy: a study of patients in long term residential care.
The causes of death in a group of patients with severe epilepsy in long term residential care over a period of 11 years were assessed and the standardised mortality rate (SMR) determined. A total of 3392 patient-years were surveyed. One hundred and thirteen deaths were recorded in the period and this represents an overall mortality rate which is almost twice the expected rate for this population (SMR = 1.9; 95% CI 1.6-2.3; p < 0.01). Most deaths were due to cancer (26%), bronchopneumonia (25%), circulatory diseases (24%), were seizure-related (12%) or due to sudden unexpected death (6%). The highest SMRs in the neoplasm sub-group were due to cancers of the pancreas (SMR = 6.2) and hepatobiliary tumours (SMR = 17.6). Twenty per cent of patients died of epilepsy or epilepsy related causes (that is accidents, during seizures, status or sudden unexpected death). One in every 480 patients died due to a sudden unexpected death. This study in a highly selected population seems to confirm suggestions that mortality rates are higher in patients with epilepsy than in the general population, but prospective studies are warranted to ascertain underlying mechanisms.


Stretch-elicited calcium responses in the intact mouse thoracic aorta.
Stretch-elicited intracellular calcium ([Ca(2+)](i)) changes in individual smooth muscle cells in a ring of aorta were measured simultaneously with the force developed by the ring. A phasic increase in [Ca(2+)](i) was observed in 30% of the cells and a sustained one in 10%. Depletion of intracellular calcium store by thapsigargin and caffeine decreased phasic and increased sustained calcium responses. The inhibition of calcium entry either by stretching the aorta in a calcium-free medium or by the inhibition of stretch-activated, non-selective cationic channels by 5 microM GsMtx-4 toxin, decreased the proportion of sustained [Ca(2+)](i) responses but increased transient responses. In this condition, a third of the cells responded to stretch by a bursts of [Ca(2+)](i) spikes. The decrease of calcium influx triggered the generation of burst of calcium spikes after the application of stretch steps to the vascular wall. We conclude that progressive recruitment of smooth muscle cells is the mechanism underlying the force-generating part of the myogenic response. Two types of stretch-elicited calcium responses were observed during the recruitment of the smooth muscle cells. One was a phasic calcium discharge generated by the sarcoplasmic reticulum. The second was a tonic response produced by the activation of the stretch-sensitive cationic channels allowing extracellular Ca(2+) entry.


Structural Features of the Telomerase RNA Gene in the Naked Mole Rat Heterocephalus glaber.
Telomere length, an important feature of life span control, is dependent on the activity of telomerase (a key enzyme of the telomere-length-maintaining system). Telomerase RNA is a component of telomerase and, thus, is crucial for its activity. The structures of telomerase RNA genes and their promoter regions were compared for the long-living naked mole rat and different organisms. Two rare polymorphisms in Heterocephalus glaber telomerase RNA (hgTER) were identified: A→G in the first loop of pseudoknot P2b-p3 (an equivalent of 111nt in hTR) and G→A in the scaRNA domain CR7-p8b (an equivalent of 421nt in hTR). Analysis of TER promoter regions allowed us to identify two new transcription factor binding sites. The first one is the ETS family site, which was found to be a conserved element for all the analyzed TER promoters. The second site is unique for the promoter region of TER of the naked mole rat and is a binding site for the SOX17 transcription factor. The absence of one Sp1 site in the TER promoter region of the naked small rat is an additional specific feature of the promoter area of hgTER. Such variation in the hgTER transcription regulation region and hgTER itself could provide increased telomerase activity in stem cells and an extended lifespan to H. glaber.


Downstaging hepatocellular carcinoma: A systematic review and pooled analysis.
Downstaging can facilitate liver transplantation (LT) for patients outside of Milan criteria with hepatocellular carcinoma (HCC); however, the optimal protocol and downstaging outcomes are poorly defined. We aimed to characterize rates of successful downstaging to within Milan criteria and post-LT recurrence and survival among patients who underwent downstaging. We performed a systematic literature review using the MEDLINE and Embase databases from January 1996 through March 2015 and a search of national meeting abstracts from 2010 to 2014. Rates of downstaging success (defined as a decrease of tumor burden to within Milan) and post-LT recurrence with 95% confidence intervals (CIs) were calculated. Prespecified subgroup analyses were conducted by treatment modality, study design, and patient characteristics. Thirteen studies (n = 950 patients) evaluating downstaging success had a pooled success rate of 0.48 (95% CI, 0.39-0.58%). In subgroup analyses, there was no significant difference comparing transarterial chemoembolization (TACE) versus transarterial radioembolization (TARE; P = 0.51), but there were higher success rates in prospective versus retrospective studies (0.68 versus 0.44; P < 0.001). The 12 studies (n = 320 patients) evaluating post-LT HCC recurrence had a pooled recurrence rate of 0.16 (95% CI, 0.11-0.23). There was no significant difference in recurrence rates between TACE and TARE (P = 0.33). Post-LT survival could not be aggregated because of heterogeneity in survival data reporting. Current data have heterogeneity in baseline tumor burden, waiting time, downstaging protocols, and treatment response assessments. There are also notable limitations including inconsistent reporting of inclusion criteria, downstaging protocols, and outcome assessment criteria. In conclusion, the success rate of downstaging HCC to within Milan criteria exceeds 40%; however, posttransplant HCC recurrence rates are high at 16%. Downstaging protocols for HCC should be systematically studied and optimized to minimize the risk of post-LT HCC recurrence.


Advances in the diagnosis and treatment of chronic granulomatous disease.
Chronic granulomatous disease (CGD), characterized 50 years ago as a primary immunodeficiency disorder of phagocytic cells (resulting in failure to kill a defined spectrum of bacteria and fungi and in concomitant chronic granulomatous inflammation) now comprises five genetic defects impairing one of the five subunits of phagocyte NADPH oxidase (Phox). Phox normally generates reactive oxygen species (ROS) engaged in intracellular and extracellular host defence and resolving accompanying inflammatory processes. 'Fatal' granulomatous disease has now changed into a chronic inflammatory condition with a median survival of 35 years and is now of interest to both paediatricians and internists. Clinical vigilance and expert knowledge are needed for early recognition and tailored treatment of this relatively rare genetic disorder. Infections by unanticipated pathogens and noncirrhotic portal hypertension need to be recognized as new CGD manifestations. Adult-onset CGD too is increasingly observed even in the elderly. Conservative treatment of fungal infections needs close monitoring due to the spread of azole resistance following extensive use of azoles in agriculture. Curative haematopoietic stem cell transplantation (HSCT) in early childhood has expanded with impressive results following use of matched, unrelated or cord blood donors and of a reduced intensity conditioning (RIC) regimen. Gene therapy, however, still has major limitations, remaining experimental. CGD is more prevalent than initially believed with a birth prevalence of 1: 120 000. As patients are increasingly diagnosed around the world and grow older, further manifestations of CGD are expected. While fungal infections have lost some threat, therapeutic research focuses on two other important aims: pharmacologic cure of chronic inflammation and long-term cure of CGD by gene therapy.


Preferential accumulation of amyloid-beta in presynaptic glutamatergic terminals (VGluT1 and VGluT2) in Alzheimer's disease cortex.
Amyloid-beta (Aβ) is thought to play a central role in synaptic dysfunction (e.g. neurotransmitter release) and synapse loss. Glutamatergic dysfunction is involved in the pathology of Alzheimer's disease (AD) and perhaps plays a central role in age-related cognitive impairment. Yet, it is largely unknown whether Aβ accumulates in excitatory boutons. To assess the possibility that glutamatergic terminals are lost in AD patients, control and AD synaptosomes were immunolabeled for the most abundant vesicular glutamate transporters (VGluT1 and VGluT2) and quantified by flow cytometry and immunoblot methods. In post-mortem parietal cortex from aged control subjects, glutamatergic boutons are fairly abundant as approximately 40% were immunoreactive for VGluT1 (37%) and VGluT2 (39%). However, the levels of these specific markers of glutamatergic synapses were not significantly different among control and AD cases. To test the hypothesis that Aβ is associated with excitatory terminals, AD synaptosomes were double-labeled for Aβ and for VGluT1 and VGluT2, and analyzed by flow cytometry and confocal microscopy. Our study demonstrated that Aβ immunoreactivity (IR) was present in glutamatergic terminals of AD patients. Quantification of Aβ and VGluT1 in a large population of glutamatergic nerve terminals was performed by flow cytometry, showing that 42% of VGluT1 synaptosomes were immunoreactive for Aβ compared to 9% of VGluT1 synaptosomes lacking Aβ-IR. Percentage of VGluT2 synaptosomes immunoreactive for Aβ (21%) was significantly higher than VGluT2 synaptosomes lacking Aβ-IR (9%). Moreover, Aβ preferentially affects VGluT1 (42% positive) compared to VGluT2 terminals (21%). These data represent the first evidence of high levels of Aβ in excitatory boutons in AD cortex and support the hypothesis that Aβ may play a role in modulating glutamate transmission in AD terminals.


The Emergence of 2-Oxoglutarate as a Master Regulator Metabolite.
The metabolite 2-oxoglutarate (also known as α-ketoglutarate, 2-ketoglutaric acid, or oxoglutaric acid) lies at the intersection between the carbon and nitrogen metabolic pathways. This compound is a key intermediate of one of the most fundamental biochemical pathways in carbon metabolism, the tricarboxylic acid (TCA) cycle. In addition, 2-oxoglutarate also acts as the major carbon skeleton for nitrogen-assimilatory reactions. Experimental data support the conclusion that intracellular levels of 2-oxoglutarate fluctuate according to nitrogen and carbon availability. This review summarizes how nature has capitalized on the ability of 2-oxoglutarate to reflect cellular nutritional status through evolution of a variety of 2-oxoglutarate-sensing regulatory proteins. The number of metabolic pathways known to be regulated by 2-oxoglutarate levels has increased significantly in recent years. The signaling properties of 2-oxoglutarate are highlighted by the fact that this metabolite regulates the synthesis of the well-established master signaling molecule, cyclic AMP (cAMP), in Escherichia coli.


The importance of estimating selection bias on prevalence estimates shortly after a disaster.
The aim was to study selective participation and its effect on prevalence estimates in a health survey of affected residents 3 weeks after a man-made disaster in The Netherlands (May 13, 2000). All affected adult residents were invited to participate. Survey (questionnaire) data were combined with electronic medical records of residents' general practitioners (GPs). Data for demographics, relocation, utilization, and morbidity 1 year predisaster and 1 year postdisaster were used. The survey participation rate was 26% (N = 1171). Women (odds ratio [OR], 1.46; 95% confidence interval [CI], 1.28-1.67), those living with a partner (OR, 2.00; 95% CI, 1.72-2.33), those aged 45 to 64 years (OR, 2.00; 95% CI, 1.59-2.52), and immigrants (OR, 1.50; 95% CI, 1.30-1.74) were more likely to participate. Participation rate was not affected by relocation because of the disaster. Participants in the survey consulted their GPs for health problems in the year before and after the disaster more often than nonparticipants. Although there was selective participation, multiple imputation barely affected prevalence estimates of health problems in the survey 3 weeks postdisaster. Estimating actual selection bias in disaster studies gives better information about the study representativeness. This is important for policy making and providing effective health care.


Questioning fairness: the relationship of mental health and psychopathic characteristics with young offenders' perceptions of procedural justice and legitimacy.
Theories of procedural justice suggest that individuals who experience the criminal justice system as fair are more likely to perceive it as legitimate and, in turn, are less likely to reoffend. However, when individuals come into contact with the legal system, they are not blank slates - they have beliefs and personality characteristics that may systematically influence such perceptions. Our aim was to establish the extent to which demographic characteristics, legal history and clinical features, including personality characteristics, systematically influenced the degree to which young people experience the justice system as fair and legitimate. Self-report, file and interview data were collected from ninety-two 12 to 17-year-olds on probation in Western Canada. Substance use and traumatic experiences were inversely correlated with perceptions of procedural justice and legal legitimacy. Young people with higher scores on interpersonal, lifestyle and antisocial facets of the psychopathy checklist: youth version believed less strongly in the legitimacy of the law, but regression analyses confirmed that only history of trauma was independently associated with perceived procedural justice and legitimacy. Those in the youngest age group were more likely to have positive perceptions of justice than older youths, but demographics and legal history otherwise did not relate to outcomes. Our findings suggest that examining the relationship between procedural justice, legitimacy and offending without taking intra-individual variables into account may neglect important influences on those relationships. Other research has begun to show that young people who do not accept the law as legitimate or the criminal justice system as fair are more likely to offend. Copyright © 2016 John Wiley & Sons, Ltd.


High rates of multidrug-resistant and rifampicin-resistant tuberculosis among re-treatment cases: where do they come from?
Globally 3.9% of new and 21% of re-treatment tuberculosis (TB) cases are multidrug-resistant or rifampicin-resistant (MDR/RR), which is often interpreted as evidence that drug resistance results mainly from poor treatment adherence. This study aims to assess the respective contributions of the different causal pathways leading to MDR/RR-TB at re-treatment. We use a simple mathematical model to simulate progression between the different stages of disease and treatment for patients diagnosed with TB. The model is parameterised using region and country-specific TB disease burden data reported by the World Health Organization (WHO). The contributions of four separate causal pathways to MDR/RR-TB among re-treatment cases are estimated: I) initial drug-susceptible TB with resistance amplification during treatment; II) initial MDR/RR-TB inappropriately treated as drug-susceptible TB; III) MDR/RR-TB relapse despite appropriate treatment; and IV) re-infection with MDR/RR-TB. At the global level, Pathways I, II, III and IV contribute 38% (28-49, 95% Simulation Interval), 44% (36-52, 95% SI), 6% (5-7, 95% SI) and 12% (7-19, 95% SI) respectively to the burden of MDR/RR-TB among re-treatment cases. Pathway II is dominant in the Western Pacific (74%; 67-80 95% SI), Eastern Mediterranean (68%; 60-74 95% SI) and European (53%; 48-59 95% SI) regions, while Pathway I makes the greatest contribution in the American (53%; 40-66 95% SI), African (43%; 28-61 95% SI) and South-East Asian (50%; 40-59 95% SI) regions. Globally, failure to diagnose MDR/RR-TB at first presentation is the leading cause of the high proportion of MDR/RR-TB among re-treatment cases. These findings highlight the need for contextualised solutions to limit the impact and spread of MDR/RR-TB.


The effect of trimethoprim on macromolecular synthesis in Escherichia coli. Ribosome maturation in RCstr and RCrel strains.
When Escherichia coli was inhibited with trimethoprim in media supplemented with nucleotide bases, glycine and methionine, both RC(str) and RC(rel) strains continued to accumulate RNA at rates very close to those in growing controls. The effects of trimethoprim on protein synthesis were studied by using as an experimental basis the rate of maturation of ribosomal particles from RNA-rich precursors. 1. In RC(str) cultures given nucleotide bases but no amino acids, RNA accumulation was inhibited because of amino acid lack. However, maturation of ribosomes from their precursors was more severely inhibited than was the synthesis of rRNA. The restraints on protein synthesis were more severe at the level of translation than the transcription of operons specific for the formation of ribosomal proteins. The kinetic delay time in the passage of rRNA from RNA-rich intermediates to the final ribosome products was therefore increased some three- to four-fold. 2. In RC(rel) cultures in the same conditions, trimethoprim inhibition stopped ribosomal particle synthesis, but rRNA-rich precursors accumulated. 3. If glycine+methionine were also added to inhibited RC(str) cultures, RNA accumulation resumed at a high rate. However, ribosomal maturation was still considerably disturbed because of a disproportionate response of the cells in the formation of protein and RNA. 4. With RC(rel) cultures, addition of the amino acids caused a large increase in the rate of ribosome maturation, though the degree of disproportionation between the rates of rRNA and ribosomal protein synthesis was now identical with that found in RC(str) strains. 5. When inhibited RC(rel) cultures were supplemented, there was still a severe inhibition of protein synthesis at the level of chain initiation, but inaccuracies in the process of polypeptide chain elongation were greatly decreased. This suggests that the effects of the RC(rel) mutation on the fidelity of protein synthesis in bacteria are not directed at the point of chain initiation.


Threading a database of protein cores.
We present an analysis of 10 blind predictions prepared for a recent conference, "Critical Assessment of Techniques for Protein Structure Prediction." The sequences of these proteins are not detectably similar to those of any protein in the structure database then available, but we attempted, by a threading method, to recognize similarity to known domain folds. Four of the 10 proteins, as we subsequently learned, do indeed show significant similarity to then-known structures. For 2 of these proteins the predictions were accurate, in the sense that a similar structure was at or near the top of the list of threading scores, and the threading alignment agreed well with the corresponding structural alignment. For the best predicted model mean alignment error relative to the optimal structural alignment was 2.7 residues, arising entirely from small "register shifts" of strands or helices. In the analysis we attempt to identify factors responsible for these successes and failures. Since our threading method does not use gap penalties, we may readily distinguish between errors arising from our prior definition of the "cores" of known structures and errors arising from inherent limitations in the threading potential. It would appear from the results that successful substructure recognition depends most critically on accurate definition of the "fold" of a database protein. This definition must correctly delineate substructures that are, and are not, likely to be conserved during protein evolution.


Magnetoresistance in two-component systems.
Two-component systems with equal concentrations of electrons and holes exhibit nonsaturating, linear magnetoresistance in classically strong magnetic fields. The effect is predicted to occur in finite-size samples at charge neutrality due to recombination. The phenomenon originates in the excess quasiparticle density developing near the edges of the sample due to the compensated Hall effect. The size of the boundary region is of the order of the electron-hole recombination length that is inversely proportional to the magnetic field. In narrow samples and at strong enough magnetic fields, the boundary region dominates over the bulk leading to linear magnetoresistance. Our results are relevant for two-and three-dimensional semimetals and narrow band semiconductors including most of the topological insulators.


Invasive plant erodes local song diversity in a migratory passerine.
Exotic plant invasions threaten ecosystems globally, but we still know little about the specific consequences for animals. Invasive plants can alter the quality of breeding habitat for songbirds, thereby impacting important demographic traits such as dispersal, philopatry, and age structure. These demographic effects may in turn alter song-learning conditions to affect song structure and diversity. We studied Chipping Sparrows (Spizella passerina) breeding in six savannas that were either dominated by native vegetation or invaded by spotted knapweed (Centaurea stoebe), an exotic forb known to diminish food resources and reproductive success. Here, we report that the prevalence of older birds was relatively low in knapweed-invaded habitat, where recruitment of yearlings compensated for diminished site fidelity to sustain territory abundance. In both habitat types, yearling males tended to adopt songs similar to their neighbors and match the songs of older birds rather than introducing new song types, a pattern seen in many songbird species. As a consequence, in invaded habitat where age structure was skewed away from older birds serving as potential song models, yearlings converged on fewer song types. Similarity of songs among individuals was significantly higher and the overall number of song types averaged nearly 20% lower in invaded relative to native habitat. Degradation of habitat quality generally impacts site fidelity and age ratios in migratory songbirds and hence may commonly alter song-learning conditions. Associated shifts in song attributes known to influence reproductive success could in turn enforce demographic declines driven by habitat degradation. Local song structure may serve as an important indicator of habitat quality and population status for songbirds.


Is the species flock concept operational? The Antarctic shelf case.
There has been a significant body of literature on species flock definition but not so much about practical means to appraise them. We here apply the five criteria of Eastman and McCune for detecting species flocks in four taxonomic components of the benthic fauna of the Antarctic shelf: teleost fishes, crinoids (feather stars), echinoids (sea urchins) and crustacean arthropods. Practical limitations led us to prioritize the three historical criteria (endemicity, monophyly, species richness) over the two ecological ones (ecological diversity and habitat dominance). We propose a new protocol which includes an iterative fine-tuning of the monophyly and endemicity criteria in order to discover unsuspected flocks. As a result nine « full » species flocks (fulfilling the five criteria) are briefly described. Eight other flocks fit the three historical criteria but need to be further investigated from the ecological point of view (here called "core flocks"). The approach also shows that some candidate taxonomic components are no species flocks at all. The present study contradicts the paradigm that marine species flocks are rare. The hypothesis according to which the Antarctic shelf acts as a species flocks generator is supported, and the approach indicates paths for further ecological studies and may serve as a starting point to investigate the processes leading to flock-like patterning of biodiversity.


Hirsutism.
The androgen status of a hirsute woman can be diagnosed today by new techniques for measuring circulating androgens. Unfortunately, a battery of expensive tests is required to make this assessment. Two specific basic screening tests, DHEA-S and total free testosterone determinations, should be done. If the patient is interested in and can afford it, further testing can be done; it includes 17-hydroxyprogesterone, prolactin, compound S (serum 11-deoxycortisol) and cortisol measurements and a dexamethasone suppression test. Elevations of androgens, whereas elevations of testosterone can be due to ovarian or adrenal secretion. Establishing the site of androgen hypersecretion allows one to be more selective regarding the antiandrogen therapy. When excess androgen secretion is primarily adrenal in origin, adrenal suppression is effective with the use of such drugs as dexamethasone. If the excess androgen is primarily of ovarian origin, cyclic estrogens, for example, Demulen or Premarin with Provera, would be helpful. The evaluation of a hirsute patient takes time, interest, and knowledge of specific androgen-dependent cutaneous syndromes involving multiple possible enzymatic defects in the conversion of cholesterol to testosterone or intercellular pathways of androgen metabolism. If the dermatologist is not interested in or lacks the knowledge for such an evaluation, the patient is best referred to an interested endocrinologist.


Spontaneous emergence of social influence in online systems.
Social influence drives both offline and online human behavior. It pervades cultural markets, and manifests itself in the adoption of scientific and technical innovations as well as the spread of social practices. Prior empirical work on the diffusion of innovations in spatial regions or social networks has largely focused on the spread of one particular technology among a subset of all potential adopters. Here we choose an online context that allows us to study social influence processes by tracking the popularity of a complete set of applications installed by the user population of a social networking site, thus capturing the behavior of all individuals who can influence each other in this context. By extending standard fluctuation scaling methods, we analyze the collective behavior induced by 100 million application installations, and show that two distinct regimes of behavior emerge in the system. Once applications cross a particular threshold of popularity, social influence processes induce highly correlated adoption behavior among the users, which propels some of the applications to extraordinary levels of popularity. Below this threshold, the collective effect of social influence appears to vanish almost entirely, in a manner that has not been observed in the offline world. Our results demonstrate that even when external signals are absent, social influence can spontaneously assume an on-off nature in a digital environment. It remains to be seen whether a similar outcome could be observed in the offline world if equivalent experimental conditions could be replicated.


Boundary effects in a quasi-two-dimensional driven granular fluid.
The effect of a confining boundary on the spatial variations in granular temperature of a driven quasi-two-dimensional layer of particles is investigated experimentally. The radial drop in the relative granular temperature ΔT/T exhibits a maximum at intermediate particle numbers which coincides with a crossover from kinetic to collisional transport of energy. It is also found that at low particle numbers, the distributions of radial velocities are increasingly asymmetric as one approaches the boundary. The radial and tangential granular temperatures split, and in the tails of the radial velocity distribution there is a higher population of fast moving particles traveling away rather than towards the boundary.


ER-shaping proteins facilitate lipid exchange between the ER and mitochondria in S. cerevisiae.
The endoplasmic reticulum (ER) forms a network of sheets and tubules that extends throughout the cell. Proteins required to maintain this complex structure include the reticulons, reticulon-like proteins, and dynamin-like GTPases called atlastins in mammals and Sey1p in Saccharomyces cerevisiae. Yeast cells missing these proteins have abnormal ER structure, particularly defects in the formation of ER tubules, but grow about as well as wild-type cells. We screened for mutations that cause cells that have defects in maintaining ER tubules to grow poorly. Among the genes we found were members of the ER mitochondria encounter structure (ERMES) complex that tethers the ER and mitochondria. Close contacts between the ER and mitochondria are thought to be sites where lipids are moved from the ER to mitochondria, a process that is required for mitochondrial membrane biogenesis. We show that ER to mitochondria phospholipid transfer slows significantly in cells missing both ER-shaping proteins and the ERMES complex. These cells also have altered steady-state levels of phospholipids. We found that the defect in ER to mitochondria phospholipid transfer in a strain missing ER-shaping proteins and a component of the ERMES complex was corrected by expression of a protein that artificially tethers the ER and mitochondria. Our findings indicate that ER-shaping proteins play a role in maintaining functional contacts between the ER and mitochondria and suggest that the shape of the ER at ER-mitochondria contact sites affects lipid exchange between these organelles.


The crystal structure of the cephalosporin deacetylating enzyme acetyl xylan esterase bound to paraoxon explains the low sensitivity of this serine hydrolase to organophosphate inactivation.
Organophosphorus insecticides and nerve agents irreversibly inhibit serine hydrolase superfamily enzymes. One enzyme of this superfamily, the industrially important (for β-lactam antibiotic synthesis) AXE/CAH (acetyl xylan esterase/cephalosporin acetyl hydrolase) from the biotechnologically valuable organism Bacillus pumilus, exhibits low sensitivity to the organophosphate paraoxon (diethyl-p-nitrophenyl phosphate, also called paraoxon-ethyl), reflected in a high K(i) for it (~5 mM) and in a slow formation (t(½)~1 min) of the covalent adduct of the enzyme and for DEP (E-DEP, enzyme-diethyl phosphate, i.e. enzyme-paraoxon). The crystal structure of the E-DEP complex determined at 2.7 Å resolution (1 Å=0.1 nm) reveals strain in the active Ser¹⁸¹-bound organophosphate as a likely cause for the limited paraoxon sensitivity. The strain results from active-site-size limitation imposed by bulky conserved aromatic residues that may exclude as substrates esters having acyl groups larger than acetate. Interestingly, in the doughnut-like homohexamer of the enzyme, the six active sites are confined within a central chamber formed between two 60°-staggered trimers. The exclusive access to this chamber through a hole around the three-fold axis possibly limits the size of the xylan natural substrates. The enzyme provides a rigid scaffold for catalysis, as reflected in the lack of movement associated with paraoxon adduct formation, as revealed by comparing this adduct structure with that also determined in the present study at 1.9 Å resolution for the paraoxon-free enzyme.


Anti-aβ oligomer IgG and surface sialic acid in intravenous immunoglobulin: measurement and correlation with clinical outcomes in Alzheimer's disease treatment.
The fraction of IgG antibodies with anti-oligomeric Aβ affinity and surface sialic acid was compared between Octagam and Gammagard intravenous immunoglobulin (IVIG) using two complementary surface plasmon resonance methods. These comparisons were performed to identify if an elevated fraction existed in Gammagard, which reported small putative benefits in a recent Phase III clinical trial for Alzheimer's Disease. The fraction of anti-oligomeric Aβ IgG was found to be higher in Octagam, for which no cognitive benefits were reported. The fraction and location of surface-accessible sialic acid in the Fab domain was found to be similar between Gammagard and Octagam. These findings indicate that anti-oligomeric Aβ IgG and total surface sialic acid alone cannot account for reported clinical differences in the two IVIG products. A combined analysis of sialic acid in anti-oligomeric Aβ IgG did reveal a notable finding that this subgroup exhibited a high degree of surface sialic acid lacking the conventional α2,6 linkage. These results demonstrate that the IVIG antibodies used to engage oligomeric Aβ in both Gammagard and Octagam clinical trials did not possess α2,6-linked surface sialic acid at the time of administration. Anti-oligomeric Aβ IgG with α2,6 linkages remains untested as an AD treatment.


A Hypothesis to Explain Divergent Findings Among Studies Comparing the Efficacy of Unilateral and Bilateral ECT in Depression.
This article explains divergent reports on the relative efficacy of unilateral and bilateral electroconvulsive therapy (ECT) by hypothesizing a therapeutic effect of both seizure and electrical stimulus, with the seizure's effect based on its intensity and generalization. The effect of the stimulus is normally obscured by the seizure but emerges with reduced electrical dosage or elevated threshold. These circumstances favor a therapeutic advantage for bilateral ECT, which introduces more electrical charge into a larger and differently distributed volume of brain and induces greater seizure generalization, more diencephalic stimulation, and a relative decrease in left relative to right hemisphere electroencephalographic (EEG) frequencies.


The acid-sensitive potassium channel TASK-1 in rat cardiac muscle.
The outward current flowing through the two-pore domain acid-sensitive potassium channel TASK-1 (I(TASK)) and its inhibition via alpha1-adrenergic receptors was studied in rat ventricular cardiomyocytes. Quantitative RT-PCR experiments were carried out with mRNA from rat heart. Patch-clamp recordings were performed in isolated rat cardiomyocytes. TASK-1 and other K+ channels were expressed in Xenopus oocytes to study the pharmacological properties of a new TASK-1 channel blocker, A293. TASK-1 channels were found to be strongly expressed in rat heart. Analysis of the sensitivity of various K+ channels to A293 in Xenopus oocytes showed that at low concentrations A293 was a selective blocker of TASK-1 channels. I(TASK) in rat cardiomyocytes was dissected by application of A293 and by extracellular acidification to pH 6.0; it had an amplitude of approximately 0.30 pA/pF at +30 mV. Application of 200 nM A293 increased action potential duration (APD(50)) by 31+/-3% at a stimulation rate of 4 Hz. The plausibility of the effects of A293 on APD50 was checked with a mathematical action potential model. Application of the alpha1-adrenergic agonist methoxamine inhibited I(TASK) in Xenopus oocytes co-injected with cRNA for TASK-1 and alpha1A-receptors. In cardiomyocytes, methoxamine inhibited an outward current with characteristics similar to I(TASK). This effect was abolished in the presence of the alpha1A-antagonist 5-methyl-urapidil. Our results suggest that in rat cardiomyocytes I(TASK) makes a substantial contribution to the outward current flowing in the plateau range of potentials and that this current component can be inhibited via alpha1A-adrenergic receptors.


CYP3A-like cytochrome P450-mediated metabolism and polarized efflux of cyclosporin A in Caco-2 cells.
Transport of cyclosporin A (CsA) across Caco-2 cells is modulated by its directional efflux, mediated by a p-glycoprotein-like pump (Augustijns et al., Biochem. Biophys. Res. Comm. 197:360-365, 1994). In addition to this unidirectional flux, oxidative metabolism of CsA by cytochrome P450 is likely to influence the absorption of this cyclic peptide across intestinal mucosa. Thus, metabolism of CsA in the in vitro Caco-2 cell culture system was investigated. Formation of several metabolites was observed during the course of CsA transport across Caco-2 cell monolayers. Results from LC/MS/MS experiments revealed that the major metabolite was 1eta-hydroxy CsA (M-17), one of the three major metabolites produced by CYP3A4 present in both the liver and small intestine in humans. Preincubation of Caco-2 cell monolayers with troleandomycin, a specific inhibitor for the microsomal CYP3A protein, reduced the formation of the metabolite M-17, suggesting that an enzyme that functionally resembles CYP3A is responsible for the formation of this metabolite. However, formation of only the M-17 metabolite suggests that the isozyme present in the Caco-2 cells is distinct from CYP3A4, which also catalyzes the formation of significant quantities of the metabolites 9gamma-hydroxy cyclosporin A (M-1) and 4N-desmethyl cyclosporin A (M-21) from CsA. Interestingly, the amount of M-17 accumulating on the apical (AP) side was much greater than that on the basolateral (BL) side during the AP --> BL transport of CsA across Caco-2 cell monolayers. This is consistent with p-glycoprotein pump-mediated efflux of the metabolite to the apical side. Furthermore, formation of the M-17 metabolite on the AP side of cell monolayers during the AP --> BL transport of CsA was much greater than that during the BL --> AP transport. This result suggests that the p-glycoprotein efflux pump causes an increase in the metabolism of CsA during the course of its AP --> BL transport by effectively slowing down the transport of CsA molecules across Caco-2 cells. Thus, Caco-2 cells serve as an excellent model to dissect the relative roles played by p-glycoprotein-mediated efflux and CYP3A-catalyzed oxidation in modulating the overall absorption of CsA and other such compounds.


Notification card to alert for methicillin-resistant Staphylococcus aureus is stigmatizing from the patient's point of view.
The importance of alerting health care systems of patients carrying multidrug-resistant bacteria (MRB) is highlighted in numerous guidelines. In the absence of electronic alert systems, notification cards are often recommended, but have rarely been evaluated. We evaluated patient experiences of receiving and using a methicillin-resistant Staphylococcus aureus (MRSA) notification card. Two cohorts of patients given a card when identified for the first time as a carrier in 1999-2003 and 2008-2010, responded to questionnaires distributed in 2004 and 2011, respectively. The response rate in 2004 was 92 (38 females)/129 and in 2011 was 110 (55 females)/209. In addition, 63% and 49%, respectively, followed the encouragement to provide written comments to the questions. These were analysed using a qualitative method. The patients took responsibility not to infect others, reported high usage, and acknowledged the importance of the card to inform health care institutions about their carrier status, despite experiencing fear, disrespect, lack of knowledge, and unprofessional behaviour when presenting it to personnel. Alarmingly these stigmatizing experiences were more frequent in 2011. Professional behaviour was reported from the infectious disease clinic. A majority of the patients were unaware of how they had acquired MRSA. The MRSA notification card was felt to stigmatize the patient, which makes its use questionable. Other alert methods need to be developed. Most importantly, the study demonstrates the importance for these patients to meet staff educated about MRB. Thus, there is an urgent need to educate health care professionals at all levels.


Radiofrequency-targeted vertebral augmentation versus traditional balloon kyphoplasty: radiographic and morphologic outcomes of an ex vivo biomechanical pilot study.
Traditional balloon kyphoplasty (BK) is a common treatment for symptomatic vertebral compression fractures. The purpose of this study was to compare a novel vertebral augmentation technique, radiofrequency-targeted vertebral augmentation (RF-TVA), to BK for restoration of vertebral height, cavity creation, and polymethylmethacrylate (PMMA) delivery and interdigitation into the surrounding trabeculae. This ex vivo biomechanical pilot study utilized 16 osteoporotic cadaveric vertebral bodies in a standardized fracture model to compare unipedicular RF-TVA (n = 8) to bipedicular BK (n = 8). Four specimens from each group were tested in loaded and unloaded conditions. All specimens were imaged, assessed for height restoration, and sectioned to observe PMMA distribution. A subset of specimens underwent computed tomography scanning to assess cavity creation and trabecular architecture prior to cement delivery. Anterior height restoration was greater with RF-TVA (median: 84%, interquartile range: 62%-95%) compared to BK (median: 69%, interquartile range: 60%-81%), although the difference did not achieve statistical significance (P = 0.16). Anterior height restoration was numerically greater under loaded (median: 70% versus 66%) and unloaded (median: 94% versus 77%) conditions with RF-TVA versus BK. RF-TVA produced more discrete cavities and less native trabecular destruction compared to marked trabecular destruction observed with BK. RF-TVA consistently showed a well-identified focal area of PMMA with an extensive peripheral zone of PMMA interdigitation, providing mechanical interlock into the adjacent intact trabecular matrix. In contrast, BK yielded little evidence of PMMA interdigitation beyond the boundaries created by the balloon tamp due to the crushed trabecular bone peripherally. RF-TVA achieves favorable vertebral height restoration with targeted PMMA delivery and less trabecular destruction compared to BK. RF-TVA has potential clinical utility in the aging population with painful osteoporotic vertebral fracture.


Identification of SER-PRO-CYS Peptide in Blood Serum of Multiple Sclerosis Patients.
Monitoring of multiple sclerosis (MS) requires additional molecular markers. Recently, we used original TCA-precipitation/extraction approach in combination with MALDI TOF/TOF mass-spectrometry and identified earlier unknown 48 kDa form of the unconventional myosin IC isoform b (Myo1C) in blood serum of the MS patients. Further examination of TCA-extracted fraction of blood serum of these patients by means of thin-layer chromatography and HPLC gel-filtration allowed detecting 300-500 Da peptides. MALDI TOF/TOF massspectrometry of these peptides showed that they contain Ser-Pro-Cys amino acid sequence. We discussed potential mechanisms of a release of these peptides that were earlier unknown in blood serum of the MS patients.


Diagnosis of Lingual Atrophic Conditions: Associations with Local and Systemic Factors. A Descriptive Review.
Atrophic glossitis is a condition characterised by absence of filiform or fungiform papillae on the dorsal surface of the tongue. Consequently, the ordinary texture and appearance of the dorsal tongue, determined by papillary protrusion, turns into a soft and smooth aspect. Throughout the years, many factors, both local and systemic, have been associated with atrophic glossitis as the tongue is currently considered to be a mirror of general health. Moreover, various tongue conditions were wrongly diagnosed as atrophic glossitis. Oral involvement can conceal underlying systemic conditions and, in this perspective, the role of clinicians is fundamental. Early recognition of oral signs and symptoms, through a careful examination of oral anatomical structures, plays a crucial role in providing patients with a better prognosis.


Effect of phospholipids and their molecular species on cholesterol solubility and nucleation in human and model biles.
Much research in the pathophysiology of gall stones has been devoted to various molecular species of bile salts. Recent findings have shown the importance of phospholipids in biliary pathophysiology. In the present study the addition of increasing doses of egg lecithin to human and model biles progressively prolonged the nucleation time. Concurrently biliary cholesterol was shifted from the vesicular to the non-vesicular carrier(s) while the cholesterol/phospholipid ratio of the remaining vesicles was progressively lowered. Model bile solutions of identical lipid concentration were prepared using phosphatidylcholine, phosphatidylserine, and phosphatidylethanolamine as the only phospholipid. With phosphatidylethanolamine most of the cholesterol was shifted to the vesicular carrier while phosphatidylserine shifted most of the cholesterol to the non-vesicular carrier(s). With phosphatidylcholine the cholesterol was distributed in both carriers. Phosphatidyl choline species composed of various acyl fatty acids in the sn-1 and sn-2 positions were used as the sole phospholipid in otherwise identical model bile solutions. With palmitic acid in the sn-1 position and arachidonic acid in the sn-2 position most of the cholesterol was found in the non-vesicular carrier. When stearic acid was used in sn-2 position instead of arachidonic acid most of the cholesterol was found in the vesicular carrier. These and other variations in phospholipid molecular species shifted cholesterol among its carriers and also modified the nucleation time of model biles. Most of these effects were also found upon addition of the various phospholipid species to human biles. These findings show the importance of phospholipid species in biliary pathophysiology and may be useful when trying to manipulate cholesterol carriers and solubility in bile.


Charge transfer in crystalline germanium/monolayer MoS2 heterostructures prepared by chemical vapor deposition.
Heterostructuring provides novel opportunities for exploring emergent phenomena and applications by developing designed properties beyond those of homogeneous materials. Advances in nanoscience enable the preparation of heterostructures formed incommensurate materials. Two-dimensional (2D) materials, such as graphene and transition metal dichalcogenides, are of particular interest due to their distinct physical characteristics. Recently, 2D/2D heterostructures have opened up new research areas. However, other heterostructures such as 2D/three-dimensional (3D) materials have not been thoroughly studied yet although the growth of 3D materials on 2D materials creating 2D/3D heterostructures with exceptional carrier transport properties has been reported. Here we report a novel heterostructure composed of Ge and monolayer MoS2, prepared by chemical vapor deposition. A single crystalline Ge (110) thin film was grown on monolayer MoS2. The electrical characteristics of Ge and MoS2 in the Ge/MoS2 heterostructure were remarkably different from those of isolated Ge and MoS2. The field-effect conductivity type of the monolayer MoS2 is converted from n-type to p-type by growth of the Ge thin film on top of it. Undoped Ge on MoS2 is highly conducting. The observations can be explained by charge transfer in the heterostructure as opposed to chemical doping via the incorporation of impurities, based on our first-principles calculations.


Fourier transform infrared for noninvasive optical diagnosis of oral, oropharyngeal, and laryngeal cancer.
The 5-year survival rate for advanced head and neck cancers is 50%. There is currently no noninvasive method or effective screening procedure available to diagnose head and neck cancer at the earliest stages when it is still highly curable. This study aims to show how Fourier transform infrared (FTIR) spectroscopy could be used as a sensitive, noninvasive, low cost technique to diagnose head and neck cancer at an earlier stage and, thus, increase the likelihood of survival. Sputum samples were collected from 16 cases with oral or oropharyngeal cancer, 8 cases with laryngeal cancer patients and 15 normal controls. Cell pellets were produced from each of these samples and used to generate FTIR spectra within the 'biochemical fingerprint' wavenumber region of 1800 to 950 cm(-1). Discrimination between cancer and normal sputum was achieved using infrared wavenumbers 1650 cm(-1), 1550 cm(-1), and 1042 cm(-1) determined by robust feature selection. These 3 wavenumbers were used to develop potential models to discriminate both oropharyngeal and laryngeal cancer from normal control. In cancer cases, the absorbance levels for 1550 cm(-1) were increased relative to controls, whereas 1042 cm(-1) absorbance was decreased suggesting changes to protein and glycoprotein structure within sputa cells. This preliminary study shows potential for how FTIR could be developed into a simplistic diagnostic tool that could easily be implemented by a nonspecialist to diagnose and monitor head and neck cancer. The method could especially provide a means for detecting laryngeal cancer hidden from noninvasive observation.


Public deliberation and private choice in genetics and reproduction.
The development of human genetics raises a wide range of important ethical questions for us all. The interpersonal dimension of genetic information in particular means that genetics also poses important challenges to the idea of patient-centredness and autonomy in medicine. How ought practical ethical decisions about the new genetics be made given that we appear, moreover, no longer to be able to appeal to unquestioned traditions and widely shared communitarian values? This paper argues that any coherent ethical approach to these questions must be able both to uphold the moral status of the individual and at the same time recognise the communitarian, interpersonal dimensions both of the world in which we live and of personal autonomy itself. The paper then goes on to propose an approach to the resolution of the ethical questions raised by the use of the new genetics in reproductive choice through the development of a coherent and principled process of public reason and justification oriented towards the support and development of personal autonomy.


A metabolic regulator modulates virulence and quorum sensing signal production in Pectobacterium atrosepticum.
Plant cell wall-degrading enzymes (PCWDE) are key virulence determinants in the pathogenesis of the potato pathogen Pectobacterium atrosepticum. In this study, we report the impact on virulence of a transposon insertion mutation in the metJ gene that codes for the repressor of the methionine biosynthesis regulon. In a mutant strain defective for the small regulatory RNA rsmB, PCWDE are not produced and virulence in potato tubers is almost totally abolished. However, when the metJ gene is disrupted in this background, the rsmB(-) phenotype is suppressed and virulence and PCWDE production are restored. Additionally, when metJ is disrupted, production of the quorum-sensing signal, N-(3-oxohexanoyl)-homoserine lactone, is increased. The metJ mutant strains showed pleiotropic transcriptional impacts affecting approximately a quarter of the genome. Genes involved in methionine biosynthesis were most highly upregulated but many virulence-associated transcripts were also upregulated. This is the first report of the impact of the MetJ repressor on virulence in bacteria.


Superfluous neuroscience information makes explanations of psychological phenomena more appealing.
Does the presence of irrelevant neuroscience information make explanations of psychological phenomena more appealing? Do fMRI pictures further increase that allure? To help answer these questions, 385 college students in four experiments read brief descriptions of psychological phenomena, each one accompanied by an explanation of varying quality (good vs. circular) and followed by superfluous information of various types. Ancillary measures assessed participants' analytical thinking, beliefs on dualism and free will, and admiration for different sciences. In Experiment 1, superfluous neuroscience information increased the judged quality of the argument for both good and bad explanations, whereas accompanying fMRI pictures had no impact above and beyond the neuroscience text, suggesting a bias that is conceptual rather than pictorial. Superfluous neuroscience information was more alluring than social science information (Experiment 2) and more alluring than information from prestigious "hard sciences" (Experiments 3 and 4). Analytical thinking did not protect against the neuroscience bias, nor did a belief in dualism or free will. We conclude that the "allure of neuroscience" bias is conceptual, specific to neuroscience, and not easily accounted for by the prestige of the discipline. It may stem from the lay belief that the brain is the best explanans for mental phenomena.


Sleep and schizophrenia: From epiphenomenon to treatable causal target.
Sleep disturbance is a common clinical issue for patients with psychosis. It has been identified as a putative causal factor in the onset and persistence of psychotic experiences (paranoia and hallucinations). Hence sleep disruption may be a potential treatment target to prevent the onset of psychosis and reduce persistent psychotic experiences. The aim of this review is to describe developments in understanding the nature, causal role, and treatment of sleep disruption in psychosis. A systematic literature search was conducted to identify studies, published in the last five years, investigating subjective sleep disruption and psychotic experiences. Fifty-eight papers were identified: 37 clinical and 21 non-clinical studies. The studies were correlational (n = 38; 20 clinical, 18 non-clinical), treatment (n = 7; 1 non-clinical), qualitative accounts (n = 6 clinical), prevalence estimates (n = 5 clinical), and experimental tests (n = 2 non-clinical). Insomnia (50%) and nightmare disorder (48%) are the most prevalent sleep problems found in patients. Sleep disruption predicts the onset and persistence of psychotic experiences such as paranoia and hallucinations, with negative affect identified as a partial mediator of this relationship. Patients recognise the detrimental effects of disrupted sleep and are keen for treatment. All psychological intervention studies reported large effect size improvements in sleep and there may be modest resultant improvements in psychotic experiences. Sleep disruption is a treatable clinical problem in patients with psychosis. It is important to treat in its own right but may also lessen psychotic experiences. Research is required on how this knowledge can be implemented in clinical services.


Serum high-mobility group box-1 levels are positively associated with micro- and macroalbuminuria but not with cardiovascular disease in type 1 diabetes: the EURODIAB Prospective Complications Study.
High-mobility group box-1 (HMGB1) is a pro-inflammatory cytokine that may contribute to the pathogenesis of micro- and macrovascular complications commonly observed in diabetes. We investigated whether HMGB1 is associated with: i) markers of low-grade inflammation (LGI) and endothelial dysfunction (ED) and pulse pressure (PP, a marker of arterial stiffness); ii) prevalent nephropathy, retinopathy and cardiovascular disease (CVD) in type 1 diabetes; and iii) the potential mediating roles of LGI, ED and PP therein. This was a cross-sectional nested case-control study of 463 patients (226 women; mean age 40±10 years) with type 1 diabetes from the EURODIAB Prospective Complications Study. We used linear and binary or multinomial logistic regression analyses adjusted for traditional risk factors. Serum Ln-HMGB1 levels were positively associated with LGI and ED (standardised β=0.07 (95% confidence interval (CI): 0.02-0.12) and β=0.08 (95% CI: 0.02-0.14) respectively), but not with PP. Higher Ln-HMGB1 (per unit) was associated with greater odds of micro- and macroalbuminuria: odds ratio (OR)=1.24 (95% CI: 0.90-1.71) and OR=1.61 (95% CI: 1.15-2.25) respectively, P for trend=0.004. Further adjustments for LGI or ED did not attenuate these associations. No such associations were found between Ln-HMGB1 and estimated glomerular filtration rate (eGFR), retinopathy or CVD, however. In type 1 diabetes, higher serum HMGB1 levels are associated with greater prevalence and severity of albuminuria, though not with eGFR, retinopathy and CVD. Prospective studies are needed to clarify the causal role of HMGB1, if any, in the pathogenesis of vascular complications in type 1 diabetes.


Pediatric off-label use of recombinant factor VIIa.
Our goal was to report our institutional experience with recombinant factor VIIa for the treatment and/or prevention of bleeding in nonhemophiliac children. This was a retrospective case series in a tertiary pediatric referral hospital. During 1999-2006, 135 patients received recombinant factor VIIa for off-label use. The median number of doses was 2; the median dose was 88 mug/kg. The most common diagnoses among patients receiving recombinant factor VIIa were disseminated intravascular coagulation/sepsis (28), surgical bleeding (19), procedural prophylaxis (16), and trauma (15). The median volume of blood products administered 24 hours before recombinant factor VIIa treatment was 29.7 vs 11.7 mL/kg 24 hours after treatment. Only 1 high-risk patient had significant bleeding after receiving prophylactic recombinant factor VIIa before an invasive procedure. Nonsurvivors had significantly increased incidence of multiple organ dysfunction syndrome (75%) compared with survivors (23%). The largest group of patients (n = 28) received recombinant factor VIIa for bleeding and/or coagulopathy because of disseminated intravascular coagulation; the mortality in this group was 26 (93%) of 28. Eleven patients received multiple doses of recombinant factor VIIa to treat bleeding complications after hematopoietic stem cell transplant, without improvement in blood use. Mortality in medical patients was 58% vs 16% in surgical patients. Three patients had significant thrombotic adverse events after receiving recombinant factor VIIa, resulting in 2 deaths and 1 leg amputation. Off-label use of recombinant factor VIIa significantly decreases blood-product administration; surgical patients had control of life-threatening bleeding with low associated mortality. Prophylactic recombinant factor VIIa may be effective in preventing bleeding if given before invasive procedures in children at high risk. Prolonged use of recombinant factor VIIa for bleeding complications after hematopoietic stem cell transplant is not effective in preventing packed red blood cell transfusion. Presence of disseminated intravascular coagulation and mulitorgan dysfunction syndrome may help predict futility of recombinant factor VIIa treatment. Off-label use of recombinant factor VIIa is associated with thromboembolic events in children.


Capturing One of the Human Gut Microbiome's Most Wanted: Reconstructing the Genome of a Novel Butyrate-Producing, Clostridial Scavenger from Metagenomic Sequence Data.
The role of the microbiome in health and disease is attracting great attention, yet we still know little about some of the most prevalent microorganisms inside our bodies. Several years ago, Human Microbiome Project (HMP) researchers generated a list of "most wanted" taxa: bacteria both prevalent among healthy volunteers and distantly related to any sequenced organisms. Unfortunately, the challenge of assembling high-quality genomes from a tangle of metagenomic reads has slowed progress in learning about these uncultured bacteria. Here, we describe how recent advances in sequencing and analysis allowed us to assemble "most wanted" genomes from metagenomic data collected from four stool samples. Using a combination of both de novo and guided assembly methods, we assembled and binned over 100 genomes from an initial data set of over 1,300 Gbp. One of these genome bins, which met HMP's criteria for a "most wanted" taxa, contained three essentially complete genomes belonging to a previously uncultivated species. This species is most closely related to Eubacterium desmolans and the clostridial cluster IV/Clostridium leptum subgroup species Butyricicoccus pullicaecorum (71-76% average nucleotide identity). Gene function analysis indicates that the species is an obligate anaerobe, forms spores, and produces the anti-inflammatory short-chain fatty acids acetate and butyrate. It also appears to take up metabolically costly molecules such as cobalamin, methionine, and branch-chained amino acids from the environment, and to lack virulence genes. Thus, the evidence is consistent with a secondary degrader that occupies a host-dependent, nutrient-scavenging niche within the gut; its ability to produce butyrate, which is thought to play an anti-inflammatory role, makes it intriguing for the study of diseases such as colon cancer and inflammatory bowel disease. In conclusion, we have assembled essentially complete genomes from stool metagenomic data, yielding valuable information about uncultured organisms' metabolic and ecologic niches, factors that may be required to successfully culture these bacteria, and their role in maintaining health and causing disease.


Modulation of podocyte phenotype in collapsing glomerulopathies.
Podocytes are well-differentiated postmitotic cells whose function is largely based on their complex cytoskeletal architecture. In diseases with proteinuria, podocytes undergo morphologic changes. Podocytes react to an injurious stimulus by a reorganization of their foot process architecture that is independent of the primary injury and the cause of the proteinuria. Collapsing glomerulopathies, including the idiopathic and secondary forms due to HIV infection, have been previously considered a part of the focal sclerosing glomerulosclerosis (FSGS) spectrum. However, in contrast to FSGS, both forms of collapsing glomerulopathy are characterized by segmental and global collapse of the glomerular basement membrane (GBM) and by characteristic ultrastructural alterations in podocytes. These alterations include loss of the actin-based cytoskeleton, a dysregulated/dedifferentiated phenotype, cellular hypertrophy, and cell proliferation. These observations raise the following questions: 1) What mechanism causes glomerular collapse and do podocytes have a role? We recently proposed that in collapsing glomerulopathies the composition of the GBM is altered and contains more immature forms of collagen IV. These observations suggest that dedifferentiated/dysregulated podocytes may participate in remodeling the GBM composition, producing fetal collagen isoforms. 2) What is the pathomechanism underlying podocyte dysregulation? Although it is still unclear which etiologic factors are responsible for the idiopathic forms of collapsing glomerulopathy, in situ hybridization studies in a transgenic mouse model of HIV-associated collapsing glomerulopathy and on renal biopsies of patients with HIV-associated collapsing glomerulopathy demonstrated the presence of the HIV-1 RNA in podocytes and tubular epithelial cells. These findings suggest a direct link between viral gene expression and the dysregulation of the podocyte phenotype. 3) Another open question is how podocytes become infected in HIV-associated collapsing glomerulopathy. HIV-1 typically uses CD4 and a co-receptor such as CCR5 or CXCR4 to enter cells. So far, there is no demonstration of the expression of these receptors in podocytes. These negative findings, however, do not exclude the possibility that in the kidney another, CD4 independent, co-receptor may be used for viral cell entry. Finally, is it important to mention that collapsing glomerulopathies have a high prevalence in black patients, suggesting a link between racial background and the virus-related podocyte injury.