Preoperative C-reactive protein predicts mid-term outcome after cardiac surgery.

Abstract: BACKGROUND C-reactive protein (CRP) is a known risk factor for cardiovascular events in the healthy population and in patients with coronary artery disease.

Abstract: High CRP levels before cardiac surgery are associated with worse short-term outcome, but its role after discharge home remains unknown.

Abstract: The study objective was to evaluate the effect of CRP on short-term and mid-term outcome after cardiac surgery.

Abstract: METHODS From August 2000 to May 2004, values for preoperative CRP were available for 597 unselected patients undergoing cardiac operations.

Abstract: CRP was used to divide this cohort in two groups: a low inflammatory status (LHS) group of 354 patients with CRP of less than 0.5 mg/dL, and a high inflammatory status (HIS) group of 243 patients with a CRP of 0.5 mg/dL or more.

Abstract: Follow-up lasted a maximum of 3 years (median, 1.8 +/-

Abstract: 1.5 years) and was 92.6% complete.

Abstract: RESULTS In-hospital mortality was 8.2% in the HIS group and 3.4% in the LIS group (odds ratio [OR], 2.61; p = 0.02).

Abstract: Incidence of postoperative infections was 16.5% in the HIS group and 5.1% in the LIS group (OR, 3.25; p = 0.0001).

Abstract: Sternal wound infections were also more frequent in the HIS group (10.7% versus 2.8%; OR, 3.43; p = 0.002).

Abstract: During follow-up, the HIS group had worse survival (88.5% +/-

Abstract: 2.9% versus 91.9% +/-

Abstract: 2.5%; OR, 1.93; p = 0.05) and a higher need of hospitalization for cardiac-related causes (73.6% +/-

Abstract: 6% versus 86.5% +/-

Abstract: 3.2%; OR, 1.82; p = 0.05).

Abstract: CONCLUSIONS Patients undergoing cardiac surgery with a CRP level of 0.5 mg/dL or more are exposed to a higher risk of in-hospital mortality and postoperative infections.

Abstract: Despite surgical correction of cardiac disease, a high preoperative CRP value is an independent risk factor for mid-term survival and hospitalization for cardiac causes.


Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer.

Abstract: Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers in part because it is insensitive to many chemotherapeutic drugs.

Abstract: Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, we found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA.

Abstract: We tested whether the delivery and efficacy of gemcitabine in the mice could be improved by coadministration of IPI-926, a drug that depletes tumor-associated stromal tissue by inhibition of the Hedgehog cellular signaling pathway.

Abstract: The combination therapy produced a transient increase in intratumoral vascular density and intratumoral concentration of gemcitabine, leading to transient stabilization of disease.

Abstract: Thus, inefficient drug delivery may be an important contributor to chemoresistance in pancreatic cancer.


Mutant SOD1 inhibits ER-Golgi transport in amyotrophic lateral sclerosis.

Abstract: Cu/Zn-superoxide dismutase is misfolded in familial and sporadic amyotrophic lateral sclerosis, but it is not clear how this triggers endoplasmic reticulum (ER) stress or other pathogenic processes.

Abstract: Here, we demonstrate that mutant SOD1 (mSOD1) is predominantly found in the cytoplasm in neuronal cells.

Abstract: Furthermore, we show that mSOD1 inhibits secretory protein transport from the ER to Golgi apparatus.

Abstract: ER-Golgi transport is linked to ER stress, Golgi fragmentation and axonal transport and we also show that inhibition of ER-Golgi trafficking preceded ER stress, Golgi fragmentation, protein aggregation and apoptosis in cells expressing mSOD1.

Abstract: Restoration of ER-Golgi transport by over-expression of coatomer coat protein II subunit Sar1 protected against inclusion formation and apoptosis, thus linking dysfunction in ER-Golgi transport to cellular pathology.

Abstract: These findings thus link several cellular events in amyotrophic lateral sclerosis into a single mechanism occurring early in mSOD1 expressing cells.


High spatial resolution mapping of malaria transmission risk in the Gambia, west Africa, using LANDSAT TM satellite imagery.

Abstract: Understanding local variability in malaria transmission risk is critically important when designing intervention or vaccine trials.

Abstract: Using a combination of field data, satellite image analysis, and GIS modeling, we developed a high-resolution map of malaria entomological inoculation rates (EIR) in The Gambia, West Africa.

Abstract: The analyses are based on the variation in exposure to malaria parasites experienced in 48 villages in 1996 and 21 villages in 1997.

Abstract: The entomological inoculation rate (EIR) varied from 0 to 166 infective bites per person per rainy season.

Abstract: Detailed field surveys identified the major Anopheles gambiae s.l.

Abstract: breeding habitats.

Abstract: These habitats were mapped by classification of a LANDSAT TM satellite image with an overall accuracy of 85%.

Abstract: Village EIRs decreased as a power function based on the breeding areas size and proximity.

Abstract: We use this relationship and the breeding habitats to map the variation in EIR over the entire 2500-km(2) study area.


Functional analysis of repressor binding sites in the iab-2 regulatory region of the abdominal-A homeotic gene.

Abstract: Spatial boundaries of homeotic gene expression are initiated and maintained by two sets of transcriptional repressors: the gap gene products and the Polycomb group proteins.

Abstract: Previously, the Hunchback (HB) protein has been implicated in setting the anterior expression limit of the UBX homeotic protein in parasegment 6.

Abstract: Here we investigate DNA elements and trans-acting repressors that control spatial expression of the Abdominal-A (ABD-A) homeotic protein.

Abstract: Analysis of a 1.7-kb enhancer element [iab-2(1.7)] from the iab-2 regulatory region shows that in contrast to Ubx enhancer elements, both HB and Krüppel (KR) are required to set the ABD-A anterior boundary in parasegment 7.

Abstract: DNase I footprinting and site-directed mutagenesis show that HB and KR are direct regulators of this iab-2 enhancer.

Abstract: The single KR site can be moved to a new location 100 bp away and still maintain repressive activity, whereas relocation by 300 bp abolishes activity.

Abstract: These results suggest that KR repression occurs through a local quenching mechanism.

Abstract: We also show that the gap repressor Giant (GT) initially establishes a posterior expression limit at PS9, which shifts posteriorly after the blastoderm stage.

Abstract: Finally, we show that this iab-2 enhancer contains multiple binding sites for the Polycomb group protein Pleiohomeotic (PHO).

Abstract: These iab-2 PHO sites are required in vivo for chromosome pairing-dependent repression of a mini-white reporter.

Abstract: However, the PHO sites are not sufficient to maintain repression of a homeotic reporter gene anterior to PS7.

Abstract: Full maintenance at late embryonic stages requires additional sequences adjacent to the iab-2(1.7) enhancer.


Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease.

Abstract: Apolipoprotein E is immunochemically localized to the senile plaques, vascular amyloid, and neurofibrillary tangles of Alzheimer disease.

Abstract: In vitro, apolipoprotein E in cerebrospinal fluid binds to synthetic beta A4 peptide (the primary constituent of the senile plaque) with high avidity.

Abstract: Amino acids 12-28 of the beta A4 peptide are required.

Abstract: The gene for apolipoprotein E is located on chromosome 19q13.2, within the region previously associated with linkage of late-onset familial Alzheimer disease.

Abstract: Analysis of apolipoprotein E alleles in Alzheimer disease and controls demonstrated that there was a highly significant association of apolipoprotein E type 4 allele (APOE-epsilon 4) and late-onset familial Alzheimer disease.

Abstract: The allele frequency of the APOE-epsilon 4 in 30 random affected patients, each from a different Alzheimer disease family, was 0.50 +/-

Abstract: 0.06; the allele frequency of APOE-epsilon 4 in 91 age-matched unrelated controls was 0.16 +/-

Abstract: 0.03 (Z = 2.44, P = 0.014).

Abstract: A functional role of the apolipoprotein E-E4 isoform in the pathogenesis of late-onset familial Alzheimer disease is suggested.


Unmarked gene deletion and host–vector system for the hyperthermophilic crenarchaeon Sulfolobus islandicus

Abstract: Sulfolobus islandicus is being used as a model for studying archaeal biology, geo-biology and evolution.

Abstract: However, no genetic system is available for this organism.

Abstract: To produce an S. islandicus mutant suitable for genetic analyses, we screened for colonies with a spontaneous pyrEF mutation.

Abstract: One mutant was obtained containing only 233 bp of the original pyrE sequence in the mutant allele and it was used as a host to delete the β-glycosidase (lacS) gene.

Abstract: Two unmarked gene deletion methods were employed, namely plasmid integration and segregation, and marker replacement and looping out, and unmarked lacS mutants were obtained by each method.

Abstract: A new alternative recombination mechanism, i.e., marker circularization and integration, was shown to operate in the latter method, which did not yield the designed deletion mutation.

Abstract: Subsequently, Sulfolobus–E. coli plasmid shuttle vectors were constructed, which genetically complemented ΔpyrEFΔlacS mutation after transformation.

Abstract: Thus, a complete set of genetic tools was established for S. islandicus with pyrEF and lacS as genetic markers.


ADAM13 disintegrin and cysteine-rich domains bind to the second heparin-binding domain of fibronectin.

Abstract: ADAM13 is a member of the disintegrin and metalloprotease protein family that is expressed on cranial neural crest cells surface and is essential for their migration.

Abstract: ADAM13 is an active protease that can cleave fibronectin in vitro and remodel a fibronectin substrate in vivo.

Abstract: Using a recombinant secreted protein containing both disintegrin and cysteine-rich domains of ADAM13, we show that this "adhesive" region of the protein binds directly to fibronectin.

Abstract: Fibronectin fusion proteins corresponding to the various functional domains were used to define the second heparin-binding domain as the ADAM13 binding site.

Abstract: Mutation of the syndecan-binding site (PPRR --> PPTM) within this domain abolishes binding of the recombinant disintegrin and cysteine-rich domains of ADAM13.

Abstract: We further show that the adhesive disintegrin and cysteine-rich domain of ADAM13 can promote cell adhesion via beta(1) integrins.

Abstract: This adhesion requires integrin activation and can be prevented by antibodies to the cysteine-rich domain of ADAM13 and beta(1) integrin.

Abstract: Finally, wild type, but not the E/A mutant of ADAM13 metalloprotease domain, can be shed from the cell surface, releasing the metalloprotease domain associated with the disintegrin and cysteine-rich domains.

Abstract: This suggests that ADAM13 shedding may involve its own metalloprotease activity and that the released protease may interact with both integrins and extracellular matrix proteins.


Clinical epidemiology of heart failure.

Abstract: The aim of this paper is to review the clinical epidemiology of heart failure.

Abstract: The last paper comprehensively addressing the epidemiology of heart failure in Heart appeared in 2000.

Abstract: Despite an increase in manuscripts describing epidemiological aspects of heart failure since the 1990s, additional information is still needed, as indicated by various editorials.


Toll-like receptor 7 agonist GS-9620 induces prolonged inhibition of HBV via a type I interferon-dependent mechanism.

Abstract: BACKGROUND & AIMS GS-9620, an oral agonist of toll-like receptor 7 (TLR7), is in clinical development for the treatment of chronic hepatitis B (CHB).

Abstract: GS-9620 was previously shown to induce prolonged suppression of serum viral DNA and antigens in the woodchuck and chimpanzee models of CHB.

Abstract: Herein, we investigated the molecular mechanisms that contribute to the antiviral response to GS-9620 using in vitro models of hepatitis B virus (HBV) infection.

Abstract: METHODS Cryopreserved primary human hepatocytes (PHH) and differentiated HepaRG (dHepaRG) cells were infected with HBV and treated with GS-9620, conditioned media from human peripheral blood mononuclear cells treated with GS-9620 (GS-9620 conditioned media [GS-9620-CM]), or other innate immune stimuli.

Abstract: The antiviral and transcriptional response to these agents was determined.

Abstract: RESULTS GS-9620 had no antiviral activity in HBV-infected PHH, consistent with low level TLR7 mRNA expression in human hepatocytes.

Abstract: In contrast, GS-9620-CM induced prolonged reduction of HBV DNA, RNA, and antigen levels in PHH and dHepaRG cells via a type I interferon (IFN)-dependent mechanism.

Abstract: GS-9620-CM did not reduce covalently closed circular DNA (cccDNA) levels in either cell type.

Abstract: Transcriptional profiling demonstrated that GS-9620-CM strongly induced various HBV restriction factors - although not APOBEC3A or the Smc5/6 complex - and indicated that established HBV infection does not modulate innate immune sensing or signaling in cryopreserved PHH.

Abstract: GS-9620-CM also induced expression of immunoproteasome subunits and enhanced presentation of an immunodominant viral peptide in HBV-infected PHH.

Abstract: CONCLUSIONS Type I IFN induced by GS-9620 durably suppressed HBV in human hepatocytes without reducing cccDNA levels.

Abstract: Moreover, HBV antigen presentation was enhanced, suggesting additional components of the TLR7-induced immune response played a role in the antiviral response to GS-9620 in animal models of CHB.

Abstract: LAY SUMMARY GS-9620 is a drug currently being tested in clinical trials for the treatment of chronic hepatitis B virus (HBV) infection.

Abstract: GS-9620 has previously been shown to suppress HBV in various animal models, but the underlying antiviral mechanisms were not completely understood.

Abstract: In this study, we determined that GS-9620 does not directly activate antiviral pathways in human liver cells, but can induce prolonged suppression of HBV via induction of an antiviral cytokine called interferon.

Abstract: However, interferon did not destroy the HBV genome, suggesting that other parts of the immune response (e.g. activation of immune cells that kill infected cells) also play an important role in the antiviral response to GS-9620.


Depletion of glutathione induces 4-hydroxynonenal protein adducts and hydroxyurea teratogenicity in the organogenesis stage mouse embryo.

Abstract: Glutathione (GSH) homeostasis is important during organogenesis.

Abstract: To elucidate the impact of GSH depletion in organogenesis stage embryos on oxidative stress and drug teratogenicity, l-buthionine-S,R-sulfoximine (BSO) was given to timed pregnant CD-1 mice 4 h before exposure to a model teratogen, hydroxyurea (HU) [400 mg/kg (HU-400) or 600 mg/kg (HU-600)].

Abstract: Treatment with BSO or HU alone or with BSO plus HU-400 did not alter the ratios of glutathione disulfide/GSH in the embryo; in contrast, the combination of BSO plus HU-600 did increase this ratio at both 0.5 and 3 h post-HU, indicating the induction of oxidative stress in the embryos.

Abstract: Immunoreactivity to a product of lipid peroxidation, 4-hydroxynonenal (4-HNE) protein adducts, was detected in saline-treated embryos; the intensity and nuclear localization of 4-HNE protein adduct immunoreactivity in specific regions in the embryo was significantly increased by exposure to BSO alone or BSO and either dose of HU.

Abstract: BSO pretreatment increased the spectrum and incidence of external and skeletal malformations (curly tail, hind limb malformations, hydrocephaly, exencephaly, open eye, spina bifida, and gastroschisis) induced by HU-400 and HU-600; BSO exposure did not alter the effects of HU on fetal mortality or fetal weights or HU induction of c-Fos heterodimer-dependent activator protein 1 DNA binding activity.

Abstract: The formation of 4-HNE protein adducts in teratogen-exposed embryos was localized to regions of the embryo that were highly susceptible to insult, namely the somites and caudal neural tube, correlating the presence of 4-HNE adducts with the disruption of pattern formation during organogenesis.


Nonproductive human immunodeficiency virus type 1 infection in nucleoside-treated G0 lymphocytes.

Abstract: Productive infection by human immunodeficiency virus type 1 (HIV-1) requires the activation of target cells.

Abstract: Infection of quiescent peripheral CD4 lymphocytes by HIV-1 results in incomplete, labile, reverse transcripts.

Abstract: We have previously identified G1b as the cell cycle stage required for the optimal completion of the reverse transcription process in T lymphocytes.

Abstract: However, the mechanism(s) involved in the blockage of reverse transcription remains undefined.

Abstract: In this study we investigated whether nucleotide levels influence viral reverse transcription in G0 cells.

Abstract: For this purpose the role of the enzyme ribonucleotide reductase was bypassed, by adding exogenous deoxyribonucleosides to highly purified T cells in the G0 or the G1a phase of the cell cycle.

Abstract: Our data showed a significant increase in the efficiency of the reverse transcription process following the addition of the deoxyribonucleosides.

Abstract: To define the stability and functionality of these full reverse transcripts, we used an HIV-1 reporter virus that expresses the murine heat-stable antigen on the surfaces of infected cells.

Abstract: Following activation of infected quiescent cells treated with exogenous nucleosides, no increased rescue of productive infection was seen.

Abstract: Thus, in addition to failure to complete reverse transcription, there was an additional nonreversible blockage of productive infection in quiescent T cells.

Abstract: These experiments have important relevance in the gene therapy arena, in terms of improving the ability of lentivirus vectors to enter metabolically inactive cells, such as hematopoietic stem cells.


Imported malaria in children: a national surveillance in the Netherlands and a review of European studies.

Abstract: BACKGROUND Falciparum malaria or malaria tropica is one of the leading causes of childhood mortality worldwide.

Abstract: Malaria-related deaths occur mainly in sub-Saharan Africa, where an estimated 365 million clinical cases of Plasmodium falciparum malaria occur each year.

Abstract: In Europe, imported malaria cases occur due to returning travellers or immigration mostly from African countries.

Abstract: Children are more at risk than adults.

Abstract: The objective of this study was to identify high risk groups for imported childhood malaria in Europe in order to guide development of strategies for prevention, early recognition and management.

Abstract: METHODS In the period May 2003-January 2005 we reviewed all cases of paediatric malaria in the Netherlands notified by the Dutch Paediatric Surveillance System (Nederland Signalerings Centrum Kindergeneeskunde, NSCK) and the literature on imported malaria in children in Europe published between 1996 and 2006.

Abstract: RESULTS Malaria occurred mainly in children of long-term (n = 15, 47%) and new (n = 8, 25%) immigrants and was mostly acquired in sub-Saharan Africa.

Abstract: The dominant species was P. falciparum.

Abstract: Only one quarter of children had used adequate malaria chemoprophylaxis.

Abstract: Complicated disease occurred in 10 (31%) of cases.

Abstract: We also reviewed the literature and found 6082 reported cases of imported malaria among children in Europe; among these, four died and only one was reported to develop neurological sequelae.

Abstract: CONCLUSION Imported malaria in children remains an important problem and is unlikely to decrease unless the reasons for inadequate prophylaxis are addressed.


Respiratory and cardiovascular responses to walking down a traffic-polluted road compared with walking in a traffic-free area in participants aged 60 years and older with chronic lung or heart disease and age-matched healthy controls: a randomised, crossover study

Abstract: BACKGROUND Long-term exposure to pollution can lead to an increase in the rate of decline of lung function, especially in older individuals and in those with chronic obstructive pulmonary disease (COPD), whereas shorter-term exposure at higher pollution levels has been implicated in causing excess deaths from ischaemic heart disease and exacerbations of COPD.

Abstract: We aimed to assess the effects on respiratory and cardiovascular responses of walking down a busy street with high levels of pollution compared with walking in a traffic-free area with lower pollution levels in older adults.

Abstract: METHODS In this randomised, crossover study, we recruited men and women aged 60 years and older with angiographically proven stable ischaemic heart disease or stage 2 Global initiative for Obstructive Lung Disease (GOLD) COPD who had been clinically stable for 6 months, and age-matched healthy volunteers.

Abstract: Individuals with ischaemic heart disease or COPD were recruited from existing databases or outpatient respiratory and cardiology clinics at the Royal Brompton & Harefield NHS Foundation Trust and age-matched healthy volunteers using advertising and existing databases.

Abstract: All participants had abstained from smoking for at least 12 months and medications were taken as recommended by participants' doctors during the study.

Abstract: Participants were randomly assigned by drawing numbered disks at random from a bag to do a 2 h walk either along a commercial street in London (Oxford Street) or in an urban park (Hyde Park).

Abstract: Baseline measurements of participants were taken before the walk in the hospital laboratory.

Abstract: During each walk session, black carbon, particulate matter (PM) concentrations, ultrafine particles, and nitrogen dioxide (NO2) concentrations were measured.

Abstract: FINDINGS Between October, 2012, and June, 2014, we screened 135 participants, of whom 40 healthy volunteers, 40 individuals with COPD, and 39 with ischaemic heart disease were recruited.

Abstract: Concentrations of black carbon, NO2, PM10, PM2.5, and ultrafine particles were higher on Oxford Street than in Hyde Park.

Abstract: Participants with COPD reported more cough (odds ratio [OR] 1·95, 95% CI 0·96-3·95; p<0·1), sputum (3·15, 1·39-7·13; p<0·05), shortness of breath (1·86, 0·97-3·57; p<0·1), and wheeze (4·00, 1·52-10·50; p<0·05) after walking down Oxford Street compared with Hyde Park.

Abstract: In all participants, irrespective of their disease status, walking in Hyde Park led to an increase in lung function (forced expiratory volume in the first second [FEV1] and forced vital capacity [FVC]) and a decrease in pulse wave velocity (PWV) and augmentation index up to 26 h after the walk.

Abstract: By contrast, these beneficial responses were attenuated after walking on Oxford Street.

Abstract: In participants with COPD, a reduction in FEV1 and FVC, and an increase in R5-20 were associated with an increase in during-walk exposure to NO2, ultrafine particles and PM2.5, and an increase in PWV and augmentation index with NO2 and ultrafine particles.

Abstract: In healthy volunteers, PWV and augmentation index were associated both with black carbon and ultrafine particles.

Abstract: INTERPRETATION Short-term exposure to traffic pollution prevents the beneficial cardiopulmonary effects of walking in people with COPD, ischaemic heart disease, and those free from chronic cardiopulmonary diseases.

Abstract: Medication use might reduce the adverse effects of air pollution in individuals with ischaemic heart disease.

Abstract: Policies should aim to control ambient levels of air pollution along busy streets in view of these negative health effects.

Abstract: FUNDING British Heart Foundation.


Overall and cancer related mortality among patients with ocular inflammation treated with immunosuppressive drugs: retrospective cohort study.

Abstract: CONTEXT Whether immunosuppressive treatment adversely affects survival is unclear.

Abstract: OBJECTIVE To assess whether immunosuppressive drugs increase mortality.

Abstract: DESIGN Retrospective cohort study evaluating overall and cancer mortality in relation to immunosuppressive drug exposure among patients with ocular inflammatory diseases.

Abstract: Demographic, clinical, and treatment data derived from medical records, and mortality results from United States National Death Index linkage.

Abstract: The cohort's mortality risk was compared with US vital statistics using standardised mortality ratios.

Abstract: Overall and cancer mortality in relation to use or non-use of immunosuppressive drugs within the cohort was studied with survival analysis.

Abstract: SETTING Five tertiary ocular inflammation clinics.

Abstract: Patients 7957 US residents with non-infectious ocular inflammation, 2340 of whom received immunosuppressive drugs during follow up.

Abstract: Exposures Use of antimetabolites, T cell inhibitors, alkylating agents, and tumour necrosis factor inhibitors.

Abstract: MAIN OUTCOME MEASURES Overall mortality, cancer mortality.

Abstract: RESULTS Over 66 802 person years (17 316 after exposure to immunosuppressive drugs), 936 patients died (1.4/100 person years), 230 (24.6%) from cancer.

Abstract: For patients unexposed to immunosuppressive treatment, risks of death overall (standardised mortality ratio 1.02, 95% confidence interval [CI] 0.94 to 1.11) and from cancer (1.10, 0.93 to 1.29) were similar to those of the US population.

Abstract: Patients who used azathioprine, methotrexate, mycophenolate mofetil, ciclosporin, systemic corticosteroids, or dapsone had overall and cancer mortality similar to that of patients who never took immunosuppressive drugs.

Abstract: In patients who used cyclophosphamide, overall mortality was not increased and cancer mortality was non-significantly increased.

Abstract: Tumour necrosis factor inhibitors were associated with increased overall (adjusted hazard ratio [HR] 1.99, 95% CI 1.00 to 3.98) and cancer mortality (adjusted HR 3.83, 1.13 to 13.01).

Abstract: CONCLUSIONS Most commonly used immunosuppressive drugs do not seem to increase overall or cancer mortality.

Abstract: Our results suggesting that tumour necrosis factor inhibitors might increase mortality are less robust than the other findings; additional evidence is needed.


Ephrin B1–mediated repulsion and signaling control germinal center T cell territoriality and function

Abstract: Follicular T helper (TFH) cells orchestrate the germinal center (GC) reaction locally.

Abstract: Local mechanisms regulating their dynamics and helper functions are not well defined.

Abstract: Here we found that GC-expressed ephrin B1 (EFNB1) repulsively inhibited T cell to B cell adhesion and GC TFH retention by signaling through TFH-expressed EPHB6 receptor.

Abstract: At the same time, EFNB1 promoted interleukin-21 production from GC TFH cells by signaling predominantly through EPHB4.

Abstract: Consequently, EFNB1-null GCs were associated with defective production of plasma cells despite harboring excessive TFH cells.

Abstract: In a competitive GC reaction, EFNB1-deficient B cells more efficiently interacted with TFH cells and produced more bone-marrow plasma cells, likely as a result of gaining more contact-dependent help.

Abstract: Our results reveal a contact-dependent repulsive guidance system that controls GC TFH dynamics and effector functions locally.


Molecular profiling and predictive value of circulating tumor cells in patients with metastatic breast cancer: an option for monitoring response to breast cancer related therapies

Abstract: Purpose We analyzed circulating tumor cells (CTC) in blood of metastatic breast cancer patients (n = 42) and determined the ability of this method to predict therapy response.

Abstract: Methods CTC from blood were analyzed before and during therapy for EpCAM, MUC1 and HER2 transcripts with the AdnaTest BreastCancer.

Abstract: The estrogen (ER) and progesterone (PR) receptor expression was assessed by RT-PCR.

Abstract: Results The overall detection rate for CTC was 52% (thereof 86% EpCAM; 86% MUC1; 32% HER2; 35% ER; 12% PR).

Abstract: CTC were ER, PR and HER2 negative in 45% (ER), 78% (PR) and 60% (HER-2) of patients with steroid receptor-positive tumors.

Abstract: 29% of patients with HER2-negative tumors had HER2-positive CTC.

Abstract: The test predicted therapy response in 78% of all cases.

Abstract: Persistence of CTC significantly correlated with shorter overall survival (P = 0.005).

Abstract: Conclusions Molecular profiling of CTC may offer superior prognostic information with regard to risk assessment for recurrence and predictive judgement of therapeutical regimens.


Alternate-day wheel access: effects on feeding, body weight, and running.

Abstract: For rats access to a running wheel results in a pronounced but temporary suppression of feeding.

Abstract: The reasons for the feeding suppression and its temporary nature are unclear.

Abstract: The effects of alternate-day wheel access were explored by comparing feeding and running in 25 male Sprague-Dawley rats given either no wheel access, continuous wheel access, or alternate-day wheel access.

Abstract: With alternate-day wheel access food intake was suppressed on wheel days and elevated on non-wheel days for the full 32 days of the experiment.

Abstract: Body weight decreased on wheel days and showed a large increase on non-wheel days.

Abstract: Acquisition of running over days was similar in both wheel groups and plateaued at the same level, but running was elevated, compared to continuous-access rats, for the first few hours when alternate-day rats were returned to the wheel.

Abstract: These results suggest that wheel-induced feeding suppression is not due to the novelty of the wheel and that this suppression can be extended by providing periods with no wheel access.

Abstract: The temporary nature of feeding suppression in chronic access conditions may be due to secondary longer term motivational changes.


Evaluation of the association between the first observation and the longitudinal change in C-reactive protein, and all-cause mortality.

Abstract: OBJECTIVE To evaluate the association between vascular inflammation as measured by subacute C-reactive protein (CRP; 1-10 mg/l) and all-cause mortality and the association between change in CRP status (normal <or=3 mg/l and elevated >3 mg/l) and all-cause mortality.

Abstract: METHODS Probabilistic record linkage was used to match hospital episode data, laboratory reports and mortality statistics in a large urban population.

Abstract: Survival was evaluated using Cox proportional hazards regression models.

Abstract: RESULTS 22 962 patients had their first CRP measurement in the subacute range (1-10 mg/l).

Abstract: Analysis grouped by each additional unit increase in CRP across the subacute range was associated with a 7.3% (95% CI 5.4% to 9.2%) increase in the hazard ratio (HR) of death over 4 years, after controlling for confounding factors (p<0.001).

Abstract: Repeated CRP observations around 1 year apart were recorded in 5811 subjects.

Abstract: After controlling for confounding factors, in patients whose CRP changed from normal (<or=3 mg/l) to elevated (>3 mg/l), the HR increased 6.7-fold (p<0.001) relative to cases whose CRP remained normal.

Abstract: By comparison, among those subjects whose CRP was reduced from elevated to normal, the hazard ratio halved to 3.5 (p = 0.018).

Abstract: In an underpowered analysis of time to cardiovascular events, an identical pattern of risk emerged.

Abstract: CONCLUSIONS CRP level predicted all-cause mortality, and additional inclusion of prior change in CRP level and current CRP level more so.

Abstract: Increasing vascular inflammation, as measured by CRP, increases the likelihood of death.


Research Priorities in Sudden Unexpected Infant Death: An International Consensus.

Abstract: Despite the success of safe sleep campaigns and the progress in understanding risk factors, the rate of reduction in the cases of sudden infant death syndrome has now slowed and it remains a leading cause of postneonatal mortality in many developed countries.

Abstract: Strategic action is needed to tackle this problem and it is now vital to identify how the sudden infant death research community may best target its efforts.

Abstract: The Global Action and Prioritization of Sudden Infant Death Project was an international consensus process that aimed to define and direct future research by investigating the priorities of expert and lay members of the sudden unexpected infant death (SUID) community across countries.

Abstract: The aim was to identify which areas of research should be prioritized to reduce the number of SUID deaths globally.

Abstract: Scientific researchers, clinicians, counselors, educators, and SUID parents from 25 countries took part across 2 online surveys to identify potential research priorities.

Abstract: Workshops subsequently took place in the United Kingdom, United States, and Australia to reach consensus and 10 priority areas for research were established.

Abstract: Three main themes among the priorities emerged: (1) a better understanding of mechanisms underlying SUID, (2) ensuring best practice in data collection, management and sharing, and (3) a better understanding of target populations and more effective communication of risk.

Abstract: SUID is a global problem and this project provides the international SUID community with a list of shared research priorities to more effectively work toward explaining and reducing the number of sudden infant deaths.


Modification of the Constant-Murley shoulder score-introduction of the individual relative Constant score Individual shoulder assessment.

Abstract: The Constant-Murley shoulder assessment score has proven to be a valuable diagnostic instrument.

Abstract: Thus, in the literature it has been mentioned that the clinical accuracy of this score varies especially when comparing patients in larger, inhomogeneous patient groups.

Abstract: The "relative Constant score" (CS(rel)) tries to minimize these problems by using reference parameters out of healthy age and gender related control groups.

Abstract: The authors of this study tried to show that it is even more accurate to use the functional performance of the uninjured collateral shoulder of the same individual as reference, introducing the "individual relative Constant score" (CS(indiv)).

Abstract: The CS(indiv) and the CS(rel) were compared for 125 consecutive patients with shoulder disorders, and a group of 125 healthy volunteers as a control group.

Abstract: In a non-parametric comparison of the reciever operating characteristics the CS(indiv) shows the higher ability to discriminate between patients and healthy volunteers (p=0.004).

Abstract: This indicates that the individual relative Constant score gives a more accurate view about the functional result for shoulder disorders.

Abstract: It is expected to be more reliable for larger and incoherent patient populations, because specific interindividual differences, regarding the patient's age, gender and constitution are eliminated as well as other individual physiological parameters.


Celiac disease screening by immunochromatographic visual assays: results of a multicenter study.

Abstract: OBJECTIVE To assay the efficiency for celiac disease (CD) screening of 2 immunochromatographic visual stick assays based on human recombinant tissue transglutaminase (tTG).

Abstract: One was the antitissue transglutaminase antibodies (AtTGA) stick for IgA/G antibodies to tTG detection, the other was the AtTGA/antigliadin antibodies (AGA) stick for IgA antibodies for tTG and/or gliadins.

Abstract: PATIENTS AND METHODS In a prospective multicenter study, 4 pediatric gastroenterology units from Spain and 2 from Latin America enrolled 72 control children with a normal small bowel mucosa and 113 untreated patients with CD with Marsh type 3 lesions.

Abstract: RESULTS Evaluation of results by the gastroenterologists and by 2 independent observers at the coordination center showed a remarkably low interobserver variability.

Abstract: For the AtTGA stick, sensitivity was 96.5% and specificity was 98.6%.

Abstract: The AtTGA/AGA stick displayed a sensitivity of 94.5% and a specificity of 98.6% for AtTGA and a sensitivity of 63.1% and a specificity of 95.2% for AGA.

Abstract: The highest efficiency and positive likelihood ratio was obtained for the AtTGA stick, higher than for IgA AtTGA by enzyme-linked immunosorbent assay.

Abstract: One additional advantage was that previous investigation of total serum IgA levels could be eluded.

Abstract: The IgA AtTGA/AGA stick, with an efficiency of 95.1%, compared with 89.2% when the combined results of the 2 enzyme-linked immunosorbent assays were considered, turned out to be an excellent diagnostic tool for infants with no IgA deficiency.

Abstract: CONCLUSION These 2 assays are extremely efficient for CD screening, by combining a high diagnostic accuracy with the simplicity and rapidity of visual methods.


Down-regulation of keratin 4 and keratin 13 expression in oral squamous cell carcinoma and epithelial dysplasia: a clue for histopathogenesis.

Abstract: AIMS This study aimed to identify relevant keratin subtypes that may associate with the pathogenesis of oral epithelial neoplasms.

Abstract: METHODS AND RESULTS Expression of all the keratin subtypes was examined by cDNA microarray analysis of 43 oral squamous cell carcinoma (OSCC) cases.

Abstract: Immunohistochemical expression of the major keratins was examined in 100 OSCC and oral epithelial dysplasia (OED) cases.

Abstract: Many changes in keratin expression were observed and, significantly, consistent down-regulation of keratin 4 (K4) and K13 expression was observed.

Abstract: Aberrant expression of K4 and K13 was associated with morphological changes in the affected oral epithelium.

Abstract: Experiments with cell cultures transfected with various keratin subtypes suggested that alterations in keratin subtype expression can cause changes in cell shape and movement.

Abstract: CONCLUSIONS Aberrant expression of K4 and K13, which are the dominant pair of differentiation-related keratins in oral keratinocytes, indicates dysregulation of epithelial differentiation in OSCC and OED.

Abstract: These keratins, especially K4, may be useful for pathological diagnosis.

Abstract: We propose that the aberrant expression of K4 and K13 and concomitant up-regulation of the other keratins may be one of the causative factors for morphological alterations in the affected epithelium.


Identification of short-lived long non-coding RNAs as surrogate indicators for chemical stress response.

Abstract: Abiotic and biotic stressors in human cells are often a result of sudden and/or frequent changes in environmental factors.

Abstract: The molecular response to stress involves elaborate modulation of gene expression and is of homeostatic, ecological, and evolutionary importance.

Abstract: Although attention has primarily focused on signaling pathways and protein networks, long non-coding RNAs (ncRNAs) are increasingly involved in the molecular mechanisms associated with responses to cellular stresses.

Abstract: We identified six novel short-lived long ncRNAs (MIR22HG, GABPB-AS1, LINC00152, IDI2-AS1, SNHG15, and FLJ33630) that responded to chemical stressors (cisplatin, cycloheximide, and mercury (II) oxide) in HeLa Tet-off cells.

Abstract: Our results indicate that short-lived long ncRNAs respond to general and specific chemical stressors.

Abstract: The expression levels of the short-lived long ncRNAs were elevated because of prolonged decay rates in response to chemical stressors and interruption of RNA degradation pathways.

Abstract: We propose that these long ncRNAs have the potential to be surrogate indicators of cellular stress responses.


Isolation of a gene encoding a functional zinc finger protein homologous to erythroid Krüppel-like factor: identification of a new multigene family.

Abstract: We have identified and characterized the gene for a novel zinc finger transcription factor which we have termed lung Krüppel-like factor (LKLF).

Abstract: LKLF was isolated through the use of the zinc finger domain of erythroid Krüppel-like factor (ELKF) as a hybridization probe and is closely related to this erythroid cell-specific gene.

Abstract: LKLF is expressed in a limited number of tissues, with the predominant expression seen in the lungs and spleen.

Abstract: The gene is developmentally controlled, with expression noted in the 7-day embryo followed by a down-regulation at 11 days and subsequent reactivation.

Abstract: A high degree of similarity is noted in the zinc finger regions of LKLF and EKLF.

Abstract: Beyond this domain, the sequences diverge significantly, although the putative transactivation domains for both LKLF and EKLF are proline-rich regions.

Abstract: In the DNA-binding domain, the three zinc finger motifs are so closely conserved that the predicted DNA contact sites are identical, suggesting that both proteins may bind to the same core sequence.

Abstract: This was further suggested by transactivation assays in which mouse fibroblasts were transiently transfected with a human beta-globin reporter gene in the absence and presence of an LKLF cDNA construct.

Abstract: Expression of the LKLF gene activates this human beta-globin promoter containing the CACCC sequence previously shown to be a binding site for EKLF.

Abstract: Mutation of this potential binding site results in a significant reduction in the reporter gene expression.

Abstract: LKLF and EKLF can thus be grouped as members of a unique family of transcription factors which have discrete patterns of expression in different tissues and which appear to recognize the same DNA-binding site.


A small molecule restores function to TRPML1 mutant isoforms responsible for mucolipidosis type IV.

Abstract: Mucolipidosis type IV (MLIV) is an autosomal recessive lysosomal storage disorder often characterized by severe neurodevelopmental abnormalities and neuro-retinal degeneration.

Abstract: Mutations in the TRPML1 gene are causative for MLIV.

Abstract: We used lead optimization strategies to identify--and MLIV patient fibroblasts to test--small-molecule activators for their potential to restore TRPML1 mutant channel function.

Abstract: Using the whole-lysosome planar patch-clamp technique, we found that activation of MLIV mutant isoforms by the endogenous ligand PI(3,5)P2 is strongly reduced, while activity can be increased using synthetic ligands.

Abstract: We also found that the F465L mutation renders TRPML1 pH insensitive, while F408Δ impacts synthetic ligand binding.

Abstract: Trafficking defects and accumulation of zinc in lysosomes of MLIV mutant fibroblasts can be rescued by the small molecule treatment.

Abstract: Collectively, our data demonstrate that small molecules can be used to restore channel function and rescue disease associated abnormalities in patient cells expressing specific MLIV point mutations.


Characterization of a murine monoclonal antibody to Cryptococcus neoformans polysaccharide that is a candidate for human therapeutic studies.

Abstract: The murine monoclonal antibody (MAb) 18B7 [immunoglobulin G1(kappa)] is in preclinical development for treatment of Cryptococcus neoformans infections.

Abstract: In anticipation of its use in humans, we defined the serological and biological properties of MAb 18B7 in detail.

Abstract: Structural comparison to the related protective MAb 2H1 revealed conservation of the antigen binding site despite several amino acid differences.

Abstract: MAb 18B7 was shown by immunofluorescence and agglutination studies to bind to all four serotypes of C. neoformans, opsonize C. neoformans serotypes A and D, enhance human and mouse effector cell antifungal activity, and activate the complement pathway leading to deposition of complement component 3 (C3) on the cryptococcal capsule.

Abstract: Administration of MAb 18B7 to mice led to rapid clearance of serum cryptococcal antigen and deposition in the liver and spleen.

Abstract: Immunohistochemical studies revealed that MAb 18B7 bound to capsular glucuronoxylomannan in infected mouse tissues.

Abstract: No reactivity of MAb 18B7 with normal human, rat, or mouse tissues was detected.

Abstract: The results show that both the variable and constant regions of MAb 18B7 are biologically functional and support the use of this MAb in human therapeutic trials.


Treatment with cyclooxygenase-2 inhibitors enables repeated administration of vaccinia virus for control of ovarian cancer.

Abstract: Metastatic ovarian cancer is the leading cause of death among women with gynecologic malignancies in the United States.

Abstract: The lack of effective treatment for patients with advanced ovarian cancer warrants development of innovative therapies.

Abstract: Cancer therapy using oncolytic viruses represents a promising new approach for controlling tumors.

Abstract: Vaccinia virus has been shown to preferentially infect tumor cells but not normal tissue.

Abstract: However, oncolytic therapy using recombinant viruses faces the limitation of viral clearance due to generation of neutralizing antibodies.

Abstract: In the current study, we found that cyclooxygenase-2 (Cox-2) inhibitors circumvented this limitation, enabling repeated administration of vaccinia virus without losing infectivity.

Abstract: We quantified the antivaccinia antibody response using enzyme-linked immunosorbent assay (ELISA) and neutralization assays to show that treatment of Cox-2 inhibitors inhibited the generation of neutralizing antibodies.

Abstract: Furthermore, we showed that combination treatment of Cox-2 inhibitors with vaccinia virus was more effective that either treatment alone in treating MOSEC/luc tumor-bearing mice.

Abstract: Thus, the combination of Cox-2 inhibitors and vaccinia virus represents a potential innovative approach to controlling ovarian tumors.


Ser-752-->Pro mutation in the cytoplasmic domain of integrin beta 3 subunit and defective activation of platelet integrin alpha IIb beta 3 (glycoprotein IIb-IIIa) in a variant of Glanzmann thrombasthenia.

Abstract: Integrins are membrane receptors which mediate cell-cell or cell-matrix adhesion.

Abstract: Integrin alpha IIb beta 3 (glycoprotein IIb-IIIa) acts as a fibrinogen receptor of platelets and mediates platelet aggregation.

Abstract: Platelet activation is required for alpha IIb beta 3 to shift from noncompetent to competent for binding soluble fibrinogen.

Abstract: The steps involved in this transition are poorly understood.

Abstract: We have studied a variant of Glanzmann thrombasthenia, a congenital bleeding disorder characterized by absence of platelet aggregation and fibrinogen binding.

Abstract: The patient's platelets did not bind fibrinogen after platelet activation by ADP or thrombin, though his platelets contained alpha IIb beta 3.

Abstract: However, isolated alpha IIb beta 3 was able to bind to an Arg-Gly-Asp-Ser affinity column, and binding of soluble fibrinogen to the patient's platelets could be triggered by modulators of alpha IIb beta 3 conformation such as the Arg-Gly-Asp-Ser peptide and alpha-chymotrypsin.

Abstract: These data suggested that a functional Arg-Gly-Asp binding site was present within alpha IIb beta 3 and that the patient's defect was not secondary to a blockade of alpha IIb beta 3 in a noncompetent conformational state.

Abstract: This was evocative of a defect in the coupling between platelet activation and alpha IIb beta 3 up-regulation.

Abstract: We therefore sequenced the cytoplasmic domain of beta 3, following polymerase chain reaction (PCR) on platelet RNA, and found a T-->C mutation at nucleotide 2259, corresponding to a Ser-752-->Pro substitution.

Abstract: This mutation is likely to be responsible for the uncoupling of alpha IIb beta 3 from cellular activation because (i) it is not a polymorphism, (ii) it is the only mutation in the entire alpha IIb beta 3 sequence, and (iii) genetic analysis of the family showed that absence of the Pro-752 beta 3 allele was associated with the normal phenotype.

Abstract: Our data thus identify the C-terminal portion of the cytoplasmic domain of beta 3 as an intrinsic element in the coupling between alpha IIb beta 3 and platelet activation.


Crossover and noncrossover pathways in mouse meiosis.

Abstract: During meiosis, recombination between homologous chromosomes generates crossover (CR) and noncrossover (NCR) products.

Abstract: CRs establish connections between homologs, whereas intermediates leading to NCRs have been proposed to participate in homologous pairing.

Abstract: How these events are differentiated and regulated remains to be determined.

Abstract: We have developed a strategy to detect, quantify, and map NCRs in parallel to CRs, at the Psmb9 meiotic recombination hot spot, in male and female mouse germ lines.

Abstract: Our results report direct molecular evidence for distinct CR and NCR pathways of DNA double-strand break (DSB) repair in mouse meiosis based on three observations: both CRs and NCRs require Spo11, NCR products have shorter conversion tracts than CRs, and only CRs require the MutL homolog Mlh1.

Abstract: We show that both products are formed from middle to late pachytene of meiotic prophase and provide evidence for an Mlh1-independent CR pathway, where mismatch repair does not require Mlh1.


IAP regulation of metastasis.

Abstract: Inhibitor-of-Apoptosis (IAP) proteins contribute to tumor progression, but the requirements of this pathway are not understood.

Abstract: Here, we show that intermolecular cooperation between XIAP and survivin stimulates tumor cell invasion and promotes metastasis.

Abstract: This pathway is independent of IAP inhibition of cell death.

Abstract: Instead, a survivin-XIAP complex activates NF-kappaB, which in turn leads to increased fibronectin gene expression, signaling by beta1 integrins, and activation of cell motility kinases FAK and Src.

Abstract: Therefore, IAPs are direct metastasis genes, and their antagonists could provide antimetastatic therapies in patients with cancer.


15-Hydroxyprostaglandin dehydrogenase is down-regulated in colorectal cancer.

Abstract: Prostaglandin E2 (PGE2) can stimulate tumor progression by modulating several proneoplastic pathways, including proliferation, angiogenesis, cell migration, invasion, and apoptosis.

Abstract: Although steady-state tissue levels of PGE2 stem from relative rates of biosynthesis and breakdown, most reports examining PGE2 have focused solely on the cyclooxygenase-dependent formation of this bioactive lipid.

Abstract: Enzymatic degradation of PGE2 involves the NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH).

Abstract: The present study examined a range of normal tissues in the human and mouse and found high levels of 15-PGDH in the large intestine.

Abstract: By contrast, the expression of 15-PGDH is decreased in several colorectal carcinoma cell lines and in other human malignancies such as breast and lung carcinomas.

Abstract: Consistent with these findings, we observe diminished 15-Pgdh expression in ApcMin+/- mouse adenomas.

Abstract: Enzymatic activity of 15-PGDH correlates with expression levels and the genetic disruption of 15-Pgdh completely blocks production of the urinary PGE2 metabolite.

Abstract: Finally, 15-PGDH expression and activity are significantly down-regulated in human colorectal carcinomas relative to matched normal tissue.

Abstract: In summary, these results suggest a novel tumor suppressive role for 15-PGDH due to loss of expression during colorectal tumor progression.


Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance

Abstract: CD25+CD4+ regulatory T cells in normal animals are engaged in the maintenance of immunological self-tolerance.

Abstract: We show here that glucocorticoid-induced tumor necrosis factor receptor family–related gene (GITR, also known as TNFRSF18)—a member of the tumor necrosis factor–nerve growth factor (TNF-NGF) receptor gene superfamily—is predominantly expressed on CD25+CD4+ T cells and on CD25+CD4+CD8− thymocytes in normal naïve mice.

Abstract: We found that stimulation of GITR abrogated CD25+CD4+ T cell–mediated suppression.

Abstract: In addition, removal of GITR-expressing T cells or administration of a monoclonal antibody to GITR produced organ-specific autoimmune disease in otherwise normal mice.

Abstract: Thus, GITR plays a key role in dominant immunological self-tolerance maintained by CD25+CD4+ regulatory T cells and could be a suitable molecular target for preventing or treating autoimmune disease.


The missing cases of tuberculosis in Malawi: the contribution from cross-border registrations.

Abstract: Low case detection rates of new smear-positive pulmonary tuberculosis (PTB) patients globally are a cause for concern.

Abstract: The aim of this study was to determine for patients registered for TB in Malawi the number and percentage who lived in a neighbouring country and the registration, recording and reporting practices for these 'foreign' patients.

Abstract: All 44 non-private hospitals, which register and treat all TB patients in the public health sector in Malawi, were visited.

Abstract: Ten (23%) hospitals in 2001 and 14 (32%) in 2002 maintained a separate register for cross-border TB cases.

Abstract: Patients recorded in these registers were not formally reported to the Malawi National TB Programme (NTP), the neighbouring country's NTP, nor to WHO.

Abstract: They therefore constitute missing cases.

Abstract: In Malawi, the number of cross-border new smear-positive PTB cases was 77 in 2001 and 91 in 2002, constituting about 3% of missing smear-positive cases in those hospitals that maintain cross-border registers and about 1% of missing cases nationally.


Parathyroid hormone induces E4bp4 messenger ribonucleic acid expression primarily through cyclic adenosine 3',5'-monophosphate signaling in osteoblasts.

Abstract: PTH binding to its receptor activates protein kinase A (PKA), protein kinase C (PKC), and calcium signaling to induce transcription of primary response genes in osteoblasts.

Abstract: Adenovirus E4 promoter-binding protein/nuclear factor regulated by IL-3 (E4BP4/NFIL3), a transcriptional repressor, is a PTH-induced primary response gene in primary mouse osteoblasts (MOBs).

Abstract: Here we investigate the signaling pathway(s) that lead to PTH induction of E4bp4 mRNA expression.

Abstract: Ten and 100 nm PTH induced maximum E4bp4 expression in MOBs.

Abstract: Forskolin (FSK), an adenylate cyclase inducer, 8-bromo-cAMP, a cAMP analog, and phorbol myristate acetate, a PKC activator, increased E4bp4 mRNA levels, whereas ionomycin, a calcium ionophore, had no effect.

Abstract: Pretreatment of cells with 30 microm H89, a PKA inhibitor, strongly inhibited PTH- and FSK-induced E4bp4 expression.

Abstract: In contrast, overnight pretreatment with 1 microm phorbol myristate acetate to down-regulate PKC signaling did not alter PTH and FSK effects.

Abstract: Moreover, PTH (3-34) that does not activate cAMP signaling did not increase E4bp4 expression.

Abstract: Prostaglandin E(2), which signals through cAMP, increased E4bp4 mRNA at all doses, whereas prostaglandin F(2alpha) that primarily activates PKC and calcium signaling, induced E4bp4 only at high doses and fluprostenol that only activates PKC and calcium signaling, had no effect.

Abstract: Finally, 80 microg/kg PTH (1-34) ip injection induced E4bp4 mRNA expression at 1 h in mice.

Abstract: In contrast, 80 microg/kg PTH (3-34) had no effect.

Abstract: Our data suggest that PTH-induced E4bp4 mRNA expression is mediated primarily through cAMP-PKA signaling in vitro and in vivo.

Abstract: In conjunction with our previous report, we hypothesize that E4bp4 attenuates transcription of osteoblastic genes possessing E4bp4 promoter binding sites.


Managing finances of shipping living donor kidneys for donor exchanges.

Abstract: Kidney donor exchanges enable recipients with immunologically incompatible donors to receive compatible living donor grafts; however, the financial management of these exchanges, especially when an organ is shipped, is complex and thus has the potential to impede the broader implementation of donor exchange programs.

Abstract: Representatives from transplant centers that utilize the National Kidney Registry database to facilitate donor exchange transplants developed a financial model applicable to paired donor exchanges and donor chain transplants.

Abstract: The first tenet of the model is to eliminate financial liability to the donor.

Abstract: Thereafter, it accounts for the donor evaluation, donor nephrectomy hospital costs, donor nephrectomy physician fees, organ transport, donor complications and recipient inpatient services.

Abstract: Billing between hospitals is based on Medicare cost report defined costs rather than charges.

Abstract: We believe that this model complies with current federal regulations and effectively captures costs of the donor and recipient services.

Abstract: It could be considered as a financial paradigm for the United Network for Organ Sharing managed donor exchange program.


Human herpesvirus 8 infection and Kaposi's sarcoma among human immunodeficiency virus-infected and -uninfected women.

Abstract: Little is known about the epidemiology of human herpesvirus 8 (HHV-8) infections among women.

Abstract: A cross-sectional study was conducted of HHV-8 infection among human immunodeficiency virus (HIV)-infected and high-risk HIV-uninfected women.

Abstract: Serological tests with noninduced (latent) and induced (lytic) HHV-8 antigens were used to detect infection among 2483 participants of a multisite cohort.

Abstract: Reactivity to latent antigen was present in 4.1% and to induced antigens in 12.0% of women.

Abstract: Seven of 8 women who reported Kaposi's sarcoma had HHV-8 antibodies.

Abstract: Among HIV-positive women, HHV-8 infection was associated with use of crack, cocaine, or heroin (76% vs. 65%; P<.001), past syphilis (29% vs. 20%; P<.001), an injection drug-using male sex partner (61% vs. 53%; P=.014), black race (P=.010), and enrollment site (P=.015).

Abstract: In multivariate analysis, HIV infection, older age, past syphilis, black race, and enrollment site were independently associated with HHV-8 infection.

Abstract: In this cohort of North American women, HHV-8 infection was associated with HIV infection, drug use, and risky sexual behavior.


Cloning of three novel neuronal Cdk5 activator binding proteins.

Abstract: Neuronal Cdc2-like kinase (Nclk) is involved in the regulation of neuronal differentiation and neuro-cytoskeleton dynamics.

Abstract: The active kinase consists of a catalytic subunit, Cdk5, and a 25 kDa activator protein (p25nck5a) derived from a 35 kDa neuronal-specific protein (p35nck5a).

Abstract: As an extension of our previous study (Qi, Z., Tang, D., Zhu, X., Fujita, D.J., Wang, J.H., 1998.

Abstract: Association of neurofilament proteins with neuronal Cdk5 activator.

Abstract: J. Biol.

Abstract: Chem.

Abstract: 270, 2329-2335), which showed that neurofilament is one of the p35nck5a-associated proteins, we now report the isolation of three other novel p35nck5a-associated proteins using the yeast two-hybrid screen.

Abstract: The full-length forms of these three novel proteins, designated C42, C48 and C53, have a molecular mass of 66, 24, and 57 kDa, respectively.

Abstract: Northern analysis indicates that these novel proteins are widely expressed in human tissues, including the heart, brain, skeletal muscle, placenta, lung, liver, kidney and pancreas.

Abstract: The bacterially expressed glutathione S-transferase (GST)-fusion forms of these three proteins were able to co-precipitate p35nck5a complexed with Cdk5 from insect cell lysate.

Abstract: Among these three proteins, only C48 and C53 can be phosphorylated by Nclk, suggesting that they may be the substrates of Nclk.

Abstract: Sequence homology searches have suggested that the C48 protein is marginally related to restin protein, whereas the C42 protein has homologues of unknown function in Caenorhabditis elegans and Arabidopsis thaliana.


The Artemis:DNA-PKcs endonuclease cleaves DNA loops, flaps, and gaps.

Abstract: In eukaryotic cells, nonhomologous DNA end joining (NHEJ) is a major pathway for repair of double-strand DNA breaks (DSBs).

Abstract: Artemis and the 469kDa DNA-dependent protein kinase (DNA-PKcs) together form a key nuclease for NHEJ in vertebrate organisms.

Abstract: The structure-specific endonucleolytic activity of Artemis is activated by binding to and phosphorylation by DNA-PKcs.

Abstract: We tested various DNA structures in order to understand the range of structural features that are recognized by the Artemis:DNA-PKcs complex.

Abstract: We find that all tested substrates that contain single-to-double-strand transitions can be cleaved by the Artemis:DNA-PKcs complex near the transition region.

Abstract: The cleaved substrates include heterologous loops, stem-loops, flaps, and gapped substrates.

Abstract: Such versatile activity on single-/double-strand transition regions is important in understanding how reconstituted NHEJ systems that lack DNA polymerases can join incompatible DNA ends and yet preserve 3' overhangs.

Abstract: Additionally, the flexibility of the Artemis:DNA-PKcs nuclease may be important in removing secondary structures that hinder processing of DNA ends during NHEJ.


A promoter derived from taro bacilliform badnavirus drives strong expression in transgenic banana and tobacco plants

Abstract: Taro bacilliform virus (TaBV) is a pararetrovirus of the genus Badnavirus which infects the monocotyledonous plant, taro (Colocasia esculenta).

Abstract: A region of the TaBV genome spanning nucleotides 6,281 to 12 (T1200), including the 3′ end of open reading frame 3 (ORF 3) and the intergenic region to the end of the tRNAmet-binding site, was tested for promoter activity along with four different 5′ deletion fragments (T600, T500, T250 and T100).

Abstract: In transient assays, only the T1200, T600, T500 fragments were shown to have promoter activity in taro leaf, banana suspension cells and tobacco callus.

Abstract: When these three promoters were evaluated in stably transformed, in vitro-grown transgenic banana and tobacco plants, all were found to drive near-constitutive expression of either the green fluorescent protein or β-glucuronidase (GUS) reporter gene in the stem (or pseudostem), leaves and roots, with strongest expression observed in the vascular tissue.

Abstract: In transgenic banana leaves, the T600 promoter directed four-fold greater GUS activity than that of the T1200, T500 and the maize polyubiquitin-1 promoters.

Abstract: In transgenic tobacco leaves, the levels of GUS expression directed by the three promoters was between four- and ten-fold lower than that of the double Cauliflower mosaic virus 35S promoter.

Abstract: These results indicate that the TaBV-derived promoters may be useful for the high-level constitutive expression of transgenes in either monocotyledonous or dicotyledonous species.


Age of ovary determines remaining life expectancy in old ovariectomized mice.

Abstract: We investigated the capacity of young ovaries, transplanted into old ovariectomized CBA mice, to improve remaining life expectancy of the hosts.

Abstract: Donor females were sexually mature 2-month-olds; recipients were prepubertally ovariectomized at 3 weeks and received transplants at 5, 8 or 11 months of age.

Abstract: Relative to ovariectomized control females, life expectancy at 11 months was increased by 60% in 11-month recipient females and by 40% relative to intact control females.

Abstract: Only 20% of the 11-month transplant females died in the 300-day period following ovarian transplantation, whereas nearly 65% of the ovariectomized control females died during this same period.

Abstract: The 11-month-old recipient females resumed oestrus and continued to cycle up to several months beyond the age of control female reproductive senescence.

Abstract: Across the three recipient age groups, transplantation of young ovaries increased life expectancy in proportion to the relative youth of the ovary.

Abstract: Our results relate to recent findings on the gonadal input upon aging in Caenorhabditis elegans and may suggest how the mammalian gonad, including that of humans, could regulate aging and determine longevity.


Use of macrolides in mother and child and risk of infantile hypertrophic pyloric stenosis: nationwide cohort study

Abstract: OBJECTIVE To assess the association between use of macrolide antibiotics in mothers and infants from pregnancy onset until 120 days after birth and infantile hypertrophic pyloric stenosis (IHPS).

Abstract: DESIGN Nationwide register based cohort study.

Abstract: SETTING Denmark, 1996-2011.

Abstract: PARTICIPANTS 999,378 liveborn singletons and linked individual level information on macrolide prescriptions (maternal use during pregnancy, n=30,091; maternal use after birth, n=21,557; use in infants, n=6591), surgery for IHPS, and potential confounders.

Abstract: MAIN OUTCOME MEASURES Surgery for IHPS by three categories of macrolide use: in mothers during pregnancy, in mothers after birth, and in infants after birth.

Abstract: RESULTS 880 infants developed IHPS (0.9 cases per 1000 births).

Abstract: Compared with infants with no use of macrolides, the adjusted rate ratio for IHPS in infants with use of macrolides during days 0 to 13 after birth was 29.8 (95% confidence interval 16.4 to 54.1) and during days 14 to 120 was 3.24 (1.20 to 8.74); the corresponding absolute risk differences were 24.4 (95% confidence interval 13.0 to 44.1) and 0.65 (0.06 to 2.21) cases per 1000 infants exposed to macrolides, respectively.

Abstract: The rate ratio for maternal use of macrolides for days 0 to 13 after birth was 3.49 (1.92 to 6.34) and for days 14 to 120 was 0.70 (0.26 to 1.90); the corresponding absolute risk differences were 2.15 (0.82 to 4.64) and -0.11 (-0.26 to 0.31).

Abstract: The rate ratios for maternal use of macrolides during pregnancy were 1.02 (0.65 to 1.59) for weeks 0 to 27 and 1.77 (0.95 to 3.31) for weeks 28 to birth; the corresponding absolute risk differences were 0.01 (-0.31 to 0.50) and 0.67 (-0.06 to 2.02).

Abstract: CONCLUSIONS Treatment of young infants with macrolide antibiotics was strongly associated with IHPS and should therefore only be administered if potential treatment benefits outweigh the risk.

Abstract: Maternal use of macrolides during the first two weeks after birth was also associated with an increased risk of IHPS.

Abstract: A possible association was also found with use during late pregnancy.


The psychiatric manifestations of mitochondrial disorders: a case and review of the literature.

Abstract: OBJECTIVE Mitochondrial disorders are caused by gene mutations in mitochondrial or nuclear DNA and affect energy-dependent organs such as the brain.

Abstract: Patients with psychiatric illness, particularly those with medical comorbidities, may have primary mitochondrial disorders.

Abstract: To date, this issue has received little attention in the literature, and mitochondrial disorders are likely underdiagnosed in psychiatric patients.

Abstract: DATA SOURCES This article describes a patient who presented with borderline personality disorder and treatment-resistant depression and was ultimately diagnosed with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) 3271.

Abstract: We also searched the literature for all case reports of patients with mitochondrial disorders who initially present with prominent psychiatric symptoms by using MEDLINE (from 1948-February 2011), Embase (from 1980-February 2011), PsycINFO (from 1806-February 2011), and the search terms mitochondrial disorder, mitochondria, psychiatry, mental disorders, major depression, anxiety, schizophrenia, and psychosis.

Abstract: STUDY SELECTION Fifty cases of mitochondrial disorders with prominent psychiatric symptomatology were identified.

Abstract: DATA EXTRACTION Information about the psychiatric presentation of the cases was extracted.

Abstract: This information was combined with our case, the most common psychiatric manifestations of mitochondrial disorders were identified, and the important diagnostic and treatment implications for patients with psychiatric illness were reviewed.

Abstract: RESULTS The most common psychiatric presentations in the cases of mitochondrial disorders included mood disorder, cognitive deterioration, psychosis, and anxiety.

Abstract: The most common diagnosis (52% of cases) was a MELAS mutation.

Abstract: Other genetic mitochondrial diagnoses included polymerase gamma mutations, Kearns-Sayre syndrome, mitochondrial DNA deletions, point mutations, twinkle mutations, and novel mutations.

Abstract: CONCLUSIONS Patients with mitochondrial disorders can present with primary psychiatric symptomatology, including mood disorder, cognitive impairment, psychosis, and anxiety.

Abstract: Psychiatrists need to be aware of the clinical features that are indicative of a mitochondrial disorder, investigate patients with suggestive presentations, and be knowledgeable about the treatment implications of the diagnosis.


Polo kinase and Asp are needed to promote the mitotic organizing activity of centrosomes

Abstract: Interfering with the activity of polo-like kinases can lead to the formation of monopolar spindles.

Abstract: Polo-like kinases also regulate mitotic entry, activation of the anaphase-promoting complex and the necessary preconditions for cytokinesis.

Abstract: Similarities between the phenotypes of the Drosophila mutants asp and polo point towards a common role in spindle pole function.

Abstract: The abnormal spindles of asp mutants are bipolar but have disorganized broad poles at which γ-tubulin has an abnormal distribution.

Abstract: Moreover, the synergism or of polo1 aspE3 double mutants indicates a possible involvement of these genes in a common process.

Abstract: Asp is a microtubule-associated protein of relative molecular mass 220,000 (Mr 220K) found at the face of the centrosome that contacts spindle microtubules.

Abstract: In partially purified centrosomes, it is required with γ-tubulin to organize microtubule asters.

Abstract: Here, we show that Asp is the previously identified Mr 220K substrate of Polo kinase.

Abstract: Polo phosphorylates Asp in vitro, converting it into an MPM2 epitope.

Abstract: Polo and Asp proteins immunoprecipitate together and exist as part of a 25–38S complex.

Abstract: Extracts of polo-derived embryos are unable to restore the ability of salt-stripped centrosomes to nucleate microtubule asters.

Abstract: This can be rescued by addition of phosphorylated Asp or active Polo kinase.


How long will long-term potentiation last?

Abstract: The paramount feature of long-term potentiation (LTP) as a memory mechanism is its characteristic persistence over time.

Abstract: Although the basic phenomenology of LTP persistence was established 30 years ago, new insights have emerged recently about the extent of LTP persistence and its regulation by activity and experience.

Abstract: Thus, it is now evident that LTP, at least in the dentate gyrus, can either be decremental, lasting from hours to weeks, or stable, lasting months or longer.

Abstract: Although mechanisms engaged during the induction of LTP regulate its subsequent persistence, the maintenance of LTP is also governed by activity patterns post-induction, whether induced experimentally or generated by experience.

Abstract: These new findings establish dentate gyrus LTP as a useful model system for studying the mechanisms governing the induction, maintenance and interference with long-term memory, including very long-term memory lasting months or longer.

Abstract: The challenge is to study LTP persistence in other brain areas, and to relate, if possible, the properties and regulation of LTP maintenance to these same properties of the information that is actually stored in those regions.


An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominated inflammatory response.

Abstract: In schistosomiasis, chronic parasite egg-induced granuloma formation can lead to tissue destruction and fibrosis, which causes much of the morbidity and mortality associated with this disease.

Abstract: Here we show the importance of IL-13 in the pathogenesis of schistosomiasis, and demonstrate, perhaps for the first time, the therapeutic efficacy of an IL-13 inhibitor, sIL-13Ralpha2-Fc, in the control of hepatic fibrosis.

Abstract: T-helper type 2 (Th2) cytokines dominate the immune response in mice infected with Schistosoma mansoni, yet the specific contributions of IL-13 and IL-4 to the development of fibrosis were not previously investigated.

Abstract: Our studies demonstrate that both cytokines play redundant roles in granuloma formation, which explains the ability of IL-4-deficient mice to form granulomas around eggs.

Abstract: More importantly, however, these studies demonstrate that IL-13 is the dominant Th2-type cytokine regulating fibrosis.

Abstract: IL-13 stimulated collagen production in fibroblasts, and procollagen I and procollagen III mRNA expression was decreased in sIL-13Ralpha2-Fc-treated mice.

Abstract: Moreover, the reduction in fibrosis observed in IL-4-deficient mice was much less pronounced than that in sIL-13Ralpha2-Fc-treated animals.

Abstract: Fibrosis is a major pathological manifestation of a number of allergic, autoimmune, and infectious diseases.

Abstract: Thus, our findings provide evidence that IL-13 inhibitors may be of general therapeutic benefit in preventing damaging tissue fibrosis resulting from Th2-dominated inflammatory responses.


Validity and reliability of observational methods for studying medication administration errors.

Abstract: The validity and reliability of observational methods for studying medication administration errors (MAEs) were studied.

Abstract: Between January and June 1998, two pharmacists observed consecutive drug administration rounds by nurses on two wards in a U.K. hospital and recorded all MAEs identified.

Abstract: The observers intervened in cases of potentially harmful errors.

Abstract: MAE records were audited to determine the percentage of omitted doses for which a corresponding reason was documented for the observation periods and for nonobservation periods.

Abstract: Error rates for each drug administration round were analyzed according to whether they were for the nurse's first, second, third (and so on) observed round.

Abstract: Error rates were calculated before and after the first intervention with nurses for whom an intervention was made.

Abstract: Observer reliability was calculated by comparing the rates of errors identified by the two observers.

Abstract: There was no difference between the observation and nonobservation periods in the percentage of omitted doses for which a reason was documented, and there was no change in the error rate with repeated observations.

Abstract: There was no difference in error rates before and after the first intervention for each nurse.

Abstract: There was also no difference in error detection between the two observers and no change with increasing duration of observation.

Abstract: Observation of nurses during drug administration at a U.K. hospital did not significantly affect the MAE rate; nor did tactful interventions by the observers.

Abstract: Observer reliability was high.

Abstract: Concerns about the validity and reliability of observational methods for identifying MAEs may be unfounded.


Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution.

Abstract: Ectopic expression of the four transcription factors Oct4, Sox2, c-Myc, and Klf4 is sufficient to confer a pluripotent state upon the fibroblast genome, generating induced pluripotent stem (iPS) cells.

Abstract: It remains unknown if nuclear reprogramming induced by these four factors globally resets epigenetic differences between differentiated and pluripotent cells.

Abstract: Here, using novel selection approaches, we have generated iPS cells from fibroblasts to characterize their epigenetic state.

Abstract: Female iPS cells showed reactivation of a somatically silenced X chromosome and underwent random X inactivation upon differentiation.

Abstract: Genome-wide analysis of two key histone modifications indicated that iPS cells are highly similar to ES cells.

Abstract: Consistent with these observations, iPS cells gave rise to viable high-degree chimeras with contribution to the germline.

Abstract: These data show that transcription factor-induced reprogramming leads to the global reversion of the somatic epigenome into an ES-like state.

Abstract: Our results provide a paradigm for studying the epigenetic modifications that accompany nuclear reprogramming and suggest that abnormal epigenetic reprogramming does not pose a problem for the potential therapeutic applications of iPS cells.


Exocrine ontogenies: on the development of pancreatic acinar, ductal and centroacinar cells.

Abstract: This review summarizes our current understanding of exocrine pancreas development, including the formation of acinar, ductal and centroacinar cells.

Abstract: We discuss the transcription factors associated with various stages of exocrine differentiation, from multipotent progenitor cells to fully differentiated acinar and ductal cells.

Abstract: Within the branching epithelial tree of the embryonic pancreas, this involves the progressive restriction of multipotent pancreatic progenitor cells to either a central "trunk" domain giving rise to the islet and ductal lineages, or a peripheral "tip" domain giving rise to acinar cells.

Abstract: This review also discusses the soluble morphogens and other signaling pathways that influence these events.

Abstract: Finally, we examine centroacinar cells as an enigmatic pancreatic cell type whose lineage remains uncertain, and whose possible progenitor capacities continue to be explored.


The history of SIVS and AIDS: epidemiology, phylogeny and biology of isolates from naturally SIV infected non-human primates (NHP) in Africa.

Abstract: Simian immunodeficiency virus (SIV) naturally infects non-human primates in Africa.

Abstract: To date, 40 SIVs have been described both in natural hosts and in heterologous species.

Abstract: These viruses are highly diverse and the majority cluster in 6 relatively equidistant phylogenetic lineages.

Abstract: At least 8 SIVs are currently considered as recombinant viruses, based on different clustering patterns in different genomic regions.

Abstract: Only three types of genomes are known, based on the number of accessory genes: vpr-containing genomes, vpr-vpx containing genomes and vpr-vpu-containing genomes.

Abstract: vpx resulted by a duplication of the vpr gene following non-homologous recombination and is characteristic of SIVs infecting the Papionini tribe of monkeys and HIV-2 in humans.

Abstract: vpu is characteristic of SIVcpz and HIV-1 and may have originated from a recombination involving SIVs from cercopitecini monkeys.

Abstract: SIV seems to be non-pathogenic in the vast majority of natural hosts in spite of a high levels of viral replication.

Abstract: This is probably a consequence of virus-host adaptation, in which the incubation period of the disease generally exceeds the life span of the African primate host.

Abstract: SIVs also have a high propensity for cross-species transmission.

Abstract: In the new host, the outcome may vary from inapparent infection to highly pathogenic, the former being reported for African monkeys, whereas the latter being observed in macaques and humans.

Abstract: The high diversity of SIVs was generated by a high mutation rate due to a low fidelity of the reverse-transcriptase and active viral and host cell turnover, host-dependent evolution and recombination.

Abstract: Cross-species transmission is not rare, however preferential host switching may drive the majority of cross-species transmissions.

Abstract: Numerous SIVs tested so far are able to grow in vitro on human PBMC, therefore it has been postulated that SIV represents a threat for infection of humans in Central Africa and that AIDS is a zoonosis.

Abstract: However, although the simian origin of the two HIV types is broadly acknowledged, there are no data that AIDS is acquired like a zoonosis.

Abstract: SIV may undergo adaptation in the new human host in order to emerge in the general population.

Abstract: The study of SIV in their natural hosts should provide important clues to the real threat to human populations and also elucidate the mechanisms associated with a long-term persistent viral infection without clinical consequences for the host.


The association between common physical impairments and dementia in low and middle income countries, and, among people with dementia, their association with cognitive function and disability. A 10/66 Dementia Research Group population-based study.

Abstract: OBJECTIVE Chronic physical comorbidity is common in dementia.

Abstract: However, there is an absence of evidence to support good practice guidelines for attention to these problems.

Abstract: We aimed to study the extent of this comorbidity and its impact on cognitive function and disability in population-based studies in low and middle income countries, where chronic diseases and impairments are likely to be both common and undertreated.

Abstract: METHODS A multicentre cross-sectional survey of all over 65 year old residents (n = 15 022) in 11 catchment areas in China, India, Cuba, Dominican Republic, Venezuela, Mexico and Peru.

Abstract: We estimated the prevalence of pain, incontinence, hearing and visual impairments, mobility impairment and undernutrition according to the presence of dementia and its severity, and, among those with dementia, the independent contribution of these impairments to cognitive function and disability, adjusting for age, gender, education and dementia severity.

Abstract: RESULTS Incontinence, hearing impairment, mobility impairment and undernutrition were consistently linearly associated with the presence of dementia and its severity across regions.

Abstract: Among people with dementia, incontinence, hearing impairment and mobility impairment were independently associated with disability in all regions while the contributions of pain, visual impairment and undernutrition were inconsistent.

Abstract: Only hearing impairment made a notable independent contribution to cognitive impairment.

Abstract: CONCLUSIONS There is an urgent need for clinical trials of the feasibility, efficacy and cost-effectiveness of regular physical health checks and remediation of identified pathologies, given the considerable comorbidity identified in our population based studies, and the strong evidence for independent impact upon functioning.


Serum biomarkers as predictors of lung function decline in chronic obstructive pulmonary disease.

Abstract: BACKGROUND Recent studies show that COPD patients exhibit low-grade systemic inflammation, and that plasma fibrinogen and high neutrophil counts are related to faster declines in lung function.

Abstract: We examined correlations between serum biomarkers and the decline of lung function in COPD patients.

Abstract: METHOD Baseline levels of 9 serum biomarkers (TIMP-1, alpha1-antitrypsin, MMP-9, TNF-alpha, TGF-beta, IL-6, IL-8, neutrophil elastase and CRP), fibrinogen and white blood cell counts (WCC) were measured in 96 COPD patients.

Abstract: Lung function was measured at the time of blood sampling and every 3-6 months during the observation period (median 25.0 months).

Abstract: RESULTS Twenty patients were rapid decliners of lung function and 53 patients were non-decliners.

Abstract: Neutrophil counts, serum CRP and MMP-9 were significantly higher in the rapid decliners (p<0.05).

Abstract: The annual change of % predicted FEV(1) was inversely correlated with MMP-9 (r=-0.288; p<0.01) and CRP (r=-0.354; p<0.005) (partial correlation coefficients adjusted for age, sex, cardiovascular disease, smoking history, and baseline % predicted FEV(1)).

Abstract: The remaining biomarkers were not correlated with the annual change of % predicted FEV(1).

Abstract: CONCLUSION Serum CRP and MMP-9 levels were related to FEV(1) decline.

Abstract: These markers are good candidates as predictors for rapid decline of FEV(1) in COPD patients.

Abstract: Additional long-term and larger size studies of COPD patients could help determine the exact roles for these biomarkers.


Phosphorylation of ATM by Cdk5 mediates DNA damage signaling and regulates neuronal death

Abstract: The phosphatidylinositol-3-kinase-like kinase ATM (ataxia-telangiectasia mutated) has a central role in coordinating DNA damage responses, including cell-cycle checkpoint control, DNA repair and apoptosis.

Abstract: Mutations of ATM cause a spectrum of defects ranging from neurodegeneration to cancer predisposition.

Abstract: However, the mechanism by which DNA damage activates ATM is poorly understood.

Abstract: Here we show that Cdk5 (cyclin-dependent kinase 5), activated by DNA damage, directly phosphorylates ATM at Ser 794 in post-mitotic neurons.

Abstract: Phosphorylation at Ser 794 precedes, and is required for, ATM autophosphorylation at Ser 1981, and activates ATM kinase activity.

Abstract: The Cdk5-ATM signal regulates phosphorylation and function of the ATM targets p53 and H2AX.

Abstract: Interruption of the Cdk5-ATM pathway attenuates DNA-damage-induced neuronal cell cycle re-entry and expression of the p53 targets PUMA and Bax, protecting neurons from death.

Abstract: Thus, activation of Cdk5 by DNA damage serves as a critical signal to initiate the ATM response and regulate ATM-dependent cellular processes.


Nerve-induced release of nitric oxide in the rabbit gastrointestinal tract as measured by in vivo microdialysis.

Abstract: Nitric oxide (NO) has been suggested as a gastrointestinal neurotransmitter, mediating the gastric receptive relaxation and the relaxation in the peristaltic reflex.

Abstract: The aim of the present study was to measure nerve-induced NO formation in vivo in the gastrointestinal tract.

Abstract: Formation of the nitric oxide oxidation products nitrite and nitrate during vagal nerve stimulation were measured in the anaesthetized rabbit.

Abstract: Microdialysis probes were inserted into the wall of the stomach and proximal colon, and nitrite and nitrate in dialysate measured by capillary electrophoresis.

Abstract: During bilateral vagal nerve stimulation there was an increase in nitrite and nitrate formation at the level of the stomach and in nitrite formation at the level of the colon.

Abstract: This increase was inhibited by intravenous administration of the NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME 30 mg kg-1).

Abstract: Furthermore, L-NAME significantly increased nerve-induced gastric and colonic contractions, as well as spontaneous colonic contractions.

Abstract: In summary, we present a new methodological procedure for quantification of small changes in nitric oxide formation in vivo.

Abstract: This study provides evidence that nitric oxide is released in the stomach and colonic wall during vagal nerve activity, at concentrations able to cause inhibition of smooth muscle contractions in vivo.


Screening for concomitant diseases in peripheral vascular patients. Results of a systematic approach.

Abstract: BACKGROUND Patients considered for arterial surgery, have been shown to have a high incidence of coexistent cardiac, vascular and other diseases, affecting operative risk and survival.

Abstract: We developed a systematic workup strategy for detecting these coexistent diseases in our vascular surgical patients, mainly based on non-invasive diagnostic techniques.

Abstract: METHODS We evaluated 200 consecutive patients, admitted to the department of vascular surgery in an academic teaching hospital, in order to establish the total incidence of relevant concomitant disorders, the extent to which this screening yielded previously unknown diagnostic information, and the impact on short-term (one year) survival.

Abstract: RESULTS Coronary artery disease was present in 46% of the patients; 22% had active ischaemia, newly diagnosed in 5.5%.

Abstract: Impaired cardiac function was found in 37%: severely impaired in 12%, newly diagnosed in 27%.

Abstract: Carotid artery disease was present in 32%: critical stenoses were found in 9%; new diagnoses in 29.9%.

Abstract: Aortic aneurysms were present in 7%, newly diagnosed in 5%.

Abstract: Severe renal artery stenosis was present in 5%, newly diagnosed in 3.5%.

Abstract: Sixteen % of the patients had chronic obstructive pulmonary disease, newly diagnosed in 3.5%, and 4.5% had unexpected disorders, which were all new diagnoses.

Abstract: Overall, new diagnoses were reached in 64.5% of the population, affecting therapeutic strategy immediately in 21% of the patients.

Abstract: The presence of coronary artery disease and of cardiac failure were clearly related to one year survival.

Abstract: CONCLUSIONS We conclude that a systematic screening strategy, mainly based on noninvasive techniques, can detect the presence of concomitant diseases in the vascular surgical patient.

Abstract: Most important seem the newly diagnosed diseases altering surgical management in one out of every five patients; they also have important implications for patient prognosis.


Archetypal trajectories of social, psychological, and spiritual wellbeing and distress in family care givers of patients with lung cancer: secondary analysis of serial qualitative interviews

Abstract: OBJECTIVE To assess if family care givers of patients with lung cancer experience the patterns of social, psychological, and spiritual wellbeing and distress typical of the patient, from diagnosis to death.

Abstract: DESIGN Secondary analysis of serial qualitative interviews carried out every three months for up to a year or to bereavement.

Abstract: SETTING South east Scotland.

Abstract: PARTICIPANTS 19 patients with lung cancer and their 19 family carers, totalling 88 interviews (42 with patients and 46 with carers).

Abstract: RESULTS Carers followed clear patterns of social, psychological, and spiritual wellbeing and distress that mirrored the experiences of those for whom they were caring, with some carers also experiencing deterioration in physical health that impacted on their ability to care.

Abstract: Psychological and spiritual distress were particularly dynamic and commonly experienced.

Abstract: In addition to the "Why us?" response, witnessing suffering triggered personal reflections in carers on the meaning and purpose of life.

Abstract: Certain key time points in the illness tended to be particularly problematic for both carers and patients: at diagnosis, at home after initial treatment, at recurrence, and during the terminal stage.

Abstract: CONCLUSIONS Family carers witness and share much of the illness experience of the dying patient.

Abstract: The multidimensional experience of distress suffered by patients with lung cancer was reflected in the suffering of their carers in the social, psychological, and spiritual domains, with psychological and spiritual distress being most pronounced.

Abstract: Carers may need to be supported throughout the period of illness not just in the terminal phase and during bereavement, as currently tends to be the case.


HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation

Abstract: HER-2/neu amplification or overexpression can make cancer cells resistant to apoptosis and promotes their growth.

Abstract: p53 is crucial in regulating cell growth and apoptosis, and is often mutated or deleted in many types of tumour.

Abstract: Moreover, many tumours with a wild-type gene for p53 do not have normal p53 function, suggesting that some oncogenic signals suppress the function of p53.

Abstract: In this study, we show that HER-2/neu-mediated resistance to DNA-damaging agents requires the activation of Akt, which enhances MDM2-mediated ubiquitination and degradation of p53.

Abstract: Akt physically associates with MDM2 and phosphorylates it at Ser166 and Ser186.

Abstract: Phosphorylation of MDM2 enhances its nuclear localization and its interaction with p300, and inhibits its interaction with p19ARF, thus increasing p53 degradation.

Abstract: Our study indicates that blocking the Akt pathway mediated by HER-2/neu would increase the cytotoxic effect of DNA-damaging drugs in tumour cells with wild-type p53.


T cell memory.

Abstract: T cell memory induced by prior infection or vaccination provides enhanced protection against subsequent microbial infections.

Abstract: The processes involved in generating and maintaining T cell memory are becoming better understood due to recent technological advances in identifying memory T cells and monitoring their behavior and function in vivo.

Abstract: Memory T cells develop in response to a progressive set of cues-starting with signals from antigen-loaded, activated antigen-presenting cells (APCs) and inflammatory mediators induced by the innate immune response, to the poorly defined subsequent signals triggered as the immune response wanes toward homeostasis.

Abstract: The persistence of the resting memory T cells that eventually develop is regulated by cytokines.

Abstract: This chapter discusses recent findings on how memory T cells develop to confer long-term protective immunity.


The impact of organisational change on outcome in an intensive care unit in the United Kingdom

Abstract: Objectives: To study the change in outcome for patients admitted to an intensive care unit following the establishment of a team of resident medical staff and a change from an "open" to a "closed" organisational format.

Abstract: Design: Database review of prospectively collected data.

Abstract: Setting: Intensive care unit of a postgraduate teaching hospital.

Abstract: Subjects: 1134 admissions to the intensive care unit over a 3-year period, of whom 476 (42%) followed elective surgery.

Abstract: Main outcome measure: Hospital mortality corrected for illness severity by using the APACHE II scoring system.

Abstract: Results: Crude hospital mortality fell from 28% before the changes to 20% afterwards (P=0.01).

Abstract: With correction for case-mix factors, the probability of death after the changes was reduced by almost half (OR 0.51; CI 0.32, 0.82, P=0.005).

Abstract: Conclusion: A "closed" format of organisation of the delivery of care may result in improved outcomes for patients admitted to intensive care units.


Monitoring effectiveness and safety of Tafamidis in transthyretin amyloidosis in Italy: a longitudinal multicenter study in a non-endemic area

Abstract: Tafamidis is a transthyretin (TTR) stabilizer able to prevent TTR tetramer dissociation.

Abstract: There have been a few encouraging studies on Tafamidis efficacy in early-onset inherited transthyretin amyloidosis (ATTR) due to Val30Met mutation.

Abstract: However, less is known about its efficacy in later disease stages and in non-Val30Met mutations.

Abstract: We performed a multi-center observational study on symptomatic ATTR patients prescribed to receive Tafamidis.

Abstract: We followed up patients according to a standardized protocol including general medical, cardiological and neurological assessments at baseline and every 6 months up to 3 years.

Abstract: Sixty-one (42 males) patients were recruited.

Abstract: Only 28 % of enrolled subjects had the common Val30Met mutation, mean age of onset was remarkably late (59 years) and 18 % was in advanced disease stage at study entry.

Abstract: Tafamidis proved safe and well-tolerated.

Abstract: One-third of patients did not show significant progression along 36 months, independently from mutation type and disease stage.

Abstract: Neurological function worsened particularly in the first 6 months but progression slowed significantly thereafter.

Abstract: Autonomic function remained stable in 33 %, worsened in 56 % and improved in 10 %.

Abstract: Fifteen percent of patients showed cardiac disease progression and 30 % new onset of cardiomyopathy.

Abstract: Overall, Tafamidis was not able to prevent functional progression of the disease in 23 (43 %) subjects, including 16 patients who worsened in their walking ability and 12 patients who reached a higher NYHA score during the follow-up period.

Abstract: A higher mBMI at baseline was associated with better preservation of neurological function.

Abstract: In conclusion, neuropathy and cardiomyopathy progressed in a significant proportion of patients despite treatment.

Abstract: However, worsening of neurological function slowed after the first 6 months and also subjects with more advanced neuropathy, as well as patients with non-Val30Met mutation, benefited from treatment.

Abstract: Body weight preservation is an important favorable prognostic factor.


The Spliceosome: Design Principles of a Dynamic RNP Machine

Abstract: Ribonucleoproteins (RNPs) mediate key cellular functions such as gene expression and its regulation.

Abstract: Whereas most RNP enzymes are stable in composition and harbor preformed active sites, the spliceosome, which removes noncoding introns from precursor messenger RNAs (pre-mRNAs), follows fundamentally different strategies.

Abstract: In order to provide both accuracy to the recognition of reactive splice sites in the pre-mRNA and flexibility to the choice of splice sites during alternative splicing, the spliceosome exhibits exceptional compositional and structural dynamics that are exploited during substrate-dependent complex assembly, catalytic activation, and active site remodeling.