Transient receptor potential channels as drug targets: from the science of basic research to the art of medicine.

Abstract: The large Trp gene family encodes transient receptor potential (TRP) proteins that form novel cation-selective ion channels.

Abstract: In mammals, 28 Trp channel genes have been identified.

Abstract: TRP proteins exhibit diverse permeation and gating properties and are involved in a plethora of physiologic functions with a strong impact on cellular sensing and signaling pathways.

Abstract: Indeed, mutations in human genes encoding TRP channels, the so-called "TRP channelopathies," are responsible for a number of hereditary diseases that affect the musculoskeletal, cardiovascular, genitourinary, and nervous systems.

Abstract: This review gives an overview of the functional properties of mammalian TRP channels, describes their roles in acquired and hereditary diseases, and discusses their potential as drug targets for therapeutic intervention.


Identification of genes associated with the astrocyte-specific gene Gfap during astrocyte differentiation.

Abstract: Chromosomes and genes are non-randomly arranged within the mammalian cell nucleus, and gene clustering is of great significance in transcriptional regulation.

Abstract: However, the relevance of gene clustering and their expression during the differentiation of neural precursor cells (NPCs) into astrocytes remains unclear.

Abstract: We performed a genome-wide enhanced circular chromosomal conformation capture (e4C) to screen for genes associated with the astrocyte-specific gene glial fibrillary acidic protein (Gfap) during astrocyte differentiation.

Abstract: We identified 18 genes that were specifically associated with Gfap and expressed in NPC-derived astrocytes.

Abstract: Our results provide additional evidence for the functional significance of gene clustering in transcriptional regulation during NPC differentiation.


Ketamine reduces LPS-induced HMGB1 via activation of the Nrf2/HO-1 pathway and NF-κB suppression.

Abstract: BACKGROUND Ketamine, as an anesthetic agent, has an anti-inflammatory effect.

Abstract: In the present study, we investigated whether ketamine inhibits release of high mobility group box 1 (HMGB1), a late-phase cytokine of sepsis, in lipopolysaccharide (LPS)-stimulated macrophages through heme oxygenase-1 (HO-1) induction.

Abstract: METHODS Macrophages were preincubated with various concentrations of ketamine and then treated with LPS (1 μg/mL).

Abstract: The cell culture supernatants were collected to measure inflammatory mediators (HMGB1, nitric oxide, tumor necrosis factor-α, and interleukin 1β) by enzyme-linked immunosorbent assay.

Abstract: Moreover, HO-1 protein expression, the phosphorylation and degradation of IκB-α, and the nuclear translocation of nuclear factor E2-related factor 2 and nuclear factor κB (NF-κB) p65 were tested by Western blot analysis.

Abstract: In addition, to further identify the role of HO-1 in this process, tin protoporphyrin (SnPP), an HO-1 inhibitor, was used.

Abstract: RESULTS Ketamine treatment dose-dependently attenuated the increased levels of proinflammatory mediators (HMGB1, nitric oxide, tumor necrosis factor α, and interleukin 1β) and increased the HO-1 protein expression in LPS-activated macrophages.

Abstract: Furthermore, ketamine suppressed the phosphorylation and degradation of IκB-α as well as the LPS-stimulated nuclear translocation of NF-κB p65 in macrophages.

Abstract: In addition, the present study also demonstrated that ketamine induced HO-1 expression through the nuclear translocation of nuclear factor E2-related factor 2 in macrophages.

Abstract: The effects of ketamine on LPS-induced proinflammatory cytokines production were partially reversed by the HO inhibitor tin protoporphyrin (SnPP).

Abstract: CONCLUSION Ketamine inhibits the release of HMGB1 in LPS-stimulated macrophages, and this effect is at least partly mediated by the activation of the Nrf2/HO-1 pathway and NF-κB suppression.


Association Between Early Screening for Patent Ductus Arteriosus and In-Hospital Mortality Among Extremely Preterm Infants.

Abstract: IMPORTANCE There is currently no consensus for the screening and treatment of patent ductus arteriosus (PDA) in extremely preterm infants.

Abstract: Less pharmacological closure and more supportive management have been observed without evidence to support these changes.

Abstract: OBJECTIVE To evaluate the association between early screening echocardiography for PDA and in-hospital mortality.

Abstract: DESIGN, SETTING, AND PARTICIPANTS Comparison of screened and not screened preterm infants enrolled in the EPIPAGE 2 national prospective population-based cohort study that included all preterm infants born at less than 29 weeks of gestation and hospitalized in 68 neonatal intensive care units in France from April through December 2011.

Abstract: Two main analyses were performed to adjust for potential selection bias, one using propensity score matching and one using neonatal unit preference for early screening echocardiography as an instrumental variable.

Abstract: EXPOSURES Early screening echocardiography before day 3 of life.

Abstract: MAIN OUTCOMES AND MEASURES The primary outcome was death between day 3 and discharge.

Abstract: The secondary outcomes were major neonatal morbidities (pulmonary hemorrhage, severe bronchopulmonary dysplasia, severe cerebral lesions, and necrotizing enterocolitis).

Abstract: RESULTS Among the 1513 preterm infants with data available to determine exposure, 847 were screened for PDA and 666 were not; 605 infants from each group could be paired.

Abstract: Exposed infants were treated for PDA more frequently during their hospitalization than nonexposed infants (55.1% vs 43.1%; odds ratio [OR], 1.62 [95% CI, 1.31 to 2.00]; absolute risk reduction [ARR] in events per 100 infants, -12.0 [95% CI, -17.3 to -6.7).

Abstract: Exposed infants had a lower hospital death rate (14.2% vs 18.5% ; OR, 0.73 [95% CI, 0.54 to 0.98]; ARR, 4.3 [95% CI, 0.3 to 8.3]) and a lower rate of pulmonary hemorrhage (5.6% vs 8.9%; OR, 0.60 [95% CI, 0.38 to 0.95]; ARR, 3.3 [95% CI, 0.4 to 6.3]).

Abstract: No differences in rates of necrotizing enterocolitis, severe bronchopulmonary dysplasia, or severe cerebral lesions were observed.

Abstract: In the overall cohort, instrumental variable analysis yielded an adjusted OR for in-hospital mortality of 0.62 [95% CI, 0.37 to 1.04].

Abstract: CONCLUSIONS AND RELEVANCE In this national population-based cohort of extremely preterm infants, screening echocardiography before day 3 of life was associated with lower in-hospital mortality and likelihood of pulmonary hemorrhage but not with differences in necrotizing enterocolitis, severe bronchopulmonary dysplasia, or severe cerebral lesions.

Abstract: However, results of the instrumental variable analysis leave some ambiguity in the interpretation, and longer-term evaluation is needed to provide clarity.


Role of birthweight in the etiology of breast cancer.

Abstract: Breast cancer may originate in utero.

Abstract: We reviewed the available evidence on the association between birthweight and the risk of breast cancer.

Abstract: To date, 26 research papers addressing this issue have been published.

Abstract: The majority of studies identified a positive link between birthweight and premenopausal, but not postmenopausal, breast cancer.

Abstract: The relative risk estimate for breast cancer comparing women with high birthweight to women with low birthweight combining all studies including both pre- and postmenopausal breast cancer was 1.23 (95% confidence interval 1.13-1.34).

Abstract: The mechanisms underlying this association likely include elevated levels of growth factors that may increase the number of susceptible stem cells in the mammary gland or initiate tumors through DNA mutations.

Abstract: Loss of imprinting (LOI) of growth hormone genes relevant for intrauterine growth, such as insulin-like growth factor 2 (IGF2), leads to abnormally high levels of these hormones evidenced by high birthweight.

Abstract: LOI of IGF2 has also been found in mammary tumor tissue.

Abstract: The role of environmental factors that stimulate such epigenetic regulation of gene expression remains to be elucidated.


An activator of the cAMP/PKA/CREB pathway promotes osteogenesis from human mesenchymal stem cells.

Abstract: Mesenchymal stem cells (MSCs) are multipotent adult stem cells capable of differentiating along the osteoblast, adipocyte, and chondrocyte lineages.

Abstract: Regulation of MSCs differentiation may be a useful tool for regenerative medicine and cell-based therapy.

Abstract: The discovery of small molecule that activates the osteogenic differentiation of MSCs could aid in the development of a new anabolic drug for osteoporosis treatment.

Abstract: We identified CW008, a derivative of pyrazole-pyridine, that stimulates osteoblast differentiation of human MSCs and increases bone formation in ovariectomized mice.

Abstract: CW008 promotes osteogenesis by activating cAMP/PKA/CREB signaling pathway and inhibiting leptin secretion.

Abstract: These results suggest that CW008 is an agonist of cAMP/PKA/CREB pathway in osteogenic differentiation and that application of CW008 may be useful for the treatment of bone-related diseases and for the study of bone biology.


Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus.

Abstract: BACKGROUND Epidemiological and basic science evidence suggests that magnesium sulphate before birth may be neuroprotective for the fetus.

Abstract: OBJECTIVES To assess the effects of magnesium sulphate as a neuroprotective agent when given to women considered at risk of preterm birth.

Abstract: SEARCH STRATEGY We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2008).

Abstract: SELECTION CRITERIA Randomised controlled trials of antenatal magnesium sulphate therapy in women threatening or likely to give birth at less than 37 weeks' gestational age.

Abstract: For one subgroup analysis, studies were broadly categorised by the primary intent of the study into "neuroprotective intent", or "other intent (maternal neuroprotective - pre-eclampsia)", or "other intent (tocolytic)".

Abstract: DATA COLLECTION AND ANALYSIS At least two authors assessed trial eligibility and quality, and extracted data.

Abstract: MAIN RESULTS Five trials (6145 babies) were eligible for this review.

Abstract: Antenatal magnesium sulphate therapy given to women at risk of preterm birth substantially reduced the risk of cerebral palsy in their child (Relative Risk (RR) 0.68; 95% Confidence interval (CI) 0.54 to 0.87; five trials; 6145 infants).

Abstract: There was also a significant reduction in the rate of substantial gross motor dysfunction (RR 0.61; 95% CI 0.44 to 0.85; four trials; 5980 infants).

Abstract: No statistically significant effect of antenatal magnesium sulphate therapy was detected on paediatric mortality (RR 1.04; 95% CI 0.92 to 1.17; five trials; 6145 infants), or on other neurological impairments or disabilities in the first few years of life.

Abstract: Overall there were no significant effects of antenatal magnesium therapy on combined rates of mortality with cerebral palsy, although there were significant reductions for the neuroprotective groups RR 0.85; 95% CI 0.74 to 0.98; four trials; 4446 infants, but not for the other intent subgroups.

Abstract: There were higher rates of minor maternal side effects in the magnesium groups, but no significant effects on major maternal complications.

Abstract: AUTHORS' CONCLUSIONS The neuroprotective role for antenatal magnesium sulphate therapy given to women at risk of preterm birth for the preterm fetus is now established.

Abstract: The number of women needed to be treated to benefit one baby by avoiding cerebral palsy is 63 (95% confidence interval 43 to 87).

Abstract: Given the beneficial effects of magnesium sulphate on substantial gross motor function in early childhood, outcomes later in childhood should be evaluated to determine the presence or absence of later potentially important neurological effects, particularly on motor or cognitive function.


The growing landscape of lysine acetylation links metabolism and cell signalling

Abstract: Lysine acetylation is a conserved protein post-translational modification that links acetyl-coenzyme A metabolism and cellular signalling.

Abstract: Recent advances in the identification and quantification of lysine acetylation by mass spectrometry have increased our understanding of lysine acetylation, implicating it in many biological processes through the regulation of protein interactions, activity and localization.

Abstract: In addition, proteins are frequently modified by other types of acylations, such as formylation, butyrylation, propionylation, succinylation, malonylation, myristoylation, glutarylation and crotonylation.

Abstract: The intricate link between lysine acylation and cellular metabolism has been clarified by the occurrence of several such metabolite-sensitive acylations and their selective removal by sirtuin deacylases.

Abstract: These emerging findings point to new functions for different lysine acylations and deacylating enzymes and also highlight the mechanisms by which acetylation regulates various cellular processes.


COMPASS, a histone H3 (Lysine 4) methyltransferase required for telomeric silencing of gene expression.

Abstract: The trithorax (Trx) family of proteins is required for maintaining a specific pattern of gene expression in some organisms.

Abstract: Recently we reported the isolation and characterization of COMPASS, a multiprotein complex that includes the Trx-related protein Set1 of the yeast Saccharomyces cerevisiae.

Abstract: Here we report that COMPASS catalyzes methylation of the fourth lysine of histone H3 in vitro.

Abstract: Set1 and several other components of COMPASS are also required for histone H3 methylation in vivo and for transcriptional silencing of a gene located near a chromosome telomere.


Free water elimination diffusion tractography: A comparison with conventional and fluid-attenuated inversion recovery, diffusion tensor imaging acquisitions.

Abstract: PURPOSE White matter tractography reconstructions using conventional diffusion tensor imaging (DTI) near cerebrospinal fluid (CSF) spaces are often adversely affected by CSF partial volume effects (PVEs).

Abstract: This study evaluates the ability of free water elimination (FWE) DTI methods to minimize the PVE of CSF for deterministic tractography applications.

Abstract: MATERIALS AND METHODS Ten healthy individuals were scanned with "traditional," FLAIR (fluid-attenuated inversion recovery), and FWE DTI scans.

Abstract: The fornix, corpus callosum, and cingulum bundles were reconstructed using deterministic tractography.

Abstract: The FWE DTI scan was performed twice to separately match total acquisition time (long FWE) and number of measurements (encoding directions, short FWE) to the FLAIR and "traditional" DTI scans.

Abstract: PVE resolution was determined based on reconstructed tract volume.

Abstract: All reconstructions underwent blinded review for anatomical correctness, symmetry, and completeness.

Abstract: RESULTS Reconstructions of the fornix demonstrated that the FWE and FLAIR scans produce more complete, anatomically plausible reconstructions than "traditional" DTI.

Abstract: Additionally, the tract reconstructions using FWE-DTI were significantly larger than when FLAIR was used with DTI (P < 0.0005).

Abstract: FLAIR and the FWE methods led to signal-to-noise ratio (SNR) reductions of 33% and 11%, respectively, compared with conventional DTI.

Abstract: The long and short FWE acquisitions did not significantly (P ≥ 0.31) differ from one another for any of the reconstructed tracts.

Abstract: CONCLUSION The FWE diffusion model overcomes CSF PVE without the time, SNR, and volumetric coverage penalties inherent to FLAIR DTI.


A systematic review of randomized controlled trials of acupuncture in the treatment of depression.

Abstract: BACKGROUND Acupuncture has become a popular complementary and alternative treatment approach.

Abstract: This review examined the randomized controlled trials (RCTs) examining the effects of acupuncture treatment of depression.

Abstract: METHODS RCTs of the treatment of depression with acupuncture were located using MEDLINE, Allied and Complementary Medicine and the Cochrane Central Register of Controlled Trials.

Abstract: The methodology of RCTs was assessed using the Jadad criteria, and elements of research design, i.e., randomization, blinding, assessment of attrition rates, were quantified for systematic comparisons among studies.

Abstract: RESULTS Among the 9 RCTs examined, five were deemed to be of low quality based upon Jadad criteria.

Abstract: The odds ratios derived from comparing acupuncture with control conditions within the RCTs suggests some evidence for the utility of acupuncture in depression.

Abstract: General trends suggest that acupuncture modalities were as effective as antidepressants employed for treatment of depression in the limited studies available for comparison.

Abstract: However, placebo acupuncture treatment was often no different from intended verum acupuncture.

Abstract: LIMITATIONS The RCTs extracted were limited by small sample sizes, imprecise enrollment criteria, problems with randomization, blinding, brief duration of study and lack of longitudinal follow-up.

Abstract: CONCLUSIONS Despite the findings that the odds ratios of existing literature suggest a role for acupuncture in the treatment of depression, the evidence thus far is inconclusive.

Abstract: However, efforts are being made to standardize complementary approaches to treat depression, and further systematized research into their use is warranted.


Genome-Wide Gene-Sodium Interaction Analyses on Blood Pressure: The Genetic Epidemiology Network of Salt-Sensitivity Study.

Abstract: We performed genome-wide analyses to identify genomic loci that interact with sodium to influence blood pressure (BP) using single-marker-based (1 and 2 df joint tests) and gene-based tests among 1876 Chinese participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study.

Abstract: Among GenSalt participants, the average of 3 urine samples was used to estimate sodium excretion.

Abstract: Nine BP measurements were taken using a random zero sphygmomanometer.

Abstract: A total of 2.05 million single-nucleotide polymorphisms were imputed using Affymetrix 6.0 genotype data and the Chinese Han of Beijing and Japanese of Tokyo HapMap reference panel.

Abstract: Promising findings (P<1.00×10(-4)) from GenSalt were evaluated for replication among 775 Chinese participants of the Multi-Ethnic Study of Atherosclerosis (MESA).

Abstract: Single-nucleotide polymorphism and gene-based results were meta-analyzed across the GenSalt and MESA studies to determine genome-wide significance.

Abstract: The 1 df tests identified interactions for UST rs13211840 on diastolic BP (P=3.13×10(-9)).

Abstract: The 2 df tests additionally identified associations for CLGN rs2567241 (P=3.90×10(-12)) and LOC105369882 rs11104632 (P=4.51×10(-8)) with systolic BP.

Abstract: The CLGN variant rs2567241 was also associated with diastolic BP (P=3.11×10(-22)) and mean arterial pressure (P=2.86×10(-15)).

Abstract: Genome-wide gene-based analysis identified MKNK1 (P=6.70×10(-7)), C2orf80 (P<1.00×10(-12)), EPHA6 (P=2.88×10(-7)), SCOC-AS1 (P=4.35×10(-14)), SCOC (P=6.46×10(-11)), CLGN (P=3.68×10(-13)), MGAT4D (P=4.73×10(-11)), ARHGAP42 (P≤1.00×10(-12)), CASP4 (P=1.31×10(-8)), and LINC01478 (P=6.75×10(-10)) that were associated with at least 1 BP phenotype.

Abstract: In summary, we identified 8 novel and 1 previously reported BP loci through the examination of single-nucleotide polymorphism and gene-based interactions with sodium.


Percentile curves for hemoglobin and red cell volume in infancy and childhood.

Abstract: Percentile curves were calculated for hemoglobin and mean corpuscular volume in children between 0.5 and 16 years of age.

Abstract: The curves were derived from several populations of non-indigent white children who lived near sea level.

Abstract: Subjects were excluded from the reference population if they had laboratory evidence of iron deficiency, thalassemia minor, and/or hemoglobinopathy.

Abstract: The final reference populations included 9,946 children for the derivation of the hemoglobin curves and 2,314 for the MCV curves.

Abstract: The percentile curves should be particularly applicable to the diagnosis and screening of iron deficiency and thalassemia minor.


Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women.

Abstract: Type 2 diabetes frequently results from progressive failure of pancreatic beta-cell function in the presence of chronic insulin resistance.

Abstract: We tested whether chronic amelioration of insulin resistance would preserve pancreatic beta-cell function and delay or prevent the onset of type 2 diabetes in high-risk Hispanic women.

Abstract: Women with previous gestational diabetes were randomized to placebo (n = 133) or the insulin-sensitizing drug troglitazone (400 mg/day; n = 133) administered in double-blind fashion.

Abstract: Fasting plasma glucose was measured every 3 months, and oral glucose tolerance tests (OGTTs) were performed annually to detect diabetes.

Abstract: Intravenous glucose tolerance tests (IVGTTs) were performed at baseline and 3 months later to identify early metabolic changes associated with any protection from diabetes.

Abstract: Women who did not develop diabetes during the trial returned for OGTTs and IVGTTs 8 months after study medications were stopped.

Abstract: During a median follow-up of 30 months on blinded medication, average annual diabetes incidence rates in the 236 women who returned for at least one follow-up visit were 12.1 and 5.4% in women assigned to placebo and troglitazone, respectively (P < 0.01).

Abstract: Protection from diabetes in the troglitazone group 1) was closely related to the degree of reduction in endogenous insulin requirements 3 months after randomization, 2) persisted 8 months after study medications were stopped, and 3) was associated with preservation of beta-cell compensation for insulin resistance.

Abstract: Treatment with troglitazone delayed or prevented the onset of type 2 diabetes in high-risk Hispanic women.

Abstract: The protective effect was associated with the preservation of pancreatic beta-cell function and appeared to be mediated by a reduction in the secretory demands placed on beta-cells by chronic insulin resistance.


Androgen regulation of micro-RNAs in prostate cancer.

Abstract: BACKGROUND Androgens play a critical role in the growth of both androgen dependent and castration-resistant prostate cancer (CRPC).

Abstract: Only a few micro-RNAs (miRNAs) have been suggested to be androgen regulated.

Abstract: We aim to identify androgen regulated miRNAs.

Abstract: METHODS We utilized LNCaP derived model, we have established, and which overexpresses the androgen receptor (AR), the VCaP cell line, and 13 intact-castrated prostate cancer (PC) xenograft pairs, as well as clinical specimens of untreated (PC) and CRPC.

Abstract: The expression of miRNAs was analyzed by microarrays and quantitative RT-PCR (Q-RT-PCR).

Abstract: Transfection of pre-miR-141 and anti-miR-141 was also used.

Abstract: RESULTS Seventeen miRNAs were > 1.5-fold up- or downregulated upon dihydrotestosterone (DHT) treatment in the cell lines, and 42 after castration in the AR-positive xenografts.

Abstract: Only four miRNAs (miR-10a, miR-141, miR-150*, and miR-1225-5p) showed similar androgen regulation in both cell lines and xenografts.

Abstract: Of those, miR-141 was found to be expressed more in PC and CRPC compared to benign prostate hyperplasia.

Abstract: Additionally, the overexpression of miR-141 enhanced growth of parental LNCaP cells while inhibition of miR-141 by anti-miR-141 suppressed the growth of the LNCaP subline overexpressing AR.

Abstract: CONCLUSIONS Only a few miRNAs were found to be androgen-regulated in both cell lines and xenografts models.

Abstract: Of those, the expression of miR-141 was upregulated in cancer.

Abstract: The ectopic overexpression of miR-141 increased growth of LNCaP cell suggesting it may contribute to the progression of PC.


Relationship between drug treatment services, retention, and outcomes.

Abstract: OBJECTIVE This longitudinal study conducted path analyses to examine the relationships between treatment processes and outcomes among patients in community-based drug treatment programs.

Abstract: METHODS A total of 1,939 patients from 36 outpatient drug-free and residential treatment programs in 13 California counties were assessed at intake, discharge, three months after admission, and nine months after admission.

Abstract: Path analyses were conducted to relate the quantity and quality of services that were received in the first three months of treatment to treatment retention and outcomes at the nine-month follow-up.

Abstract: Patients were determined to have a favorable outcome if for at least 30 days before the follow-up assessment they did not use drugs, were not involved in criminal activity, and lived in the community.

Abstract: The path analyses controlled for patients' baseline characteristics.

Abstract: RESULTS Greater service intensity and satisfaction were positively related to either treatment completion or longer treatment retention, which in turn was related to favorable treatment outcomes.

Abstract: Patients with greater problem severity received more services and were more likely to be satisfied with treatment.

Abstract: These patterns were similar for patients regardless of whether they were treated in outpatient drug-free programs or residential programs.

Abstract: CONCLUSIONS The positive association between process measures-that is, greater levels of service intensity, satisfaction, and either treatment completion or retention-and treatment outcome strongly suggests that improvements in these key elements of the treatment process will improve treatment outcomes.


Breast cancer mortality trends in the United States according to estrogen receptor status and age at diagnosis.

Abstract: PURPOSE Since 1990, overall breast cancer mortality rates in the United States decreased 24%.

Abstract: This decline has been attributed to mammography screening and adjuvant systemic therapy.

Abstract: However, the efficacy of these modalities may depend on estrogen receptor (ER) expression and age.

Abstract: We therefore examined breast cancer mortality trends in the United States according to ER status and age.

Abstract: METHODS Using the Surveillance, Epidemiology, and End Results (SEER) program (1990-2003), we calculated trends in incidence-based mortality (IBM), annual hazard rates for breast cancer deaths after diagnosis, and relative hazard rates for women with ER-positive and ER-negative tumors.

Abstract: Relative hazard rates were assessed with Cox proportional hazards models, adjusted for stage and grade, and stratified by age at diagnosis.

Abstract: RESULTS During the study period, IBM and annual hazard rates for breast cancer deaths decreased among women with ER-positive and ER-negative tumors, although declines were greater for those with ER-positive tumors.

Abstract: Among women younger than 70 years, relative hazard rates declined 38% for those with ER-positive tumors versus 19% for those with ER-negative tumors.

Abstract: Among women 70 years or older, relative hazard rates declined 14% for those with ER-positive tumors versus no significant decline for those with ER-negative tumors.

Abstract: CONCLUSION In the United States, breast cancer mortality rates have declined among women with ER-positive and ER-negative tumors, with greater declines among younger women and those with ER-positive tumors.

Abstract: Although mortality in all groups remains unacceptably high, additional emphasis should be placed on improving outcomes of breast cancer patients older than 70 years and those of all ages with ER-negative tumors.


An adenovirus mutant that replicates selectively in p53-deficient human tumor cells.

Abstract: The human adenovirus E1B gene encodes a 55-kilodalton protein that inactivates the cellular tumor suppressor protein p53.

Abstract: Here it is shown that a mutant adenovirus that does not express this viral protein can replicate in and lyse p53-deficient human tumor cells but not cells with functional p53.

Abstract: Ectopic expression of the 55-kilodalton EIB protein in the latter cells rendered them sensitive to infection with the mutant virus.

Abstract: Injection of the mutant virus into p53-deficient human cervical carcinomas grown in nude mice caused a significant reduction in tumor size and caused complete regression of 60 percent of the tumors.

Abstract: These data raise the possibility that mutant adenoviruses can be used to treat certain human tumors.


Immune reconstitution after cord blood transplantation: peculiarities, clinical implications and management strategies.

Abstract: Umbilical cord blood (UCB) is now widely used as an alternative hematopoietic stem cell source for patients lacking closely matched related or unrelated adult donors.

Abstract: UCB transplantation has traditionally been associated with delayed engraftment, poor immune reconstitution and consequent increased risk of infection.

Abstract: More recent clinical studies, however, suggest that conditioning regimens and in particular the omission of in vivo T-cell depletion may play a crucial role in post-transplant T-cell expansion, facilitating a uniquely rapid immune recovery after UCB transplantation.

Abstract: The peculiar characteristics of UCB cells, the importance of thymic function and the role of conditioning regimens and graft-versus-host disease influencing immune reconstitution are described.

Abstract: The last part of the review reports available data on UCB, as well as third-party peripheral blood derived anti-viral cell therapy, which provides a novel approach to rescue UCB recipients with viral complications in the post-transplant period.


OVEREXPRESSION OF BOTH CLOCK AND BMAL1 INHIBITS ENTRY TO S PHASE IN HUMAN COLON CANCER CELLS.

Abstract: Many physiological, biochemical and behavioral processes operate under the circadian rhythm, which is generated by an internal time-keeping mechanism commonly referred to as the biological clock, in almost all organisms from bacteria to mammals.

Abstract: The core circadian oscillator is composed of an autoregulatory transcription-translation feedback loop, in which CLOCK and BMAL1 are positive regulators.

Abstract: A cell has two mechanisms, "cell cycle" and "cell rhythm", the relationship between which remains controversial.

Abstract: Therefore, the aim of this study was to explore the effect of Clock and Bmal1 on cell cycle, especially on the G1 phase, using vectors with the tetracycline operator-repressor system.

Abstract: The present study revealed that simultaneous induction of Bmal1 and Clock had an influential effect on the cell cycle in SW480/T-REx/Clock/Bmal1 cells, in which both Clock and Bmal1 could be induced by tetracycline.

Abstract: The observation that induction of both Clock and Bmal1 inhibited cell growth and the significant increase of the G1 phase proportion of in SW480/T-REx/Clock/Bmal1 cells indicated that entry from the G1 to S phase was inhibited by the induction of Clock and Bmal1.

Abstract: Furthermore, overexpression of Clock and Bmal1 prevented the cells from entering into the G2/M phase induced by Paclitaxel, and made the cells more resistant to the agent.

Abstract: In conclusion, we found that overexpression of both Clock and Bmal1 suppressed cell growth.

Abstract: In addition, the present study raised the possibility that Clock and Bmal1 may in part play a role in preventing the cells from entering G1 to S phase of cell cycle via suppression of CyclinD1 expression, and thus acquiring resistance to Paclitaxel.


Composition of gall bladder stones associated with octreotide: response to oral ursodeoxycholic acid.

Abstract: Octreotide, an effective treatment for acromegaly, induces gall bladder stones in 13-60% of patients.

Abstract: Because knowledge of stone composition is essential for studies of their pathogenesis, treatment, and prevention, this was investigated by direct and indirect methods in 14 octreotide treated acromegalic patients with gall stones.

Abstract: Chemical analysis of gall stones retrieved at cholecystectomy from two patients, showed that they contained 71% and 87% cholesterol by weight.

Abstract: In the remaining 12 patients, localised computed tomography of the gall bladder showed that eight had stones with maximum attenuation scores of < 100 Hounsfield units (values of < 100 HU predict cholesterol rich, dissolvable stones).

Abstract: Gall bladder bile was obtained by ultrasound guided, fine needle puncture from six patients.

Abstract: All six patients had supersaturated bile (mean (SEM) cholesterol saturation index of 1.19 (0.08) (range 1.01-1.53)) and all had abnormally rapid cholesterol microcrystal nucleation times (< 4 days (range 1-4)), whilst in four, the bile contained cholesterol microcrystals immediately after sampling.

Abstract: Of the 12 patients considered for oral ursodeoxycholic acid (UDCA) treatment, two had a blocked cystic duct and were not started on UDCA while one was lost to follow up.

Abstract: After one year of treatment, five of the remaining nine patients showed either partial (n = 3) or complete (n = 2) gall stone dissolution, suggesting that their stones were cholesterol rich.

Abstract: This corresponds, by actuarial (life table) analysis, to a combined gall stone dissolution rate of 58.3 (15.9%).

Abstract: In conclusion, octreotide induced gall stones are generally small, multiple, and cholesterol rich although, in common with spontaneous gall stone disease, at presentation some patients will have a blocked cystic duct and some gall stones containing calcium.


Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from a randomized vehicle-controlled phase III study in Europe.

Abstract: BACKGROUND Imiquimod is an immune response modifier that acts through toll-like receptor 7 to induce cytokine production and a subsequent innate and adaptive cell-mediated immune response.

Abstract: Clinical studies have demonstrated clinical and histological clearance of superficial basal cell carcinoma (sBCC) after treatment with imiquimod 5% cream.

Abstract: OBJECTIVES To evaluate the safety and clinical efficacy of imiquimod (Aldaratrade mark; 3M Pharmaceuticals, St Paul, MN, U.S.A.) 5% cream for the treatment of sBCC in a multicentre, randomized, parallel, vehicle-controlled, double-blind, phase III clinical study conducted at 26 centres in Europe.

Abstract: METHODS Subjects who had at least one histologically confirmed sBCC tumour were randomized to apply imiquimod or vehicle cream to the target tumour once daily, seven times per week (7 x/week) for 6 weeks.

Abstract: The target tumour location was identified with an indelible ink mark before treatment initiation.

Abstract: The treated tumour site was clinically assessed for treatment response at 12 weeks post-treatment and was then excised for histological evaluation.

Abstract: Efficacy assessments included the composite response rates (proportion of subjects with clinical and histological clearance) and response rates solely based on histology (proportion of subjects with histological clearance).

Abstract: Safety assessments, which included adverse events and scoring of local skin reactions (LSRs), were carried out throughout the study.

Abstract: RESULTS In total, 166 subjects were enrolled in this study.

Abstract: For the intent-to-treat dataset, there was a statistically significant difference between imiquimod and vehicle groups for both composite clearance rates (clinical and histological assessments) and histological clearance rates.

Abstract: Composite clearance was demonstrated in 77% and 6% of subjects treated with imiquimod and vehicle cream, respectively.

Abstract: Histological clearance was demonstrated in 80% and 6% of subjects treated with imiquimod and vehicle cream, respectively.

Abstract: The most frequently reported safety findings were investigator-assessed LSRs and spontaneous reports by subjects of application site reactions, which occurred more frequently in the imiquimod group than in the vehicle group.

Abstract: CONCLUSIONS Imiquimod 5% cream administered 7 x/week for 6 weeks is a safe and effective treatment for sBCC when compared with vehicle cream.


Changing the course of pancreatic cancer--Focus on recent translational advances.

Abstract: In the past decade, insightful preclinical research has led to important breakthroughs in our understanding of pancreatic cancer.

Abstract: Even though the vast majority of pancreatic cancers are KRAS mutated, not all pancreatic cancer tumors are "KRAS equal"; there seems to be varying dependencies on the KRAS pathway.

Abstract: While KRAS-targeting therapies have been disappointing in the clinic, 'synthetic lethal' approaches hold promise in this setting.

Abstract: The pancreatic cancer stromal microenvironment appears to have contradictory roles.

Abstract: While there is evidence to suggest that stromal barrier prevents drug delivery, in other circumstances, stroma can play a protective role and its disruption enhances tumor dissemination.

Abstract: Clinical trials aimed at manipulating the various stromal components are in progress.

Abstract: BRCA mutation-related pancreatic tumors illustrate a unique subtype with enhanced susceptibility to DNA damaging agents and PARP-inhibition.

Abstract: DNA repair defects in cancer extend beyond germ line BRCA mutation and may extend the indications for DNA repair-targeting agents.

Abstract: Immune strategies are an area of active investigation in pancreatic cancer.

Abstract: Although the initial trials of single-agent checkpoint inhibitors have been negative, combinational approaches using immune-modifying agents and vaccines appear promising and goal is to identify an 'immune-therapy responsive' profile in pancreatic cancer.


Swc2 is a widely conserved H2AZ-binding module essential for ATP-dependent histone exchange

Abstract: The histone variant H2AZ is incorporated preferentially at specific locations in chromatin to modulate chromosome functions.

Abstract: In Saccharomyces cerevisiae, deposition of histone H2AZ is mediated by the multiprotein SWR1 complex, which catalyzes ATP-dependent exchange of nucleosomal histone H2A for H2AZ.

Abstract: Here, we define interactions between SWR1 components and H2AZ, revealing a link between the ATPase domain of Swr1 and three subunits required for the binding of H2AZ.

Abstract: We discovered that Swc2 binds directly to and is essential for transfer of H2AZ.

Abstract: Swc6 and Arp6 are necessary for the association of Swc2 and for nucleosome binding, whereas other subunits, Swc5 and Yaf9, are required for H2AZ transfer but neither H2AZ nor nucleosome binding.

Abstract: Finally, the C-terminal α-helix of H2AZ is crucial for its recognition by SWR1.

Abstract: These findings provide insight on the initial events of histone exchange.


Detection, characterization, and spontaneous differentiation in vitro of very small embryonic-like putative stem cells in adult mammalian ovary.

Abstract: The present study was undertaken to detect, characterize, and study differentiation potential of stem cells in adult rabbit, sheep, monkey, and menopausal human ovarian surface epithelium (OSE).

Abstract: Two distinct populations of putative stem cells (PSCs) of variable size were detected in scraped OSE, one being smaller and other similar in size to the surrounding red blood cells in the scraped OSE.

Abstract: The smaller 1-3 μm very small embryonic-like PSCs were pluripotent in nature with nuclear Oct-4 and cell surface SSEA-4, whereas the bigger 4-7 μm cells with cytoplasmic localization of Oct-4 and minimal expression of SSEA-4 were possibly the tissue committed progenitor stem cells.

Abstract: Pluripotent gene transcripts of Oct-4, Oct-4A, Nanog, Sox-2, TERT, and Stat-3 in human and sheep OSE were detected by reverse transcriptase-polymerase chain reaction.

Abstract: The PSCs underwent spontaneous differentiation into oocyte-like structures, parthenote-like structures, embryoid body-like structures, cells with neuronal-like phenotype, and embryonic stem cell-like colonies, whereas the epithelial cells transformed into mesenchymal phenotype by epithelial-mesenchymal transition in 3 weeks of OSE culture.

Abstract: Germ cell markers like c-Kit, DAZL, GDF-9, VASA, and ZP4 were immuno-localized in oocyte-like structures.

Abstract: In conclusion, as opposed to the existing view of OSE being a bipotent source of oocytes and granulosa cells, mammalian ovaries harbor distinct very small embryonic-like PSCs and tissue committed progenitor stem cells population that have the potential to develop into oocyte-like structures in vitro, whereas mesenchymal fibroblasts appear to form supporting granulosa-like somatic cells.

Abstract: Research at the single-cell level, including complete gene expression profiling, is required to further confirm whether postnatal oogenesis is a conserved phenomenon in adult mammals.


Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia.

Abstract: Gene expression profiling of 207 uniformly treated children with high-risk B-progenitor acute lymphoblastic leukemia revealed 29 of 207 cases (14%) with markedly elevated expression of CRLF2 (cytokine receptor-like factor 2).

Abstract: Each of the 29 cases harbored a genomic rearrangement of CRLF2: 18 of 29 (62%) had a translocation of the immunoglobulin heavy chain gene IGH@ on 14q32 to CRLF2 in the pseudoautosomal region 1 of Xp22.3/Yp11.3, whereas 10 (34%) cases had a 320-kb interstitial deletion centromeric of CRLF2, resulting in a P2RY8-CRLF2 fusion.

Abstract: One case had both IGH@-CRLF2 and P2RY8-CRLF2, and another had a novel CRLF2 rearrangement.

Abstract: Only 2 of 29 cases were Down syndrome.

Abstract: CRLF2 rearrangements were significantly associated with activating mutations of JAK1 or JAK2, deletion or mutation of IKZF1, and Hispanic/Latino ethnicity (Fisher exact test, P < .001 for each).

Abstract: Within this cohort, patients with CRLF2 rearrangements had extremely poor treatment outcomes compared with those without CRLF2 rearrangements (35.3% vs 71.3% relapse-free survival at 4 years; P < .001).

Abstract: Together, these observations suggest that activation of CRLF2 expression, mutation of JAK kinases, and alterations of IKZF1 cooperate to promote B-cell leukemogenesis and identify these pathways as important therapeutic targets in this disease.


Substrate requirements for ErmC' methyltransferase activity.

Abstract: ErmC' is a methyltransferase that confers resistance to the macrolide-lincosamide-streptogramin B group of antibiotics by catalyzing the methylation of 23S rRNA at a specific adenine residue (A-2085 in Bacillus subtilis; A-2058 in Escherichia coli).

Abstract: The gene for ErmC' was cloned and expressed to a high level in E. coli, and the protein was purified to virtual homogeneity.

Abstract: Studies of substrate requirements of ErmC' have shown that a 262-nucleotide RNA fragment within domain V of B. subtilis 23S rRNA can be utilized efficiently as a substrate for methylation at A-2085.

Abstract: Kinetic studies of the monomethylation reaction showed that the apparent Km of this 262-nucleotide RNA oligonucleotide was 26-fold greater than the value determined for full-size and domain V 23S rRNA.

Abstract: In addition, the Vmax for this fragment also rose sevenfold.

Abstract: A model of RNA-ErmC' interaction involving multiple binding sites is proposed from the kinetic data presented.


Validity of the World Health Organization Adult ADHD Self-Report Scale (ASRS) Screener in a representative sample of health plan members.

Abstract: The validity of the six-question World Health Organization Adult ADHD Self-Report Scale (ASRS) Screener was assessed in a sample of subscribers to a large health plan in the US.

Abstract: A convenience subsample of 668 subscribers was administered the ASRS Screener twice to assess test-retest reliability and then a third time in conjunction with a clinical interviewer for DSM-IV adult ADHD.

Abstract: The data were weighted to adjust for discrepancies between the sample and the population on socio-demographics and past medical claims.

Abstract: Internal consistency reliability of the continuous ASRS Screener was in the range 0.63-0.72 and test-retest reliability (Pearson correlations) in the range 0.58-0.77.

Abstract: A four-category version The ASRS Screener had strong concordance with clinician diagnoses, with an area under the receiver operating characteristic curve (AUC) of 0.90.

Abstract: The brevity and ability to discriminate DSM-IV cases from non-cases make the six-question ASRS Screener attractive for use both in community epidemiological surveys and in clinical outreach and case-finding initiatives.


The body-mass index of twins who have been reared apart.

Abstract: To assess the relative importance of genetic and environmental effects on the body-mass index (weight in kilograms divided by the square of the height in meters), we studied samples of identical and fraternal twins, reared apart or reared together.

Abstract: The samples consisted of 93 pairs of identical twins reared apart, 154 pairs of identical twins reared together, 218 pairs of fraternal twins reared apart, and 208 pairs of fraternal twins reared together.

Abstract: The intrapair correlation coefficients of the values for body-mass index of identical twins reared apart were 0.70 for men and 0.66 for women.

Abstract: These are the most direct estimates of the relative importance of genetic influences (heritability) on the body-mass index, and they were only slightly lower than those for twins reared together in this and earlier studies.

Abstract: Similar estimates were derived from maximum-likelihood model-fitting analyses--0.74 for men and 0.69 for women.

Abstract: Nonadditive genetic variance made a significant contribution to the estimates of heritability, particularly among men.

Abstract: Of the potential environmental influences, only those unique to the individual and not those shared by family members were important, contributing about 30 percent of the variance.

Abstract: Sharing the same childhood environment did not contribute to the similarity of the body-mass index of twins later in life.

Abstract: We conclude that genetic influences on body-mass index are substantial, whereas the childhood environment has little or no influence.

Abstract: These findings corroborate and extend the results of earlier studies of twins and adoptees.


A study of high cell density cultivation process of recombinant Helicobacter pylori multi-epitope vaccine engineering bacteria.

Abstract: OBJECTIVE To establish high cell density cultivation process of recombinant Helicobacter pylori multi-epitope vaccine engineering bacteria BIB.

Abstract: METHODS Based on the results of shake flask fermentation, the process was magnified into volume of a 50 L fermenter to optimize and verify the factors affecting the yield of the target protein, such as the fermentation medium, working seed inoculation amount, inducer concentration, induction starting time, induction duration, inducer adding mode and feeding strategy.

Abstract: RESULTS After activated in modified TB medium at 37°C for 8 h, the BIB working seed was inoculated at 5% (v/v) and was induced for expression for another 11 h by the final concentration of 5 mmol/L lactose.

Abstract: In growth phase, glucose at rate of 80 ml/h was used as carbon source, and in induction phase, glycerol at rate of 40 ml/h was used as carbon source; ammonia water was added dropwise to control pH at about 7.0, and revolution speed is adjusted to control the dissolved oxygen at above 30%; ultimately the output of bacterial body was 70 g/L and protein expression amount was about 32%.

Abstract: CONCLUSION After high cell density cultivation of the recombinant engineering bacteria, expression and yield of the target protein rBIB significantly increased.


Phorbol esters and cytokines regulate the expression of the NEMO-related protein, a molecule involved in a NF-kappa B-independent pathway.

Abstract: The NF-kappaB signaling pathway plays a crucial role in the immune, inflammatory, and apoptotic responses.

Abstract: Recently, we identified the NF-kappaB Essential Modulator (NEMO) as an essential component of this pathway.

Abstract: NEMO is a structural and regulatory subunit of the high molecular kinase complex (IKK) responsible for the phosphorylation of NF-kappaB inhibitors.

Abstract: Data base searching led to the isolation of a cDNA encoding a protein we called NRP (NEMO-related protein), which shows a strong homology to NEMO.

Abstract: Here we show that NRP is present in a novel high molecular weight complex, that contains none of the known members of the IKK complex.

Abstract: Consistently, we could not observe any effect of NRP on NF-kappaB signaling.

Abstract: Nonetheless, we could demonstrate that treatment with phorbol esters induces NRP phosphorylation and decreases its half-life.

Abstract: This phosphorylation event could only be inhibited by K-252a and stauroporin.

Abstract: We also show that de novo expression of NRP can be induced by interferon and tumor necrosis factor alpha and that these two stimuli have a synergistic effect on NRP expression.

Abstract: In addition, we observed that endogenous NRP is associated with the Golgi apparatus.

Abstract: Analogous to NEMO, we find that NRP is associated in a complex with two kinases, suggesting that NRP could play a similar role in another signaling pathway.


Tailoring Nutritional Advice for Mexicans Based on Prevalence Profiles of Diet-Related Adaptive Gene Polymorphisms

Abstract: Diet-related adaptive gene (DRAG) polymorphisms identified in specific populations are associated with chronic disorders in carriers of the adaptive alleles due to changes in dietary and lifestyle patterns in recent times.

Abstract: Mexico's population is comprised of Amerindians (AM) and Mestizos who have variable AM, European (EUR) and African genetic ancestry and an increased risk of nutrition-related chronic diseases.

Abstract: Nutritional advice based on the Mexican genome and the traditional food culture is needed to develop preventive and therapeutic strategies.

Abstract: Therefore, we aimed to provide a prevalence profile of several DRAG polymorphisms in the Mexican population, including Central West (CW) Mexico subpopulations.

Abstract: Geographic heat maps were built using ArcGIS10 (Esri, Redlands, CA, USA) software, based on the published data of the MTHFR C677T (rs1801133), ABCA1 Arg230Cys (rs9282541), APOE T388C (rs429358)/C526T (rs7412), LCT C-13910T (rs4988235) polymorphisms and AMY1 copy number variation (CNV).

Abstract: Also, new data obtained by allelic discrimination-real-time polymerase chain reaction (RT-PCR) assays for the MTHFR, ABCA1, and APOE polymorphisms as well as the AMY1 CNV in the CW Mexico subpopulations with different proportions of AM and EUR ancestry were included.

Abstract: In the CW region, the highest frequency of the MTHFR 677T, ABCA1 230C and APOE ε4 adaptive alleles was observed in the AM groups, followed by Mestizos with intermediate AM ancestry.

Abstract: The LCT-13910T allele frequency was highest in Mestizos-EUR but extremely low in AM, while the AMY1 diploid copy number was 6.82 ± 3.3 copies.

Abstract: Overall, the heat maps showed a heterogeneous distribution of the DRAG polymorphisms, in which the AM groups revealed the highest frequencies of the adaptive alleles followed by Mestizos.

Abstract: Given these genetic differences, genome-based nutritional advice should be tailored in a regionalized and individualized manner according to the available foods and Mexican traditional food culture that may lead to a healthier dietary pattern.


Prevention of Type 2 Diabetes Mellitus Through Inhibition of the Renin-Angiotensin System

Abstract: Type 2 diabetes mellitus is becoming a major health problem associated with excess morbidity and mortality.

Abstract: As the prevalence of type 2 diabetes is rapidly increasing, prevention of the disease should be considered as a key objective in the near future.

Abstract: Besides lifestyle changes, various pharmacological treatments have proven their efficacy in placebo-controlled clinical trials, including antidiabetic drugs such as metformin, acarbose and troglitazone, or antiobesity agents such as orlistat.

Abstract: Arterial hypertension, a clinical entity in which insulin resistance is common, is strongly associated with type 2 diabetes and may precede the disease by several years.

Abstract: While antihypertensive agents such as diuretics or β-adrenoceptor antagonists may worsen insulin resistance and impair glucose tolerance, newer antihypertensive agents exert neutral or even slightly positive metabolic effects.

Abstract: Numerous clinical trials have investigated the effects of ACE inhibitors or angiotensin II receptor antagonists (ARAs) on insulin sensitivity in hypertensive patients, with or without diabetes, with no consistent results.

Abstract: Almost half of the studies with ACE inhibitors in hypertensive nondiabetic individuals demonstrated a slight but significant increase in insulin sensitivity as assessed by insulin-stimulated glucose disposal during a euglycaemic hyperinsulinaemic clamp, while the other half failed to reveal any significant change.

Abstract: The effects of ARAs on insulin sensitivity are neutral in most studies.

Abstract: Mechanisms of improvement of glucose tolerance and insulin sensitivity through the inhibition of the renin-angiotensin system (RAS) are complex.

Abstract: They may include improvement of blood flow and microcirculation in skeletal muscles and, thereby, enhancement of insulin and glucose delivery to the insulin-sensitive tissues, facilitating insulin signalling at the cellular level and improvement of insulin secretion by the β cells.

Abstract: Six recent large-scale clinical studies reported a remarkably consistent reduction in the incidence of type 2 diabetes in hypertensive patients treated with either ACE inhibitors or ARAs for 3–6 years, compared with a thiazide diuretic, β-adrenoceptor antagonist, the calcium channel antagonist amlodipine or even placebo.

Abstract: The relative risk reduction averaged 14% (p = 0.034) in the CAPPP (Captopril Prevention Project) with captopril compared with a thiazide or β1-adrenoceptor antagonist, 34% (p < 0.001) in the HOPE (Heart Outcomes Prevention Evaluation) study with ramipril compared with placebo, 30% (p < 0.001) in the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) with lisinopril compared with chlortalidone, 25% (p < 0.001) in the LIFE (Losartan Intervention For Endpoint reduction in hypertension study) with losartan compared with atenolol, and 25% (p = 0.09) in the SCOPE (Study on Cognition and Prognosis in the Elderly) with candesartan cilexetil compared with placebo, and 23% (p < 0.0001) in the VALUE (Valsartan Antihypertensive Long-term Use Evaluation) trial with valsartan compared with amlodipine.

Abstract: All these studies considered the development of diabetes as a secondary endpoint, except the HOPE trial where it was a post hoc analysis.

Abstract: These encouraging observations led to the initiation of two large, prospective, placebo-controlled randomised clinical trials whose primary outcome is the prevention of type 2 diabetes: the DREAM (Diabetes REduction Approaches with ramipril and rosiglitazone Medications) trial with the ACE inhibitor ramipril and the NAVIGATOR (Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research) trial with the ARA valsartan.

Abstract: Finally, ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) will also investigate as a secondary endpoint whether it is possible to prevent the development of type 2 diabetes by blocking the RAS with either an ACE inhibitor or an ARA or a combination of both.

Abstract: Thus, the recent consistent observations of a 14–34% reduction of the development of diabetes in hypertensive patients receiving ACE inhibitors or ARAs are exciting.

Abstract: From a theoretical point of view, they emphasise that there are many aspects of the pathogenesis, prevention and treatment of type 2 diabetes that still need to be uncovered.

Abstract: From a practical point of view, they may offer a new strategy to reduce the ongoing epidemic and burden of type 2 diabetes.


Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer

Abstract: Oncolytic viruses and active immunotherapeutics have complementary mechanisms of action (MOA) that are both self amplifying in tumors, yet the impact of dose on subject outcome is unclear.

Abstract: JX-594 (Pexa-Vec) is an oncolytic and immunotherapeutic vaccinia virus.

Abstract: To determine the optimal JX-594 dose in subjects with advanced hepatocellular carcinoma (HCC), we conducted a randomized phase 2 dose-finding trial (n = 30).

Abstract: Radiologists infused low- or high-dose JX-594 into liver tumors (days 1, 15 and 29); infusions resulted in acute detectable intravascular JX-594 genomes.

Abstract: Objective intrahepatic Modified Response Evaluation Criteria in Solid Tumors (mRECIST) (15%) and Choi (62%) response rates and intrahepatic disease control (50%) were equivalent in injected and distant noninjected tumors at both doses.

Abstract: JX-594 replication and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression preceded the induction of anticancer immunity.

Abstract: In contrast to tumor response rate and immune endpoints, subject survival duration was significantly related to dose (median survival of 14.1 months compared to 6.7 months on the high and low dose, respectively; hazard ratio 0.39; P = 0.020).

Abstract: JX-594 demonstrated oncolytic and immunotherapy MOA, tumor responses and dose-related survival in individuals with HCC.


Misread protein creates membrane channels: an essential step in the bactericidal action of aminoglycosides.

Abstract: Among the pleiotropic effects of aminoglycosides, their irreversible uptake and their blockade of initiating ribosomes have appeared to explain their bactericidal action, while the contributions of translational misreading and membrane damage and the mechanism of that damage have remained uncertain.

Abstract: We now present evidence that incorporation of misread proteins into the membrane can account for the membrane damage.

Abstract: The bactericidal action thus appears to result from the following sequence, in which each step is essential: slight initial entry of the antibiotic; interaction with chain-elongating ribosomes, resulting in misreading; incorporation of misread protein into the membrane, creating abnormal channels; increased (and irreversible) entry through these channels, and hence increased misreading and formation of channels; and, finally, blockade of initiating ribosomes.

Abstract: This mechanism can account for several previously unexplained observations: that streptomycin uptake requires protein synthesis during, but not after, the lag before the membrane damage; that streptomycin-resistant cells, which fail to take up streptomycin, can do so after treatment by another aminoglycoside; and that puromycin at moderate concentrations accelerates streptomycin uptake, while high concentrations (which release shorter chains) prevent it.

Abstract: In addition, puromycin, prematurely releasing polypeptides of normal sequence, also evidently creates channels, since it is reported to promote streptomycin uptake even in streptomycin-resistant cells.

Abstract: These findings imply that normal membrane proteins must be selected not only for a hydrophobic anchoring surface, but also for a tight fit in the membrane.


Rate of cervical cancer, severe intraepithelial neoplasia, and adenocarcinoma in situ in primary HPV DNA screening with cytology triage: randomised study within organised screening programme.

Abstract: OBJECTIVE To assess the performance and impact of primary human papillomavirus (HPV) DNA screening with cytology triage compared with conventional cytology on cervical cancer and severe pre-cancerous lesions.

Abstract: DESIGN Randomised trial.

Abstract: SETTING Population based screening programme for cervical cancer in southern Finland in 2003-5.

Abstract: PARTICIPANTS 58 076 women, aged 30-60, invited to the routine population based screening programme for cervical cancer.

Abstract: INTERVENTIONS Primary HPV DNA test (hybrid capture II) with cytology triage if the result was positive or conventional cytological screening (reference).

Abstract: MAIN OUTCOME MEASURES Rate of cervical cancer, cervical intraepithelial neoplasia (CIN) grade III, and adenocarcinoma in situ (as a composite outcome referred to as CIN III+) during 2003-7 through record linkage between files from the screening registry and the national cancer registry.

Abstract: RESULTS In the HPV and conventional arms there were 95 600 and 95 700 woman years of follow-up and 76 and 53 cases of CIN III+, respectively (of which six and eight were cervical cancers).

Abstract: The relative rate of CIN III+ in the HPV arm versus the conventional arm was 1.44 (95% confidence interval 1.01 to 2.05) among all women invited for screening and 1.77 (1.16 to 2.74) among those who attended.

Abstract: Among women with a normal or negative test result, the relative rate of subsequent CIN III+ was 0.28 (0.04 to 1.17).

Abstract: The rate of cervical cancer between arms was 0.75 (0.25 to 2.16) among women invited for screening and 1.98 (0.52 to 9.38) among those who attended.

Abstract: CONCLUSIONS When incorporated into a well established organised screening programme, primary HPV screening with cytology triage was more sensitive than conventional cytology in detecting CIN III+ lesions.

Abstract: The number of cases of cervical cancer was small, but considering the high probability of progression of CIN III the findings are of importance regarding cancer prevention.

Abstract: TRIAL REGISTRATION Current Controlled Trials ISRCTN23885553.


Metabolic syndrome as a risk factor for diabetes.

Abstract: The metabolic syndrome was initially described as an insulin-resistance syndrome characterized by the clustering of metabolic traits such as high triglycerides, low high-density lipoprotein cholesterol, high blood pressure, abdominal obesity and different degrees of impaired glucose regulation.

Abstract: Although different definitions have been developed by various consensus groups, epidemiological studies demonstrate that they all associate the metabolic syndrome with a similar cardiometabolic risk, which is high for diabetes (ranging between three- and 20-fold), depending on the number of components and the inclusion of impaired fasting glucose, impaired glucose tolerance or both.

Abstract: The latter appear to indicate the failure of the beta cell to produce enough insulin to compensate for the increased demand due to insulin resistance.

Abstract: There is a hyperbolic relationship between insulin production and insulin sensitivity, which can be calculated by the disposition index.

Abstract: When this is altered there is a higher risk of developing Type 2 diabetes.

Abstract: There have been no clinical trials in subjects selected by the diagnosis of metabolic syndrome, but structured lifestyle changes have been tested in people with impaired fasting glucose/impaired glucose tolerance and have been able to reduce incident Type 2 diabetes by almost 50%, as long as a weight loss of at least 5% is achieved.

Abstract: Oral antidiabetic and anti-obesity drugs have also been successful to a lesser degree.

Abstract: Some fibrates have reduced or delayed incident diabetes.

Abstract: Extended-release niacin has a neutral effect and statins are controversial.

Abstract: ACE inhibitors and ARBs are the antihypertensive agents least associated with incident diabetes.


The fallacy of the ecological fallacy: the potential misuse of a concept and the consequences.

Abstract: Ecological studies have been evaluated in epidemiological contexts in terms of the "ecological fallacy.

Abstract: Although the empirical evidence for a lack of comparability between correlations derived from ecological- and individual-level analyses is compelling, the conceptual meaning of the ecological fallacy remains problematic.

Abstract: This paper argues that issues in cross-level inference can be usefully conceptualized as validity problems, problems not peculiar to ecological-level analyses.

Abstract: Such an approach increases the recognition of both potential inference problems in individual-level studies and the unique contributions of ecological variables.

Abstract: This, in turn, expands the terrain for the location of causes for disease and interventions to improve the public's health.


Blocking caspase-activated apoptosis improves contractility in failing myocardium.

Abstract: Cardiac myocyte apoptosis has been demonstrated in end-stage failing human hearts.

Abstract: The therapeutic utility of blocking apoptosis in congestive heart failure (CHF) has not been elucidated.

Abstract: This study investigated the role of caspase activation in cardiac contractility and sarcomere organization in the development of CHF.

Abstract: In a rabbit model of heart failure obtained by rapid ventricular pacing, we demonstrate, using in vivo transcoronary adenovirus-mediated gene delivery of the potent caspase inhibitor p35, that caspase activation is associated with a reduction in contractile force of failing myocytes by destroying sarcomeric structure.

Abstract: In this animal model gene transfer of p35 prevented the rise in caspase 3 activity and DNA-histone formation.

Abstract: Genetically manipulated hearts expressing p35 had a significant improvement in left ventricular pressure rise (+dp/dt), decreased end-diastolic chamber pressure (LVEDP), and the development of heart failure was delayed.

Abstract: To better understand this benefit, we examined the effects of caspase 3 on cardiomyocyte dysfunction in vitro.

Abstract: Microinjection of activated caspase 3 into the cytoplasm of intact myocytes induced sarcomeric disorganization and reduced contractility of the cells.

Abstract: These results demonstrate a direct impact of caspases on cardiac function and may lead to novel therapeutic strategies via antiapoptotic regimens.


Development and validation of QRISK3 risk prediction algorithms to estimate future risk of cardiovascular disease: prospective cohort study

Abstract: Objectives To develop and validate updated QRISK3 prediction algorithms to estimate the 10 year risk of cardiovascular disease in women and men accounting for potential new risk factors.

Abstract: Design Prospective open cohort study.

Abstract: Setting General practices in England providing data for the QResearch database.

Abstract: Participants 1309 QResearch general practices in England: 981 practices were used to develop the scores and a separate set of 328 practices were used to validate the scores.

Abstract: 7.89 million patients aged 25-84 years were in the derivation cohort and 2.67 million patients in the validation cohort.

Abstract: Patients were free of cardiovascular disease and not prescribed statins at baseline.

Abstract: Methods Cox proportional hazards models in the derivation cohort to derive separate risk equations in men and women for evaluation at 10 years.

Abstract: Risk factors considered included those already in QRISK2 (age, ethnicity, deprivation, systolic blood pressure, body mass index, total cholesterol: high density lipoprotein cholesterol ratio, smoking, family history of coronary heart disease in a first degree relative aged less than 60 years, type 1 diabetes, type 2 diabetes, treated hypertension, rheumatoid arthritis, atrial fibrillation, chronic kidney disease (stage 4 or 5)) and new risk factors (chronic kidney disease (stage 3, 4, or 5), a measure of systolic blood pressure variability (standard deviation of repeated measures), migraine, corticosteroids, systemic lupus erythematosus (SLE), atypical antipsychotics, severe mental illness, and HIV/AIDs).

Abstract: We also considered erectile dysfunction diagnosis or treatment in men.

Abstract: Measures of calibration and discrimination were determined in the validation cohort for men and women separately and for individual subgroups by age group, ethnicity, and baseline disease status.

Abstract: Main outcome measures Incident cardiovascular disease recorded on any of the following three linked data sources: general practice, mortality, or hospital admission records.

Abstract: Results 363 565 incident cases of cardiovascular disease were identified in the derivation cohort during follow-up arising from 50.8 million person years of observation.

Abstract: All new risk factors considered met the model inclusion criteria except for HIV/AIDS, which was not statistically significant.

Abstract: The models had good calibration and high levels of explained variation and discrimination.

Abstract: In women, the algorithm explained 59.6% of the variation in time to diagnosis of cardiovascular disease (R2, with higher values indicating more variation), and the D statistic was 2.48 and Harrell's C statistic was 0.88 (both measures of discrimination, with higher values indicating better discrimination).

Abstract: The corresponding values for men were 54.8%, 2.26, and 0.86.

Abstract: Overall performance of the updated QRISK3 algorithms was similar to the QRISK2 algorithms.

Abstract: Conclusion Updated QRISK3 risk prediction models were developed and validated.

Abstract: The inclusion of additional clinical variables in QRISK3 (chronic kidney disease, a measure of systolic blood pressure variability (standard deviation of repeated measures), migraine, corticosteroids, SLE, atypical antipsychotics, severe mental illness, and erectile dysfunction) can help enable doctors to identify those at most risk of heart disease and stroke.


The importance of engaging policy-makers at the outset to guide research on and introduction of vaccines: the use of policy-maker surveys.

Abstract: Face-to-face surveys of policy-makers and other influential leaders are a useful tool to identify, at an early stage, (a) major issues regarding the introduction of a new vaccine, (b) persons and groups in a country who play a major decision-making or influential role in the introduction of vaccines, (c) potential obstacles to the introduction of vaccines, and (d) data-needs of policy-makers to overcome these obstacles.

Abstract: By surveying the opinions and beliefs of those who will make or influence decisions on whether to introduce a new vaccine, these studies can help ensure that research activities respond to the needs of policy-makers in countries endemic for the target diseases.

Abstract: These surveys can also inform vaccine-introduction strategies by identifying financially and politically feasible means of distributing, targeting, and financing the vaccines.

Abstract: This paper describes the methodology used in conducting such surveys and discusses methodological issues.

Abstract: It also presents lessons learnt from two policy-maker surveys carried out in several Asian countries in regard to new-generation vaccines against cholera, typhoid fever, and shigellosis; and future vaccines against dengue fever/dengue haemorrhagic fever.


Histone acetyltransferase PCAF regulates inflammatory molecules in the development of renal injury.

Abstract: Kidney diseases, including chronic kidney disease (CKD) and acute kidney injury (AKI), are associated with inflammation.

Abstract: The mechanism that regulates inflammation in these renal injuries remains unclear.

Abstract: Here, we demonstrated that p300/CBP-associated factor (PCAF), a histone acetyltransferase, was overexpressed in the kidneys of db/db mice and lipopolysaccharide (LPS)-injected mice.

Abstract: Moreover, elevated histone acetylation, such as H3K18ac, and up-regulation of some inflammatory genes, such as ICAM-1, VCAM-1, and MCP-1, were found upon these renal injuries.

Abstract: Furthermore, increased H3K18ac was recruited to the promoters of ICAM-1, VCAM-1, and MCP-1 in the kidneys of LPS-injected mice.

Abstract: In vitro studies demonstrated that PCAF knockdown in human renal proximal tubule epithelial cells (HK-2) led to downregulation of inflammatory molecules, including VCAM-1, ICAM-1, p50 subunit of NF-κB (p50), and MCP-1 mRNA and protein levels, together with significantly decreased H3K18ac level.

Abstract: Consistent with these, overexpression of PCAF enhanced the expression of inflammatory molecules.

Abstract: Furthermore, PCAF deficiency reduced palmitate-induced recruitment of H3K18ac on the promoters of ICAM-1 and MCP-1, as well as inhibited palmitate-induced upregulation of these inflammatory molecules.

Abstract: In summary, the present work demonstrates that PCAF plays an essential role in the regulation of inflammatory molecules through H3K18ac, which provides a potential therapeutic target for inflammation-related renal diseases.


T1 mapping for myocardial extracellular volume measurement by CMR: bolus only versus primed infusion technique.

Abstract: OBJECTIVES The aim of this study was to determine the accuracy of the contrast "bolus only" T1 mapping cardiac magnetic resonance (CMR) technique for measuring myocardial extracellular volume fraction (ECV).

Abstract: BACKGROUND Myocardial ECV can be measured with T1 mapping before and after contrast agent if the contrast agent distribution between blood/myocardium is at equilibrium.

Abstract: Equilibrium distribution can be achieved with a primed contrast infusion (equilibrium contrast-CMR [EQ-CMR]) or might be approximated by the dynamic equilibration achieved by delayed post-bolus measurement.

Abstract: This bolus only approach is highly attractive, but currently limited data support its use.

Abstract: We compared the bolus only technique with 2 independent standards: collagen volume fraction (CVF) from myocardial biopsy in aortic stenosis (AS); and the infusion technique in 5 representative conditions.

Abstract: METHODS One hundred forty-seven subjects were studied: healthy volunteers (n = 50); hypertrophic cardiomyopathy (n = 25); severe AS (n = 22); amyloid (n = 20); and chronic myocardial infarction (n = 30).

Abstract: Bolus only (at 15 min) and infusion ECV measurements were performed and compared.

Abstract: In 18 subjects with severe AS the results were compared with histological CVF.

Abstract: RESULTS The ECV by both techniques correlated with histological CVF (n = 18, r² = 0.69, p < 0.01 vs. r² = 0.71, p < 0.01, p = 0.42 for comparison).

Abstract: Across health and disease, there was strong correlation between the techniques (r² = 0.97).

Abstract: However, in diseases of high ECV (amyloid, hypertrophic cardiomyopathy late gadolinium enhancement, and infarction), Bland-Altman analysis indicates the bolus only technique has a consistent and increasing offset, giving a higher value for ECVs above 0.4 (mean difference ± limit of agreement for ECV <0.4 = -0.004 ± 0.037 vs. ECV >0.4 = 0.040 ± 0.075, p < 0.001).

Abstract: CONCLUSIONS Bolus only, T1 mapping-derived ECV measurement is sufficient for ECV measurement across a range of cardiac diseases, and this approach is histologically validated in AS.

Abstract: However, when ECV is >0.4, the bolus only technique consistently measures ECV higher compared with infusion.


Cytomegalovirus US2 destroys two components of the MHC class II pathway, preventing recognition by CD4+ T cells

Abstract: Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that causes life-threatening disease in patients who are immunosuppressed for bone marrow or tissue transplantation or who have AIDS (ref.

Abstract: HCMV establishes lifelong latent infections and, after periodic reactivation from latency, uses a panel of immune evasion proteins to survive and replicate in the face of robust, fully primed host immunity.

Abstract: Monocyte/macrophages are important host cells for HCMV, serving as a latent reservoir and as a means of dissemination throughout the body.

Abstract: Macrophages and other HCMV-permissive cells, such as endothelial and glial cells, can express MHC class II proteins and present antigens to CD4+ T lymphocytes.

Abstract: Here, we show that the HCMV protein US2 causes degradation of two essential proteins in the MHC class II antigen presentation pathway: HLA-DR-α and DM-α.

Abstract: This was unexpected, as US2 has been shown to cause degradation of MHC class I (refs.

Abstract: 5,6), which has only limited homology with class II proteins.

Abstract: Expression of US2 in cells reduced or abolished their ability to present antigen to CD4+ T lymphocytes.

Abstract: Thus, US2 may allow HCMV-infected macrophages to remain relatively 'invisible' to CD4+ T cells, a property that would be important after virus reactivation.


CD169-positive macrophages dominate antitumor immunity by crosspresenting dead cell-associated antigens.

Abstract: The generation of tumor-directed cytotoxic T lymphocytes is considered crucial for the induction of antitumor immunity.

Abstract: To activate these CD8(+) T cells, antigen-presenting cells (APCs) must initially acquire tumor cell-associated antigens.

Abstract: The major source of tumor antigens is dead tumor cells, but little is known about how APCs in draining lymph nodes acquire and crosspresent these antigens.

Abstract: Here we show that CD169(+) macrophages phagocytose dead tumor cells transported via lymphatic flow and subsequently crosspresent tumor antigens to CD8(+) T cells.

Abstract: Subcutaneous immunization with irradiated tumor cells protects mice from syngenic tumor.

Abstract: However, tumor antigen-specific CD8(+) T cell activation and subsequent antitumor immunity are severely impaired in mice depleted with CD169(+) macrophages.

Abstract: Neither migratory dendritic cells (DCs) nor lymph node-resident conventional DCs are essential for the crosspresentation of tumor antigens.

Abstract: Thus, we have identified CD169(+) macrophages as lymph node-resident APCs dominating early activation of tumor antigen-specific CD8(+) T cells.


Emerging mechanisms in morphogen-mediated axon guidance.

Abstract: Early in animal development, gradients of secreted morphogenic molecules, such as Sonic hedgehog (Shh), Wnt and TGFbeta/Bmp family members, regulate cell proliferation and determine the fate and phenotype of the target cells by activating well-characterized signalling pathways, which ultimately control gene transcription.

Abstract: Shh, Wnt and TGFbeta/Bmp signalling also play an important and evolutionary conserved role in neural circuit assembly.

Abstract: They regulate neuronal polarization, axon and dendrite development and synaptogenesis, processes that require rapid and local changes in cytoskeletal organization and plasma membrane components.

Abstract: A key question then is whether morphogen signalling at the growth cone uses similar mechanisms and intracellular pathway components to those described for morphogen-mediated cell specification.

Abstract: This review discusses recent advances towards the understanding of this problem, showing how Shh, Wnt and TGFbeta/Bmp have adapted their 'classical' signalling pathways or adopted alternative and novel molecular mechanisms to influence different aspects of neuronal circuit formation.


Lessons learnt from malaria epidemics in the Islamic Republic of Iran.

Abstract: The Islamic Republic of Iran is in the pre-elimination phase of malaria control, but malaria epidemics are still a concern in the south of the country.

Abstract: This retrospective study presents the epidemiological characteristics and predisposing factors of 60 of the malaria epidemics reported in Sistan va Baluchestan province during 2005-09.

Abstract: A zero-truncated negative binomial model was used to investigate the relation between predictor variables and the total number of malaria cases.

Abstract: Malaria epidemics occurred mainly in the southern part of the province, mostly between July and October, peaking in August.

Abstract: Most malaria epidemics were small-scale (68.3% were < 100 cases) and short (51.7% lasted < 1 month).

Abstract: Plasmodium falciparum was present in 46.7% of the epidemics.

Abstract: An increase in the rainfall rate as well as population movements were the most significant predisposing factors.

Abstract: The results may help inform an epidemic investigation and reporting system as the country approaches the malaria elimination phase.


Autoradiography of chromosomal DNA fibers from Chinese hamster cells.

Abstract: Ignorance of the true length of the DNA molecules in the chromosomes of higher organisms has always been a major obstacle to understanding chromosome structure.

Abstract: Consequently, attempts have been made, usually with the aid of electron microscopy, to estimate the size of DNA in higher organisms.

Abstract: Solari (1) has reported the longest such DNA measured before now-a DNA fiber from a sea urchin sperm at least 93 μ, long.


Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells.

Abstract: Human induced pluripotent stem cells (HiPSCs) appear to be highly similar to human embryonic stem cells (HESCs).

Abstract: Using two genetic lineage-tracing systems, we demonstrate the generation of iPSC lines from human pancreatic islet beta cells.

Abstract: These reprogrammed cells acquired markers of pluripotent cells and differentiated into the three embryonic germ layers.

Abstract: However, the beta cell-derived iPSCs (BiPSCs) maintained open chromatin structure at key beta-cell genes, together with a unique DNA methylation signature that distinguishes them from other PSCs.

Abstract: BiPSCs also demonstrated an increased ability to differentiate into insulin-producing cells both in vitro and in vivo, compared with ESCs and isogenic non-beta iPSCs.

Abstract: Our results suggest that the epigenetic memory may predispose BiPSCs to differentiate more readily into insulin producing cells.

Abstract: These findings demonstrate that HiPSC phenotype may be influenced by their cells of origin, and suggest that their skewed differentiation potential may be advantageous for cell replacement therapy.


CCL2/monocyte chemoattractant protein-1 mediates enhanced transmigration of human immunodeficiency virus (HIV)-infected leukocytes across the blood-brain barrier: a potential mechanism of HIV-CNS invasion and NeuroAIDS.

Abstract: Encephalitis and dementia associated with acquired immunodeficiency syndrome (AIDS) are characterized by leukocyte infiltration into the CNS, microglia activation, aberrant chemokine expression, blood-brain barrier (BBB) disruption, and eventual loss of neurons.

Abstract: Little is known about whether human immunodeficiency virus 1 (HIV-1) infection of leukocytes affects their ability to transmigrate in response to chemokines and to alter BBB integrity.

Abstract: We now demonstrate that HIV infection of human leukocytes results in their increased transmigration across our tissue culture model of the human BBB in response to the chemokine CCL2, as well as in disruption of the BBB, as evidenced by enhanced permeability, reduction of tight junction proteins, and expression of matrix metalloproteinases (MMP)-2 and MMP-9.

Abstract: HIV-infected cells added to our model did not transmigrate in the absence of CCL2, nor did this condition alter BBB integrity.

Abstract: The chemokines CXCL10/interferon-gamma-inducible protein of 10 kDa, CCL3/macrophage inflammatory protein-1alpha, or CCL5/RANTES (regulated on activation normal T-cell expressed and secreted) did not enhance HIV-infected leukocyte transmigration or BBB permeability.

Abstract: The increased capacity of HIV-infected leukocytes to transmigrate in response to CCL2 correlated with their increased expression of CCR2, the chemokine receptor for CCL2.

Abstract: These data suggest that CCL2, but not other chemokines, plays a key role in infiltration of HIV-infected leukocytes into the CNS and the subsequent pathology characteristic of NeuroAIDS.


Prostaglandin E2 as an inhibitory modulator of fibrogenesis in human lung allografts.

Abstract: RATIONALE Donor mesenchymal stromal/stem cell (MSC) expansion and fibrotic differentiation is associated with development of bronchiolitis obliterans syndrome (BOS) in human lung allografts.

Abstract: However, the regulators of fibrotic differentiation of these resident mesenchymal cells are not well understood.

Abstract: OBJECTIVES This study examines the role of endogenous and exogenous prostaglandin (PG)E2 as a modulator of fibrotic differentiation of human lung allograft-derived MSCs.

Abstract: METHODS Effect of PGE2 on proliferation, collagen secretion, and α-smooth muscle actin (α-SMA) expression was assessed in lung-resident MSCs (LR-MSCs) derived from patients with and without BOS.

Abstract: The response pathway involved was elucidated by use of specific agonists and antagonists.

Abstract: MEASUREMENT AND MAIN RESULTS PGE2 treatment of LR-MSCs derived from normal lung allografts significantly inhibited their proliferation, collagen secretion, and α-SMA expression.

Abstract: On the basis of pharmacologic and small-interfering RNA approaches, a PGE2/E prostanoid (EP)2/adenylate cyclase pathway was implicated in these suppressive effects.

Abstract: Stimulation of endogenous PGE2 secretion by IL-1β was associated with amelioration of their myofibroblast differentiation in vitro, whereas its inhibition by indomethacin augmented α-SMA expression.

Abstract: LR-MSCs from patients with BOS secreted significantly less PGE2 than non-BOS LR-MSCs.

Abstract: Furthermore, BOS LR-MSCs were found to be defective in their ability to induce cyclooxygenase-2, and therefore unable to up-regulate PGE2 synthesis in response to IL-1β.

Abstract: BOS LR-MSCs also demonstrated resistance to the inhibitory actions of PGE2 in association with a reduction in the EP2/EP1 ratio.

Abstract: CONCLUSIONS These data identify the PGE2 axis as an important autocrine-paracrine brake on fibrotic differentiation of LR-MSCs, a failure of which is associated with BOS.


Association of DNA polymerase mu (pol mu) with Ku and ligase IV: role for pol mu in end-joining double-strand break repair.

Abstract: Mammalian DNA polymerase mu (pol mu) is related to terminal deoxynucleotidyl transferase, but its biological role is not yet clear.

Abstract: We show here that after exposure of cells to ionizing radiation (IR), levels of pol mu protein increase.

Abstract: pol mu also forms discrete nuclear foci after IR, and these foci are largely coincident with IR-induced foci of gammaH2AX, a previously characterized marker of sites of DNA double-strand breaks.

Abstract: pol mu is thus part of the cellular response to DNA double-strand breaks.

Abstract: pol mu also associates in cell extracts with the nonhomologous end-joining repair factor Ku and requires both Ku and another end-joining factor, XRCC4-ligase IV, to form a stable complex on DNA in vitro.

Abstract: pol mu in turn facilitates both stable recruitment of XRCC4-ligase IV to Ku-bound DNA and ligase IV-dependent end joining.

Abstract: In contrast, the related mammalian DNA polymerase beta does not form a complex with Ku and XRCC4-ligase IV and is less effective than pol mu in facilitating joining mediated by these factors.

Abstract: Our data thus support an important role for pol mu in the end-joining pathway for repair of double-strand breaks.


Stromal-epithelial metabolic coupling in cancer: integrating autophagy and metabolism in the tumor microenvironment.

Abstract: Cancer cells do not exist as pure homogeneous populations in vivo.

Abstract: Instead they are embedded in "cancer cell nests" that are surrounded by stromal cells, especially cancer associated fibroblasts.

Abstract: Thus, it is not unreasonable to suspect that stromal fibroblasts could influence the metabolism of adjacent cancer cells, and visa versa.

Abstract: In accordance with this idea, we have recently proposed that the Warburg effect in cancer cells may be due to culturing cancer cells by themselves, out of their normal stromal context or tumor microenvironment.

Abstract: In fact, when cancer cells are co-cultured with fibroblasts, then cancer cells increase their mitochondrial mass, while fibroblasts lose their mitochondria.

Abstract: An in depth analysis of this phenomenon reveals that aggressive cancer cells are "parasites" that use oxidative stress as a "weapon" to extract nutrients from surrounding stromal cells.

Abstract: Oxidative stress in fibroblasts induces the autophagic destruction of mitochondria, by mitophagy.

Abstract: Then, stromal cells are forced to undergo aerobic glycolysis, and produce energy-rich nutrients (such as lactate and ketones) to "feed" cancer cells.

Abstract: This mechanism would allow cancer cells to seed anywhere, without blood vessels as a food source, as they could simply induce oxidative stress wherever they go, explaining how cancer cells survive during metastasis.

Abstract: We suggest that stromal catabolism, via autophagy and mitophagy, fuels the anabolic growth of tumor cells, promoting tumor progression and metastasis.

Abstract: We have previously termed this new paradigm "The Autophagic Tumor Stroma Model of Cancer Metabolism", or the "Reverse Warburg Effect".

Abstract: We also discuss how glutamine addiction (glutaminolysis) in cancer cells fits well with this new model, by promoting oxidative mitochondrial metabolism in aggressive cancer cells.


Oxidative stress in renal dysfunction: mechanisms, clinical sequelae and therapeutic options

Abstract: Oxidative stress has been increasingly linked to the high incidence of cardiovascular events in patients with chronic kidney disease (CKD), especially as traditional cardiovascular risk factors seem to not be able to account for the huge cardiovascular morbidity and mortality in this population group.

Abstract: Oxidative stress is increased in patients with renal impairment as a result of increased oxidant activity and reduced antioxidant capacity, and this is increased in a graded manner with increasing renal dysfunction.

Abstract: Inflammation, which is also present in CKD, further amplifies the oxidant generation process.

Abstract: The two clinical sequelae of oxidative stress are endothelial dysfunction and left ventricular hypertrophy, which have adverse cardiovascular consequences.

Abstract: With our new understanding of oxidative stress, it is now important to assess treatment options that reduce it in the hope that they reverse endothelial dysfunction and left ventricular hypertrophy and the clinical sequelae of these abnormalities.


Effect of age, sex, and sites on the cellularity of the adipose tissue in mice and rats rendered obese by a high-fat diet.

Abstract: Cell size and number of parametrial fat pads were determined in Swiss mice made obese by means of a high-fat diet (40% lard w/w) given ad lib.

Abstract: This diet and a control were introduced to two groups of mothers during gestation and lactation, and sucklings were given the same diets as their mothers at weaning and throughout life.2-wk old mice suckled by mothers fed a high-fat diet have fatter parametrial pads.

Abstract: This difference is due solely to an increase in fat cell size.

Abstract: After weaning, until the 18th wk, the two groups differed with a striking fat cell enlargement seen in the obese group.

Abstract: Later on, whereas cell numbers did not change in the control group, a constant and uninterrupted increase in number is shown in those of obese mice until the 52nd wk.

Abstract: Hyperplasia was observed only in adults.

Abstract: When the high-fat diet was introduced to adult rats it also triggered an increase in fat cell number.

Abstract: Three sites of fat pads were compared in both sexes at 32 wk of age.

Abstract: All sites increased in weight in the high-fat fed group.

Abstract: This was due to: hyperplasia in perirenal site, hypertrophy in epididymal and subcutaneous sites, and hyperplasia plus hypertrophy in the parametrial one.

Abstract: So, in each sex, adipose sites in the obese mice reacted to the diet in a site-specific way.

Abstract: It was concluded that the level of fat in a diet is involved in both formation and maturation of new fat cells and in the regulation of fat cell lipid content.

Abstract: The two processes may be separated or may act together according to the adipose tissue site.


Transcriptional integration of mitochondrial biogenesis.

Abstract: Gene regulatory factors encoded by the nuclear genome are essential for mitochondrial biogenesis and function.

Abstract: Some of these factors act exclusively within the mitochondria to regulate the control of mitochondrial transcription, translation, and other functions.

Abstract: Others govern the expression of nuclear genes required for mitochondrial metabolism and organelle biogenesis.

Abstract: The peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1) family of transcriptional coactivators play a major role in transducing and integrating physiological signals governing metabolism, differentiation, and cell growth to the transcriptional machinery controlling mitochondrial functional capacity.

Abstract: Thus, the PGC-1 coactivators serve as a central component of the transcriptional regulatory circuitry that coordinately controls the energy-generating functions of mitochondria in accordance with the metabolic demands imposed by changing physiological conditions, senescence, and disease.


RFID system evaluation against radiated transient noise

Abstract: In this paper a radiofrequency identification system according to standard ISO/IEC 14443 type-B is evaluated in  presence of transient noise.

Abstract: This real time communication system working at 13.56 MHz is interfered in a controlled environment by different transient bursts varying their level, frequency and duration.

Abstract: The transient burst interference is applied in an AC main wire close to the system and the effect over the digital communication system is evaluated using two different methods.

Abstract: The first one is observing directly an RFID equipment in presence of transient signals, and the second one is capturing the  interference in time domain an evaluating its effect by means of simulation.

Abstract: The RFID system is affected by these transient noises  causing different types of errors.

Abstract: It is shown that it is essential to measure and evaluate in time domain the transient phenomena to ensure that the RFID system do not have susceptibility problems.


Musculoskeletal pain in Europe: its impact and a comparison of population and medical perceptions of treatment in eight European countries.

Abstract: OBJECTIVES To describe the impact of musculoskeletal pain (MP); to compare management of MP by the population and by primary care physicians; and to identify misconceptions about treatment.

Abstract: METHODS 5803 people with MP and 1483 primary care physicians, randomly selected, in eight European countries were interviewed by telephone.

Abstract: A structured questionnaire was used to ask about usual management of MP and perceived benefits and risks of treatment.

Abstract: Current health status (SF-12) was also assessed.

Abstract: RESULTS From primary care physicians' perceptions, MP appears to be well managed.

Abstract: All presenting patients are offered some form of treatment, 90% or more doctors are trying to improve patients' quality of life, and most are aware and concerned about the risks of treatment with NSAIDs.

Abstract: From a population perspective, up to 27% of people with pain do not seek medical help and of those who do, several wait months/years before seeing a doctor.

Abstract: 55% or fewer patients who have seen a doctor are currently receiving prescription treatment for their pain.

Abstract: Communication between doctors and patients is poor; few patients are given information about their condition; and many have misconceptions about treatment.

Abstract: CONCLUSIONS Management of MP is similar across eight European countries, but there is discordance between physician and patient perspectives of care.

Abstract: Some people with pain have never sought medical help despite being in constant/daily pain.

Abstract: Those who do seek help receive little written information or explanation and many have misperceptions about the benefits and risks of treatment that limit their ability to actively participate in decisions about their care.


[Palliative care in Germany].

Abstract: The delivery of palliative care in Germany is still characterized by a wide-spread undersupply both for inpatients and outpatients.

Abstract: Nevertheless over the last 15 years progress has also been made in Germany, which is pleasing and which has directed professional and public attention increasingly to the situation of the incurably ill and dying.

Abstract: In the course of this development the first structures for specialized palliative care have been established.

Abstract: In particular the situation for inpatients in hospitals and hospices is pleasing, even if a satisfaction for total coverage is not yet reached.

Abstract: More seriously however is the demand for the outpatients.

Abstract: Financial means, which are steered so far only rudimentarily for palliative care, must be made sufficiently available, in order to be able to meet the demand with the help of appropriate structural offers.

Abstract: It is important to realize the needs of the incurably ill and dying and of their relatives and friends.

Abstract: Our society has to call attention to this subject and it should be placed on the healthpolitical agenda as a topic of the highest priority level.

Abstract: The current developments in the federation and in the federal states are encouraging and allowing hope that the delivery of palliative care for all who need it (and not only the ill) will improve further in the coming years.