BMP receptor ALK3 controls collecting system development.

Abstract: The molecular signals that regulate growth and branching of the ureteric bud during formation of the renal collecting system are largely undefined.

Abstract: Members of the bone morphogenetic protein (BMP) family signal through the type I BMP receptor ALK3 to inhibit ureteric bud and collecting duct cell morphogenesis in vitro.

Abstract: We investigated the function of the BMP signaling pathway in vivo by generating a murine model of ALK3 deficiency restricted to the ureteric bud lineage (Alk3(UB-/-) mice).

Abstract: At the onset of branching morphogenesis, Alk3(UB-/-) kidneys are characterized by an abnormal primary (1 degrees ) ureteric bud branch pattern and an increased number of ureteric bud branches.

Abstract: However, during later stages of renal development, Alk3(UB-/-) kidneys have fewer ureteric bud branches and collecting ducts than wild-type kidneys.

Abstract: Postnatal Alk3(UB-/-) mice exhibit a dysplastic renal phenotype characterized by hypoplasia of the renal medulla, a decreased number of medullary collecting ducts, and abnormal expression of beta-catenin and c-MYC in medullary tubules.

Abstract: In summary, normal kidney development requires ALK3-dependent BMP signaling, which controls ureteric bud branching.


Increased release of ferritin and iron by iron-loaded alveolar macrophages in cigarette smokers.

Abstract: The lower respiratory tract of cigarette smokers contains an increased amount of iron that is predominantly sequestered within alveolar macrophages (AM), but is also present in alveolar epithelial fluid.

Abstract: Extracellular ferritin-bound iron could potentially be released by reductants present in cigarette smoke and catalyze generation of highly reactive hydroxyl radicals capable of causing oxidant injury.

Abstract: To determine whether AM are a source of alveolar extracellular ferritin and iron, we assessed in vitro release of iron, ferritin, and transferrin by AM recovered by bronchoalveolar lavage (BAL) of 27 healthy subjects including nine nonsmokers (NS), nine light smokers (LS), and nine heavy smokers (HS).

Abstract: Release of iron in vitro over 20 h was increased in AM recovered from LS (2.24 +/-

Abstract: 0.21 nmol/10(6) AM/20 h, p < 0.001) and HS (3.11 +/-

Abstract: 0.32 nmol/10(6) AM, p < 0.001) compared with NS (1.28 +/-

Abstract: 0.08 nmol/10(6) AM).

Abstract: Release of ferritin in vitro over 20 h was also increased in AM recovered from LS (71 +/-

Abstract: 24 ng/10(6) AM, p < 0.05) and HS (176 +/-

Abstract: 35 ng/10(6), p < 0.001) compared with NS (18 +/-

Abstract: 3 ng/10(6) AM).

Abstract: AM recovered from 12 smokers (8 HS, 4 LS) contained greater than 10 nmol of iron per 10(6) cells.

Abstract: These iron-loaded AM released a greater percentage of cell ferritin stores in vitro over 4 h (8.4% +/-

Abstract: 1.1, p < 0.01) than did AM from NS (3.2% +/- 0.6).

Abstract: Release of lactate dehydrogenase (LDH) over 4 h was substantially less (2.9% +/-

Abstract: 0.3, p < 0.001) than ferritin release.(ABSTRACT TRUNCATED AT 250 WORDS)


The spectrum of retinopathy in adults with Plasmodium falciparum malaria

Abstract: A specific retinopathy has been described in African children with cerebral malaria, but in adults this has not been extensively studied.

Abstract: Since the structure and function of the retinal vasculature greatly resembles the cerebral vasculature, study of retinal changes can reveal insights into the pathophysiology of cerebral malaria.

Abstract: A detailed observational study of malarial retinopathy in Bangladeshi adults was performed using high-definition portable retinal photography.

Abstract: Retinopathy was present in 17/27 adults (63%) with severe malaria and 14/20 adults (70%) with cerebral malaria.

Abstract: Moderate or severe retinopathy was more frequent in cerebral malaria (11/20, 55%) than in uncomplicated malaria (3/15, 20%; P=0.039), bacterial sepsis (0/5, 0%; P=0.038) or healthy controls (0/18, 0%; P<0.001).

Abstract: The spectrum of malarial retinopathy was similar to that previously described in African children, but no vessel discolouration was observed.

Abstract: The severity of retinal whitening correlated with admission venous plasma lactate (P=0.046), suggesting that retinal ischaemia represents systemic ischaemia.

Abstract: In conclusion, retinal changes related to microvascular obstruction were common in adults with severe falciparum malaria and correlated with disease severity and coma, suggesting that a compromised microcirculation has important pathophysiological significance in severe and cerebral malaria.

Abstract: Portable retinal photography has potential as a valuable tool to study malarial retinopathy.


Prospective randomized open blinded end-point (PROBE) study. A novel design for intervention trials. Prospective Randomized Open Blinded End-Point.

Abstract: A novel design for intervention studies is presented, the so called PROBE study (Prospective Randomized Open, Blinded End-point).

Abstract: This design is compared to the classical double-blind design.

Abstract: Among the advantages of the PROBE design are lower cost and greater similarity to standard clinical practice, which should make the results more easily applicable in routine medical care.

Abstract: Since end-points are evaluated by a blinded end-point committee it is obvious that there should be no difference between the two types of trials in this regard.


PSGL-1 function in immunity and steady state homeostasis.

Abstract: The substantial importance of P-selectin glycoprotein ligand 1 (PSGL-1) in leukocyte trafficking has continued to emerge beyond its initial identification as a selectin ligand.

Abstract: PSGL-1 seemed to be a relatively simple molecule with an extracellular mucin domain extended as a flexible rod, teleologically consistent with its primary role in tethering leukocytes to endothelial selectins.

Abstract: The rolling interaction between leukocyte and endothelium mediated by this selectin-PSGL-1 interaction requires branched O-glycan extensions on specific PSGL-1 amino acid residues.

Abstract: In some cells, such as neutrophils, the glycosyltransferases involved in formation of the O-glycans are constitutively expressed, while in other cells, such as T cells, they are expressed only after appropriate activation.

Abstract: Thus, PSGL-1 supports leukocyte recruitment in both innate and adaptive arms of the immune response.

Abstract: A complex array of amino acids within the selectins engage multiple sugar residues of the branched O-glycans on PSGL-1 and provide the molecular interactions responsible for the velcro-like catch bonds that support leukocyte rolling.

Abstract: Such binding of PSGL-1 can also induce signaling events that influence cell phenotype and function.

Abstract: Scrutiny of PSGL-1 has revealed a better understanding of how it performs as a selectin ligand and yielded unexpected insights that extend its scope from supporting leukocyte rolling in inflammatory settings to homeostasis including stem cell homing to the thymus and mature T-cell homing to secondary lymphoid organs.

Abstract: PSGL-1 has been found to bind homeostatic chemokines CCL19 and CCL21 and to support the chemotactic response to these chemokines.

Abstract: Surprisingly, the O-glycan modifications of PSGL-1 that support rolling mediated by selectins in inflammatory conditions interfere with PSGL-1 binding to homeostatic chemokines and thereby limit responsiveness to the chemotactic cues used in steady state T-cell traffic.

Abstract: The multi-level influence of PSGL-1 on cell traffic in both inflammatory and steady state settings is therefore substantially determined by the orchestrated addition of O-glycans.

Abstract: However, central as specific O-glycosylation is to PSGL-1 function, in vivo regulation of PSGL-1 glycosylation in T cells remains poorly understood.

Abstract: It is our purpose herein to review what is known, and not known, of PSGL-1 glycosylation and to update understanding of PSGL-1 functional scope.


Ligand binding determines whether CD46 is internalized by clathrin-coated pits or macropinocytosis.

Abstract: CD46 is a ubiquitous human cell surface receptor for the complement components C3b and C4b and for various pathogens, including the measles virus and human herpes virus 6.

Abstract: Ligand binding to CD46 affects (i) protection of autologous cells from complement attack by breakdown of complement components, (ii) intracellular signals that affect the regulation of immune cell function, (iii) antigen presentation, and (iv) down-regulation of cell surface CD46.

Abstract: Recent evidence indicates that CD46 signaling can link innate and acquired immune function.

Abstract: The molecular mechanisms for these processes and the importance of intracellular trafficking of the receptor have not yet been elucidated.

Abstract: We demonstrate here that, in nonlymphoid cells, CD46 is constitutively internalized via clathrin-coated pits, traffics to multivesicular bodies, and is recycled to the cell surface.

Abstract: However, cross-linking of CD46 at the cell surface, by either multivalent antibody or by measles virus, induces pseudopodia that engulf the ligand in a process similar to macropinocytosis, and leads to the degradation of cell surface CD46.

Abstract: Thus, we have elucidated two pathways for CD46 internalization, which are regulated by the valence of cross-linking of CD46 and which utilize either clathrin-coated pits or pseudopodial extension.

Abstract: This has important implications for CD46 signaling, antigen presentation, CD46 down-regulation, and engulfment of pathogens.


A three-dimensional cell biology model of human hepatocellular carcinoma in vitro

Abstract: We established an in vitro 3-D model of metastatic hepatocellular carcinoma (HCC) by culturing MHCC97H cells on molecular scaffolds within a rotating wall vessel bioreactor.

Abstract: Morphological and biochemical analyses revealed that the 3-D HCC model mirrored many clinical pathological features of HCC in vivo, including cancer cell morphology, tissue ultrastructure, protein production and secretion, glucose metabolism, tissue-specific gene expression, and apoptosis.

Abstract: Xenografts into livers of nude mice resulted in tumorigenesis and distant metastasis.

Abstract: This 3-D HCC spheroid is a promising model for HCC tumor biology, anticancer drug screening, and for the establishment of HCC animal models.


Patterns of age-specific mortality in children in endemic areas of sub-Saharan Africa.

Abstract: Understanding of the age- and season- dependence of malaria mortality is an important prerequisite for epidemiologic models of malaria immunity.

Abstract: However, most studies of malaria mortality have aggregated their results into broad age groups and across seasons, making it hard to predict the likely impact of interventions targeted at specific age groups of children.

Abstract: We present age-specific mortality rates for children aged < 15 years for the period of 2001-2005 in 7 demographic surveillance sites in areas of sub-Saharan Africa with stable endemic Plasmodium falciparum malaria.

Abstract: We use verbal autopsies (VAs) to estimate the proportion of deaths by age group due to malaria, and thus calculate malaria-specific mortality rates for each site, age-group, and month of the year.

Abstract: In all sites a substantial proportion of deaths (ranging from 20.1% in a Mozambican site to 46.2% in a site in Burkina Faso) were attributed to malaria.

Abstract: The overall age patterns of malaria mortality were similar in the different sites.

Abstract: Deaths in the youngest children (< 3 months old) were only rarely attributed to malaria, but in children over 1 year of age the proportion of deaths attributed to malaria was only weakly age-dependent.

Abstract: In most of the sites all-cause mortality rates peaked during the rainy season, but the strong seasonality in malaria transmission in these sites was not reflected in strong seasonality in the proportion of deaths attributed to malaria, except in the two sites in Burkina Faso.

Abstract: Improvement in the specificity of malaria verbal autopsies would make it easier to interpret the age and season patterns in such data.


Obesity due to melanocortin 4 receptor (MC4R) deficiency is associated with increased linear growth and final height, fasting hyperinsulinemia, and incompletely suppressed growth hormone secretion.

Abstract: CONTEXT Melanocortin receptor 4 (MC4R) deficiency is characterized by increased linear growth greater than expected for the degree of obesity.

Abstract: OBJECTIVE The objective of the investigation was to study the somatotroph axis in obese MC4R-deficient patients and equally obese controls.

Abstract: PATIENTS AND METHODS We obtained anthropometric measurements and insulin concentrations in 153 MC4R-deficient subjects and 1392 controls matched for age and severity of obesity.

Abstract: We measured fasting IGF-I, IGF-II, IGF binding protein (IGFBP)-1, IGFBP-3, and acid-labile subunit levels in a subset of 33 MC4R-deficient patients and 36 control subjects.

Abstract: We examined pulsatile GH secretion in six adult MC4R-deficient subjects and six obese controls.

Abstract: RESULTS Height sd score was significantly greater in MC4R-deficient children under 5 yr of age compared with controls (mean ± SEM: 2.3 ± 0.06 vs. 1.8 ± 0.04, P < 0.001), an effect that persisted throughout childhood.

Abstract: Final height (cm) was greater in MC4R-deficient men (mean ± SEM 173 ± 2.5 vs. 168 ± 2.1, P < 0.001) and women (mean 165 ± 2.1 vs. 158 ± 1.9, P < 0.001).

Abstract: Fasting IGF-I, IGF-II, acid-labile subunit, and IGFBP-3 concentrations were similar in the two groups.

Abstract: GH levels were markedly suppressed in obese controls, but pulsatile GH secretion was retained in MC4R deficiency.

Abstract: The mean maximal GH secretion rate per burst (P < 0.05) and mass per burst (P < 0.05) were increased in MC4R deficiency, consistent with increased pulsatile and total GH secretion.

Abstract: Fasting insulin levels were markedly elevated in MC4R-deficient children.

Abstract: CONCLUSIONS In MC4R deficiency, increased linear growth in childhood leads to increased adult final height, greater than predicted by obesity alone.

Abstract: GH pulsatility is maintained in MC4R deficiency, a finding consistent with animal studies, suggesting a role for MC4R in controlling hypothalamic somatostatinergic tone.

Abstract: Fasting insulin levels are significantly higher in children carrying MC4R mutations.

Abstract: Both of these factors may contribute to the accelerated growth phenotype characteristic of MC4R deficiency.


The selectivity of beta-adrenoceptor antagonists on isoprenaline-induced changes in heart rate, blood pressure, soleus muscle contractility and airways function in anaesthetized cats.

Abstract: The beta-adrenoceptor antagonist of propranolol, metoprolol, atenolol and butoxamine in anaesthetized cats has been measured and compared with the activity of four synthetic phenylethanolamine derivatives.

Abstract: The effects of isoprenaline on four parameters in the anaesthetized cat: heart rate, blood pressure, soleus muscle contractility and airway reactance, were measured and the modification of the isoprenaline dose-response relation by each of the antagonist drugs assessed.

Abstract: Parallel shifts in log dose-response curves for isoprenaline were caused by propranolol for all parameters, by metoprolol and atenolol for each parameter except blood pressure, and butoxamine for each except soleus muscle and heart rate.

Abstract: Selectivity of action of the antagonists between different organs was measured by comparing DR10 values, computed from isoprenaline dose-ratios.

Abstract: Propranolol was the most potent antagonist and showed slight selectivity of action on soleus muscle compared with heart.

Abstract: Atenolol and metoprolol were approximately equipotent and were cardioselective at low doses only.

Abstract: Butoxamine was the least potent antagonist and possessed non-beta-adrenoceptor effects on the parameters measured.

Abstract: Each of the new compounds, 4'-bromo-2'-methoxy-N-isopropyl phenylethanolamine, the 4'-chloro- and 4'-methyl analogues, and 4'-methoxy-N-t-butyl phenylethanolamine, was a potent antagonist but did not exhibit any selectivity of action.

Abstract: The results suggest no clear separation of beta-adrenoceptors into beta 1- and beta 2-subclasses in organs of the cat.

Abstract: There is no apparent separation of beta-adrenoceptor-mediated effects on skeletal muscle and airways.


Breast cancer and obesity: an update.

Abstract: Obesity has a complicated relationship to both breast cancer risk and the clinical behavior of the established disease.

Abstract: In postmenopausal women, particularly the elderly, various measures of obesity have been positively associated with risk.

Abstract: However, before menopause increased body weight is inversely related to breast cancer risk.

Abstract: In both premenopausal and postmenopausal breast cancer, the mechanisms by which body weight and obesity affect risk have been related to estrogenic activity.

Abstract: Obesity has also been related to advanced disease at diagnosis and with a poor prognosis in both premenopausal and postmenopausal breast cancer.

Abstract: Breast cancer in African-American women, considering its relationship to obesity, exhibits some important differences from those described in white women, although the high prevalence of obesity in African-American women may contribute to the relatively poor prognosis compared with white American women.

Abstract: Despite the emphasis on estrogens to explain the effects of obesity on breast cancer, other factors may prove to be equally or more important, particularly as they relate to expression of an aggressive tumor phenotype.

Abstract: Among these, this review serves to stress insulin, insulin-like growth factor-I, and leptin, and their relationship to angiogenesis, and transcriptional factors.


Dietary saturated and unsaturated fats as determinants of blood pressure and vascular function.

Abstract: The amount and type of dietary fat have long been associated with the risk of CVD.

Abstract: Arterial stiffness and endothelial dysfunction are important risk factors in the aetiology of CHD.

Abstract: A range of methods exists to assess vascular function that may be used in nutritional science, including clinic and ambulatory blood pressure monitoring, pulse wave analysis, pulse wave velocity, flow-mediated dilatation and venous occlusion plethysmography.

Abstract: The present review focuses on the quantity and type of dietary fat and effects on blood pressure, arterial compliance and endothelial function.

Abstract: Concerning fat quantity, the amount of dietary fat consumed habitually appears to have little influence on vascular function independent of fatty acid composition, although single high-fat meals postprandially impair endothelial function compared with low-fat meals.

Abstract: The mechanism is related to increased circulating lipoproteins and NEFA which may induce pro-inflammatory pathways and increase oxidative stress.

Abstract: Regarding the type of fat, cross-sectional data suggest that saturated fat adversely affects vascular function whereas polyunsaturated fat (mainly linoleic acid (18 : 2n-6) and n-3 PUFA) are beneficial.

Abstract: EPA (20 : 5n-3) and DHA (22 : 6n-3) can reduce blood pressure, improve arterial compliance in type 2 diabetics and dyslipidaemics, and augment endothelium-dependent vasodilation.

Abstract: The mechanisms for this vascular protection, and the nature of the separate physiological effects induced by EPA and DHA, are priorities for future research.

Abstract: Since good-quality observational or interventional data on dietary fatty acid composition and vascular function are scarce, no further recommendations can be suggested in addition to current guidelines at the present time.


Very small embryonic-like stem cells with maximum regenerative potential get discarded during cord blood banking and bone marrow processing for autologous stem cell therapy.

Abstract: Very small embryonic-like stem cells (VSELs) are possibly lost during cord blood banking and bone marrow (BM) processing for autologus stem cell therapy mainly because of their small size.

Abstract: The present study was conducted on human umbilical cord blood (UCB, n=6) and discarded red blood cells (RBC) fraction obtained after separation of mononuclear cells from human BM (n=6), to test this hypothesis.

Abstract: The results show that VSELs, which are pluripotent stem cells with maximum regenerative potential, settle along with the RBCs during Ficoll-Hypaque density separation.

Abstract: These cells are very small in size (3-5 μm), have high nucleo-cytoplasmic ratio, and express nuclear Oct-4, cell surface protein SSEA-4, and other pluripotent markers such as Nanog, Sox-2, Rex-1, and Tert as indicated by immunolocalization and quantitative polymerase chain reaction (Q-PCR) studies.

Abstract: Interestingly, a distinct population of slightly larger, round hematopoietic stem cells (HSCs) with cytoplasmic Oct-4 were detected in the "buffy" coat, which usually gets banked or used during autologus stem cell therapy.

Abstract: Immunohistochemical studies on the umbilical cord tissue (UCT) sections (n=3) showed the presence of nuclear Oct-4-positive VSELs and many fibroblast-like mesenchymal stem cells (MSCs) with cytoplasmic Oct-4.

Abstract: These VSELs with nuclear Oct-4, detected in UCB, UCT, and discarded RBC fraction obtained after BM processing, may persist throughout life, maintain tissue homeostasis, and undergo asymmetric cell division to self-renew as well as produce larger progenitor stem cells, viz.

Abstract: HSCs or MSCs, which follow differentiation trajectories depending on the somatic niche.

Abstract: Hence, it can be concluded that the true stem cells in adult body tissues are the VSELs, whereas the HSCs and MSCs are actually progenitor stem cells that arise by asymmetric cell division of VSELs.

Abstract: The results of the present study may help explain low efficacy reported during adult autologous stem cell trials, wherein unknowingly progenitor stem cells are injected rather than the pluripotent stem cells with maximum regenerative potential.


CNS repair requires both effector and regulatory T cells with distinct temporal and spatial profiles.

Abstract: Monocyte-derived macrophages (mo-MΦs) and T cells have been shown to contribute to spinal cord repair.

Abstract: Recently, the remote brain choroid plexus epithelium (CP) was identified as a portal for monocyte recruitment, and its activation for leukocyte trafficking was found to be IFN-γ-dependent.

Abstract: Here, we addressed how the need for effector T cells can be reconciled with the role of inflammation-resolving immune cells in the repair process.

Abstract: Using an acute spinal cord injury model, we show that in mice deficient in IFN-γ-producing T cells, the CP was not activated, and recruitment of inflammation-resolving mo-MΦ to the spinal cord parenchyma was limited.

Abstract: We further demonstrate that mo-MΦ locally regulated recruitment of thymic-derived Foxp3(+) regulatory T (Treg) cells to the injured spinal cord parenchyma at the subacute/chronic phase.

Abstract: Importantly, an ablation protocol that resulted in reduced Tregs at this stage interfered with tissue remodeling, in contrast to Treg transient ablation, restricted to the 4 d period before the injury, which favored repair.

Abstract: The enhanced functional recovery observed following such a controlled decrease of Tregs suggests that reduced systemic immunosuppression at the time of the insult can enhance CNS repair.

Abstract: Overall, our data highlight a dynamic immune cell network needed for repair, acting in discrete compartments and stages, and involving effector and regulatory T cells, interconnected by mo-MΦ.

Abstract: Any of these populations may be detrimental to the repair process if their level or activity become dysregulated.

Abstract: Accordingly, therapeutic interventions must be both temporally and spatially controlled.


Sperm function tests and fertility.

Abstract: Traditionally, the diagnosis of male infertility has depended upon a descriptive evaluation of human semen with emphasis on the number of spermatozoa that are present in the ejaculate, their motility and their morphology.

Abstract: The fundamental tenet underlying this approach is that male fertility can be defined by reference to a threshold concentration of motile, morphologically normal spermatozoa that must be exceeded in order to achieve conception.

Abstract: Many independent studies have demonstrated that this fundamental concept is flawed and, in reality, it is not so much the absolute number of spermatozoa that determines fertility, but their functional competence.

Abstract: In the light of this conclusion, a range of in vitro tests have been developed to monitor various aspects of sperm function including their potential for movement, cervical mucus penetration, capacitation, zona recognition, the acrosome reaction and sperm-oocyte fusion.

Abstract: Such functional assays have been found to predict the fertilizing capacity of human spermatozoa in vitro and in vivo with some accuracy.

Abstract: Recent developments in this field include the introduction of tests to assess the degree to which human spermatozoa have suffered oxidative stress as well as the integrity of their nuclear and mitochondrial DNA.

Abstract: Such assessments not only yield information on the fertilizing capacity of human spermatozoa but also their ability to support normal embryonic development.


Isolation and characterization of the cDNA encoding BKLF/TEF-2, a major CACCC-box-binding protein in erythroid cells and selected other cells.

Abstract: CACCC boxes are among the critical sequences present in regulatory elements of genes expressed in erythroid cells, as well as in selected other cell types.

Abstract: While an erythroid cell-specific CACCC-box-binding protein, EKLF, has been shown to be required in vivo for proper expression of the adult beta-globin gene, it is dispensable for the regulation of several other globin and nonglobin erythroid cell-expressed genes.

Abstract: In the work described here, we searched for additional CACCC-box transcription factors that might be active in murine erythroid cells.

Abstract: We identified a major gel shift activity (termed BKLF), present in yolk sac and fetal liver erythroid cells, that could be distinguished from EKLF by specific antisera.

Abstract: Through relaxed-stringency hybridization, we obtained the cDNA encoding BKLF, a highly basic, novel zinc finger protein that is related to EKLF and other Krüppel-like members in its DNA-binding domain but unrelated elsewhere.

Abstract: BKLF, which is widely but not ubiquitously expressed in cell lines, is highly expressed in the midbrain region of embryonic mice and appears to correspond to the gel shift activity TEF-2, a transcriptional activator implicated in regulation of the simian virus 40 enhancer and other CACCC-box-containing regulatory elements.

Abstract: Because BKLF binds with high affinity and preferentially over Sp1 to many CACCC sequences of erythroid cell expressed genes, it is likely to participate in the control of many genes whose expression appears independent of the action of EKLF.


Effect of osteoporosis treatments on risk of non-vertebral fractures: review and meta-analysis of intention-to-treat studies

Abstract: Most osteoporosis treatments have proven efficacy in reducing the risk of vertebral fractures, whereas evidence is less straightforward for prevention of non-vertebral fractures.

Abstract: Conclusions as to the efficacy of a treatment should be based primarily on analyses of the intention to treat (ITT) population rather than on exploratory subgroup analyses; however, non-vertebral anti-fracture efficacy has been largely derived by post-hoc subgroup analyses.

Abstract: This review and meta-analysis was performed to assess non-vertebral anti-fracture efficacy of several osteoporosis therapies, including a more stringent assessment of the ITT populations.

Abstract: Data on non-vertebral anti-fracture efficacy, a defined endpoint of the ITT analyses and confirmed by radiographs, were obtained from randomized, placebo-controlled, phase III clinical trials of at least 3-year duration.

Abstract: Meta-analyses were performed for the two bisphosphonates, alendronate and risedronate.

Abstract: Relative risks (RR), 95% confidence intervals (CI) and statistical significance for active treatment compared with placebo were calculated.

Abstract: Eleven clinical trials met the criteria for review, three of which showed statistically significant ( P ≤0.05) non-vertebral anti-fracture efficacy in the ITT population: two trials with risedronate and one trial with strontium.

Abstract: A meta-analysis showed significant reductions in the relative risk of non-vertebral fracture for both alendronate (RR=0.86; 95% CI: 0.76–0.97, P =0.012) and risedronate (RR=0.81; 95% CI: 0.71–0.92, P =0.001).

Abstract: Risedronate and strontium ranelate were the only treatments to show non-vertebral anti-fracture efficacy in this robust assessment of anti-fracture efficacy of osteoporosis therapy using ITT populations in trials of 3 years or more in duration.

Abstract: Risedronate was the only agent shown to demonstrate efficacy in more than one trial.

Abstract: Meta-analysis showed that both alendronate and risedronate provide non-vertebral anti-fracture efficacy.


Islet1 deletion causes kidney agenesis and hydroureter resembling CAKUT.

Abstract: Islet1 (Isl1) is a transcription factor transiently expressed in a subset of heart and limb progenitors.

Abstract: During studies of limb development, conditional Isl1 deletion produced unexpected kidney abnormalities.

Abstract: Here, we studied the renal expression of Isl1 and whether it has a role in kidney development.

Abstract: In situ hybridization revealed Isl1 expression in the mesenchymal cells surrounding the base of the ureteric bud in mice.

Abstract: Conditional deletion of Isl1 caused kidney agenesis or hypoplasia and hydroureter, a phenotype resembling human congenital anomalies of the kidney and urinary tract (CAKUT).

Abstract: The absence of Isl1 led to ectopic branching of the ureteric bud out from the nephric duct or to the formation of accessory buds, both of which could lead to obstruction of the ureter-bladder junction and consequent hydroureter.

Abstract: The abnormal elongation and poor branching of the ureteric buds were the likely causes of the kidney agenesis or hypoplasia.

Abstract: Furthermore, the lack of Isl1 reduced the expression of Bmp4, a gene implicated in the CAKUT-like phenotype, in the metanephric region before ureteric budding.

Abstract: In conclusion, Isl1 is essential for proper development of the kidney and ureter by repressing the aberrant formation of the ureteric bud.

Abstract: These observations call for further studies to investigate whether Isl1 may be a causative gene for human CAKUT.


Tissue transglutaminase (TG2)--a wound response enzyme.

Abstract: Repair of tissue after injury depends on a series of concerted but overlapping events including, inflammation, re-epithelialization, neovascularization and synthesis and stabilization of a fibrous extracellular matrix (ECM) that is remodeled to emulate normal tissue over time.

Abstract: Particular members of the transglutaminase (TG) family are upregulated during wound healing and act as a novel class of wound-healing mediators during the repair process.

Abstract: This group of enzymes which crosslink proteins via epsilon(gamma-glutamyl) lysine bridges are involved in wound healing through their ability to stabilize proteins and also by regulating the behavior of a wide variety of cell types that are recruited to the damaged area in order to carry out tissue repair.

Abstract: In this article we discuss the function of the most widely expressed member of the TG family "tissue transglutaminase" (TG2) in wound repair.

Abstract: Using both early and recent evidence from the literature we demonstrate how the multifunctional TG2 affects the stability of the ECM, cell-ECM interactions and as a consequence cell behavior within the different phases of wound healing, and highlight how TG2 itself might be exploited for therapeutic use.


Crystal structures of the glutamate receptor ion channel GluK3 and GluK5 amino-terminal domains.

Abstract: Ionotropic glutamate receptors (iGluRs) mediate the majority of fast excitatory synaptic neurotransmission in the central nervous system.

Abstract: The selective assembly of iGluRs into AMPA, kainate, and N-methyl-d-aspartic acid (NMDA) receptor subtypes is regulated by their extracellular amino-terminal domains (ATDs).

Abstract: Kainate receptors are further classified into low-affinity receptor families (GluK1-GluK3) and high-affinity receptor families (GluK4-GluK5) based on their affinity for the neurotoxin kainic acid.

Abstract: These two families share a 42% sequence identity for the intact receptor but only a 27% sequence identity at the level of ATD.

Abstract: We have determined for the first time the high-resolution crystal structures of GluK3 and GluK5 ATDs, both of which crystallize as dimers but with a strikingly different dimer assembly at the R1 interface.

Abstract: By contrast, for both GluK3 and GluK5, the R2 domain dimer assembly is similar to those reported previously for other non-NMDA iGluRs.

Abstract: This observation is consistent with the reports that GluK4-GluK5 cannot form functional homomeric ion channels and require obligate coassembly with GluK1-GluK3.

Abstract: Our analysis also reveals that the relative orientation of domains R1 and R2 in individual non-NMDA receptor ATDs varies by up to 10°, in contrast to the 50° difference reported for the NMDA receptor GluN2B subunit.

Abstract: This restricted domain movement in non-NMDA receptor ATDs seems to result both from extensive intramolecular contacts between domain R1 and domain R2 and from their assembly as dimers, which interact at both R1 and R2 domains.

Abstract: Our results provide the first insights into the structure and function of GluK4-GluK5, the least understood family of iGluRs.


Effectiveness of screening older people for impaired vision in community setting: systematic review of evidence from randomised controlled trials.

Abstract: OBJECTIVE To assess whether population screening for impaired vision among older people in the community leads to improvements in vision.

Abstract: DESIGN Systematic review of randomised controlled trials of population screening in the community that included any assessment of vision or visual function with at least 6 months' follow up.

Abstract: SUBJECTS Adults aged 65 or over.

Abstract: MAIN OUTCOME MEASURE Proportions with visual impairment in intervention and control groups with any method of assessing visual impairment.

Abstract: RESULTS There were no trials that primarily assessed visual screening.

Abstract: Outcome data on vision were available for 3494 people in five trials of multiphasic assessment.

Abstract: All the trials used self reported measures for vision impairment, both as screening tools and as outcome measures.

Abstract: The inclusion of a visual screening component in the assessment did not result in improvements in self reported visual problems (pooled odds ratio 1.04:95% confidence interval 0.89 to 1.22).

Abstract: A small reduction (11%) in the number of older people with self reported visual problems cannot be excluded.

Abstract: CONCLUSIONS Screening of asymptomatic older people in the community is not justified on present evidence.

Abstract: Visual impairment in this age group can usually be reduced with treatment.

Abstract: It is unclear why no benefit was seen.

Abstract: Further work is needed to clarify what interventions are appropriate for older people with unreported impairment of vision.


Protein interaction network of the mammalian Hippo pathway reveals mechanisms of kinase-phosphatase interactions.

Abstract: The Hippo pathway regulates organ size and tissue homeostasis in response to multiple stimuli, including cell density and mechanotransduction.

Abstract: Pharmacological inhibition of phosphatases can also stimulate Hippo signaling in cell culture.

Abstract: We defined the Hippo protein-protein interaction network with and without inhibition of serine and threonine phosphatases by okadaic acid.

Abstract: We identified 749 protein interactions, including 599 previously unrecognized interactions, and demonstrated that several interactions with serine and threonine phosphatases were phosphorylation-dependent.

Abstract: Mutation of the T-loop of MST2 (mammalian STE20-like protein kinase 2), which prevented autophosphorylation, disrupted its association with STRIPAK (striatin-interacting phosphatase and kinase complex).

Abstract: Deletion of the amino-terminal forkhead-associated domain of SLMAP (sarcolemmal membrane-associated protein), a component of the STRIPAK complex, prevented its association with MST1 and MST2.

Abstract: Phosphatase inhibition produced temporally distinct changes in proteins that interacted with MOB1A and MOB1B (Mps one binder kinase activator-like 1A and 1B) and promoted interactions with upstream Hippo pathway proteins, such as MST1 and MST2, and with the trimeric protein phosphatase 6 complex (PP6).

Abstract: Mutation of three basic amino acids that are part of a phospho-serine- and phospho-threonine-binding domain in human MOB1B prevented its interaction with MST1 and PP6 in cells treated with okadaic acid.

Abstract: Collectively, our results indicated that changes in phosphorylation orchestrate interactions between kinases and phosphatases in Hippo signaling, providing a putative mechanism for pathway regulation.


Differential Effects of N-Acetylcysteine, Theophylline or Bicarbonate on Contrast-Induced Rat Renal Vasoconstriction

Abstract: Background: Vasoconstriction and reactive oxygen species (ROS) accumulation following contrast media (CM) injection are the key factors triggering CM-induced nephropathy.

Abstract: We compared the effects of N-acetylcysteine (NAC), theophylline or sodium bicarbonate on intrarenal vasoconstriction and ROS generation in a rat model of CM-induced nephropathy.

Abstract: Methods: Following a 3-day dehydration, Sprague-Dawley rats received CM (Telebrix) or sham ‘CM’ injection of 0.9% saline.

Abstract: Part of them received NAC, theophylline or bicarbonate prior to CM.

Abstract: Medullar renal blood flow was estimated by laser Doppler.

Abstract: The animals were sacrificed 1, 15 or 30 min after the respective treatments, their kidneys allocated and intrarenal STAT-8 isoprostane, PGE2 and NO assessed.

Abstract: Results: Vasoconstriction was significantly attenuated by NAC.

Abstract: Theophylline only mildly attenuated the perfusion drop at 15 min, and was ineffective following 30 min.

Abstract: Unlike theophylline or bicarbonate, NAC significantly augmented intrarenal PGE2.

Abstract: NAC, theophylline but not bicarbonate, gradually increased intrarenal NO.

Abstract: In all experimental variables, CM-induced ROS accumulation, represented by STAT-8 isoprostane estimation, progressed undisturbed.

Abstract: Conclusions: (1) CM-induced intrarenal vasoconstriction was efficiently prohibited by NAC but not bicarbonate or theophylline; (2) the vasodilatory effect of NAC was mediated via increased PGE2 synthesis, and (3) ROS accumulation was a primary renal response to CM-induced injury, not affected by any pharmacologic manipulations.


Induction of AMPK activity corrects early pathophysiological alterations in the subtotal nephrectomy model of chronic kidney disease.

Abstract: The rat kidney ablation and infarction (A/I) model of subtotal or 5/6th nephrectomy is the most commonly studied model of nondiabetic chronic kidney disease (CKD).

Abstract: The A/I kidney at 1 wk exhibits reductions in kidney function, as determined by glomerular filtration rate, and diminished metabolic efficiency as determined by oxygen consumption per sodium transport (QO2/TNa).

Abstract: As renoprotective AMPK activity is affected by metabolic changes and cellular stress, we evaluated AMPK activity in this model system.

Abstract: We show that these early pathophysiological changes are accompanied by a paradoxical decrease in AMPK activity.

Abstract: Over time, these kidney parameters progressively worsen with extensive kidney structural, functional, metabolic, and fibrotic changes observed at 4 wk after A/I. We show that induction of AMPK activity with either metformin or 5-aminoimidazole-4-carboxamide ribonucleotide increases AMPK activity in this model and also corrects kidney metabolic inefficiency, improves kidney function, and ameliorates kidney fibrosis and structural alterations.

Abstract: We conclude that AMPK activity is reduced in the subtotal nephrectomy model of nondiabetic CKD, that altered regulation of AMPK is coincident with the progression of disease parameters, and that restoration of AMPK activity can suppress the progressive loss of function characteristic of this model.

Abstract: We propose that induction of AMPK activity may prove an effective therapeutic target for the treatment of nondiabetic CKD.


Magnetic resonance imaging for volume estimation of large multinodular goitres: a comparison with scintigraphy.

Abstract: As a result of increasing interest in non-surgical treatment for the reduction of goitre size the use of magnetic resonance (MR) imaging for volume estimation of large multinodular goitres was evaluated in 20 patients (three males and 17 females; age 61 +/-

Abstract: 21 years) with a multinodular goitre larger than 100 ml.

Abstract: In addition, MR measurements were compared with scintigraphic (SC) volume estimations.

Abstract: Intraobserver coefficient of variation (CV) of MR measurements was 2.2 +/-

Abstract: 2.0% (Observer 1) and interobserver CV 4.1 +/-

Abstract: 2.2% (Observers 1 and 2).

Abstract: In all 20 patients signs of mechanical complications were shown on MR images.

Abstract: For SC measurements intraobserver CV was 7.5 +/-

Abstract: 5.7% (Observer 3) and 5.4 +/-

Abstract: 5.1% (Observer 4).

Abstract: Interobserver CV was 10.1 +/-

Abstract: The correlation between measurements with both methods was not strong (r = 0.665) and the resulting CV was 17.3 +/-

Abstract: Underestimation of SC volumes could not be explained by the presence of cysts on the surface of the thyroid.

Abstract: It is concluded that MR imaging can be used for in vivo thyroid volume estimation in large multinodular goitres.

Abstract: The high precision of MR measurements makes this technique potentially useful for the evaluation of thyroid growth and non-surgical treatment for reducing goitre size.

Abstract: Scintigraphic volume measurements do not suffice for this purpose.

Abstract: An additional advantage of MR imaging is the detailed anatomical information it provides with regard to mechanical complications of large goitres.


Differential role of CbpA and PspA in modulation of in vitro CXC chemokine responses of respiratory epithelial cells to infection with Streptococcus pneumoniae.

Abstract: Respiratory epithelial cells play an active part in the host response to respiratory pathogens, such as Streptococcus pneumoniae, by releasing chemokines responsible for neutrophil recruitment.

Abstract: In order to investigate the role of specific pneumococcal virulence factors in eliciting CXC chemokine responses, type II pneumocytes (A549) and nasopharyngeal cells (Detroit-562) were infected with S. pneumoniae D39 or mutants lacking choline-binding protein A (CbpA), pneumococcal surface protein A (PspA), or specific domains thereof.

Abstract: In response to wild-type D39, both A549 and Detroit-562 cells showed a significant increase in CXC chemokine mRNA and interleukin-8 protein.

Abstract: This response was increased twofold when a cbpA deletion mutant (DeltaCbpA) was used, suggesting that CbpA inhibits CXC chemokine induction.

Abstract: All three N-terminal domains of CbpA are required for this effect, as in-frame deletion of the respective region of cbpA had the same effect on the CXC chemokine response as deletion of cbpA altogether.

Abstract: Infection with a pspA deletion mutant (DeltaPspA) led to a twofold decrease in the CXC chemokine response of A549 but not Detroit-562 cells, compared to infection with D39 at 2 h. Thus, PspA appears to have the ability to stimulate early CXC chemokine release from A549 cells.

Abstract: Deletion of the region of pspA encoding the first N-terminal alpha-helical domain reduced the ability of S. pneumoniae to elicit a chemokine response to the same degree as deletion of pspA altogether.

Abstract: Thus, the N termini of CbpA and PspA exert differential effects on CXC chemokine induction in epithelial cells infected with S. pneumoniae.


HIV-1 therapy with monoclonal antibody 3BNC117 elicits host immune responses against HIV-1

Abstract: 3BNC117 is a broad and potent neutralizing antibody to HIV-1 that targets the CD4 binding site on the viral envelope spike.

Abstract: When administered passively, this antibody can prevent infection in animal models and suppress viremia in HIV-1–infected individuals.

Abstract: Here we report that HIV-1 immunotherapy with a single injection of 3BNC117 affects host antibody responses in viremic individuals.

Abstract: In comparison to untreated controls that showed little change in their neutralizing activity over a 6-month period, 3BNC117 infusion significantly improved neutralizing responses to heterologous tier 2 viruses in nearly all study participants.

Abstract: We conclude that 3BNC117-mediated immunotherapy enhances host humoral immunity to HIV-1.


Safety and efficacy of RNAi therapy for transthyretin amyloidosis.

Abstract: BACKGROUND Transthyretin amyloidosis is caused by the deposition of hepatocyte-derived transthyretin amyloid in peripheral nerves and the heart.

Abstract: A therapeutic approach mediated by RNA interference (RNAi) could reduce the production of transthyretin.

Abstract: METHODS We identified a potent antitransthyretin small interfering RNA, which was encapsulated in two distinct first- and second-generation formulations of lipid nanoparticles, generating ALN-TTR01 and ALN-TTR02, respectively.

Abstract: Each formulation was studied in a single-dose, placebo-controlled phase 1 trial to assess safety and effect on transthyretin levels.

Abstract: We first evaluated ALN-TTR01 (at doses of 0.01 to 1.0 mg per kilogram of body weight) in 32 patients with transthyretin amyloidosis and then evaluated ALN-TTR02 (at doses of 0.01 to 0.5 mg per kilogram) in 17 healthy volunteers.

Abstract: RESULTS Rapid, dose-dependent, and durable lowering of transthyretin levels was observed in the two trials.

Abstract: At a dose of 1.0 mg per kilogram, ALN-TTR01 suppressed transthyretin, with a mean reduction at day 7 of 38%, as compared with placebo (P=0.01); levels of mutant and nonmutant forms of transthyretin were lowered to a similar extent.

Abstract: For ALN-TTR02, the mean reductions in transthyretin levels at doses of 0.15 to 0.3 mg per kilogram ranged from 82.3 to 86.8%, with reductions of 56.6 to 67.1% at 28 days (P<0.001 for all comparisons).

Abstract: These reductions were shown to be RNAi-mediated.

Abstract: Mild-to-moderate infusion-related reactions occurred in 20.8% and 7.7% of participants receiving ALN-TTR01 and ALN-TTR02, respectively.

Abstract: CONCLUSIONS ALN-TTR01 and ALN-TTR02 suppressed the production of both mutant and nonmutant forms of transthyretin, establishing proof of concept for RNAi therapy targeting messenger RNA transcribed from a disease-causing gene.

Abstract: (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov numbers, NCT01148953 and NCT01559077.).


The mechanosensitive ion channel Piezo1 is inhibited by the peptide GsMTx4.

Abstract: Cells can respond to mechanical stress by gating mechanosensitive ion channels (MSCs).

Abstract: The cloning of Piezo1, a eukaryotic cation selective MSC, defines a new system for studying mechanical transduction at the cellular level.

Abstract: Because Piezo1 has electrophysiological properties similar to those of endogenous cationic MSCs that are selectively inhibited by the peptide GsMTx4, we tested whether the peptide targets Piezo1 activity.

Abstract: Extracellular GsMTx4 at micromolar concentrations reversibly inhibited ∼80% of the mechanically induced current of outside-out patches from transfected HEK293 cells.

Abstract: The inhibition was voltage insensitive, and as seen with endogenous MSCs, the mirror image d enantiomer inhibited like the l. The rate constants for binding and unbinding based on Piezo1 current kinetics provided association and dissociation rates of 7.0 × 10(5) M(-1) s(-1) and 0.11 s(-1), respectively, and a K(D) of ∼155 nM, similar to values previously reported for endogenous MSCs.

Abstract: Consistent with predicted gating modifier behavior, GsMTx4 produced an ∼30 mmHg rightward shift in the pressure-gating curve and was active on closed channels.

Abstract: In contrast, streptomycin, a nonspecific inhibitor of cationic MSCs, showed the use-dependent inhibition characteristic of open channel block.

Abstract: The peptide did not block currents of the mechanical channel TREK-1 on outside-out patches.

Abstract: Whole-cell Piezo1 currents were also reversibly inhibited by GsMTx4, and although the off rate was nearly identical to that of outside-out patches, differences were observed for the on rate.

Abstract: The ability of GsMTx4 to target the mechanosensitivity of Piezo1 supports the use of this channel in high-throughput screens for pharmacological agents and diagnostic assays.


Thiazolidinediones improve beta-cell function in type 2 diabetic patients.

Abstract: Thiazolidinediones (TZDs) improve glycemic control and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM).

Abstract: There is growing evidence from in vivo and in vitro studies that TZDs improve pancreatic beta-cell function.

Abstract: The aim of this study was to determine whether TZD-induced improvement in glycemic control is associated with improved beta-cell function.

Abstract: We studied 11 normal glucose-tolerant and 53 T2DM subjects [age 53+/-2 yr; BMI 29.4+/-0.8 kg/m2; fasting plasma glucose (FPG) 10.3+/-0.4 mM; Hb A1c 8.2+/-0.3%].

Abstract: Diabetic patients were randomized to receive placebo or TZD for 4 mo.

Abstract: Subjects received 1) 2-h OGTT with determination of plasma glucose, insulin, and C-peptide concentrations and 2) two-step euglycemic insulin (40 and 160 mU.m-2.min-1) clamp with [3-(3)H]glucose.

Abstract: T2DM patients were then randomized to receive 4 mo of treatment with pioglitazone (45 mg/day), rosiglitazone (8 mg/day), or placebo.

Abstract: Pioglitazone and rosiglitazone similarly improved FPG, mean plasma glucose during OGTT, Hb A1c, and insulin-mediated total body glucose disposal (Rd) and decreased mean plasma FFA during OGTT (all P<0.01, ANOVA).

Abstract: The insulin secretion/insulin resistance (disposition) index [DeltaISR(AUC)/Deltaglucose(AUC)/IR] was significantly improved in all TZD-treated groups: +1.8+/-0.7 (PIO+drug-naïve diabetics), +0.7+/-0.3 (PIO+sulfonylurea-treated diabetics), and 0.7+/-0.2 (ROSI+sulfonylurea-withdrawn diabetics) vs. -0.2+/-0.3 in the two placebo groups (P<0.01, all TZDs vs. placebo, ANOVA).

Abstract: Improved insulin secretion correlated positively with increased body weight, fat mass, and Rd and inversely with decreased plasma glucose and FFA during the OGTT.

Abstract: In T2DM patients, TZD treatment leads to improved beta-cell function, which correlates strongly with improved glycemic control.


A novel Ku70 function in colorectal homeostasis separate from nonhomologous end joining

Abstract: Ku70, a known nonhomologous end-joining (NHEJ) factor, also functions in tumor suppression, although this molecular mechanism remains uncharacterized.

Abstract: Previously, we showed that mice deficient for DNA ligase IV (Lig4), another key NHEJ factor, succumbed to aggressive lymphoma in the absence of tumor suppressor p53.

Abstract: However, the tumor phenotype is abrogated by the introduction of a hypomorphic mutant p53R172P, which impaired p53-mediated apoptosis but not cell-cycle arrest.

Abstract: However, Lig4−/−p53R172P mice succumbed to severe diabetes.

Abstract: To further elucidate the role of NHEJ and p53-mediated apoptosis in vivo, we bred Ku70−/− p53R172P mice.

Abstract: Unexpectedly, these mice were free of diabetes, although 80% of the mutant mice had abnormally enlarged colons with pronounced inflammation.

Abstract: Remarkably, most of these mutant mice progressed to dysplasia, adenoma and adenocarcinoma; this is in contrast to the Lig4−/−p53R172P phenotype, strongly suggesting an NHEJ-independent function of Ku70.

Abstract: Significantly, our analyses of Ku70−/−p53R172P colonic epithelial cells show nuclear stabilization of β-catenin accompanied by higher expression of cyclin D1 and c-Myc in affected colon sections than in control samples.

Abstract: This is not due to the p53 mutation, as Ku70−/− mice share this phenotype.

Abstract: Our results not only unravel a novel function of Ku70 essential for colon homeostasis, but also establish an excellent in vivo model in which to study how chronic inflammation and abnormal cellular proliferation underlie tumorigenesis and tumor progression in the colon.


Association of Sickle Cell Trait With Hemoglobin A1c in African Americans

Abstract: Importance Hemoglobin A1c (HbA1c) reflects past glucose concentrations, but this relationship may differ between those with sickle cell trait (SCT) and those without it.

Abstract: Objective To evaluate the association between SCT and HbA1c for given levels of fasting or 2-hour glucose levels among African Americans.

Abstract: Design, Setting, and Participants Retrospective cohort study using data collected from 7938 participants in 2 community-based cohorts, the Coronary Artery Risk Development in Young Adults (CARDIA) study and the Jackson Heart Study (JHS).

Abstract: From the CARDIA study, 2637 patients contributed a maximum of 2 visits (2005-2011); from the JHS, 5301 participants contributed a maximum of 3 visits (2000-2013).

Abstract: All visits were scheduled at approximately 5-year intervals.

Abstract: Participants without SCT data, those without any concurrent HbA1c and glucose measurements, and those with hemoglobin variants HbSS, HbCC, or HbAC were excluded.

Abstract: Analysis of the primary outcome was conducted using generalized estimating equations (GEE) to examine the association of SCT with HbA1c levels, controlling for fasting or 2-hour glucose measures.

Abstract: Exposures Presence of SCT.

Abstract: Main Outcomes and Measures Hemoglobin A1c stratified by the presence or absence of SCT was the primary outcome measure.

Abstract: Results The analytic sample included 4620 participants (mean age, 52.3 [SD, 11.8] years; 2835 women [61.3%]; 367 [7.9%] with SCT) with 9062 concurrent measures of fasting glucose and HbA1c levels.

Abstract: In unadjusted GEE analyses, for a given fasting glucose, HbA1c values were statistically significantly lower in those with (5.72%) vs those without (6.01%) SCT (mean HbA1c difference, −0.29%; 95% CI, −0.35% to −0.23%).

Abstract: Findings were similar in models adjusted for key risk factors and in analyses using 2001 concurrent measures of 2-hour glucose and HbA1c concentration for those with SCT (mean, 5.35%) vs those without SCT (mean, 5.65%) for a mean HbA1c difference of −0.30% (95% CI, −0.39% to −0.21%).

Abstract: The HbA1c difference by SCT was greater at higher fasting (P = .02 for interaction) and 2-hour (P = .03) glucose concentrations.

Abstract: The prevalence of prediabetes and diabetes was statistically significantly lower among participants with SCT when defined using HbA1c values (29.2% vs 48.6% for prediabetes and 3.8% vs 7.3% for diabetes in 572 observations from participants with SCT and 6877 observations from participants without SCT; P<.001 for both comparisons).

Abstract: Conclusions and Relevance Among African Americans from 2 large, well-established cohorts, participants with SCT had lower levels of HbA1c at any given concentration of fasting or 2-hour glucose compared with participants without SCT.

Abstract: These findings suggest that HbA1c may systematically underestimate past glycemia in black patients with SCT and may require further evaluation.


PGAP2 mutations, affecting the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation syndrome.

Abstract: Recently, mutations in genes involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor have been identified in a new subclass of congenital disorders of glycosylation (CDGs) with a distinct spectrum of clinical features.

Abstract: To date, mutations have been identified in six genes (PIGA, PIGL, PIGM, PIGN, PIGO, and PIGV) encoding proteins in the GPI-anchor-synthesis pathway in individuals with severe neurological features, including seizures, muscular hypotonia, and intellectual disability.

Abstract: We developed a diagnostic gene panel for targeting all known genes encoding proteins in the GPI-anchor-synthesis pathway to screen individuals matching these features, and we detected three missense mutations in PGAP2, c.46C>T, c.380T>C, and c.479C>T, in two unrelated individuals with hyperphosphatasia with mental retardation syndrome (HPMRS).

Abstract: The mutations cosegregated in the investigated families.

Abstract: PGAP2 is involved in fatty-acid GPI-anchor remodeling, which occurs in the Golgi apparatus and is required for stable association between GPI-anchored proteins and the cell-surface membrane rafts.

Abstract: Transfection of the altered protein constructs, p.

Abstract: Arg16Trp (NP_001243169.1), p.

Abstract: Leu127Ser, and p.

Abstract: Thr160Ile, into PGAP2-null cells showed only partial restoration of GPI-anchored marker proteins, CD55 and CD59, on the cell surface.

Abstract: In this work, we show that an impairment of GPI-anchor remodeling also causes HPMRS and conclude that targeted sequencing of the genes encoding proteins in the GPI-anchor-synthesis pathway is an effective diagnostic approach for this subclass of CDGs.


Screening for Lung Cancer: U.S. Preventive Services Task Force Recommendation Statement

Abstract: The U.S. Preventive Services Task Force (USPSTF) makes recommendations about the effectiveness of specific preventive care services for patients without related signs or symptoms.

Abstract: It bases its recommendations on the evidence of both the benefits and harms of the service and an assessment of the balance.

Abstract: The USPSTF does not consider the costs of providing a service in this assessment.

Abstract: The USPSTF recognizes that clinical decisions involve more considerations than evidence alone.

Abstract: Clinicians should understand the evidence but individualize decision making to the specific patient or situation.

Abstract: Similarly, the USPSTF notes that policy and coverage decisions involve considerations in addition to the evidence of clinical benefits and harms.

Abstract: Summary of Recommendation and Evidence The USPSTF recommends annual screening for lung cancer with low-dose computed tomography (LDCT) in adults aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years.

Abstract: Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery.

Abstract: (B recommendation)

Abstract: See the Clinical Considerations section for suggestions for implementation in practice.

Abstract: See the Figure for a summary of the recommendation and suggestions for clinical practice.

Abstract: Figure.

Abstract: Screening for lung cancer: clinical summary of U.S. Preventive Services Task Force recommendation.

Abstract: Appendix Table 1 describes the USPSTF grades, and Appendix Table 2 describes the USPSTF classification of levels of certainty about net benefit.

Abstract: Appendix Table 1.

Abstract: What the USPSTF Grades Mean and Suggestions for Practice Appendix Table 2.

Abstract: USPSTF Levels of Certainty Regarding Net Benefit Supplement.

Abstract: Consumer Fact Sheet.

Abstract: Rationale Importance Lung cancer is the third most common cancer and the leading cause of cancer-related death in the United States (1).

Abstract: The most important risk factor for lung cancer is smoking, which results in approximately 85% of all U.S. lung cancer cases (2).

Abstract: Although the prevalence of smoking has decreased, approximately 37% of U.S. adults are current or former smokers (2).

Abstract: The incidence of lung cancer increases with age and occurs most commonly in persons aged 55 years or older.

Abstract: Increasing age and cumulative exposure to tobacco smoke are the 2 most common risk factors for lung cancer.

Abstract: Lung cancer has a poor prognosis, and nearly 90% of persons with lung cancer die of the disease.

Abstract: However, early-stage nonsmall cell lung cancer (NSCLC) has a better prognosis and can be treated with surgical resection.

Abstract: Detection Most lung cancer cases are NSCLC, and most screening programs focus on the detection and treatment of early-stage NSCLC.

Abstract: Although chest radiography and sputum cytologic evaluation have been used to screen for lung cancer, LDCT has greater sensitivity for detecting early-stage cancer (3).

Abstract: Benefits of Detection and Early Treatment Although lung cancer screening is not an alternative to smoking cessation, the USPSTF found adequate evidence that annual screening for lung cancer with LDCT in a defined population of high-risk persons can prevent a substantial number of lung cancerrelated deaths.

Abstract: Direct evidence from a large, well-conducted, randomized, controlled trial (RCT) provides moderate certainty of the benefit of lung cancer screening with LDCT in this population (4).

Abstract: The magnitude of benefit to the person depends on that person's risk for lung cancer because those who are at highest risk are most likely to benefit.

Abstract: Screening cannot prevent most lung cancerrelated deaths, and smoking cessation remains essential.

Abstract: Harms of Detection and Early Intervention and Treatment The harms associated with LDCT screening include false-negative and false-positive results, incidental findings, overdiagnosis, and radiation exposure.

Abstract: False-positive LDCT results occur in a substantial proportion of screened persons; 95% of all positive results do not lead to a diagnosis of cancer.

Abstract: In a high-quality screening program, further imaging can resolve most false-positive results; however, some patients may require invasive procedures.

Abstract: The USPSTF found insufficient evidence on the harms associated with incidental findings.

Abstract: Overdiagnosis of lung cancer occurs, but its precise magnitude is uncertain.

Abstract: A modeling study performed for the USPSTF estimated that 10% to 12% of screen-detected cancer cases are overdiagnosedthat is, they would not have been detected in the patient's lifetime without screening.

Abstract: Radiation harms, including cancer resulting from cumulative exposure to radiation, vary depending on the age at the start of screening; the number of scans received; and the person's exposure to other sources of radiation, particularly other medical imaging.

Abstract: USPSTF Assessment The USPSTF concludes with moderate certainty that annual screening for lung cancer with LDCT is of moderate net benefit in asymptomatic persons who are at high risk for lung cancer based on age, total cumulative exposure to tobacco smoke, and years since quitting smoking.

Abstract: The moderate net benefit of screening depends on limiting screening to persons who are at high risk, the accuracy of image interpretation being similar to that found in the NLST (National Lung Screening Trial), and the resolution of most false-positive results without invasive procedures (4).

Abstract: Clinical Considerations Patient Population Under Consideration The risk for lung cancer increases with age and cumulative exposure to tobacco smoke and decreases with time since quitting smoking.

Abstract: The best evidence for the benefit of screening comes from the NLST, which enrolled adults aged 55 to 74 years who had at least a 30 pack-year smoking history and were current smokers or had quit within the past 15 years.

Abstract: As with all screening trials, the NLST tested a specific intervention over a finite period.

Abstract: Because initial eligibility extended through age 74 years and participants received 3 annual screening computed tomographic scans, the oldest participants in the trial were aged 77 years.

Abstract: The USPSTF used modeling studies to predict the benefits and harms of screening programs that use different screening intervals, age ranges, smoking histories, and times since quitting.

Abstract: A program that annually screens adults aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years is projected to have a reasonable balance of benefits and harms.

Abstract: The model assumes that persons who achieve 15 years of smoking cessation during the screening program discontinue screening.

Abstract: This model predicts the outcomes of continuing the screening program used in the NLST through age 80 years.

Abstract: Screening may not be appropriate for patients with substantial comorbid conditions, particularly those at the upper end of the screening age range.

Abstract: The NLST excluded persons who were unlikely to complete curative lung cancer surgery and those with medical conditions that posed a substantial risk for death during the 8-year trial.

Abstract: The baseline characteristics of the NLST showed a relatively healthy sample, and fewer than 10% of enrolled participants were older than 70 years (5).

Abstract: Persons with serious comorbid conditions may experience net harm, no net benefit, or at least substantially less net benefit.

Abstract: Similarly, persons who are unwilling to have curative lung surgery are unlikely to benefit from a screening program.

Abstract: Assessment of Risk Age, total exposure to tobacco smoke, and years since quitting smoking are important risk factors for lung cancer and were used to determine eligibility in the NLST.

Abstract: Other risk factors include specific occupational exposures, radon exposure, family history, and history of pulmonary fibrosis or chronic obstructive lung disease.

Abstract: The incidence of lung cancer is relatively low in persons younger than 50 years but increases with age, especially after age 60 years.

Abstract: In current and former smokers, age-specific incidence rates increase with age and cumulative exposure to tobacco smoke.

Abstract: Smoking cessation substantially reduces a person's risk for developing and dying of lung cancer.

Abstract: Among persons enrolled in the NLST, those who were at highest risk because of additional risk factors or a greater cumulative exposure to tobacco smoke experienced most of the benefit (6).

Abstract: A validated multivariate model showed that persons in the highest 60% of risk accounted for 88% of all deaths preventable by screening.

Abstract: Screening Tests Low-dose computed tomography has shown high sensitivity and acceptable specificity for the detection of lung cancer in high-risk persons.

Abstract: Chest radiography and sputum cytologic evaluation have not shown adequate sensitivity or specificity as screening tests.

Abstract: Therefore, LDCT is currently the only recommended screening test for lung cancer.

Abstract: Treatment Surgical resection is the current standard of care for localized NSCLC.

Abstract: This type of cancer is treated with surgical resection when possible and also with radiation and chemotherapy.

Abstract: Annual LDCT screening may not be useful for patients with life-limiting comorbid conditions or poor functional status who may not be candidates for surgery.

Abstract: Other Approaches to Prevention Smoking cessation is the most important intervention to prevent NSCLC.

Abstract: Advising smokers to stop smoking and preventing nonsmokers from being exposed to tobacco smoke are the most effective ways to decrease the morbidity and mortality associated with lung cancer.

Abstract: Current smokers should be informed of their continuing risk for lung cancer and offered cessation treatments.

Abstract: Screening with LDCT should be viewed as an adjunct to tobacco cessation interventions.

Abstract: Useful Resources Clinicians have many resources to help patients stop smoking.

Abstract: The Centers for Disease Control and Prevention has developed a Web site with many such resources, including information on tobacco quit lines, available in several languages (www.cdc.gov/tobacco/campaign/tips).

Abstract: Quit l


Dual role of interleukin-10 in the regulation of respiratory syncitial virus (RSV)-induced lung inflammation.

Abstract: RSV lower respiratory tract infections (LRTI) are among the most common diseases necessitating hospital admission in children.

Abstract: In addition to causing acute respiratory failure, RSV infections are associated with sequelae such as secondary bacterial infections and reactive airway disease.

Abstract: One characteristic host response observed in severe RSV-induced LRTI and/or subsequent development of asthma is increased expression of interleukin (IL)-10.

Abstract: However, contradictory results have been reported regarding whether IL-10 inhibits asthmatic responses or intensifies the disease.

Abstract: We aimed to reconcile these discordant observations by elucidating the role of IL-10 in regulating the host response to RSV LRTI.

Abstract: In this study, we used a lung-specific, inducible IL-10 over-expression (OE) transgenic mouse model to address this question.

Abstract: Our results showed that the presence of IL-10 at the time of RSV infection not only attenuated acute inflammatory process (i.e. 24 h post-infection), but also late inflammatory changes [characterized by T helper type 2 (Th2) cytokine and chemokine expression].

Abstract: While this result appears contradictory to some clinical observations where elevated IL-10 levels are observed in asthmatic patients, we also found that delaying IL-10 OE until the late immune response to RSV infection, additive effects rather than inhibitory effects were observed.

Abstract: Importantly, in non-infected, IL-10 OE mice, IL-10 OE alone induced up-regulation of Th2 cytokine (IL-13 and IL-5) and Th2-related chemokine [monocyte chemoattractant protein 1 (MCP-1), chemokine (C-C motif) ligand 3 (CCL3) and regulated upon activation normal T cell expressed and secreted (RANTES)] expression.

Abstract: We identified a subset of CD11b(+)CD11c(+)CD49b(+)F4/80(-)Gr-1(-) myeloid cells as a prinicipal source of IL-10-induced IL-13 production.

Abstract: Therefore, the augmented pathological responses observed in our 'delayed' IL-10 over-expression model could be attributed to IL-10 OE alone.

Abstract: Taken together, our study indicated dual roles of IL-10 on RSV-induced lung inflammation which appear to depend upon the timing of when elevated IL-10 is expressed in the lung.


Latent membrane protein 1 of Epstein–Barr virus coordinately regulates proliferation with control of apoptosis

Abstract: Latent membrane protein 1 (LMP1), an oncoprotein encoded by Epstein–Barr virus (EBV), is an integral membrane protein, which acts like a constitutively active receptor.

Abstract: LMP1 is critical for some facet of EBV's induction and maintenance of proliferation of infected B cells.

Abstract: It, in part, mimics signaling by the CD40 receptor and has been implicated in regulating proliferation, survival, or both properties of EBV-infected cells.

Abstract: We established a conditional LMP1 allele in the context of the intact EBV genome to define the immediate-early cellular target genes regulated by LMP1 in order to assess its contributions to infected human B cells.

Abstract: The functional analysis of this conditional system indicated that LMP1 specifically induces mitogenic B-cell activation through c-myc and Jun/AP1 family members and confirms its direct role in upregulating expression of multiple genes with opposing activities involved in cell survival.

Abstract: LMP1's signals were found to be essential for the G1/S transition in human B cells; cells lacking LMP1's signals are cell cycle arrested and survive quiescently.

Abstract: LMP1's activities are therefore not required to maintain survival in nonproliferating cells.

Abstract: LMP1 does induce both pro- and antiapoptotic genes whose balance seems to permit survival during LMP1's induction and maintenance of proliferation.


Crizotinib in ROS1-rearranged non-small-cell lung cancer.

Abstract: BACKGROUND Chromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase (ROS1) define a distinct molecular subgroup of non-small-cell lung cancers (NSCLCs) that may be susceptible to therapeutic ROS1 kinase inhibition.

Abstract: Crizotinib is a small-molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and another proto-oncogene receptor tyrosine kinase, MET.

Abstract: METHODS We enrolled 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement in an expansion cohort of the phase 1 study of crizotinib.

Abstract: Patients were treated with crizotinib at the standard oral dose of 250 mg twice daily and assessed for safety, pharmacokinetics, and response to therapy.

Abstract: ROS1 fusion partners were identified with the use of next-generation sequencing or reverse-transcriptase-polymerase-chain-reaction assays.

Abstract: RESULTS The objective response rate was 72% (95% confidence interval [CI], 58 to 84), with 3 complete responses and 33 partial responses.

Abstract: The median duration of response was 17.6 months (95% CI, 14.5 to not reached).

Abstract: Median progression-free survival was 19.2 months (95% CI, 14.4 to not reached), with 25 patients (50%) still in follow-up for progression.

Abstract: Among 30 tumors that were tested, we identified 7 ROS1 fusion partners: 5 known and 2 novel partner genes.

Abstract: No correlation was observed between the type of ROS1 rearrangement and the clinical response to crizotinib.

Abstract: The safety profile of crizotinib was similar to that seen in patients with ALK-rearranged NSCLC.

Abstract: CONCLUSIONS In this study, crizotinib showed marked antitumor activity in patients with advanced ROS1-rearranged NSCLC.

Abstract: ROS1 rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active.

Abstract: (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).


The S. cerevisiae Rrm3p DNA helicase moves with the replication fork and affects replication of all yeast chromosomes.

Abstract: The Saccharomyces cerevisiae DNA helicase Rrm3p is needed for normal fork progression through >1000 discrete sites scattered throughout the genome.

Abstract: Here we show that replication of all yeast chromosomes was markedly delayed in rrm3 cells.

Abstract: Delayed replication was seen even in a region that lacks any predicted Rrm3p-dependent sites.

Abstract: Based on the pattern of replication intermediates in two-dimensional gels, the rate of fork movement in rrm3 cells appeared similar to wild-type except at known Rrm3p-dependent sites.

Abstract: These data suggest that although Rrm3p has a global role in DNA replication, its activity is needed only or primarily at specific, difficult-to-replicate sites.

Abstract: By the criterion of chromatin immunoprecipitation, Rrm3p was associated with both Rrm3p-dependent and -independent sites, and moved with the replication fork through both.

Abstract: In addition, Rrm3p interacted with Pol2p, the catalytic subunit of DNA polymerase epsilon, in vivo.

Abstract: Thus, rather than being recruited to its sites of action when replication forks stall at these sites, Rrm3p is likely a component of the replication fork apparatus.


The pathophysiology of protein-overload proteinuria.

Abstract: Alterations in glomerular function and structure were studied in protein-overload nephrosis in the rat induced by intraperitoneal administration of bovine serum albumin (BSA).

Abstract: Fractional clearance (C/GFR) studies using inulin and tracer proteins of different molecular size and charge revealed in proteinuric rats 1) unchanged glomerular filtration rate and renal plasma flow; 2) a 34-fold increase in C/GFR of rat serum albumin, reaching values similar to BSA; 3) a 2-fold increase in C/GFR for anionic horse radish peroxidase (HRP), but normal values for neutral and cationic HRP, and 4) an 11- and 3-fold increase for heterologous IgG and IgM, respectively.

Abstract: Glomerular epithelial cells showed degenerative changes, but the distribution of anionic sites in the glomerular basement membrane was found to be unaltered, as determined by polyethyleneimine binding studies.

Abstract: In summary, an elevation of serum albumin concentration resulted in an increased transcapillary albumin transport.

Abstract: This was found to lead to degenerative changes of glomerular epithelial cells with development of large pore defects, which were completely reversible.


Effects of aging on central and peripheral mammalian clocks.

Abstract: Circadian organization changes with age, but we do not know the extent to which age-related changes are the result of alterations in the central pacemakers, the peripheral oscillators, or the coupling mechanisms that hold the system together.

Abstract: By using transgenic rats with a luciferase (luc) reporter, we assessed the effects of aging on the rhythm of expression of the Period 1 (Per1) gene in the suprachiasmatic nucleus (SCN) and in peripheral tissues.

Abstract: Young (2 months) and aged (24-26 months) Per1-luc transgenic rats, entrained to light-dark cycles, were killed, and tissues were removed and cultured.

Abstract: Per1-luc expression was measured from 10 tissues.

Abstract: In the SCN, the central mammalian pacemaker, Per1-luc expression was robustly rhythmic for more than 7 weeks in culture.

Abstract: The only difference between SCN rhythmicity in young and old rats was a small but significant age-related shortening of the free-running period.

Abstract: Circadian rhythmicity in some peripheral tissues was unaffected by aging, whereas rhythmicity in other tissues was either phase advanced relative to the light cycle or absent.

Abstract: Those tissues that were arrhythmic could be induced to oscillate by application of forskolin, suggesting that they retained the capacity to oscillate but were not being appropriately driven in vivo.

Abstract: Overall, the results provide new insights into the effects of aging on the mammalian circadian system.

Abstract: Aging seems to affect rhythms in some but not in all tissues and may act primarily on interactions among circadian oscillators, perhaps attenuating the ability of the SCN to drive damped oscillators in the periphery.


CtBP3/BARS drives membrane fission in dynamin-independent transport pathways

Abstract: Membrane fission is a fundamental step in membrane transport.

Abstract: So far, the only fission protein machinery that has been implicated in in vivo transport involves dynamin, and functions in several, but not all, transport pathways.

Abstract: Thus, other fission machineries may exist.

Abstract: Here, we report that carboxy-terminal binding protein 3/brefeldin A-ribosylated substrate (CtBP3/BARS) controls fission in basolateral transport from the Golgi to the plasma membrane and in fluid-phase endocytosis, whereas dynamin is not involved in these steps.

Abstract: Conversely, CtBP3/BARS protein is inactive in apical transport to the plasma membrane and in receptor-mediated endocytosis, both steps being controlled by dynamin.

Abstract: This indicates that CtBP3/BARS controls membrane fission in endocytic and exocytic transport pathways, distinct from those that require dynamin.


Influenza A myocarditis developing in an adult liver transplant recipient despite vaccination: a case report and review of the literature.

Abstract: Solid organ transplant recipients receiving chronic immunosuppressive agents are at increased risk to acquire influenza virus despite vaccination.

Abstract: Myocarditis is a known but rare complication of influenza infection.

Abstract: We present the first adult liver transplant recipient who received prophylactic vaccination but developed influenza A myocarditis.

Abstract: This may occur in solid organ transplant recipients, because they have reduced response to protein vaccines, which may leave them vulnerable to infections.

Abstract: Studies are needed to evaluate if antiviral chemoprophylaxis in solid organ transplant recipients during influenza season would be an effective preventive therapy against influenza in this high-risk population.


Extrapulmonary effects of chronic obstructive pulmonary disease on physical activity: a cross-sectional study.

Abstract: RATIONALE Physical activity is reduced in patients with chronic obstructive pulmonary disease (COPD).

Abstract: COPD has a systemic component that includes significant extrapulmonary effects that may contribute to its severity in individual patients.

Abstract: OBJECTIVES To investigate the association of extrapulmonary effects of the disease and its comorbidities with reduced physical activity in patients with COPD.

Abstract: METHODS In a cross-sectional study, 170 outpatients with COPD (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stages I-IV; BODE [body mass index, airway obstruction, dyspnea, and exercise capacity] score 0-10) underwent a series of tests.

Abstract: Physical activity was assessed over 5 to 6 consecutive days by using a multisensor accelerometer armband that records steps per day and the physical activity level (total daily energy expenditure divided by whole-night sleeping energy expenditure).

Abstract: Cardiovascular status was assessed by echocardiography, vascular Doppler sonography, and levels of N-terminal pro-B-type natriuretic peptide.

Abstract: Mental status, metabolic/muscular status, systemic inflammation, and anemia were assessed by Beck Depression Inventory, bioelectrical impedance analysis, handgrip strength, high-sensitivity C-reactive protein/fibrinogen, and hemoglobin, respectively.

Abstract: MEASUREMENTS AND MAIN RESULTS In a multivariate linear regression analysis using either steps per day or physical activity level as a dependent variable, the extrapulmonary parameters that were associated with reduced physical activity in patients with COPD independently of GOLD stages or BODE score were N-terminal pro-B-type natriuretic peptide levels, echocardiographically measured left ventricular diastolic function, and systemic inflammation.

Abstract: CONCLUSIONS Higher values of systemic inflammation and left cardiac dysfunction are associated with reduced physical activity in patients with COPD.


Cleavage efficient 2A peptides for high level monoclonal antibody expression in CHO cells.

Abstract: Linking the heavy chain (HC) and light chain (LC) genes required for monoclonal antibodies (mAb) production on a single cassette using 2A peptides allows control of LC and HC ratio and reduces non-expressing cells.

Abstract: Four 2A peptides derived from the foot-and-mouth disease virus (F2A), equine rhinitis A virus (E2A), porcine teschovirus-1 (P2A) and Thosea asigna virus (T2A), respectively, were compared for expression of 3 biosimilar IgG1 mAbs in Chinese hamster ovary (CHO) cell lines.

Abstract: HC and LC were linked by different 2A peptides both in the absence and presence of GSG linkers.

Abstract: Insertion of a furin recognition site upstream of 2A allowed removal of 2A residues that would otherwise be attached to the HC.

Abstract: Different 2A peptides exhibited different cleavage efficiencies that correlated to the mAb expression level.

Abstract: The relative cleavage efficiency of each 2A peptide remains similar for expression of different IgG1 mAbs in different CHO cells.

Abstract: While complete cleavage was not observed for any of the 2A peptides, GSG linkers did enhance the cleavage efficiency and thus the mAb expression level.

Abstract: T2A with the GSG linker (GT2A) exhibited the highest cleavage efficiency and mAb expression level.

Abstract: Stably amplified CHO DG44 pools generated using GT2A had titers 357, 416 and 600 mg/L for the 3 mAbs in shake flask batch cultures.

Abstract: Incomplete cleavage likely resulted in incorrectly processed mAb species and aggregates, which were removed with a chromatin-directed clarification method and protein A purification.

Abstract: The vector and methods presented provide an easy process beneficial for both mAb development and manufacturing.


The complexity of human ribosome biogenesis revealed by systematic nucleolar screening of Pre-rRNA processing factors.

Abstract: Mature ribosomal RNAs (rRNAs) are produced from polycistronic precursors following complex processing.

Abstract: Precursor (pre)-rRNA processing has been extensively characterized in yeast and was assumed to be conserved in humans.

Abstract: We functionally characterized 625 nucleolar proteins in HeLa cells and identified 286 required for processing, including 74 without a yeast homolog.

Abstract: For selected candidates, we demonstrated that pre-rRNA processing defects are conserved in different cell types (including primary cells), defects are not due to activation of a p53-dependent nucleolar tumor surveillance pathway, and they precede cell-cycle arrest and apoptosis.

Abstract: We also investigated the exosome's role in processing internal transcribed spacers (ITSs) and report that 3' end maturation of 18S rRNA involves EXOSC10/Rrp6, a yeast ITS2 processing factor.

Abstract: We conclude that human cells adopt unique strategies and recruit distinct trans-acting factors to carry out essential processing steps, posing fundamental implications for understanding ribosomopathies at the molecular level and developing effective therapeutic agents.


Maximal aerobic capacity in African-American and Caucasian prepubertal children.

Abstract: The purpose of this study was to examine differences in resting, submaximal, and maximal (VO2max) oxygen consumption (VO2) in African-American (n = 44) and Caucasian (n = 31) prepubertal children aged 5-10 yr.

Abstract: Resting VO2 was measured via indirect calorimetry in the fasted state.

Abstract: Submaximal VO2 and VO2max were determined during an all out, progressive treadmill exercise test appropriate for children.

Abstract: Dual-energy X-ray absorptiometry was used to determine total fat mass (FM), soft lean tissue mass (LTM), and leg soft LTM.

Abstract: Doubly labeled water was used to determine total energy expenditure (TEE) and activity energy expenditure (AEE).

Abstract: A significant effect of ethnicity (P < 0.01) was found for VO2max but not resting or submaximal VO2, with African-American children having absolute VO2max approximately 15% lower than Caucasian children (1.21 +/- 0.032 vs. 1.43 +/-

Abstract: 0.031 l/min, respectively).

Abstract: The lower VO2max persisted in African-American children after adjustment for soft LTM (1.23 +/- 0.025 vs. 1.39 +/-

Abstract: 0.031 l/min; P < 0.01), leg soft LTM (1.20 +/-

Abstract: 0.031 vs. 1.43 +/-

Abstract: 0.042 l/min; P < 0.01), and soft LTM and FM (1.23 +/-

Abstract: 0.025 vs. 1.39 +/-

Abstract: 0.031 l/min; P < 0.01).

Abstract: The lower VO2max persisted also after adjustment for TEE (1.20 +/-

Abstract: 0.02 vs. 1.38 +/-

Abstract: 0.0028 l/min P < 0.001) and AEE (1.20 +/- 0.024 vs. 1.38 +/-

Abstract: 0.028 l/min; P < 0.001).

Abstract: In conclusion, our data indicate that African-American and Caucasian children have similar rates of VO2 at rest and during submaximal exercise, but VO2max is approximately 15% lower in African-American children, independent of soft LTM, FM, leg LTM, TEE, and AEE.


Penaeus monodon Dscam (PmDscam) has a highly diverse cytoplasmic tail and is the first membrane-bound shrimp Dscam to be reported.

Abstract: Down syndrome cell adhesion molecule (Dscam) seems likely to play a key role in the "alternative adaptive immunity" that has been reported in invertebrates.

Abstract: Dscam consists of a cytoplasmic tail that is involved in signal transduction and a hypervariable extracellular region that might use a pathogen recognition mechanism similar to that used by the vertebrate antibodies.

Abstract: In our previous paper, we isolated a unique tail-less form of Dscam from Litopenaeus vannamei.

Abstract: In this study, we report the first membrane-bound form of shrimp Dscam: PmDscam was isolated from Penaeus monodon, and it occurred in both membrane-bound and tail-less forms.

Abstract: Phylogenetic analysis showed that while the crustacean Dscams from shrimp and water flea did not share a single subclade, they were distinct from the invertebrate Dscam-like molecules and from the insecta Dscams.

Abstract: In the extracellular region, the variable regions of PmDscam were located in N-terminal Ig2, N-terminal Ig3 and the entire Ig7 domain.

Abstract: The PmDscam extracellular variants and transmembrane domain variants were produced by mutually exclusive alternative splicing events.

Abstract: The cytoplasmic tail variants were produced by exon inclusion/exclusion.

Abstract: Based on the genomic organization of Daphnia Dscam's cytoplasmic tail, we propose a model of how the shrimp Dscam genomic locus might use Type III polyadenylation to generate both the tail-less and membrane-bound forms.


The different biological effects of telomestatin and TMPyP4 can be attributed to their selectivity for interaction with intramolecular or intermolecular G-quadruplex structures.

Abstract: Demonstration of the existence of G-quadruplex structures in telomeres of Stylonychia macronuclei and in the promoter of c-myc in human cells has validated these secondary DNA structures as potential targets for drug design.

Abstract: The next important issue is the selectivity of G-quadruplex-interactive agents for the different types of G-quadruplex structures.

Abstract: In this study, we have taken an important step in associating specific biological effects of these drugs with selective interaction with either intermolecular or intramolecular G-quadruplex structures formed in telomeres.

Abstract: Telomestatin is a natural product isolated from Streptomyces anulatus 3533-SV4 and has been shown to be a very potent telomerase inhibitor through its G-quadruplex interaction.

Abstract: We have demonstrated that telomestatin interacts preferentially with intramolecular versus intermolecular G-quadruplex structures and also has a 70-fold selectivity for intramolecular G-quadruplex structures over duplex DNA.

Abstract: Telomestatin is able to stabilize G-quadruplex structures that are formed from duplex human telomeric DNA as well as from single-stranded DNA.

Abstract: Importantly, telomestatin stabilizes these G-quadruplex structures in the absence of monovalent cations, which is a unique characteristic among G-quadruplex-interactive compounds.

Abstract: At noncytotoxic concentrations, telomestatin suppresses the proliferation of telomerase-positive cells within several weeks.

Abstract: In contrast, TMPyP4, a compound that preferentially facilitates the formation of intermolecular G-quadruplex structures, suppresses the proliferation of alternative lengthening of telomeres (ALT)-positive cells as well as telomerase-positive cells.

Abstract: We have also demonstrated that TMPyP4 induces anaphase bridges in sea urchin embryos, whereas telomestatin did not have this effect, leading us to conclude that the selectivity of telomestatin for intramolecular G-quadruplex structures and TMPyP4 for intermolecular G-quadruplex structures is important in mediating different biological effects: stabilization of intramolecular G-quadruplex structures produces telomerase inhibition and accelerated telomere shortening, whereas facilitation of the formation of intermolecular G-quadruplex structures induces the formation of anaphase bridges.


Targeting oxidative stress to treat endometriosis.

Abstract: INTRODUCTION Endometriosis affects 10% of women of reproductive age.

Abstract: It is defined as the presence of implanted active endometrial tissue outside the uterine cavity.

Abstract: The exact pathophysiology of endometriosis is still uncertain, although several optional etiological theories have been suggested.

Abstract: Being so common, a novel treatment for endometriosis is widely quested.

Abstract: Recent studies addressing the pathological characteristics of endometriosis have revealed a vicious cycle in which oxidative stress (OS) is generated, which in turn facilitates the implantation of the ectopic endometrium.

Abstract: At the same time, the generation of high amounts of reactive oxygen species further triggers a state of OS.

Abstract: AREAS COVERED The author examined the evidence associating OS and endometriosis.

Abstract: After establishing an association, a search for antioxidant agents that were investigated specifically on endometriosis patients are described including Vitamins C and E, melatonin, resveratrol, xanthohumol and epigallocatechin-3-gallate.

Abstract: A significant effect of all the reviewed antioxidants on endometriosis is reported.

Abstract: EXPERT OPINION Aiming for the reduction of OS as the treatment goal for endometriosis looks promising.

Abstract: However, since most of the studies are either in vitro or are animal based, further studies on human subjects are deemed necessary to elucidate the impact of OS reduction on patients with endometriosis.


Interferon alpha for the treatment of chronic hepatitis C in patients infected with human immunodeficiency virus. Hepatitis-HIV Spanish Study Group.

Abstract: Liver disease secondary to hepatitis C virus (HCV) infection is a rising cause of morbidity and mortality among individuals who have been infected parenterally with human immunodeficiency virus (HIV) such as injection drug users, hemophiliacs, and transfused patients.

Abstract: We analyzed both the efficacy of interferon (IFN) alpha therapy in these patients and the predictors of response to this agent.

Abstract: A total of 119 patients with chronic hepatitis C (90 of whom were infected with HIV and 29 of whom were not) were included in a multicenter, prospective, open, nonrandomized observational study.

Abstract: IFN-alpha was given subcutaneously in a dosage of 5 million units three times a week during a 3-month period; those patients who responded received a dose of 3 million units given subcutaneously three times a week for an additional 9 months.

Abstract: One hundred seven patients completed the study; the level of aminotransferases returned to normal and sera became negative (complete response) for HCV RNA in 26 (32.5%) of 80 HIV-infected patients and 10 (37.0%) of 27 non-HIV-infected patients (P = .666) after completion of the treatment.

Abstract: Two variables were independently associated with a response in HIV-infected patients: a CD4+ T lymphocyte count of > 500 x 10(6)/L and a baseline HCV viremia level of < 10(7) copies/mL. In the 12 months following treatment, relapses occurred in 30.8% of the HIV-infected patients and 12.5% of non-HIV-infected patients (P = .403).


Vanishing cerebellar infarcts in a migraine patient.

Abstract: Recent population-based studies have suggested that migraine is a risk factor for the development of infarct-like lesions in the territory of the posterior circulation.

Abstract: These lesions are thought to be true vascular infarcts based on their size, location and magnetic resonance imaging (MRI) characteristics.

Abstract: However, as there are no postmortem studies identifying the pathology of these MRI findings, their true aetiology is unknown.

Abstract: A case patient with migraine is presented, who developed what appeared to be cerebellar infarcts on MRI, but these lesions vanished on repeat imaging 16 days later, questioning their aetiology as vascular ischaemic based infarcts.


A novel viral transcript with homology to human interleukin-10 is expressed during latent human cytomegalovirus infection.

Abstract: Human cytomegalovirus (CMV) establishes latent infections in hematopoietic cells such as granulocyte-macrophage progenitors (GM-Ps).

Abstract: During latency the virus is sequestered in a nonreplicating state, although limited transcriptional activity has been previously reported.

Abstract: In this study we sought to further examine viral gene expression during the latent phase of infection.

Abstract: Using an experimental model of latency, primary human GM-Ps were latently infected with CMV strain Toledo and extracted RNA subjected to reverse transcription-PCR by using CMV gene-specific primers.

Abstract: Using this approach, we detected transcription from the UL111.5A region of the viral genome.

Abstract: This transcription was also detected in GM-Ps latently infected with AD169 and Towne strains, indicating that expression was CMV strain independent.

Abstract: Significantly, we detected UL111.5A-region transcripts in mononuclear cells from healthy bone marrow and mobilized peripheral blood allograft donors, demonstrating expression during natural latent infection.

Abstract: Mapping experiments with RNA extracted from latently infected GM-Ps revealed the expression of a novel UL111.5A region transcript with a splicing pattern that differed from that reported during productive infection of permissive cells.

Abstract: This UL111.5A region transcript expressed during latent infection is predicted to encode a 139-amino-acid protein with homology to the potent immunosuppressor interleukin-10 (IL-10) and to the viral IL-10 homolog that is expressed during productive CMV infection.

Abstract: Expression of a latency-associated cmvIL-10 may confer upon the virus an ability to avoid immune recognition and clearance during the latent phase of infection.