Miracle-dz/UniFAR-FTUs huggingface dataset:
Atrial natriuretic peptide modulates baroreceptor reflex in spontaneously hypertensive rat.

Our previous studies have suggested that atrial natriuretic peptide in the caudal nucleus tractus solitarii is involved in the centrally mediated regulation of blood pressure in the salt-sensitive spontaneously hypertensive rat (SHR). The current study tested the hypothesis that endogenous atrial natriuretic peptide in the caudal nucleus tractus solitarii participates in baroreceptor reflex control of heart rate in this hypertensive model. Salt-sensitive SHR and control Wistar-Kyoto (WKY) rats maintained on basal (1%) salt intake were studied. Arterial baroreceptor reflex-mediated changes in heart rate were recorded in conscious unrestrained rats during phenylephrine (5-40 micrograms.kg-1.min-1 infusion; 30 minutes later, atrial natriuretic peptide (50 ng), monoclonal antibody to atrial natriuretic peptide (0.55 micrograms), purified mouse immunoglobulin G (0.55 micrograms), or artificial cerebrospinal fluid vehicle (50 nl) was microinjected into the caudal nucleus tractus solitarii. Phenylephrine infusion was then repeated and mean arterial pressure and heart rate were monitored as before. The slope of the heart rate/mean arterial pressure relation was significantly less (p less than 0.05) in the salt-sensitive SHR than in the WKY control, indicating that baroreceptor reflex control of heart rate was blunted in this hypertensive model. Microinjection of atrial natriuretic peptide into the caudal nucleus tractus solitarii further blunted (p less than 0.05) baroreceptor reflex control of heart rate in salt-sensitive SHR but not in WKY rats. In contrast, microinjection of the monoclonal antibody enhanced the sensitivity of baroreceptor reflex control of heart rate in salt-sensitive SHR but not in WKY rats. (ABSTRACT TRUNCATED AT 250 WORDS)
TIMP-2 Promotes Activation of Progelatinase A by Membrane-type 1 Matrix Metalloproteinase Immobilized on Agarose Beads*

Membrane-type 1 matrix metalloproteinase (MT1-MMP)/MMP-14 is the activator of progelatinase A (proGelA)/proMMP-2 on the cell surface. However, it was a paradox that a tissue inhibitor of metalloproteinase-2 (TIMP-2), which is an inhibitor of MT1-MMP, is required for proGelA activation by the cells expressing MT1-MMP. In this study, a truncated MT1-MMP having a FLAG-tag sequence at the C terminus (MT1-F) was immobilized onto agarose beads (MT1-F/B) and used to analyze the role of TIMP-2. The proteolytic activity of MT1-F/B against a synthetic peptide substrate was inhibited by TIMP-2 in a dose-dependent manner. In contrast, TIMP-2 promoted the processing of proGelA by MT1-F/B at low concentrations and inhibited it at higher concentrations. TIMP-2 promoted the binding of proGelA to the MT1-F on the beads by forming a trimolecular complex, which was followed by processing of proGelA. A stimulatory effect of TIMP-2 was observed under conditions in which unoccupied MT1-F was still available. Thus, the ternary complex is thought to act as a means to concentrate the substrate to the bead surface and to present it to the neighboring free MT1-F.
The activated anaplastic lymphoma kinase increases cellular proliferation and oncogene up‐regulation in rat la fibroblasts

More than 60% of anaplastic large‐cell lymphomas (Ki‐1 lymphoma) are associated with a t(2;5)(p23;q35) translocation that produces an 80 kDa hyperphosphorylated chimeric protein (p80) derived from the fusion of the anaplastic lymphoma kinase (ALK) with nucleophosmin (NPM). The NPM‐ALK chimeric gene is an activated tyrosine kinase that has been shown to be a potent oncogene. We have developed a cellular model for the study of p80 action in rat la fibroblasts. Expression of cDNA's encoding NPM‐ALK (p80) in rat la fibroblasts induces anchorage‐independent growth in soft agar and promotes foci formation in culture. Cells expressing exogenous p80 showed significantly increased proliferation characterized by accelerated cell cycle entry into S‐phase. Consistent with increased G0/G1 to S‐phase transition, there is also marked up‐regulation of cyclin A and cyclin D1 expression. In addition, p80 transformed cells showed elevated expression of several immediate early genes involved in cellular proliferation, including fos, jun, and c‐myc. DNA binding analysis of nuclear extracts prepared from p80 transformed cells reveal marked up‐regulation of AP‐1 DNA binding activity. Functional AP‐1‐specific transfection assays also show up‐regulation of AP‐1‐dependent transcriptional activation. These finding demonstrate that p80 transformed rat la fibroblast can be a highly useful model system for the molecular and biochemical characterization of the mechanisms of action of this interesting new oncogene. —Wellmann, A. , Doseeva, V. , Butscher, W. , Raffeld, M. , Fukushima, P., Stetler‐Stevenson, M. , Gardner, K. The activated anaplastic lymphoma kinase increases cellular proliferation and oncogene up‐regulation in rat la fibroblasts. FASEB J. 11, 965–972 (1997)
Metabolic effect of obesity on polycystic ovary syndrome in adolescents: a meta-analysis

Abstract This meta-analysis provides an updated and comprehensive estimate of the effects of obesity on metabolic disorders in adolescent polycystic ovary syndrome (PCOS). Relevant articles consistent with the search terms published up to 31 January 2014 were retrieved from PubMed, EMBASE, PsycINFO and CENTRAL. Thirteen articles (16 independent studies) conformed to the inclusion criteria. The evaluated outcomes were the metabolic parameters of obese adolescents with PCOS (case group) relative to normal-weight adolescents with PCOS, or obese adolescents without PCOS. Compared with normal-weight adolescents with PCOS, the case group had significantly lower sex hormone-binding globulin and high-density lipoprotein cholesterol, and significantly higher triglycerides, leptin, fasting insulin, low-density lipoprotein cholesterol and free testosterone levels. Relative to obese adolescents without PCOS, the case group had significantly higher fasting insulin, low-density lipoprotein cholesterol, free testosterone levels and 2-h glucose during the oral glucose tolerance test. These results indicate that metabolic disorders in adolescent PCOS are worsened by concomitant obesity. This study highlights the importance of preventing obesity during the management of adolescent PCOS. Impact statement What is already known about this subject: Obesity and PCOS share many of the same metabolic disorders, for example, hyperandrogenism and hyperinsulinemia with subsequent insulin resistance. Knowledge regarding metabolic features in obese adolescents with PCOS is limited, and there is concern whether obesity and PCOS are related. What do the results of this study add: Relative to PCOS adolescents of normal weight, obese adolescents with PCOS (the case group) had significantly lower SHBG and HDL-C, and significantly higher triglycerides, leptin, fasting insulin, LDL-C and free testosterone levels. The results indicate that metabolic disorders in adolescent PCOS are worsened by concomitant obesity. What are the implications of these findings for clinical practice and/or further research: Obesity, metabolic disorders and PCOS in adolescents are associated. Obesity exacerbates metabolic disorders in adolescent PCOS. This study highlights the importance of preventing obesity during the management of adolescent PCOS. Therapeutic intervention combined with lifestyle modification may provide better treatment for adolescent PCOS. The aetiologies of PCOS combined with obesity in adolescents require further investigation.
Identification and characterization of a novel PrfA-regulated gene in Listeria monocytogenes whose product, IrpA, is highly homologous to internalin proteins, which contain leucine-rich repeats

The expression of all virulence factors in Listeria monocytogenes characterized to date is controlled by the virulence regulator protein, PrfA. To identify further PrfA-regulated proteins, we examined supernatants of L. monocytogenes EGD harboring additional copies of the PrfA regulator for the presence of novel proteins. This led to the identification and biochemical purification of a hitherto uncharacterized PrfA-dependent 30-kDa protein (A. Lingnau, T. Chakraborty, K. Niebuhr, E. Domann, and J. Wehland, Infect. Immun. 64:1002-1006, 1996). Oligonucleotide primers derived from internal peptide sequences of this protein allowed the cloning and determination of the entire sequence of the respective gene. The protein comprised 297 amino acids with strong overall homology to the internalins, InlA and InlB, particularly in the region harboring the leucine-rich repeats. The gene has been designated irpA for internalin-related protein A gene. Transcriptional studies revealed that the gene was monocistronic and, like the inlA and inlB genes, was transcribed by PrfA-dependent and PrfA-independent mechanisms. Monoclonal antibodies raised against IrpA indicated that it was produced by L. monocytogenes but not by the nonpathogenic species Listeria innocua. To examine the role of IrpA in pathogenesis, we constructed an isogenic in-frame deletion mutant that removed all but 116 amino acids of the IrpA protein. This mutant was neither defective for invasion into many tissue culture cell lines nor did it demonstrate reduced intracellular survival. However, in vivo studies using the mouse infection model revealed that the irpA mutant showed reduced virulence compared to the parental strain. These results suggest a role for IrpA during disseminated infection by L. monocytogenes.
Activation of APCs Through CD40 or Toll-Like Receptor 9 Overcomes Tolerance and Precipitates Autoimmune Disease1

Some autoreactive T cells normally escape thymic selection and persist in the periphery. This is true of myelin-reactive CD4+ T cells, the effectors of experimental autoimmune encephalomyelitis (EAE) in laboratory animals and the presumed mediators of multiple sclerosis in humans. Nonetheless, most individuals do not succumb to autoimmune disease. There is growing evidence that while peripheral APCs stimulate immune responses against foreign Ags in the setting of tissue destruction and “danger,” they actually maintain tolerance against self Ags under steady state conditions. We hypothesized that tolerance against candidate autoantigens could be reversed by activation of APCs via CD40 or Toll-like receptor 9 signaling. Adult SJL mice injected i.p. with a peptide fragment of proteolipid protein (a candidate autoantigen in multiple sclerosis) emulsified in IFA fail to mount lymphoproliferative or cytokine responses and are protected from EAE upon subsequent challenge with the Ag combined with adjuvants. Here we report that tolerized proteolipid protein-specific lymph node cells regain the ability to divide, differentiate along a Th1 lineage, and transfer EAE when reactivated in the presence of agonistic Abs against CD40 or CpG oligonucleotides. The effects of both anti-CD40 and CpG oligonucleotides are dependent upon induction of IL-12. Our findings suggest two mechanisms to explain the well-documented association between infectious illnesses and flare-ups of multiple sclerosis. Microbial pathogens could 1) release molecules that bind Toll-like receptors, and/or 2) stimulate microbe-specific T cells to express CD40 ligand, thereby licensing APCs that bear both microbial and autoantigens to break tolerance.
Modulation of intestinal immune system by dietary fat intake: Relevance to Crohn's disease

Gut‐associated lymphoid tissue is the major inductive site of the mucosal immune system, which is functionally independent of the systemic immune system. Both the amount and type of dietary fat modulate intestinal immune function. Absorption of long‐chain fatty acids stimulates lymphocyte flux and lymphocyte blastogenesis in intestinal lymphatics. Long‐chain fatty acid absorption also significantly enhances migration of T lymphocytes to Peyer's patches, possibly due to up‐regulation of adhesion molecules, such as α4‐integrin and L‐selectin. Lipoproteins are involved in stimulation of lymphocyte function by both receptor‐dependent and independent mechanisms. However, unsaturated fatty acids at higher concentrations have a suppressive effect on cell‐mediated immunity via eicosanoid release, receptor affinity changes or interactions with intracellular signal transduction. Fat absorption also influences various other cells in the intestinal mucosa: increased cytokine release from intestinal epithelial cells follows long‐chain fatty acid absorption. In Crohn's disease, elemental diets and total parenteral nutrition often induce remission, possibly by reducing antigenic load on activated immune cells in the intestine and, thus, down‐regulating hyperreactive CD4 cells. Dietary oleic acid supplements caused an immunological reversal effect in the intestinal immune system of animals fed an elemental diet. An excess of long‐chain fatty acids in an elemental diet, therefore, may negate its beneficial effect on gut‐associated lymphoid tissues in Crohn's disease. In contrast, supplemental dietary fish oil apparently tends to prevent relapse of Crohn's disease. Because dietary fat intake is closely associated with immunological function of the intestinal mucosa, careful manipulation of dietary fat can be important in management of this disease.
Mild Core Hypothermia and Anesthetic Requirement for Loss of Responsiveness During Propofol Anesthesia for Craniotomy

Mild hypothermia may be induced during neurosurgery for brain protection. However, its effect on propofol requirement has not been defined. Accordingly, we tested the hypothesis that 3°C of core hypothermia decreases the propofol blood concentration at which patients respond to command (CP50-awake) in neurosurgical patients. Forty patients were anesthetized with alfentanil 50 &mgr;g/kg IV, nitrous oxide, propofol target-controlled infusion, and rocuronium. The bispectral index (version 3.12) was monitored continuously. Patients were randomized to a core temperature of 34°C or 37°C. At the end of surgery, neuromuscular blockade was reversed, nitrous oxide was ceased, and propofol was infused to achieve a blood target determined by the previous patient’s response. Responsiveness to command was assessed 15 min later. Results were analyzed with logistic regression models;P < 0.05 was considered statistically significant. The CP50-awake of propofol was 3.05 &mgr;g/mL (95% confidence interval, 2.34–3.66). Propofol concentration, but not core temperature, predicted loss of response to command (odds ratio, 11.76; 95% confidence interval, 2.40–57.63;P < 0.01). Core temperature did not alter the relationship between bispectral index and response to command. Propofol infusion regimens may not require adjustment during mild hypothermia.
Increased mean glucose levels in patients with polycystic ovary syndrome and hyperandrogenemia as determined by continuous glucose monitoring

Objective. Women with polycystic ovary syndrome are at risk of developing type 2 diabetes mellitus. This study aimed to evaluate the influence of hyperandrogenemia on glucose metabolism in polycystic ovarian syndrome patients. Design. Cohort study. Setting. Reproductive Endocrinology Clinic of the Shanghai Sixth People's Hospital. Sample. Fifty‐three patients were recruited from June 2008 to December 2009, including 28 women with hyperandrogenism and 25 without hyperandrogenemia. Methods. Anthropometric parameters, including weight, height, body mass index and waist‐to‐hip ratio, as well as sex hormones, were measured. An oral glucose tolerance test, including fasting and two hour glucose and insulin levels, was recorded. Insulin resistance was evaluated by homeostatic model assessment of insulin resistance, and patients underwent continuous glucose monitoring. Main outcome measures. Mean blood glucose level, mean amplitude of glycemic excursion, frequency of glycemic excursion and the percentage of time of hypoglycemia and hyperglycemia during a 48 h period. Results. No differences in age, body mass index, waist‐to‐hip ratio, fasting and two hour glucose and insulin concentrations were observed between the groups. The hyperandrogenism group had higher levels of luteinizing hormone and dehydroepiandrosterone sulfate (p < 0.05). However, continuous glucose monitoring showed that the minimal blood glucose and mean blood glucose were significantly higher in hyperandrogenemia group (p = 0.004). The percentage of time for hypoglycemia (≤70 mg/dL) was higher in the hyperandrogenemia group (p = 0.002). Conclusions. Polycystic ovarian syndrome patients with hyperandrogenemia had an increased mean glucose value, which may place them at increased risk for developing type 2 diabetes.
Obstetric complications in women with diagnosed mental illness: the relative success of California's county mental health system.

OBJECTIVE To examine disparities in serious obstetric complications and quality of obstetric care during labor and delivery for women with and without mental illness. DATA SOURCE Linked California hospital discharge (2000-2001), birth, fetal death, and county mental health system (CMHS) records. STUDY DESIGN This population-based, cross-sectional study of 915,568 deliveries in California, calculated adjusted odds ratios (AORs) for obstetric complication rates for women with a mental illness diagnosis (treated and not treated in the CMHS) compared with women with no mental illness diagnosis, controlling for sociodemographic, delivery hospital type, and clinical factors. RESULTS Compared with deliveries in the general non-mentally ill population, deliveries to women with mental illness stand a higher adjusted risk of obstetric complication: AOR=1.32 (95 percent confidence interval [CI]=1.25, 1.39) for women treated in the CMHS and AOR=1.72 (95 percent CI=1.66, 1.79) for women not treated in the CMHS. Mentally ill women treated in the CMHS are at lower risk than non-CMHS mentally ill women of experiencing conditions associated with suboptimal intrapartum care (postpartum hemorrhage, major puerperal infections) and inadequate prenatal care (acute pyelonephritis). CONCLUSION Since mental disorders during pregnancy adversely affect mothers and their infants, care of the mentally ill pregnant woman by mental health and primary care providers warrants special attention.
Specificity of Processing α-Glucosidase I Is Guided by the Substrate Conformation

Background: The enzyme “GluI” is key to the synthesis of critical glycoproteins in the cell. Results: We have determined the structure of GluI, and modeled binding with its unique sugar substrate. Conclusion: The specificity of this interaction derives from a unique conformation of the substrate. Significance: Understanding the mechanism of the enzyme is of basic importance and relevant to potential development of antiviral inhibitors. Processing α-glucosidase I (GluI) is a key member of the eukaryotic N-glycosylation processing pathway, selectively catalyzing the first glycoprotein trimming step in the endoplasmic reticulum. Inhibition of GluI activity impacts the infectivity of enveloped viruses; however, despite interest in this protein from a structural, enzymatic, and therapeutic standpoint, little is known about its structure and enzymatic mechanism in catalysis of the unique glycan substrate Glc3Man9GlcNAc2. The first structural model of eukaryotic GluI is here presented at 2-Å resolution. Two catalytic residues are proposed, mutations of which result in catalytically inactive, properly folded protein. Using Autodocking methods with the known substrate and inhibitors as ligands, including a novel inhibitor characterized in this work, the active site of GluI was mapped. From these results, a model of substrate binding has been formulated, which is most likely conserved in mammalian GluI.
Molecular signatures for the dynamic process of establishing intestinal host–microbial homeostasis: potential for disease diagnostics?

Purpose of review The dynamic interplay of the intestinal microbiota and host has been the focus of many studies because of its impact on the health status in human life. Recent reports on the time-resolved immune and metabolic interactions between the host and microbiota, as well as the molecular signatures that mark this communication during the process of establishing a host–microbial relationship, are addressed here. Recent findings During microbial colonization, the progressive impact of de-novo introduction of the gut microbiota on the host's physiology is tightly controlled by highly intertwined regulatory networks and achieves an efficient and balanced interplay between the host and its developing microbial community. Recent findings from germ-free mouse models have unravelled core transcriptional, metabolic and microbial signatures, which are proposed to orchestrate the molecular responses during the establishment of the multifaceted state of intestinal host–microbe homeostasis. Summary Exploring the time-resolved dynamics of the host responses to the newly colonizing gut microbiota provides mechanistically critical understanding of the sequential host–microbe response cascades that lead to a homeostatic relationship. Thereby, these approaches can provide novel diagnostic tools and therapeutic targets, or either of the two, in humans for specific disorders associated with intestinal dysbiosis and loss of homeostasis.
Analysis of subcutaneous angiogenesis by gradient echo magnetic resonance imaging

The goal of this study was to develop an experimental method for noninvasive analysis of angiogenesis, namely the sprouting of capillaries from existing blood vessels. Angiogenesis was assayed in the subcutaneous vasculature of nude mice in a region of 3 × 3 cm that included in its center a defined angiogenic stimulus. Angiogenic stimuli included agarose beads containing angiogenic growth factors, multicellular tumor spheroids, and dermal incisions. Highly significant correlation (r = 0.905, P = 0.0001) was found between the apparent vessel density determined by gradient echo MRI and the density of blood‐containing vessels determined postmortem. The functionality of the neovasculature was demonstrated in mice breathing alternatingly carbogen or 95% air/5% CO2. Large signal enhancement with carbogen breathing corresponded to regions of high vessel density. The assay reported here can be applied for the study of dermal wound healing, primary vascularization of subcutaneous implants, and for measuring the activity of angiogenic and antiangiogenic agents.
Analgesic Rebound Headache in Children and Adolescents

For more than a decade, the frequent use of analgesics has been recognized to lead to daily headaches in adults. To date, no studies on the occurrence of analgesic rebound headache have been done on the pediatric population. We retrospectively reviewed all charts of patients with the diagnosis of headache seen in our pediatric headache clinic between January 1996 and May 1997. Among the 98 patients seen, 46 (47%) suffered from daily or near daily headaches; 30 of them were consuming daily analgesics. Twenty-four patients (mean age 12.1 years, and mean follow-up 6.2 months) successfully discontinued their analgesics. Twenty-two patients were also placed on amitriptyline. A significant reduction in the frequency (80%), severity (47%), and number of school days missed (74%) were seen. In conclusion, this data is comparable to previous observations reported in adults, and suggests that the daily use of analgesics might result in daily or near daily headaches in the pediatric population. Discontinuing daily analgesics, with the concomitant use of amitriptyline, is an effective treatment for analgesic rebound headache in this population. (J Child Neurol 1998;13:443-447).