gebhart/patrepeval huggingface dataset:
Farnesoid X receptor is essential for normal glucose homeostasis (2006)

The bile acid receptor farnesoid X receptor (FXR; NR1H4) is a central regulator of bile acid and lipid metabolism. We show here that FXR plays a key regulatory role in glucose homeostasis. FXR-null mice developed severe fatty liver and elevated circulating FFAs, which was associated with elevated serum glucose and impaired glucose and insulin tolerance. Their insulin resistance was confirmed by the hyperinsulinemic euglycemic clamp, which showed attenuated inhibition of hepatic glucose production by insulin and reduced peripheral glucose disposal. In FXR-/- skeletal muscle and liver, multiple steps in the insulin signaling pathway were markedly blunted. In skeletal muscle, which does not express FXR, triglyceride and FFA levels were increased, and we propose that their inhibitory effects account for insulin resistance in that tissue. In contrast to the results in FXR-/- mice, bile acid activation of FXR in WT mice repressed expression of gluconeogenic genes and decreased serum glucose. The absence of this repression in both FXR-/- and small heterodimer partner-null (SHP-/-) mice demonstrated that the previously described FXR-SHP nuclear receptor cascade also targets glucose metabolism. Taken together, our results identify a link between lipid and glucose metabolism mediated by the FXR-SHP cascade.
Apoptosis Induced by p75NTR Overexpression Requires Jun Kinase-Dependent Phosphorylation of Bad (2003)

The p75 neurotrophin receptor (p75NTR), a member of the tumor necrosis factor receptor superfamily, facilitates apoptosis during development and after injury to the CNS. The signaling cascades activated by p75NTR that result in apoptosis remain poorly understood. In this study, we show that overexpression of p75NTR in primary cortical neurons, in pheochromocytoma cell line (PC12) cells, and in glioma cells results in activation of Jun kinase (JNK), accumulation of cytochrome c within the cytosol, and activation of caspases 9, 6, and 3. To link p75NTR-dependent JNK activation to mitochondrial cytochrome c release, regulation of BH3-domain-only family members was examined. Transcription of BH3-domain-only family members was not induced by p75NTR, but p75NTR-dependent JNK activation resulted in phosphorylation and oligomerization of the BH3-domain-only family member Bad. Loss of function experiments using Bad dominant negatives or RNA interference demonstrated a requirement for Bad in p75NTR-induced apoptosis. Together, these studies provide the first data linking apoptosis induced by p75NTR to the phosphorylation of BH3-domain-only family members.
In vitro differentiation of endothelial cells from AC133-positive progenitor cells (2000)

Abstract Recent findings support the hypothesis that the CD34+-cell population in bone marrow and peripheral blood contains hematopoietic and endothelial progenitor and stem cells. In this study, we report that human AC133+ cells from granulocyte colony-stimulating factor–mobilized peripheral blood have the capacity to differentiate into endothelial cells (ECs). When cultured in the presence of vascular endothelial growth factor (VEGF) and the novel cytokine stem cell growth factor (SCGF), AC133+ progenitors generate both adherent and proliferating nonadherent cells. Phenotypic analysis of the cells within the adherent population reveals that the majority display endothelial features, including the expression of KDR, Tie-2, Ulexeuropaeus agglutinin-1, and von Willebrand factor. Electron microscopic studies of these cells show structures compatible with Weibel-Palade bodies that are found exclusively in vascular endothelium. AC133-derived nonadherent cells give rise to both hematopoietic and endothelial colonies in semisolid medium. On transfer to fresh liquid culture with VEGF and SCGF, nonadherent cells again produce an adherent and a nonadherent population. In mice with severe combined immunodeficiency, AC133-derived cells form new blood vessels in vivo when injected subcutaneously together with A549 lung cancer cells. These data indicate that the AC133+-cell population consists of progenitor and stem cells not only with hematopoietic potential but also with the capacity to differentiate into ECs. Whether these hematopoietic and endothelial progenitors develop from a common precursor, the hemangioblast will be studied at the single-cell level.
American Academy of Pediatrics. Committee on Injury and Poison Prevention. Safe transportation of newborns at hospital discharge. (1999)

All hospitals should set policies that require the discharge of every newborn in a car safety seat that is appropriate for the infant's maturity and medical condition. Discharge policies for newborns should include a parent education component, regular review of educational materials, and periodic in-service education for responsible staff. Appropriate child restraint systems should become a benefit of coverage by Medicaid, managed care organizations, and other third-party insurers.
Modulation of lung inflammation by vessel dilator in a mouse model of allergic asthma (2009)

Abstract Background Atrial natriuretic peptide (ANP) and its receptor, NPRA, have been extensively studied in terms of cardiovascular effects. We have found that the ANP-NPRA signaling pathway is also involved in airway allergic inflammation and asthma. ANP, a C-terminal peptide (amino acid 99–126) of pro-atrial natriuretic factor (proANF) and a recombinant peptide, NP73-102 (amino acid 73–102 of proANF) have been reported to induce bronchoprotective effects in a mouse model of allergic asthma. In this report, we evaluated the effects of vessel dilator (VD), another N-terminal natriuretic peptide covering amino acids 31–67 of proANF, on acute lung inflammation in a mouse model of allergic asthma. Methods A549 cells were transfected with pVD or the pVAX1 control plasmid and cells were collected 24 hrs after transfection to analyze the effect of VD on inactivation of the extracellular-signal regulated receptor kinase (ERK1/2) through western blot. Luciferase assay, western blot and RT-PCR were also performed to analyze the effect of VD on NPRA expression. For determination of VD's attenuation of lung inflammation, BALB/c mice were sensitized and challenged with ovalbumin and then treated intranasally with chitosan nanoparticles containing pVD. Parameters of airway inflammation, such as airway hyperreactivity, proinflammatory cytokine levels, eosinophil recruitment and lung histopathology were compared with control mice receiving nanoparticles containing pVAX1 control plasmid. Results pVD nanoparticles inactivated ERK1/2 and downregulated NPRA expression in vitro, and intranasal treatment with pVD nanoparticles protected mice from airway inflammation. Conclusion VD's modulation of airway inflammation may result from its inactivation of ERK1/2 and downregulation of NPRA expression. Chitosan nanoparticles containing pVD may be therapeutically effective in preventing allergic airway inflammation.
Near-minimum-time control of distributed parameter systems - Analytical and experimental results (1991)

We present a method for generating globally stable feedback control laws for maneuvers of distributed parameter structural systems. The method can accommodate system nonlinearity, and our proof of Lyapunov stability does not rely upon spatially discretizing distributed parameter systems. The approach applies directly to controllable distributed parameter systems that are open-loop conservative or dissipative. The most fundamental version of the formulation leads to controls that drive the system to a fixed point in the state space, but more generally, we develop tracking-type control laws to null the departure of the system state from a smooth target trajectory. Both analytical developments and experimental results are presented. The analytical results provide a theoretical foundation for the approach, whereas the experimental results provide conclusive evidence that the approach can be efficiently realized in actual hardware.
Renal Denervation in Moderate to Severe CKD (2012)

Sympathetic activation contributes to the progression of CKD and is associated with adverse cardiovascular outcomes. Ablation of renal sympathetic nerves reduces sympathetic nerve activity and BP in patients with resistant hypertension and preserved renal function, but whether this approach is safe and effective in patients with an estimated GFR (eGFR) < 45 ml/min per 1.73 m(2) is unknown. We performed bilateral renal denervation in 15 patients with resistant hypertension and stage 3-4 CKD (mean eGFR, 31 ml/min per 1.73 m(2)). We used CO(2) angiography in six patients to minimize exposure to contrast agents. Estimated GFR remained unchanged after the procedure, irrespective of the use of CO(2) angiography. Mean baseline BP ± SD was 174 ± 22/91 ± 16 mmHg despite the use of 5.6 ± 1.3 antihypertensive drugs. Mean changes in office systolic and diastolic BP at 1, 3, 6, and 12 months were -34/-14, -25/-11, -32/-15, and -33/-19 mmHg, respectively. Night-time ambulatory BP significantly decreased (P<0.05), restoring a more physiologic dipping pattern. In conclusion, this study suggests a favorable short-term safety profile and beneficial BP effects of catheter-based renal nerve ablation in patients with stage 3-4 CKD and resistant hypertension.
Spinal muscular atrophy: Diagnosis and management in a new therapeutic era (2014)

Spinal muscular atrophy (SMA) describes a group of disorders associated with spinal motor neuron loss. In this review we provide an update regarding the most common form of SMA, proximal or 5q-SMA, and discuss the contemporary approach to diagnosis and treatment. Electromyography and muscle biopsy features of denervation were once the basis for diagnosis, but molecular testing for homozygous deletion or mutation of the SMN1 gene allows efficient and specific diagnosis. In combination with loss of SMN1, patients retain variable numbers of copies of a second similar gene, SMN2, which produces reduced levels of the survival motor neuron (SMN) protein that are insufficient for normal motor neuron function. Despite the fact that understanding of how ubiquitous reduction of SMN protein leads to motor neuron loss remains incomplete, several promising therapeutics are now being tested in early-phase clinical trials.
A rapid method for purification of monoclonal human IgM from mass culture. (1996)

We describe in this paper the rapid and cheap purification of human immunoglobulin M from hybridoma supernatant of mass culture. The method consists of two steps: 1. concentration of supernatant by ultrafiltration and 2. dialysis against distilled water, pH 6.4. To produce the supernatant, the hybridomas are grown in RPMI media with fetal calf serum (10% FCS) in 250 ml flasks under normal tissue culture conditions. More than 14 mg IgM can be nearly selectively purified within 6 h from 5 l of antibody containing hybridoma supernatant. Most of the IgM molecules stay in a penta- and monomeric form and are positive in physiological and immunohistochemical studies.
Cancer chemotherapy-induced lactose malabsorption in children (1982)

To determine whether lactose malabsorption can be induced in children receiving cancer chemotherapy, lactose breath hydrogen tests (LBHT) were performed on 27 patients (ages 2 months to 16 10/12 years, mean 4 3/12 years) with neoplastic disease. Nine patients had an LBHT before their first course of chemotherapy and then 7--26 days afterwards. Eighteen other patients, less than 5 years old and presumed by virtue of age to be normal lactose absorbers, had an LBHT 7--24 days after their last course of chemotherapy. All nine in the first group had a normal LBHT before chemotherapy, and three had an abnormal LBHT 7--21 days later. Six of eighteen patients in the second group had an abnormal LBHT. Of the nine patients with an abnormal LBHT, six had a history of diarrhea associated with chemotherapy. These findings have important implications for children receiving cancer chemotherapy. High-calorie, milk-containing solutions used in nutritional support may precipitate cramps and diarrhea in some of these patients. A therapeutic trial of a low lactose diet in children in whom diarrhea develops during chemotherapy may be indicated.
Polymeric biodegradable lipospheres™ as vaccine delivery systems (1992)

Abstract This study describes the preparation and use of polymeric lipospheres TM as a potential vehicle for the controlled‐release of vaccines. Lipospheres are a new encapsulation technology for parenteral drug delivery that have been also used successfully as carriers of vaccines. A recombinant malaria antigen, R32NS1, derived from the circumsporozoite protein of Plasmodium falciparum , was incorporated in biodegradable polymeric lipospheres in the absence or presence of lipid A as an adjuvant. The immunogenicity of polymeric lipospheres composed of polylactide (PLD) or polycaprolactone (PCL) was tested in rabbits after intramuscular injection of the formulations. High levels of specific IgG antibodies were observed in the sera of the immunized rabbits up to 12 weeks after primary immunization, using a solid phase ELISA assay. PCL lipospheres containing the malaria antigen were able to induce sustained antibody activity after one single injection in the absence of immunomodulators. PCL lipospheres showed superior immunogenicity compared to PLD lipospheres, the difference being attributed to the different biodegradation rates of the polymers. Biodegradable polymeric lipospheres represent a pharmaceutically acceptable vaccine delivery system with immunopotentiating activity for humoral antibody responses. The high permeability to many therapeutic drugs, and a lack of toxicity, has made PCL and its derivatives well suited for controlled drug delivery. The results obtained in this study are very promising, with the expectation that the use of biodegradable polymeric lipospheres might be very useful in the conversion of multiple‐dose vaccines to single‐dose vaccination, avoiding the need for repeated immunizations.
Immobilization, mineralization and availability to rice plants of nitrogen derived from heterotrophic nitrogen fixation in flooded soil (1981)

Abstract The distribution of nitrogen immobilized by heterotrophic N2-fixing microorganisms in anaerobic soils amended with glucose among various components of the soil-N was determined by a 15N tracer method, and the immobilization and mineralization processes were compared with those from ammonium and native soil nitrogen. The availability of biologically fixed-N to wetland rice plants was also investigated. About 66% of the nitrogen originated from N2 and 72% of that from NH4 + was converted to an amino acid-N fraction after 4 days. At 20 days, 7% of the fixed-N and 13% of the applied-N was mineralized. By drying the soils, most of the mineralized-N was re. immobilized to an amino acid-N fraction. These results suggest that biologically fixed-N undergoes transformation processes almost similar to those of immobilized fertilizer-N. The mineralization rates were 23.4% for the fixed-N and 4.6% for the native soil-N after 16 days. The rice plants had absorbed 34% of the fixed-N and 8% of the soil-N in 42 days. In the newly immobilized-N from N2, nearly 68% of that taken up by the plants was derived from the amino acid-N fraction. It is concluded that the fixed-N remained as readily decomposable compounds, which were susceptible to microbial attack, making biologically fixed-N more available to the plants than native soil-N.
The Vascular Endothelial Growth Factor/fms-Like Tyrosine Kinase System in Human Ovary during the Menstrual Cycle and Early Pregnancy (1999)

In human ovaries, angiogenesis is known to be associated with the development of follicles and the formation of the corpus luteum (CL). A complex vascular network is formed within the thecal cell layer during follicular growth, and rapid neovascularization occurs toward the granulosa cell layer after ovulation. Vascular endothelial growth factor (VEGF) is a multifunctional cytokine, stimulating endothelial cell growth and enhancing microvascular permeability. A specific receptor for VEGF, fms-like tyrosine kinase (Flt-1), is expressed in vascular endothelial cells that mediates the action of VEGF. We examined the localization and expression of VEGF and Flt-1, using an immunohistochemical technique and RT-PCR analysis, in human follicles and corpora lutea during the normal menstrual cycle and early pregnancy. We measured concentrations of VEGF in extracts of human CL using an enzyme-linked immunosorbent assay during the luteal phase and early pregnancy. Immunostaining for VEGF was observed in granulosa cells from small antral follicles to preovulatory follicles. The staining was detected in thecal cells from medium-sized to preovulatory follicles. The intensity of the staining was gradually increased as a follicle grew. Flt-1 was localized in granulosa and thecal cells of preovulatory follicles as well as in endothelial cells. In the human CL, the intense staining for VEGF was observed in granulosa and thecal lutein cells, especially in the midluteal phase. The immunostaining for Flt-1 was faint in endothelial cells in the CL, whereas it was distinct in granulosa and thecal lutein cells. The concentrations of VEGF in lutein extracts were high in the early and midluteal phases and tended to decrease toward the late luteal phase. During early pregnancy, a measurable amount of VEGF was detected. RT-PCR analysis demonstrated that messenger ribonucleic acids encoding VEGF121, VEGF165, and Flt-1 were expressed in the CL. These results suggest that VEGF might have an autocrine role in the ovulatory process and luteal function as well as a paracrine role in angiogenesis.
Mexiletine Reverses Oxaliplatin-Induced Neuropathic Pain in Rats (2010)

Oxaliplatin is a platinum-based chemotherapy drug characterized by the development of acute and chronic peripheral neuropathies. Mexiletine, an orally available Na(+)-channel blocker, has widely been used in patients with chronic painful diabetic neuropathy. In the present study, we examined the effect of mexiletine on oxaliplatin-induced neuropathic pain in rats. Mexiletine (100, but not 10 and 30, mg/kg, p.o.) completely reversed both mechanical allodynia and cold hyperalgesia induced by oxaliplatin (4 mg/kg, i.p., twice a week). Lidocaine (30, but not 3 and 10, mg/kg, i.p.) also significantly relieved both pain behaviors. These results suggest that mexiletine may be effective in relieving the oxaliplatin-induced neuropathic pain clinically.
A Computer Algorithm for Calculating the Adequacy of Antidepressant Treatment in Unipolar and Bipolar Depression (2003)

The computer algorithm can be used to analyze large databases and may help reduce the morbidity and mortality associated with major depression by improving the assessment of adequacy of pharmacologic treatments for research and quality assurance purposes. The availability of the updated ATHF on the Internet for downloading allows for modifications according to the user's purposes.
Delineation of suppressor and helper activity within the OKT4-defined T lymphocyte subset in human newborns. (1983)

Lymphocytes taken from the cord blood of newborns have active suppressor activity. Using in vitro PWM-stimulated cocultures, unfractionated T cells from newborns potently suppressed the expected immunoglobulin G (IgG) synthesis of their mothers' peripheral blood lymphocytes (PBL). Using positive and negative selection techniques, we characterized the active suppressor cell as expressing the OKT4+T8- phenotype. This cord blood lymphocyte subset suppressed maternal IgG synthesis after depletion of maternal suppressor cells, implicating the ability of newborn T cells to suppress directly rather than by inducing adult suppressor activity. Sublethal amounts (1500 rad) of gamma-irradiation fully abrogated the suppressor activity of cord blood T lymphocytes. Radioresistant cord T cells provided T cell help. Irradiation of cord OKT4+ and OKT8+ populations and their subsequent culture with maternal B cells determined that helper activity was a radioresistant subpopulation of the OKT4+ subset. These results indicate significant differences in the functional properties of T cell subsets from adults and newborns. Population studies determined that cord blood lymphocytes had a greater proportion of OKT4+ cells and lower proportion of OKT8+ cells than PBL from unrelated adults. The mothers tested had similar proportions of OKT4+ cells as their babies, and these levels are significantly higher than those of unrelated adults.
Relative antithrombotic effect of soluble GPVI dimer compared with anti-GPVI antibodies in mice (2004)

Glycoprotein VI (GPVI) is an essential platelet collagen receptor; therefore, the inhibition of GPVI-collagen interactions may be an attractive antithrombotic strategy. We have previously shown that targeting of GPVI with antibodies leads to the depletion of the receptor and to long-term antithrombotic protection in mice. An alternative agent to interfere with GPVI-collagen interactions might be soluble GPVI acting as a competitive inhibitor, thereby averting undesired effects on platelets. To test this, we expressed soluble dimeric human GPVI, comprising the extracellular domain of the receptor fused to the human immunoglobulin Fc domain (GPVI-Fc), and compared its antithrombotic potential with that of anti-GPVI antibodies in mice. In contrast to a recent report, we found by intravital fluorescence microscopy and ultrasonic flow measurements that GPVI-Fc had no effect on platelet adhesion and thrombus formation at the injured arterial wall, whereas anti-GPVI antibodies profoundly inhibited these processes. Similar results were obtained with a fusion protein comprising the extracellular domain of mouse GPVI and human IgG-Fc. This indicates that direct targeting of GPVI provides significantly stronger protection against arterial thrombosis than soluble GPVI dimer.
Plasminogen binds the heparin-binding domain of insulin-like growth factor-binding protein-3 (1998)

Limited proteolysis lowers affinity of insulin-like growth factor (IGF)-binding protein (IGFBP)-3 for bound IGFs, resulting in greater IGF bioavailability. Plasmin is one of many proteases that cleave IGFBP-3, and the plasmin system may regulate IGFBP-3 proteolysis and IGF bioavailability in cultured cells in vitro. A role for the plasmin system in IGFBP-3 proteolysis in vivo is suggested by data presented here showing that IGFBP-3 binds plasminogen (Pg; Glu-Pg) with a dissociation constant (Kd) ranging from 1.43 to 3.12 nM. IGF-I and Glu-Pg do not compete for IGFBP-3 binding; instead, the binary IGFBP-3/Glu-Pg complex binds IGF-I with high affinity (Kd = 0. 47 nM) to form a ternary complex. Competitive binding studies suggest that the kringle 1, 4, and 5 domains of Glu-Pg and the heparin-binding domain of IGFBP-3 participate in forming the IGFBP-3/Glu-Pg complex, and other studies show that Glu-Pg in this complex is activated at a normal rate by tissue Pg activator. Importantly, IGFBP-3/Glu-Pg complexes were detected in both human citrate plasma and serum, indicating that these complexes exist in vivo. Binding of IGFBP-3 to Glu-Pg in vivo suggests how Glu-Pg activation can specifically lead to IGFBP-3 proteolysis with subsequent release of IGFs to local target tissues.