Miracle-dz/UniFAR-FTUs huggingface dataset:
Vildagliptin Stimulates Endothelial Cell Network Formation and Ischemia-induced Revascularization via an Endothelial Nitric-oxide Synthase-dependent Mechanism*

Background: DPP-4 inhibitors exert pleiotropic effects that modulate cardiovascular disease. Results: The DPP-4 inhibitor vildagliptin stimulates ischemia-induced revascularization through eNOS signaling. The angiogenic actions of vildagliptin are mediated by both GLP-1-dependent and -independent mechanisms. Conclusion: DPP-4 inhibitor promotes endothelial cell function via eNOS signaling. Significance: DPP-4 inhibitor could be beneficial in patients with diabetes-related vascular complications. Dipeptidyl peptidase-4 inhibitors are known to lower glucose levels and are also beneficial in the management of cardiovascular disease. Here, we investigated whether a dipeptidyl peptidase-4 inhibitor, vildagliptin, modulates endothelial cell network formation and revascularization processes in vitro and in vivo. Treatment with vildagliptin enhanced blood flow recovery and capillary density in the ischemic limbs of wild-type mice, with accompanying increases in phosphorylation of Akt and endothelial nitric-oxide synthase (eNOS). In contrast to wild-type mice, treatment with vildagliptin did not improve blood flow in ischemic muscles of eNOS-deficient mice. Treatment with vildagliptin increased the levels of glucagon-like peptide-1 (GLP-1) and adiponectin, which have protective effects on the vasculature. Both vildagliptin and GLP-1 increased the differentiation of cultured human umbilical vein endothelial cells (HUVECs) into vascular-like structures, although vildagliptin was less effective than GLP-1. GLP-1 and vildagliptin also stimulated the phosphorylation of Akt and eNOS in HUVECs. Pretreatment with a PI3 kinase or NOS inhibitor blocked the stimulatory effects of both vildagliptin and GLP-1 on HUVEC differentiation. Furthermore, treatment with vildagliptin only partially increased the limb flow of ischemic muscle in adiponectin-deficient mice in vivo. GLP-1, but not vildagliptin, significantly increased adiponectin expression in differentiated 3T3-L1 adipocytes in vitro. These data indicate that vildagliptin promotes endothelial cell function via eNOS signaling, an effect that may be mediated by both GLP-1-dependent and GLP-1-independent mechanisms. The beneficial activity of GLP-1 for revascularization may also be partially mediated by its ability to increase adiponectin production.
Renal effects of vasodilators in acute heart failure

Vasodilator therapy is common in acute heart failure (AHF) patients, although evidence for morbidity and mortality benefits is limited for many of these drugs. AHF is frequently accompanied by renal dysfunction, which is a strong, independent predictor for poor prognosis. Several hemodynamic and neurohormonal effects of vasodilators—including preload and afterload reduction, activation or inhibition of neurohormonal and inflammatory cascades—have the potential to modulate cardiorenal interaction and impact renal function. However, the effect of vasodilators on renal function in acute heart failure is often poorly described. In this review, we provide an overview of the known cardiorenal effects of traditional and novel vasodilators in patients with acute heart failure.
Caracterización de pacientes tratados por Cirugía Maxilofacial en la Clínica CES 2005-2007

Introduccion y Objetivo: La cirugia maxilofacial se ocupa de la prevencion, estudio, diagnostico, tratamiento quirurgico y medicamentoso de las patologias que afectan la cavidad bucal y la cara, asi como las estructuras cervicales relacionadas. El presente trabajo se orienta a evaluar las principales causas por las que se realiza cirugia maxilofacial, los diferentes tipos de patologias, la edad, el genero, los dias de estancia y las complicaciones que se presentaron en los pacientes de cirugia maxilofacial de la clinica CES. Materiales y Metodos: Se realizo un estudio descriptivo, transversal, retrospectivo basado en la informacion tomada de historias clinicas de 648 pacientes intervenidos por cirugia maxilofacial en la clinica CES entre los anos 2005 a 2007. Resultados: El tipo de atencion que mas se presento fue particular 52.6%, el tipo de cirugia mas frecuente fue electiva 90%, las causas mas comunes de los traumas fueron accidentes de transito y lesiones por caidas, la localizacion mas frecuente de las fracturas fue el tercio inferior y la zona mas afectada fue el angulo mandibular, el procedimiento quirurgico que predomino fue la cirugia ortognatica 55%, requirieron fijacion intermaxilar el 30.7%. El 50% de los pacientes fueron hospitalizados y el 0.92% presento alguna complicacion. Conclusiones: La mayoria de las cirugias realizadas fueron electivas, particulares y ortognaticas, predominando la poblacion adulta joven de sexo femenino, la causa principal de los traumas fueron accidentes de transito y lesiones por caidas, la mitad de los pacientes requirio hospitalizacion y el promedio fue un dia. ABSTRACT Introduction and Objective: Maxillofacial surgery deals with the prevention, study, diagnosis and surgical treatment of disorders affecting the oral cavity and face, neck and related structures. The purpose was to assess the main causes for the performance of that surgery, different types of diseases, age, gender, days of hospitalization, and complications that were presented at the CES clinic in the area of maxillofacial surgery. Materials and Methods: A descriptive, cross-sectional, retrospective study was performed. The information for analysis was taken from medical records of 648 patients operated by maxillofacial surgery at the CES clinic between 2005 and 2007. Results: The type of treatment most prevalent was private 52.6%, the most common surgery was elective 90%, the most common causes of trauma were from traffic accidents and injuries from falls; the most common site of fractures were the facial lower third and the most affected area was the mandibular angle, the predominant surgical procedure was orthognathic surgery 55%, requiring intermaxillar fixation 30.7%. The 50% of patients were hospitalized and only 0.92% had a complication. Conclusions: The majority of surgeries performed were elective, private and orthognathic, mainly of young female adults, the main cause of trauma were traffic accidents and injuries from falls, half of the patients required hospitalization with one day of average.
Animal clinical chemistry : a practical handbook for toxicologists and biomedical researchers

Introduction General Enzymology Assessment of Hepatotoxicity Assessment of Nephrotoxicity Assessment of Gastrointestinal and Pancreatic Toxicities Fluid Balance, Electrolytes, and Mineral Metabolism Assessment of Cardiotoxicity and Myotoxicity Proteins Lipids Assessment of Endocrine Toxicity Assessment of Neurotoxicity Preanalytical Variables Analytical Variables and Biosafety Data Processing and Interpretation References for Laboratory Animal Clinical Chemistry Data Appendix A References for Laboratory Animal Clinical Chemistry Data Appendix B SI Unitage and Conversions Appendix C "Expectable" Ranges for Plasma/Serum Appendix D General Abbreviations Appendix E Some Common Biochemical Abbreviations Index
Anti-Fas2 IgM antibodies in Fasciola hepatica infected patients with positive IgG serology

Background Fascioliasis is an infectious disease caused by parasites Fasciola hepatica and F. gigantica. Humans are infected by the consumption of vegetables and water contaminated with the infective form of the parasite. Materials and Methods In this study, an IgM-ELISA with the cysteine proteinase Fas2 antigen was evaluated with sera from 76 patients infected with F. hepatica, 24 patients with other parasite infections and 84 healthy volunteers. Results IgM-ELISA resulted in 43% positives in F. hepatica patients with positive serology to Fas2-ELISA, but no positives resulted from testing healthy volunteers and individuals infected with other parasites. The IgM-ELISA diagnostic parameters showed a sensitivity of 43.4% (95% CI 0.321-0.553), specificity of 100% (95% CI 0.957-1), and no cross-reactivity with other parasitic infection. Interference by rheumatoid factor in the IgM immunoassay was controlled by treating sera with rheumatoid factor absorbent before testing. Conclusions Fas2 antigen is detected by circulating IgM in patients infected with F. hepatica and IgM-ELISA using Fas2 appears as a specific immunoassay to detect the acute phase of the acute phase of F. hepatica infection in humans.
Seleção de linhagens de Biomphalaria tenagophila e Biompnalaria glabrata visando maior suscetibilidade ao Schistosoma mansoni

Utilizando um esquema de selecao individual em progenies autofecundadas, foram obtidas, apos quatro geracoes, populacoes de Biomphalaria tenagophila e de Biomphalaria glabrata, altamente suscetiveis as linhagens do Schistosoma mansoni do Vale do Rio Paraiba do Sul, SP e de Belo Horizonte, MG (Brasil), respectivamente. Os rapidos ganhos geneticos obtidos confirmam ser a suscetibilidade de moluscos a infeccao esquistossomotica, uma caracteristica de alta herdabilidade, sendo aparentemente condicionada por um pequeno numero de genes.
Mitochondrial function and morphology are impaired in parkin‐mutant fibroblasts

There are marked mitochondrial abnormalities in parkin‐knock‐out Drosophila and other model systems. The aim of our study was to determine mitochondrial function and morphology in parkin‐mutant patients. We also investigated whether pharmacological rescue of impaired mitochondrial function may be possible in parkin‐mutant human tissue.
Prodromal Alzheimer's disease: Successive emergence of the clinical symptoms

Whereas cognitive deficits are known to be detectable long before the typical symptoms of Alzheimer's disease (AD) are evident, previous studies have failed to determine when cognitive functioning actually begins to decline before dementia. Utilizing the long follow‐up of the PAQUID study, we examined the emergence of the first clinical symptoms over a 14‐year period of follow‐up before the dementia phase of AD.
NHERF2/NHERF3 Protein Heterodimerization and Macrocomplex Formation Are Required for the Inhibition of NHE3 Activity by Carbachol*

Background: Previous characterization of NHERF dimerizations is inconsistent and any physiological function is largely unknown. Results: NHERF2/NHERF3 heterodimerization is the strongest NHERF dimerization and is necessary for carbachol inhibition of NHE3. Conclusion: NHERF2/NHERF3 heterodimerization brings PDZ domains together to assemble macrocomplexes for NHE3 regulation. Significance: Macrocomplexes mediated by NHERF dimerizations could increase the complicity of their regulation of NHE3 and other proteins. NHERF1, NHERF2, and NHERF3 belong to the NHERF (Na+/H+ exchanger regulatory factor) family of PSD-95/Discs-large/ZO-1 (PDZ) scaffolding proteins. Individually, each NHERF protein has been shown to be involved in the regulation of multiple receptors or transporters including Na+/H+ exchanger 3 (NHE3). Although NHERF dimerizations have been reported, results have been inconsistent, and the physiological function of NHERF dimerizations is still unknown. The current study semiquantitatively compared the interaction strength among all possible homodimerizations and heterodimerizations of these three NHERF proteins by pulldown and co-immunoprecipitation assays. Both methods showed that NHERF2 and NHERF3 heterodimerize as the strongest interaction among all NHERF dimerizations. In vivo NHERF2/NHERF3 heterodimerization was confirmed by FRET and FRAP (fluorescence recovery after photobleach). NHERF2/NHERF3 heterodimerization is mediated by PDZ domains of NHERF2 and the C-terminal PDZ domain recognition motif of NHERF3. The NHERF3-4A mutant is defective in heterodimerization with NHERF2 and does not support the inhibition of NHE3 by carbachol. This suggests a role for NHERF2/NHERF3 heterodimerization in the regulation of NHE3 activity. In addition, both PDZ domains of NHERF2 could be simultaneously occupied by NHERF3 and another ligand such as NHE3, α-actinin-4, and PKCα, promoting formation of NHE3 macrocomplexes. This study suggests that NHERF2/NHERF3 heterodimerization mediates the formation of NHE3 macrocomplexes, which are required for the inhibition of NHE3 activity by carbachol.
In situ analysis of microbial consortia in activated sludge using fluorescently labelled, rRNA‐targeted oligonucleotide probes and confocal scanning laser microscopy

Activated sludge flocs are complex consortia of various micro‐organisms. The community structures of samples taken from municipal sewage treatment plants were characterized using fluorescently labelled, 16S and 23S rRNA‐targeted oligonucleotide probes in combination with confocal scanning laser microscopy (CSLM). In comparison with conventional epifluorescence microscopy, CSLM considerably improved the capability to visualize directly the spatial distribution of defined bacterial populations inside the sludge flocs. Analyses could be performed at high resolution undisturbed by problems such as autofluorescence or limited spatial resolution in thick samples. In addition, CSLM was used to analyse some structural properties of paraformaldehyde‐fixed activated sludge flocs, such as floc size and homogeneity. Typical floc sizes were found to be in the range between 5 and 50 μm. Whereas most of the flocs were completely colonized by bacteria, there were also examples of flocs containing gas bubbles or particles in the interior.
A Structural and Biochemical Model of Processive Chitin Synthesis

Background: Chitin synthesis is an attractive drug target in a range of organisms but is not understood at the molecular level. Results: The chitooligosaccharide synthase NodC can be assayed with a novel HTS assay, and the mechanism/fold can be probed by site-directed mutagenesis and topology mapping. Conclusion: NodC is a model system to probe chitin synthesis. Significance: This work enables the exploitation of chitin synthesis as a drug target. Chitin synthases (CHS) produce chitin, an essential component of the fungal cell wall. The molecular mechanism of processive chitin synthesis is not understood, limiting the discovery of new inhibitors of this enzyme class. We identified the bacterial glycosyltransferase NodC as an appropriate model system to study the general structure and reaction mechanism of CHS. A high throughput screening-compatible novel assay demonstrates that a known inhibitor of fungal CHS also inhibit NodC. A structural model of NodC, on the basis of the recently published BcsA cellulose synthase structure, enabled probing of the catalytic mechanism by mutagenesis, demonstrating the essential roles of the DD and QXXRW catalytic motifs. The NodC membrane topology was mapped, validating the structural model. Together, these approaches give insight into the CHS structure and mechanism and provide a platform for the discovery of inhibitors for this antifungal target.
Efficacy of systemic morpholino exon‐skipping in duchenne dystrophy dogs

Duchenne muscular dystrophy (DMD) is caused by the inability to produce dystrophin protein at the myofiber membrane. A method to rescue dystrophin production by antisense oligonucleotides, termed exon‐skipping, has been reported for the mdx mouse and in four DMD patients by local intramuscular injection. We sought to test efficacy and toxicity of intravenous oligonucleotide (morpholino)‐induced exon skipping in the DMD dog model.
Lower motor neuron loss in multiple sclerosis and experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is considered a chronic inflammatory and demyelinating disease of the central nervous system. Evidence that axonal and neuronal pathology contributes to the disease is accumulating, however, the distribution of neuronal injury as well as the underlying mechanisms have not yet been fully clarified. Here, we investigated the role of neuronal cell loss in MS and its animal model, experimental autoimmune encephalomyelitis (EAE).
Acute stroke therapy with tissue plasminogen activator (tPA) since it was approved by the U.S. Food and Drug Administration (FDA)

Tissue plasminogen activator (tPA) for acute ischemic stroke was approved by the U.S. Food and Drug Administration (FDA) in 1996. Since then it has been severely underutilized. At the time when most practitioners were first being exposed to the literature concerning tPA, there were many concerns about safety and the restrictions on use were quite onerous. Since then a good deal of further work has been done to loosen the restrictions and allay concerns about the risks. The true risk to benefit ratio is far better than is generally realized. Now it is mostly economic problems related to the costs of constantly supplying emergency care that is limiting access. Furthermore, in the current litigious environment, failure to treat is likely to be a more hazardous course of action than legal exposure due to poor outcomes. It must be emphasized that the drug is quite safe and highly effective, and current utilization rates are unacceptably low. Ann Neurol 2009;66:6–10
Response Gene to Complement 32 Protein Promotes Macrophage Phagocytosis via Activation of Protein Kinase C Pathway*

Background: Response gene to complement 32 (RGC-32) was initially identified in oligodendrocytes, suggesting an immune-related function. Results: RGC-32 deficiency did not affect macrophage differentiation but attenuated macrophage phagocytosis by reducing protein kinase C activity and F-actin formation. Conclusion: RGC-32 is a novel regulator for macrophage phagocytosis. Significance: RGC-32 may serve as a novel target for modulating immune function. Macrophage phagocytosis plays an important role in host defense. The molecular mechanism, especially factors regulating the phagocytosis, however, is not completely understood. In the present study, we found that response gene to complement 32 (RGC-32) is an important regulator of phagocytosis. Although RGC-32 is induced and abundantly expressed in macrophage during monocyte-macrophage differentiation, RGC-32 appears not to be important for this process because RGC-32-deficient bone marrow progenitor can normally differentiate to macrophage. However, both peritoneal macrophages and bone marrow-derived macrophages with RGC-32 deficiency exhibit significant defects in phagocytosis, whereas RGC-32-overexpressed macrophages show increased phagocytosis. Mechanistically, RGC-32 is recruited to macrophage membrane where it promotes F-actin assembly and the formation of phagocytic cups. RGC-32 knock-out impairs F-actin assembly. RGC-32 appears to interact with PKC to regulate PKC-induced phosphorylation of F-actin cross-linking protein myristoylated alanine-rich protein kinase C substrate. Taken together, our results demonstrate for the first time that RGC-32 is a novel membrane regulator for macrophage phagocytosis.
Dopaminergic transplantation for parkinson's disease: Current status and future prospects

Cell‐based therapies that involve transplantation into the striatum of dopaminergic cells have attracted considerable interest as possible treatments for Parkinson's disease (PD). However, all double‐blind, sham‐controlled, studies have failed to meet their primary endpoints, and transplantation of dopamine cells derived from the fetal mesencephalon is associated with a potentially disabling form of dyskinesia that persists even after withdrawal of levodopa (off‐medication dyskinesia). In addition, disability in advanced patients primarily results from features such as gait dysfunction, freezing, falling, and dementia, which are likely due to nondopaminergic pathology. These features are not adequately controlled with dopaminergic therapies and are thus unlikely to respond to dopaminergic grafts. More recently, implanted dopamine neurons have been found to contain Lewy bodies, suggesting that they are dysfunctional and may have been affected by the PD pathological process. Collectively, these findings do not bode well for the short‐term future of cell‐based dopaminergic therapies in PD. Ann Neurol 2009;66:591–596
Pharmacology practice and South Africa physiotherapists - part two needs analysis

A national survey of pharmaceutical practice by South African physiotherapists was conducted. In this second paper, the needs relating to administration, storage and prescription of medicines are discussed. Seventy percent of respondents reported a need to legally administer and 58% reported a need to store certain medicines. More than 60% of respondents were in favour of the expansion of the scope of physiotherapy practice to include prescription of a limited range of medications after training and within certain areas of specialization or clinical competence. It is recommended that a basic pharmacology module be part of the undergraduate curriculum with the option to expand or update knowledge and skills via CPD activities and through specialization and that legislation be revised to accommodate these suggestions.
Local institutional review board (IRB) review of a multicenter trial: Local costs without local context

Multicenter clinical research involves parallel Institutional Review Board (IRB) reviews based on the premise that local review reflects aspects of the research environment. We examined the costs and effects of local IRB review of the consent and protocol in a multicenter clinical trial in Parkinson disease. Seventy‐six percent of changes to the consent reflected standard institutional language, with no substantive changes to the protocol. The costs of this process exceeded $100,000. These findings support initiatives by the Office of Human Research Protections (OHRP) and the National Cancer Institute (NCI) to facilitate centralized reviews. This may be an opportune time for the National Institute of Neurological Disorders and Stroke (NINDS) to adopt a central review model. ANN NEUROL 2010;67:258–260
Choline Kinase β Mutant Mice Exhibit Reduced Phosphocholine, Elevated Osteoclast Activity, and Low Bone Mass*

Background: Bone homeostasis requires constant remodeling by bone-resorbing osteoclasts and bone-forming osteoblasts. Results: Choline kinase β (CHKB)-deficient mice have reduced bone mass, increased osteoclast number, and impaired osteoblast function. Conclusion: CHKB activity controls bone homeostasis via regulation of osteoclasts and osteoblasts. Significance: This is the first report implicating a role for CHKB in bone homeostasis. The maintenance of bone homeostasis requires tight coupling between bone-forming osteoblasts and bone-resorbing osteoclasts. However, the precise molecular mechanism(s) underlying the differentiation and activities of these specialized cells are still largely unknown. Here, we identify choline kinase β (CHKB), a kinase involved in the biosynthesis of phosphatidylcholine, as a novel regulator of bone homeostasis. Choline kinase β mutant mice (flp/flp) exhibit a systemic low bone mass phenotype. Consistently, osteoclast numbers and activity are elevated in flp/flp mice. Interestingly, osteoclasts derived from flp/flp mice exhibit reduced sensitivity to excessive levels of extracellular calcium, which could account for the increased bone resorption. Conversely, supplementation of cytidine 5′-diphosphocholine in vivo and in vitro, a regimen that bypasses CHKB deficiency, restores osteoclast numbers to physiological levels. Finally, we demonstrate that, in addition to modulating osteoclast formation and function, loss of CHKB corresponds with a reduction in bone formation by osteoblasts. Taken together, these data posit CHKB as a new modulator of bone homeostasis.