tbuckley/cabot-search huggingface dataset:
Evaluation of Pathological Manifestations of Disease in Mucopolysaccharidosis VII Mice after Neonatal Hepatic Gene Therapy
Authors: Lingfei Xu, Robert L. Mango, Mark S. Sands, Mark E. Haskins, N.Matthew Ellinwood, Katherine Parker Ponder
Journal: Molecular Therapy (2002)

Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease caused by β-glucuronidase (GUSB) deficiency. Intravenous injection of a retroviral vector expressing canine GUSB into neonatal MPS VII mice resulted in transduction of 6 to 35% of hepatocytes, which secreted GUSB into blood. Serum GUSB activity was stable for 6 months at 600 (low expression) to 10,000 (high expression) U/ml, and enzyme was modified appropriately with mannose 6-phosphate. The average serum GUSB activity (3531 U/ml) is the highest long-term expression reported for MPS VII mice after gene therapy. Secreted enzyme was taken up by other tissues, as the average enzyme activity was >13% of normal in somatic organs and 2% of normal in brain. Low expression markedly reduced histopathological evidence of lysosomal storage in liver, spleen, kidney, small intestine, neurons, and glial cells. High expression appeared to be more effective than low expression at reducing lysosomal storage in aorta, heart valves, thymus, bronchial epithelium, cornea, and retinal pigmented epithelium. Future experiments will determine if greater pathological improvements will consistently be observed in retrovirus-treated MPS VII mice with higher serum GUSB activity relative to animals with lower activity and if these result in clinical benefits.
Diagnosed only if considered: isolated renal mucormycosis
Authors: Harpal S Dhaliwal, Anupam Singh, Saroj K Sinha, Ram V Nampoothiri, Ajay Goyal, Debajyoti Chatterjee, Sudheer K Dewana, Anupam Lal, Ashim Das, K L Gupta, Rakesh Kochhar
Journal: The Lancet (2015)
Albuminuria, Just a Marker for Cardiovascular Disease, Or Is It More?
Authors: Dick de Zeeuw
Journal: Journal of the American Society of Nephrology (2005)

Excess excretion of protein(s) in the urine has, until very recently, generally been considered to be a consequence of renal damage: Severity of renal disease was estimated by the level of proteinuria, and success of therapy targeted on the renal disease was estimated by measuring the lowering of
Stroke volume determination using transcardiopulmonary thermodilution and arterial pulse contour analysis in severe aortic valve disease
Authors: Martin Petzoldt, Carsten Riedel, Jan Braeunig, Sebastian Haas, Matthias S. Goepfert, Hendrik Treede, Stephan Baldus, Alwin E. Goetz, Daniel A. Reuter
Journal: Intensive Care Medicine (2013)
Phosphoproteome analysis of isoflurane-protected heart mitochondria: phosphorylation of adenine nucleotide translocator-1 on Tyr194 regulates mitochondrial function
Authors: Jianhua Feng, Min Zhu, Marcus C. Schaub, Peter Gehrig, Bernd Roschitzki, Eliana Lucchinetti, Michael Zaugg
Journal: Cardiovascular Research (2008)

Reversible phosphorylation of mitochondrial proteins is essential in the regulation of respiratory function, energy metabolism, and mitochondrion-mediated cell death. We hypothesized that mitochondrial protein phosphorylation plays a critical role in cardioprotection during pre and postconditioning, two of the most efficient anti-ischaemic therapies. Using phosphoproteomic approaches, we investigated the profiles of phosphorylated proteins in Wistar rat heart mitochondria protected by pharmacological pre and postconditioning elicited by isoflurane. Sixty-one spots were detected by two-dimensional blue-native gel electrophoresis-coupled Western blotting using a phospho-Ser/Thr/Tyr-specific antibody, and 45 of these spots were identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Eleven protein spots related to oxidative phosphorylation, energy metabolism, chaperone, and carrier functions exhibited significant changes in their phosphorylation state when protected mitochondria were compared with unprotected. Using a phosphopeptide enrichment protocol followed by liquid chromatography-MS/MS, 26 potential phosphorylation sites were identified in 19 proteins. Among these, a novel phosphorylation site was detected in adenine nucleotide translocator-1 (ANT1) at residue Tyr194. Changes in ANT phosphorylation between protected and unprotected mitochondria were confirmed by immunoprecipitation. The biological significance of ANT phosphorylation at Tyr194 was further tested with site-directed mutagenesis in yeast. Substitution of Tyr194 with Phe, mimicking the non-phosphorylated state, resulted in the inhibition of yeast growth on non-fermentable carbon sources, implying a critical role of phosphorylation at this residue in regulating ANT function and cellular respiration. Our analysis emphasizes the regulatory functions of the phosphoproteome in heart mitochondria and reveals a novel, potential link between bioenergetics and cardioprotection.
Potassium and Calcium Channels in Lymphocytes
Authors: Richard S. Lewis, Michael D. Cahalan
Journal: Annual Review of Immunology (1995)

Over the past decade, a variety of ion channels have been identified and characterized in lymphocytes by use of the patch-clamp technique. This review discusses biophysical and regulatory aspects of lymphocyte potassium and calcium channels with the aim of understanding the role of these channels in lymphocyte functions. Lymphocytes express both voltage-dependent potassium [K(V)] channels and calcium-activated potassium [K(Ca)] channels, and each is upregulated as cells progress toward division following mitogenic stimulation. The genes encoding two K(V) channels, Kv1.3 (type n) and Kv3.1 (type l), have cloned. Mutational analysis is revealing functionally important regions of these channel proteins. Exogenous expression studies and the use of highly specific channel blockers have helped to establish the roles of type n K(V) channels sustaining the resting membrane potential, in regulating cell volume, and in enabling lymphocyte activation. Blockade of K(V) and K(Ca) channels effectively inhibits the antigen-driven activation of lymphocytes, probably by inducing membraned epolarization and thereby diminishing calcium influx. A prolonged rise in intracellular calcium ([ Ca 2+ ] i ) is a required signal for lymphocyte activation by antigen or mitogens. Single-cell fluorescence measurements have revealed underlying [Ca 2+ ] i oscillations that are linked closely to the opening and closing of Ca 2+ and K + channels. Sustained Ca 2+ signaling and oscillations depend absolutely on plasma-membrane Ca 2+ channels that are activated by the depletion of intracellular calcium stores. Under physiological conditions these channels open as a consequence of store depletion induced by inositol 1,4,5-trisphosphate (IP 3 ), but they can also be activated experimentally by several agents that empty the stores without generating IP 3 , such as the microsomal Ca 2+ -ATPase inhibitor thapsigargin. The intricate causal relationships among ion channels, membrane potential, [Ca 2+ ] i , and lymphokine gene expression can now be pursued at the single-cell level with patch-clamp recording, calcium-dependent dyes, reporter genes, and fluorescence video techniques. These approaches will help to clarify the essential roles of ion channels in the molecular pathways subserving activation and other lymphocyte behaviors.
SQUID-Detected Magnetic Resonance Imaging in Microtesla Fields
Authors: John Clarke, Michael Hatridge, Michael Mößle
Journal: Annual Review of Biomedical Engineering (2007)

The use of very low noise magnetometers based on Superconducting QUantum Interference Devices (SQUIDs) enables nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) in microtesla magnetic fields. An untuned superconducting flux transformer coupled to a SQUID achieves a magnetic field noise of 10(-15) T Hz(-1/2). The frequency-independent response of this magnetometer combined with prepolarization of the nuclear spins yields an NMR signal that is independent of the Larmor frequency omega0. An MRI system operating in a field of 132 microT, corresponding to a proton frequency of 5.6 kHz, achieves an in-plane resolution of 0.7 x 0.7 mm2 in phantoms. Measurements of the longitudinal relaxation time T1 in different concentrations of agarose gel over five decades of frequency reveal much greater T1-differentiation at fields below a few millitesla. Microtesla MRI has the potential to image tumors with substantially greater T1-weighted contrast than is achievable in high fields in the absence of a contrast agent.
Mediation systems in bacterial lipopolysaccharide-induced hypotension and disseminated intravascular coagulation. I. The role of complement.
Authors: R J Ulevitch, C G Cochrane, P M Henson, D C Morrison, W F Doe
Journal: The Journal of Experimental Medicine (1975)

We have studied the role of complement in lipopolysaccharide (LPS)-induced hypotension and disseminated intravascular coagulation (DIC) by comparing the effects of injection of three preparations of LPS from E. Coli 0111:B4, S. minnesota Re595, and S. marcescens. Injections of nonlethal doses of these LPS preparations into normal rabbits produced decreases in mean arterial blood pressure during a 5-h period. When rabbits treated with cobra venom factor (CoF) to deplete C3 were injected with the various LPS preparations, mean arterial pressures fell at a rate and extent essentially identical to that observed in normal rabbits. Rabbits genetically deficient in C6 also demonstrated LPS-induced hypotensive changes. Only minimal, or no changes in plasma C3 levels or serum CH50 values were detected in normal rabbits after LPS injection. Hypotensive changes were also induced in rabbits when complement was rapidly activated by intravenous injection of CoF. In contrast to the hypotension induced by LPS, the fall in arterial pressure associated with the consumption of complement was short lived and required the rapid consumption of considerable amounts of C3. The occurrence of DIC noted in normal rabbits injected with each preparation of LPS was not inhibited in either rabbits treated with cobra factor or in C6-deficient rabbits. The DIC was most pronounced after injection of Re595 and S. marcescens LPS. Injection of the various LPS preparations produced a rapid disappearance of circulating neutrophils and mononuclear cells, which occurred with the same kinetics and to the same extent in normal, CoF-treated, and C6-deficient rabbits. Injection of either Re595 LPS or S. marcescens LPS produced a biphasic disappearance of circulating 51Cr-platelets. In contrast, injection of 0111:B4 LPS affected only slightly the rate of disappearance of 51Cr-platelets. Depletion of C3 by cobra factor treatment had no effect on the disappearance of platelets in animals injected with 0111:B4. In marked contrast cobra factor treatment greatly reduced the initial rapid disappearance of platelets in rabbits injected with either Re595 or S. marcescens LPS, but had no effect in the secondary disappearance phase.
Fructosamine and Glycated Albumin and the Risk of Cardiovascular Outcomes and Death
Authors: Elizabeth Selvin, Andreea M. Rawlings, Pamela L. Lutsey, Nisa Maruthur, James S. Pankow, Michael Steffes, Josef Coresh
Journal: Circulation (2015)

Background— Hemoglobin A1c (HbA1c) is the standard measure to monitor glucose control in diabetes mellitus and is a marker of future cardiovascular risk. Fructosamine and glycated albumin are markers of short-term glycemic control, but their associations with cardiovascular outcomes are uncharacterized. Methods and Results— We measured glycated albumin and fructosamine in 11 104 participants with and without diabetes in the community-based Atherosclerosis Risk in Communities (ARIC) Study in 1990 to 1992 (baseline). We evaluated associations of fructosamine and glycated albumin with risk of coronary heart disease, ischemic stroke, heart failure, and mortality. We compared associations with those observed for HbA1c. During two decades of follow-up there were 1096 new cases of coronary heart disease, 605 of ischemic stroke, 1432 of heart failure, and 2860 deaths. Elevated baseline concentrations of fructosamine and glycated albumin were significantly associated with each of the outcomes even after adjustment for traditional cardiovascular risk factors, with especially strong associations in persons with diabetes mellitus. Associations were of similar magnitude to those observed for HbA1c and—as has been previously observed for HbA1c—the associations tended to be J-shaped, with an elevation of risk at the lowest levels of each biomarker. Conclusions— The acceptance of new measures of hyperglycemia is partly dependent on establishing their association with long-term outcomes. We found that fructosamine and glycated albumin were associated with vascular outcomes and mortality and that these associations were similar to those observed for HbA1c.
Weaning diet induces sustained metabolic phenotype shift in the pig and influences host response to<i>Bifidobacterium lactis</i>NCC2818
Authors: Claire Alexandra Merrifield, Marie Claire Lewis, Sandrine Paule Claus, Jake Thomas Midwinter Pearce, Olivier Cloarec, Swantje Duncker, Silke Sophie Heinzmann, Marc-Emmanuel Dumas, Sunil Kochhar, Serge Rezzi, Annick Mercenier, Jeremy Kirk Nicholson, Mick Bailey, Elaine Holmes
Journal: Gut (2012)

The process of weaning causes a major shift in intestinal microbiota and is a critical period for developing appropriate immune responses in young mammals.To use a new systems approach to provide an overview of host metabolism and the developing immune system in response to nutritional intervention around the weaning period.Piglets (n=14) were weaned onto either an egg-based or soya-based diet at 3 weeks until 7 weeks, when all piglets were switched onto a fish-based diet. Half the animals on each weaning diet received Bifidobacterium lactis NCC2818 supplementation from weaning onwards. Immunoglobulin production from immunologically relevant intestinal sites was quantified and the urinary (1)H NMR metabolic profile was obtained from each animal at post mortem (11 weeks).Different weaning diets induced divergent and sustained shifts in the metabolic phenotype, which resulted in the alteration of urinary gut microbial co-metabolites, even after 4 weeks of dietary standardisation. B lactis NCC2818 supplementation affected the systemic metabolism of the different weaning diet groups over and above the effects of diet. Additionally, production of gut mucosa-associated IgA and IgM was found to depend upon the weaning diet and on B lactis NCC2818 supplementation.The correlation of urinary (1)H NMR metabolic profile with mucosal immunoglobulin production was demonstrated, thus confirming the value of this multi-platform approach in uncovering non-invasive biomarkers of immunity. This has clear potential for translation into human healthcare with the development of urine testing as a means of assessing mucosal immune status. This might lead to early diagnosis of intestinal dysbiosis and with subsequent intervention, arrest disease development. This system enhances our overall understanding of pathologies under supra-organismal control.
Phase I/II Trial of Tremelimumab in Patients With Metastatic Melanoma
Authors: Luis H. Camacho, Scott Antonia, Jeffrey Sosman, John M. Kirkwood, Thomas F. Gajewski, Bruce Redman, Dmitri Pavlov, Cecile Bulanhagui, Viviana A. Bozon, Jesus Gomez-Navarro, Antoni Ribas
Journal: Journal of Clinical Oncology (2009)

Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blockade with tremelimumab (CP-675,206), a fully human anti-CTLA4 monoclonal antibody, was tolerated and demonstrated antitumor activity in a single dose, dose-escalation phase I trial in patients with solid tumors. This phase I/II trial was conducted to examine safety of multiple doses of tremelimumab, to further assess efficacy, and to identify an appropriate dosing regimen for further development.Twenty-eight patients with metastatic melanoma received monthly intravenous infusions of tremelimumab at 3, 6, or 10 mg/kg for up to 1 year to determine recommended monthly phase II dose. During phase II, 89 patients received tremelimumab 10 mg/kg once every month or 15 mg/kg every 3 months.No dose-limiting toxicity was observed in phase I once every month dosing. In phase II, 8 (10%) of 84 response-assessable patients attained objective antitumor responses; best overall objective response was one complete response and three partial responses in each dosing regimen. Most responses were durable (range, 3 to 30+ months). Most frequent treatment-related adverse events (AEs) were diarrhea, rash, and pruritus. Frequency of grade 3/4 AEs was 13% in the 15 mg/kg every 3 months arm and 27% in the 10 mg/kg once every month. Serious AEs were also less frequent in the 15 mg/kg once every 3 months cohort (9% v 23% in 10 mg/kg arm).Multiple infusions of tremelimumab were generally tolerable and demonstrated single-agent antitumor activity. Both phase II regimens generated durable tumor responses. Based on its more favorable safety profile, 15 mg/kg every 3 months was selected for further clinical testing.
Detection of differentiation‐ and activation‐linked cell surface antigens on cultured mast cell progenitors
Authors: G.‐H. Schernthaner, A. W. Hauswirth, M. Baghestanian, H. Agis, M. Ghannadan, C. Worda, M.‐T. Krauth, D. Printz, G. Fritsch, W. R. Sperr, P. Valent
Journal: Allergy (2005)

Background: Mast cells (MC) are multifunctional effector cells of the immune system. They derive from uncommitted CD34 + hemopoietic progenitor cells (HPC). Depending on the stage of maturation and the environment, MC variably express differentiation‐ and activation‐linked antigens. Little is known, however, about the regulation of expression of such antigens in immature human MC. Methods: We analyzed expression of CD antigens on human MC grown from cord blood‐derived CD34 + HPC. The HPC were isolated by magnetic cell sorting (MACS) and FACS to &gt;97% purity, and were cultured in stem cell factor (SCF) and interleukin (IL)‐6 with or without additional cytokines (IL‐4 or IL‐10) in serum‐free medium. The cell surface phenotype of MC was determined by monoclonal antibodies and flow cytometry. Results: Cultured MC progenitors were found to react with antibodies against various CD antigens including CD58, CD63, CD117, CD147, CD151, CD203c, and CD172a, independent of the growth factors used and time‐point investigated (days 14–42). CD116 [granulocyte–macrophage colony‐stimulating factor receptor α (GM‐CSFR α )] and CD123 (IL‐3R α ) were expressed on MC precursors on day 14, but disappeared thereafter. Cultured MC did not express CD2, CD3, CD5, CD10, CD19, or CD25. Addition of IL‐10 to MC cultures showed no effect on expression of CD antigens. However, IL‐4 was found to promote expression of CD35 and CD88 on cultured MC without changing expression of other CD antigens. Conclusions: Most MC antigens may already be expressed at an early stage of mastopoiesis. Whereas IL‐3R and GM‐CSFRs are lost during differentiation of MC, these cells may acquire complement receptors (CD35, CD88) under the influence of distinct cytokines.
Government considers a national implant register in review of cosmetic procedures
Authors: A. O'Dowd
Journal: BMJ (2012)

The government has launched a national review of how the cosmetic surgery industry is regulated in England that could mean tighter restrictions on its practices.

A national implant register for products such as breast implants and other medical devices is also up for debate as part of the review 1 published on 15 August by the Department of Health.

The move follows the scandal over breast implants that came to light last year.

Around 47 000 women in the UK are thought to have received the former French manufacturer Poly Implant Prosthese (PIP) breast implants, which were found to contain non-medical grade silicone, prompting concerns about their safety.2 3

As part of the response to the scandal, health …
Time matters! Implications from mentally imaged motor actions
Authors: Markus Raab, Marc Boschker
Journal: Behavioral and Brain Sciences (2002)

Pylyshyn provides sound arguments against the dominant picture theory of mental imagery. However, we claim that mental imagery is intrinsically dynamic and that the very nature of mental imagery will not be uncovered by studying static pictures. Understanding mental imagery of motor actions reveals that any theory of mental imagery should start off with the temporal nature of real-life experiences.
Gonadotropin-Releasing Hormone Receptors
Authors: Robert P. Millar, Zhi-Liang Lu, Adam J. Pawson, Colleen A. Flanagan, Kevin Morgan, Stuart R. Maudsley
Journal: Endocrine Reviews (2004)

GnRH and its analogs are used extensively for the treatment of hormone-dependent diseases and assisted reproductive techniques. They also have potential as novel contraceptives in men and women. A thorough delineation of the molecular mechanisms involved in ligand binding, receptor activation, and intracellular signal transduction is kernel to understanding disease processes and the development of specific interventions. Twenty-three structural variants of GnRH have been identified in protochordates and vertebrates. In many vertebrates, three GnRHs and three cognate receptors have been identified with distinct distributions and functions. In man, the hypothalamic GnRH regulates gonadotropin secretion through the pituitary GnRH type I receptor via activation of G(q). In-depth studies have identified amino acid residues in both the ligand and receptor involved in binding, receptor activation, and translation into intracellular signal transduction. Although the predominant coupling of the type I GnRH receptor in the gonadotrope is through productive G(q) stimulation, signal transduction can occur via other G proteins and potentially by G protein-independent means. The eventual selection of intracellular signaling may be specifically directed by variations in ligand structure. A second form of GnRH, GnRH II, conserved in all higher vertebrates, including man, is present in extrahypothalamic brain and many reproductive tissues. Its cognate receptor has been cloned from various vertebrate species, including New and Old World primates. The human gene homolog of this receptor, however, has a frame-shift and stop codon, and it appears that GnRH II signaling occurs through the type I GnRH receptor. There has been considerable plasticity in the use of different GnRHs, receptors, and signaling pathways for diverse functions. Delineation of the structural elements in GnRH and the receptor, which facilitate differential signaling, will contribute to the development of novel interventive GnRH analogs.
New Immune Globulin Subcutaneous (Human), 10% (IGSC) Product is Well Tolerated in Subjects with Primary Immunodeficiency Diseases (PIDD)
Authors: W.J. Grossman, R.L. Wasserman, I. Melamed, M. Stein, W. Engl, H. Leibl, R.I. Schiff, D. Gelmont
Journal: Journal of Allergy and Clinical Immunology (2011)