tbuckley/cabot-search huggingface dataset:
The linked roles of nitric oxide, aldose reductase and, (Na+,K+)-ATPase in the slowing of nerve conduction in the streptozotocin diabetic rat.
Authors: M J Stevens, J Dananberg, E L Feldman, S A Lattimer, M Kamijo, T P Thomas, H Shindo, A A Sima, D A Greene
Journal: Journal of Clinical Investigation (1994)

Metabolic and vascular factors have been invoked in the pathogenesis of diabetic neuropathy but their interrelationships are poorly understood. Both aldose reductase inhibitors and vasodilators improve nerve conduction velocity, blood flow, and (Na+,K+)-ATPase activity in the streptozotocin diabetic rat, implying a metabolic-vascular interaction. NADPH is an obligate cofactor for both aldose reductase and nitric oxide synthase such that activation of aldose reductase by hyperglycemia could limit nitric oxide synthesis by cofactor competition, producing vasoconstriction, ischemia, and slowing of nerve conduction. In accordance with this construct, N-nitro-L-arginine methyl ester, a competitive inhibitor of nitric oxide synthase reversed the increased nerve conduction velocity afforded by aldose reductase inhibitor treatment in the acutely diabetic rat without affecting the attendant correction of nerve sorbitol and myo-inositol. With prolonged administration, N-nitro-L-arginine methyl ester fully reproduced the nerve conduction slowing and (Na+,K+)-ATPase impairment characteristic of diabetes. Thus the aldose reductase-inhibitor-sensitive component of conduction slowing and the reduced (Na+,K+)-ATPase activity in the diabetic rat may reflect in part impaired nitric oxide activity, thus comprising a dual metabolic-ischemic pathogenesis.
Proliferative activity of intrahepatic colorectal metastases after preoperative hemihepatic portal vein embolization
Authors: Norihiro Kokudo, Keiichiro Tada, Makoto Seki, Hirotoshi Ohta, Kaoru Azekura, Masashi Ueno, Keiichiro Ohta, Toshiharu Yamaguchi, Toshiki Matsubara, Takashi Takahashi, Toshifusa Nakajima, Tetsuichiro Muto, Takaaki Ikari, Akio Yanagisawa, Yo Kato
Journal: Hepatology (2001)

Although hemihepatic portal vein embolization (PVE) has been used preoperatively to extend indications for hepatectomy in patients with colorectal metastases, the effects of this procedure on tumor growth and outcome remain controversial. To address this issue, we assessed the proliferative activity of intrahepatic metastases after PVE and the long–term outcome of this procedure. Eighteen patients with colorectal metastases underwent preoperative PVE between 1996 and 2000 (PVE group). Twenty–nine patients who underwent major hepatic resection without PVE served as control (non–PVE group). The hepatic parenchymal fraction of the left lobe had significantly increased from 38.1 ± 3.2% to 45.9 ± 2.9% 3 weeks after PVE (+20.5%, P &lt; .0001). Tumor volume and percent tumor volume had also significantly increased from 223 ± 89 mL to 270 ± 97 mL (+20.8%, P = .016) and from 13.7 + 4.3% to 16.2 + 4.9% (+18.5%, P = .014), respectively. There was no apparent correlation between the increase in parenchymal volume and that in tumor volume. The Ki–67 labeling index of metastatic lesions was 46.6 ± 7.2% in the PVE group and 35.4 ± 12.6% in the non–PVE group ( P = .013). Long–term survival was similar in the PVE and non–PVE groups, however, disease–free survival was significantly poorer in the PVE group than in the non–PVE group ( P = .004). We conclude that PVE increases tumor growth and probably is associated with enhanced recurrence of disease. Although PVE is effective in extending indications for surgery, patient selection for PVE should be cautious.
Gastrointestinal complications of HIV infection: changing priorities in the HAART era
Authors: C M Wilcox, M S Saag
Journal: Gut (2008)

It has now been some 25 years since the initial description of AIDS. Following these observations, the epidemiology, natural history and manifestations of this disease have been well characterised. Intense investigation has better characterised HIV, resulting in the development of effective drug therapies to arrest disease progression. These multidrug combinations, termed highly active antiretroviral therapy or HAART, can suppress the viral load to the undetectable range and secondarily halt the destruction of CD4 T lymphocytes. This virological response is associated with a marked improvement in survival and absence of the many complications related to immunodeficiency. For patients who respond to HAART, the current emphasis is on treating side effects from the medications as well as treating other non-AIDS-related disorders. However, given the cost and complexities of these regimens, there are many patients who continue to present with the classic manifestations of AIDS, and, especially in the developing world, we will continue to see these patients for years to come.
Studies of lipopolysaccharide effects on the induction of α-synuclein pathology by exogenous fibrils in transgenic mice
Authors: Nicola J. Rutherford, Amanda N. Sacino, Mieu Brooks, Carolina Ceballos-Diaz, Thomas B. Ladd, Jasie K. Howard, Todd E. Golde, Benoit I. Giasson
Journal: Molecular Neurodegeneration (2015)

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is pathologically characterized by loss of dopaminergic neurons from the substantia nigra, the presence of aggregated α-synuclein (αS) and evidence of neuroinflammation. Experimental studies have shown that the cerebral injection of recombinant fibrillar αS, especially in αS transgenic mouse models, can induce the formation and spread of αS inclusion pathology. However, studies reporting this phenomenon did not consider the presence of lipopolysaccharide (LPS) in the injected αS, produced in E. coli, as a potential confound. The objectives of this study are to develop a method to remove the LPS contamination and investigate the differences in pathologies induced by αS containing LPS or αS highly purified of LPS. We were able to remove >99.5 % of the LPS contamination from the αS preparations through the addition of a cation exchange step during purification. The αS pathology induced by injection of fibrils produced from αS containing LPS or purified of LPS, showed a similar distribution pattern; however, there was less spread into the cortex of the mice injected with αS containing higher levels of LPS. As previously reported, injection of αS fibrils could induce astrogliosis, and αS inclusions were present within astrocytes in mice injected with fibrils comprised of αS with or without cation exchange purification. Furthermore, we identified the presence of αS pathology in ependymal cells in both groups of mice, which suggests the involvement of a novel mechanism for spread in this model of αS pathology.
Denis Dunbar Gibbs
Authors: J. W. K. W. J. M. T. Ford
Journal: BMJ (2015)

Denis Dunbar Gibbs had his early education in Southern Rhodesia before attending the Diocesan College in Cape Town, the University of Cape Town Medical School, Keble College Oxford, and St Mary’s Hospital Medical School. He trained in London and Oxford and obtained a Fulbright award and a research grant from the US Public Health Service to spend a year in Boston, Massachusetts, as a fellow in gastroenterology. He spent his national service as a medical specialist …
Dietary Intervention in Patients With Gestational Diabetes Mellitus: A Systematic Review and Meta-analysis of Randomized Clinical Trials on Maternal and Newborn Outcomes
Authors: Luciana Verçoza Viana, Jorge Luiz Gross, Mirela Jobim Azevedo
Journal: Diabetes Care (2014)

OBJECTIVE Diet is the cornerstone treatment of patients with gestational diabetes mellitus (GDM), but its role in maternal and newborn outcomes has been scarcely studied. The purpose of this study was to analyze the efficacy of dietary interventions on maternal or newborn outcomes in patients with GDM. RESEARCH DESIGN AND METHODS A systematic review and meta-analysis of randomized clinical trials (RCTs) of dietary intervention in GDM or pregnancy with hyperglycemia was performed. MEDLINE, Embase, ClinicalTrials.gov, Cochrane, and Scopus were searched through to March 2014. The main evaluated maternal outcomes were proportion of patients using insulin and proportion of cesarean delivery; the newborn outcomes were proportion of macrosomia and hypoglycemia and newborn weight. RESULTS From 1,170 studies, nine RCTs, including 884 women aged 31.5 years (28.7–33.2) with 27.4 weeks (24.1–30.3) of gestation, were eligible. We divided the RCTs according to the type of dietary intervention: low glycemic index (GI) (n = 4; 257 patients), total energy restriction (n = 2; 425 patients), low carbohydrates (n = 2; 182 patients), and others (n = 1; 20 patients). Diet with low GI reduced the proportion of patients who used insulin (relative risk 0.767 [95% CI 0.597, 0.986]; P = 0.039) and the newborn birth weight (weight mean differences −161.9 g [95% CI −246.4, −77.4]; P = 0.000) as compared with control diet. Total restriction and low carbohydrate diets did not change either maternal or newborn outcomes. CONCLUSIONS A low GI diet was associated with less frequent insulin use and lower birth weight than control diets, suggesting that it is the most appropriate dietary intervention to be prescribed to patients with GDM.
Cardiac Exercise Hemodynamics Late After Partial Left Ventriculectomy
Authors: K. B. James, G. Haas, S. R. Lutton, D. Prior, K. Wolski, T. Buda, P. M. McCarthy
Journal: Circulation (2000)

Although some patients report favorable activity levels late after partial left ventriculectomy (PLV), their exercise physiology has not been well described.We performed upright bicycle hemodynamics in 10 patients (9 men) aged 56+/-12 years at 1.7 years after PLV. Ejection fraction was 25+/-4%. Patients biked 10+/-7 minutes. With exercise, the mean pulmonary arterial pressure rose from 36+/-12 to 52+/-10 mm Hg (P:=0.0003). The mean pulmonary capillary wedge pressure rose from 25+/-14 to 36+/-9 mm Hg (P:=0.0566), and the cardiac index rose from 2.2+/-0.5 to 3.8+/-1.6 L. min(-1). m(-2) (P:=0.0077). The mixed venous oxygenation with exercise declined from 44+/-9% to 24+/-17% (P:=0. 0220), and the pulmonary vascular resistance increased from 2.0+/-0. 9 to 2.3+/-1.1 Wood units (P:=0.5566).In late follow-up after PLV with exercise, the cardiac index is significantly augmented. However, there are further rises in pulmonary artery and pulmonary capillary wedge pressures, suggesting abnormal compliance, with marked decline in mixed venous oxygenation. Elucidating late physiology after PLV may help pave the way for future innovative heart failure surgeries.
The Head Direction Signal: Origins and Sensory-Motor Integration
Authors: Jeffrey S. Taube
Journal: Annual Review of Neuroscience (2007)

Navigation first requires accurate perception of one's spatial orientation within the environment, which consists of knowledge about location and directional heading. Cells within several limbic system areas of the mammalian brain discharge allocentrically as a function of the animal's directional heading, independent of the animal's location and ongoing behavior. These cells are referred to as head direction (HD) cells and are believed to encode the animal's perceived directional heading with respect to its environment. Although HD cells are found in several areas, the principal circuit for generating this signal originates in the dorsal tegmental nucleus and projects serially, with some reciprocal connections, to the lateral mammillary nucleus --> anterodorsal thalamus --> PoS, and terminates in the entorhinal cortex. HD cells receive multimodal information about landmarks and self-generated movements. Vestibular information appears critical for generating the directional signal, but motor/proprioceptive and landmark information are important for updating it.
Complement-Mediated Dysfunction of Glomerular Filtration Barrier Accelerates Progressive Renal Injury
Authors: Mauro Abbate, Carla Zoja, Daniela Corna, Daniela Rottoli, Cristina Zanchi, Nadia Azzollini, Susanna Tomasoni, Silvia Berlingeri, Marina Noris, Marina Morigi, Giuseppe Remuzzi
Journal: Journal of the American Society of Nephrology (2008)

Intrarenal complement activation leads to chronic tubulointerstitial injury in animal models of proteinuric nephropathies, making this process a potential target for therapy. This study investigated whether a C3-mediated pathway promotes renal injury in the protein overload model and whether the abnormal exposure of proximal tubular cells to filtered complement could trigger the resulting inflammatory response. Mice with C3 deficiency were protected to a significant degree against the protein overload-induced interstitial inflammatory response and tissue damage, and they had less severe podocyte injury and less proteinuria. When the same injury was induced in wild-type (WT) mice, antiproteinuric treatment with the angiotensin-converting enzyme inhibitor lisinopril reduced the amount of plasma protein filtered, decreased the accumulation of C3 by proximal tubular cells, and protected against interstitial inflammation and damage. For determination of the injurious role of plasma-derived C3, as opposed to tubular cell-derived C3, C3-deficient kidneys were transplanted into WT mice. Protein overload led to the development of glomerular injury, accumulation of C3 in podocytes and proximal tubules, and tubulointerstitial changes. Conversely, when WT kidneys were transplanted into C3-deficient mice, protein overload led to a more mild disease and abnormal C3 deposition was not observed. These data suggest that the presence of C3 increases the glomerular filtration barrier's susceptibility to injury, ultrafiltered C3 contributes more to tubulointerstitial damage induced by protein overload than locally synthesized C3, and local C3 synthesis is irrelevant to the development of proteinuria. It is speculated that therapies targeting complement combined with interventions to minimize proteinuria would more effectively prevent the progression of renal disease.
Visualization of Myelin Basic Protein (Mbp) T Cell Epitopes in Multiple Sclerosis Lesions Using a Monoclonal Antibody Specific for the Human Histocompatibility Leukocyte Antigen (Hla)-Dr2–Mbp 85–99 Complex
Authors: Michelle Krogsgaard, Kai W. Wucherpfennig, Barbara Canella, Bjarke E. Hansen, Arne Svejgaard, Jason Pyrdol, Henrik Ditzel, Cedric Raine, Jan Engberg, Lars Fugger
Journal: The Journal of Experimental Medicine (2000)

Susceptibility to multiple sclerosis (MS) is associated with the human histocompatibility leukocyte antigen (HLA)-DR2 haplotype, suggesting that major histocompatibility complex class II–restricted presentation of central nervous system–derived antigens is important in the disease process. Antibodies specific for defined HLA-DR2–peptide complexes may therefore be valuable tools for studying antigen presentation in MS. We have used phage display technology to select HLA-DR2–peptide-specific antibodies from HLA-DR2–transgenic mice immunized with HLA-DR2 molecules complexed with an immunodominant myelin basic protein (MBP) peptide (residues 85–99). Detailed characterization of one clone (MK16) demonstrated that both DR2 and the MBP peptide were required for recognition. Furthermore, MK16 labeled intra- and extracellular HLA-DR2–MBP peptide complexes when antigen-presenting cells (APCs) were pulsed with recombinant MBP. In addition, MK16 inhibited interleukin 2 secretion by two transfectants that expressed human MBP–specific T cell receptors. Analysis of the structural requirement for MK16 binding demonstrated that the two major HLA-DR2 anchor residues of MBP 85–99 and the COOH-terminal part of the peptide, in particular residues Val-96, Pro-98, and Arg-99, were important for binding. Based on these results, the antibody was used to determine if the HLA-DR2–MBP peptide complex is presented in MS lesions. The antibody stained APCs in MS lesions, in particular microglia/macrophages but also in some cases hypertrophic astrocytes. Staining of APCs was only observed in MS cases with the HLA-DR2 haplotype but not in cases that carried other haplotypes. These results demonstrate that HLA-DR2 molecules in MS lesions present a myelin-derived self-peptide and suggest that microglia/macrophages rather than astrocytes are the predominant APCs in these lesions.
Retinoic Acid Inhibits the Proliferative Response Induced by CD40 Activation and Interleukin-4 in Mantle Cell Lymphoma
Authors: Massimo Guidoboni, Paola Zancai, Roberta Cariati, Silvana Rizzo, Jessica Dal Col, Alessandro Pavan, Annunziata Gloghini, Michele Spina, Antonio Cuneo, Fabrizio Pomponi, Antonio Bononi, Claudio Doglioni, Roberta Maestro, Antonino Carbone, Mauro Boiocchi, Riccardo Dolcetti
Journal: Cancer Research (2005)

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma with poor response to therapy and unfavorable prognosis. Here, we show that retinoic acid (RA) isomers significantly inhibit the proliferation of both primary MCL cultures (n = 7) and established cell lines (Granta 519 and SP-53) as shown by [(3)H]thymidine uptake and carboxyfluorescein diacetate succinimidyl ester labeling coupled with cyclin D1 staining. RA induces cell accumulation in G(0)-G(1) together with a marked up-regulation of p27(Kip1) by inhibiting ubiquitination and proteasome-dependent degradation of the protein. The p21(Cip1) inhibitor was also up-regulated by RA in Granta 519 cells, whereas the expression of cyclin D1 is unaffected. Most of RA-induced p27(Kip1) was bound to cyclin D1/cyclin-dependent kinase 4 complexes, probably contributing to the decreased cyclin-dependent kinase 4 kinase activity and pRb hypophosphorylation observed in RA-treated cells. Experiments with receptor-selective ligands indicate that RA receptor alpha cooperates with retinoid X receptors in mediating RA-dependent MCL cell growth inhibition. Notably, RA isomers, and particularly 9-cis-RA, also inhibited the growth-promoting effect induced in primary MCL cells by CD40 activation alone or in combination with interleukin-4. Immunohistochemical analysis showed that significant numbers of CD40L-expressing lymphoid cells are present in lymph node biopsies of MCL patients. These results therefore further strengthen the possibility that triggering of CD40 by infiltrating CD40L+ cells may continuously promote the growth of MCL cells in vivo. On these grounds, our findings that RA inhibits basal MCL proliferation as well as MCL growth-promoting effects exerted by microenvironmental factors make these compounds highly attractive in terms of potential clinical efficacy in this setting.
Selection of restriction specificities of virus-specific cytotoxic T cells in the thymus: no evidence for a crucial role of antigen-presenting cells.
Authors: R M Zinkernagel
Journal: The Journal of Experimental Medicine (1982)

The proposal was tested that (P1 X P2) F1 leads to P1 irradiation bone marrow chimeras expressed predominantly P1-restricted T cells because donor derived stem cells were exposed to recipient derived antigen-presenting cells in the thymus. Because P1 recipient-derived antigen-presenting cells are replaced only slowly after 6-8 wk by (P1 X P2) donor-derived antigen-presenting cells in the thymus and because replenished pools of mature T cells may by then prevent substantial numbers of P2-restricted T cells to be generated, a large portion of thymus cells and mature T cells were eliminated using the following treatments of 12-20-wk-old (P1 X P2) F1 leads to P1 irradiation bone marrow chimeras: (a) cortisone plus antilymphocyte serum, (b) Cytoxan, (c) three doses of sublethal irradiation (300 rad) 2d apart, and (d) lethal irradiation (850 rad) and reconstitution with T cell-depleted (P1 X P2) F1 stem cells. 12-20 wk after this second treatment, (P1 X P2) leads to P1 chimeras were infected with vaccinia-virus. Virus-specific cytotoxic T cell reactivity was expressed by chimeric T cells of (P1 X P[2) F1 origin and was restricted predominantly to P1. Virus-specific cytotoxic T cells, therefore, do not seem to be selected to measurable extent by the immigrating donor-derived antigen-presenting cells in the thymus; their selection depends apparently from the recipient-derived radioresistant thymus cells.
Stretch-Induced Activation of the Transcription Factor Activator Protein-1 Controls Monocyte Chemoattractant Protein-1 Expression During Arteriogenesis
Authors: Elena Demicheva, Markus Hecker, Thomas Korff
Journal: Circulation Research (2008)

Cerebral, coronary, and peripheral artery diseases combined represent the most frequent cause of death in developed nations. The underlying progressive occlusion of large conductance arteries can partially be compensated for by transformation of preexisting collateral arterioles to small artery bypasses, a process referred to as arteriogenesis. Because biomechanical forces have been implicated in the initiation of arteriogenesis, we have investigated the mechanosensitive expression of a pivotal proarteriogenic molecule, monocyte chemoattractant protein (MCP)-1, which governs the recruitment of circulating monocytes to the wall of the remodeling collateral arterioles. Using a new ear artery ligation model and the classic hindlimb ischemia model in mice, we noted that MCP-1 expression is significantly increased in collateral arterioles undergoing arteriogenesis already 24 hours after its onset. By mimicking proarteriogenic perfusion conditions in small mouse arteries, we observed that MCP-1 expression is predominantly upregulated in the smooth muscle cells, which solely sense changes in circumferential wall tension or stretch. Subsequent analyses of cultured endothelial and smooth muscle cells confirmed that cyclic stretch but not shear stress upregulates MCP-1 expression in these cells. Blockade of the mechanosensitive transcription factor activator protein-1 by using a specific decoy oligodeoxynucleotide abolished this stretch-induced MCP-1 expression. Likewise, topical administration of the decoy oligodeoxynucleotide to the mouse ear abrogated arteriogenesis through downregulation of MCP-1 expression and monocyte recruitment. Collectively, these findings point toward a stretch-induced activator protein-1–mediated rise in MCP-1 expression in vascular smooth muscle cells as a critical determinant for the initiation of arteriogenesis.
Examining injury risk and pain perception in runners using minimalist footwear
Authors: Michael Ryan, Maha Elashi, Richard Newsham-West, Jack Taunton
Journal: British Journal of Sports Medicine (2013)

This study examines the effect of progressive increases in footwear minimalism on injury incidence and pain perception in recreational runners.One hundred and three runners with neutral or mild pronation were randomly assigned a neutral (Nike Pegasus 28), partial minimalist (Nike Free 3.0 V2) or full minimalist shoe (Vibram 5-Finger Bikila). Runners underwent baseline testing to record training and injury history, as well as selected anthropometric measurements, before starting a 12-week training programme in preparation for a 10 km event. Outcome measures included number of injury events, Foot and Ankle Disability (FADI) scores and visual analogue scale pain rating scales for regional and overall pain with running.99 runners were included in final analysis with 23 injuries reported; the neutral shoe reporting the fewest injuries (4) and the partial minimalist shoe (12) the most. The partial minimalist shoe reported a significantly higher rate of injury incidence throughout the 12-week period. Runners in the full minimalist group reported greater shin and calf pain.Running in minimalist footwear appears to increase the likelihood of experiencing an injury, with full minimalist designs specifically increasing pain at the shin and calf. Clinicians should exercise caution when recommending minimalist footwear to runners otherwise new to this footwear category who are preparing for a 10 km event.