tbuckley/cabot-search huggingface dataset:
Evolution of Trypsinogen Activation Peptides
Authors: J.-M. Chen
Journal: Molecular Biology and Evolution (2003)

The activation peptide of mammalian trypsinogens contains a highly conserved tetra-aspartate sequence (D19-D20-D21-D22) preceding the K23-I24 scissile peptide bond, which is hydrolyzed as the first step in the activation process. Here, we examined the evolution and function of trypsinogen activation peptides through integrating functional characterization of disease-associated mutations with comparative genomic analysis. Activation properties of three chronic pancreatitis-associated activation peptide mutants (the novel D19A and the previously reported D22G and K23R) were simultaneously analyzed, for the first time, in the context of recombinant human cationic trypsinogen. A dramatic increase in autoactivation of cationic trypsinogen was observed in all three mutants, with D22G and K23R exhibiting the most marked increases. The physiological activator enteropeptidase activated the D19A mutant normally, activated the D22G mutant very poorly, and stimulated activation of the K23R mutant. The biochemical and structural data, taken together with a comprehensive sequence comparison, indicates that the tetra-aspartate sequence in mammalian trypsinogen activation peptides has evolved not only for optimal enteropeptidase recognition in the duodenum but also for efficient inhibition of trypsinogen autoactivation within the pancreas. Moreover, the use of lysine instead of arginine at the P1 position of activation peptides also has an advantageous effect against trypsinogen autoactivation. Finally, fixed substitutions in the key residues of the trypsinogen activation peptide may suggest the evolution of new functions unrelated to digestion, as found in the group III trypsinogens of cold-adapted fishes.
MicroRNA, hsa-miR-200c, is an independent prognostic factor in pancreatic cancer and its upregulation inhibits pancreatic cancer invasion but increases cell proliferation
Authors: Jun Yu, Kenoki Ohuchida, Kazuhiro Mizumoto, Norihiro Sato, Tadashi Kayashima, Hayato Fujita, Kouhei Nakata, Masao Tanaka
Journal: Molecular Cancer (2010)

Abstract Background Recently, the microRNA-200 family was reported to affect cancer biology by regulating epithelial to mesenchymal transition (EMT). Especially, the expression of miR-200c has been shown to be associated with upregulating the expression of E-cadherin , a gene known to be involved in pancreatic cancer behavior. However, the significance of miR-200c in pancreatic cancer is unknown. Methods In the present study, we investigated the relationship between E-cadherin and miR-200c expression in a panel of 14 pancreatic cancer cell lines and in macro-dissected formalin-fixed paraffin-embedded (FFPE) tissue samples obtained from 99 patients who underwent pancreatectomy for pancreatic cancer. We also investigated the effects of miR-200c on the proliferation and invasion of pancreatic cancer cells. Results We found that patients with high levels of miR-200c expression had significantly better survival rates than those with low levels of miR-200c expression. We also found a remarkably strong correlation between the levels of miR-200c and E-cadherin expression. Conclusions These data indicate that miR-200c may play a role in the pancreatic cancer biology and may be a novel marker for the prognosis of pancreatic cancer.
Hypoxia Impairs Systemic Endothelial Function in Individuals Prone to High-Altitude Pulmonary Edema
Authors: Marc M. Berger, Christiane Hesse, Christoph Dehnert, Heike Siedler, Petra Kleinbongard, Hubert J. Bardenheuer, Malte Kelm, Peter Bärtsch, Walter E. Haefeli
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

High-altitude pulmonary edema (HAPE) is characterized by excessive pulmonary vasoconstriction and is associated with decreased concentrations of nitric oxide (NO) in the lung.We hypothesized that individuals susceptible to HAPE (HAPE-S) would also have dysfunction of the vascular NO vasodilator pathway during hypoxia in the systemic vasculature.During normoxia (FI(O(2)) = 0.21) and 4 hours of normobaric hypoxia (FI(O(2)) = 0.12, corresponding to an altitude of 4,500 m above sea level) endothelium-dependent and endothelium-independent vasodilator responses to intraarterial infusion of acetylcholine (ACh) and sodium nitroprusside, respectively, were measured by forearm venous occlusion plethysmography in nine HAPE-S subjects and in nine HAPE-resistant control subjects.Pulmonary artery systolic pressure increased from 22 +/- 3 to 33 +/- 6 mm Hg (p < 0.001) during hypoxia in control subjects, and from 25 +/- 4 to 50 +/- 9 mm Hg in HAPE-S subjects (p < 0.001). Despite similar responses during normoxia in both groups, ACh-induced changes in forearm blood flow markedly decreased during hypoxia in HAPE-S subjects (p = 0.01) but not in control subjects. The attenuated vascular response to ACh infusion during hypoxia inversely correlated with increased pulmonary artery systolic pressure (p = 0.04) and decreased plasma nitrite correlated with attenuated ACh-induced vasodilation in HAPE-S subjects (p = 0.02).Hypoxia markedly impairs vascular endothelial function in the systemic circulation in HAPE-S subjects due to a decreased bioavailability of NO. Impairment of the NO pathway could contribute to the enhanced hypoxic pulmonary vasoconstriction that is central to the pathogenesis of HAPE.
P248 Measuring physical recovery in the critical care population: development of the Chelsea critical care physical assessment tool (CPAx)
Authors: E. J. Corner, H. Wood, C. Englebretsen, S. Boot, D. Nikoletou
Journal: Thorax (2010)

<h3>Introduction</h3> The secondary physical effects of critical illness, for example, muscle atrophy, can be detrimental to functional outcome and quality of life in critical care survivors. To minimise these problems early physiotherapy in the Intensive Care Unit (ICU) is advocated. However, research to identify the optimal rehabilitation strategy is hindered by lack of an ICU specific objective measure of physical recovery. Current measures are either impairment specific, thus not capturing the full picture, or their validity is unproven in this population. <h3>Aim</h3> To develop a measurement tool to assess physical recovery in the heterogeneous general adult critical care population. <h3>Method</h3> <h3>Face/content validity</h3> The initial tool was developed in a clinical setting by specialist physiotherapists and is called the Chelsea Critical Care Physical Assessment tool (CPAx). It is a pictorial composite of 10 numerical evaluations of pertinent functions and impairments. It was tested for face and content validity with a content validity index questionnaire (CVIQ), a subsequent focus group and a repeat CVIQ. <h3>Inter-rater reliability</h3> Five physiotherapists using the CPAx regularly all assessed the same two patients. Data were analysed for intra-class correlation co-efficient (ICC) and internal consistency. <h3>Construct validity</h3> A dual centred cohort study of 32 ICU patients was completed. Treating physiotherapists assessed patients using the CPAx thrice weekly. Additionally, biceps and quadriceps strength, cough peak flow (CPF) and components of the AusTOMs scores (a physiotherapy outcome measure) were tested by a researcher blinded to the CPAx scores. Correlation co-efficients were then used to analyse the data. <h3>Results</h3> <h3>Face/content validity</h3> Pre and post focus group CVIs were 0.67 (p&gt;0.05) and 0.83 (p&lt;0.05), respectively. <h3>Reliability</h3> Reliability was strong with internal consistency of 0.98 and ICC 0.902 (95% CI 0.799 to 0.969; p=&lt;0.001). <h3>Construct validity</h3> Pilot data showed strong positive correlations (0.744–0.922, p&lt;0.01), between the CPAx, muscle strength and AusTOMs scores. Data were insufficient to analyse CPF results. <h3>Conclusion</h3> Preliminary data show that the CPAx is a reliable and valid measure of physical function in ICU patients. It can now be used as an outcome measure for physiotherapy research and has potential to act as a predictor of functional outcome in the ICU population.
Superior Temporal Gyrus Abnormalities in Early-Onset Schizophrenia: Similarities and Differences With Adult-Onset Schizophrenia
Authors: Hideo Matsumoto, Andrew Simmons, Steven Williams, Michael Hadjulis, Roderic Pipe, Robin Murray, Sophia Frangou
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: The superior temporal gyrus is associated with developmental mechanisms of brain lateralization and the pathogenesis of language-related schizophrenic symptoms. It therefore lends itself to investigation of developmental deviance in the early onset of schizophrenia. METHOD: Using stereological methods, the authors obtained bilateral measurements of the superior temporal gyrus (total, gray matter, and white matter volumes) from 40 adolescents with recent-onset schizophrenia and an equal number of matched healthy volunteers. Symptoms were rated by using the Positive and Negative Syndrome Scale. RESULTS: The total and gray matter volume of the right superior temporal gyrus was significantly lower in patients with early-onset schizophrenia than in the healthy volunteers, even after differences in whole brain volume were controlled. Bilateral superior temporal gyrus volumes were positively correlated with the age at onset of psychosis, while severity of thought disorder and hallucinations were inversely related to right superior temporal gyrus volume. CONCLUSIONS: In patients with early-onset schizophrenia, the predominantly right-sided volumetric abnormalities found in the superior temporal gyrus may reflect a particularly early neurodevelopmental disruption. The relationship between language-related symptoms and superior temporal gyrus volume is similar to that seen in adult-onset cases but not as lateralized.
Immunosuppressive drugs and hypertrophic cardiomyopathy
Authors: PaulL.P. Brand, Frank Brus, Toshiki Natazuka, Ryoichi Ogawa, Tomohiko Kizaki, Hiroshi Ueno, Hideyuki Shiotani, Tamio Koizumi, Ryuichiro Nishimura, Toshitaro Nakagawa, Anil Dhawan, DavidR. Mack, AlanN. Langnas, ByersW. Shaw, JonA. Vanderhoof
Journal: The Lancet (1995)
Clinical, immunological, and immunogenetic aspects of autoantibody production against Ro/SSA, La/SSB and their linear epitopes in primary Sjogren's syndrome (pSS): a European multicentre study
Authors: A G Tzioufas
Journal: Annals of the Rheumatic Diseases (2002)

Objectives: To investigate the clinical and immunogenetic aspects of antibody formation against Ro/SSA and La/SSB as well as their linear B cell epitopes in patients with primary Sjögren9s syndrome (pSS) from different European countries. Patients and methods: Ninety patients with pSS from six European centres were studied. Serum samples from all patients were tested in a control laboratory for anti-Ro/SSA and anti-La/SSB autoantibodies by RNA precipitation assay and autoantibodies to the previously reported B cell linear epitopes of Ro 60 kDa (p169–190aa and p211–232aa) and La/SSB (p147–154aa, p291–302aa, p301–318aa, and p349–364aa). DNA from 88 patients was used for the determination of HLA-DRB1, -DQA1, and -DQB1 genotypes. Analysis of the results was performed in the 88 patients who were genotyped and tested also for antipeptide antibodies. Results: Antibodies to B cell epitopes of Ro 60 kDa were detected at a low frequency (range 10–37%). In contrast, B cell epitopes of La/SSB were detected frequently (range 58–86%) among the anti-La/SSB positive sera. Autoantibodies to the La/SSB epitope, p349–364aa, were significantly positively associated with longer disease duration (p&lt;0.05), recurrent or permanent parotid gland enlargement (p&lt;0.005), and a higher proportion of non-exocrine manifestations (p&lt;0.005), compared with patients without autoantibodies. The presence of anti-Ro/SSA and anti-La/SSB autoantibodies was significantly associated with the presence of HLA-DRB1*03 and DQB1*02 (p=0.038 and p=0.034, respectively). This association was even more prominent and extended to HLA-DQA1*0501 when patients were stratified according the presence of autoantibodies to discrete La/SSB B cell epitopes in comparison with autoantibody negative patients (p&lt;0.01). They were found also to be highly associated with the alleles HLA-DQB1*02 and HLA-DQA1*0501 as well as the presence of a shared amino acid motif in the region 59–69aa of DQB1 first domain (p&lt;0.01, respectively). Conclusions: Autoantibodies against La/SSB, binding to four synthetic peptides, derived from the sequence of the La protein were identified with increased frequency in sera of patients with pSS. The formation of autoantibodies against B cell epitope analogues of La/SSB in European patients with pSS may be dependent on the presence of a permissive HLA-DQ heterodimer, most prominently represented by the HLA-DQA1*0501/DQB1*0201 heterodimer, suggesting that a model of HLA restricted presentation of La/SSB peptide determinants is crucial for the autoimmune response against La/SSB.
Whole body protein turnover in childhood Crohn's disease.
Authors: A G Thomas, V Miller, F Taylor, P Maycock, C M Scrimgeour, M J Rennie
Journal: Gut (1992)

In order to investigate the effects of treatment on protein metabolism in childhood Crohn9s disease whole body protein turnover was measured using a primed constant intravenous infusion of L-[1-13C]leucine and mass spectrometry in 10 children with active disease. Mean rates of protein synthesis and breakdown markedly decreased after treatment with steroids (four) or an elemental diet (six). This suggests that protein synthesis and breakdown are increased during active Crohn9s disease in children and are reduced after induction of remission regardless of the type of treatment.
Serum bilirubin and platelet count: A simple predictive model for survival in patients with refractory ascites treated by TIPS
Authors: Christophe Bureau, Sophie Métivier, Mario D’Amico, Jean Marie Péron, Philippe Otal, Juan Carlos Garcia Pagan, Valérie Chabbert, Carine Chagneau-Derrode, Bogdan Procopet, Hervé Rousseau, Jaume Bosch, Jean Pierre Vinel
Journal: Journal of Hepatology (2010)
FEMALE SEX IS ASSOCIATED WITH ADVERSE CLINICAL AND ECHOCARDIOGRAPHIC MEASURES IN A GENETICALLY TESTED HYPERTROPHIC CARDIOMYOPATHY COHORT
Authors: Susie Nam Hong, Christiane Gruner, Raymond Chan, Melanie Care, Lynne Williams, Qin Li, Balint Laczay, Katherine Siminovitch, Anna Woo, Warren Manning, Harry Rakowski
Journal: Journal of the American College of Cardiology (2013)
Nerve gas antidotes
Authors: J. Smythies, B. Golomb
Journal: Journal of the Royal Society of Medicine (2003)

Organophosphorus nerve gases such as sarin, soman and VX act mainly by inhibiting cholinesterase at cholinergic synapses. The consequent accumulation of acetylcholine results in muscle twitching, glandular hypersecretion and cognitive and mood effects. High doses cause seizures and death from respiratory failure. Nerve agents affect both main types of cholinergic receptor—muscarinic and nicotinic.1

Treatment of nerve agent poisoning at present relies on two approaches. In the first, an oxime is given to detach the agent from cholinesterase, thus reactivating the enzyme.2 This mitigates both nicotinic and muscarinic effects, for those nerve agents against which oximes are effective (which do not include soman). In the second, the muscarinic antagonist atropine is used to quell the effects of excessive acetylcholine action. Atropine is of special value when the nerve agent is oxime-resistant or when symptoms are already severe. However, atropine targets only excessive muscarinic activity. What about the nicotinic effects? These too are surely important yet seem to be neglected in the published work. We found no mention in conventional sources, in numerous declassified US Department of Defense documents or in about fifty UK Ministry of Defence documents declassified expressly to allow work issues related to nerve agent protection. Nicotine is a convulsant poison,3,4 and nerve agents enhance nicotinic depolarizations5 and modulate nicotinic receptor ion channels directly by an allosteric effect6,7—as does pyridostigmine,8 which is used as a protective measure against nerve gases. Khan et al.9 injected rats intramuscularly with sarin and examined the brains at intervals afterwards (up to 20 h). They noted a biphasic effect on ligand binding (reduced at 1–3 h and increased at 6–12 h) which was much stronger at nicotinic receptors than at muscarinic receptors.

More importantly, published evidence suggests that organophosphate exposure causes persistent changes in both muscarinic and nicotinic function. With repeated low-level exposure chronic changes have been reported in muscarinic (M1 and M3) receptors.10 But, in addition, persistent downregulation of nicotinic receptor expression has been demonstrated in rats exposed to a cholinesterase inhibitor.11 These changes were associated, in the animals, with impaired function on cognitive tests, and the nicotinic character of the impairments was confirmed by reversal with nicotine.

Thus it would seem appropriate to examine nicotinic antagonists as well as muscarinic ones, as possible therapeutic agents for anticholinesterase nerve gas toxicity.
Mitochondrial Disorders: Clinical and Genetic Features
Authors: D.K. Simon, MD, PhD, D.R. Johns, MD
Journal: Annual Review of Medicine (1999)

Virtually all cells in humans depend on mitochondrial oxidative phosphorylation to generate energy, accounting for the remarkable diversity of clinical disorders associated with mitochondrial DNA mutations. However, certain tissues are particularly susceptible to mitochondrial dysfunction, resulting in recognizable clinical syndromes. Mitochondrial DNA mutations have been linked to seizures, strokes, optic atrophy, neuropathy, myopathy, cardiomyopathy, sensorineural hearing loss, diabetes mellitus, and other clinical features. Mitochondrial DNA mutations also may play an important role in aging, as well as in common age-related neurodegenerative disorders such as Parkinson's disease. Therefore, it is becoming increasingly important for clinicians to recognize the clinical syndromes suggestive of a mitochondrial disorder, and to understand the unique features of mitochondrial genetics that complicate diagnosis and genetic counseling.
Efficacy and Safety of Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage
Authors: Stephan A. Mayer, Nikolai C. Brun, Kamilla Begtrup, Joseph Broderick, Stephen Davis, Michael N. Diringer, Brett E. Skolnick, Thorsten Steiner
Journal: New England Journal of Medicine (2008)

Intracerebral hemorrhage is the least treatable form of stroke. We performed this phase 3 trial to confirm a previous study in which recombinant activated factor VII (rFVIIa) reduced growth of the hematoma and improved survival and functional outcomes.
The role of adiponectin in inflammatory gastrointestinal diseases
Authors: A. Schaffler, J. Scholmerich
Journal: Gut (2009)

Adiponectin was discovered in 1995 by Phillip Scherer’s research group and described as a novel serum protein similar to C1q, being produced exclusively in adipocytes.1 Adiponectin represents an anti-inflammatory, anti-diabetic and anti-fibrotic adipokine that is highly abundant in human plasma. Adiponectin is induced during adipocyte differentiation and secreted from mature adipocytes into the blood stream where it circulates as homo-trimeric, hexameric, nonameric and higher molecular weight isoforms. Mutations in the gene encoding adiponectin result in an impaired multimer formation and cause lower levels of high-molecular weight isoforms in the plasma as well as a reduced abundance of all isoforms due to a disturbed secretion from the adipocyte.2 There are two receptors for adiponectin, AdipoR1 and AdipoR2, which are expressed in a wide variety of organs and cell types. The full-length and the truncated globular isoforms of adiponectin exhibit different receptor binding activities. Processes leading to a cleavage of the full-length protein and the exact mode of receptor interaction of different isoforms are only poorly understood. Adiponectin represents the only adipokine that is downregulated in obesity. Adiponectin exerts pleiotropic effects in several organs and its role in metabolism3 and in inflammation,4–7 in general, are reviewed elsewhere.

Obesity can be regarded as a chronic and low-grade state of inflammation8 and the interpretation of the role of the adipose tissue has developed from a simple energy store to a highly active endocrine,9 inflammatory5 and immunological4 organ. In the context of obesity, the adipose tissue undergoes an inflammatory transformation10 and becomes infiltrated by significant amounts of macrophages.8 11 Since adiponectin is secreted by intra-abdominal adipose tissue and acts on monocytes in an anti-inflammatory way, it seems reasonable to review the role of adiponectin with respect to inflammatory gastrointestinal diseases, especially to those …
Treatment of early Pseudomonas aeruginosa infection in patients with cystic fibrosis: the ELITE trial
Authors: F. Ratjen, A. Munck, P. Kho, G. Angyalosi
Journal: Thorax (2009)

Rationale Antibiotic therapy for early Pseudomonas aeruginosa infection in patients with cystic fibrosis (CF) is effective, but the optimal therapeutic regimen and duration for early treatment remains unclear. The EarLy Inhaled Tobramycin for Eradication (ELITE) study was designed to assess the efficacy and safety of two regimens (28 and 56 days) of tobramycin inhalation solution (TIS) 300 mg/5 ml twice daily for the treatment of early onset P aeruginosa infection in patients with CF. Methods In this open-label randomised multicentre study, patients with CF (aged ≥6 months) with early P aeruginosa infection were treated for 28 days with TIS twice daily administered by the PARI LC PLUS (PARI GmbH, Starnberg, Germany) jet nebuliser. After 28 days, patients were randomised 1:1 to either stop TIS (n=45) or to receive a further 28 days of TIS (n=43). The primary endpoint was the median time to recurrence of P aeruginosa (any strain). Secondary endpoints included the proportion of patients free of P aeruginosa infection 1 month after cessation of therapy and safety assessments. Results The median time to recurrence of P aeruginosa (any strain) was similar between the two groups. In total, 93% and 92% of the patients were free of P aeruginosa infection 1 month after the end of treatment and 66% and 69% remained free at the final visit in the 28-day and 56-day groups, respectively. TIS was well tolerated. Conclusions Treatment with TIS for 28 days is an effective and well tolerated therapy for early P aeruginosa infection in patients with CF. Trial registration number NCT00391976.
Altered regulation of IL-2 production in systemic lupus erythematosus: an evolving paradigm
Authors: Gary M. Kammer
Journal: Journal of Clinical Investigation (2005)

In systemic lupus erythematosus (SLE), IL-2 production by T lymphocytes in vitro is impaired. Deficient IL-2 production may be an outcome of a primary SLE T cell disorder that is due to impaired signal transduction. In this issue of the JCI, evidence is presented that an anti-TCR/CD3 complex autoantibody present in SLE sera can bind to T cells and activate the Ca(2+)-calmodulin kinase IV (CaMKIV) signaling cascade, resulting in downregulation of IL-2 transcription and IL-2 production. Because IL-2 may contribute to the maintenance of T cell tolerance, deficient IL-2 production could promote a breach of T cell tolerance that results in autoantibody production in SLE.