tbuckley/cabot-search huggingface dataset:
Missense mutations in pancreatic secretory trypsin inhibitor (SPINK1) cause intracellular retention and degradation
Authors: O. Kiraly, T. Wartmann, M. Sahin-Toth
Journal: Gut (2007)

Mutations of the SPINK1 gene encoding pancreatic secretory trypsin inhibitor have been identified in association with chronic pancreatitis. The vast majority of patients carry the N34S variant, whereas other genetic variants are relatively rare and their disease association is uncertain. The aim of this study was to characterise and compare the functional defects caused by the six published missense mutations that affect mature SPINK1-namely, N34S, D50E, Y54H, P55S, R65Q, and R67C.Wild type and mutant SPINK1 were expressed in human embryonic kidney 293T cells via transient transfection. SPINK1 expression was characterised by RT-PCR, activity assays, and western blots.Mutations N34S and P55S did not alter secretion of SPINK1 from HEK 293T cells, whereas mutation R65Q decreased secretion about twofold. Remarkably, mutations D50E, Y54H, and R67C abolished or markedly diminished secretion, but all three mutants were detected in cell extracts, indicating intracellular retention and degradation.The results identify intracellular folding defects as a novel mechanism of SPINK1 deficiency associated with chronic pancreatitis. The dramatic effects of the D50E and Y54H mutations indicate that the interaction between Asp50 and Tyr54 is critical for proper folding of the inhibitor. The disease-causing biochemical defect in the N34S mutant is unrelated to secretion or trypsin inhibitory activity and remains enigmatic. Finally, the patent functional defects in mutants D50E, Y54H, and R67C suggest disease association of these rare SPINK variants.
Divergence of Recently Duplicated M -Type MADS-Box Genes in Petunia
Authors: M. Bemer, J. Gordon, K. Weterings, G. C. Angenent
Journal: Molecular Biology and Evolution (2009)

The MADS-box transcription factor family has expanded considerably in plants via gene and genome duplications and can be subdivided into type I and MIKC-type genes. The two gene classes show a different evolutionary history. Whereas the MIKC-type genes originated during ancient genome duplications, as well as during more recent events, the type I loci appear to experience high turnover with many recent duplications. This different mode of origin also suggests a different fate for the type I duplicates, which are thought to have a higher chance to become silenced or lost from the genome. To get more insight into the evolution of the type I MADS-box genes, we isolated nine type I genes from Petunia, which belong to the Mγ subclass, and investigated the divergence of their coding and regulatory regions. The isolated genes could be subdivided into two categories: two genes were highly similar to Arabidopsis Mγ-type genes, whereas the other seven genes showed less similarity to Arabidopsis genes and originated more recently. Two of the recently duplicated genes were found to contain deleterious mutations in their coding regions, and expression analysis revealed that a third paralog was silenced by mutations in its regulatory region. However, in addition to the three genes that were subjected to nonfunctionalization, we also found evidence for neofunctionalization of one of the Petunia Mγ-type genes. Our study shows a rapid divergence of recently duplicated Mγ-type MADS-box genes and suggests that redundancy among type I paralogs may be less common than expected.
THE GRANULATION OF JUXTAGLOMERULAR CELLS IN RENAL HYPERTENSION, DESOXYCORTICOSTERONE AND POST-DESOXYCORTICOSTERONE HYPERTENSION, ADRENAL REGENERATION HYPERTENSION, AND ADRENAL INSUFFICIENCY12
Authors: Louis Tobian, Janet Thompson, Robert Twedt, Jeanette Janecek
Journal: Journal of Clinical Investigation (1958)
Hallucinations in schizophrenia, sensory impairment, and brain disease: A unifying model
Authors: Ralf-Peter Behrendt, Claire Young
Journal: Behavioral and Brain Sciences (2004)

Based on recent insight into the thalamocortical system and its role in perception and conscious experience, a unified pathophysiological framework for hallucinations in neurological and psychiatric conditions is proposed, which integrates previously unrelated neurobiological and psychological findings. Gamma-frequency rhythms of discharge activity from thalamic and cortical neurons are facilitated by cholinergic arousal and resonate in networks of thalamocortical circuits, thereby transiently forming assemblies of coherent gamma oscillations under constraints of afferent sensory input and prefrontal attentional mechanisms. If perception is based on synchronisation of intrinsic gamma activity in the thalamocortical system, then sensory input to specific thalamic nuclei may merely play a constraining role. Hallucinations can be regarded as underconstrained perceptions that arise when the impact of sensory input on activation of thalamocortical circuits and synchronisation of thalamocortical gamma activity is reduced. In conditions that are accompanied by hallucinations, factors such as cortical hyperexcitability, cortical attentional mechanisms, hyperarousal, increased noise in specific thalamic nuclei, and random sensory input to specific thalamic nuclei may, to a varying degree, contribute to underconstrained activation of thalamocortical circuits. The reticular thalamic nucleus plays an important role in suppressing random activity of relay cells in specific thalamic nuclei, and its dysfunction may be implicated in the biological vulnerability to hallucinations in schizophrenia. Combined with general activation during cholinergic arousal, this leads to excessive disinhibition in specific thalamic nuclei, which may allow cortical attentional mechanisms to recruit thalamic relay cells into resonant assemblies of gamma oscillations, regardless of their actual sensory input, thereby producing an underconstrained perceptual experience.
The selective ablation of interleukin 2-producing cells isolated from transgenic mice.
Authors: L E Minasi, Y Kamogawa, S Carding, K Bottomly, R A Flavell
Journal: The Journal of Experimental Medicine (1993)

To better understand the requirement for interleukin 2 (IL-2) in specific immune responses, we have established the use of cell ablation to selectively eliminate T cells that produce IL-2. To accomplish this we have generated transgenic mice that express the herpes simplex virus 1-thymidine kinase (HSV-TK) gene under the transcriptional control of the murine IL-2 promoter that renders IL-2-producing cells sensitive to the cytotoxic effects of the antiviral drug ganciclovir (GANC). HSV-TK activity was specifically expressed in activated T cells from transgenic mice. When CD4 T cells from transgenic mice were stimulated with the superantigen staphylococcal enterotoxin A (SEA) in the presence of GANC, proliferation and IL-2 production were almost completely inhibited and the activated CD4+V beta 3+ T cell population, eliminated. Proliferation was not restored by adding IL-2, showing that most proliferating cells are not bystander cells. In contrast, the proliferative response to concanavalin A (Con A) was only partially inhibited by treatment of CD4 T cells with GANC, although the efficiency of eliminating IL-2-producing cells was shown to be comparable with that achieved using SEA. This suggests that a portion of the proliferative response to Con A occurs via an alternative pathway not requiring IL-2 synthesis and release.
Phase II, randomized, biomarker identification trial (MARK) for erlotinib in patients with advanced pancreatic carcinoma
Authors: D. Propper, I. Davidenko, J. Bridgewater, L. Kupcinskas, A. Fittipaldo, C. Hillenbach, B. Klughammer, M. Ducreux
Journal: Annals of Oncology (2014)

BackgroundA prospective, randomized phase II study, with mandatory tumor sampling at current disease stage, aimed to identify biomarkers predictive of improved progression-free survival (PFS) in patients with pancreatic cancer treated with erlotinib.Patients and methodsPatients with histologically/cytologically confirmed, unresectable, locally advanced/metastatic pancreatic cancer, who had failed on or were unsuitable for first-line chemotherapy, underwent a tumor biopsy and were then randomized to receive once-daily erlotinib 150 mg or placebo. The primary end point was identification of biomarkers predicting improved PFS with erlotinib. Secondary end points included PFS, overall survival, response and toxicity.ResultsAt data cut-off, 207 patients were enrolled and analyzed. Prespecified biomarker analyses of EGFR protein expression, EGFR gene copy number/mutations/polymorphisms and KRAS mutations did not identify any subgroups with a detrimental effect or a strong benefit for PFS with erlotinib. In the primary analysis, the median PFS was 6.1 versus 5.9 weeks in the erlotinib and placebo arms, respectively [hazard ratio (HR) 0.83; 95% confidence interval (CI) 0.63–1.10; P = 0.1909]. However, observed baseline imbalances indicated worse prognosis in the erlotinib arm. After adjustment for baseline characteristics, a significant PFS benefit for erlotinib was observed (HR 0.68; 95% CI 0.50–0.91; P = 0.0102). Exploratory biomarker analyses showed patients with high baseline serum amphiregulin levels might benefit from erlotinib.ConclusionThis study in patients with inoperable pancreatic cancer did not identify any prespecified biomarkers predictive of PFS benefit with erlotinib. Exploratory analyses suggested high amphiregulin might predict PFS benefit from erlotinib.ClinicalTrials.gov numberNCT00674973.
Local opsonization by secreted macrophage complement components. Role of receptors for complement in uptake of zymosan.
Authors: R A Ezekowitz, R B Sim, M Hill, S Gordon
Journal: The Journal of Experimental Medicine (1984)

We have examined the role of macrophage (M phi plasma membrane receptors for the cleaved third complement component (iC3b; CR3) and mannosyl, fucosyl terminated glycoproteins (MFR) in uptake of unopsonized zymosan. Monoclonal antibodies against CR3, M1/70 (Mac-1) and MO1, each inhibited approximately 50% of uptake of 125I-zymosan by murine and human M phi, respectively. Yeast mannan inhibited 0-50% of zymosan uptake in various M phi, in parallel with their expression of MFR. We demonstrated that M phi were the source of C3 in our assay and that the activity of other components of the complement system, namely a C3 convertase, factor I, and a factor I cofactor were also present in serum-free cultures of human monocytes. Macrophage C3 was deposited rapidly, within 10 min, on the zymosan particles and mediated binding, ingestion, and stimulation of superoxide release in BCG-activated and thioglycollate-elicited peritoneal M phi via CR3. Local secretion of complement proteins by M phi themselves can therefore opsonize pathogens and cells able to activate the alternative pathway and effect their destruction.
Antiproliferative Effects of Phosphodiesterase Type 5 Inhibition in Human Pulmonary Artery Cells
Authors: John Wharton, Julian W. Strange, Gigi M. O. Møller, Ellena J. Growcott, Xiaohui Ren, Angela P. Franklyn, Stephen C. Phillips, Martin R. Wilkins
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Rationale: Phosphodiesterase Type 5 (PDE5) inhibition represents a novel strategy for the treatment of pulmonary hypertension. Objectives: Our aim was to establish the distribution of PDE5 in the pulmonary vasculature and effects of PDE5 inhibition on pulmonary artery smooth muscle cells (PASMCs). Methods and Measurements: PDE5 expression was examined by immunohistochemistry and Western blotting, in both normal and hypertensive lung tissues. DNA synthesis, proliferation, PDE activity, and apoptosis were measured in distal human PASMCs treated with soluble guanylyl cyclase activators (nitric oxide donors and BAY41–2272) and sildenafil. Main Results: Cells containing PDE5 and α-smooth muscle actin occurred throughout the pulmonary vasculature, including obstructive intimal lesions. Three molecular forms of PDE5 were identified and protein expression was greater in hypertensive than control lung tissue. Most cyclic guanosine monophosphate hydrolysis (about 80%) in cultured cells was attributed to PDE5. Sildenafil induced a greater elevation of intracellular cyclic guanosine monophosphate levels compared with nitric oxide donors and BAY41–2272 (about 10-fold versus about 2-fold) and cotreatment had a synergistic effect, increasing cyclic nucleotide levels up to 50-fold. Dual stimulation of soluble guanylyl cyclase and inhibition of PDE5 activities also had significant downstream effects, increasing phosphorylation of vasodilator-stimulated phosphoprotein, reducing DNA synthesis and cell proliferation, and stimulating apoptosis, and these effects were mimicked by cyclic guanosine monophosphate analogs. Conclusions: Phosphodiesterase Type 5 is the main factor regulating cyclic guanosine monophosphate hydrolysis and downstream signaling in human PASMCs. The antiproliferative effects of this signaling pathway may be significant in the chronic treatment of pulmonary hypertension with PDE5 inhibitors such as sildenafil.
Odor Information Processing by the Olfactory Bulb Analyzed in Gene-Targeted Mice
Authors: Jie Tan, Agnès Savigner, Minghong Ma, Minmin Luo
Journal: Neuron (2010)

In mammals, olfactory sensory neurons (OSNs) expressing a specific odorant receptor (OR) gene project with precise stereotypy onto mitral/tufted (M/T) cells in the main olfactory bulb (MOB). It remains challenging to understand how incoming olfactory signals are transformed into outputs of M/T cells. By recording from OSNs expressing mouse I7 receptor and their postsynaptic neurons in the bulb, we found that I7 OSNs and their corresponding M/T cells exhibit similarly selective tuning profiles at low concentrations. Increasing the concentration significantly reduces response selectivity for both OSNs and M/T cells, although the tuning curve of M/T cells remains comparatively narrow. By contrast, interneurons in the MOB are broadly tuned, and blocking GABAergic neurotransmission reduces selectivity of M/T cells at high odorant concentrations. Our results indicate that olfactory information carried by an OR is channeled to its corresponding M/T cells and support the role of lateral inhibition via interneurons in sharpening the tuning of M/T cells.Video AbstracteyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiI1ODBkZWExMWFiNDkxZDFiOTEwYzZkMzFmMGVkM2U5NCIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc4OTA5MTA5fQ.LXX7btePv-HPF9sl27uGiPFmpXyfzuvWlZ3fHN5wT9CHW_59DECTiN7UhDD6WC6LT4_jaHps3FOtkOaQ0LurqCv9vKWtx3PDzKmcyWcBsTkOj35uzT3ohwsoWRjYMXxCsuBD8bVcBh7Wh8kZxFqFJB0Ad6twN9mKsL_uO5L_xdAg60U-cXLfNy5FG-VcF748IesLcSr0NZ4W7PUhH0YlfgC-b3Wywt8uw2854-bA6ZPacYL2bODc70hUKQLCNrv4Y8fZrmZAhvRnpFx9mzTsPPUjDQR8vnGRrS4GWDf3hFOt-5JZBahwvaxw5bo8qPU32rnhy-9XuCyfI2BxN34T4A(mp4, (32.56 MB) Download video
Which is the most reliable method for teaching dermoscopy for melanoma diagnosis to residents in dermatology?
Authors: G. Argenziano, I. Zalaudek, H.P. Soyer
Journal: British Journal of Dermatology (2004)

Journal Article Which is the most reliable method for teaching dermoscopy for melanoma diagnosis to residents in dermatology? Get access G. Argenziano, G. Argenziano Department of Dermatology, Second University of Naples, Via S.Pansini 5, I‐80131 Naples, Italy *Department of Dermatology, University of Graz, Graz, Austria E‐mail: argenziano@tin.it Search for other works by this author on: Oxford Academic Google Scholar I. Zalaudek, I. Zalaudek Department of Dermatology, Second University of Naples, Via S.Pansini 5, I‐80131 Naples, Italy *Department of Dermatology, University of Graz, Graz, Austria E‐mail: argenziano@tin.it Search for other works by this author on: Oxford Academic Google Scholar H.P. Soyer H.P. Soyer Department of Dermatology, Second University of Naples, Via S.Pansini 5, I‐80131 Naples, Italy *Department of Dermatology, University of Graz, Graz, Austria E‐mail: argenziano@tin.it Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 151, Issue 2, 1 August 2004, Pages 512–513, https://doi.org/10.1111/j.1365-2133.2004.06122.x Published: 01 August 2004
Continuous positive airway pressure is effective in treating upper airway oedema
Authors: F Barbe, S Pons, B Togores, J Sauleda, R Soler, AG Agusti
Journal: European Respiratory Journal (1996)

The case of a patient with diffuse idiopathic skeletal hyperostosis (DISH) and upper airway oedema, is described. The patient presented with alveolar hypoventilation and obstructive apnoeas during sleep. Intravenous steroids (methylprednisolone, 160 mg.day-1) for 5 days did not reduce the oedema. However, it was rapidly reversed by the use of nasal continuous positive airway pressure (nCPAP). In addition, daytime pulmonary gas exchange was improved and sleep apnoea abolished. This beneficial effect made tracheostomy unnecessary. This case report suggests that CPAP can be a potentially useful therapeutic alternative to tracheostomy in the clinical management of upper airway oedema.
REVIEW OF NEUROPSYCHIATRIC CASES IN THE SOUTH WEST PACIFIC AREA
Authors: DAVID ROTHSCHILD
Journal: American Journal of Psychiatry (1946)

A study was made of cases observed on a neuropsychiatric service in a rear installation of the Army in the South West Pacific Area. The psychoses were of greatest importance from the point of view of permanent loss of manpower. The possibility that environmental conditions peculiar to the area played an etiologic rôle was discussed. Atypical pictures were common. The impression was obtained that some of the acute cases might be essentially severe emotional reactions brought on by intense stress, perhaps representing "war psychoses" analogous to the acute war neuroses. Among the psychoneuroses, anxiety states occurred with greatest frequency. In the acute conditions the stresses associated with combat played the most important etiologic rôle. In the more chronic cases previous neurotic tendencies were significant factors. Conscious attitudes and problems of morale influenced the picture in a considerable number of cases. Of the whole neurotic group, 69.1 percent of the patients were returned to duty. Measures which might lessen the frequency of psychoneuroses and psychoses in the Army were discussed. Brief mention was made of less common psychiatric conditions and neurologic disorders.
Gastric adaptation to injury by repeated doses of aspirin strengthens mucosal defence against subsequent exposure to various strong irritants in rats.
Authors: T Brzozowski, P C Konturek, S J Konturek, H Ernst, J Stachura, E G Hahn
Journal: Gut (1995)

Gastric adaptation to injury during repeated doses of acetyl salicylic acid (ASA) is a well documented finding but it is not known whether this adaptation affects the tolerance of the mucosa to other strong irritants. Gastric adaptation was induced by repeated daily doses of acidified ASA (100 mg/kg in 1.5 ml of 0.2 N HCl) given intragastrically (series A rats). Control rats with an intact stomach were given daily intragastric vehicle only (1.5 ml of 0.2 N HCl) (series B). After full adaptation to ASA (5 days), rats were challenged again with acidified ASA or, for comparison, with strong irritants such as 100% ethanol, 200 mM acidified taurocholate, or 25% NaCl for 1 hour or with water immersion and restraint for 3.5 hours. The first dose of ASA produced numerous gastric lesions and deep histological necrosis accompanied by a fall in the gastric blood flow, negligible expression of epidermal growth factor (EGF) and transforming growth factor alpha (TGF alpha) or their receptors, and no evidence of mucosal proliferation. As adaptation to ASA developed, however, the areas of gastric lesions were reduced by more than 80% and there was a noticeable decrease in deep necrosis, a partial restoration of gastric blood flow, an approximately four-fold increase in EGF expression (but not in TGF alpha) and its receptors, and an appreciable increase in mucosal cell proliferation compared with vehicle treated rats. Increases in the mucosal expression of EGF receptors and the luminal content of EGF were also found in ASA adapted animals. In ASA adapted rats subsequently challenged with 100% ethanol, 200 mM TC, 25% NaCl, or stress, the area of the gastric lesions and deep histological necrosis were appreciably reduced compared with values in vehicle treated rats. This increased mucosal tolerance to strong irritants was also accompanied by the return of the gastric blood flow towards control levels and further significant increases in the mucosal expression of EGF receptors and mucosal cell proliferation. Gastric adaptation to ASA enhances the mucosal resistance to injury by strong irritants probably as a result of the restoration of the gastric blood flow and increased cell proliferation that may result from increased mucosal expression of EGF and its receptors.
One-Year Treatment With Exenatide Improves β-Cell Function, Compared With Insulin Glargine, in Metformin-Treated Type 2 Diabetic Patients
Authors: Mathijs C. Bunck, Michaela Diamant, Anja Cornér, Bjorn Eliasson, Jaret L. Malloy, Rimma M. Shaginian, Wei Deng, David M. Kendall, Marja-Riitta Taskinen, Ulf Smith, Hannele Yki-Järvinen, Robert J. Heine
Journal: Diabetes Care (2009)

OBJECTIVE Traditional blood glucose–lowering agents do not sustain adequate glycemic control in most type 2 diabetic patients. Preclinical studies with exenatide have suggested sustained improvements in β-cell function. We investigated the effects of 52 weeks of treatment with exenatide or insulin glargine followed by an off-drug period on hyperglycemic clamp–derived measures of β-cell function, glycemic control, and body weight. RESEARCH DESIGN AND METHODS Sixty-nine metformin-treated patients with type 2 diabetes were randomly assigned to exenatide (n = 36) or insulin glargine (n = 33). β-Cell function was measured during an arginine-stimulated hyperglycemic clamp at week 0, at week 52, and after a 4-week off-drug period. Additional end points included effects on glycemic control, body weight, and safety. RESULTS Treatment-induced change in combined glucose- and arginine-stimulated C-peptide secretion was 2.46-fold (95% CI 2.09–2.90, P &amp;lt; 0.0001) greater after a 52-week exenatide treatment compared with insulin glargine treatment. Both exenatide and insulin glargine reduced A1C similarly: −0.8 ± 0.1 and −0.7 ± 0.2%, respectively (P = 0.55). Exenatide reduced body weight compared with insulin glargine (difference −4.6 kg, P &amp;lt; 0.0001). β-Cell function measures returned to pretreatment values in both groups after a 4-week off-drug period. A1C and body weight rose to pretreatment values 12 weeks after discontinuation of either exenatide or insulin glargine therapy. CONCLUSIONS Exenatide significantly improves β-cell function during 1 year of treatment compared with titrated insulin glargine. After cessation of both exenatide and insulin glargine therapy, β-cell function and glycemic control returned to pretreatment values, suggesting that ongoing treatment is necessary to maintain the beneficial effects of either therapy.