tbuckley/cabot-search huggingface dataset:
Major Histocompatibility Complex Class II Molecules Can Protect from Diabetes by Positively Selecting T Cells with Additional Specificities
Authors: Fred Lühder, Jonathan Katz, Christophe Benoist, Diane Mathis
Journal: The Journal of Experimental Medicine (1998)

Insulin-dependent diabetes is heavily influenced by genes encoded within the major histocompatibility complex (MHC), positively by some class II alleles and negatively by others. We have explored the mechanism of MHC class II–mediated protection from diabetes using a mouse model carrying the rearranged T cell receptor (TCR) transgenes from a diabetogenic T cell clone derived from a nonobese diabetic mouse. BDC2.5 TCR transgenics with C57Bl/6 background genes and two doses of the H-2g7 allele exhibited strong insulitis at ∼3 wk of age and most developed diabetes a few weeks later. When one of the H-2g7 alleles was replaced by H-2b, insulitis was still severe and only slightly delayed, but diabetes was markedly inhibited in both its penetrance and time of onset. The protective effect was mediated by the Aβb gene, and did not merely reflect haplozygosity of the Aβg7 gene. The only differences we observed in the T cell compartments of g7/g7 and g7/b mice were a decrease in CD4+ cells displaying the transgene-encoded TCR and an increase in cells expressing endogenously encoded TCR α-chains. When the synthesis of endogenously encoded α-chains was prevented, the g7/b animals were no longer protected from diabetes. g7/b mice did not have a general defect in the production of Ag7-restricted T cells, and antigen-presenting cells from g7/b animals were as effective as those from g7/g7 mice in stimulating Ag7-restricted T cell hybridomas. These results argue against mechanisms of protection involving clonal deletion or anergization of diabetogenic T cells, or one depending on capture of potentially pathogenic Ag7-restricted epitopes by Ab molecules. Rather, they support a mechanism based on MHC class II–mediated positive selection of T cells expressing additional specificities.
Right Ventricular Perforation and Pulmonary Embolism With Polymethylmethacrylate Cement After Percutaneous Kyphoplasty
Authors: Igor Gosev, Luigi Nascimben, Pei-Hsiu Huang, Laura Mauri, Michael Steigner, Annette Mizuguchi, Amil M. Shah, Sari F. Aranki
Journal: Circulation (2013)
Cortical Processing of Respiratory Occlusion Stimuli in Children with Central Hypoventilation Syndrome
Authors: Jingtao Huang, Carole L. Marcus, Preetam Bandla, Michael S. Schwartz, Michelle E. Pepe, John M. Samuel, Howard B. Panitch, Ruth M. Bradford, Yael P. Mosse, John M. Maris, Ian M. Colrain
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Rationale: The ability of patients with central hypoventilation syndrome (CHS) to produce and process mechanoreceptor signals is unknown.Objectives: Children with CHS hypoventilate during sleep, although they generally breathe adequately during wakefulness. Previous studies suggest that they have compromised central integration of afferent stimuli, rather than abnormal sensors or receptors. Cortical integration of afferent mechanical stimuli caused by respiratory loading or upper airway occlusion can be tested by measuring respiratory-related evoked potentials (RREPs). We hypothesized that patients with CHS would have blunted RREP during both wakefulness and sleep.Methods: RREPs were produced with multiple upper airway occlusions and were obtained during wakefulness, stage 2, slow-wave, and REM sleep. Ten patients with CHS and 20 control subjects participated in the study, which took place at the Children's Hospital of Philadelphia. Each patient was age- and sex-matched to two control subjects. Wakefulness data were collected from 9 patients and 18 control subjects.Measurements and Main Results: During wakefulness, patients demonstrated reduced Nf and P300 responses compared with control subjects. During non-REM sleep, patients demonstrated a reduced N350 response. In REM sleep, patients had a later P2 response.Conclusions: CHS patients are able to produce cortical responses to mechanical load stimulation during both wakefulness and sleep; however, central integration of the afferent signal is disrupted during wakefulness, and responses during non-REM are damped relative to control subjects. The finding of differences between patients and control subjects during REM may be due to increased intrinsic excitatory inputs to the respiratory system in this state.
A Reappraisal of Some Psychosomatic Concepts
Authors: Linford Rees
Journal: Psychotherapy and Psychosomatics (1979)

The paper presents a critical reappraisal of some psychosomatic concepts which have become entrenched in the literature. The limitations of concepts of specificity relating to stimuli, emotional changes and various psychosocial stresses are discussed. The available evidence indicates the importance of the patient's personality, but does not support the claims of specific personality types for each disorder. Concepts of aetiology are discussed. The importance of heterogeneity rather than homogeneity is stressed. Relationships between psychiatric and psychosomatic disorders are considered. The significance of somatopsychic as well as psychosomatic sequences of events arc emphasised, finally, the importance of multifactorial causation in psychosomatic disorders is underlined.
Lung colonization with Aeromonas hydrophila in cystic fibrosis believed to have come from a tropical fish tank
Authors: David Cremonesini, Anne Thomson
Journal: Journal of the Royal Society of Medicine (2008)

People with cystic fibrosis (CF) are at risk of contracting Pseudomonas aeruginosa and other potentially harmful organisms from the environment.1 The Cystic Fibrosis Trust consider tropical fish tanks to be a risk only if the patient is in direct contact with the water.1 We report a boy with CF who at 11 months isolated Pseudomonas species identified as mucoid Aeromonas hydrophila, non-mucoid Aeromonas hydrophila and Pseudomonas aeruginosa from cough swabs. We believe he became infected by aerosol spread of the bacterium secondary to the aeration process in fish tanks in his home. Isolations only ceased on removal of the tanks from the home.

The patient was born at term after antenatal detection of echogenic bowel at 20 weeks gestation. There were no neonatal concerns and genetic testing confirmed the diagnosis of CF (homozygous ΔF508). He was started on routine CF treatment including flucloxacillin. He has had numerous microbiological isolations, all from cough swabs (Table 1).



Table 1

A summary of the child’s microbiological isolations from cough swabs



Before six months of age he had two episodes of symptomatic cough and he grew two different organisms. He was asymptomatic at seven months when a fully sensitive, non-mucoid Pseudomonas species was isolated from a cough swab. Despite treatment with ciprofloxacin and colomycin nebulizers, the same organisms were identified three weeks later (asymptomatic). Treatment was stopped at 10 months after two clear cough swabs.

At 11 months of age he developed a productive cough and this time grew a fully sensitive mucoid Pseudomonas species. He was restarted on ciprofloxacin and colomycin and an extended microbiological identification was requested. This revealed three different bacteria: a mucoid A. hydrophila type 1, a non-mucoid A. hydrophila type 2 and a non-mucoid P. aeruginosa. Chest X ray was normal and symptoms responded promptly to treatment but a Pseudomonas species grew again after one month. His home environment was reviewed as he had isolated a type of organism that usually inhabits aquatic environments. Our CF nurse had visited his home on several occasions: she reported that the family had four large fish tanks in their living room, and had expressed concerns that these may be the cause of the patient's infections. The tanks had oxygen pumps and appeared poorly maintained (the tank water was very cloudy). The family were advised to have the tanks removed, and after discussion they were removed when the patient was 15 months old. At the time of writing, nine months after the tanks were removed, repeated cough swabs have been clear.
Systematic Kinome shRNA Screening Identifies CDK11 (PITSLRE) Kinase Expression Is Critical for Osteosarcoma Cell Growth and Proliferation
Authors: Zhenfeng Duan, Jianming Zhang, Edwin Choy, David Harmon, Xianzhe Liu, Petur Nielsen, Henry Mankin, Nathanael S. Gray, Francis J. Hornicek
Journal: Clinical Cancer Research (2012)

Identification of new targeted therapies is critical to improving the survival rate of patients with osteosarcoma. The goal of this study is to identify kinase based potential therapeutic target in osteosarcomas.We used a lentiviral-based shRNA kinase library to screen for kinases which play a role in osteosarcoma cell survival. The cell proliferation assay was used to evaluate cell growth and survival. siRNA assays were applied to confirm the observed phenotypic changes resulting from the loss of kinase gene expression. CDK11 (PITSLRE) was identified as essential for the survival of osteosarcoma cells, and its expression was confirmed by Western blot analysis and immunohistochemistry. Overall patient survival was correlated with the CDK11 expression and its prognosis. The role of CDK11 expression in sustaining osteosarcoma growth was further evaluated in an osteosarcoma xenograft model in vivo.Osteosarcoma cells display high levels of CDK11 expression. CDK11 expression knocked down by either lentiviral shRNA or siRNA inhibit cell growth and induce apoptosis in osteosarcoma cells. Immunohistochemical analysis showed that patients with osteosarcoma with high CDK11 tumor expression levels were associated with significantly shorter survival than patients with osteosarcoma with low level of tumor CDK11 expression. Systemic in vivo administration of in vivo ready siRNA of CDK11 reduced the tumor growth in an osteosarcoma subcutaneous xenograft model.We show that CDK11 signaling is essential in osteosarcoma cell growth and survival, further elucidating the regulatory mechanisms controlling the expression of CDK11 and ultimately develop a CDK11 inhibitor that may provide therapeutic benefit against osteosarcoma.
Scanning for Clues to Better Use Selective Estrogen Receptor Modulators
Authors: Mitchell J. Machiela, Stephen J. Chanock
Journal: Cancer Discovery (2013)

Ingle and colleagues present timely findings identifying genetic variants associated with response to selective estrogen receptor modulator therapy that when substantiated in follow-up may represent an important step toward understanding estrogen-dependent induction of BRCA1 expression and advancing individualized preventive medicine in women at high risk for developing breast cancer.
Critical role of matrix metalloprotease-9 in chronic high fat diet-induced cerebral vascular remodelling and increase of ischaemic brain injury in mice
Authors: J. Deng, J. Zhang, C. Feng, L. Xiong, Z. Zuo
Journal: Cardiovascular Research (2014)

About one-third of American adults and 20% of teenagers are obese. Obesity and its associated metabolic disturbances including hyperlipidaemia are risk factors for cardiovascular diseases including stroke. They can worsen neurological outcome after stroke. We determined whether obesity and hyperlipidaemia could induce cerebral vascular remodelling via matrix metalloproteases (MMP) and whether this remodelling affected neurological outcome after brain ischaemia.Six-week-old male CD1, C57BL/6J, and MMP-9(-/-) mice were fed regular diet (RD) or high-fat diet (HFD) for 10 weeks. They were subjected to vascular casting or a 90 min middle cerebral arterial occlusion (MCAO). Mice on HFD were heavier and had higher blood glucose and lipid levels than those on RD. HFD-fed CD1 and C57BL/6J mice had an increased cerebral vascular tortuosity index and decreased inner diameters of the middle cerebral arterial root. HFD increased microvessel density in CD1 mouse cerebral cortex. After MCAO, CD1 and C57BL/6J mice on HFD had a bigger infarct volume, more severe brain oedema and blood-brain barrier damage, higher haemorrhagic transformation rate, greater haemorrhagic volume, and worse neurological function. HFD increased MMP-9 activity in the ischaemic and non-ischaemic brain tissues. Although HFD increased the body weights, blood glucose, and lipid levels in the MMP-9(-/-) mice on a C57BL/6J genetic background, the HFD-induced cerebral vascular remodelling and worsening of neurological outcome did not occur in these mice.HFD induces cerebral vascular remodelling and worsens neurological outcome after transient focal brain ischaemia. MMP-9 activation plays a critical role in these HFD effects.
17-Allylamino-17-Demethoxygeldanamycin Synergistically Potentiates Tumor Necrosis Factor–Induced Lung Cancer Cell Death by Blocking the Nuclear Factor-κB Pathway
Authors: Xia Wang, Wei Ju, Jordan Renouard, James Aden, Steven A. Belinsky, Yong Lin
Journal: Cancer Research (2006)

Abstract Nuclear factor-κB (NF-κB), a survival signal induced by tumor necrosis factor (TNF), contributes substantially to the resistance to TNF-induced cell death. Previous studies suggest that heat shock protein 90 (Hsp90) regulates the stability and function of receptor-interaction proteins (RIP) and IκB kinase β (IKKβ), the key components of the TNF-induced NF-κB activation pathway. In this study, we showed that the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17AAG) was synergistic with TNF to induce apoptotic cell death in a panel of lung tumor-derived cell lines. Treatment with 17AAG caused degradation of RIP and IKKβ that, in turn, blocked TNF-induced NF-κB activation and antiapoptotic gene expression. The synergistic cytotoxicity was detected only when TNF treatment followed 17AAG preexposure. Importantly, the potentiation of cell death was abolished in NF-κB-disabled cells that express a nondegradable IκBα mutant (IκBαAA). These results suggest that the cytotoxicity seen with 17AAG and TNF treatment results from blocking TNF-induced NF-κB activation. The other components of the TNF receptor I signaling cascade were not altered, whereas TNF-induced c-Jun NH2-terminal kinase activation and apoptosis were potentiated. A similar synergism for inducing apoptosis was also observed in 17AAG-treated and TNF-related apoptosis-inducing ligand (TRAIL)–treated cancer cells. Our results suggest that NF-κB plays a key role in the resistance of lung cancer cells to TNF and TRAIL and that disabling this survival signal with 17AAG followed by TNF or TRAIL treatment could be an effective new therapeutic strategy for lung cancer. (Cancer Res 2006; 66(2): 1089-95)
The Treatment of Pulmonary Consumption at High Altitudes
Authors: A. T. Wise
Journal: BMJ (1887)

69-an4 6Q), buta4ot-one of these o¢e, -unfortunately, is laapable of affording any conclusive evidence on the.point now in question.Some of thep are doubtful cases, where there was more than one lesion; others are oases in which the lesion was too extensive to be at all con- clusive!; and others again are cases in which no adequate clinical aetails are given to enable us to say whether the defect of.speechfrom which.the patient suffered was aphasic or aphemic in character.This Xa a point, therefore, to which I hope future workers will direct special attention, both clinically and in post-mortem examinations, in order that we may know for certain whether with Broca's region thoroughly intact, but with a lesion in the left centrum ovale or in- teTral capsule (cutting across or otherwise damaging the fibres between this centre and the motor centres of the bulb), the speech defect is of the kind which I name aphemia, that is with mental power intact, so that if the hand be not paralysed, thoughts can be expressed: freely, by writing, and if speech be not entirely lost, of such a kind that the patient will, when bidden, make an attempt (however rude) to pro.nounce any simple word or vowel sound, whilst the true aphasic patient will not, when bidden, attempt to repeat the most simple
Beta 2-microglobulin. A reliable parameter for differentiating between graft rejection and severe infection after cardiac transplantation.
Authors: H Teufelsbauer, F C Prischl, M Havel, C Holzinger, T Lion, J D Schwarzmeier, A Laczkovics
Journal: Circulation (1989)

We investigated the role of beta 2-microglobulin as a noninvasive parameter to monitor acute rejection and severe infection in 45 consecutive heart transplant recipients. Endomyocardial biopsy revealed moderate (41 patients) or severe (three patients) rejection in 44 patients. Severe infections of bacterial septicemia (11 patients), bronchopneumonia (two patients), and viral infection (seven patients) were detected by a meticulous schedule of various clinical and laboratory tests. beta 2-Microglobulin levels in serum, generally corrected for serum creatinine, were significantly elevated in patients with infections (median, 6.3 mg/l; range Q10-Q90, 3.47-10.27 mg/l) compared with levels in patients with rejection (p less than 0.0001) or in patients in obviously good condition (p less than 0.0001). At the onset of acute rejection, the median corrected beta 2-microglobulin serum level was 1.56 mg/l (range Q10-Q90, -0.05-3.46 mg/l) and was significantly different from the control group (p less than 0.01). In addition, density function and empirical quantile analyses allowed us to define ranges of beta 2-microglobulin levels that would differentiate between rejection (2.05-3.46 mg/l) and infection (greater than 3.46 mg/l). With these values, sensitivity and specificity were 0.9 and 0.938 for detection of infection and 0.23 and 0.925 for detection of rejection, respectively. By means of beta 2-microglobulin, two cases of infection were misinterpreted as rejection (10%), and four of 44 rejections were mistaken for infections (9%). We conclude that measurements of beta 2-microglobulin may improve the management of heart transplant patients.
Regression of cardiomyocyte hypertrophy in SHR following chronic inhibition of the Na+/H+ exchanger
Authors: María C Camilión de Hurtado, Enrique L Portiansky, Néstor G Pérez, Oscar R Rebolledo, Horacio E Cingolani
Journal: Cardiovascular Research (2002)

Objective: Experiments were performed to examine the effect of chronic inhibition of the Na+/H+ exchanger isoform-1 (NHE-1) on cardiac hypertrophy of spontaneously hypertensive rats (SHR). Methods: SHR were orally treated during 1 month with two different doses (0.3 and 3.0 mg/kg/day) of the NHE-1 inhibitor, cariporide, or nifedipine (10.0 mg/kg/day). Results: The two doses of cariporide did not differ in their effects after 1 month of treatment, since both induced a slight decrease in systolic blood pressure (SBP) of ∼6 mmHg and regression of the heart weight to body weight ratio (mg/g) from 3.28±0.05 to 3.04±0.05 (0.3 mg) and 2.99±0.10 (3.0 mg, P<0.05). Nifedipine, given for the same period, produced similar reduction in the hypertrophy index (3.03±0.05), but with a much greater decrease in arterial pressure (35.6±7.4 mmHg). Chronic treatment with cariporide induced a complete regression of the augmented cross sectional area of left ventricular myocytes without significant changes in collagen content, serum procollagen 1 propeptide levels or myocardial distensibility. Conclusions: NHE inhibition represents a novel approach to induce regression of pathological hypertrophy of the heart. The finding can be rationalized mechanistically by previous in vitro studies suggesting a role of the NHE in the development of myocardial hypertrophy.
Activated Mammalian Target of Rapamycin Is an Adverse Prognostic Factor in Patients with Biliary Tract Adenocarcinoma
Authors: Beata Herberger, Harald Puhalla, Martina Lehnert, Fritz Wrba, Sabine Novak, Anita Brandstetter, Birgit Gruenberger, Thomas Gruenberger, Robert Pirker, Martin Filipits
Journal: Clinical Cancer Research (2007)

Abstract Purpose: The mammalian target of rapamycin (mTOR) is a protein kinase that plays a key role in cellular growth and homeostasis. Because its regulation is frequently altered in tumors, mTOR is currently under investigation as a potential target for anticancer therapy. The purpose of our study was to determine the prognostic value of activated mTOR (p-mTOR) in patients with biliary tract adenocarcinoma (BTA), in order to strengthen the rationale for targeted therapy of BTA using mTOR inhibitors. Experimental Design: We determined expression of p-mTOR in paraffin-embedded surgical specimens of BTA by immunohistochemistry with a monoclonal antibody to phosphorylated mTOR. Overall survival was analyzed with a Cox model adjusted for clinical and pathologic factors. Results: Immunostaining for p-mTOR was positive in 56 of 88 (64%) tumors. Activated mTOR was not associated with any of the clinical or pathologic variables of the patients but predicted overall survival of the patients. Overall survival was significantly shorter in patients with p-mTOR–positive tumors as compared with patients with p-mTOR–negative tumors (hazard ratio for death 2.57; 95% confidence interval, 1.35-4.89; P = 0.004). Multivariate Cox proportional hazards regression analyses identified p-mTOR to be an independent prognostic factor for death (adjusted hazard ratio for death, 2.44; 95% confidence interval, 1.24-4.80; P = 0.01). Conclusions: Patients with BTA and p-mTOR–positive tumors have a significantly shorter overall survival than patients with p-mTOR–negative tumors and may benefit from targeted therapy with mTOR inhibitors in the future.
TRPC6 Enhances Angiotensin II-induced Albuminuria
Authors: Jason Eckel, Peter J. Lavin, Elizabeth A. Finch, Nirvan Mukerji, Jarrett Burch, Rasheed Gbadegesin, Guanghong Wu, Brandy Bowling, Alison Byrd, Gentzon Hall, Matthew Sparks, Zhu Shan Zhang, Alison Homstad, Laura Barisoni, Lutz Birbaumer, Paul Rosenberg, Michelle P. Winn
Journal: Journal of the American Society of Nephrology (2011)

Mutations in the canonical transient receptor potential cation channel 6 (TRPC6) are responsible for familial forms of adult onset focal segmental glomerulosclerosis (FSGS). The mechanisms by which TRPC6 mutations cause kidney disease are not well understood. We used TRPC6-deficient mice to examine the function of TRPC6 in the kidney. We found that adult TRPC6-deficient mice had BP and albumin excretion rates similar to wild-type animals. Glomerular histomorphology revealed no abnormalities on both light and electron microscopy. To determine whether the absence of TRPC6 would alter susceptibility to hypertension and renal injury, we infused mice with angiotensin II continuously for 28 days. Although both groups developed similar levels of hypertension, TRPC6-deficient mice had significantly less albuminuria, especially during the early phase of the infusion; this suggested that TRPC6 adversely influences the glomerular filter. We used whole-cell patch-clamp recording to measure cell-membrane currents in primary cultures of podocytes from both wild-type and TRPC6-deficient mice. In podocytes from wild-type mice, angiotensin II and a direct activator of TRPC6 both augmented cell-membrane currents; TRPC6 deficiency abrogated these increases in current magnitude. Our findings suggest that TRPC6 promotes albuminuria, perhaps by promoting angiotensin II-dependent increases in Ca(2+), suggesting that TRPC6 blockade may be therapeutically beneficial in proteinuric kidney disease.