tbuckley/cabot-search huggingface dataset:
Transcriptional regulator early growth response gene 2 (Egr2) is required for T cell anergy in vitro and in vivo
Authors: Yan Zheng, Yuanyuan Zha, Gregory Driessens, Frederick Locke, Thomas F. Gajewski
Journal: The Journal of Experimental Medicine (2012)

T cell receptor engagement in the absence of costimulation results in a hyporesponsive state termed anergy. Understanding the transcriptional regulation of other T cell differentiation states has provided critical information regarding the biology of T cell regulation in vivo. However, the transcriptional regulation of T cell anergy has been poorly understood. Using the key anergy target gene diacylglycerol kinase (DGK) α as a focal point, we identified early growth response gene 2 (Egr2) as a central transcription factor that regulates the anergic state. Conditional Egr2 deletion in peripheral T cells abolishes induced expression of DGK-α and other anergy genes and restores Ras/MAPK signaling, IL-2 production, and proliferation upon attempted anergy induction. Using superantigen- and tumor-induced anergy models, we found that Egr2 is necessary for anergy induction in vivo. Collectively, our results implicate Egr2 as an essential transcriptional regulator of the T cell anergy program.
The development of anti-hepatitis C virus agents
Authors: Kunitada Shimotohno
Journal: Hepatology (1995)

We have built a model of the specificity pocket of the protease of hepatitis C virus on the basis of the known structures of trypsin-like serine proteases and of the conservation pattern of the protease sequences among various hepatitis C strains. The model allowed us to predict that the substrate of this protease should have a cysteine residue in position P1. This hypothesis was subsequently proved by N-terminal sequencing of two products of the protease. The success of this “blind” test increases our confidence in the overall correctness of our proposed alignment of the enzyme sequence with those of other proteases of known structure and constitutes a first step in the construction of a complete model of the viral protease domain.
Assessment of the Accuracy of the Gail Model in Women With Atypical Hyperplasia
Authors: V. Shane Pankratz, Lynn C. Hartmann, Amy C. Degnim, Robert A. Vierkant, Karthik Ghosh, Celine M. Vachon, Marlene H. Frost, Shaun D. Maloney, Carol Reynolds, Judy C. Boughey
Journal: Journal of Clinical Oncology (2008)

Purpose An accurate estimate of a woman's breast cancer risk is essential for optimal patient counseling and management. Women with biopsy-confirmed atypical hyperplasia of the breast (atypia) are at high risk for breast cancer. The Gail model is widely used in these women, but has not been validated in them. Patients and Methods Women with atypia were identified from the Mayo Benign Breast Disease (BBD) cohort (1967 to 1991). Their risk factors for breast cancer were obtained, and the Gail model was used to predict 5-year–and follow-up–specific risks for each woman. The predicted and observed numbers of breast cancers were compared, and the concordance between individual risk levels and outcomes was computed. Results Of the 9,376 women in the BBD cohort, 331 women had atypia (3.5%). At a mean follow-up of 13.7 years, 58 of 331 (17.5%) patients had developed invasive breast cancer, 1.66 times more than the 34.9 predicted by the Gail model (95% CI, 1.29 to 2.15; P &lt; .001). For individual women, the concordance between predicted and observed outcomes was low, with a concordance statistic of 0.50 (95% CI, 0.44 to 0.55). Conclusion The Gail model significantly underestimates the risk of breast cancer in women with atypia. Its ability to discriminate women with atypia into those who did and did not develop breast cancer is limited. Health care professionals should be cautious when using the Gail model to counsel individual patients with atypia.
Diagnosing dissociative disorders in The Netherlands: a pilot study with the Structured Clinical Interview for DSM-III-R Dissociative Disorders
Authors: S Boon, N Draijer
Journal: American Journal of Psychiatry (1991)

To improve the ability to diagnose dissociative disorders in The Netherlands, the authors conducted a study using a Dutch version of the Structured Clinical Interview for DSM-III-R Dissociative Disorders (SCID-D) with additional questions on childhood trauma and symptoms of borderline and histrionic personality disorders.All interviews were audiotaped or videotaped and rated by two investigators separately. Forty-four patients (42 women and two men) participated in the study. Most of the patients had been referred for evaluation of dissociative symptoms; five had participated in a nationwide survey on incest. None of the patients had ever received a diagnosis of a dissociative disorder, and none had evidence of organic brain syndrome or mental retardation. All patients were in active treatment; 23 were being treated in an outpatient psychiatric service, 13 in an inpatient psychiatric service, and eight in private practice. Thirty-two patients had been psychiatric inpatients at least once.Four diagnostic groups of patients were identified: two with dissociative disorders (12 patients with multiple personality disorder and 11 with dissociative disorder not otherwise specified), one with DSM-III-R personality disorders (11 patients), and one without dissociative or personality disorders (10 patients).Dissociative disorders are clearly not only an American phenomenon. The diagnosis can be made outside of the United States if the symptoms are sought. The SCID-D proved to be a promising instrument.
Respiratory muscle strength and the risk of incident cardiovascular events
Authors: J van der Palen
Journal: Thorax (2004)

Maximal inspiratory pressure (MIP) is a measure of inspiratory muscle strength. The prognostic importance of MIP for cardiovascular events among elderly community dwelling individuals is unknown. Diminished forced vital capacity (FVC) is a risk factor for cardiovascular events which remains largely unexplained.MIP was measured at the baseline examination of the Cardiovascular Health Study. Participants had to be free of prevalent congestive heart failure (CHF), myocardial infarction (MI), and stroke.Subjects in the lowest quintile of MIP had a 1.5-fold increased risk of MI (HR 1.48, 95% CI 1.07 to 2.06) and cardiovascular disease (CVD) death (HR 1.54, 95% CI 1.09 to 2.15) after adjustment for non-pulmonary function covariates. There was a potential inverse relationship with stroke (HR 1.36, 95% CI 0.97 to 1.90), but there was little evidence of an association between MIP and CHF (HR 1.22, 95% CI 0.93 to 1.60). The addition of FVC to models attenuated the HR associated with MIP only modestly; similarly, addition of MIP attenuated the HR associated with FVC only modestly.A reduced MIP is an independent risk factor for MI and CVD death, and a suggestion of an increased risk for stroke. This association with MIP appeared to be mediated through mechanisms other than inflammation.
Interleukin (IL)-6 gene expression in the central nervous system is necessary for fever response to lipopolysaccharide or IL-1 beta: a study on IL-6-deficient mice.
Authors: Z Chai, S Gatti, C Toniatti, V Poli, T Bartfai
Journal: The Journal of Experimental Medicine (1996)

Interleukin (IL)-6, IL-1 beta, and tumor necrosis factor alpha (TNF-alpha) are considered to act as endogenous pyrogens. Because of the complex pattern of cross-inductions between these cytokines, the relative role of the central and peripheral production of these cytokines in eliciting the fever response has not yet been clarified. The purpose of this study was to determine the role of IL-6 in the fever response by making use of mice carrying a null mutation in the IL-6 gene. The intraperitoneal injections of lipopolysaccharide (LPS) (50 micrograms/kg) and recombinant murine (rm) IL-1 beta (10 micrograms/kg), respectively, failed to evoke fever response in IL-6-deficient mice, whereas the same doses of LPS and rmIL-1 beta caused fever response in wild-type mice. The fever response could be induced in the IL-6-deficient mice by intracerebroventricular injection of recombinant human (rh) IL-6 (500 ng/mouse), whereas intracerebroventricular injection of rmIL-1 beta (100 ng/mouse) failed to produce fever response in the IL-6-deficient mice. These results suggest that central IL-6 is a necessary component of the fever response to both endogenous (IL-1 beta) and exogenous (LPS) pyrogens in mice and that IL-6 acts downstream from both peripheral and central IL-1 beta.
A global emerging disease of Klebsiella pneumoniae liver abscess: is serotype K1 an important factor for complicated endophthalmitis?
Authors: C.-P. Fung, F.-Y. Chang, S.-C. Lee, B.-S. Hu, B. I.-T. Kuo, C.-Y. Liu, M. Ho, L. K. Siu
Journal: Gut (2002)

Background and aims: Over the past two decades in Taiwan, pyogenic liver abscess has usually been caused by a single microorganism, <i>Klebsiella pneumoniae</i>, and is frequently associated with the serious complication of endophthalmitis, especially in diabetic patients. However, the relationship between the clinical presentation and bacterial factors remains unclear. The aim of this study was to investigate the clinical features of patients and the serotype and ribotype of <i>K pneumoniae</i> liver abscess. Methods: From July 1991 to June 1998, a total of 134 cases of <i>K pneumoniae</i> liver abscess with 248 <i>K pneumoniae</i> isolates from the same patients were collected from two large medical centres in northern Taiwan. Clinical data were collected from medical records. Serotyping and ribotyping were performed using the countercurrent immunoelectrophoresis method and automated Riboprinter. Results: Serotyping revealed that the most common serotypes were K1 (63.4%) and K2 (14.2%). K1 isolates occurred at a significantly higher frequency (p&lt;0.01) than all other serotypes. Among 134 patients, 105 (78.4%) had suffered from diabetes mellitus for 3–15 years. Fourteen patients (10.4%) had metastatic infection to the eye causing septic endophthalmitis. Liver aspirates, and blood and vitreous pus cultures yielded the same serotype of <i>K pneumoniae</i> in all patients. Among patients with septic endophthalmitis, 92.3% (13/14) were diabetic, and 85.7% (12/14) of the isolates belonged to serotype K1. For molecular typing, different degrees of genetic polymorphism among isolates with the same K1 serotype suggested no particular prevalence of any one strain in <i>K pneumoniae</i> liver abscess. Conclusion: <i>K pneumoniae</i> serotype K1 was significantly associated with liver abscess and the complication of endophthalmitis, especially in diabetic patients. Physicians should request an immediate report of serotyping and susceptibility test results simultaneously if a diagnosis of pyogenic liver abscess has been made so that early and appropriate management for possible complications will not be delayed. The use of ceftriaxone because of its higher concentration in the aqueous humor is suggested to decrease the chance of septic endophthalmitis.
Retrospective observational study of pulmonary hypertension patients dosed with greater than 9 breaths qid of inhaled treprostinil
Authors: Abby Poms, Sandra McNeilly, Terry Fortin, Victor F. Tapson
Journal: European Respiratory Journal (2013)

Purpose: The objective of this retrospective cohort study was to determine the tolerability and safety of inhaled treprostinil (iTRE) dosed at a higher target maintenance dosage than previously studied in pulmonary hypertension (PH).  Methods: World Health Organization (WHO) Group I-V PH patients treated at Duke prior to 8/2012 that have been prescribed iTRE at higher than target maintenance dose of 9 breaths qid (54mcg) were included in this analysis. Tolerability and safety parameters were assessed. Data were collected by chart abstraction and verified against source documents. Baseline data were collected at least 3 months prior to the increased dose. Follow up data were collected 3 to 6 months after the elevated dose.  Results: 75 patients were analyzed; 67% female, 67% Caucasian, 51% WHO Group I and 35% Group III. Of the 75 patients, 73 received 12 breaths qid (72 mcg) while 2 only reached 10-11 breaths.  Cough (41%) was the most common side effect at baseline decreasing to 18% at follow-up. Headache was present in 28% patients and decreased over time. Throat irritation was present in 8% patients and disappeared subsequently. One patient was hypotensive but did not discontinue. Another had a syncopal episode at baseline and later discontinued.  Overall 20 of 75 (25%) patients discontinued iTRE; 9 transitioned to parenteral therapy, 4 stopped due to side effects, 3 died (worsening PH, post-op complications), and 4 had other reasons.  Conclusions: Overall, inhaled iTRE dosed at a higher target maintenance dose than previously studied appeared safe and well-tolerated. These results warrant further investigation into the risk/benefit of elevated dosages.
HIV associated pulmonary emphysema: a review of the literature and inquiry into its mechanism
Authors: I Petrache, K Diab, K S Knox, H L Twigg, R S Stephens, S Flores, R M Tuder
Journal: Thorax (2008)

Chronic lung diseases are increasingly recognised complications of the human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS). Of these, pulmonary emphysema, characterised by permanent destruction of the lung parenchyma distal to the terminal bronchioles accompanied by various degrees of inflammation, is emerging as a distinct source of morbidity for patients infected with HIV. Similarly, HIV is now frequently cited as a susceptibility factor for the development of emphysema, independent of cigarette smoking status. The presence of common coexistent confounding factors that may predispose patients to chronic lung injury such as drugs, opportunistic infections and malnutrition, limits the scope of studies of direct mechanisms involved in HIV associated emphysematous lung disease. We review the clinical studies supporting a direct association between HIV infection and emphysema. Recent developments in the basic understanding of HIV infection and emphysema are also reviewed, since they may aid in understanding the pathobiology of HIV associated emphysema. The authors emphasise how HIV infection may affect cytotoxic lymphocyte activation, lung capillary endothelial cell injury and apoptosis, sphingolipid imbalance and oxidative stress in the lung. A better understanding of the pathogenesis of HIV associated pulmonary emphysema may provide clues and therapeutic targets that have broader application in this disease, including cigarette smoke induced emphysema.
Skin Replacement Therapies for Diabetic Foot Ulcers
Authors: Eva Blozik, Martin Scherer
Journal: Diabetes Care (2008)

Diabetic ulcer complications are a leading cause of hospitalization and amputation. Of the 20 million individuals with diabetes, 10–15% are at risk for developing diabetic ulcers. Standard therapy involves the use of dressings to protect the wound bed from trauma and to absorb exsudate; offloading high pressure from the wound bed, e.g., by prescribing protective footwear; and wound bed preparation to accelerate endogenous healing and facilitate the effectiveness of topically applied substances. But these measures are often deficient in healing all diabetic ulcers when the patient's own intrinsic wound-healing system is insufficient. In such patients, skin replacement therapies are second-line treatment options; however, the effectiveness of skin replacement therapies in treatment of diabetic ulcers is unclear. The objective of this study is to assess their effectiveness using evidence from randomized trials in diabetic leg and foot ulceration.

We searched the Cochrane Controlled Trials Register (1970–2006), MEDLINE (1966–2006), EMBASE (1980–2006), and CINAHL (1982–2006) using a combination of text and keywords in addition to a filter for controlled clinical trials. The last update of searches was performed on 30 September 2007. We included trials if the allocation of participants was described as randomized, with participants of any age and in any care setting having diabetic leg or foot ulceration. We included studies that compared the following types of grafts with any other intervention: 1 ) autografts (pinch, split or full-thickness skin grafts, cultured keratinocytes, or fibroblasts), 2 ) allografts (cultured keratinocytes or fibroblasts), 3 ) xerografts, and 4 ) bioengineered skin.

Two reviewers independently evaluated …
Mal de Meleda keratoderma with pseudoainhum
Authors: R. BKRGMAN, O. BITTERMAN-DEUTSCH, M. FARTASCH, R. GERSHONI-BARUCH, R. FRIEDMAN-BIRNBAUM
Journal: British Journal of Dermatology (1993)

Pseudoainhum is an infrequent complication in the autosomal-recessive keratodermas. We describe two related families in which the diagnosis of mal de Meleda keratoderma has been confirmed by mode of inheritance and ultrastructural findings. One family member, a 9-year-old girl, developed pseudoainhum which threatened the viability of her little fingers. This responded to treatment with etretinate. The treatment dilemma posed by keratoderma-induced pseudoainhum in children, i.e. the concern over the possible skeletal toxic effects of long-term etretinate treatment vs. the risks and outcome of surgery, is discussed.
Specific Cell-Adhesion Mechanisms Determining Migration Pathways of Recirculating Lymphocytes
Authors: J J Woodruff, L M Clarke, Y H Chin
Journal: Annual Review of Immunology (1987)

Recirculating lymphocytes traffic continuously between blood and lymph moving by a route that takes them through various lymphoid organs in the body. Though the cells circulate freely in the bloodstream and have opportunity for interaction elsewhere, they are not promiscuous but faith­ fully seek out those blood vessels that provide entry into these tissues (1-15). Lymphocytes gain access to lymph nodes and mucosal-associated lymphoid tissues, e.g. Peyer's patches, via a system of specialized mic­ rovascular structures, the high endothelial cell venules (HEV) (4). Such interactions are crucial for recirculation and reassortment of lymphocytes because the vascular endothelium is the first barrier these cells must nego­ tiate as they move from blood into tissue. Prime .importance is therefore attached to the understanding of lymphocyte-high endothelial cell inter­ actions. This review thus focuses on properties of lymphocytes and high endothelium that play a role in their affinity and specificity for each other.
Fas/FasL-dependent Apoptosis of Alveolar Cells after Lipopolysaccharide-induced Lung Injury in Mice
Authors: YOSHIHIRO KITAMURA, SATORU HASHIMOTO, NARUHIKO MIZUTA, ATSUKO KOBAYASHI, KUNIHIKO KOOGUCHI, IKUYA FUJIWARA, HIROO NAKAJIMA
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

To determine the possible contribution of apoptosis in the pathogenesis of acute lung injury (ALI), we investigated Fas antigen (Fas), Fas ligand (FasL), perforin, granzyme A, and granzyme B expressions in a murine model of ALI after intratracheal instillation of Escherichia coli lipopolysaccharide (LPS: 0.3–30 μ g) into the left lung. Lung injury, examined by water-to-dry weight ratio and albumin leakage, demonstrated maximal epithelial injury 1 d after 30 μ g LPS instillation. Expressions of the proapoptosis molecules' mRNA were dose-dependently up-regulated, with maximal expression in the early phase in the instilled lung and most apparent 1 d after LPS instillation. Negligible mRNA expression of proapoptosis molecules was observed in noninstilled lungs. The terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling (TUNEL) demonstrated positive signals in neutrophils and macrophages as well as in alveolar wall cells of the instilled lung 1 d after LPS instillation. Immunohistochemistry demonstrated that Fas was up-regulated in alveolar and inflammatory cells and FasL-positive inflammatory cells migrated into the air spaces in the LPS-instilled lung. Intratracheal administration of P2 antibody, which is an anti-Fas blocking antibody, attenuated the lung injury after 30 μ g LPS instillation without attenuating mRNA expressions of proapoptosis molecules and neutrophil accumulation in the lung. In contrast, concanamycin A, which inhibits the function of perforin, did not alter the outcome after LPS instillation. These results indicate that the Fas/FasL system could be important in the pathogenesis of LPS-induced ALI, and proper regulation of the FasL/Fas system might be important for potential treatment of ARDS.
Should we treat concussion pharmacologically?
Authors: P McCrory
Journal: British Journal of Sports Medicine (2002)

The need for evidence based pharmacological treatment for the concussed athlete

The medical management of concussion in sport has traditionally involved close observation and “masterly inactivity”. With the use of clinical assessment and neuropsychological testing we have the ability to individualise patient management and determine safe and appropriate return to play strategies. At the present time, the sports physician has no evidence based pharmacological treatment to offer the concussed athlete. The ability to treat concussion with specific drug therapy requires an understanding of the pathophysiological changes that accompany concussive injuries.

Concussive brain injury has long been thought to evoke immediate and irreversible damage to the brain. While this may be true in moderate to severe traumatic brain injury, the evidence that this occurs in milder injuries such as concussion is not compelling. Recent experimental evidence suggests that the pathogenesis of axonal dysfunction resulting from head trauma is complex.1

In addition, studies of moderate to severe traumatic brain injury have revealed that a cascade of neurochemical, ionic, and metabolic changes occur following experimental brain injury.2 The assumption is that similar changes occur in milder injury although this remains controversial. Most notably, an injury induced ionic flux across the cell membrane due to the release of the excitatory amino acids, has been shown to increase glycolysis that results in a state of metabolic depression due to a decrease in both glucose and oxidative metabolism accompanied by a decrease in cerebral blood flow.2, 3 Each element of this cascade has a different time window that may have important implications in treating concussed individuals.

There are many pharmacological management options that have been proposed for all grades of brain injury. Readers are …
Slow Rate of Evolution in the Mitochondrial Control Region of Gulls (Aves: Laridae)
Authors: Pierre-André Crochet, Eric Desmarais
Journal: Molecular Biology and Evolution (2000)

We sequenced part of the mitochondrial control region and the cytochrome b gene in 72 specimens from 32 gull species (Laridae, Larini) and 2 outgroup representatives (terns: Laridae, Sternini). Our control region segment spanned the conserved central domain II and the usually hypervariable 3' domain III. Apart from some heteroplasmy at the 3' end of the control region, domain III was not more variable than domain II or the cytochrome b gene. Furthermore, variation in the tempo of evolution of domain III was apparent between phyletic species groups. The lack of variation of the gull control region could not be explained by an increase in the proportion of conserved sequences in these birds, and the gull control region showed an organization similar to those of other avian control regions studied to date. A novel invariant direct repeat was identified in domain II of gulls, and in domain III, two to three inverted, sometimes imperfect, repeats are able to form a significantly stable stem-and-loop structure. These putative secondary structures have not been reported before, and a comparison between species groups showed that they are more stable in the group with the more conserved control region. The unusually slow rate of evolution of control region part III of the gulls could thus be partly explained by the existence of secondary structures in domain III of these species.