tbuckley/cabot-search huggingface dataset:
Nod2 sensing of lysozyme-digested peptidoglycan promotes macrophage recruitment and clearance of S. pneumoniae colonization in mice
Authors: Kimberly M. Davis, Shigeki Nakamura, Jeffrey N. Weiser
Journal: Journal of Clinical Investigation (2011)

Streptococcus pneumoniae colonizes the mucosal surface of the human upper respiratory tract. A colonization event is gradually cleared through phagocytosis by monocytes/macrophages that are recruited to the airway lumen. Here, we sought to define the bacterial and host factors that promote monocyte/macrophage influx and S. pneumoniae clearance using intranasal bacterial challenge in mice. We found that the recruitment of monocytes/macrophages required their expression of the chemokine receptor CCR2 and correlated with expression of the CCR2 ligand CCL2. Production of CCL2 and monocyte/macrophage recruitment were deficient in mice lacking digestion of peptidoglycan by lysozyme (LysM) and cytosolic sensing of the products of digestion by Nod2. Ex vivo macrophages produced CCL2 following bacterial uptake, digestion by LysM, and sensing of peptidoglycan by Nod2. Sensing of digested peptidoglycan by Nod2 also required the pore-forming toxin pneumolysin. The generation of an adaptive immune response, as measured by anti-pneumococcal antibody titers, was also LysM- and Nod2-dependent. Together, our data suggest that bacterial uptake by professional phagocytes is followed by LysM-mediated digestion of S. pneumoniae-derived peptidoglycan, sensing of the resulting products by Nod2, release of the chemokine CCL2, and CCR2-dependent recruitment of the additional monocytes/macrophages required for the clearance of an S. pneumoniae colonization event.
Functional assessment in older people
Authors: T. J. Quinn, K. McArthur, G. Ellis, D. J. Stott
Journal: BMJ (2011)

Older people often present to healthcare services with acute and chronic problems that act together to adversely affect function.A common pathway comprises functional decline, followed by loss of independence and need for institutional care.However, this process is not necessarily inevitable or irreversible.Timely recognition of functional difficulties can lead to interventions that may prevent or arrest the decline.This article focuses on the functional assessment of older adults by generalist clinicians (see box 1 for terminology used in this broad field).
Intravenous drug misuse among prison inmates: implications for spread of HIV.
Authors: S Dye, C Isaacs
Journal: BMJ (1991)

clubs as opposed to playing golf properly.It is not a dangerous sport if played properly.However, in the hands of children playing unsupervised, golf clubs are potentially lethal weapons.We recommend that children are supervised at all times when playing with golf clubs and that this should be done on a golf course.
Stromal Matrix Protein Expression Following Preoperative Systemic Therapy in Breast Cancer
Authors: Anna-Maria Tokes, Attila Marcell Szasz, Andrea Farkas, Adrienn Ildiko Toth, Magdolna Dank, Laszlo Harsanyi, Bela Akos Molnar, Istvan Arthur Molnar, Zsolt Laszlo, Zoltan Rusz, Janina Kulka
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Stromal alterations are observed following preoperative systemic therapy in breast cancer. The aim of the present study was to analyze the qualitative and quantitative changes of representative tumor stroma proteins in the context of neoadjuvant therapy and the response of patients undergoing preoperative systemic therapy. Experimental Design: Fifty women receiving preoperative systemic therapy were evaluated for clinical and pathologic parameters. Clinical response was defined according to International Union against Cancer (UICC) criteria, whereas pathologic responses to preoperative systemic therapy were defined according to the Chevallier and Sataloff classifications. The expression of tenascin-C, syndecan-1, collagen IV, and smooth muscle actin proteins was investigated using morphometric analysis of immunohistochemical reactions. Quantitative reverse transcription-PCR was done to evaluate the mRNA expression level of syndecan-1 and tenascin-C. The data were compared with 20 breast cancer samples of patients not treated with preoperative systemic therapy. Results: According to UICC criteria, the expression levels of collagen IV were up-regulated in all preoperative systemic therapy–treated patients (P = 0.002). Collagen IV was up-regulated in the preoperative systemic therapy group in both Chevallier and Sataloff classifications compared with the control cases (P = 0.025 and P = 001, respectively). There were no significant differences in the expression of smooth muscle actin between the treated and nontreated groups. The syndecan-1 proteoglycan level was significantly down-regulated in the preoperative systemic therapy group (Chevallier classes P = 0.015, Sataloff classes P = 0.015). Tenascin-C was up-regulated in women with progressive disease (P = 0.005). Conclusion: We have observed that the stromal component of breast carcinomas following preoperative systemic therapy differs from the nontreated tumors, which can be evaluated with the analysis of the above mentioned proteins.
Aspirin increases the bleeding side effects in essential thrombocythemia independent of the cyclooxygenase pathway: Role of the lipoxygenase pathway
Authors: Sergio Cortelazzo, Marina Marchetti, Elisabetta Orlando, Anna Falanga, Tiziano Barbui, Michael R. Buchanan
Journal: American Journal of Hematology (1998)

Acetylsalicylic acid (ASA) is currently recommended as an antithrombotic for patients with essential thrombocythemia (ET) who are at an increased risk of thrombotic events. However, ASA is also associated with an increased risk of bleeding in these patients as compared to the risk of bleeding in other patients treated with ASA. Recent data suggest that while ASA inhibits platelet thromboxane A2 (TxA2) synthesis in all individuals, ASA has little effect or inhibits the lipoxygenase pathway (i.e., 12-hydroxyeicosatetranoic acid or 12-HETE synthesis) in some individuals, and enhances 12-HETE synthesis in others. These differential effects are associated with a pronounced prolongation of the bleeding time vs. no prolongation of the bleeding time, respectively, i.e., in ASA responders and ASA nonresponders, respectively. To determine if the increased risk of ASA-induced bleeding seen in ET patients is associated with an effect on 12-HETE synthesis, we compared the relative effects of ASA on the bleeding time, platelet TxA2 and 12-HETE synthesis, and platelet aggregation and adhesion in ET patients and healthy volunteers. ASA (300 mg, taken orally) prolonged the bleeding time in 82% of the ET patients but only 27% of the healthy volunteers although platelet TxA2 synthesis and ADP- and collagen-induced aggregation were inhibited significantly in both groups. In contrast, platelet 12-HETE synthesis was unchanged and platelet adhesion was decreased in those patients and volunteers whose bleeding times were prolonged by ASA, whereas platelet 12-HETE synthesis was increased significantly and platelet adhesion was unaffected in those patients and volunteers whose bleeding times were not prolonged, and in some cases shortened by ASA. These results confirm previous data that demonstrate that ASA has different effects on platelet 12-HETE synthesis and platelet adhesion in different individuals, i.e., inhibitory or no effect in ASA responders (in whom ASA prolonged bleeding) vs. enhancing effects in ASA nonresponders (in whom ASA did not prolong bleeding). These results also indicate that there is a greater percentage of ASA responders in patients with ET than that seen in the general population, a difference that is associated with an effect of ASA on the lipoxygenase pathway. This may explain the increased bleeding side effects seen in the ET patient population. Am. J. Hematol. 57:277–282, 1998. © 1998 Wiley-Liss, Inc.
Five-Year Outcomes After Prostatectomy or Radiotherapy for Prostate Cancer: The Prostate Cancer Outcomes Study
Authors: A. L. Potosky, W. W. Davis, R. M. Hoffman, J. L. Stanford, R. A. Stephenson, D. F. Penson, L. C. Harlan
Journal: JNCI Journal of the National Cancer Institute (2004)

Men treated for clinically localized prostate cancer with either radical prostatectomy or external beam radiotherapy usually survive many years with the side effects of these treatments. We present treatment-specific quality-of-life outcomes for prostate cancer patients 5 years after initial diagnosis.The cohort consisted of men aged 55-74 years who were newly diagnosed with clinically localized prostate cancer in 1994-1995 and were treated with radical prostatectomy (n = 901) or external beam radiotherapy (n = 286). We used clinical and quality-of-life data previously collected at the time of diagnosis (i.e., baseline) and at the 2-year follow-up and data newly collected at 5 years after diagnosis to compare urinary, bowel, and sexual function and to examine temporal changes in those functions. Odds ratios (ORs) and adjusted percentages were calculated by logistic regression. All statistical tests were two-sided.At 5 years after diagnosis, overall sexual function declined in both groups to approximately the same level. However, at 5 years after diagnosis, erectile dysfunction was more prevalent in the radical prostatectomy group than in the external beam radiotherapy group (79.3% versus 63.5%; OR = 2.5, 95% confidence interval [CI] = 1.6 to 3.8). Approximately 14%-16% of radical prostatectomy and 4% of external beam radiotherapy patients were incontinent at 5 years (OR = 4.4, 95% CI = 2.2 to 8.6). Bowel urgency and painful hemorrhoids were more common in the external beam radiotherapy group than in the radical prostatectomy group. All of these differences remained statistically significant after adjustment for confounders and for differences between treatment groups in some baseline characteristics.At 5 years after diagnosis, men treated with radical prostatectomy for localized prostate cancer continue to experience worse urinary incontinence than men treated with external beam radiotherapy. However, the two treatment groups were more similar to each other with respect to overall sexual function, mostly because of a continuing decline in erectile function among the external beam radiotherapy patients between years 2 and 5.
A case of epidermolysis bullosa acquisita with bleeding tendency due to factor VIII inhibitor (acquired haemophilia)
Authors: T. Nagano, M. Tani, Y. Hiramatsu, K. Kohriyama, K. Ishihara, M. Nei, T. Hashimoto
Journal: British Journal of Dermatology (2004)

Sir, Our patient, a 61‐year‐old woman with diffuse panbronchitis, presented in September 2000 with spontaneous formation of bullae on her extremities and severe oral ulceration. Gastric fibroscopy revealed that the oesophageal mucosa was eroded, but no stenosis of the oesophagus due to scarring was detected. Skin biopsy from the hand revealed subepidermal blisters with a dermal infiltrate of neutrophils and eosinophils. Direct immunofluorescence revealed linear deposition of IgG and C3 along the basement membrane zone (BMZ). Indirect immunofluorescence on 1 mol L−1 NaCl‐split skin showed binding of IgG to the dermal side. Western immunoblot analysis of the patient's serum using epidermal and dermal extracts revealed that autoantibodies in the dermal extracts bound to a 290‐kDa antigen (Fig. 1). We further analysed the serum by immunoblotting against the recombinant noncollagenous (NC) 1 domain, a minor protein of 145 kDa in BMZ extracts. Our patient's serum recognized this 145‐kDa recombinant NC1 protein. These findings led to a diagnosis of epidermolysis bullosa acquisita (EBA). Combination therapy with minocycline and dapsone was ineffective. After admission, a bleeding tendency appeared, accompanied with macrohaematuria, formation of haemorrhagic bullae (Fig. 2) and gastric haemorrhage. Laboratory examination revealed a prolonged activated partial thromboplastin time (APTT), reduced factor VIII activity and the presence of factor VIII inhibitor at a titre of 14·0 Bethesda Units mL−1. Treatment with oral prednisolone (up to 60 mg daily) and intravenous methylprednisolone (500 mg on three consecutive days) led to an improvement in EBA. The bleeding tendency markedly subsided and the APTT normalized. Tapering of prednisolone to 30 mg daily resulted in new bulla formation, but the worsening condition of her pulmonary disease did not allow an increase in the dose of prednisolone. Additional topical corticosteroid therapy (fluocinonide) was successful, and the bullae healed with milia formation.
What’s new on the HPA axis?
Authors: Johannes Hofland, Jan Bakker, Richard A. Feelders
Journal: Intensive Care Medicine (2015)

The human body depends on an integrated neuro-endocrine response in order to adapt to external and internal stressors. In critical illness this stress response coordinates endocrine, neural, cardiovascular and immune systems with the aim to maximize survival chances. The hypothalamus–pituitary–adrenal (HPA) axis, which also includes elements producing the neurohypophysial hormone arginine–vasopressin (AVP), is one the key effectors within this system [1]. Relative HPA or AVP deficiency contributes to cardiovascular collapse in critically ill patients, leading to the rationale of therapy with these hormones in shock. Recent developments have implicated copeptin, a by-product of the AVP precursor, as a novel biomarker for early stages of critical illness that could influence clinical decision-making.
Nucleation of protein aggregation kinetics as a basis for genotype-phenotype correlations in polyglutamine diseases
Authors: Keizo Sugaya, Shiro Matsubara
Journal: Molecular Neurodegeneration (2009)

Recent studies of inherited neurodegenerative disorders have suggested a linkage between the propensity toward aggregation of mutant protein and disease onset. This is particularly apparent for polyglutamine (polyQ) diseases caused by expansion of CAG-trinucleotide repeats. However, a quantitative framework for relating aggregation kinetics with molecular mechanisms of neurodegeneration initiation is lacking. Here, using the repeat-length-dependent age-of-onset in polyQ diseases, we derived a mathematical model based on nucleation of aggregation kinetics to describe genotype-phenotype correlations, and validated the model using both in vitro data and clinical data. Instead of describing polyQ aggregation kinetics with a derivative equation, our model divided age-of-onset (equivalent to the time required for aggregation) into two processes: nucleation lag time (a first-order exponential function of CAG-repeat length) and elongation time. With the exception of spinocerebellar ataxia (SCA) 3, the relation between CAG-repeat length and age-of-onset in all examined polyQ diseases, including Huntington's disease, dentatorubral-pallidoluysian atrophy and SCA1, -2, -6 and -7, could be well explained by three parameters derived from linear regression analysis based on the nucleated growth polymerization model. These parameters composed of probability of nucleation at an individual repeat, a protein concentration associated factor, and elongation time predict the overall features of neurodegeneration initiation, including constant risk for cell death, toxic polyQ species, main pathological subcellular site and the contribution of cellular factors. Our model also presents an alternative therapeutic strategy according to the distinct subcellular loci by the finding that nuclear localization of soluble mutant protein monomers itself has great impact on disease onset.
Lymphotoxin-α (LTα) Supports Development of Splenic Follicular Structure That Is Required for IgG Responses
Authors: Yang-Xin Fu, Hector Molina, Mitsuru Matsumoto, Guangming Huang, Jingjuan Min, David D. Chaplin
Journal: The Journal of Experimental Medicine (1997)

LTα-deficient (LTα−/−) mice show altered splenic microarchitecture. This includes loss of normal B cell–T cell compartmentalization, of follicular dendritic cell (FDC) clusters, and of ability to form germinal centers (GC). LTα−/− mice immunized with sheep red blood cells (SRBC) produced high levels of antigen-specific IgM but no IgG in either primary or secondary responses, demonstrating failure of Ig class switching. This inability to switch to IgG could have been due to the altered splenic microarchitecture in these mice. Alternatively, it could have been due directly to a requirement for LTα expression by lymphocytes cooperating in the antibody response. To investigate this, we performed reciprocal spleen cell transfers. When irradiated LTα−/− mice were reconstituted with wild-type splenocytes and immunized immediately with SRBC, splenic microarchitecture remained disturbed and there was no IgG response. In contrast, when irradiated wild-type animals received splenocytes from LTα−/− mice, follicle structure and a strong IgG response were retained. These data indicate that LTα-deficient B cells and T cells have no intrinsic defect in ability to generate an IgG response. Rather, the altered microenvironment characteristic of LTα−/− mice appears to result in impaired ability to switch to a productive IgG response. To investigate whether prolonged expression of LTα could alter the structure and function of spleen follicles, reciprocal bone marrow (BM) transplantation was performed. Six weeks after reconstitution of LTα−/− mice with wild-type BM, spleen follicle structure was partially restored, with return of FDC clusters and GC. B cell/T cell compartmentalization remained abnormal and white pulp zones were small. This was accompanied by restoration of IgG response to SRBC. Reconstitution of wild-type mice with LTα−/− BM resulted in loss of FDC clusters and GC, and loss of the IgG response, although compartmentalized B cell and T cell zones were largely retained. Thus, defective IgG production is not absolutely associated with abnormal B cell and T cell compartmentalization. Rather, expression of LTα supports the maturation of spleen follicle structure, including the development and maintenance of FDC clusters, which supports Ig class switching and an effective IgG response.
Place of cryotherapy, brachytherapy and photodynamic therapy in therapeutic bronchoscopy of lung cancers
Authors: J-M. Vergnon, R. M. Huber, K. Moghissi
Journal: European Respiratory Journal (2006)

Cryotherapy, brachytherapy and photodynamic therapy (PDT) are three different methods proposed in the endoluminal treatment of lung cancers. The current article presents an overview of the specific indications and limits of each technique. These three methods were first proposed with palliative intent in inoperable patients with centrally located lung cancers. Now, the best indication is a curative intent in early stage lung cancers. Of the three, cryotherapy is the cheapest method. It induces cell necrosis in a 3-mm radius around the probe, and is suitable for treatment of superficial tumours. However, clinical trials are limited. In contrast, many clinical studies have confirmed the efficacy of PDT in treatment of superficial lung cancers. Brachytherapy can cure more aggressive tumours with deeper invasion into the bronchial wall. Unfortunately, no comparative studies have been published. Each of these methods induces a delayed tumour necrosis, and thus neither is indicated in the treatment of obstructive tumours with acute dyspnoea. In many situations, these methods should be complementary, particularly cryotherapy and brachytherapy or PDT and brachytherapy. The combination of these endoscopic methods with chemotherapy should be widely tested to promote the adjuvant role of the endoscopic methods in the treatment of lung cancers.
Cd1-Reactive Natural Killer T Cells Are Required for Development of Systemic Tolerance through an Immune-Privileged Site
Authors: Koh-Hei Sonoda, Mark Exley, Scott Snapper, Steven P. Balk, Joan Stein-Streilein
Journal: The Journal of Experimental Medicine (1999)

Systemic tolerance can be elicited by introducing antigen into an immune-privileged site, such as the eye, or directly into the blood. Both routes of immunization result in a selective deficiency of systemic delayed type hypersensitivity. Although the experimental animal model of anterior chamber–associated immune deviation (ACAID) occurs in most mouse strains, ACAID cannot be induced in several mutant mouse strains that are coincidentally deficient in natural killer T (NKT) cells. Therefore, this model for immune-privileged site–mediated tolerance provided us with an excellent format for studying the role of NKT cells in the development of tolerance. The following data show that CD1-reactive NKT cells are required for the development of systemic tolerance induced via the eye as follows: (a) CD1 knockout mice were unable to develop ACAID unless they were reconstituted with NKT cells together with CD1+ antigen-presenting cells; (b) specific antibody depletion of NKT cells in vivo abrogated the development of ACAID; and (c) anti-CD1 monoclonal antibody treatment of wild-type mice prevented ACAID development. Significantly, CD1-reactive NKT cells were not required for intravenously induced systemic tolerance, thereby establishing that different mechanisms mediate development of tolerance to antigens inoculated by these routes. A critical role for NKT cells in the development of systemic tolerance associated with an immune-privileged site suggests a mechanism involving NKT cells in self-tolerance and their defects in autoimmunity.
Confocal Microscopic Localization of Constitutive and Heat Shock–Induced Proteins HSP70 and HSP27 in the Rat Heart
Authors: James P. Leger, Frank M. Smith, R. William Currie
Journal: Circulation (2000)

Background —Heat-shock treatment of rats elevates expression of heat-shock proteins, which play a role in improving the contractile recovery and reducing infarct size in hearts after ischemic injury. However, the location of these proteins in the heart is unknown. Methods and Results —Anesthetized rats were heat-shocked by elevation of body temperature to 42°C to 42.5°C for 15 minutes, followed by 24 hours of recovery. Control and heat-shocked hearts were extirpated and perfused briefly with saline followed by 2% paraformaldehyde in PBS. Confocal immunofluorescence microscopy of control hearts revealed that HSP27 was localized in cardiomyocytes in a pattern reminiscent of Z bands and was colocalized with neuronal markers in somata and axons. No obvious change in HSP27 content or distribution occurred after heat shock. Confocal microscopy revealed little or no HSP70 in control hearts. After heat shock, HSP70 was detected neither in cardiomyocytes nor in neuronal elements within the heart, but HSP70 was abundant in small blood vessels found between the ventricular cardiomyocytes. Conclusions —Heat shock induces a cell type–specific expression of HSP70 in blood vessels but not myocytes or intrinsic cardiac neurons, suggesting that blood vessels play a primary role in myocardial protection.
THE TREATMENT OF PSORIASIS WITH TRIACETOXYANTHRACENE
Authors: F. F. HELLIER, M. WHITEFIELD
Journal: British Journal of Dermatology (1967)

Journal Article THE TREATMENT OF PSORIASIS WITH TRIACETOXYANTHRACENE Get access F. F. HELLIER, M.D., F.R.C.P., F. F. HELLIER, M.D., F.R.C.P. Physician in Charge, The Skin Department, The General infirmary, Leeds Search for other works by this author on: Oxford Academic Google Scholar M. WHITEFIELD, B.Pharm., Ph.D., M.P.S. M. WHITEFIELD, B.Pharm., Ph.D., M.P.S. Director of Research and Development, Dermal Laboratories Limited Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 79, Issue 8-9, 1 August 1967, Pages 491–496, https://doi.org/10.1111/j.1365-2133.1967.tb11537.x Published: 01 August 1967