tbuckley/cabot-search huggingface dataset:
Will worms really cure Crohn's disease?
Authors: G L Radford-Smith
Journal: Gut (2004)

Treatment of Crohn’s disease patients with the intestinal helminth Trichuris suis appears safe and effective in the short term, even with concurrent immunosuppressive therapy

There are a wealth of data that support an immunoregulatory role for helminth infection in animal models and the human host.1–3 Recently, this concept has been utilised therapeutically for the treatment of patients with inflammatory bowel disease (IBD). Specifically, Summers and colleagues4 report the results of their open study of live Trichuris suis ova therapy in 29 patients with Crohn’s disease (CD) in this issue of Gut (see page 87) .4 Treatment with T suis appears safe and effective in the short term, even with concurrent immunosuppressive therapy. Extension of this concept into the “hygiene hypothesis”5 may seem increasingly attractive in terms of an explanation for some epidemiological observations in patients with IBD, in particular the north-south gradient for IBD prevalence in both North America and Europe, and the lack of IBD in developing nations.6–8 However, some of these epidemiological observations should be viewed with caution. Studies that find a north-south gradient are limited to determining incidence rates and do not attempt to tackle the more difficult task of finding epidemiological reasons behind the gradient. In addition, the stringent “rules” that are now being applied to replication of genetic association and linkage studies have not been applied to all epidemiological studies in IBD. Recent data on paediatric IBD and twin studies would support an increasingly important role for environmental factors over genetics. Specifically, paediatric IBD has increased in frequency in the recent past (1990–2001), is becoming increasingly multi-ethnic, and less often familial, and repeat twin studies from Scandinavia using a new (younger) cohort show reduced concordance rates for CD.9–11 Multiple environmental factors, including pathogen exposure, diet, …
Evaluation of epidermal nerve density and opioid receptor levels in psoriatic itch
Authors: Kenichi Taneda, Mitsutoshi Tominaga, Osamu Negi, Suhandy Tengara, Atsuko Kamo, Hideoki Ogawa, Kenji Takamori
Journal: British Journal of Dermatology (2011)

Psoriasis is a complex, multifactorial inflammatory skin disease with genetic and environmental interactions. Patients with psoriasis exhibit erythematous plaques with itch, but the mechanisms of psoriatic itch are poorly understood.This study was performed to investigate epidermal nerve density and opioid receptor levels in psoriatic skin with or without itch.Twenty-four patients with psoriasis aged between 39 and 82 years were included in this study. The number of epidermal nerve fibres, the levels of semaphorin 3A (Sema3A) and the expression patterns of μ- and κ-opioid systems were examined immunohistologically in skin biopsies from psoriatic patients with or without itch and healthy volunteers as controls.The number of epidermal nerve fibres tended to increase in approximately 40% of psoriatic patients with itch compared with healthy controls, while such intraepidermal nerves were not observed in other itchy patients. In comparison with healthy controls, Sema3A levels also tended to decrease in the epidermis of psoriatic patients with itch. However, no relationship was found between nerve density and Sema3A levels in the epidermis of psoriatic patients with itch. The levels of μ-opioid receptor and β-endorphin in the epidermis were the same in healthy controls and psoriatic patients with or without itch. The levels of κ-opioid receptor and dynorphin A were significantly decreased in the epidermis of psoriatic patients with itch compared with healthy controls.Based on Sema3A levels in the epidermis, epidermal opioid systems, rather than hyperinnervation, may be involved in the pathogenesis of psoriatic itch.
MD-2 is required for disulfide HMGB1–dependent TLR4 signaling
Authors: Huan Yang, Haichao Wang, Zhongliang Ju, Ahmed A. Ragab, Peter Lundbäck, Wei Long, Sergio I. Valdes-Ferrer, Mingzhu He, John P. Pribis, Jianhua Li, Ben Lu, Domokos Gero, Csaba Szabo, Daniel J. Antoine, Helena E. Harris, Doug T. Golenbock, Jianmin Meng, Jesse Roth, Sangeeta S. Chavan, Ulf Andersson, Timothy R. Billiar, Kevin J. Tracey, Yousef Al-Abed
Journal: The Journal of Experimental Medicine (2015)

Innate immune receptors for pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) orchestrate inflammatory responses to infection and injury. Secreted by activated immune cells or passively released by damaged cells, HMGB1 is subjected to redox modification that distinctly influences its extracellular functions. Previously, it was unknown how the TLR4 signalosome distinguished between HMGB1 isoforms. Here we demonstrate that the extracellular TLR4 adaptor, myeloid differentiation factor 2 (MD-2), binds specifically to the cytokine-inducing disulfide isoform of HMGB1, to the exclusion of other isoforms. Using MD-2–deficient mice, as well as MD-2 silencing in macrophages, we show a requirement for HMGB1-dependent TLR4 signaling. By screening HMGB1 peptide libraries, we identified a tetramer (FSSE, designated P5779) as a specific MD-2 antagonist preventing MD-2–HMGB1 interaction and TLR4 signaling. P5779 does not interfere with lipopolysaccharide-induced cytokine/chemokine production, thus preserving PAMP-mediated TLR4–MD-2 responses. Furthermore, P5779 can protect mice against hepatic ischemia/reperfusion injury, chemical toxicity, and sepsis. These findings reveal a novel mechanism by which innate systems selectively recognize specific HMGB1 isoforms. The results may direct toward strategies aimed at attenuating DAMP-mediated inflammation while preserving antimicrobial immune responsiveness.
Acquired von willebrand disease in patients with polycythemia rubra vera
Authors: Hiroshi Mohri
Journal: American Journal of Hematology (1987)

Abstract Platelet function and factor VIII complex were evaluated in ten patients with polycythemia rubra vera. Seven patients showed abnormal epinephrine‐induced aggregation. The intracellular concentrations of adenosine diphosphate (ADP) were below normal, and the ratio of adenosine triphosphate (ATP)/ADP was greater than normal. In four of eight cases, there was a decrease in ristocetin cofactor activity and a reduction in the slowly migrating forms of vWF:Ag on crossed immunoelectrophoresis. Defect of large multimers of vWF:Ag was also observed. The ratio of vWF:Ag to ristocetin cofactor was elevated in these patients. Plasma from the patients had no effect on normal plasma except in one case, in which isolated IgG appeared to cause inactivation of ristocetin cofactor. Treatment with 1‐deamino‐8‐arginine vasopressin caused correction of the vWF abnormalities with rapid return of ristocetin cofactor to baseline in some patients. The present study shows that the alterations of multimeric structure of vWF occur in more than 50% of patients with polycythemia rubra vera and are in some part due to the inhibitor specific for vWF.
Anakinra for the management of resistant idiopathic recurrent pericarditis. Initial experience in 10 adult cases: Table 1
Authors: George Lazaros, Panagiotis Vasileiou, Christos Koutsianas, Katerina Antonatou, Christodoulos Stefanadis, Dimitrios Pectasides, Dimitrios Vassilopoulos
Journal: Annals of the Rheumatic Diseases (2014)

Recurrent idiopathic pericarditis is a common, problematic complication of acute pericarditis, occurring in approximately 30% of cases.1 Despite appropriate management with non-steroidal anti-inflammatory drugs (NSAIDs), colchicine and corticosteroids (CS), a number of patients are either resistant to treatment requiring long-term therapy with high doses of CS or intolerant to therapy.2–4 

This disease is currently viewed as an autoinflammatory disease based on its clinical and laboratory features (recurrent episodes of sterile serosal inflammation in the absence of specific autoreactive antibodies or T cells),5–7 and the preliminary results showing favourable response to intereleukin-1 (IL-1) inhibition.8–10 Anakinra, a known IL-1 receptor antagonist, has been successfully used in small series of paediatric patients8 ,9 while we have recently first reported its efficacy and safety in three adult patients.10 In this report, we extend our follow-up on these three patients, and present data on seven more adult patients treated with anakinra. …
InSilico DB genomic datasets hub: an efficient starting point for analyzing genome-wide studies in GenePattern, Integrative Genomics Viewer, and R/Bioconductor
Authors: Alain Coletta, Colin Molter, Robin Duqué, David Steenhoff, Jonatan Taminau, Virginie de Schaetzen, Stijn Meganck, Cosmin Lazar, David Venet, Vincent Detours, Ann Nowé, Hugues Bersini, David Y Weiss Solís
Journal: Genome biology (2012)

Genomics datasets are increasingly useful for gaining biomedical insights, with adoption in the clinic underway. However, multiple hurdles related to data management stand in the way of their efficient large-scale utilization. The solution proposed is a web-based data storage hub. Having clear focus, flexibility and adaptability, InSilico DB seamlessly connects genomics dataset repositories to state-of-the-art and free GUI and command-line data analysis tools. The InSilico DB platform is a powerful collaborative environment, with advanced capabilities for biocuration, dataset sharing, and dataset subsetting and combination. InSilico DB is available from https://insilicodb.org .
The effect of comedication with conventional synthetic disease modifying antirheumatic drugs on TNF inhibitor drug survival in patients with ankylosing spondylitis and undifferentiated spondyloarthritis: results from a nationwide prospective study
Authors: Elisabeth Lie, Lars Erik Kristensen, Helena Forsblad-d'Elia, Tatiana Zverkova-Sandström, Johan Askling, Lennart T Jacobsson
Journal: Annals of the Rheumatic Diseases (2015)

Objective To assess the effect of comedication with conventional synthetic disease modifying antirheumatic drugs (csDMARDs) on retention to tumour necrosis factor inhibitor (TNFi) therapy in patients with ankylosing spondylitis (AS) and undifferentiated spondyloarthritis (uSpA). Methods Data on patients with a clinical diagnosis of AS or uSpA starting treatment with adalimumab, etanercept or infliximab as their first TNFi during 2003–2010 were retrieved from the Swedish national biologics register and linked to national population based registers. Five-year drug survival was analysed by Cox regression with age, sex, baseline csDMARD comedication, TNFi type, prescription year and covariates representing frailty and socioeconomic status. AS and uSpA were analysed separately. Sensitivity analyses included models with csDMARD as a time-dependent covariate and adjustments for additional potential confounders. Results 1365 patients with AS and 1155 patients with uSpA were included, of whom 40.8% versus 50.3% used csDMARD comedication at baseline. In the unadjusted analyses superior drug survival was observed for patients using versus not using csDMARD comedication among patients with AS (p&lt;0.001) but not among patients with uSpA (p=0.175). In the multivariable Cox regression analyses comedication with csDMARD was associated with better retention to TNFi therapy both in AS (HR 0.71, p&lt;0.001) and uSpA (HR 0.82, p=0.020). The results were similar with csDMARD comedication as a time-dependent covariate, and the associations were retained when adjusting for erythrocyte sedimentation rate, C-reactive protein, patient global, swollen joints, uveitis, psoriasis and inflammatory bowel disease. Conclusions In this large register study of patients with AS and uSpA, use of csDMARD comedication was associated with better 5-year retention to the first TNFi.
Control of breathing in obstructive sleep apnoea patients: Role of CPAP therapy
Authors: Antonina Re, Flaminio Mormile, Alessandro Di Marco Berardino, Dina Visca, Bruno Iovene, Salvatore Valente
Journal: European Respiratory Journal (2012)

Aim: Control of breathing during wakefulness in obstructive sleep apnoea (OSA) and the role of CPAP therapy is an ongoing controversy. We studied the ventilatory response of healthy controls and OSA patients before and after at least 1 year of CPAP therapy.

Methods: 17 never treated OSA patients (16 M; 53±13.2yrs; BMI=34.5±8.1; AHI=45±14.7) underwent nocturnal cardiopulmonary monitoring, spirometry and blood gas analysis. Read's rebreathing test was used to evaluate hypercapnic ventilatory response (HVR CO2); hypoxic ventilator response (HVRO2) was studied by both progressive and transient methods, to explore both peripheral oxygen chemoceptors and the central modulation. The relationship between minute ventilation (VE) or mean inspiratory flow (VT/Ti) and PETCO2 or PETO2 was expressed in terms of slope of linear regression for HVRCO2 and of parameter A of hyperbolic relation for HVRO2.

Results: OSA patients showed an increased responsiveness to transient, but not to progressive, hypoxemia, and a reduced response to hypercapnia when compared to controls. Transient HVRO2 showed a significant reduction during CPAP therapy (p<0.01), whereas HVRCO2 increased only slightly. Progressive HVRO2 was not modified by CPAP [Tab 1].

Conclusions: the daytime glomic reactivity to transient hypoxia is increased by repeated nocturnal hypoxic stimuli; CPAP significantly restores the ventilatory stability during sleep.

View this table:

Chemosensitivity in Controls and in OSAS pre e post CPAP
An analysis of the mechanism by which cetiedil inhibits the gardos phenomenon
Authors: Lee R. Berkowitz, Eugene P. Orringer
Journal: American Journal of Hematology (1984)

Abstract Energy depletion in the human erythrocyte causes a rise in intracellular calcium. This in turn accelerates the transmembrane movement of potassium and chloride, resulting in cell dehydration. This process, known as the Gardos phenomenon, is inhibited by cetiedil. The present study examines the mechanism by which cetiedil inhibits the Gardos phenomenon. The ability of cetiedil to retard the initial step in the Gardos phenomenon, a rise in intracellular calcium, was first tested. Cetiedil did not prevent calcium accumulation. Cetiedil's ability to inhibit anion movement was next evaluated, as cetiedil could appear to be blocking K movement when in fact it was preventing the movement of its accompanying anion. No inhibitory effect on anion movement was seen. Since cetiedil prevented neither calcium accumulation nor anion movement, it must inhibit the Gardos phenomenon by preventing the opening of the K‐specific gate in the erythrocyte membrane. The fact that cetiedil's effect on the Gardos phenomenon could not be removed with repeated cell washing indicates that this effect is irreversible.
KIELLAND'S FORCEPS
Authors: J. C. Moir
Journal: BMJ (1954)

<h3>Objective</h3> Administering medication to hospitalised infants and children is a complex process at high risk of error. Failure mode and effect analysis (FMEA) is a proactive tool used to analyse risks, identify failures before they happen and prioritise remedial measures. To examine the hazards associated with the process of drug delivery to children, we performed a proactive risk-assessment analysis. <h3>Design and setting</h3> Five multidisciplinary teams, representing different divisions of the paediatric department at Padua University Hospital, were trained to analyse the drug-delivery process, to identify possible causes of failures and their potential effects, to calculate a risk priority number (RPN) for each failure and plan changes in practices. <h3>Primary outcome</h3> To identify higher-priority potential failure modes as defined by RPNs and planning changes in clinical practice to reduce the risk of patients harm and improve safety in the process of medication use in children. <h3>Results</h3> In all, 37 higher-priority potential failure modes and 71 associated causes and effects were identified. The highest RPNs related (&gt;48) mainly to errors in calculating drug doses and concentrations. Many of these failure modes were found in all the five units, suggesting the presence of common targets for improvement, particularly in enhancing the safety of prescription and preparation of endovenous drugs. The introductions of new activities in the revised process of administering drugs allowed reducing the high-risk failure modes of 60%. <h3>Conclusions</h3> FMEA is an effective proactive risk-assessment tool useful to aid multidisciplinary groups in understanding a process care and identifying errors that may occur, prioritising remedial interventions and possibly enhancing the safety of drug delivery in children.
FoxO1 mediates insulin-dependent regulation of hepatic VLDL production in mice
Authors: Adama Kamagate, Shen Qu, German Perdomo, Dongming Su, Dae Hyun Kim, Sandra Slusher, Marcia Meseck, H. Henry Dong
Journal: Journal of Clinical Investigation (2008)

Excessive production of triglyceride-rich VLDL is attributable to hypertriglyceridemia. VLDL production is facilitated by microsomal triglyceride transfer protein (MTP) in a rate-limiting step that is regulated by insulin. To characterize the underlying mechanism, we studied hepatic MTP regulation by forkhead box O1 (FoxO1), a transcription factor that plays a key role in hepatic insulin signaling. In HepG2 cells, MTP expression was induced by FoxO1 and inhibited by exposure to insulin. This effect correlated with the ability of FoxO1 to bind and stimulate MTP promoter activity. Deletion or mutation of the FoxO1 target site within the MTP promoter disabled FoxO1 binding and resulted in abolition of insulin-dependent regulation of MTP expression. We generated mice that expressed a constitutively active FoxO1 transgene and found that increased FoxO1 activity was associated with enhanced MTP expression, augmented VLDL production, and elevated plasma triglyceride levels. In contrast, RNAi-mediated silencing of hepatic FoxO1 was associated with reduced MTP and VLDL production in adult mice. Furthermore, we found that hepatic FoxO1 abundance and MTP production were increased in mice with abnormal triglyceride metabolism. These data suggest that FoxO1 mediates insulin regulation of MTP production and that augmented MTP levels may be a causative factor for VLDL overproduction and hypertriglyceridemia in diabetes.
The Kidney Is the Principal Organ Mediating Klotho Effects
Authors: Karolina Lindberg, Risul Amin, Orson W. Moe, Ming-Chang Hu, Reinhold G. Erben, Annika Östman Wernerson, Beate Lanske, Hannes Olauson, Tobias E. Larsson
Journal: Journal of the American Society of Nephrology (2014)

Klotho was discovered as an antiaging gene, and α-Klotho (Klotho) is expressed in multiple tissues with a broad set of biologic functions. Membrane-bound Klotho binds fibroblast growth factor 23 (FGF23), but a soluble form of Klotho is also produced by alternative splicing or cleavage of the extracellular domain of the membrane-bound protein. The relative organ-specific contributions to the levels and effects of circulating Klotho remain unknown. We explored these issues by generating a novel mouse strain with Klotho deleted throughout the nephron (Six2-KL(-/-)). Klotho shedding from Six2-KL(-/-) kidney explants was undetectable and the serum Klotho level was reduced by approximately 80% in Six2-KL(-/-) mice compared with wild-type littermates. Six2-KL(-/-) mice exhibited severe growth retardation, kyphosis, and premature death, closely resembling the phenotype of systemic Klotho knockout mice. Notable biochemical changes included hyperphosphatemia, hypercalcemia, hyperaldosteronism, and elevated levels of 1,25-dihydroxyvitamin D and Fgf23, consistent with disrupted renal Fgf23 signaling. Kidney histology demonstrated interstitial fibrosis and nephrocalcinosis in addition to absent dimorphic tubules. A direct comparative analysis between Six2-KL(-/-) and systemic Klotho knockout mice supports extensive, yet indistinguishable, extrarenal organ manifestations. Thus, our data reveal the kidney as the principal contributor of circulating Klotho and Klotho-induced antiaging traits.
Nutritionist Visits, Diabetes Classes, and Hospitalization Rates and Charges
Authors: Jessica M. Robbins, Gail E. Thatcher, David A. Webb, Vivian G. Valdmanis
Journal: Diabetes Care (2008)

OBJECTIVE—We evaluated the association of different types of educational visits for diabetic patients of the eight Philadelphia Health Care Centers (PHCCs) (public safety-net primary care clinics), with hospital admission rates and charges reported to the Pennsylvania Health Care Cost Containment Council. RESEARCH DESIGN AND METHODS—The study population included 18,404 patients who had a PHCC visit with a diabetes diagnosis recorded between 1 March 1993 and 31 December 2001 and had at least 1 month follow-up time. RESULTS—A total of 31,657 hospitalizations were recorded for 7,839 (42.6%) patients in the cohort. After adjustment for demographic variables, baseline comorbid conditions, hospitalizations before the diabetes diagnosis, and number of other primary care visits, having had any type of educational visit was associated with 9.18 (95% CI 5.02–13.33) fewer hospitalizations per 100 person-years and $11,571 ($6,377 to $16,765) less in hospital charges per person. Each nutritionist visit was associated with 4.70 (2.23–7.16) fewer hospitalizations per 100 person-years and a $6,503 ($3,421 to $9,586) reduction in total hospital charges. CONCLUSIONS—Any type of educational visit was associated with lower hospitalization rates and charges. Nutritionist visits were more strongly associated with reduced hospitalizations than diabetes classes. Each nutritionist visit was associated with a substantial reduction in hospital charges, suggesting that providing these services in the primary care setting may be highly cost-effective for the health care system.
HOST-PARASITE RELATIONS IN MOUSE TYPHOID
Authors: G. B. Mackaness, R. V. Blanden, F. M. Collins
Journal: The Journal of Experimental Medicine (1966)

The development of acquired resistance to Salmonella typhimurium has been studied in mice infected intravenously with small numbers of streptomycin-sensitive or streptomycin-resistant organisms. By the 14th day of a primary infection the mouse develops a mechanism capable of destroying completely a super infecting dose of organisms, but is unable to eliminate organisms of the primary infection. The latter are constantly returned to the circulation from necrotic foci at the sites of implantation. Passive transfer of serum from actively infected or vaccinated animals, and immunization with heat-killed organisms, increase the capacity of the host to clear organisms from the blood, but do not interfere to any significant extent with their subsequent multiplication in the tissues. It is concluded that the resistance of actively infected animals depends on a nonhumoral mechanism capable of destroying organisms from endogenous or exogenous sources.
Out of breath: GM-CSFRα mutations disrupt surfactant homeostasis
Authors: Luigi D. Notarangelo, Itai Pessach
Journal: The Journal of Experimental Medicine (2008)

Pulmonary alveolar proteinosis (PAP) is a rare disorder in which surfactant homeostasis in the lung is impaired, causing respiratory distress and, in severe cases, respiratory failure. Most cases of PAP are associated with the formation of autoantibodies against the cytokine granulocyte/macrophage colony-stimulating factor (GM-CSF), which is required for normal surfactant homeostasis and lung function. New studies now identify three patients in whom PAP was caused by mutations in the gene encoding the ligand-binding α chain of the GM-CSF receptor.