tbuckley/cabot-search huggingface dataset:
Inflammation and ankylosis: still an enigmatic relationship in spondyloarthritis
Authors: Rik J U Lories, Maxime Dougados
Journal: Annals of the Rheumatic Diseases (2012)

The introduction of targeted therapies against cytokine tumour necrosis factor (TNF) alpha has dramatically changed the management, prognosis and perspectives of patients with ankylosing spondylitis (AS) and related forms of spondyloarthritis.1 Both the soluble TNF receptor etanercept and the different anti-TNF antibodies are highly successful in reducing the signs and symptoms of disease, thereby improving quality of life, participation in the work force and the overall wellbeing of patients.2 3 Clinical evidence suggests that anti-TNF therapies are more successful and the effect more sustained than in other diseases such as rheumatoid arthritis (RA) and inflammatory bowel disease.4 However, in contrast to what is seen in patients with RA, anti-TNF does not appear to have an impact on the structural progression of disease, a process characterised by ankylosis of the spine and sacroiliac joints in spondyloarthritis patients.5,–,7 This aspect of the disease contrasts with the typical pattern of erosive joint destruction seen in patients with RA and with the associated protective effect of anti-TNF.8

Two hypotheses have been put forw to explain this clinical conundrum. The first hypothesis states that inflammation, including the upregulation of TNF, triggers local damage and subsequently repair leading to new bone formation and ankylosis, thereby establishing a causal coupling between inflammation and this process of ankylosis.9 A decrease in inflammation may be necessary for repair to occur, with TNF acting as a brake on the specific mechanisms involved.10 The second hypothesis states that a common trigger is responsible for both inflammation and new bone formation, but that both phenomena further develop in a largely molecularly independent way.11 The question asked by these hypotheses is critical for the …
Insulin Analogs Versus Human Insulin in the Treatment of Patients With Diabetic Ketoacidosis
Authors: Guillermo E. Umpierrez, Sidney Jones, Dawn Smiley, Patrick Mulligan, Trevor Keyler, Angel Temponi, Crispin Semakula, Denise Umpierrez, Limin Peng, Miguel Cerón, Gonzalo Robalino
Journal: Diabetes Care (2009)

OBJECTIVE To compare the safety and efficacy of insulin analogs and human insulins both during acute intravenous treatment and during the transition to subcutaneous insulin in patients with diabetic ketoacidosis (DKA). RESEARCH DESIGN AND METHODS In a controlled multicenter and open-label trial, we randomly assigned patients with DKA to receive intravenous treatment with regular or glulisine insulin until resolution of DKA. After resolution of ketoacidosis, patients treated with intravenous regular insulin were transitioned to subcutaneous NPH and regular insulin twice daily (n = 34). Patients treated with intravenous glulisine insulin were transitioned to subcutaneous glargine once daily and glulisine before meals (n = 34). RESULTS There were no differences in the mean duration of treatment or in the amount of insulin infusion until resolution of DKA between intravenous treatment with regular and glulisine insulin. After transition to subcutaneous insulin, there were no differences in mean daily blood glucose levels, but patients treated with NPH and regular insulin had a higher rate of hypoglycemia (blood glucose &amp;lt;70 mg/dl). Fourteen patients (41%) treated with NPH and regular insulin had 26 episodes of hypoglycemia and 5 patients (15%) in the glargine and glulisine group had 8 episodes of hypoglycemia (P = 0.03). CONCLUSIONS Regular and glulisine insulin are equally effective during the acute treatment of DKA. A transition to subcutaneous glargine and glulisine after resolution of DKA resulted in similar glycemic control but in a lower rate of hypoglycemia than with NPH and regular insulin. Thus, a basal bolus regimen with glargine and glulisine is safer and should be preferred over NPH and regular insulin after the resolution of DKA.
Quantitative ascending aortic Doppler blood velocity in normal human subjects
Authors: B. LEVY, R. C TARGETT, A. BARDOU, M. B McILROY
Journal: Cardiovascular Research (1985)

We have developed digital, Apple II microcomputer-based methods for the numerical analysis of pulsed, range-gated, ultrasonic Doppler blood velocity signals. These methods were then used to analyse Doppler data recorded every 5 ms from the ascending aorta via the suprasternal notch in normal subjects ranging in age from 3 to 62 years. Normal values for peak velocity, the integral of velocity over the time of systole, and the rate of change of velocity in early ejection are reported. It was found that, after an initial step increase, the velocity of blood flow in early ejection increased in a linear manner in more than two thirds of the individual beats analysed. The time for which the linear acceleration in the aorta was constant (circa 50 ms) was unrelated to the age or size of the subject.
Navigating in a volumetric world: Metric encoding in the vertical axis of space
Authors: Theresa Burt de Perera, Robert Holbrook, Victoria Davis, Alex Kacelnik, Tim Guilford
Journal: Behavioral and Brain Sciences (2013)

Abstract Animals navigate through three-dimensional environments, but we argue that the way they encode three-dimensional spatial information is shaped by how they use the vertical component of space. We agree with Jeffery et al. that the representation of three-dimensional space in vertebrates is probably bicoded (with separation of the plane of locomotion and its orthogonal axis), but we believe that their suggestion that the vertical axis is stored “contextually” (that is, not containing distance or direction metrics usable for novel computations) is unlikely, and as yet unsupported. We describe potential experimental protocols that could clarify these differences in opinion empirically.
Cytoplasmic remodeling of erythrocyte raft lipids during infection by the human malaria parasite Plasmodium falciparum
Authors: Sean C. Murphy, Sebastian Fernandez-Pol, Paul H. Chung, S. N. Prasanna Murthy, Stephen B. Milne, Marcela Salomao, H. Alex Brown, Jon W. Lomasney, Narla Mohandas, Kasturi Haldar
Journal: Blood (2007)
Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome?
Authors: D.H. Abbott, D.K. Barnett, C.M. Bruns, D.A. Dumesic
Journal: Human Reproduction Update (2005)

The aetiology of polycystic ovary syndrome (PCOS) remains unknown. This familial syndrome is prevalent among reproductive-aged women and its inheritance indicates a dominant regulatory gene with incomplete penetrance. However, promising candidate genes have proven unreliable as markers for the PCOS phenotype. This lack of genetic linkage may represent both extreme heterogeneity of PCOS and difficulty in establishing a universally accepted PCOS diagnosis. Nevertheless, hyperandrogenism is one of the most consistently expressed PCOS traits. Animal models that mimic fetal androgen excess may thus provide unique insight into the origins of the PCOS syndrome. Many female mammals exposed to androgen excess in utero or during early post-natal life typically show masculinized and defeminized behaviour, ovulatory dysfunction and virilized genitalia, although behavioural and ovulatory dysfunction can coexist without virilized genitalia based upon the timing of androgen excess. One animal model shows particular relevance to PCOS: the prenatally androgenized female rhesus monkey. Females exposed to androgen excess early in gestation exhibit hyperandrogenism, oligomenorrhoea and enlarged, polyfollicular ovaries, in addition to LH hypersecretion, impaired embryo development, insulin resistance accompanying abdominal obesity, impaired insulin response to glucose and hyperlipidaemia. Female monkeys exposed to androgen excess late in gestation mimic these programmed changes, except for LH and insulin secretion defects. In utero androgen excess may thus variably perturb multiple organ system programming and thereby provide a single, fetal origin for a heterogeneous adult syndrome.
Heat waves and dehydration in the elderly
Authors: M. G M O. Rikkert, R. J F Melis, J. A H R Claassen
Journal: BMJ (2009)

Recognising the early warning signs can save lives

The heat wave of 2003 caused an excess mortality of 150% across all age groups, with the largest increase (160-200%) in older people.1 Excess mortality was high across the whole of western Europe (>50 000 deaths) but highest in big cities such as Paris (1854 deaths).1 The death rate was particularly high in cities that were unaccustomed to high temperatures, and cities with warmer climates, such as those in southern France, were spared. This death toll was not followed by a subsequent decline in death rate, which can occur when serious environmental stress causes premature mortality in the frailest people.

No universally accepted definition of a heat wave exists. An alarm signal should be given for frail older people when the outdoor temperature exceeds 90°F (32°C) for three days or more, which is the most universally accepted definition of a heat wave. Meteorologists predict that global warming will dramatically increase the number of such periods.

The main causes …
Autoantibodies against C1q: view on association between systemic lupus erythematosus disease manifestation and C1q autoantibodies
Authors: D Monova
Journal: Annals of the Rheumatic Diseases (2002)

Blockade of tumour necrosis factor alpha (TNFα) using infliximab, a chimeric monoclonal antibody against TNFα, is an effective treatment in rheumatoid arthritis and Crohn's disease. 1 2 Sifikakis reported success using infliximab in sight threatening Behçet's disease. 3 A preliminary study has also reported clinical improvements in the primary systemic vasculitis, Wegener's granulomatosis, with the soluble TNFα receptor etanercept. 4 The benefit of lenercept, a soluble p55 TNFα receptor fusion protein, on digital vasculitis in rheumatoid arthritis has also been reported. 5 We report the compassionate treatment of six patients with refractory vasculitis using infliximab.Diagnoses were Wegener's granulomatosis in three and microscopic polyangiitis in three.Three patients were positive for proteinase-3 antineutrophil cytoplasmic antibodies (PR3-ANCA) and one for myeloperoxidase (MPO)-ANCA.Four were female, with a mean age of 58 years (range 23-77) and mean disease duration of 3.5 years.All had had at least three clinical relapses and had received prolonged treatment with corticosteroids and at least four immunosuppressive drugs.At the time of infliximab treatment the eyes were affected in four patients and the lung in three; in addition, five had profound constitutional symptoms.The mean prednisolone dose was 17 mg.Three intravenous doses of infliximab 200 mg were given at monthly intervals for three months.One patient complained of fatigue, myalgia, and blurred vision 24 hours after the first infusion, which did not recur on rechallenge.Infliximab was otherwise well tolerated.Five patients had remission of their disease, four within two weeks of treatment.This allowed steroid withdrawal in three and reduction by more than 50% in two.Disease activity assessed by the Birmingham Vasculitis Activity Scores (BVAS) improved from a mean of 6.3 to 0.8 at three months (fig 1). 6 One patient receiving continued infliximab for six months relapsed when the treatment interval was extended to two months.Mean falls in erythrocyte sedimentation rate and C reactive protein were 17 mm/1st h and 13 mg/l, respectively.The ANCA status was unchanged.Anti-TNFα treatment heralds a new wave of specifically targeted biological interventions of potential value in the treatment of vasculitis.It offers the hope of improved therapeutic efficacy over current agents and the possibility of reducing exposure to steroids and immunosuppressive drugs.Further studies are warranted to confirm these observations and explore the role of infliximab as a component of initial protocols.. . . . . .
Characterization of the Breakpoints of a Polymorphic Inversion Complex Detects Strict and Broad Breakpoint Reuse at the Molecular Level
Authors: Eva Puerma, Dorcas J. Orengo, David Salguero, Montserrat Papaceit, Carmen Segarra, Montserrat Aguadé
Journal: Molecular Biology and Evolution (2014)

Inversions are an integral part of structural variation within species, and they play a leading role in genome reorganization across species. Work at both the cytological and genome sequence levels has revealed heterogeneity in the distribution of inversion breakpoints, with some regions being recurrently used. Breakpoint reuse at the molecular level has mostly been assessed for fixed inversions through genome sequence comparison, and therefore rather broadly. Here, we have identified and sequenced the breakpoints of two polymorphic inversions—E1 and E2 that share a breakpoint—in the extant Est and E1+2 chromosomal arrangements of Drosophila subobscura. The breakpoints are two medium-sized repeated motifs that mediated the inversions by two different mechanisms: E1 via staggered breaks and subsequent repair and E2 via repeat-mediated ectopic recombination. The fine delimitation of the shared breakpoint revealed its strict reuse at the molecular level regardless of which was the intermediate arrangement. The occurrence of other rearrangements in the most proximal and distal extended breakpoint regions reveals the broad reuse of these regions. This differential degree of fragility might be related to their sharing the presence outside the inverted region of snoRNA-encoding genes.
Comparative Trial of Pancrex V Forte and Nutrizym in Treatment of Malabsorption in Cystic Fibrosis
Authors: M. C. Goodchild, E. Sagaro, G. A. Brown, P. M. Cruchley, H. R. Jukes, C. M. Anderson
Journal: BMJ (1974)

A cross-over trial of pancreatic enzyme replacement therapy has been conducted on 12 children with cystic fibrosis using Pancrex V forte and Nutrizym tablets in equivalent dosage. No differences were found in the effectiveness of these products as measured by stool volume, number of bowel actions, faecal fat excretion, and urine urea excretion. Neither product eliminated the steatorrhoea. Though there was no laboratory evidence to support their choice nine patients expressed a preference for Nutrizym at the conclusion of the trial. This preference was based partly on the smaller number of tablets which are required.
Irradiation-Induced Pneumonitis Mediated by the CD95/CD95-Ligand System
Authors: Frank Heinzelmann, Verena Jendrossek, Kirsten Lauber, Kerstin Nowak, Therese Eldh, Ruzica Boras, Rene Handrick, Marco Henkel, Christian Martin, Stefan Uhlig, David Köhler, Holger K. Eltzschig, Manfred Wehrmann, Wilfried Budach, Claus Belka
Journal: JNCI Journal of the National Cancer Institute (2006)

Pneumonitis is a dose-limiting side effect of radiotherapy. However, the underlying mechanisms of irradiation-induced pneumonitis are unclear. Several observations suggest that the CD95/CD95-ligand (CD95L) system is involved in this process. Therefore, we examined the development of pneumonitis in CD95- and CD95L-deficient and wild-type mice after single irradiation with 0 or 12.5 Gy by measuring breathing frequency, pulmonary resistance, and histopathologic changes. Although wild-type mice developed pathognomonic alterations characteristic of pneumonitis (judged by alveolar wall thickness, interstitial edema, and interstitial and peribronchial inflammation) that paralleled increased breathing frequency ratio on days 5-70 (P < .03) with a maximum at day 37 (12.5 Gy, mean ratio = 1.05, 95% confidence interval [CI] = 1.01 to 1.08; P = .004 versus 0 Gy, mean ratio = 0.997, 95% CI = 0.976 to 1.02; P = .05) and pulmonary resistance (day 42, 12.5 Gy, mean = 0.51, 95% CI = 0.44 to 0.58 versus 0 Gy, mean = 0.40, 95% CI = 0.32 to 0.47; P = .03) after irradiation, no such changes were detected in CD95- or CD95L-deficient mice. This report demonstrates for the first time, to our knowledge, that the CD95/CD95L system is important for the development of irradiation-induced pneumonitis.
Long-term Oxygen Treatment in Chronic Obstructive Pulmonary Disease: Recommendations for Future Research
Authors: Thomas L. Croxton, William C. Bailey
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Long-term oxygen treatment (LTOT) prolongs life in patients with chronic obstructive pulmonary disease (COPD) and severe resting hypoxemia. Although this benefit is proven by clinical trials, scientific research has not provided definitive guidance regarding who should receive LTOT and how it should be delivered. Deficiencies in knowledge and in current research activity related to LTOT are especially striking in comparison to the importance of LTOT in the management of COPD and the associated costs. The National Heart, Lung, and Blood Institute, in collaboration with the Centers for Medicare and Medicaid Services, convened a working group to discuss research on LTOT. Participants in this meeting identified specific areas in which further investigation would likely lead to improvements in the care of patients with COPD or reductions in the cost of their care. The group recommended four clinical trials in subjects with COPD: (1) efficacy of ambulatory O(2) supplementation in subjects who experience oxyhemoglobin desaturation during physical activity but are not severely hypoxemic at rest; (2) efficacy of LTOT in subjects with severe COPD and only moderate hypoxemia; (3) efficacy of nocturnal O(2) supplementation in subjects who show episodic desaturation during sleep that is not attributable to obstructive sleep apnea; and (4) effectiveness of an activity-dependent prescription for O(2) flow rate that is based on clinical tests performed at rest, during exercise, and during sleep.
CD4+FoxP3+ regulatory T cells confer infectious tolerance in a TGF-β–dependent manner
Authors: John Andersson, Dat Q. Tran, Marko Pesu, Todd S. Davidson, Heather Ramsey, John J. O'Shea, Ethan M. Shevach
Journal: The Journal of Experimental Medicine (2008)

CD4+FoxP3+ regulatory T (T reg) cells comprise a separate lineage of T cells that are essential for maintaining immunological tolerance to self. The molecular mechanism(s) by which T reg cells mediate their suppressive effects remains poorly understood. One molecule that has been extensively studied in T reg cell suppression is transforming growth factor (TGF)-β, but its importance remains controversial. We found that TGF-β complexed to latency-associated peptide (LAP) is expressed on the cell surface of activated but not resting T reg cells. T reg cell LAP–TGF-β plays an important role in the suppression of the proliferation of activated T cells, but it is not required for the suppression of naive T cell activation. More importantly, T reg cell–derived TGF-β could generate de novo CD4+FoxP3+ T cells in vitro from naive precursors in a cell contact–dependent, antigen-presenting cell–independent and αV integrin–independent manner. The newly induced CD4+FoxP3+ T cells are suppressive both in vitro and in vivo. Transfer of activated antigen-specific T reg cells with naive antigen-specific responder T cells to normal recipients, followed by immunization, also results in induction of FoxP3 expression in the responder cells. T reg cell–mediated generation of functional CD4+FoxP3+ cells via this TGF-β–dependent pathway may represent a major mechanism as to how T reg cells maintain tolerance and expand their suppressive abilities.
Mice Display Sex Differences in Halothane-Induced Polymorphic Ventricular Tachycardia
Authors: Milou-Daniel Drici, Linda Baker, Patricia Plan, Jacques Barhanin, Georges Romey, Guy Salama
Journal: Circulation (2002)

Background — Molecularly engineered mice are extensively used as models of cardiovascular diseases, yet little is known about sex differences in the electrophysiology of mouse hearts. Methods and Results — This study investigated the influence of sex on drug-induced polymorphic ventricular tachycardia (PVT) in Langendorff-perfused male and female mice hearts (n=54) by injecting a bolus of halothane (1.75 mmol/L) in the perfusate while recording ECGs or optical action potentials (APs). There were no statistically significant differences between male and female hearts (n=54) with respect to mean RR (193±5 ms), PR (47±1 ms), QT intervals (101±3 ms), optical AP durations (APD 75 =23.11±4.2 ms), dispersion of refractory periods, and conduction velocities (n=5 male and 5 female). Halothane induced PVTs lasting a mean duration of 90 seconds; in female hearts, 55% of PVTs lasted longer than the median, whereas in male hearts 17% exceeded the mean ( P &lt;0.05). The total duration of PVTs exposed a marked sex difference, 378±144 seconds in female versus 27±10 seconds in male hearts ( P &lt;0.05). In optically mapped male hearts, halothane reduced APD 75 (17.61±1.6 ms) and then elicited VTs (n=6 of 6), but in female hearts, halothane elicited PVTs (n=1 of 6) or arrested the hearts (n=5 of 6). Except for KCNE1, Northern blots (KCNQ1, MERG, Kv1.5, connexins 40 and 43, TREK1, and TASK1) did not detect sex differences. Conclusions — This mouse model reveals sex difference in response to a pharmacological challenge yet does not display sex differences in standard electrophysiological parameters. Differences in KCNE1 may contribute to sex differences uncovered by halothane.
Osteopontin Synthesis and Localization along the Human Nephron
Authors: Anja Verhulst, Veerle P. Persy, An R. Van Rompay, Walter A. Verstrepen, Mark F. Helbert, Marc E. De Broe
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. In normal human and rat kidneys, osteopontin (OPN) is present at the apical surface of cells in the distal nephron. After ischemic or toxic renal damage in rats, OPN is upregulated in distal tubular cells (DTC) and expressed de novo in perinuclear vesicles in proximal tubular cells (PTC). In the first phase of this study, OPN localization in ischemic human biopsies was compared with that in ischemic rat kidneys. In the second phase, cultures of PTC and DTC were used to investigate human renal OPN synthesis, secretion, and localization. OPN localization in human biopsies after renal ischemia was comparable to that in ischemic rat kidneys. Microscopic and flow cytometric detection of immunofluorescent OPN staining in tubular cell cultures demonstrated strong plasma membrane localization in DTC, whereas mainly perinuclear intracellular expression was observed in PTC. Northern blotting and reverse transcription-PCR demonstrated production of a single OPN mRNA in PTC and DTC. Detection of OPN by Western blotting and enzyme-linked immunosorbent assay demonstrated that PTC and DTC synthesized and secreted the same three molecular mass OPN forms, in comparable amounts. Finally, confocal microscopy demonstrated different staining patterns for endocytotic/lysosomal vesicles and perinuclear OPN; however, perinuclear OPN exhibited colocalization with the Golgi apparatus. In conclusion, human renal OPN localization in cell cultures demonstrated differences between PTC and DTC comparable to those observed after renal ischemia in vivo . Therefore, these cell cultures represented an excellent model for the study of human OPN synthesis, secretion, and localization in PTC versus DTC. It is reported for the first time that intracellular OPN is located in the Golgi apparatus of both PTC and DTC and that PTC and DTC are able to produce and secrete the same OPN isoforms, in comparable amounts.