tbuckley/cabot-search huggingface dataset:
Hyperkeratosis in Flegel's Disease
Authors: Veronika Burmeister
Journal: JAMA (1985)

Hyperkeratosis lenticularis perstans was first described by Flegel1in 1958. It may rightly be redefined as an autosomal dominant mucocutaneous syndrome of variable expressivity, characterized by an aberration in the keratinization process.  A 67-year-old woman presented with numerous asymptomatic keratotic lesions, confined to the anterior aspect of the legs and the dorsa of the feet. These skin-colored papules varied in size from 1 to 4 mm in diameter. Other manifestations were palmar pits and mucosal lesions on the tongue. The patient was treated with vitamin A (Aquasol A) and topical tretinoin 0.01% gel (Retin-A), with some response. The lack of patient compliance ruled out the use of isotretinoin (Accutane).  A specimen from a skin biopsy was examined under a light microscope and displayed massive hyperkeratosis and spotty parakeratosis, with the granular layer being absent in most areas except in the relatively normal margin. There was some irregular acanthosis in
Mechanical ineffectiveness of augmented genioglossus activity in OSA during sleep is associated with diminished co-activation of the styloglossus
Authors: Yaniv Dotan, Giora Pillar, Luis Gaitini, Arie Oliven
Journal: European Respiratory Journal (2012)

The pathophysiological cause of OSA is sleep-induced decline in dilator muscle activation. However, dilator muscles activity often increases during obstructive apneas and hypopneas (OAHs), but fails to improve airflow. It has been postulated that neuromuscular activity does not increase sufficiently to overcome the negative pressures that develop during obstructed breathing. The present study evaluate this hypothesis.

Methods: Intramuscular GG-EMG, esophageal pressure (Pes) and airflow were recorded in 7 OSA patients. In 6 of the patients, we recorded also EMG of the tongue retractor styloglossus (SG-EMG). While awake, EMG/Pes was assessed while patients breathed through a variable resistor, to estimate the EMG required to prevent pharyngeal collapse. During sleep, EMG/Pes was evaluated during flow limitation. Pre-arousal peak inspiratory EMG (sleepEMG) was compared to peak EMG at the same Pes during wakefulness (awakeEMG). SleepEMG/awakeEMG (at equal Pes)>1 indicated a level of EMG sufficient to prevent pharyngeal collapse.

Results: Patients had AHI of 51.7±10.5/hr. OAHs triggered increasing negative Pes and increasing GG-EMG. SleepEMG/awakeEMG >1 was observed in all but one patient, with highest (mean of 5 events) ratios of 3.27±1.81. In contrast, SG-EMG maintained tonic activity in 4/6 of the patients during OAHs, and the ratio exceeded 1 in one patient only (0.68±0.58).

Conclusions: In OSA patients, large augmentation of GG-EMG can be observed without improvement in airflow. This mechanical inefficiency is not explained by high inspiratory suction pressures. Co-activation of tongue retractors appears to be reduced during sleep.
Proapoptotic Kinase MST2 Coordinates Signaling Crosstalk between RASSF1A, Raf-1, and Akt
Authors: David Romano, David Matallanas, Gregory Weitsman, Christian Preisinger, Tony Ng, Walter Kolch
Journal: Cancer Research (2010)

Mammalian MST kinases function in stress-induced apoptosis to limit tumor progression. However, there is limited understanding about MST2 control by key regulators of cell division and survival. Raf-1 binds and inhibits MST2 kinase, whereas dissociation from Raf-1 and binding to tumor suppressor protein RASSF1A activates MST2. Akt phosphorylates MST2 in response to mitogens, oncogenic Ras, or depletion of tumor suppressor phosphatase and tensin homologue deleted on chromosome 10. We identified T117 and T384 as Akt phosphorylation sites in MST2. Mutation of these sites inhibited MST2 binding to Raf-1 kinase but enhanced binding to tumor suppressor RASSF1A, accentuating downstream c-Jun NH(2)-terminal kinase and p38 mitogen-activated protein kinase signaling and promoting apoptosis. We determined that MST2 phosphorylation by Akt limits MST2 activity in two ways: first, by blocking its binding to RASSF1A and by promoting its association into the Raf-1 inhibitory complex, and second, by preventing homodimerization of MST2, which is needed for its activation. Dissociation of the Raf-1-MST2 complex promoted mitogenic signaling and coordinately licensed apoptotic risk. Using Ras effector domain mutants, we found that Akt is essential to prevent MST2 activation after mitogenic stimulation. Our findings elucidate how MST2 serves as a hub to integrate biological outputs of the Raf-1 and Akt pathways.
Slowly Progressive, Angiotensin II–Independent Glomerulosclerosis in Human (Pro)renin Receptor–Transgenic Rats
Authors: Yuki Kaneshiro, Atsuhiro Ichihara, Mariyo Sakoda, Tomoko Takemitsu, A.H.M. Nurun Nabi, M. Nasir Uddin, Tsutomu Nakagawa, Akira Nishiyama, Fumiaki Suzuki, Tadashi Inagami, Hiroshi Itoh
Journal: Journal of the American Society of Nephrology (2007)

For defining the pathogenic effects of the (pro)renin receptor–transgenic rat, strains that overexpressed the human receptor were generated. Although transgenic rats were normotensive and euglycemic and had a renal angiotensin II (AngII) level that was comparable to that of wild-type rats, transgenic rats developed proteinuria with aging and significant glomerulosclerosis at 28 wk of age. In kidneys of 28-wk-old transgenic rats, mitogen-activated protein kinases (MAPK) were activated without recognizable tyrosine phosphorylation of the EGF receptor, and expression of TGF-β1 was enhanced. In vivo infusion of the (pro)renin receptor blocker peptide (formerly handle region decoy peptide) significantly inhibited the development of glomerulosclerosis, proteinuria, MAPK activation, and TGF-β1 expression in the kidneys, but the angiotensin-converting enzyme inhibitor did not attenuate these changes despite a significant decrease in the renal AngII level. In addition, recombinant rat prorenin stimulated MAPK activation in the human receptor–expressed cultured cells, but human receptor was unable to evoke the enzyme activity of rat prorenin. Thus, human (pro)renin receptor elicits slowly progressive nephropathy by AngII-independent MAPK activation in rats. This study clearly provided in vivo evidence for the AngII-independent MAPK activation by human (pro)renin receptor and induction of glomerulosclerosis with increased TGF-β1 expression.
Adenosine kinase is a target for the prediction and prevention of epileptogenesis in mice
Authors: Tianfu Li, Gaoying Ren, Theresa Lusardi, Andrew Wilz, Jing Q. Lan, Takuji Iwasato, Shigeyoshi Itohara, Roger P. Simon, Detlev Boison
Journal: Journal of Clinical Investigation (2008)

Astrogliosis is a pathological hallmark of the epileptic brain. The identification of mechanisms that link astrogliosis to neuronal dysfunction in epilepsy may provide new avenues for therapeutic intervention. Here we show that astrocyte-expressed adenosine kinase (ADK), a key negative regulator of the brain inhibitory molecule adenosine, is a potential predictor and modulator of epileptogenesis. In a mouse model of focal epileptogenesis, in which astrogliosis is restricted to the CA3 region of the hippocampus, we demonstrate that upregulation of ADK and spontaneous focal electroencephalographic seizures were both restricted to the affected CA3. Furthermore, spontaneous seizures in CA3 were mimicked in transgenic mice by overexpression of ADK in this brain region, implying that overexpression of ADK without astrogliosis is sufficient to cause seizures. Conversely, after pharmacological induction of an otherwise epileptogenesis-precipitating acute brain injury, transgenic mice with reduced forebrain ADK were resistant to subsequent epileptogenesis. Likewise, ADK-deficient ES cell-derived brain implants suppressed astrogliosis, upregulation of ADK, and spontaneous seizures in WT mice when implanted after the epileptogenesis-precipitating brain injury. Our findings suggest that astrocyte-based ADK provides a critical link between astrogliosis and neuronal dysfunction in epilepsy.
Low Cardiorespiratory Fitness Is Associated With Elevated C-Reactive Protein Levels in Women With Type 2 Diabetes
Authors: Jonathan M. McGavock, Sandra Mandic, Isabelle Vonder Muhll, Richard Z. Lewanczuk, H. Arthur Quinney, Dylan A. Taylor, Robert C. Welsh, Mark Haykowsky
Journal: Diabetes Care (2004)

The purpose of this study was to examine differences in novel markers of cardiovascular disease (CVD) in women with type 2 diabetes stratified according to cardiorespiratory fitness.A total of 28 women (mean age 57 +/- 6 years) with type 2 diabetes who were free from overt CVD were placed into low cardiorespiratory fitness (LCF) or average cardiorespiratory fitness (ACF) groups based on a graded exercise test to exhaustion. A group of eight women without type 2 diabetes were also examined and served as healthy control subjects. The median VO(2peak) value was used as a cutoff for group determination. We assessed both conventional CVD risk factors, including blood pressure, BMI, and lipid profile, as well as novel CVD risk factors, such as left ventricular filling dynamics, arterial stiffness, fasting insulin, and C-reactive protein (CRP).VO(2peak) values were 69 +/- 14 and 91 +/- 24% of predicted values for sedentary age-matched healthy individuals in the LCF and ACF groups, respectively. BMI was significantly greater in the LCF group (P < 0.05); however, no differences were observed in age, lipid profile, or resting hemodynamics. CRP was 3.3-fold higher in the LCF group (6.3 +/- 41. vs. 1.9 +/- 1.7 mg/l, P < 0.05), whereas other novel markers of CVD were not significantly different between the groups. Significant negative relationships were observed between VO(2peak) and both CRP (r = -0.49) and the homeostasis model assessment index (r = -0.48) (P < 0.05).The novel finding of this investigation is that low cardiorespiratory fitness is associated with elevated CRP and reduced fasting glucose control in women with type 2 diabetes.
Use of contingency management incentives to improve completion of hepatitis B vaccination in people undergoing treatment for heroin dependence: a cluster randomised trial
Authors: Tim Weaver, Nicola Metrebian, Jennifer Hellier, Stephen Pilling, Vikki Charles, Nicholas Little, Dilkushi Poovendran, Luke Mitcheson, Frank Ryan, Owen Bowden-Jones, John Dunn, Anthony Glasper, Emily Finch, John Strang
Journal: The Lancet (2014)

Poor adherence to treatment diminishes its individual and public health benefit. Financial incentives, provided on the condition of treatment attendance, could address this problem. Injecting drug users are a high-risk group for hepatitis B virus (HBV) infection and transmission, but adherence to vaccination programmes is poor. We aimed to assess whether contingency management delivered in routine clinical practice increased the completion of HBV vaccination in individuals receiving opioid substitution therapy.In our cluster randomised controlled trial, we enrolled participants at 12 National Health Service drug treatment services in the UK that provided opioid substitution therapy and nurse-led HBV vaccination with a super-accelerated schedule (vaccination days 0, 7, and 21). Clusters were randomly allocated 1:1:1 to provide vaccination without incentive (treatment as usual), with fixed value contingency management (three £10 vouchers), or escalating value contingency management (£5, £10, and £15 vouchers). Both contingency management schedules rewarded on-time attendance at appointments. The primary outcome was completion of clinically appropriate HBV vaccination within 28 days. We also did sensitivity analyses that examined vaccination completion with full adherence to appointment times and within a 3 month window. The trial is registered with Current Controlled Trials, number ISRCTN72794493.Between March 16, 2011, and April 26, 2012, we enrolled 210 eligible participants. Compared with six (9%) of 67 participants treated as usual, 35 (45%) of 78 participants in the fixed value contingency management group met the primary outcome measure (odds ratio 12·1, 95% CI 3·7-39·9; p<0·0001), as did 32 (49%) of 65 participants in the escalating value contingency management group (14·0, 4·2-46·2; p<0·0001). These differences remained significant with sensitivity analyses.Modest financial incentives delivered in routine clinical practice significantly improve adherence to, and completion of, HBV vaccination programmes in patients receiving opioid substitution therapy. Achievement of this improvement in routine clinical practice should now prompt actual implementation. Drug treatment providers should employ contingency management to promote adherence to vaccination programmes. The effectiveness of routine use of contingency management to achieve long-term behaviour change remains unknown.National Institute for Health Research (RP-PG-0707-10149).
Correlation of Duodenal Histology With Tissue Transglutaminase and Endomysial Antibody Levels in Pediatric Celiac Disease
Authors: Matthew R. Donaldson, Sean D. Firth, Holly Wimpee, Kristin M. Leiferman, John J. Zone, Wyatt Horsley, Molly A. O’Gorman, W. Daniel Jackson, Susan L. Neuhausen, Christopher M. Hull, Linda S. Book
Journal: Clinical Gastroenterology and Hepatology (2007)
A9.9 Treatment with BGP-15, a Novel Insulin Sensitiser Attenuates Collagen-Induced Arthritis in DBA/1 Mice
Authors: P Mandl, S Hayer, S Blüml, V Saferding, D Sykoutri, J Smolen, K Redlich
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background and Objectives</h3> BGP-15, a small synthetic hydroxylamine derivative is a member of a new class of insulin-sensitising medications also known as chaperone-inducers. Beside its beneficial effects on glycemic control and insulin sensitivity in patients with Type 2 diabetes, BGP-15 is known to induce heat shock protein Hsp72 and heat shock transcription factor HSF1, which in turn are involved in joint inflammation. Moreover, BGP-15 also inhibits poly-ADP-ribose polymerase (PARP) and the phosphorylation of c-JUN N-terminal kinase via Hsp72 overexpression. Therefore it might also play a role in the regulation of inflammatory joint disease. Our objective was to evaluate the in vivo effects of BGP-15 on collagen-induced arthritis (CIA) in DBA/1 mice. <h3>Materials and Methods</h3> Arthritis was induced by intradermal injection of bovine type II collagen (bCII) and incomplete Freund's adjuvant (CFA) in male DBA/1 mice. BGP-15 was administered either one week prior to the first immunisation (prophylactic experiment, n:14 in both groups) or upon the appearance of symptoms (therapeutic experiment, n:12 in both groups) in drinking water. Arthritis incidence and severity was assessed for 28 days following the second immunisation (boost) with bCII and CFA on day 21. Histological evaluation was carried out on hind paws using Osteomeasure® software. Anticollagen antibodies were measured by enzyme-linked immunosorbent assay. The cellular composition of the draining lymph nodes was measured by flow cytometry. <h3>Results</h3> BGP-15 significantly reduced the incidence of CIA by 28% and also reduced both paw swelling (p ≤ 0.01) and grip strength (p ≤ 0.05) in the prophylactic experiment. In the therapeutic experiment BGP-15 significantly attenuated both paw swelling (p ≤ 0.01) and grip strength (p ≤ 0.05). Histological evaluation of the hind paws demonstrated reduced area of inflammation (p ≤ 0.05), area of erosion (p ≤ 0.01) and number of osteoclasts (p ≤ 0.05) in the BGP-15 treated group when compared to the control group. No significant differences were revealed between anti-collagen antibody levels or in the distribution of T-cells, B-cells, dendritic cells and monocyte/macrophages harvested from draining lymph nodes, suggesting an effect predominantly involving the innate immune system. <h3>Conclusions</h3> Our results demonstrate that the novel chaperone-inducer BGP-15 has a profound prophylactic and therapeutic effect on autoimmune arthritis, likely due to an effect on the effector phase.
Peritraumatic and Persistent Dissociation in the Presumed Etiology of PTSD
Authors: John Briere, Catherine Scott, Frank Weathers
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: Dissociative responses that occur at the time of a trauma (peritraumatic dissociation) have been described as a major risk factor for subsequent posttraumatic stress disorder (PTSD). The current study evaluated peritraumatic dissociation and PTSD from a multivariate perspective, along with a less-investigated phenomenon: trauma-specific dissociation that begins during or after an event and continues until the time of assessment (persistent dissociation). METHOD: In two studies, 52 local community participants and 386 participants from the general population with histories of exposure to at least one traumatic event were assessed for the presence of PTSD and were administered measures of dissociation and peritraumatic distress. RESULTS: In both studies, peritraumatic dissociation, persistent dissociation, peritraumatic distress, and generalized dissociative symptoms were associated with PTSD by univariate analyses. However, multivariate analyses in both studies indicated that PTSD status was no longer related to peritraumatic dissociation once other variables (especially persistent and generalized dissociation) were taken into account. In contrast, persistent dissociation was a strong predictor at univariate and multivariate levels. CONCLUSIONS: Trauma-related persistent dissociation is a substantial predictor of PTSD, whereas peritraumatic dissociation ceases to predict PTSD at the multivariate level. These findings suggest that it is less what happens at the time of a trauma (e.g., disrupted encoding) that predicts PTSD than what occurs thereafter (i.e., persistent avoidance).
FII haemagglutination test for serum antigammaglobulin factors in Still's disease.
Authors: D W Zutshi, B M Ansell, E G Bywaters, W V Epstein, E J Holborow, C A Reading
Journal: Annals of the Rheumatic Diseases (1969)

The nosological status of Still's disease (juvenile chronic polyarthritis) in relation to adult rheumatoid arthritis has been widely debated; one of the major differences is the markedly lower frequency of rheumatoid factor in the former even at low titres.Bywaters, Carter, and Scott (1959) reported that only 13-4 per cent. of 142 patients had a positive Waaler-Rose or differential agglutination test (DAT) of 1: 16 or more on initial testing.Cassidy and Valkenburg (1967), using the human erythrocyte agglutination test and the latex-fixation test, showed 22 per cent. of 110 patients with juvenile rheumatoid arthritis of onset before the age of 15 years to be positive by one or other test.In the largest pub- lished series, Laaksonen (1966) showed that the latex-fixation test was positive in 29 5 per cent. of 363 cases and the Waaler-Rose in 112 per cent. of 384 cases; and, further, that positivity in either test was more common in cases in which the age at onset was over 6 years.an immunofluorescence test for antinuclear factor using calf thyroid sections (Holborow and Johnson, 1967) was performed on the same specimen in 211 cases of Still's disease and 31 cases of probable Still's disease.541
Neutrophil airway inflammation in childhood asthma
Authors: C M McDougall, P J Helms
Journal: Thorax (2006)

A novel and inviting therapeutic target?

Although asthma has its highest prevalence in childhood, it is generally less severe than in adolescents and adults.1 Whether the high population prevalence is because symptoms are more noticed by parents or whether the more physically active lifestyle and natural inquisitiveness of children, particularly young children, unmasks bronchial hyperresponsiveness and related symptoms remains elusive to investigation. Whatever the explanation, the population prevalence of asthma and associated symptoms including wheeze and cough remains high, although with recent evidence of stabilisation or even a decline in those countries (including the UK) at the top of national prevalence “league tables”.1–4

The investigation of underlying mechanisms is challenging in children because of ethical considerations and the limited applicability of invasive procedures such as bronchoscopy, bronchoalveolar lavage (BAL), and bronchial biopsy. In this context, the report by Li et al in the present issue of Thorax 5 using the sputum induction technique raises a number of important issues and points to lines of investigation and management that merit further development.

As pointed out by Li et al ,5 cough is a well recognised and frequent accompaniment of asthma and wheezing illness, although when an isolated and prominent symptom it is a poor predictor of subsequent wheezing illness and asthma.6,7 Cough can have important habit and psychogenic contributions, appears to be viewed as an important and worrying symptom by parents,8 and is poorly responsive to a range of popular and widely available “over the counter” treatments including antihistamines and antitussives,9 as well as inhaled corticosteroids.10 However, in the context of a confirmed diagnosis of asthma, cough is a well established although imprecisely quantifiable feature, unless assessed objectively by recording devices such as that described by Li et al .5 As …
Allergic bronchopulmonary stemphyliosis.
Authors: S R Benatar, B Allan, R P Hewitson, P A Don
Journal: Thorax (1980)

A patient is described in whom a clinical picture resembling allergic bronchopulmonary aspergillosis was found to be caused by hypersensitivity to the fungus Stemphylium lanuginosum. Bronchopulmonary reactions to antigens other than Aspergillus may be more frequent than is currently believed.
FK409, a Spontaneous Nitric Oxide Releaser, Attenuates Allograft Vasculopathy in a Rat Aortic Transplant Model
Authors: Johji Fukada, Stefano Schena, Ivan Tack, Phillip Ruiz, Yoshihiko Kurimoto, Manhui Pang, Abdelouahab Aitouche, Tomio Abe, Liliane J. Striker, Si M. Pham
Journal: Circulation Research (2000)

Abstract —Although systemic administration of NO donors has been shown to attenuate the development of neointimal hyperplasia in the balloon injury model, this strategy has not been tested in a model of allograft vasculopathy. In this study, we investigated the effect of FK409, a spontaneous NO releaser, on the development of allograft vasculopathy, using a rat aortic transplant model. Thoracic aortas from ACI rats were transplanted heterotopically into the abdominal aorta of Wistar-Furth rats. Postoperatively, recipients received FK409 orally every 8 hours from the day of transplantation to the time of euthanization. Morphometric and immunohistochemical analyses were performed on the aortic grafts 8 weeks after transplantation. Control allografts showed severe neointimal hyperplasia, which consists mainly of α-actin–containing vascular smooth muscle cells. The FK409-treated allografts showed a dose-dependent reduction (statistically significant compared with the control) in the neointimal thickness as the dose increased from 1 to 10 mg/kg (thrice per day). However, there was no significant difference in the neointimal thickness between groups treated with 10 and with 20 mg/kg. FK409 treatment (10 mg/kg) caused a significant decrease in DNA synthesis (5-bromo-2-deoxyuridine [BrdU] uptake), an increase in DNA fragmentation (terminal deoxynucleotidyltransferase–mediated uridine nick-end labeling [TUNEL]), and upregulation of Fas expression, in the neointimal vascular smooth muscle cells. These data suggest that FK409 attenuates the allograft vasculopathy in a rat aortic transplant model. ( Circ Res. 2000;87:66-72.)