tbuckley/cabot-search huggingface dataset:
Abstract 16318: Niacin Dramatically Raises the Endothelial Inflammatory Marker Lp-PLA2: The Reason the AIM-HIGH Trail Failed Despite Improvements in HDL and Triglycerides
Authors: Steven R Gundry, Jean Epstein
Journal: Circulation (2011)

The recent cancellation of the AIM-HIGH Niaspan/Simvastatin trial, despite increased HDL levels and decreased Triglyceride levels, throws into question the entire paradigm of HDL elevation in preve...
Abstract 321: Goal Directed Resuscitation in Post Cardiac Arrest Patient and Differences in Outcomes
Authors: Nishit Vaghasia, Patrick Coppler, Sajid Kadir, Jonathan Janiczek, Monish Sheth, Kunal Joshi, Vishal Patel, Hanumantha Jogu, Pinsky Michael, Dezfulian Cameron
Journal: Circulation (2013)

Background: There is no consensus about the optimal strategy of hemodynamic support after cardiac arrest (CA) though some preclinical work supports higher perfusion pressures. We hypothesized that goal directed resuscitation after ROSC aimed at improving cardiac index (CI) ≥2 lpm/m 2 and achieving mean arterial pressures (MAP) ≥80 mm Hg could improve lactate clearance and potentially clinical outcomes. Methods: We began a quality improvement initiative within all ICUs of a single hospital by designing and educating staff about a hemodynamic resuscitation protocol. Patients on protocol had cardiac index (CI) and stroke volume variability (SVV) calculated using pulse pressure analysis of their arterial waveform (Vigeleo, Edwards Scientific). Patients received volume boluses (SVV≥13%) or inotropes (SVV&lt;13%; CI&lt;2) or vasopressors (SVV&lt;13%; MAP&lt;80) to achieve goals. Lactate levels were checked q2 hour for initial 6h then q6 h for the next 24h. Fluid intake and output were recorded hourly. These were ICU standards. 18 patients managed on the protocol were propensity matched with 18 historical controls from the last year on the basis of initial lactate, MAP, cumulative vasopressor index (CVI) and Pittsburgh Cardiac Arrest Category (PCAC). 6h lactate clearance, mean MAP and CVI, fluid balance and inotrope use were measured as well as survival to hospital discharge. Comparisons were by Mann Whitney U test. Results: Protocol patients were well matched with controls ( Table 1): Protocol patients showed trends towards better lactate clearance and higher MAP, attributable to higher fluid delivery and lower vasopressor and inotrope use. Survival between groups was unchanged (27.8% protocol Vs 22.2% control). Conclusion: Goal directed resuscitation to optimize CI and MAP resulted in more fluid administration achieving higher blood pressures with less inotrope and pressor use. Greater power is needed to conclude clinical benefit but the strategy is promising.
A New Prognostic Model for Response in Myelofibrosis Patients Treated with JAK2 Inhibitors: A Study from Three US Academic Centers
Authors: Menghrajani Kamal, Philip S. Boonstra, Alissa A. Weber, Cecelia Perkins, Krisstina L. Gowin, Huong (Marie) Nguyen, Ruben Mesa, Jason R. Gotlib, Moshe Talpaz
Journal: Blood (2014)
Improving outcomes in depression
Authors: C. Manning
Journal: BMJ (2002)

Editor—An overview by experts in the field reasoning for and recommending the better quality and delivery of care to a substantial population is greatly to be welcomed.1 We need a person centred, whole system approach, with medical management being but a part of the best practice “prescription.” Early intervention and active management work for every other condition known to man and prevent the long term complications of potentially recurrent or chronic ill health, whether it be asthma, diabetes, hypertension, or depression. The cerebral dysfunction associated with depression (which is far more than a mood disorder) produces lost quality of life, disability, comorbidity, and somatisation—all of which cost the health, social, and employers' budgets billions of pounds a year and place a huge burden of work on practitioners of primary healthcare and social care.

The voluntary and private sectors also have a major part to play. However, integrated solutions should not be provided at the expense of reduced participation of the statutory sector, simply to enable government to keep taxation down or avoid responsibility for service provision under the guise of increasing the flexibility for local solutions.

The key educational message must also be that psychological issues themselves generate some 40% of consultations in general practice and should be dealt with as a priority at the beginning, not as a door handle exit strategy at the end. The national service framework for mental health underpins all the others and provides the template for the generic issues and highest common factor “doables” that weave through all of them, from information and communication strategies through to the necessity for attitudinal and behavioural change. Learning how to work more effectively together and moving towards a culture in which, if we are all agreed on something, then only one of us needs to go to the meeting, would contribute enormously to the mental wellbeing of service providers, let alone users.

Introducing depression management into general practitioners' management remit for chronic disease and their remuneration and commissioning system would also help to improve standards of care for this group of patients much more quickly. This must happen under the contractual arrangements of the new primary care trusts, and when it does, as a service user, I will be finally convinced that people are genuinely committed to doing something real, rather than rhetorical, about the care of this now extremely common, and for many, severe and enduring mental illness.
Abstract 144: Good Neurological Survival After Cardiac Arrest with Initial Shockable Rhythm Increased Year by Year but with Unshockable Rhythm Did Not in Japan
Authors: Hiroyuki Hanada, Hiroshi Nonogi, Ken Nagao
Journal: Circulation (2014)

Backgrounds: Early good cardiopulmonary resuscitation (CPR) and early defibrillation are essential for good neurological survival (GNS) in out-of-hospital cardiac arrest (OHCA). Both automated external defibrillator (AED) equipped in public place and CPR educated people in Japan have been increased. We hypothesized that GNS in patients resuscitated from initial shockable rhythm have been increasing in Japan and that GNS from initial unshockable rhythm might not. Methods and Results: From January 2005 through December 2012, we conducted a prospective, population-based, observational study involving the consecutive patients across Japan who had OHCA (n= 925,288). We identified 73,751 witnessed cardiogenic cardiac arrest with the age &gt;18 years old and transported to hospitals within 60 minutes from the witness. Among them, 18,436 cases had the initial shockable rhythm of ventricular fibrillation (VF) or pulsless ventricular tachycardia (VT) and 55,315 cases had the initial unshockable rhythm of pulseless electrical activity (PEA) or asystole (Asys). GNS was defined as cerebral performance category scale 1 or 2 one month after the arrest. Results were shown in the figure. Although the rate of increase in number of OHCA with unshockable arrest over the year was greater than that with shockable arrest, GNS ratio was increasing only in OHCA with shockable arrest. Conclusion: Good neurological survival resuscitated from initial arrest rhythm with VF/VT had been increasing year by year, but that with PEA/Asys was very low and not changed these 8 years in Japan. We need new strategy for those OHCA patients with initial unshockable rhythm.
The aging suppressor klotho interacts with the insulin-like growth factor-1 receptor, inhibits it activation and reduces growth of breast cancer cells.
Authors: Tami Rubinek, Shikha Bose, Smadar Levanon, Hagai Ligumski, Bella Kaufman, H. Phillip Koeffler, Ido Wolf
Journal: Cancer Research (2008)

5171   Activation of the IGF pathway plays an important role in breast cancer pathogenesis. Recent data indicate the aging suppressor klotho as a potent inhibitor of IGF-1 receptor (IGFR) activation. Klotho is a transmembrane protein, which is expressed in the brain and kidney, and also in various endocrine-related tissues. We have shown previously high klotho expression in normal breast, but low expression in breast cancer and noted an association between low klotho expression and adverse tumor characteristics. Moreover, klotho overexpression inhibited growth of breast cancer cells. We aimed to analyze mechanisms associated with klotho-induced growth inhibition and modulation of the IGF pathway. Also, as klotho extracellular domain can be shed and serve as a circulating hormone, we aimed to elucidate its activities in breast cancer.  Klotho effects on proliferation were assessed using MTT and colony assays in MCF-7 and MDA-MB-231 breast cancer cells and in the non-tumorous HEK293 cells. While klotho overexpression reduced breast cancer cells proliferation, it had no effect on HEK293 cells. Moreover, klotho silencing in MCF-7 cells, which express detectable klotho levels, enhanced their proliferation. Klotho effects on the IGF pathway were analyzed in MCF-7 cells. We conducted immunoprecipitation assays and identified, for the first time, direct interaction between klotho and the IGFR. Moreover, localization studies, using GFP-tagged klotho, revealed translocation of klotho from the cytoplasm to the cell membrane following IGF stimulation. Klotho overexpression in breast cancer cells inhibited IGF-induced phosphorylation of the IGFR and its downstream targets, but activated GSK3beta, a negative regulator of the IGF pathway, and increased expression of p53 and of the tumor suppressor gene C/EBPbeta. Klotho silencing using siRNA in MCF-7 cells induced opposite effects. Importantly, klotho overexpression did not inhibit IGF pathway activation in HEK293 cells, thus suggesting cell-type dependent activity.  In order to assess the activity of klotho extracellular soluble form, breast cancer cells were treated with either recombinant soluble klotho or with a conditioned media taken from klotho overexpressing cells. Complete inhibition of IGFR activation was observed following either treatment, and soluble klotho at a concentration of 1 nM was sufficient to induce maximal effect.  These data indicate, for the first time, cell-type specific growth suppression and IGF pathway inhibition by klotho. Two novel aspects of klotho activity were identified: interaction with the IGFR and changes in subcellular localization. Importantly, our data may indicate soluble klotho as a potent inhibitor of the IGF pathway in breast cancer. As soluble klotho is an endogenous hormone, its use as a novel therapeutic model may be feasible and should be further explored.
Results may have been confounded by viral infections and faulty equipment
Authors: G. Bentham, P. Brimblecombe
Journal: BMJ (1996)

Peacetime assault-related injuries amongst soldiers are common. Whilst the majority of incidents of assault do not result in permanent physical incapacity, some may be devastating, ruining careers and lives. Here we describe one such injury. There is no national register of such injuries; they may, therefore, be under-reported.
Abstract 21621: Lipoprotein-Phospholipase A2 is Associated with Abnormal Digital Reactive Hyperemia and Impaired Coronary Flow Reserve in Stable CAD
Authors: Ignatios Ikonomidis, John Lekakis, Vlasis Tritakis, Stavros Tzortzis, Charis Koukoulis, Kostas Kontsas, Nikos Kadoglou, Ioannis Paraskevaidis, Maria Anastasiou-Nana
Journal: Circulation (2010)

Lipoprotein phospholipase A2 (Lp-PLA2) is an emerging inflammatory marker with prognostic value. Reactive hyperemia peripheral arterial tonometry (RH-PAT) is a method to assess peripheral microvasc...
Lesson of the week: Rare presentation of maternal primary hyperparathyroidism
Authors: G C Beattie
Journal: BMJ (2000)

Maternal primary hyperparathyroidism should be excluded when infants present with hypocalcaemic convulsions or tetany 

Primary hyperparathyroidism is a relatively common condition, being the third most common endocrine disorder after diabetes and thyroid disease. It is most often seen in patients in their 50s and 60s,1 but it can occur in juveniles, although rarely, when the diagnosis may be delayed.2 In women of childbearing age, there is an estimated incidence of 8 per 100 000 population per year.3 Pregnant patients with primary hyperparathyroidism may be asymptomatic or have subtle symptoms such as fatigue, thirst, constipation, or transient depression. These are common complaints in the general population and pregnant patients may attribute them to pregnancy. We describe two patients, seen within one year, in whom primary hyperparathyroidism was diagnosed after convulsions in their infants. Large parathyroid adenomas were localised in both patients by using technetium sestamibi scanning, and these were surgically removed.4

### Case 1

A 33 year old multiparous woman with no major medical history delivered a girl weighing 3200 g by spontaneous vertex delivery at 39 weeks' gestation. Her first child had been born three years earlier. The baby was referred to hospital at five days of age with projectile vomiting for 12 hours. A feeding test for pyloric stenosis gave negative results. On the third day of admission the infant had a major convulsion. An infection screen gave negative results.

Routine blood tests …
Abstract 2630: Evidence of Early Heart Mitochondrial Dysfunction after Resuscitation from Cardiac Arrest
Authors: Natalia A Riobo, Fei Han, Tong Da, Lance B Becker
Journal: Circulation (2007)

Background: Reperfusion injury post-resuscitation is associated with metabolic dysfunction and free radicals production. It has been hypothesized that mitochondrial permeability changes induced by calcium overload underlies this uncoupling of respiration from ATP synthesis and initiates cytochrome c-dependent apoptotic cascades. Our goal is to evaluate the intrinsic status of the mitochondrial electron transfer chain, i.e. irreversible modifications, in resuscitated animals independently of transient changes in calcium and permeability. Methods: Female mice were subjected to 8 min cardiac arrest by KCl injection followed by mechanical ventilation and CPR until return of spontaneous circulation (resuscitation rate: 86%, 24 h survival: 40%) under continuous blood pressure and temperature monitoring. Animals were divided in 4 groups: SHAM (instrumented, no cardiac arrest), CA (8 min cardiac arrest), R30 (30 min post-resuscitation), and R60 (60 min post-resuscitation). Heart mitochondria were immediately isolated and physically disrupted to dissipate ionic gradients in the presence of a calcium chelator. Production of hydrogen peroxide (H 2 O 2 ) by Complex I and III was determined fluorometrically with the Amplex Red-HRP system and the activities of Complex I, II, and the Complex I-III and II-III segments by spectrophotometric techniques using appropriate substrates and inhibitors. Cytochrome c content and the COX IV subunit (as a loading control) were analyzed by western blot and densitometry. Results: A 40% increase in H 2 O 2 production by Complex I and III was evident after just 8 min of cardiac arrest (ECA group, p&lt;0.05), which was followed by a progressive reduction in Complex I activity (ECA&gt;R30&gt;R60), resulting in a relative doubling of electron leak. In contrast, Complex II and II-III activities and cytochrome c content remained unaffected at all times evaluated. Conclusions: Using an animal model that closely mimics resuscitation in humans, we have found signs of early mitochondrial dysfunction independently of transient changes in permeability and calcium. These changes are consistent with increased ROS production at expense of impaired oxidative phosphorylation.
Abstract 899: FHL-2 Suppresses VEGF-induced Angiogenesis via Sphingosine Kinase-1
Authors: Hiroki Hayashi, Hironori Nakagami, Yoichi Takami, Hiroshi Koriyama, Masaki Mori, Yasufumi Kaneda
Journal: Circulation (2007)

Sphingosine-1-phosphate (S1P) produced by sphingosine kinase-1 (SK1) is a bioactive sphingolipid as a potent angiogenic or arteriosclerotic mediator, and its modulator can be novel therapeutic targ...
Abstract 19167: Depression is an Independent Predictor of Subclinical Inflammation Onset Among Healthy Individuals: A Cohort Study
Authors: Antonio G Laurinavicius, Fabio G Franco, Raquel D Conceicao, José Antonio M Carvalho, Mauricio Wajngarten, Raul D Santos
Journal: Circulation (2013)

Background: Depression increases the risk of coronary artery disease (CAD) by about 1.5 times among healthy individuals. The mechanisms underlying this association, however, are still unclear. Although traditional cardiovascular risk factors tend to cluster in depressed patients as a consequence of an unhealthy lifestyle, part of the excess risk remains unexplained. Inflammation has been pointed as a possible mechanistic link between depression and CAD. We intended to assess the role of depression as an independent predictor of subclinical inflammation onset in a cohort study. Methods: We studied 4,222 asymptomatic individuals (mean age: 42.1 years; 20.6% female) who underwent two consecutive routine health evaluations between 2007 and 2012. All the participants were submitted to an extensive baseline clinical and laboratory evaluation and completed the Beck Depression Inventory (BDI). A BDI score &gt;10 was adopted to identify individuals with significant depressive symptoms. Subclinical inflammation was characterized by C-Reactive Protein (hs-CRP) levels &gt;3mg/L. Metabolic syndrome was defined according to the ATP-III criteria. We assessed subclinical inflammation incidence at the following evaluation among those with and without baseline depressive symptoms. Results: Baseline prevalence of depression (BDI&gt;10) was 15%. Depressive symptoms were significantly more frequent among women (21.7% vs. 13.3%; OR 1.8 CI 1.49-2.20; p&lt;0,001). Mean follow-up was 21.7 months (SD 9.6). Baseline BDI&gt;10 was associated with a significantly higher incidence of subclinical inflammation at the following evaluation (RR 1.67; CI 1.22-2.29; p=0.002). Even after adjustment for age, gender, smoking status, physical activity, metabolic syndrome, fatty liver and overweight, baseline BDI&gt;10 remained an independent predictor of future subclinical inflammation onset (RR 1.49; CI 1.02-2.16; p=0.037). Conclusion: Depression is an independent predictor of future subclinical inflammation onset among healthy individuals. Since depression-related inflammation is only partially driven by behavioral cofactors such as smoking status and the metabolic syndrome, it can represent a mechanistic link between depression and CAD.
Abstract 905: Influence of high fat diet and APC status on epigenetic regulation of FXR in colon cells
Authors: Ornella I. Selmin, Adam M. Lyon, Changming Fang, Tom C. Doetschman, Patricia A. Thompson, Jesse D. Martinez, Jeffrey Smith, Peter M. Lance, Donato F. Romagnolo
Journal: Cancer Research (2015)

Abstract Bile acids (BAs) not recycled through the enterohepatic system can be modified in the colon into cancer-promoting secondary BAs such as deoxycholic acid (DCA). The farnesoid-X-receptor (FXR) regulates hepatic and intestinal BA homeostasis. However, in intestinal cells carrying defective adenomatous polyposis coli (Apc) gene the expression of FXR is reduced through yet unknown mechanisms. To investigate if Western high-fat diet (HFD) and Apc status influence epigenetic regulation of the Fxr in colonic mucosa. Weaned C57BL/6J male mice were fed a HFD (22% safflower oil = SO) or control low fat diet (LFD; 5% SO) for 6 wks. We examined the effects on CpG pmethylation of Fxr, and expression of FXR, peroxisome-proliferator activated receptor-gamma (PPARγ), and cyclooxygenase-2 (COX-2) mRNA. Also, we studied the influence of APC status on CpG methylation of the Fxr gene, and expression of FXR, ileal bile acid-binding protein (IBABP), small heterodimer partner (SHP), and COX-2 mRNA in normal colonic mucosa and colon tumors from APCMin/+ mice. Mice fed the HFD had reduced (60%) Fxr promoter methylation and increased (2∼3-fold) FXR, COX-2, and PPARγ mRNA levels. Conversely, APC-deficiency was associated with constitutive hypermethylation of the Fxr gene, elevation of COX-2, and reduced (60-90%) baseline FXR, IBABP, and SHP mRNA. In human HCT-116 colon cells, siRNA knock-down of APC reduced (50%) basal FXR mRNA expression, which was further reduced to 80% by DCA. We conclude that APC deficiency leads to constitutive epigenetic silencing of Fxr increasing the risk of inflammation and colon cancer associated with a Western HFD. Note: This abstract was not presented at the meeting. Citation Format: Ornella I. Selmin, Adam M. Lyon, Changming Fang, Tom C. Doetschman, Patricia A. Thompson, Jesse D. Martinez, Jeffrey Smith, Peter M. Lance, Donato F. Romagnolo. Influence of high fat diet and APC status on epigenetic regulation of FXR in colon cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 905. doi:10.1158/1538-7445.AM2015-905