tbuckley/cabot-search huggingface dataset:
Maturational and Adaptive Modulation of Left Ventricular Torsional Biomechanics
Authors: Yuichi Notomi, Gowdagere Srinath, Takahiro Shiota, Maureen G. Martin-Miklovic, Lisa Beachler, Kelly Howell, Stephanie J. Oryszak, Dimitri G. Deserranno, Alan D. Freed, Neil L. Greenberg, Adel Younoszai, James D. Thomas
Journal: Circulation (2006)

Left ventricular (LV) torsional deformation, based in part on the helical myocardial fiber architecture, is an important component of LV systolic and diastolic performance. However, there is no comprehensive study describing its normal development during childhood and adult life.Forty-five normal subjects (25 children and 20 adults; aged 9 days to 49 years; divided into 5 groups: infants, children, adolescents, and young and middle-age adults) underwent assessment of LV torsion and untwisting rate by Doppler tissue imaging. LV torsion increased with age, primarily owing to augmentation in basal clockwise rotation during childhood and apical counterclockwise rotation during adulthood. Although LV torsion and untwisting overall showed age-related increases, when normalized by LV length, they showed higher values in infancy and middle age. The proportion of untwisting during isovolumic relaxation was lowest in infancy, increased during childhood, and leveled off thereafter, whereas peak untwisting performance (peak untwisting velocity normalized by peak LV torsion) showed a decrease during adulthood.We have shown the maturational process of LV torsion in normal subjects. Net LV torsion increases gradually from infancy to adulthood, but the determinants of this were different in the 2 age groups. The smaller LV isovolumic untwisting recoil during infancy and its decline in adulthood may suggest mechanisms for alterations in diastolic function.
Gender differences in oesophageal mucosal injury in a reflux oesophagitis model of rats
Authors: Tomohiro Masaka, Katsunori Iijima, Hiroyuki Endo, Kiyotaka Asanuma, Nobuyuki Ara, Fumitake Ishiyama, Naoki Asano, Tomoyuki Koike, Akira Imatani, Tooru Shimosegawa
Journal: Gut (2012)

<h3>Objective</h3> There is a strong male predominance of oesophageal adenocarcinoma, which might be related to the higher prevalence of precursor lesions such as erosive reflux oesophagitis in men compared with women. This experiment investigated the gender difference in a reflux oesophagitis model of rats and explored the potential role of oestrogen in controlling oesophageal tissue damage. <h3>Design</h3> An acid-reflux oesophagitis model was surgically produced in male and female rats, and ascorbic acid in the diet and sodium nitrite in the drinking water were administered to half of either group to provoke luminal exogenous nitric oxide (NO) as an exacerbating agent. Seven days after the surgery, the oesophagus was excised, and the injury area, myeloperoxidase activity and pro-inflammatory cytokine levels were measured. Furthermore, 17β-oestradiol was administered to ovariectomised female rats or male rats, which then underwent reflux oesophagitis surgery. <h3>Results</h3> While there was no gender difference in oesophageal damage in the baseline model, oesophageal damage was more intensively observed in males than in females in the presence of exogenous NO administration. While oesophageal damage was increased in ovariectomised rats compared with sham ovariectomised, exacerbated oesophageal damage was attenuated by the replacement of 17β-oestradiol. In addition, exacerbated oesophageal damage in male rats was suppressed by 17β-oestradiol. <h3>Conclusion</h3> This is the first study showing the prominent gender difference in the severity of oesophageal tissue damage in a gastro-oesophageal reflux disease-related animal model, highlighting the critical involvement of oestrogen in controlling gastro-oesophageal reflux disease-related oesophageal epithelial injury.
Too much medicine
Authors: F. Godlee
Journal: BMJ (2015)

Overdiagnosis means different things to different people, say S M Carter and colleagues in their exploration of the social and ethical dimensions of too much medicine (doi:10.1136/bmj.h869). Born out of the Preventing Overdiagnosis 2014 conference in Oxford, their article and others in this special collection (thebmj.com/specialties/digital-theme-issue-overdiagnosis) serve to presage the next conference in Washington, DC, in October 2015, for which registration is now open (www.preventingoverdiagnosis.net). There is much to discuss: how should we define overdiagnosis and its ugly siblings overtreatment, medicalisation, and disease mongering; what do we know of their causes; and what evidence based solutions are available, both general and specific? Above all, who …
Epigenetic and experimental modifications in early mammalian development: Part I: Mitochondria: potential roles in embryogenesis and nucleocytoplasmic transfer
Authors: J M Cummins
Journal: Human Reproduction Update (2001)

This review examines current understanding of mammalian mitochondria and mitochondrial DNA in the light of new reproductive technologies. Mitochondria are central to ageing, apoptosis, metabolism and many diseases. They are controlled by a dual genome system, with cooperation between endogenous mitochondrial genes and mitochondrial genes translocated to the nucleus over the course of evolution. This translocation has been accompanied by extreme compression of the mitochondrial genome, with little tolerance for mutations or heteroplasmy (multiple genomes). The highly compact mitochondrial genome appears to be maintained by a stringent numerical bottleneck in embryogenesis and oogenesis, followed by clonal expansion from a highly selected subset of precursor molecules. The dual nature of control between nucleus and cytoplasm sets up potential conflicts, which are normally resolved by natural selection. Such potentially opposing interests and mechanisms are probably partly to blame for the poor rates of success in cloning animals by nuclear transfer. The ability to construct cell systems and animal embryos with novel combinations and permutations of nuclear and cytoplasmic genes will provide powerful tools for examining these fundamental biological questions. Clinically, attempts to 'rescue' abnormal human oocytes or embryos by cytoplasmic transfer risk complex and unpredictable outcomes emerging from disharmonious nuclear–cytoplasmic interactions.
Maternal smoking during pregnancy induces airway remodelling in mice offspring
Authors: M. J. Blacquiere, W. Timens, B. N. Melgert, M. Geerlings, D. S. Postma, M. N. Hylkema
Journal: European Respiratory Journal (2009)

Children from smoking mothers have an increased risk of developing asthma for reasons largely unknown. The effects of maternal smoking during pregnancy on remodelling, allergic airway inflammation and hyperresponsiveness in offspring were investigated in an experimental asthma model. Mice were exposed to fresh air or cigarette smoke from 3 weeks prior to conception until birth. Offspring were exposed to house dust mite (HDM) or PBS intranasally four times per week from week 5 to week 10 after birth onwards. Maternal smoking increased airway smooth muscle layer, collagen III deposition and HDM-induced goblet cell numbers in offspring. It additionally increased methacholine responsiveness, which correlated significantly with increased airway smooth muscle layer and collagen deposition. Maternal smoking increased HDM-induced numbers of neutrophils and mast cells in lung tissue. No further effects were observed. Smoking during pregnancy induces airway remodelling in mice offspring, which may contribute to increased methacholine responsiveness. This takes place irrespective of allergen exposure but may worsen the outcome of the allergic stimulus, resulting in higher methacholine responsiveness in house dust mite-exposed offspring from smoking mothers when compared to nonsmoking mothers. The results provide a possible mechanism behind the association between maternal smoking and asthma.
Contrasting effects of spontaneous and induced cardiomyopathy on the nucleoproteins of turkey hearts
Authors: C. J LIMAS, S. EINZIG, G. NOREN
Journal: Cardiovascular Research (1982)

The possible involvement of nuclear proteins in the pathogenesis of cardiomyopathy was studied in a spontaneously occurring and a furazolidone-induced model of turkey cardiomyopathy. Both models are characterised by cardiac hypertrophy and dilatation, systemic hypotension and depressed contractility. The protein composition of myocardial nuclei was compared in normal (n = 9) and cardiomyopathic (spontaneous n = 6, furazolidone-induced n = 21) turkeys. Cardiac nuclei from spontaneously myopathic animals had a higher histone content (1.827 +/- 0.058 (mean +/- SD) mg . mg DNA-1 vs 1.688 +/- 0.187 in controls, P less than 0.05) and histone/nonhistone protein ratio (1.122 +/- 0.020 vs 0.882 +/- 0.128 in controls, P less than 0.01). Nuclear protein phosphorylation was lower in spontaneously cardiomyopathic turkeys primarily because of decreased nonhistone protein phosphorylation (5.100 +/- 0.759 pmol 32 P . mg prot-1 .15 min-1 vs 8.456 +/- 0.886 in controls, P less than 0.01). In contrast, furazolidone-induced cardiomyopathy of similar severity to the spontaneously occurring model was not associated with changes in nucleoprotein composition or degree of phosphorylation. These results indicate that development of spontaneous cardiomyopathy in turkeys may be related to the composition and function of nuclear nonhistone proteins. These changes are not secondary to the cardiac hypertrophy/dilatation accompanying the myopathic process.
The Emerging Paradigm of Network Medicine in the Study of Human Disease
Authors: Stephen Y. Chan, Joseph Loscalzo
Journal: Circulation Research (2012)

The molecular pathways that govern human disease consist of molecular circuits that coalesce into complex, overlapping networks. These network pathways are presumably regulated in a coordinated fashion, but such regulation has been difficult to decipher using only reductionistic principles. The emerging paradigm of "network medicine" proposes to utilize insights garnered from network topology (eg, the static position of molecules in relation to their neighbors) as well as network dynamics (eg, the unique flux of information through the network) to understand better the pathogenic behavior of complex molecular interconnections that traditional methods fail to recognize. As methodologies evolve, network medicine has the potential to capture the molecular complexity of human disease while offering computational methods to discern how such complexity controls disease manifestations, prognosis, and therapy. This review introduces the fundamental concepts of network medicine and explores the feasibility and potential impact of network-based methods for predicting individual manifestations of human disease and designing rational therapies. Wherever possible, we emphasize the application of these principles to cardiovascular disease.
Association of IQ Changes and Progressive Brain Changes in Patients With Schizophrenia
Authors: Manabu Kubota, Neeltje E. M. van Haren, Sander V. Haijma, Hugo G. Schnack, Wiepke Cahn, Hilleke E. Hulshoff Pol, René S. Kahn
Journal: JAMA Psychiatry (2015)

<h3>Importance</h3> Although schizophrenia is characterized by impairments in intelligence and the loss of brain volume, the relationship between changes in IQ and brain measures is not clear. <h3>Objective</h3> To investigate the association between IQ and brain measures in patients with schizophrenia across time. <h3>Design, Setting, and Participants</h3> Case-control longitudinal study at the Department of Psychiatry at the University Medical Center Utrecht, Utrecht, the Netherlands, comparing patients with schizophrenia and healthy control participants between September 22, 2004, and April 17, 2008. Magnetic resonance imaging of the brain and IQ scores were obtained at baseline and the 3-year follow-up. Participants included 84 patients with schizophrenia (mean illness duration, 4.35 years) and 116 age-matched healthy control participants. <h3>Main Outcomes and Measures</h3> Associations between changes in IQ and the total brain, cerebral gray matter, cerebral white matter, lateral ventricular, third ventricles, cortical, and subcortical volumes; cortical thickness; and cortical surface area. <h3>Results</h3> Cerebral gray matter volume (<i>P</i> = .006) and cortical volume (<i>P</i> = .03) and thickness (<i>P</i> = .02) decreased more in patients with schizophrenia across time compared with control participants. Patients showed additional loss in cortical volume and thickness of the right supramarginal, posterior superior temporal, left supramarginal, left postcentral, and occipital regions (<i>P</i>values were between &lt;.001 and .03 after clusterwise correction). Although IQ increased similarly in patients with schizophrenia and control participants, changes in IQ were negatively correlated with changes in lateral ventricular volume (<i>P</i> = .05) and positively correlated with changes in cortical volume (<i>P</i> = .007) and thickness (<i>P</i> = .004) only in patients with schizophrenia. Positive correlations between changes in IQ and cortical volume and thickness were found globally and in widespread regions across frontal, temporal, and parietal cortices (<i>P</i>values were between &lt;.001 and .03 after clusterwise correction). These findings were independent of symptom severity at follow-up, cannabis use, and the use of cumulative antipsychotic medications during the 3 years of follow-up. <h3>Conclusions and Relevance</h3> Progressive brain tissue loss in schizophrenia is related to relative cognitive decline during the early course of illness.
Effect of ADAM28 on Carcinoma Cell Metastasis by Cleavage of von Willebrand Factor
Authors: Satsuki Mochizuki, Kenji Soejima, Masayuki Shimoda, Hitoshi Abe, Aya Sasaki, Hirotaka James Okano, Hideyuki Okano, Yasunori Okada
Journal: JNCI Journal of the National Cancer Institute (2012)

A disintegrin and metalloproteinase 28 (ADAM28) is implicated in tumor growth and metastasis in human breast and non–small cell lung carcinomas. We explored the mechanism of ADAM28-mediated metastasis by searching for new substrates of ADAM28. We used a yeast two-hybrid system to screen the human lung cDNA library for ADAM28-binding proteins and identified von Willebrand factor (VWF) as a potential candidate. Binding was confirmed using yeast two-hybrid and protein binding assays, and ADAM28-mediated cleavage of VWF was analyzed by immunoblotting. Exogenous VWF-induced apoptosis in vitro was examined in human lung carcinoma (PC-9 and Calu-3), breast carcinoma (MDA-MB231 and MCF-7), renal cell carcinoma (Caki-2 and 769P), and hepatocellular carcinoma (HepG2) cells, and expression of ADAM28 was assessed by reverse transcription–polymerase chain reaction and immunoblotting. Effect on lung metastasis of PC-9 and MDA-MB231 cells was assessed by knockdown of ADAM28 expression using short hairpin RNAs (ADAM28-shRNA) and small interfering RNAs (ADAM28-siRNA), and inhibition of activity using neutralizing anti-ADAM28 antibody, in a mouse xenograft model by in vivo imaging (n = 9 mice per group). All statistical tests were two-sided. ADAM28 could bind to and cleave native VWF. Cells with very low ADAM28 expression (MCF-7, 769P, and HepG2) were susceptible to VWF-induced apoptosis, whereas cells with high expression (PC-9, Calu-3, MDA-MB231, and Caki-2) were resistant. Knockdown of ADAM28 expression in PC-9 and MDA-MB231 cells by shRNA showed increased carcinoma cell apoptosis mainly in lung blood vessels and statistically significantly decreased lung metastasis at week 3 after injection (PC-9-control [n = 9 mice] vs PC-9-ADAM28-shRNA [n = 9 mice]: mean count = 198 × 106 vs 37 × 106 photons/s, difference = 161 × 106 photons/s, 95% confidence interval = 134 × 106 to 188 × 106 photons/s, P < .001). Similar inhibition of lung metastasis was observed with ADAM28-siRNA and anti-ADAM28 antibody. ADAM28 cleaves and inactivates proapoptotic VWF in carcinoma cells and enhances lung metastasis probably by promoting carcinoma cell survival within the blood vessels.
Liposomal-encapsulated doxorubicin plus cyclophosphamide as first-line therapy in metastatic breast cancer: a phase II multicentric study
Authors: F. Giotta, V. Lorusso, E. Maiello, G. Filippelli, M.R. Valerio, M. Caruso, F. Verderame, A. Latorre, G. Colucci
Journal: Annals of Oncology (2007)
Regulation of the Renal Circulation during Severe Exercise in Normal Dogs and Dogs with Experimental Heart Failure
Authors: RONALD W. MILLARD, CHARLES B. HIGGINS, DEAN FRANKLIN, STEPHEN F. VATNER
Journal: Circulation Research (1972)

The role of sympathetic nerves and circulating catecholamines in mediating the renal vascular response to severe exercise was examined in normal dogs and dogs with experimental heart failure, using paired normal and denervated kidneys. In normal dogs, mean arterial blood pressure increased gradually from 97 ± 4 to 137 ± 6 mm Hg, renal blood flow remained at control levels, and renal vascular resistance rose from 0.57 ± 0.04 to 0.84 ± 0.15 mm Hg/ml min -1 during peak steady-state exercise. The increase in resistance was similar in the denervated renal bed and persisted after alpha-receptor blockade. Exercise in dogs with heart failure increased mean arterial blood pressure slightly from 103 ± 4 to 111 ± 5 mm Hg. In the innervated kidney, blood flow dropped precipitously from 148 ± 6 to 46 ± 9 ml/min, and renal resistance increased from 0.73 ± 0.08 to 3.35 ± 0.53 mm Hg/ml min -1 . In the denervated kidney, renal blood flow decreased from 174 ± 12 to 120 ± 1 ml/min, and resistance increased from 0.59 ± 0.07 to 0.94 ± 0.09 mm Hg/ml min -1 . After alpha-receptor blockade, the decrease in flow and the increase in resistance to the denervated kidney were further attenuated. Thus, in normal, healthy dogs, the contribution of adrenergic mechanisms to renal vascular regulation appears to be minimal; blood flow remains constant in the presence of elevated pressure, suggesting that autoregulation is responsible for the elevated renal resistance during exercise. In dogs with experimental heart failure, intense renal sympathetic vasoconstriction prevails throughout exercise; the major portion of this response is neurally mediated, with an additional contribution by circulating catecholamines.
Tenofovir disoproxil fumarate rescue therapy following failure of both lamivudine and adefovir dipivoxil in chronic hepatitis B
Authors: S. J. Patterson, J. George, S. I. Strasser, A. U. Lee, W. Sievert, A. J. Nicoll, P. V. Desmond, S. K. Roberts, S. Locarnini, S. Bowden, P. W. Angus
Journal: Gut (2010)

<h3>Objective</h3> To determine the efficacy of tenofovir disoproxil fumarate (TDF) in adults with chronic hepatitis B virus (HBV) infection who had previously failed lamivudine (LAM) and had significant viral replication (HBV DNA &gt;10<sup>5</sup> copies/ml if HBeAg positive, &gt;10<sup>4</sup> copies/ml if HBeAg negative) despite at least 24 weeks of treatment with adefovir dipivoxil (ADV). <h3>Design</h3> A prospective open-label study of TDF 300 mg daily. Patients receiving combination ADV/LAM prior to baseline were switched to TDF/LAM. <h3>Setting</h3> Multiple tertiary referral centres. <h3>Methods</h3> Sixty patients were enrolled. The median age was 48.5 years (range 21–80), 46 (77%) were male and 40 (67%) were HBeAg positive. Thirty-eight patients (63%) were switched from ADV to TDF, the remainder from ADV/LAM to TDF/LAM. At baseline, substitutions conferring resistance to LAM or ADV were present in 20 patients (33%) and 17 patients (28%), respectively. The median baseline viral load was 5.33 log<sub>10</sub> IU/ml (range 2.81–8.04). Patients initially treated with TDF monotherapy with persistent viral replication at or after 24 weeks were switched to TDF/LAM. The main outcome measures were change in HBV viral load from baseline and percentage of patients achieving an undetectable viral load (&lt;15 IU/ml). <h3>Results</h3> Results are reported at 96 weeks of treatment. One patient discontinued TDF at 10 days due to rash. The time-weighted change in viral load from baseline to week 12 was −2.19 log<sub>10</sub> IU/ml overall. The median change in HBV DNA from baseline to weeks 12, 24, 48 and 96 was −2.86, −3.23, −3.75 and −4.03 log<sub>10</sub> IU/ml, respectively. At 48 and 96 weeks, 27/59 (46%) and 38/59 (64%) patients achieved a HBV DNA &lt;15 IU/ml. The response was independent of baseline LAM therapy or mutations conferring ADV resistance. <h3>Conclusions</h3> In heavily pretreated patients with a high rate of genotypic resistance, TDF retains significant activity against HBV although this appears diminished in comparison with studies of naïve patients.
General Circulatory Alterations Induced by Intravenous Infusion of Synthetic Bradykinin in Man
Authors: FLAVIO M. DE FREITAS, EDUARDO Z. FARACO, DECIO F. DE AZEVEDO
Journal: Circulation (1964)

The general hemodynamic effects induced by a continuous intravenous infusion of synthetic bradykinin were studied in ten patients submitted to simultaneous right- and left-heart catheterization. A significant drop in systemic arterial pressure and in total peripheral resistance was observed, coincident with an increase of the cardiac output, heart rate, and stroke volume. There was no consistent change of the pulmonary arterial and left atrial pressures, but the pulmonary vascular resistance decreased significantly.
NC-10 * TRAINING THE BRAIN TO REPAIR ITSELF: AN EXERCISE TRIAL IN PEDIATRIC BRAIN TUMOR SURVIVORS
Authors: D. Mabbott, L. Riggs, J. Piscione, S. Laughlin, T. Cunningham, B. Timmons, K. Courneya, U. Bartels, J. Skocic, F. Liu, N. Scantlebury, E. Bouffet
Journal: Neuro-Oncology (2014)

BACKGROUND: Children treated with life saving cranial radiation for a brain tumor experience long-term cognitive impairments - including intellectual decline, difficulties in attention, slowed speed of thinking, and memory impairment. These deficits are related to white matter damage and hippocampal atrophy. No intervention has demonstrated significant benefit in ameliorating adverse effects. Recent studies show that aerobic exercise promotes endogenous repair mechanisms in the brain and improves cognitive performance. It is not known whether these benefits translate to brain injury in humans, particularly the significant injury observed in children treated for malignant brain tumors. METHODS: We conducted a quasi-randomized crossover trial of exercise training (n = 18) in children treated for brain tumors with cranial radiation. Training consisted of 90-minute group sessions, 3 times a week for 12 weeks. The primary outcome was change in brain structure. White matter (i.e. fractional anisotropy, FA) and hippocampal volume (mm3) were measured by DTI and structural MRI, respectively. The secondary outcome was change in reaction time and accuracy across CANTAB tests of attention, processing speed, and short term memory. Linear mixed modeling was used to evaluate time, training, and carryover effects. RESULTS: Training effects on brain structure and cognitive performance were observed. Training versus no training resulted in increased white matter organization (difference: 0.05, P < 0.001) and total hippocampal volume (difference: 110.04 mm3; P < 0.001) and decreased mean reaction time (difference: -434.82 ms, P < 0.001). Notably, carryover effects of training were observed. At ∼12 weeks after training versus no training, participants continued to exhibit increased white matter organization (difference: 0.07, P < 0.001) and total hippocampal volume (difference: 207.76 mm3; P < 0.001), and a decreased mean reaction time (difference: -1084.74 ms, P < 0.01). There were no significant changes in accuracy. CONCLUSIONS: Aerobic exercise is an effective means of promoting brain repair and cognitive restoration in children treated with cranial radiation for brain tumors.