tbuckley/cabot-search huggingface dataset:
Histone acetyltransferase-deficient p300 mutants in diffuse large B cell lymphoma have altered transcriptional regulatory activities and are required for optimal cell growth
Authors: Leila Haery, Julián G Lugo-Picó, Ryan A Henry, Andrew J Andrews, Thomas D Gilmore
Journal: Molecular Cancer (2014)

Abstract Background Recent genome-wide studies have shown that approximately 30% of diffuse large B-cell lymphoma (DLBCL) cases harbor mutations in the histone acetyltransferase (HAT) coactivators p300 or CBP. The majority of these mutations reduce or eliminate the catalytic HAT activity. We previously demonstrated that the human DLBCL cell line RC-K8 expresses a C-terminally truncated, HAT-defective p300 protein (p300ΔC-1087), whose expression is essential for cell proliferation. Methods Using results from large-scale DLBCL studies, we have identified and characterized a second C-terminally truncated, HAT-defective p300 mutant, p300ΔC-820, expressed in the SUDHL2 DLBCL cell line. Properties of p300ΔC-820 were characterized in the SUDHL2 DLBCL cell line by Western blotting, co-immunoprecipitation, and shRNA gene knockdown, as well by using cDNA expression vectors for p300ΔC-820 in pull-down assays, transcriptional reporter assays, and immunofluorescence experiments. A mass spectrometry-based method was used to compare the histone acetylation profile of DLBCL cell lines expressing various levels of wild-type p300. Results We show that the SUDHL2 cell line expresses a C-terminally truncated, HAT-defective form of p300 (p300ΔC-820), but no wild-type p300. The p300ΔC-820 protein has a wild-type ability to localize to subnuclear “speckles,” but has a reduced ability to enhance transactivation by transcription factor REL. Knockdown of p300ΔC-820 in SUDHL2 cells reduced their proliferation and soft agar colony-forming ability. In RC-K8 cells, knockdown of p300ΔC-1087 resulted in increased expression of mRNA and protein for REL target genes A20 and IκBα, two genes that have been shown to limit the growth of RC-K8 cells when overexpressed. Among a panel of B-lymphoma cell lines, low-level expression of full-length p300 protein, which is characteristic of the SUDHL2 and RC-K8 cells, was associated with decreased acetylation of histone H3 at lysines 14 and 18. Conclusions The high prevalence of p300 mutations in DLBCL suggests that HAT-deficient p300 activity defines a subtype of DLBCL, which we have investigated using human DLBCL cell lines RC-K8 and SUDHL2. Our results suggest that truncated p300 proteins contribute to DLBCL cell growth by affecting the expression of specific genes, perhaps through a mechanism that involves alterations in global histone acetylation.
A single genetic element in H-2K affects mouse T-cell antiviral function in poxvirus infection.
Authors: U Kees, R V Blanden
Journal: The Journal of Experimental Medicine (1976)

Cell transfer experiments using mice with recombinant H-2 haplotypes were used to map the H-2 regions which must be shared by ectromelia-immune T-cell donors and virus-infected recipients for transfer of virus clearance mechanisms in the spleen. K- or D-region genes were necessary and sufficient; I-region genes were not involved. The remainder of the mouse genome could be varied widely without impairing the efficacy of T-cell antiviral function, provided either a K or a D region was shared in the donor-receipient combination. A mutation in a single genetic element of the K region of the H-2 complex abolished the antiviral effect of immune T-cell transfer in a donor-recipient combination which shared the K end.
Liver transplantation in the management of porphyria
Authors: Ashwani K. Singal, Charles Parker, Christine Bowden, Manish Thapar, Lawrence Liu, Brendan M. McGuire
Journal: Hepatology (2014)

Porphyrias are a group of eight metabolic disorders, each resulting from a mutation that affects an enzyme of the heme biosynthetic pathway. Porphyrias are classified as hepatic or erythropoietic, depending upon the site where the gene defect is predominantly expressed. Clinical phenotypes are classified as follows: (1) acute porphyrias with neurovisceral symptoms: acute intermittent porphyria; delta amino-levulinic acid hydratase deficiency porphyria; hereditary coproporphyria; and variegate porphyria and (2) cutaneous porphyrias with skin blistering and photosensitivity: porphyria cutanea tarda; congenital erythropoietic porphyria; hepatoerythropoietic porphyria and both erythropoietic protoporphyrias: autosomal dominant and X-linked. Liver transplantation (LT) may be needed for recurrent and/or life-threatening acute attack in acute intermittent porphyria or acute liver failure or end-stage chronic liver disease in erythropoietic protoporphyria. LT in acute intermittent porphyria is curative. Erythropoietic protoporphyria patients needing LT should be considered for bone marrow transplantation to achieve cure. Conclusion : This article provides an overview of porphyria with diagnostic approaches and management strategies for specific porphyrias and recommendations for LT with indications, pretransplant evaluation, and posttransplant management. (Hepatology 2014;60:1082–1089)
Identification of Specific Gene Copy Number Changes in Asbestos-Related Lung Cancer
Authors: Penny Nymark, Harriet Wikman, Salla Ruosaari, Jaakko Hollmén, Esa Vanhala, Antti Karjalainen, Sisko Anttila, Sakari Knuutila
Journal: Cancer Research (2006)

Abstract Asbestos is a well-known lung cancer-causing mineral fiber. In vitro and in vivo experiments have shown that asbestos can cause chromosomal damage and aberrations. Lung tumors, in general, have several recurrently amplified and deleted chromosomal regions. To investigate whether a distinct chromosomal aberration profile could be detected in the lung tumors of heavily asbestos-exposed patients, we analyzed the copy number profiles of 14 lung tumors from highly asbestos-exposed patients and 14 matched tumors from nonexposed patients using classic comparative genomic hybridization (CGH). A specific profile could lead to identification of the underlying genes that may act as mediators of tumor formation and progression. In addition, array CGH analyses on cDNA microarrays (13,000 clones) were carried out on 20 of the same patients. Classic CGH showed, on average, more aberrations in asbestos-exposed than in nonexposed patients, and an altered region in chromosome 2 seemed to occur more frequently in the asbestos-exposed patients. Array CGH revealed aberrations in 18 regions that were significantly associated with either of the two groups. The most significant regions were 2p21-p16.3, 5q35.3, 9q33.3-q34.11, 9q34.13-q34.3, 11p15.5, 14q11.2, and 19p13.1-p13.3 (P &amp;lt; 0.005). Furthermore, 11 fragile sites coincided with the 18 asbestos-associated regions (P = 0.08), which may imply preferentially caused DNA damage at these sites. Our findings are the first evidence, indicating that asbestos exposure may produce a specific DNA damage profile. (Cancer Res 2006; 66(11): 5737-43)
Oxidative stress in resuscitation and in ventilation of newborns
Authors: E. Gitto, S. Pellegrino, S. D'Arrigo, I. Barberi, R. J. Reiter
Journal: European Respiratory Journal (2009)

The lungs of newborns are especially prone to oxidative damage induced by both reactive oxygen and reactive nitrogen species. Yet, these infants are often 1) exposed to high oxygen concentrations, 2) have infections or inflammation, 3) have reduced antioxidant defense, and 4) have high free iron levels which enhance toxic radical generation. Oxidative stress has been postulated to be implicated in several newborn conditions with the phrase “oxygen radical diseases of neonatology” having been coined. There is, however, reason to believe that oxidative stress is increased more when resuscitation is performed with pure oxygen compared with ambient air and that the most effective ventilatory strategy is the avoidance of mechanical ventilation with the use of nasopharyngeal continuous positive airway pressure whenever possible. Multiple ventilation strategies have been attempted to reduce injury and improve outcomes in newborn infants. In this review, the authors summarise the scientific evidence concerning oxidative stress as it relates to resuscitation in the delivery room and to the various modalities of ventilation.
How to assess eyes and vision in infants and preschool children
Authors: A. J. Blaikie, G. N. Dutton
Journal: BMJ (2015)

#### The bottom line 

Children for whom concerns exist about eyes or vision need competent assessment and management. For a young child, however, the general clinician in the community may find mastery of the requisite skills daunting. This article gives practical tips to guide eye assessment in infants and preschool children.

Waiting and consultation areas should be welcoming and uncluttered. A feed, a recent sleep, and a short wait enhance comfort, cooperation, and the “window of opportunity.”



Beginning the consultation 

Read any available salient information before seeing the child. Be friendly, calm, and confident and avoid appearing anxious. Smile as the child and parent(s) enter the room. Look to see if eye contact is returned and, if so, from how far away (table 1⇓). Look at what the child looks at and consider its detail to get an idea of what the child is probably seeing.

View this table:

Table 1 
Approximate maximum distances at which eye contact with a young child can be maintained and “rule of thumb” equivalent visual acuities



Take a brief initial open history of the presenting complaint and then seek salient additional information to help in planning the examination (tables 2⇓ and 3⇓). Next, examine the child while he or she is still engaged, using this to guide subsequent diagnostic history taking.

View this table:

Table 2 
Conditions commonly managed in the …
Transepithelial Migration of<i>Toxoplasma gondii</i>Is Linked to Parasite Motility and Virulence
Authors: Antonio Barragan, L. David Sibley
Journal: The Journal of Experimental Medicine (2002)

After oral ingestion, Toxoplasma gondii crosses the intestinal epithelium, disseminates into the deep tissues, and traverses biological barriers such as the placenta and the blood-brain barrier to reach sites where it causes severe pathology. To examine the cellular basis of these processes, migration of T. gondii was studied in vitro using polarized host cell monolayers and extracellular matrix. Transmigration required active parasite motility and the highly virulent type I strains consistently exhibited a superior migratory capacity than the nonvirulent type II and type III strains. Type I strain parasites also demonstrated a greater capacity for transmigration across mouse intestine ex vivo, and directly penetrated into the lamina propria and vascular endothelium. A subpopulation of virulent type I parasites exhibited a long distance migration (LDM) phenotype in vitro, that was not expressed by nonvirulent type II and type III strains. Cloning of parasites expressing the LDM phenotype resulted in substantial increase of migratory capacity in vitro and in vivo. The potential to up-regulate migratory capacity in T. gondii likely plays an important role in establishing new infections and in dissemination upon reactivation of chronic infections.
Clinical Interview Skills and Identification of Emotional Disorders in Primary Care
Authors: Manuel Girón, Purificación Manjón-Arce, Juana Puerto-Barber, Elisa Sánchez-García, Manuel Gómez-Beneyto
Journal: American Journal of Psychiatry (1998)

The aim of this research was to study the relationship between the clinical interview skills of primary care physicians and their psychodiagnostic ability during office visits.Ten doctors took part in the study, and 233 patients were assessed. The patients were seen and diagnosed by their physicians and interviewed afterward by a psychiatrist using the Present State Examination. All the interviews with the primary care physicians were recorded on videotape, and the Physician's Skills Observation Scale was used to analyze 10 interviews per doctor, five psychiatric cases and five nonpsychiatric cases.The physician's active listening (eye contact, posture, and absence of verbal interruptions) and ability to ask questions with psychological content were associated with the ability to identify the patient's emotional problems. This association was shown to be independent of the physician's characteristics (social, academic, attitudinal, and professional), the sociodemographic characteristics of the patients, the time spent in exploration during the office visit, and the severity of the emotional or somatic disorder.The findings of this research highlight the need to train primary care physicians in specific interview skills, in order to improve their ability to identify mental disorders in their practices.
Effects of monophasic and biphasic shocks on action potentials during ventricular fibrillation in dogs.
Authors: X Zhou, P D Wolf, D L Rollins, Y Afework, W M Smith, R E Ideker
Journal: Circulation Research (1993)

This study determined the response of action potentials during ventricular fibrillation (VF) to timed monophasic and biphasic shocks. A floating glass microelectrode was used to record intracellularly from the anterior right ventricle in 10 open-chest dogs. After 10 seconds of electrically induced VF, 5-millisecond monophasic and 2.5/2.5-millisecond biphasic shocks or 16-millisecond monophasic and 8/8-millisecond biphasic shocks were given via mesh electrodes on either side of the microelectrode. Monophasic and biphasic truncated exponential shocks of 5 V/cm were given with coupling intervals timed from the beginning of a VF action potential to the shock ranging from 50 to 70 milliseconds in 5-millisecond increments. Each coupling interval for each waveform was tested during a different VF episode. The interval between successive activations during VF was 86 +/- 15 milliseconds (mean +/- SD). The refractory period during VF was 61 +/- 5 milliseconds for 5-millisecond monophasic shocks and 66 +/- 6 milliseconds for 2.5/2.5-millisecond biphasic shocks (P &lt; .05). At each coupling interval, action potential duration at 50% repolarization (APD50) was significantly prolonged by the shocks compared with the mean preshock APD50 (P &lt; .05). ADP50 duration increased significantly with increases in the coupling interval (P &lt; .05) for both monophasic and biphasic waveforms. For all coupling intervals together, APD50 prolongation as a percent of the mean preshock APD50 was 170 +/- 55%, 192 +/- 45%, 151 +/- 44%, and 175 +/- 45% for 5- and 16-millisecond monophasic and 2.5/2.5- and 8/8-millisecond biphasic waveforms, respectively. This APD50 prolongation was greater for monophasic than biphasic shocks and was greater for longer than shorter waveforms (P &lt; .05). Thus, during VF, (1) the refractory period for 5-V/cm truncated exponential waveforms lasting 5 milliseconds is approximately 75% of the VF activation interval; (2) the refractory period is shorter for monophasic than for comparable biphasic waveforms; (3) both monophasic and biphasic 5-V/cm shock fields cause prolongation of action potential duration; (4) prolongation of action potential duration increases as the coupling interval increases; and (5) prolongation of action potential duration is greater for monophasic shocks and for longer shock waveforms.
Prevalence of Symptomless Urinary Tract Disease in Birmingham Schoolchildren. I--Pyuria and Bacteriuria
Authors: S. R. Meadow, R. H. R. White, N. M. Johnston
Journal: BMJ (1969)

In a pilot project 2,122 schoolchildren were screened for symptomless urinary tract disease by the examination of midstream urine specimens. These were tested for albumin, blood, and glucose with Labstix commercial strips, together with microscopy for abnormal cellular excretion. One case of renal glycosuria was found but none of previously undiagnosed diabetes mellitus. Out of 1,096 boys, 11 (1%) had pyuria—a leucocyte count greater than 10/cu.mm.—but only four showed abnormal counts on retesting. None had urinary tract infection. Out of 1,026 girls, 96 (9·3%) had pyuria initially but 35 were normal on retesting. Of the remaining 61 girls, 59 attended the outpatients department for further investigation, and in 30 vulvitis appeared to be the sole cause. Ten were proved to have significant bacteriuria and six of them showed radiological abnormalities. It is suggested that careful long-term studies are needed to study the economics and the implications of screening on a national scale.
Urinary Incontinence Before and After Bariatric Surgery
Authors: Leslee L. Subak, Wendy C. King, Steven H. Belle, Jia-Yuh Chen, Anita P. Courcoulas, Faith E. Ebel, David R. Flum, Saurabh Khandelwal, John R. Pender, Sheila K. Pierson, Walter J. Pories, Kristine J. Steffen, Gladys W. Strain, Bruce M. Wolfe, Alison J. Huang
Journal: JAMA Internal Medicine (2015)

Among women and men with severe obesity, evidence for improvement in urinary incontinence beyond the first year after bariatric surgery-induced weight loss is lacking.To examine change in urinary incontinence before and after bariatric surgery and to identify factors associated with improvement and remission among women and men in the first 3 years after bariatric surgery.The Longitudinal Assessment of Bariatric Surgery 2 is an observational cohort study at 10 US hospitals in 6 geographically diverse clinical centers. Participants were recruited between February 21, 2005, and February 17, 2009. Adults undergoing first-time bariatric surgical procedures as part of clinical care by participating surgeons between March 14, 2006, and April 24, 2009, were followed up for 3 years (through October 24, 2012).Participants undergoing bariatric surgery completed research assessments before the procedure and annually thereafter.The frequency and type of urinary incontinence episodes in the past 3 months were assessed using a validated questionnaire. Prevalent urinary incontinence was defined as at least weekly urinary incontinence episodes, and remission was defined as change from prevalent urinary incontinence at baseline to less than weekly urinary incontinence episodes at follow-up.Of 2458 participants, 1987 (80.8%) completed baseline and follow-up assessments. At baseline, the median age was 47 years (age range, 18-78 years), the median body mass index was 46 kg/m2 (range, 34-94 kg/m2), and 1565 of 1987 (78.8%) were women. Urinary incontinence was more prevalent among women (49.3%; 95% CI, 46.9%-51.9%) than men (21.8%; 95% CI, 18.2%-26.1%) (P < .001). After a mean 1-year weight loss of 29.5% (95% CI, 29.0%-30.1%) in women and 27.0% (95% CI, 25.9%-28.6%) in men, year 1 urinary incontinence prevalence was significantly lower among women (18.3%; 95% CI, 16.4%-20.4%) and men (9.8%; 95% CI, 7.2%-13.4%) (P < .001 for all). The 3-year prevalence was higher than the 1-year prevalence for both sexes (24.8%; 95% CI, 21.8%-26.5% among women and 12.2%; 95% CI, 9.0%-16.4% among men) but was substantially lower than baseline (P < .001 for all). Weight loss was independently related to urinary incontinence remission (relative risk, 1.08; 95% CI, 1.06-1.10 in women and 1.07; 95% CI, 1.02-1.13 in men) per 5% weight loss, as were younger age and the absence of a severe walking limitation.Among women and men with severe obesity, bariatric surgery was associated with substantially reduced urinary incontinence over 3 years. Improvement in urinary incontinence may be an important benefit of bariatric surgery.
Cardiac Myocyte-Specific Excision of the β1 Integrin Gene Results in Myocardial Fibrosis and Cardiac Failure
Authors: Shaw-Yung Shai, Alice E. Harpf, Christopher J. Babbitt, Maria C. Jordan, Michael C. Fishbein, Ju Chen, Michelle Omura, Tarek A. Leil, K. David Becker, Meisheng Jiang, Desmond J. Smith, Simon R. Cherry, Joseph C. Loftus, Robert S. Ross
Journal: Circulation Research (2002)

Integrins link the extracellular matrix to the cellular cytoskeleton and serve important roles in cell growth, differentiation, migration, and survival. Ablation of β1 integrin in all murine tissues results in peri-implantation embryonic lethality. To investigate the role of β1 integrin in the myocardium, we used Cre-LoxP technology to inactivate the β1 integrin gene exclusively in ventricular cardiac myocytes. Animals with homozygous ventricular myocyte β1 integrin gene excision were born in appropriate numbers and grew into adulthood. These animals had 18% of control levels of β1D integrin protein in the heart and displayed myocardial fibrosis. High-fidelity micromanometer-tipped catheterization of the intact 5-week-old β1 integrin knockout mice showed depressed left ventricular basal and dobutamine-stimulated contractility and relaxation (LV dP/dt max and LV dP/dt min ) as compared with control groups (n=8 to 10 of each, P &lt;0.01). Hemodynamic loading imposed by 7 days of transverse aortic constriction showed that the β1 integrin knockout mice were intolerant of this stress as they had 53% survival versus 88% in controls (n=15 each). By 6 months of age, mice with depressed ventricular expression of β1 integrin developed a dilated cardiomyopathy that was not evident in any control animals and had patchy decrease in glucose metabolism as determined by positron emission tomography. Myocyte membrane integrity as determined via Evan’s blue dye staining was disrupted in the β1 integrin knockout mice. This model provides strong evidence for the importance of β1 integrin in cardiac form and function and indicates that integrins can be linked to development of cardiomyopathies.
How does psoriasis affect quality of life? Assessing an Ingram-regimen outpatient programme and validating the WHOQOL-100
Authors: S.M. Skevington, J. Bradshaw, A. Hepplewhite, K. Dawkes, C.R. Lovell
Journal: British Journal of Dermatology (2005)

Background, objectives and methods This paper reports a longitudinal study of the quality of life (QOL) of outpatients receiving treatment for psoriasis in secondary care that was designed to validate a new QOL measure for use in psoriasis: the WHOQOL‐100. Additional aims were to monitor the changes to the QOL of psoriasis patients (n = 83) following a course of topical treatment—a modified Ingram regimen—and to compare their QOL with healthy people (n = 105). Results General QOL was much improved following treatment; psychological facets of body image and appearance, self‐esteem and negative feelings were particularly responsive to clinical change, in addition to positive feelings and cognitive capacity. Domains on spirituality, independence and physical health also improved. Compared with healthy controls, pretreatment psoriasis patients showed poorer physical, psychological, independence and spiritual QOL. Validity and reliability were investigated and found to be good to excellent. Internal consistency was very good in 23 facets out of 25. Domains and facets were strongly correlated (weaker for spirituality) largely reaffirming the WHOQOL concept. While physical, independence and psychological domains have some components similar to the Short Form‐36, the social and environment domains represent novel conceptual areas for the WHOQOL. Facets about positive and negative feelings were validated by results from the Profile of Mood States. Psoriasis severity was associated with QOL in only six facets out of 25. Conclusions The WHOQOL‐100 is reliable and valid, and hence a new and important measure for assessing quality of life in psoriasis.