tbuckley/cabot-search huggingface dataset:
Familial adenomatous polyposis: more evidence for disease diversity and genetic heterogeneity
Authors: R J Scott
Journal: Gut (2001)

Familial adenomatous polyposis (FAP) is characterised by the presence of profuse colonic carpeting of adenomas throughout the entire colon and rectum. The genetic basis of FAP has been shown to be primarily associated with germline mutations in the<i>APC</i> gene. Notwithstanding, several reports have been published indicating that there is genetic heterogeneity in FAP and that the most likely explanation is the existence of another gene. In this report we further delineate the genotype/phenotype correlation in families that harbour germline mutations in the<i>APC</i> gene and identify some previously unreported changes in the <i>APC</i> gene which predispose to an attenuated disease phenotype. From 53 index patients diagnosed with either FAP or attenuated FAP, 27 harboured changes in the <i>APC</i> gene. The remaining 26 patients were further subgrouped according to their colonic phenotype. There were nine patients with a mixed hyperplastic/adenomatous colonic phenotype and there were 17 patients with an adenomatous colonic phenotype. Evaluation of the disease characteristics of these patients and their families is presented which may aid in the identification of new genes associated with colonic polyposis.
Nicotinic antagonists and nerve gas poisoning
Authors: S M White
Journal: Journal of the Royal Society of Medicine (2005)

Whilst commending their article (March 2005 JRSM1), we disagree with Dr Sheridan and his co-workers that use of a non-depolarizing neuromuscular blocker (NDNMB) would ever 'normalize function at the neuromuscular junction' in the case of nerve agent or organophosphate poisoning. In this instance any dose of NDNMBs would effect neuromuscular blockade through nicotinic receptor occupancy, thus augmenting the dual block associated with excessive intrasynaptic acetylcholine.2 In addition, we suggest that shorter-acting drugs such as cisatracurium or vecuronium are preferable to pancuronium and gallamine, since the latter are vagolytic (leading to inadvertent underdosing of antidotal atropine) and less amenable to careful titration in an intensive-care setting.

It would seem more rational to accept that paralysis is inevitable after significant exposure to nerve agents (necessitating ventilation), but to give large doses of NDNMBs anyway, in order to saturate nicotinic receptor binding sites with the idea of possibly preventing acetylcholine mediated receptor damage at the neuromuscular junction. NDNMBs could continue to be given by infusion, until either oxime therapy had achieved significant acetylcholinesterase reactivation, or sufficient acetylcholinesterase had been synthesized de novo. This rationale may help shorten the paralysis that occurs during the 'intermediate phase' of recovery from nerve agent poisoning.

Needless to say, this is an area that requires more research but in which research is very controversial. The development of a novel, short-acting acetylcholine chelator or inactivator might provide a possible antidote in cases of nerve agent or organophosphate poisoning.
Role of sarcoplasmic reticulum in arterial contraction: comparison of ryanodines's effect in a conduit and a muscular artery.
Authors: T Ashida, J Schaeffer, W F Goldman, J B Wade, M P Blaustein
Journal: Circulation Research (1988)

Ryanodine interferes with sarcoplasmic reticulum function in various types of muscle; in vascular smooth muscle, it can inhibit contractions that depend on sarcoplasmic reticulum calcium release, probably by depleting the sarcoplasmic reticulum calcium store. We tested ryanodine and calcium channel blockers (verapamil, diltiazem, and nitrendipine) on small rings of rat thoracic aorta (RA) and bovine tail artery (BTA) to determine the relative contributions of sarcoplasmic reticulum calcium release and gated calcium entry to contractions induced by norepinephrine, caffeine, and 100 mM K depolarization. Ryanodine blocked caffeine contractions in both tissues and attenuated norepinephrine responses (by 52% in RA, 14% in BTA) but minimally altered potassium contractions. Calcium channel blockers almost completely abolished potassium contractions and reduced norepinephrine contractions (by 45% in RA, 82% in BTA) but hardly affected caffeine responses. The blocking effects of ryanodine and calcium channel antagonists on the norepinephrine responses were additive. Ryanodine had no effect on baseline tension in the standard media; however, when calcium extrusion via Na-Ca exchange was inhibited by low external sodium (0-calcium, low-sodium solution), tension increased progressively after introduction of ryanodine. This indicates that the sarcoplasmic reticulum calcium released by ryanodine then accumulated in the cytosol and activated contraction; restoration of external sodium caused prompt relaxation. The smaller effects of caffeine and ryanodine in BTA indicate that sarcoplasmic reticulum plays a less important role in calcium control in this tissue, with gated calcium entry dominating. These functional findings are correlated with electron-microscopic evidence that BTA has about 60% less sarcoplasmic reticulum than does RA. Ryanodine appears to be a useful tool for determining the functional relevance of sarcoplasmic reticulum for contraction in different arterial smooth muscles.
Effectiveness of Antiepileptic Drug Combination Therapy for Partial-Onset Seizures Based on Mechanisms of Action
Authors: Jay M. Margolis, Bong-Chul Chu, Zhixiao J. Wang, Ronda Copher, Jose E. Cavazos
Journal: JAMA Neurology (2014)

To our knowledge, the current study is the first to describe antiepileptic drug (AED) combination therapy patterns according to their mechanism of action (MOA) in a real-world setting and to evaluate the differences in outcomes comparing different-MOA combination therapy with same-MOA combination therapy for patients with partial-onset seizure.To compare treatment persistence and health care use with AED combinations categorized by MOA in patients with partial-onset seizures.Using the Truven Health MarketScan Commercial Claims Database containing 96 million covered lives from July 1, 2004, through March 31, 2011, adults with concomitant use of 2 different AEDs and a recent partial-onset seizure diagnosis were selected. Antiepileptic drugs were categorized by MOA: sodium channel blockers (SC), gamma-aminobutyric acid analogs (G), synaptic vesicle protein 2A binding (SV2), and multiple mechanisms (M). Patients were assigned a combination category based on their concomitant AED use.Treatment persistence was measured from the start of AED combination therapy until the end of the combination. Health care resource use was measured during the combination treatment duration. Multivariate analyses evaluated AED discontinuation risk and health care use according to MOA combinations.Distribution of 8615 selected patients by combination was 3.3% for G+G, 7.5% for G+SV2, 8.6% for G+M, 13.9% for SC+SC, 19.0% for G+SC, 21.5% for SC+M, and 26.3% for SC+SV2. The same-MOA (G+G and SC+SC) combinations had the shortest persistence (mean [SD], 344 [345] days and 513 [530] days, respectively) and greater hazard of discontinuation compared with different-MOA combinations. Patients with different-MOA G combinations had a significantly lower risk for inpatient admission (odds ratio, 0.716; 95% CI, 0.539-0.952; P = .02) compared with G+G combinations. Patients with different-MOA SC combinations had significantly lower risks for emergency department visits (odds ratio, 0.853; 95% CI, 0.742-0.980; P = .03) compared with SC+SC combinations.The findings suggest that AED combinations with different MOAs have greater effectiveness as measured by treatment persistence and lower risks for hospitalization and emergency department visits. Further research is needed to more fully understand the role of the MOA in achieving optimal outcomes.
Altered Heart Rate and Sinoatrial Node Function in Mice Lacking the cAMP Regulator Phosphoinositide 3-Kinase-γ
Authors: Robert A. Rose, M. Golam Kabir, Peter H. Backx
Journal: Circulation Research (2007)

Ablation of the enzyme phosphoinositide 3-kinase (PI3K)gamma (PI3Kgamma(-/-)) in mice increases cardiac contractility by elevating intracellular cAMP and enhancing sarcoplasmic reticulum Ca(2+) handling. Because cAMP is a critical determinant of heart rate, we investigated whether heart rate is altered in mice lacking PI3Kgamma. Heart rate was similar in anesthetized PI3Kgamma(-/-) and wild-type (PI3Kgamma(+/+)) mice. However, IP injection of atropine (1 mg/kg), propranolol (1 mg/kg), or both drugs in combination unmasked elevated heart rates in PI3Kgamma(-/-) mice, suggesting altered sinoatrial node (SAN) function. Indeed, spontaneous action potential frequency was approximately 35% greater in SAN myocytes isolated from PI3Kgamma(-/-) mice compared with PI3Kgamma(+/+) mice. These differences in action potential frequency were abolished by intracellular dialysis with the cAMP/protein kinase A antagonist Rp-cAMP but were unaffected by treatment with ryanodine to inhibit sarcoplasmic reticulum Ca(2+) release. Voltage-clamp experiments demonstrated that elevated action potential frequencies in PI3Kgamma(-/-) SAN myocytes were more strongly associated with cAMP-dependent increases in L-type Ca(2+) current (I(Ca,L)) than elevated hyperpolarization-activated current (I(f)). In contrast, I(Ca,L) was not increased in working atrial myocytes, suggesting distinct subcellular regulation of L-type Ca(2+) channels by PI3Kgamma in the SAN compared with the working myocardium. In summary, PI3Kgamma regulates heart rate by the cAMP-dependent modulation of SAN function. The effects of PI3Kgamma ablation in the SAN are unique from those in the working myocardium.
Koilonychia in Sherpas
Authors: D. Murdoch
Journal: British Journal of Dermatology (1993)

Journal Article Koilonychia in Sherpas Get access D. Murdoch D. Murdoch Kunde Hospital, c/o The Himalayan Trust, P.O. Box 224, Kathmandu, Nepal Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 128, Issue 5, 1 May 1993, Pages 592–593, https://doi.org/10.1111/j.1365-2133.1993.tb00248.x Published: 01 May 1993
Current State of the Art and Science of Patient-Clinician Communication in Progressive Disease: Patients' Need to Know and Need to Feel Known
Authors: Liesbeth M. van Vliet, Andrew S. Epstein
Journal: Journal of Clinical Oncology (2014)

Effective communication rests at the core of medicine, especially when patients are confronted with progressive disease and death. Communication can mitigate the distress of receiving bad news and influence patients’ psychological functioning and adaptation to a new situation. 1-3 Whereas the benefits of good communication might seem clear, the costs of its failure are perhaps even clearer. Especially in progressive disease (which we define as entailing palliative and endof-life care in worsening serious illness) with guarded prognoses and significant psychosocial stressors, the stakes are high in most if not every clinical encounter with patients and families. Communication deficits cause unnecessary distress not only for patients but also their loved ones. 4 It is not surprising that most formal complaints in health care are believed to be related to communication. 5,6 Herein, we therefore tackle the central question that remains: what is good, effective communication in progressive disease and how can it be taught, evaluated, and implemented to improve patient outcomes? In medical consultations, patients experience a double-need: to
Site-specific human papillomavirus infection in adolescent men who have sex with men (HYPER): an observational cohort study
Authors: Huachun Zou, Sepehr N Tabrizi, Andrew E Grulich, Jane S Hocking, Catriona S Bradshaw, Alyssa M Cornall, Andrea Morrow, Garrett Prestage, Matthew G Law, Suzanne M Garland, Marcus Y Chen, Christopher K Fairley
Journal: The Lancet Infectious Diseases (2014)
Cardioversion of persistent atrial fibrillation by a combination of atrial specific and non-specific class III drugs in the goat
Authors: Y BLAAUW, U SCHOTTEN, A VANHUNNIK, H NEUBERGER, M ALLESSIE
Journal: Cardiovascular Research (2007)

Objective In electrically remodeled atria the effect of blockers of the delayed rectifier K+ current IKr on repolarization is reduced, whereas the efficacy of 'early' class III drugs (IKur/Ito/IKach blockers) is enhanced. We evaluated the electrophysiological and antifibrillatory effects of AVE0118, dofetilide, and ibutilide (alone and in combination) on persistent atrial fibrillation (AF) in the goat.
Apoptosis in human endometrium and endometriosis
Authors: T. Harada
Journal: Human Reproduction Update (2004)

Apoptosis plays a critical role in maintaining tissue homeostasis and represents a normal function to eliminate excess or dysfunctional cells. Accumulated evidence suggests that apoptosis helps to maintain cellular homeostasis during the menstrual cycle by eliminating senescent cells from the functional layer of the uterine endometrium during the late secretory and menstrual phase of the cycle. The BCL-2 family and Fas/FasL system have been extensively studied in human endometrium and endometriotic tissues. Eutopic endometrium from women with endometriosis reportedly has some fundamental differences compared with normal endometrium of women without endometriosis. The differences could contribute to the survival of regurgitating endometrial cells into the peritoneal cavity and the development of endometriosis. One mechanism that recently gained a lot of interest is the finding that apoptosis appeared in eutopic and ectopic endometrium of patients with endometriosis. This study is a current review of the literature focused on the physiological role of apoptosis in normal endometrium and the alterations in regulation of apoptosis in eutopic and ectopic endometrium from women with endometriosis. Similarities in characteristics of endometriosis at a molecular level with gynaecological tumours are also discussed. Finally, the role of apoptosis in the treatment of endometriosis is reviewed to link the basic research findings into clinical applications.
Thymic cytotoxic T lymphocytes are primed in vivo to minor histocompatibility antigens.
Authors: P J Fink, M J Bevan, I L Weissman
Journal: The Journal of Experimental Medicine (1984)

Potent cytotoxic T lymphocyte (CTL) activity can be derived from cultures of thymocyte responders and minor H different spleen cell stimulators. As is the case of the spleen cell response previously reported, this cytotoxic activity requires in vivo priming. We performed several experiments designed to determine whether the in vivo priming effect is due to the in situ priming of the thymocyte CTL precursors, to contamination of thymus cell preparations with cells of neighboring lymph nodes, or to the appearance in the thymus of antigen-reactive peripheral T cells. We show by depletion of peripheral cells with antilymphocyte serum and part body irradiation that recent thymic immigrants derived from the bone marrow contribute to the primed thymic response. Thymic CTL were primed in animals in which peripheral T cell responses were completely eliminated by repeated treatment in vivo with monoclonal anti-Thy-1 reagents. Primed, antigen-activated lymph node cells were also demonstrated to contribute to the thymus-derived CTL response. Thus, the minor H-specific thymic CTL response is due both to in situ priming and the immigration of activated peripheral T cells. We discuss the possible significance for models of T cell differentiation of the presence within the thymus of antigen and antigen-reactive mature T cells.
Unusual cystic presentation of pulmonary nodular amyloidosis associated with MALT-type lymphoma
Authors: S. Lantuejoul, N. Moulai, S. Quetant, P. Y. Brichon, C. Brambilla, E. Brambilla, G. R. Ferretti
Journal: European Respiratory Journal (2007)

The case reported herein consists of nodular pulmonary amyloidosis presenting with unusual cystic radiological features which reveal a pulmonary localisation of an extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). The present case is the first to report a radiological presentation of nodular pulmonary amyloidosis in the absence of Sjögren's syndrome. Although transthoracic fine-needle biopsy was helpful for the diagnostic of amyloidosis, final diagnosis of associated MALT-type lymphoma required an open lung biopsy. This emphasises the importance of performing surgical investigations in pulmonary nodular amyloidosis in order to depict the presence of underlying lung tumours or lymphoproliferative disorders.
Forkhead Transcription Factor FOXO3a Is a Negative Regulator of Angiogenic Immediate Early Gene CYR61, Leading to Inhibition of Vascular Smooth Muscle Cell Proliferation and Neointimal Hyperplasia
Authors: Hae-Young Lee, Jae-Woong Chung, Seock-Won Youn, Ju-Young Kim, Kyung-Woo Park, Bon-Kwon Koo, Byung-Hee Oh, Young-Bae Park, Brahim Chaqour, Kenneth Walsh, Hyo-Soo Kim
Journal: Circulation Research (2007)

Cysteine-rich angiogenic protein 61 (CYR61, CCN1) is an immediate early gene expressed in vascular smooth muscle cells (VSMCs) on growth factor stimulation, and its expression has been suggested to be associated with postangioplasty restenosis. The forkhead transcription factors are reported to play various roles in cellular proliferation, apoptosis, and even adaptation to cellular stress. We hypothesized that the forkhead transcription factor FOXO3a may regulate CYR61 expression in VSMCs and investigated the CYR61-modulating effect of FOXO3a in the process of vascular response to vasoactive signals and vascular injury. To evaluate the effect of FOXO3a on CYR61 expression, rat VSMCs were infected with adenoviral vectors expressing constitutively active FOXO3a (Ad-TM-FOXO3a). Constitutively active FOXO3a gene transduction suppressed CYR61 expression. Luciferase assay with the deletion constructs of the forkhead factor binding motif in CYR61 promoter region, which resulted in a significant decrease in luciferase expression compared with the intact construct, and chromatin immunoprecipitation analysis confirmed transcriptional regulation of CYR61 by FOXO3a. Serum and angiotensin II rapidly induced CYR61 expression, which was significantly reduced by Ad-TM-FOXO3a. Reduction of VSMC proliferation and migration associated with FOXO3a activation was significantly reversed by cotransfection of adenoviral vector expressing CYR61, whereas apoptosis induction by FOXO3a was not influenced. In a rat balloon carotid arterial injury model, CYR61 was rapidly induced in VSMCs in the early stage of injury and remained elevated until 14 days, which was suppressed by Ad-TM-FOXO3a transfection. After 14 days, there was a significant reduction in neointima by FOXO3a transduction compared with the control group (0.06+/-0.02 versus 0.20+/-0.07 mm(2), P<0.01). Such reduction of neointimal hyperplasia by Ad-TM-FOXO3a was reversed by CYR61 replenishment. These data suggest that FOXO3a is a negative transcription factor of CYR61 and that suppression of CYR61 is among several mechanisms by which FOXO3a inhibits VSMC proliferation and neointimal hyperplasia.
COMBINED DRUG THERAPY OF CHRONIC SCHIZOPHRENICS
Authors: JESSE F. CASEY, LEO E. HOLLISTER, C. JAMES KLETT, JULIAN J. LASKY, EUGENE M. CAFFEY
Journal: American Journal of Psychiatry (1961)

Five hundred and twenty chronic, withdrawn and apathetic schizophrenic men were selected for 20 weeks of treatment with combined drug therapy. All had been on maintenance doses of chlorpromazine (200-600 mg.) for 2 or more months. Activator drugs were added to chlorpromazine adlibidum in the following maximum daily dosage (or less): dextro-amphetamine, 60 mg.; isocarboxazid and trifluoperazine, 30 mg.; imipramine, 225 mg.; and placebo. Prior to the study and after 4 and 20 weeks of treatment, 462 patients were rated on 17 measures from an interview scale (IMPS) and a ward scale (PRP). Changes after 4 weeks of combined drugs were not impressive. At the end of 20 weeks, every treatment group except dextro-amphetamine improved, including the chlorpromazine-placebo group. None of the drug combinations was superior to chlorpromazine and placebo. Adding dextro-amphetamine increased hostile and paranoid belligerency and thinking disturbance. Only 5% of the patients were dropped from the study because of side effects or complications. Abnormal laboratory tests were also infrequent and evenly distributed among the treatment groups. Trifluoperazine added to chlorpromazine increased the prevalence of extra-pyramidal syndromes, while dextro-amphetamine produced appetite and weight loss. All other treatment groups gained weight, significantly more from adding imipramine and isocarboxazid than from adding trifluoperazine or placebo. Although the present study did not demonstrate substantial benefit from combined drug therapy, the chronicity of the patients and the method of drug administration limit generalization.
Catechins induced acute promyelocytic leukemia cell apoptosis and triggered PML-RARα oncoprotein degradation
Authors: Li Zhang, Qiu-Sheng Chen, Peng-Peng Xu, Ying Qian, Ai-Hua Wang, Dan Xiao, Yan Zhao, Yan Sheng, Xiang-Qin Wen, Wei-Li Zhao
Journal: Journal of Hematology & Oncology (2014)

It has recently been reported that the extracts of green tea polyphenol have cancer preventive effects. In this study, we investigated the effect of the natural composition from green tea leaves Catechins on acute promyelocytic leukemia (APL).In vitro, APL cell lines NB4, retinoic acid-resistant NB4-R1 and NB4-R2 were treated with different concentrations of Catechins. Cell viability and cell apoptosis were analyzed using MTT assay and flow cytometric assay, respectively. Expression of proteins related to apoptosis and PML-RARα oncoprotein were assessed by Western blot. In vivo anti-tumor activity of Catechins was examined in nude mice xenografted with NB4 cells and in situ cell apoptosis was detected by terminal deoxytransferase-catalyzed DNA nick-end labeling assay.Catechins at micromolar concentration levels significantly inhibited APL cell proliferation and induced cell apoptosis, in association with mitochondria damage, ROS production and caspase activation. The anti-apoptotic Bcl-2 family member Bcl-xL was down regulated, with pro-apoptotic member Bax remaining unchanged. Moreover, Catechins induced the degradation of PML-RARα oncoprotein. Catechins-mediated apoptotic effect was also observed in primary APL cells without affecting normal hematopoietic progenitor cells. In the murine xenograft model, Catechins remarkably inhibited tumor growth and induced in situ leukemic cell apoptosis.Catechins might be a potential candidate for APL treatment by activating intrinsic apoptotic pathway and targeting PML-RARα oncoprotein.