tbuckley/cabot-search huggingface dataset:
Antiplatelet Therapy in Diabetes: Efficacy and Limitations of Current Treatment Strategies and Future Directions
Authors: Dominick J. Angiolillo
Journal: Diabetes Care (2009)

Cardiovascular disease is the leading cause of morbidity and mortality in patients with diabetes (1). The concomitant presence of multiple classical cardiovascular risk factors in diabetic subjects contributes to enhanced atherothrombotic risk (2). However, other risk factors may be important such as abnormal platelet function (3). Platelets, in fact, play a key role in atherogenesis, and its thrombotic complications and measures, which lead to blockade of one or multiple pathways modulating platelet activation and aggregation processes, are pivotal in reducing ischemic risk in diabetic subjects (4). This article reviews currently available antiplatelet agents on ischemic events in diabetic patients, limitations of currently available treatment strategies, and antiplatelet agents currently under clinical development that may potentially overcome these limitations.

### Antiplatelet therapy

There are three different classes of platelet-inhibiting drugs: cyclooxygenase-1 (COX-1) inhibitors (aspirin), ADP P2Y12 receptor antagonists (thienopyridines), and platelet glycoprotein (GP) IIb/IIIa inhibitors, which are mostly used for the prevention and treatment of atherothrombotic disorders (4) (Fig. 1). Aspirin inhibits the COX-1 enzyme and therefore blocks platelet thromboxane A2 synthesis (5). However, patients on aspirin therapy, particularly those at high risk, may continue to have recurrent thrombotic events. GP IIb/IIIa inhibitors are very potent antiplatelet agents, which exert effects through inhibition of the final common pathway that mediates platelet aggregation processes, and have been shown to be effective in preventing thrombotic complications in high-risk patients undergoing percutaneous coronary interventions (PCI) (4). However, these agents are available only for parenteral use and have a short duration of action, which impedes their use for long-term protection. The need for alternative antiplatelet treatment strategies led to the evaluation of effects obtained from a combination of oral antiplatelet agents inhibiting other platelet-activating pathways. Ticlopidine is a first-generation thienopyridine, which irreversibly blocks the platelet ADP P2Y12 receptor (6). Its combination with aspirin is associated …
Hazards of solid waste management: bioethical problems, principles, and priorities
Authors: Margaret N. Maxey
Journal: Environmental Health Perspectives (1978)

The putative hazards of solid waste management cannot be evaluated without placing the problem within a cultural climate of crisis where some persons consider such by-products of "high, hard technology" to have raised unresolved moral and ethical issues. In order to assist scientific and technical efforts to protect public health and safety, a bioethical perspective requires us to examine three controversial aspects of policy-making about public safety. Failure to recognize the qualitative difference between two cognitive activities-risk-measurements (objective, scientific probabilities) and safety-judgments (subjective, shifting value priorities)-has had three unfortunate consequences. Sophisticated methods of risk analysis have been applied in a piecemeal, haphazard, ad hoc fashion within traditional institutions with the false expectation that incremental risk-reducing programs automatically ensure public health and safety. Ethical priorities require, first and foremost, a whole new field of data arranged for comparable risk-analyses. Critics of cost/risk/benefit quantifications attack the absurdity of "putting a price on human life" but have not been confronted with its threefold ethical justification. The widening discrepancy in risk-perceptions and loss of mutual confidence between scientific experts and ordinary citizens has placed a burden of social responsibility on members of the scientific and technical community to engage in more effective public education through the political process, notwithstanding advocates of a nonscientific adversary process. The urgency of effective public education has been demonstrated by the extent to which we have lost our historically balanced judgment about the alleged environmental hazards posed by advanced technology.
Abnormal Hippocampal Functioning and Impaired Spatial Navigation in Depressed Individuals: Evidence From Whole-Head Magnetoencephalography
Authors: Brian R. Cornwell, Giacomo Salvadore, Veronica Colon-Rosario, David R. Latov, Tom Holroyd, Frederick W. Carver, Richard Coppola, Husseini K. Manji, Carlos A. Zarate, Christian Grillon
Journal: American Journal of Psychiatry (2010)

Dysfunction of the hippocampus has long been suspected to be a key component of the pathophysiology of major depressive disorder. Despite evidence of hippocampal structural abnormalities in depressed patients, abnormal hippocampal functioning has not been demonstrated. The authors aimed to link spatial navigation deficits previously documented in depressed patients to abnormal hippocampal functioning using a virtual reality navigation task.Whole-head magnetoencephalography (MEG) recordings were collected while participants (19 patients diagnosed with major depressive disorder and 19 healthy subjects matched by gender and age) navigated a virtual Morris water maze to find a hidden platform; navigation to a visible platform served as a control condition. Behavioral measures were obtained to assess navigation performance. Theta oscillatory activity (4-8 Hz) was mapped across the brain on a voxel-wise basis using a spatial-filtering MEG source analysis technique.Depressed patients performed worse than healthy subjects in navigating to the hidden platform. Robust group differences in theta activity were observed in right medial temporal cortices during navigation, with patients exhibiting less engagement of the anterior hippocampus and parahippocampal cortices relative to comparison subjects. Left posterior hippocampal theta activity was positively correlated with individual performance within each group.Consistent with previous findings, depressed patients showed impaired spatial navigation. Dysfunction of right anterior hippocampus and parahippocampal cortices may underlie this deficit and stem from structural abnormalities commonly found in depressed patients.
Intensive Care Nursery
Authors: Susan Grafeld Long
Journal: JAMA (1999)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Accelerated course of human immunodeficiency virus infection after tuberculosis.
Authors: C Whalen, C R Horsburgh, D Hom, C Lahart, M Simberkoff, J Ellner
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

To determine the effect of active tuberculosis on survival and the incidence of opportunistic infections in HIV-infected patients, we performed a retrospective cohort study at four U.S. medical centers to compare the survival and incidence rate of opportunistic infections in 106 HIV-infected patients with active tuberculosis (cases) with that of 106 HIV-infected patients without tuberculosis (control subjects) but with a similar level of immunosuppression (measured by the absolute CD4+ lymphocyte count) as the cases. Cases and control subjects were similar with regard to age, sex, race, previous opportunistic infection, and use of antiretroviral therapy, but they were more likely than control subjects to have a history of intravenous drug use (49 versus 19%). The mean CD4+ counts were similar for cases and control subjects (154 versus 153 cells/microliters, respectively). The incidence rate of new AIDS-defining opportunistic infections in cases was 4.0 infections per 100 person-months compared with 2.8 infections per 100 person-months in control subjects for an incidence rate ratio (RR) of 1.42 (95% confidence interval: 0.94-2.11). Cases also had a shorter overall survival than did controls subjects (p = 0.001). Active tuberculosis was associated with an increased risk for death (odds ratio = 2.17), even when controlling for age, intravenous drug use, previous opportunistic infection, baseline CD4+ count, and antiretroviral therapy. Although active tuberculosis may be an independent marker of advanced immunosuppression in HIV-infected patients, it may also act as a cofactor to accelerate the clinical course of HIV infection.
Rheumatoid arthritis and Epstein-Barr virus: a case of living with the enemy?
Authors: W OLLIER
Journal: Annals of the Rheumatic Diseases (2000)

The cause of rheumatoid arthritis (RA) still eludes us, though we know from twin studies that both genetic and environmental factors are important contributory components to disease susceptibility1; the latter is estimated to account for about one half of this risk.2 At least one major RA susceptibility gene resides within the major histocompatibility complex (MHC) region. Current dogma is that this is explained by a conserved sequence of amino acids within the third hypervariable region of the DRB1 β chain molecule encoded by a number of alleles. This is usually referred to as being the RA shared epitope hypothesis.3Although DRB1 molecules present peptide fragments to T cell receptors on CD4 positive lymphocytes, the exact mechanism through which the RA shared epitope exerts its effect remains unclear.4 Given that class II molecules such as DRB1 serve an immunoregulatory role, it is not surprising that polymorphisms within these structures will influence variation in immune response in both health and disease states. It is likely that the RA shared epitope conveys disease susceptibility through its interaction with the environment. Characterising such interactions will be fundamental to our understanding of RA aetiopathogenesis.

A specific environmental/infectious trigger(s) for RA has yet to be identified, though there has been no shortage of contenders for this role, including mycoplasmas, parvovirus B19, cytomegalovirus, herpes virus 6, and Epstein-Barr virus (EBV).5-7 The involvement of EBV in RA has been investigated and speculated about for over 15 years. Although definite proof is lacking, an increasing body of circumstantial evidence points at a close relation between the two. This evidence has been added to by the study conducted by Toussirot and colleagues (presented in this issue, p 533). These workers show that patients with RA have decreased T cell precursor frequencies to EBV gp110 …
The burden of tuberculosis drug resistance in Eastern Europe: The Moldavian experience
Authors: Valeriu Crudu, Liliana Domente, Sofia Alexandru, Elena Romancenco, Viorel Soltan, Andrei Mosneaga
Journal: European Respiratory Journal (2012)

Aims: Surveillance the TB drug resistance on the national level and its impact upon public health in the Republic of Moldova;  The objective: to characterize the evolution of tuberculosis drug resistance in Moldova (2001-2011).  Methods. The study was retrospective, being based on the assessment results of M.tuberculosis complex drugs resistance obtained in the reference laboratories from the country.  Results. Prevalence of MDRTB among New TB cases increase from 6.3% in 2001 up to 26.4% in 2011. Trough previously treated patients (relapses, re-treatment after default, re-treatment after failure, chronic) prevalence of MDR TB was detected in 37.7% cases in 2001 and 64.3% cases in 2011. Extensively drug-resistant tuberculosis (XDR-TB) is present in some territories. The rate of XDR TB among the patients with MDR TB is 6.1% (2010). The prevalence of TB-HIV co-infection in country is 5.4%. The prevalence of MDRTB among all TB-HIV is higher such from HIV negative patients (67.8%). Reasons of high level of TB resistance in Moldova: poor in infection control in TB hospitals -exogenous re-infection of TB patients; low compliance of treatment; the lack of a rigid control of TB patients, TB/HIV co-infection.  Conclusions: At the current stage MDR TB is a serious problem for National TB Program, bringing serious public health and economic consequences. It is a very alarming phenomenon, because the success of treatment (with first-line drugs) for this form of TB is less effective than for the susceptible tuberculosis and the accumulation of a greater number of resistant strains in society can lead to the infection of population and to an increase in the number of patients with MDR&XDR TB.
N488I Mutation of the γ2-Subunit Results in Bidirectional Changes in AMP-Activated Protein Kinase Activity
Authors: Liqun Zou, Mei Shen, Michael Arad, Huamei He, Bo Løfgren, Joanne S. Ingwall, Christine E. Seidman, Jon G. Seidman, Rong Tian
Journal: Circulation Research (2005)

Mutations in the human gene encoding the nucleotide-binding region in the gamma-subunit of AMP-activated protein kinase (AMPK) cause cardiomyopathy with preexcitation syndrome. Mutant AMPK showed reduced binding affinity to nucleotides in vitro raising the possibility that altered regulation of AMPK activity by AMP/ATP could contribute to the disease phenotype. In this study, we determined the sensitivity of AMPK activity to AMP/ATP in the beating hearts using transgenic mice expressing a mutant (N488I, gamma2-mutant) or wild-type gamma2-subunit (gamma2-TG). The [ATP] and [AMP] were unaltered in all hearts but the AMPK activity was increased by 2.5-fold in gamma2-mutant hearts freeze-clamped at normal AMP/ATP compared with nontransgenic (WT) or gamma2-TG. The increased basal AMPK activity was caused by increased Thr-172 phosphorylation of the alpha-subunit (p-AMPK, by 4-fold) at normal [ATP] and was not changed by reducing glycogen content by 60% in the gamma2-mutant hearts. A reversal of AMP/ATP, caused by ATP degradation, increased p-AMPK by 7-fold in WT but caused no change in gamma2-mutant hearts. These results demonstrate that the mutation renders AMPK insensitive to the inhibitory and stimulatory effects of the regulatory nucleotides ATP and AMP, respectively, suggesting that the pathogenesis of the human disease may not be attributable to a simple loss- or gain-of-function.
Influence of comorbid conditions on asthma
Authors: L-P. Boulet
Journal: European Respiratory Journal (2009)

Various conditions such as rhinosinusitis, gastro-oesophageal reflux disease, psychological disturbances, chronic infections and obstructive sleep apnoea are often observed in asthmatic patients and may affect asthma control and outcomes. These comorbidities may change the asthma phenotype, be part of the same pathophysiological process, act as confounding factors in the diagnosis or assessment of control of asthma, and/or result from specific environmental exposures. The influences of these conditions on asthma are variable and for many of them still uncertain; nevertheless, they may alter asthma responses to current therapy. A systematic evaluation and an appropriate treatment of asthma-associated comorbid conditions should be part of asthma management, particularly for severe disease. With regard to clinical research, associated conditions may influence the results of trials and should be taken into account in the subjects' inclusion criteria and analysis of data.
Results of a Phase II Trial of Brentuximab Vedotin for CD30<sup>+</sup> Cutaneous T-Cell Lymphoma and Lymphomatoid Papulosis
Authors: Madeleine Duvic, Michael T. Tetzlaff, Pamela Gangar, Audra L. Clos, Dawen Sui, Rakhshandra Talpur
Journal: Journal of Clinical Oncology (2015)

Brentuximab vedotin, a monoclonal antibody (cAC10) conjugated to monomethyl auristatin E, targets CD30(+) receptors. This phase II open-label trial was conducted to evaluate safety and efficacy in CD30(+) cutaneous T-cell lymphomas.Forty-eight patients with CD30(+) lymphoproliferative disorders or mycosis fungoides (MF) received an infusion of 1.8 mg/kg every 21 days.Forty-eight evaluable patients (22 women and 26 men; median age, 59.5 years) had an overall response rate of 73% (95% CI, 60% to 86%; 35 of 48 patients) and complete response rate of 35% (95% CI, 22% to 49%; 17 of 48 patients). Fifteen (54%; 95% CI, 31% to 59%) of 28 patients with MF responded, independent of CD30 expression. In patients with MF/Sézary syndrome, the overall response rate was 50% (five of 10 patients) in patients with low CD30 expression (< 10%), 58% (seven of 12 patients) in patients with medium expression (10% to 50%), and 50% (three of six patients) in patients with high expression (≥ 50%). Time to response was 12 weeks (range, 3 to 39 weeks), and duration of response was 32 weeks (range, 3 to 93 weeks). All patients with lymphomatoid papulosis (n = 9) and primary cutaneous anaplastic T-cell lymphomas (n = 2) responded; time to response was 3 weeks (range, 3 to 9 weeks), and median duration of response was 26 weeks (range, 6 to 44 weeks). Soluble baseline CD30 levels were lowest in complete responders (P = .036). Grade 1 to 2 peripheral neuropathy was observed in 65% of patients (95% CI, 52% to 79%; 31 of 48 patients), is still ongoing in 55% of patients (95% CI, 41% to 69%; 17 of 31 patients), and resolved in 45% of patients (95% CI, 31% to 59%; 14 of 31 patients), with a median time to resolution of 41.5 weeks. Grade 3 to 4 events were neutropenia (n = 5), nausea (n = 2), chest pain (n = 2), deep vein thrombosis (n = 1), transaminitis (n = 1), and dehydration (n = 1). Dose reductions to 1.2 mg/kg were instituted as a result of grade 2 neuropathy (n = 6), transaminitis (n = 1), and arthralgias and fatigue (n = 2).Brentuximab vedotin is both active and well tolerated in cutaneous T-cell lymphoma and lymphomatoid papulosis, with an overall response rate of 73% and complete response rate of 35%.
Muscle fibre type shifting in the vastus lateralis of patients with COPD is associated with disease severity: a systematic review and meta-analysis
Authors: H. R Gosker, M. P Zeegers, E. F M Wouters, A. M W J Schols
Journal: Thorax (2007)

Background: Skeletal muscle dysfunction is a common feature in chronic obstructive pulmonary disease (COPD) which is associated with intrinsic muscular abnormalities. One of the most consistently reported alterations is a shift from fibre type I to II in the vastus lateralis of these patients. Surprisingly, the relationship between this shift and the severity and phenotype of COPD remains unclear. A study was conducted to determine whether vastus lateralis muscle fibre type proportions are associated with COPD disease severity and to provide reference values for the proportions of fibre types in the vastus lateralis in COPD. Methods: A systematic review and a meta-analysis were conducted in which muscle fibre type data and markers of disease severity were collected from the literature. Results: The forced expiratory volume in 1 s (FEV1), the ratio of FEV1 to forced vital capacity (FVC) and body mass index were positively associated with the proportion of type I fibres in COPD. A proportion of 51% for vastus lateralis fibre type I and 13% for fibre type IIX were calculated from the combined data as normal values for patients with typical GOLD stage 3–4 COPD aged 60–70 years. Based on these reference values, a proportion of fibre type I <27% and of fibre type IIX >29% were defined as pathologically abnormal. Conclusions: This review sheds new light on the relationship between skeletal muscle abnormalities and important hallmarks of the disease in severe COPD, and identifies absence of data in GOLD stages 1–2. This review also provides reference values on fibre type composition for diagnostic purposes in COPD.
Nitric oxide and coronary endothelial dysfunction in humans
Authors: H Drexler
Journal: Cardiovascular Research (1999)

Time for primary review 21 days. 

The endothelium provides a variety of important functions involved in the cardiovascular homeostasis. The assessment of endothelial function in humans has focused primarily on endothelial dependent vasomotion in response to the release of NO. In particular, clinical studies have evaluated vasomotor tone following changes in flow or stimuli for the release of NO from the endothelium, such as acetylcholine, substance P or serotonin [1]. However, NO not only acts as a vasodilating substance but also affects other functions of the endothelium such as the adhesive properties of the endothelium with respect to the interaction with leucocytes and platelets [2]. Despite the pivotal contribution of in vitro studies for the elucidation of underlying mechanisms, the clinical implication of endothelial function can only be appreciated by studies in humans in vivo, since tissue or cells are exposed to an artificial environment i.e. lacking the neurohumoral influences present in vivo. To critically review the role of NO in coronary endothelial dysfunction in humans the present review focuses on observations made by the in vivo assessment of endothelial dependent vascular responses.

In normal individuals increases in blood flow is associated with flow-dependent, endothelium-mediated vasodilation [3] which is related to the release of NO from the endothelium [4,5]. Similarly, acetylcholine, bradykinin or substance P elicit endothelium-dependent dilation of large and small vessels, which, in part, is due to the stimulated release of NO. However, the effect of acetylcholine, the most commonly used agent in the clinical setting, is composed of two divergent actions, that is, vasodilation by the stimulated release of NO and other vasodilating substances such as EDHF from the endothelium, and direct vasoconstricting effects on the underlying vascular smooth muscle, particularly with higher doses. In contrast to acetylcholine, bradykinin—and possibly substance P—is likely to … 

* Corresponding author. Tel.: +49-511-532-3841; fax: +49-511-532-5412 Drexler.Helmut{at}MH-Hannover.de
Proteolytic processing of dynamin by cytoplasmic cathepsin L is a mechanism for proteinuric kidney disease
Authors: Sanja Sever, Mehmet M. Altintas, Sharif R. Nankoe, Clemens C. Möller, David Ko, Changli Wei, Joel Henderson, Elizabetta C. del Re, Lianne Hsing, Ann Erickson, Clemens D. Cohen, Matthias Kretzler, Dontscho Kerjaschki, Alexander Rudensky, Boris Nikolic, Jochen Reiser
Journal: Journal of Clinical Investigation (2007)

Kidney podocytes and their foot processes maintain the ultrafiltration barrier and prevent urinary protein loss (proteinuria). Here we show that the GTPase dynamin is essential for podocyte function. During proteinuric kidney disease, induction of cytoplasmic cathepsin L leads to cleavage of dynamin at an evolutionary conserved site, resulting in reorganization of the podocyte actin cytoskeleton and proteinuria. Dynamin mutants that lack the cathepsin L site, or render the cathepsin L site inaccessible through dynamin self-assembly, are resistant to cathepsin L cleavage. When delivered into mice, these mutants restored podocyte function and resolve proteinuria. Our study identifies dynamin as a critical regulator of renal permselectivity that is specifically targeted by proteolysis under pathological conditions.