ABSTRACT
BACKGROUND: Despite progress in diagnosis and therapy of heart failure (HF), etiology and risk stratification remain elusive in many patients. METHODS: The My Biopsy HF Study (German clinical trials register number: DRKS22178) is a retrospective monocentric study investigating an all-comer population of patients with unexplained HF based on a thorough workup including endomyocardial biopsy (EMB). RESULTS: 655 patients (70.9% men, median age 55 [45/66] years) with non-ischemic, non-valvular HF were included in the analyses. 489 patients were diagnosed with HF with reduced ejection fraction (HFrEF), 52 patients with HF with mildly reduced ejection fraction (HFmrEF) and 114 patients with HF with preserved ejection fraction (HFpEF). After a median follow-up of 4.6 (2.5/6.6) years, 94 deaths were enumerated (HFrEF: 68; HFmrEF: 8; HFpEF: 18), equating to mortality rates of 3.3% and 11.6% for patients with HFrEF, 7.7% and 15.4% for patients with HFmrEF and 5.3% and 11.4% for patients with HFpEF after 1 and 5 years, respectively. In EMB, we detected a variety of putative etiologies of HF, including incidental cardiac amyloidosis (CA, 5.8%). In multivariate logistic regression analysis adjusting for age, sex and comorbidities only CA, age and NYHA functional class III + IV remained independently associated with all-cause mortality (CA: HRperui 3.13, 95% CI 1.5-6.51; p = 0.002). CONCLUSIONS: In an all-comer population of patients presenting with HF of unknown etiology, incidental finding of CA stands out to be independently associated with all-cause mortality. Our findings suggest that prospective trials would be helpful to test the added value of a systematic and holistic work-up of HF of unknown etiology.
Subject(s)
Heart Failure , Ventricular Dysfunction, Left , Male , Humans , Middle Aged , Female , Stroke Volume , Retrospective Studies , Prospective Studies , PrognosisABSTRACT
Fieldworkers (FWs) are community members employed by research teams to support access to participants, address language barriers, and advise on culturally appropriate research conduct. The critical role that FWs play in studies, and the range of practical and ethical dilemmas associated with their involvement, is increasingly recognised. In this paper, we draw on qualitative observation and interview data collected alongside a six month basic science study which involved a team of FWs regularly visiting 47 participating households in their homes. The qualitative study documented how relationships between field workers and research participants were initiated, developed and evolved over the course of the study, the shifting dilemmas FWs faced and how they handled them. Even in this one case study, we see how the complex and evolving relationships between fieldworkers and study participants had important implications for consent processes, access to benefits and mutual understanding and trust. While the precise issues that FWs face are likely to depend on the type of research and the context in which that research is being conducted, we argue that appropriate support for field workers is a key requirement to strengthen ethical research practice and for the long term sustainability of research programmes.
Subject(s)
Clinical Trials as Topic/ethics , Community-Based Participatory Research/ethics , Conflict of Interest , Conflict, Psychological , Friends , Research Personnel/ethics , Researcher-Subject Relations/ethics , Trust , Adult , Clinical Trials as Topic/standards , Clinical Trials as Topic/trends , Community-Based Participatory Research/standards , Community-Based Participatory Research/trends , Ethics, Research , Family Characteristics , Female , Friends/psychology , Health Services Accessibility/ethics , Humans , Informed Consent/ethics , Kenya , Negotiating , Qualitative Research , Respiratory Syncytial Virus Infections/diagnosis , Respiratory Syncytial Viruses/isolation & purification , Social Environment , Surveys and Questionnaires , Trust/psychology , Young AdultABSTRACT
BACKGROUND: The objective of this study was to determine the relationship between perioperative complications and the severity of obstructive sleep apnoea (OSA) in patients undergoing bariatric surgery who had undergone preoperative polysomnography (PSG). METHODS: The records of 797 patients, age >18 yr, who underwent bariatric operations (442 open and 355 laparoscopic procedures) at Mayo Clinic and were assessed before operation by PSG, were reviewed retrospectively. OSA was quantified using the apnoea-hypopnoea index (AHI) as none (≤ 4), mild (5-15), moderate (16-30), and severe (≥ 31). Pulmonary, surgical, and 'other' complications within the first 30 postoperative days were analysed according to OSA severity. Logistic regression was used to assess the multivariable association of OSA, age, sex, BMI, and surgical approach with postoperative complications. RESULTS: Most patients with OSA (93%) received perioperative positive airway pressure therapy, and all patients were closely monitored after operation with pulse oximetry on either regular nursing floors or in intensive or intermediate care units. At least one postoperative complication occurred in 259 patients (33%). In a multivariable model, the overall complication rate was increased with open procedures compared with laparoscopic. In addition, increased BMI and age were associated with increased likelihood of pulmonary and other complications. Complication rates were not associated with OSA severity. CONCLUSIONS: In obese patients evaluated before operation by PSG before bariatric surgery and managed accordingly, the severity of OSA, as assessed by the AHI, was not associated with the rate of perioperative complications. These results cannot determine whether unrecognized and untreated OSA increases risk.
Subject(s)
Bariatric Surgery/adverse effects , Sleep Apnea, Obstructive/complications , Adult , Body Mass Index , Continuous Positive Airway Pressure , Epidemiologic Methods , Female , Humans , Length of Stay/statistics & numerical data , Male , Middle Aged , Polysomnography/methods , Postoperative Complications , Preoperative Care/methods , Respiration Disorders/etiologyABSTRACT
Inflammatory cardiomyopathy diagnosed by endomyocardial biopsy (EMB) is common in non-ischemic heart failure (HF) and might be associated with adverse outcome. We aimed to identify markers predicting myocardial inflammation in HF. We screened 517 patients with symptomatic non-ischemic HF who underwent EMB; 397 patients (median age 54 [IQR 43/64], 28.7% females) were included in this study. 230 patients were diagnosed with myocardial inflammation, defined as ≥ 7.0 CD3+ lymphocytes/mm2 and/or ≥ 35.0 Mac1 macrophages/mm2 and were compared to 167 inflammation negative patients. Patients with myocardial inflammation were more often smokers (52.4% vs. 39.8%, p = 0.013) and had higher C-reactive protein (CRP) levels (5.4 mg/dl vs. 3.7 mg/dl, p = 0.003). In logistic regression models CRP ≥ 8.15 mg/dl (OR 1.985 [95%CI 1.160-3.397]; p = 0.012) and Troponin I (TnI) ≥ 136.5 pg/ml (OR 3.011 [1.215-7.464]; p = 0.017) were independently associated with myocardial inflammation, whereas no association was found for elevated brain natriuretic peptide (OR 1.811 [0.873-3.757]; p = 0.111). In prognostic performance calculation the highest positive predictive value (90%) was detected for the combination of Global longitudinal strain (GLS) ≥ -13.95% and TnI ≥ 136.5 pg/ml (0.90 (0.74-0.96)). Elevated CRP, TnI and GLS in combination with TnI can be useful to detect myocardial inflammation. Smoking seems to predispose for myocardial inflammation.
Subject(s)
C-Reactive Protein/genetics , Glutaminase/blood , Heart Failure/blood , Inflammation/blood , Troponin I/blood , Adult , Biomarkers/blood , Female , Genetic Predisposition to Disease , Heart Failure/genetics , Heart Failure/pathology , Humans , Inflammation/genetics , Inflammation/pathology , Male , Middle Aged , Myocardial Infarction/blood , Myocardial Infarction/genetics , Myocardial Infarction/pathology , Myocardium/metabolism , Myocardium/pathology , Predictive Value of Tests , Prognosis , Risk Assessment , Smoking/adverse effects , Troponin I/geneticsABSTRACT
BACKGROUND: Möbius sequence is a rare condition usually defined as uni- or bilateral congenital facial weakness with impairment of ocular abduction. Mental retardation is estimated to occur in 10-15% of cases, but at present there have been no studies focusing on the intellectual capacities of children and adolescents with Möbius sequence. METHODS: Twenty-three children and adolescents aged 6-16 years could be recruited following a request of the German Möbius foundation. The primary caregivers of all subjects filled out a special questionnaire to compile personal, somatic and psychosocial history of the probands. All subjects had a physical examination. To assess intellectual capacities, the German version of the Wechsler Intelligence Test-III (WISC-III) was administered. In case of a severe mental retardation, the Vineland Adaptive Behavior Rating Form was used as an alternative. RESULTS: Twenty-two subjects [12 males, 10 females; mean age: 11.3 (6-16) years] could be included; 21 could be examined with the WISC-III. Compared with the normative sample, Full Scale IQ (mean: 92.05; standard deviation: 14.84) was significantly lower (P = 0.023) which was the consequence of a very low Performance IQ (mean: 80.48; standard deviation: 15.84). Compared with the normative sample, the results of all performance subtests were significantly lower (P = 0.033-0.000), whereas verbal subtest scores did not differ or were even higher ['Similarities' (P = 0.026) and 'Vocabulary' (P = 0.019)]. Verbal IQ (mean: 106.24; standard deviation: 15.31) was not significantly different from the normative sample. Two boys met ICD-10 criteria for mental retardation. Full Scale IQ was not predictive for academic success. CONCLUSIONS: The WISC-III is not an adequate predictor for academic success in Möbius patients; intelligence tests which are less dependant on time constraints should be preferred for subjects with Möbius sequence.
Subject(s)
Cognition Disorders/diagnosis , Mobius Syndrome/diagnosis , Wechsler Scales/standards , Adolescent , Child , Cognition Disorders/psychology , Female , Humans , Male , Mobius Syndrome/psychologyABSTRACT
Atherothrombosis is a leading cause of cardiovascular mortality and long-term morbidity. Platelets and coagulation proteases, interacting with circulating cells and in different vascular beds, modify several complex pathologies including atherosclerosis. In the second Maastricht Consensus Conference on Thrombosis, this theme was addressed by diverse scientists from bench to bedside. All presentations were discussed with audience members and the results of these discussions were incorporated in the final document that presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following five topics: 1. Risk factors, biomarkers and plaque instability: In atherothrombosis research, more focus on the contribution of specific risk factors like ectopic fat needs to be considered; definitions of atherothrombosis are important distinguishing different phases of disease, including plaque (in)stability; proteomic and metabolomics data are to be added to genetic information. 2. Circulating cells including platelets and atherothrombosis: Mechanisms of leukocyte and macrophage plasticity, migration, and transformation in murine atherosclerosis need to be considered; disease mechanism-based biomarkers need to be identified; experimental systems are needed that incorporate whole-blood flow to understand how red blood cells influence thrombus formation and stability; knowledge on platelet heterogeneity and priming conditions needs to be translated toward the in vivo situation. 3. Coagulation proteases, fibrin(ogen) and thrombus formation: The role of factor (F) XI in thrombosis including the lower margins of this factor related to safe and effective antithrombotic therapy needs to be established; FXI is a key regulator in linking platelets, thrombin generation, and inflammatory mechanisms in a renin-angiotensin dependent manner; however, the impact on thrombin-dependent PAR signaling needs further study; the fundamental mechanisms in FXIII biology and biochemistry and its impact on thrombus biophysical characteristics need to be explored; the interactions of red cells and fibrin formation and its consequences for thrombus formation and lysis need to be addressed. Platelet-fibrin interactions are pivotal determinants of clot formation and stability with potential therapeutic consequences. 4. Preventive and acute treatment of atherothrombosis and arterial embolism; novel ways and tailoring? The role of protease-activated receptor (PAR)-4 vis à vis PAR-1 as target for antithrombotic therapy merits study; ongoing trials on platelet function test-based antiplatelet therapy adjustment support development of practically feasible tests; risk scores for patients with atrial fibrillation need refinement, taking new biomarkers including coagulation into account; risk scores that consider organ system differences in bleeding may have added value; all forms of oral anticoagulant treatment require better organization, including education and emergency access; laboratory testing still needs rapidly available sensitive tests with short turnaround time. 5. Pleiotropy of coagulation proteases, thrombus resolution and ischaemia-reperfusion: Biobanks specifically for thrombus storage and analysis are needed; further studies on novel modified activated protein C-based agents are required including its cytoprotective properties; new avenues for optimizing treatment of patients with ischaemic stroke are needed, also including novel agents that modify fibrinolytic activity (aimed at plasminogen activator inhibitor-1 and thrombin activatable fibrinolysis inhibitor.
Subject(s)
Thromboembolism/therapy , Thrombosis/blood , Thrombosis/therapy , Anticoagulants/therapeutic use , Biomarkers/blood , Blood Coagulation , Erythrocytes/metabolism , Factor VIII/metabolism , Factor XII/metabolism , Factor XIII/metabolism , Humans , Macrophages/metabolism , Netherlands , Phenotype , Plaque, Atherosclerotic/blood , Plaque, Atherosclerotic/diagnosis , Plaque, Atherosclerotic/therapy , Polyphosphates/metabolism , Risk Factors , Signal Transduction , Thromboembolism/blood , Thromboembolism/diagnosis , Thrombosis/diagnosisABSTRACT
BACKGROUND AND PURPOSE: Mitochondrial aldehyde dehydrogenase (ALDH-2) has been shown to provide a pathway for bioactivation of organic nitrates and to be prone to desensitization in response to highly potent, but not to less potent, nitrates. We therefore sought to support the hypothesis that bioactivation by ALDH-2 critically depends on the number of nitrate groups within the nitrovasodilator. EXPERIMENTAL APPROACH: Nitrates with one (PEMN), two (PEDN; GDN), three (PETriN; glyceryl trinitrate, GTN) and four (pentaerithrityl tetranitrate, PETN) nitrate groups were investigated. Vasodilatory potency was measured in isometric tension studies using isolated aortic segments of wild type (WT) and ALDH-2-/- mice. Activity of the cGMP-dependent kinase-I (reflected by levels of phosphorylated VAsodilator Stimulated Phosphoprotein, P-VASP) was quantified by Western blot analysis, mitochondrial dehydrogenase activity by HPLC. Following incubation of isolated mitochondria with PETN, PETriN-chromophore and PEDN, metabolites were quantified using chemiluminescence nitrogen detection and mass spectrometry. KEY RESULTS: Compared to WT, vasorelaxation in response to PETN, PETriN and GTN was attenuated about 10fold in ALDH-2-/- mice, identical to WT vessels preincubated with inhibitors of ALDH-2. Reduced vasodilator potency correlated with reduced P-VASP formation and diminished biotransformation of the tetranitrate- and trinitrate-compounds. None of these findings were observed for PEDN, GDN and PEMN. CONCLUSIONS AND IMPLICATIONS: Our results support the crucial role of ALDH-2 in bioactivating highly reactive nitrates like GTN, PETN and PETriN. ALDH-2-mediated relaxation by organic nitrates therefore depends mainly on the number of nitrate groups. Less potent nitrates like PEDN, GDN and PEMN are apparently biotransformed by other pathways.
Subject(s)
Aldehyde Dehydrogenase/genetics , Nitrates/chemistry , Nitrates/pharmacology , Aldehyde Dehydrogenase, Mitochondrial , Animals , Blotting, Western , Cell Adhesion Molecules/metabolism , Cyclic GMP-Dependent Protein Kinases/metabolism , Isometric Contraction/drug effects , Luminescence , Mass Spectrometry , Mice , Mice, Inbred C57BL , Mice, Knockout , Microfilament Proteins/metabolism , Mitochondria, Muscle/enzymology , Nitroglycerin/analogs & derivatives , Nitroglycerin/pharmacology , Nitroprusside/pharmacology , Oxadiazoles/pharmacology , Pentaerythritol Tetranitrate/pharmacology , Phosphoproteins/metabolism , Quinoxalines/pharmacology , Structure-Activity Relationship , Vasodilator Agents/pharmacologyABSTRACT
The pathogenesis of venous thromboembolism (VTE) is still not completely understood. Experimental animals in which human deep vein thrombosis can be modeled are useful tools to investigate the pathogenesis of VTE. Besides the availability of transgenic and genetically modified mice, the use of high frequency ultrasound and intravital microscopy plays an important role in identifying thrombotic processes in mouse models. In this article, an overview about the application of various new technologies and existing mouse models is provided, and the impact of venous side branches on deep vein thrombosis in the mouse model is discussed.
ABSTRACT
Recent advances in molecular subtyping of Pancreatic Ductal Adenocarcinoma (PDAC) support individualization of therapeutic strategies in this most aggressive disease. With the emergence of various novel therapeutic strategies and neoadjuvant approaches in this quickly deteriorating disease, robust approaches for fast evaluation of therapy response are urgently needed. To this aim, we designed a preclinical imaging-guided therapy trial where genetically engineered mice harboring endogenous aggressive PDAC were treated with the MEK targeting drug refametinib, which induces rapid and profound tumor regression in this model system. Multi-parametric non-invasive imaging was used for therapy response monitoring. A significant increase in the Diffusion-Weighted Magnetic Resonance Imaging derived Apparent Diffusion Coefficient (ADC) was noted already 24 hours after treatment onset. Histopathological analyses showed increased apoptosis and matrix remodeling at this time point. Our findings suggest the ADC parameter as an early predictor of therapy response in PDAC.
Subject(s)
Carcinoma, Pancreatic Ductal/pathology , Pancreatic Neoplasms/pathology , Animals , Carcinoma, Pancreatic Ductal/diagnostic imaging , Carcinoma, Pancreatic Ductal/drug therapy , Diffusion Magnetic Resonance Imaging , Diphenylamine/analogs & derivatives , Diphenylamine/therapeutic use , Disease Models, Animal , Humans , Image Processing, Computer-Assisted , MAP Kinase Kinase Kinases/antagonists & inhibitors , MAP Kinase Kinase Kinases/metabolism , Mice , Neoadjuvant Therapy , Pancreatic Neoplasms/diagnostic imaging , Pancreatic Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Response Evaluation Criteria in Solid Tumors , Sulfonamides/therapeutic use , Pancreatic NeoplasmsABSTRACT
Mutation of p53 is a frequent genetic lesion in pancreatic cancer being an unmet clinical challenge. Mutants of p53 have lost the tumour-suppressive functions of wild type p53. In addition, p53 mutants exert tumour-promoting functions, qualifying them as important therapeutic targets. Here, we show that the class I histone deacetylases HDAC1 and HDAC2 contribute to maintain the expression of p53 mutants in human and genetically defined murine pancreatic cancer cells. Our data reveal that the inhibition of these HDACs with small molecule HDAC inhibitors (HDACi), as well as the specific genetic elimination of HDAC1 and HDAC2, reduce the expression of mutant p53 mRNA and protein levels. We further show that HDAC1, HDAC2 and MYC directly bind to the TP53 gene and that MYC recruitment drops upon HDAC inhibitor treatment. Therefore, our results illustrate a previously unrecognized class I HDAC-dependent control of the TP53 gene and provide evidence for a contribution of MYC. A combined approach targeting HDAC1/HDAC2 and MYC may present a novel and molecularly defined strategy to target mutant p53 in pancreatic cancer.
Subject(s)
Gene Expression Regulation, Neoplastic , Genes, p53 , Histone Deacetylase 1/metabolism , Histone Deacetylase 2/metabolism , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Animals , Disease Models, Animal , Gene Expression Regulation, Neoplastic/drug effects , Histone Deacetylase 1/antagonists & inhibitors , Histone Deacetylase 2/antagonists & inhibitors , Histone Deacetylase Inhibitors/pharmacology , Humans , Mice , Mice, Knockout , Mutation , Pancreatic Neoplasms/pathology , Promoter Regions, Genetic , Proteasome Endopeptidase Complex/metabolism , Proto-Oncogene Proteins c-mdm2/metabolism , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , RNA, Messenger/geneticsABSTRACT
Consent processes have attracted significant research attention over the last decade, including in the global south. Although relevant studies suggest consent is a complex negotiated process involving multiple actors, most guidelines assume consent is a one-off encounter with a clear 'yes' or 'no' decision. In this paper we explore the concept of 'silent refusals', a situation where it is not clear whether potential participants want to join studies or those in studies want to withdraw from research, as they were not actively saying no. We draw on participant observation, in-depth interviews and group discussions conducted with a range of stakeholders in two large community based studies conducted by the KEMRI Wellcome Trust programme in coastal Kenya. We identified three broad inter-related rationales for silent refusals: 1) a strategy to avoid conflicts and safeguard relations within households, - for young women in particular-to appear to conform to the wishes of elders; 2) an approach to maintain friendly, appreciative and reciprocal relationships with fieldworkers, and the broader research programme; and 3) an effort to retain study benefits, either for individuals, whole households or wider communities. That refusals and underlying rationales were silent posed multiple dilemmas for fieldworkers, who are increasingly recognised to play a key interface role between researchers and communities in many settings. Silent refusals reflect and reinforce complex power relations embedded in decisions about research participation, with important implications for consent processes and broader research ethics practice. Fieldworkers need support to reflect upon and respond to the ethically charged environment they work in.
Subject(s)
Informed Consent/ethics , Research Personnel/ethics , Research Personnel/standards , Research/standards , Adolescent , Adult , Cooperative Behavior , Developing Countries , Ethics, Research , Female , Humans , Kenya , Male , Middle Aged , Negotiating , Young AdultABSTRACT
A morphometric and immunohistochemical study was performed on 354 bone marrow trephine biopsies derived from 126 patients with chronic myeloid leukaemia (CML) before and after allogeneic bone marrow transplantation (BMT). The purpose of this investigation was to evaluate the macrophage population, including several subsets and their dynamics in the posttransplant period. In addition to the total CD68+ resident (mature) macrophages the so-called activated fraction identified by its capacity to express alpha-D-galactosyl residues, the pseudo-Gaucher cells (PGCs) and the iron-laden histiocytic reticular cells were also considered. Following immuno- and lectin-histochemical staining morphometric analysis was carried out on sequential postgraft bone marrow specimens at standardized intervals. Compared to the normal bone marrow and calculated per haematopoiesis (cellularity) an overall decrease of about 40-50% in the quantity of CD68+ macrophages and the BSA-I+ subpopulation was detectable in the early posttransplant period (9-45 days after BMT). Noteworthy was the temporal recurrence of PGCs in the engrafted bone marrow, which was not associated with a clonally transformed cell population or leukaemic relapse. Reappearance of postgraft PGCs was most prominent in the first 2 months after BMT. This conspicuous feature was presumed to be functionally associated with a pronounced degradation of cell debris following pretransplant myelo-ablative therapy (scavenger macrophages). Evidence for an activation of the BSA-I+ macrophage subset was derived from the identical carbohydrate-binding capacity shown by the PGCs. In the regenerating haematopoiesis shortly after BMT a significant correlation between the number of BSA-I+ macrophages and erythroid precursor cells was determinable. This result implicates a close functional relationship between postgraft reconstitution of erythropoietic islets and centrally localized activated macrophages. In conclusion, findings emerging from this study included the reappearance of PCGs in the engrafted bone marrow independently of a leukaemic relapse and the significant association of the activated BSA-I+ macrophage subset with the recovery of erythropoiesis.
Subject(s)
Bone Marrow Transplantation , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/surgery , Macrophages/pathology , Adult , Antigens, CD/analysis , Antigens, Differentiation, Myelomonocytic/analysis , Bone Marrow/immunology , Bone Marrow/pathology , Female , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/immunology , Macrophages/immunology , Male , Postoperative Period , Transplantation, HomologousABSTRACT
Despite existence of effective tools for malaria control, malaria continues to be one of the leading killer diseases especially among under-five year children and pregnant women in poor rural populations of Sub Saharan Africa. In Tanzania Mainland the disease contributes to 39.4% of the total OPD attendances. In terms of mortality, malaria is known to be responsible for more than one third of deaths among children of age below 5 years and also contributes for up to one fifth of deaths among pregnant women. This paper is based on a study conducted in a rural community along the shores of Lake Victoria in Mwanza region, North-Western Tanzania. The study explores reasons for scepticism and low uptake of insecticide treated mosquito nets (ITNs) that were promoted through social marketing strategy for malaria control prior to the introduction of long lasting nets (LLN). The paper breaks from traditional approach that tend to study low uptake of health interventions in terms of structural practical constraints--cost, accessibility, everyday priorities--or in terms of cognition--insufficient knowledge of benefits e.g. ignorance of public health messages. This paper has shown that, the majority of people who could afford the prices of ITNs and who knew where to obtain the insecticides did not necessarily buy them. This suggests that, although people tend to report cost-related factors as a barrier against the use of ITNs, there are other critical concerns at work. Without underestimating the practical factors, our study have recommended to consider critical examinations of those other concerns that hinder optimal utilization of ITN for malaria control, and the basis for those concerns.
Subject(s)
Insecticide-Treated Bednets/statistics & numerical data , Malaria/prevention & control , Mosquito Control/methods , Female , Focus Groups , Humans , Interviews as Topic , Malaria/epidemiology , Male , Observation , Rural Population , Tanzania/epidemiologyABSTRACT
The hemodynamic and anti-ischemic effects of nitroglycerin (GTN) are rapidly blunted as a result of the development of nitrate tolerance. Long-term nitrate treatment also is associated with decreased vascular responsiveness caused by changes in intrinsic mechanisms of the tolerant vasculature itself. According to the oxidative stress concept, increased vascular superoxide and peroxynitrite production as well as an increased sensitivity to vasoconstrictors secondary to activation of protein kinase C as well as vascular NADPH oxidases contribute to the development of tolerance. Recent experimental work has defined new tolerance mechanisms, including inhibition of the enzyme that bioactivates GTN (e.g. mitochondrial aldehyde dehydrogenase [ALDH-2]) and mitochondria as potential sources of reactive oxygen species (ROS). GTN-induced ROS inhibit the bioactivation of GTN by ALDH-2. Both mechanisms impair GTN bioactivation, and now converge at the level of ALDH-2 to support a new theory for GTN tolerance and GTN-induced endothelial dysfunction. The consequences of these processes for GTN downstream targets (e.g. soluble guanylyl cyclase, cyclic guanosine monophosphate-dependent protein kinase) and toxic effects contributing to endothelial dysfunction (e.g. prostacyclin synthase inhibition and NO synthase uncoupling) are discussed. Tolerance and endothelial dysfunction are distinct processes which rely on different sources of ROS and there is good evidence for a crosstalk between these distinct processes. Finally, we will address the question whether ALDH-2 inactivation by nitroglycerin could be a useful marker for clinical nitrate tolerance and discuss the redox-regulation of this enzyme by oxidative stress and dihydrolipoic acid.
Subject(s)
Aldehyde Dehydrogenase/metabolism , Nitrates/therapeutic use , Nitroglycerin/therapeutic use , Aldehyde Dehydrogenase, Mitochondrial , Drug Tolerance , Humans , Mitochondria/enzymology , Oxidative StressABSTRACT
BACKGROUND AND PURPOSE: The chronic use of organic nitrates is limited by serious side effects including oxidative stress, nitrate tolerance and/or endothelial dysfunction. The side effects and potency of nitroglycerine depend on mitochondrial aldehyde dehydrogenase (ALDH-2). We sought to determine whether this concept can be extended to a new class of organic nitrates with amino moieties (aminoalkyl nitrates). EXPERIMENTAL APPROACH: Vasodilator potency of the organic nitrates, in vitro tolerance and in vivo tolerance (after continuous infusion for 3 days) were assessed in wild-type and ALDH-2 knockout mice by isometric tension studies. Mitochondrial oxidative stress was analysed by L-012-dependent chemiluminescence and protein tyrosine nitration. KEY RESULTS: Aminoethyl nitrate (AEN) showed an almost similar potency to glyceryl trinitrate (GTN), even though it is only a mononitrate. AEN-dependent vasodilatation was mediated by cGMP and nitric oxide. In contrast to triethanolamine trinitrate (TEAN) and GTN, AEN bioactivation did not depend on ALDH-2 and caused no in vitro tolerance. In vivo treatment with TEAN and GTN, but not with AEN, induced cross-tolerance to acetylcholine (ACh)-dependent and GTN-dependent relaxation. Although all nitrates tested induced tolerance to themselves, only TEAN and GTN significantly increased mitochondrial oxidative stress in vitro and in vivo. CONCLUSIONS AND IMPLICATIONS: The present results demonstrate that not all high potency nitrates are bioactivated by ALDH-2 and that high potency of a given nitrate is not necessarily associated with induction of oxidative stress or nitrate tolerance. Obviously, there are distinct pathways for bioactivation of organic nitrates, which for AEN may involve xanthine oxidoreductase rather than P450 enzymes.
Subject(s)
Drug Tolerance , Nitrates/pharmacology , Oxidative Stress/drug effects , Acetylcholine/pharmacology , Aldehyde Dehydrogenase/genetics , Aldehyde Dehydrogenase, Mitochondrial , Animals , Ethanolamines/administration & dosage , Ethanolamines/pharmacology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mitochondria/metabolism , Nitrates/administration & dosage , Nitrates/chemistry , Nitroglycerin/administration & dosage , Nitroglycerin/pharmacology , Vasodilation/drug effectsABSTRACT
Organic nitrates still represent a group of very effective anti-ischemic drugs used for the treatment of patients with stable angina, acute myocardial infarction and chronic congestive heart failure. Long-term therapy with organic nitrates, however, results in a rapid development of nitrate tolerance blunting their hemodynamic and antiischemic efficacy. Recent studies revealed that mitochondrial reactive oxygen species (ROS) formation and a subsequent oxidative inactivation of nitrate reductase, the mitochondrial aldehyde dehydrogenase (ALDH-2), play an important role for the development of nitrate and crosstolerance. The present review focuses firstly on the role of ALDH-2 for organic nitrate bioactivation and secondly on the role of oxidative stress in the development of tolerance and cross-tolerance (endothelial dysfunction) in response to various organic nitrates. Finally, we would like to draw the reader's attention to the protective properties of the organic nitrate pentaerithrityl tetranitrate (PETN), which, in contrast to all other organic nitrates, is able to upregulate enzymes with a strong antioxidative capacity thereby preventing tolerance and the development of endothelial dysfunction.
Subject(s)
Drug Tolerance , Heart Diseases/drug therapy , Nitrates/pharmacology , Aldehyde Dehydrogenase/metabolism , Humans , Mitochondria/enzymology , Nitrates/administration & dosage , Oxidative Stress/drug effects , Pentaerythritol Tetranitrate/administration & dosage , Pentaerythritol Tetranitrate/pharmacology , Reactive Oxygen Species/metabolism , Up-Regulation/drug effects , Vasodilator Agents/administration & dosage , Vasodilator Agents/pharmacologyABSTRACT
A 27-year-old patient had firm, subcutaneous nodules on both legs. Histological examination revealed that they were epitheloid granulomas with necrotic areas. After the exclusion of infectious granulomas this finding suggested an association with Crohn's disease. Clinical investigations showed an acute form of Crohn's disease. We interpreted our findings as a cutaneous granulomatous reaction in Crohn's disease. In the literature this is referred to as metastatic Crohn's disease.
Subject(s)
Crohn Disease/pathology , Granuloma, Giant Cell/pathology , Skin Diseases/pathology , Adipose Tissue/pathology , Adult , Biopsy , Giant Cells, Langhans/pathology , Humans , Male , Necrosis , Skin/pathologyABSTRACT
Gardner's syndrome is accompanied by numerous cutaneous neoplasias, cysts of hair follicles being the most frequent. We report a case of Gardner's syndrome with multiple hair follicle cysts. Histologically, parts of the cyst linings showed features of pilomatricomas. We discuss the histopathological findings and their significance as possible markers for the disease.
Subject(s)
Cysts/pathology , Gardner Syndrome/pathology , Hair/pathology , Skin Neoplasms/pathology , Adult , Female , Gardner Syndrome/genetics , Humans , Skin/pathology , Skin Neoplasms/geneticsABSTRACT
Gas-phase acidities of CH3Y (Y: NO, C identical to CH, CH=NH, and CH=S), barriers to the identity proton-transfer CH3Y + CH2=Y- reversible CH2=Y- + CH3Y, as well as geometries and charge distributions of CH3Y, CH2=Y- and the transition states of the proton transfers were determined by ab initio methods at the MP2/6-311 + G(d,p)//MP2/6-311 + G(d,p), B3LYP/6-311 + G(d,p), and BPW-91/6-311 + G-(d,p) levels of theory. The acidities were also calculated at the CCSD(T)/6-311 + G(2df,2p) level. To make more meaningful comparisons, the same quantities for previously studied systems (Y: H, CH=CH2, CH=O, CN, NO2) were recalculated at the levels used in the present work. The geometric parameters as well as the group charges indicate that the transition states for all the reactions are imbalanced, although there is no correlation between the degree of imbalance and the pi-acceptor strength of the Y group. Based on multi-parameter correlations with the field (sigma F), resonance (sigma R), and polarizability effect (sigma alpha) substituent constants, the contributions of each of these effects to the acidities and barriers were evaluated. For the Y groups whose sigma F, sigma R, and sigma alpha are unknown (CH=NH, CH=S, C identical to CH), a method for estimating these substituent constants is proposed. The barriers for the CH3Y/CH2=Y- systems are all lower than for the CH4/CH3- system; this contrasts with the situation in solution where the Y groups lead to an increase in the barrier. The reasons for this reversal are analyzed. We also make an attempt to clarify the issue as to why the transition states of these reactions are imbalanced, a question which continues to draw attention in the literature.