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Human Data (human + data)
Selected AbstractsLiver fat and lipid oxidation in humansLIVER INTERNATIONAL, Issue 9 2009Anna Kotronen Abstract Background: Studies in animals show that changes in hepatic fatty acid oxidation alter liver fat content. Human data regarding whole-body and hepatic lipid oxidation are controversial and based on studies of only a few subjects. Aims: We examined whether whole-body and hepatic lipid oxidation are altered in subjects with non-alcoholic fatty liver disease (NAFLD) compared with controls. Methods: In vivo measurements of rates of substrate oxidation and insulin sensitivity (using the euglycaemic hyperinsulinaemic clamp technique in combination with indirect calorimetry and infusion of [3- 3H]glucose) were performed in subjects with NAFLD [mean liver fat 14.0% (interquartile range 7.5,20.5%), n=29] and in control subjects [1.6% (1.0,3.0%), n=29]. Liver fat was measured using proton magnetic resonance spectroscopy. Plasma concentrations of 3-hydroxybutyrate (3-OHB) were measured as markers of hepatic lipid oxidation. Results: In the basal state, substrate oxidation rates and serum 3-OHB concentrations were comparable in subjects with and without NAFLD. Plasma 3-OHB concentrations were similarly suppressed by insulin in both the groups. During the insulin infusion, whole-body lipid oxidation was inversely correlated with insulin-stimulated glucose disposal (r=,0.48, P<0.0001), which was lower in subjects with NAFLD [3.7±0.2 mg/(kg fat-free mass min)] than in the control subjects [5.0±0.3 mg/(kg fat-free mass min), P=0.0008]. Conclusions: Hepatic lipid oxidation is unchanged in NAFLD. Whole-body lipid oxidation is increased because of peripheral insulin resistance. These data imply that alterations in hepatic fatty acid oxidation do not contribute to liver fat content in humans. [source] Identification and classification of skin sensitizers: identifying false positives and false negativesCONTACT DERMATITIS, Issue 5 2006David A. Basketter The first step in regulatory evaluation of substances involves the identification of their intrinsic hazards, including the potential for skin sensitization. This is, quite properly, entirely different from assessment of the risks to human health, which might arise from incorporation of substances in products. EU guidance on regulations concerning the classification of skin sensitizers suggests a range of sources of information be deployed in the hazard identification process. These include chemical structure, predictive animal tests, and various types of human data. Where the information is clear-cut, then uncertainties rarely arise. However, for some materials, discordant information arises, perhaps because the substance is on the borderline of test sensitivity and classification (sensitizing materials of insufficient potency do not classified according to the EU scheme), due to conflicting results in predictive tests or for other reasons. In this study, we review data on a number of substances where a classification decision is complicated by such discordances and seek to use these examples to demonstrate how best to make a weight of evidence decision on whether a substance should, or should not, be classified as a skin sensitizer. [source] Predictive identification of human skin sensitization thresholdsCONTACT DERMATITIS, Issue 5 2005David A. Basketter For years, methods have been available for the predictive identification of chemicals that possess the intrinsic potential to cause skin sensitization. However, many have proven less suitable for the determination of relative sensitizing potency. In this respect, the local lymph node assay (LLNA) has been shown to have a number of important advantages. Through interpolation of LLNA dose,response data, the concentration of a chemical required to produce a threshold positive response (a 3-fold increase in activity compared with concurrent vehicle controls, the EC3 value) can be measured. The robustness of this parameter has been demonstrated rigorously in terms of inter- and intralaboratory reproducibility. Additionally, the relationship between potency estimates from the LLNA and an appreciation of human potency based on clinical experience has been reported previously. In the present investigations, we have sought to consolidate further our understanding of the association between EC3 values and human skin-sensitization potency by undertaking a thorough and extensive analysis of existing human predictive assays, particularly where dose,response information is available, from historical human repeated insult patch tests (HRIPTs). From these human data, information on the approximate threshold for the induction of skin sensitization in the HRIPT was determined for 26 skin-sensitizing chemicals. These data were then compared with LLNA-derived EC3 values. The results from each assay, expressed as dose per unit area (,g/cm2), revealed a clear linear relationship between the 2 values, thereby substantiating further the utility of LLNA EC3 values for prediction of the relative human sensitizing potency of newly identified skin sensitizers. [source] Perioperative Management of Medications for Psoriasis and Psoriatic Arthritis: A Review for the DermasurgeonDERMATOLOGIC SURGERY, Issue 4 2008CLAUDIA HERNANDEZ MD BACKGROUND Psoriasis affects an estimated 3% of the world's population. Many are on chronic immunosuppressive therapy for the cutaneous and joint manifestations of this disorder. The management of these medications in the perioperative period is controversial. Psoriasis and psoriatic arthritis medications can affect wound healing, hemostasis, and infection risk during cutaneous surgery. OBJECTIVES The objective of this article is to provide a critical review of various medications used for care of the psoriatic patient and their potential effect on cutaneous surgical procedures. CONCLUSIONS This review summarizes current understanding of wound healing, hemostatic effects, and infectious risks regarding many psoriasis medications including nonsteroidal anti-inflammatory drugs, cyclooxygenase inhibitors, corticosteroids, various immunosuppressants, and biologic response modifiers. Recommendations vary depending on the agent in question, type of procedure, and comorbid conditions in the patient. Caution is advised when using many of the medications reviewed due to lack of human data of their effects in the perioperative period. [source] Task-related gamma-band dynamics from an intracerebral perspective: Review and implications for surface EEG and MEGHUMAN BRAIN MAPPING, Issue 6 2009Karim Jerbi Abstract Although non-invasive techniques provide functional activation maps at ever-growing spatio-temporal precision, invasive recordings offer a unique opportunity for direct investigations of the fine-scale properties of neural mechanisms in focal neuronal populations. In this review we provide an overview of the field of intracranial Electroencephalography (iEEG) and discuss its strengths and limitations and its relationship to non-invasive brain mapping techniques. We discuss the characteristics of invasive data acquired from implanted epilepsy patients using stereotactic-electroencephalography (SEEG) and electrocorticography (ECoG) and the use of spectral analysis to reveal task-related modulations in multiple frequency components. Increasing evidence suggests that gamma-band activity (>40 Hz) might be a particularly efficient index for functional mapping. Moreover, the detection of high gamma activity may play a crucial role in bridging the gap between electrophysiology and functional imaging studies as well as in linking animal and human data. The present review also describes recent advances in real-time invasive detection of oscillatory modulations (including gamma activity) in humans. Furthermore, the implications of intracerebral findings on future non-invasive studies are discussed. Hum Brain Mapp, 2009. © 2009 Wiley-Liss, Inc. [source] Brominated flame retardants as possible endocrine disruptersINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 2 2008P. O. Darnerud Summary Brominated flame retardants (BFR) are endocrine disrupters in experimental systems, both in vitro and in vivo. Although BFR effects on thyroid hormones are well confirmed, studies of effects on oestrogen/androgen systems are fewer but today growing in numbers. The effects of BFR on other hormone systems are still unknown. Hormonal effect levels in animals start from ca 1 mg/kg b.w., but there are exceptions: effects on spermatogenesis, suggesting hormonal causes, have been observed at a low dose (60 ,g/kg b.w.) of a polybrominated diphenyl ether (PBDE) congener, BDE-99. It could be concluded that hormonal effects are of importance in risk assessment, and in some cases where effects are seen at low levels safety margins may be insufficient. One additional uncertainty is the lack of reliable human data that could be used to support animal BFR observations. In spite of the recent regulation of PBDE production, levels of both PBDE and of other BFR groups are still present in environmental samples. Thus, we have to deal with the possible effects of human BFR exposure for times to come. In order to reduce BFR exposure, the routes of exposure should be carefully examined and ways to reduce levels in major exposure routes considered. [source] Lung, liver and bone cancer mortality in Mayak workers,INTERNATIONAL JOURNAL OF CANCER, Issue 4 2008Mikhail E. Sokolnikov Abstract Workers at the Mayak nuclear facility in the Russian Federation offer the only adequate human data for evaluating cancer risks from exposure to plutonium. Risks of mortality from cancers of the lung, liver and bone, the organs receiving the largest doses from plutonium, were evaluated in a cohort of 17,740 workers initially hired 1948-1972 using, for the first time, recently improved individual organ dose estimates. Excess relative risk (ERR) models were used to evaluate risks as functions of internal (plutonium) dose, external (primarily gamma) dose, gender, attained age and smoking. By December 31, 2003, 681 lung cancer deaths, 75 liver cancer deaths and 30 bone cancer deaths had occurred. Of these 786 deaths, 239 (30%) were attributed to plutonium exposure. Significant plutonium dose-response relationships (p < 0.001) were observed for all 3 endpoints, with lung and liver cancer risks reasonably described by linear functions. At attained age 60, the ERRs per Gy for lung cancer were 7.1 for males and 15 for females; the averaged-attained age ERRs for liver cancer were 2.6 and 29 for males and females, respectively; those for bone cancer were 0.76 and 3.4. This study is the first to present and compare dose-response analyses for cancers of all 3 organs. The unique Mayak cohort with its high exposures and well characterized doses has allowed quantification of the plutonium dose-response for lung, liver and bone cancer risks based on direct human data. These results will play an important role in plutonium risk assessment. Published 2008 Wiley-Liss, Inc. [source] Spinal degenerative disk disease (DDD) in female macaque monkeys: epidemiology and comparison with womenJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 3 2002Patricia Ann Kramer Spinal degenerative disk disease (DDD) in a radiographic, cross-sectional sample of 192 female macaque monkeys, approximately 5,30 years old, is described. The presence and extent of disk space narrowing (DSN) and anterior osteophytosis were assessed with reference to age, average lifetime body mass, and distribution within the thoracolumbar spine. Age was a strong correlate of disk narrowing and osteophytosis, with early signs appearing at equivalent ages in both species and increasing in prevalence thereafter. Macaques showed a far greater prevalence of DDD, especially in the oldest age group, than has been reported in the human data. Body mass was associated with disk narrowing in the macaque, but not with osteophytosis. The two species differed little in the pattern of distribution of DDD along the spine. Our results suggest that bipedality is not the singular, or even the most important, biomechanical factor in the development of human DDD. Rather, others shared postural regimes, e.g., sitting, may be responsible for the onset and progression of DDD in both species. The macaque model could substantially add to the under-standing and, potentially, treatment of this oftentimes debilitating condition. © 2002 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved. [source] Non-invasive cryolipolysisÔ for subcutaneous fat reduction does not affect serum lipid levels or liver function tests,LASERS IN SURGERY AND MEDICINE, Issue 10 2009Kenneth B. Klein MD Abstract Background and Objective Cryolipolysis provides a method of non-invasive fat reduction that significantly reduces subcutaneous fat without injury to adjacent tissues. Preliminary animal and human data have suggested that cryolipolysis has no effect on serum lipid profiles or liver tests. This study was intended to more fully document any effect of this procedure on lipid and liver-related blood tests. Study Design/Materials and Methods Forty subjects with fat bulges on their flanks ("love handles") were treated bilaterally with a non-invasive device (Zeltiq Aesthetics, Pleasanton, CA) that precisely cools tissue to achieve a reduction in the fat layer. Serum lipid levels and liver tests were measured prior to treatment, and at 1 day and 1, 4, 8, and 12 weeks post-treatment. Results No meaningful changes in mean values were observed for any blood lipid level or liver test at any point over the 12-week follow-up period. Conclusion Cryolipolysis, when used for reduction of subcutaneous flank fat, is not associated with changes in serum lipids or liver test results. Lasers Surg. Med. 41:785,790, 2009. © 2009 Wiley-Liss, Inc. [source] Toxicology and risk assessment of coumarin: Focus on human dataMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 2 2010Klaus Abraham Abstract Coumarin is a secondary phytochemical with hepatotoxic and carcinogenic properties. For the carcinogenic effect, a genotoxic mechanism was considered possible, but was discounted by the European Food Safety Authority in 2004 based on new evidence. This allowed the derivation of a tolerable daily intake (TDI) for the first time, and a value of 0.1,mg/kg body weight was arrived at based on animal hepatotoxicity data. However, clinical data on hepatotoxicity from patients treated with coumarin as medicinal drug is also available. This data revealed a subgroup of the human population being more susceptible for the hepatotoxic effect than the animal species investigated. The cause of the high susceptibility is currently unknown; possible mechanisms are discussed. Using the human data, a TDI of 0.1,mg/kg body weight was derived, confirming that of the European Food Safety Authority. Nutritional exposure may be considerably, and is mainly due to use of cassia cinnamon, which is a popular spice especially, used for cookies and sweet dishes. To estimate exposure to coumarin during the Christmas season in Germany, a telephone survey was performed with more than 1000 randomly selected persons. Heavy consumers of cassia cinnamon may reach a daily coumarin intake corresponding to the TDI. [source] Vaccination as a Therapeutic Approach to Alzheimer's DiseaseMOUNT SINAI JOURNAL OF MEDICINE: A JOURNAL OF PERSONALIZED AND TRANSLATIONAL MEDICINE, Issue 1 2010Thomas Wisniewski MD Abstract Alzheimer's disease is the most common cause of dementia worldwide. Alzheimer's disease is a member of a broad range of neurodegenerative diseases characterized pathologically by the conformational change of a normal protein into a pathological conformer with a high ,-sheet content that renders it neurotoxic. In the case of Alzheimer's disease, the normal soluble amyloid , peptide is converted into oligomeric/fibrillar amyloid ,. The oligomeric forms of amyloid , have been hypothesized to be the most toxic, whereas fibrillar amyloid , becomes deposited as amyloid plaques and congophilic angiopathy, which both serve as neuropathological markers of the disease. In addition, the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is a critical part of the pathology. Numerous therapeutic interventions are under investigation to prevent and treat Alzheimer's disease. Among the most exciting and advanced of these approaches is vaccination. Immunomodulation is being tried for a range of neurodegenerative disorders, with great success being reported in most model animal trials; however, the much more limited human data have shown more modest clinical success so far, with encephalitis occurring in a minority of patients treated with active immunization. The immunomodulatory approaches for neurodegenerative diseases involve targeting a self-protein, albeit in an abnormal conformation; hence, effective enhanced clearance of the disease-associated conformer has to be balanced with the potential risk of stimulating excessive toxic inflammation within the central nervous system. The design of future immunomodulatory approaches that are more focused is dependent on addressing a number of questions, including when is the best time to start immunization, what are the most appropriate targets for vaccination, and is amyloid central to the pathogenesis of Alzheimer's disease or is it critical to target tau-related pathology also. In this review, we discuss the past experience with vaccination for Alzheimer's disease and the development of possible future strategies that target both amyloid ,,related and tau-related pathologies. Mt Sinai J Med 77:17&–31, 2010. © 2010 Mount Sinai School of Medicine [source] Contractile properties of human motor units in health, aging, and diseaseMUSCLE AND NERVE, Issue 9 2001FRCPC, K. Ming Chan MD Abstract The primary function of skeletal muscle is to produce force for postural control and movement. Although the contractile properties of the whole muscle are useful functional indicators, they do not accurately reflect the heterogeneity of the constituent motor units (MUs) and their changes in health and disease. However, data on the contractile properties of human MUs, in comparison to other animal species, are relatively sparse. This, in part, is due to greater methodological challenges of in vivo studies of MUs in the human. The purpose of this review is to critically appraise the methods used in humans; to describe the normative data from different muscle groups; to discuss differences between data from healthy humans and other animal species; and, last, to characterize changes of the MU contractile properties in aging, disease, and in response to intervention. Because the spike-triggered averaging technique can only be used to study the twitch properties, other methods were subsequently developed to measure a wider range of contractile properties. Although there is general agreement between human data and those from other animal species, major differences do exist. Potential reasons for these discrepancies include true biological differences, but differences in the techniques used may also be responsible. Although limited, measurement of MU contractile properties in humans has provided insight into the changes associated with aging and motoneuronal diseases and provides a means of gauging their adaptive capacity for training and immobilization. © 2001 John Wiley & Sons, Inc. Muscle Nerve 24: 1113,1133 [source] Enteric neurodegeneration in ageingNEUROGASTROENTEROLOGY & MOTILITY, Issue 4 2008M. Camilleri Abstract, The objective of this article is to review the clinical presentation and neurobiology of degeneration of the enteric nervous system with emphasis on human data where available. Constipation, incontinence and evacuation disorders are frequently encountered in the ageing population. Healthy lower gastrointestinal function is essential for successful ageing as it is critical to maintaining independence and autonomy to pursue further activity. One clinical expression of enteric neurodegeneration is constipation. However, the aetiology may be multifactorial as disturbances of epithelial, muscle or neural function may all result from neurodegeneration. There is evidence of loss of excitatory (e.g. cholinergic) enteric neurons and interstitial cells of Cajal, whereas inhibitory (including nitrergic) neurons appear unaffected. Understanding neurodegeneration in the enteric nervous system is key to developing treatments to reverse it. Neurotrophins have been shown to accelerate colonic transit and relieve constipation in the medium term; they are also implicated in maintenance programmes in adult enteric neurons through a role in antioxidant defence. However, their effects in ageing colon require further study. There is evidence that 5-HT2 and 5-HT4 mechanisms are involved in development, maintenance and survival of enteric neurons. Further research is needed to understand and potentially reverse enteric neurodegeneration. [source] Evidence for shutter-speed variation in CR bolus-tracking studies of human pathologyNMR IN BIOMEDICINE, Issue 3 2005Thomas E. Yankeelov Abstract The standard pharmacokinetic model for the analysis of MRI contrast reagent (CR) bolus-tracking (B-T) data assumes that the mean intracellular water molecule lifetime (,i) is effectively zero. This assertion is inconsistent with a considerable body of physiological measurements. Furthermore, theory and simulation show the B-T time-course shape to be very sensitive to the ,i magnitude in the physiological range (hundreds of milliseconds to several seconds). Consequently, this standard model aspect can cause significant underestimations (factors of 2 or 3) of the two parameters usually determined: Ktrans, the vascular wall CR transfer rate constant, and ve, the CR distribution volume (the extracellular, extravascular space fraction). Analyses of animal model data confirmed two predicted behaviors indicative of this standard model inadequacy: (1) a specific temporal pattern for the mismatch between the best-fitted curve and data; and (2) an inverse dependence of the curve's Ktrans and ve magnitudes on the CR dose. These parameters should be CR dose-independent. The most parsimonious analysis allowing for realistic ,i values is the ,shutter-speed' model. Its application to the experimental animal data essentially eliminated the two standard model signature inadequacies. This paper reports the first survey for the extent of this ,shutter-speed effect' in human data. Retrospective analyses are made of clinical data chosen from a range of pathology (the active multiple sclerosis lesion, the invasive ductal carcinoma breast tumor, and osteosarcoma in the leg) that provides a wide variation, particularly of Ktrans. The signature temporal mismatch of the standard model is observed in all cases, and is essentially eliminated by use of the shutter-speed model. Pixel-by-pixel maps show that parameter values from the shutter-speed analysis are increased by more than a factor of 3 for some lesion regions. This endows the lesions with very high contrast, and reveals heterogeneities that are often not seen in the standard model maps. Normal muscle regions in the leg allow validation of the shutter-speed model Ktrans, ve, and ,i magnitudes, by comparison with results of previous careful rat leg studies not possible for human subjects. Copyright © 2004 John Wiley & Sons, Ltd. [source] Upregulation of TNF Receptor Type 2 in Human and Experimental Renal Allograft RejectionAMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2009U. Hoffmann An important role of TNF interacting with TNFR2 has been shown in different models of ischemic, nephrotoxic and immune-mediated renal injury. To systematically evaluate the expression of TNFR2 in renal allograft rejection, we investigated human renal allograft biopsies and, in addition, established an experimental transplantation model in rats to verify the human data under standardized conditions. The expression of TNFR2 was analyzed in 96 human renal allograft biopsies with different disease entities. In a 6-day and a 28-day experimental protocol, TNFR2 was examined in kidney specimens and in the urine of control, uni-nephrectomized and transplanted rats ± cyclosporine treatment (n = 114). In human biopsies and in rat allografts on day 6 with acute allograft rejection, significantly elevated expression of TNFR2 was observed in tubular epithelial cells, podocytes, B cells and monocytes/macrophages. The expression level was associated with renal function. The TNFR2 expression level at day 28 was significantly lower compared to day 6. TNFR2 is markedly upregulated both in human and experimental acute renal allograft rejection. Our data are robust and consistent between different species, suggesting a role for TNFR2 in the early course of rejection. [source] Strategy Generalization Across Orientation Tasks: Testing a Computational Cognitive ModelCOGNITIVE SCIENCE - A MULTIDISCIPLINARY JOURNAL, Issue 5 2008Glenn Gunzelmann Abstract Humans use their spatial information processing abilities flexibly to facilitate problem solving and decision making in a variety of tasks. This article explores the question of whether a general strategy can be adapted for performing two different spatial orientation tasks by testing the predictions of a computational cognitive model. Human performance was measured on an orientation task requiring participants to identify the location of a target either on a map (find-on-map) or within an egocentric view of a space (find-in-scene). A general strategy instantiated in a computational cognitive model of the find-on-map task, based on the results from Gunzelmann and Anderson (2006), was adapted to perform both tasks and used to generate performance predictions for a new study. The qualitative fit of the model to the human data supports the view that participants were able to tailor a general strategy to the requirements of particular spatial tasks. The quantitative differences between the predictions of the model and the performance of human participants in the new experiment expose individual differences in sample populations. The model provides a means of accounting for those differences and a framework for understanding how human spatial abilities are applied to naturalistic spatial tasks that involve reasoning with maps. [source] Instance-based learning in dynamic decision makingCOGNITIVE SCIENCE - A MULTIDISCIPLINARY JOURNAL, Issue 4 2003Cleotilde Gonzalez Abstract This paper presents a learning theory pertinent to dynamic decision making (DDM) called instancebased learning theory (IBLT). IBLT proposes five learning mechanisms in the context of a decision-making process: instance-based knowledge, recognition-based retrieval, adaptive strategies, necessity-based choice, and feedback updates. IBLT suggests in DDM people learn with the accumulation and refinement of instances, containing the decision-making situation, action, and utility of decisions. As decision makers interact with a dynamic task, they recognize a situation according to its similarity to past instances, adapt their judgment strategies from heuristic-based to instance-based, and refine the accumulated knowledge according to feedback on the result of their actions. The IBLT's learning mechanisms have been implemented in an ACT-R cognitive model. Through a series of experiments, this paper shows how the IBLT's learning mechanisms closely approximate the relative trend magnitude and performance of human data. Although the cognitive model is bounded within the context of a dynamic task, the IBLT is a general theory of decision making applicable to other dynamic environments. [source] | |||||||||||||