Conceptualising, evaluating and communicating uncertainty in forensic science: Identifying commonly used tools through an interdisciplinary configurative review.

This study provides a set of tools for conceptualising, evaluating and communicating uncertainty in forensic science. Given that the concept of uncertainty is one that transcends disciplinary boundaries, an interdisciplinary configurative review was carried out incorporating the disciplines of medicine, environmental science and economics, in order to identify common themes which could have valuable applications to the discipline of forensic science. Critical Interpretive Synthesis was used to develop sub-synthetic and synthetic constructs which interpreted and synthesised the underlying evidence and codes. This study provides three toolkits, one each for conceptualisation, evaluation and communication. The study identified an underlying theme concerning the obstacles that would need to be overcome for the effective application of these toolkits and achieving effective conceptualisation, evaluation and communication of uncertainty in forensic science to lay-stakeholders. These toolkits offer a starting point for developing the conversation for achieving greater transparency in the communication of uncertainty. They also have the potential to offer stakeholders enhanced understanding of the nuances and limitations of forensic science evidence and enable more transparent evaluation and scrutiny of the reliability, relevance and probative value of forensic materials in a crime reconstruction.

A device for high-throughput monitoring of degradation in soft tissue samples.

This work describes the design and validation of a novel device, the High-Throughput Degradation Monitoring Device (HDD), for monitoring the degradation of 24 soft tissue samples over incubation periods of several days inside a cell culture incubator. The device quantifies sample degradation by monitoring its deformation induced by a static gravity load. Initial instrument design and experimental protocol development focused on quantifying cartilage degeneration. Characterization of measurement errors, caused mainly by thermal transients and by translating the instrument sensor, demonstrated that HDD can quantify sample degradation with <6 µm precision and <10 µm temperature-induced errors. HDD capabilities were evaluated in a pilot study that monitored the degradation of fresh ex vivo human cartilage samples by collagenase solutions over three days. HDD could robustly resolve the effects of collagenase concentration as small as 0.5 mg/ml. Careful sample preparation resulted in measurements that did not suffer from donor-to-donor variation (coefficient of variance <70%). Due to its unique combination of sample throughput, measurement precision, temporal sampling and experimental versality, HDD provides a novel biomechanics-based experimental platform for quantifying the effects of proteins (cytokines, growth factors, enzymes, antibodies) or small molecules on the degradation of soft tissues or tissue engineering constructs. Thereby, HDD can complement established tools and in vitro models in important applications including drug screening and biomaterial development.

Morphological approach of the sternal foramen: an anatomic study and a short review of the literature.

BACKGROUND: The sternal foramen (SF) constitutes a specific anatomic defect in sternum, indicating an impaired fusion of ossificated segments, which occurs either in an anatomical part of the sternum or in sternal joints. The aim of this article is to provide baseline statistical data about the variations of the SF, to present a short review of the relevant literature and to compare results with other studies and populations. MATERIALS AND METHODS: We review relevant literature, and we present data obtai-ned from skeletal samples of known population and sex. A total of 35 well-preserved dried sterna from the prefecture of Eastern Macedonia and Thrace, Greece, were selected: 20 men and 15 women with a mean age of 55 ± 6 years old. Measurements were made with a sliding calliper and photographic documentation. RESULTS: The incidence of the SF in the 35 dried specimens was 14.2%, 4 men (20% of male sample) and 1 woman (6.6% of female sample) and 80% of sternal foramina were observed in male individuals. The SF was found in the sternum body (2 cases, 40% of foramina), in xiphoid process (2 cases, 40% of foramina) and in sternoxiphoidal junction (1 case, 20% of foramina). All of the sterna presented 1 single visible SF. Two anatomically unique cases were identified throughout these 5 sterna, both belonging in male subjects. CONCLUSIONS: The SF constitutes a relatively common variation with great radiological, clinical, and forensic significance. Presence of a SF with irregular bony margins complicates considerably radiological differential diagnosis. Awareness of this important anatomic variation is fundamental for clinicians and autopsy pathologists, in order to avoid severe fatal complications and elucidate the exact cause of death, respectively.

Association between serum levels of pro-metalloproteinase 1, tissue inhibitor of metalloproteinases 1 and 2 and prevalent cardiovascular disease in a population-based study.

AIM: The aim of the study was to test the association between circulating levels of matrix prometalloproteinase1 (pro-MMP1) and its tissue inhibitors TIMP1 and TIMP2 with prevalent cardiovascular events. METHODS: Prevalent cardiovascular events were documented in 500 participants of the Cyprus study (46% men) over the age of 40. Serum levels of pro-MMP1, TIMP1 and TIMP2 were measured with ELISA and the association between quartiles of serum levels and presence of cardiovascular disease (CVD) was tested using multivariable binary regression models. RESULTS: Lower serum levels of pro-MMP1 and TIMP1 were strongly associated with presence of CVD at baseline even after adjustment for conventional risk factors (P(for trend)=0.006 and P=0.001, respectively) and inflammatory factors (P(for trend)=0.005 and P=0.002, respectively) with people in the highest quartile of pro-MMP1 having a reduced odds for cardiovascular disease by about 70% compared to the lowest quartile (OR(adjusted)=0.26; 95% CI=0.19 to 0.75; P=0.01), whereas people with TIMP1 levels >1000 ng/mL had a 75% reduced odds for CVD compared to the rest (OR(adjusted)=0.25; 95% CI=0.11 to 0.60; P(for trend)=0.002). TIMP2 levels were not associated with prevalent cardiovascular disease. CONCLUSION: A strong association between lower levels of circulating pro-MMP1 and TIMP1 and risk of prevalent cardiovascular disease in a general population cohort over 40 years is evident, independent from common cardiovascular and inflammatory risk factors. The role of MMP1 and its tissue inhibitors, should be tested further in prospective studies of cardiovascular disease.

The immunomodulatory nutritional intervention NR100157 reduced CD4+ T-cell decline and immune activation: a 1-year multicenter randomized controlled double-blind trial in HIV-infected persons not receiving antiretroviral therapy (The BITE Study).

BACKGROUND: The immunomodulatory nutritional product NR100157 was developed for human immunodeficiency virus (HIV)-infected individuals. We hypothesized that targeting the compromised gastrointestinal tract of HIV-infected individuals would result in systemic immunological benefits. METHODS: In a multicenter, randomized, controlled, double-blind trial, 340 HIV-1-positive adults not on antiretroviral therapy, with CD4(+) T-cell counts <800/µL, were given either NR100157 or an isocaloric and isonitrogenous control for 52 weeks. Primary outcome was CD4(+) T-cell count. Secondary outcomes included plasma viral load (pVL), safety, and tolerability. In a pilot study (n = 20), levels of CD4(+)CD25(+) and CD8(+)CD38(+) activation were measured (n = 20). The trial is registered at the Dutch Trial Register (NTR886) and ISRCTN81868024. RESULTS: At 52 weeks, CD4(+) T-cell decline showed a 40-cell/µL difference (P = .03) in the intention-to-treat population in favor of the immunomodulatory NR100157 (control vs active, -68 ± 15 vs -28 ± 16 cells/µL/year). The change in pVL from baseline was similar between groups (P = .81). In the pilot study, the percentage of CD4(+)CD25(+) was lower in the active group (P < .05) and correlated with changes in CD4(+) T-cell count (r = -0.55, P < .05). The percentage of CD8(+)CD38(+) levels was unaffected. CONCLUSIONS: The specific immunonutritional product NR100157 significantly reduces CD4(+) decline in HIV-1-infected individuals, and this is associated with decreased levels of CD4(+)CD25(+). (This nutritional intervention is likely to affect local gut integrity and gut-associated lymphoid tissue homeostasis, which in turn translates positively to systemic effects.) Clinical Trials Registration. ISRCTN81868024.

Automated carotid IMT measurement and its validation in low contrast ultrasound database of 885 patient Indian population epidemiological study: results of AtheroEdge™ Software.

AIM: The aim of this paper was to demonstrate the usage of an automated computer-based IMT measurement system called - CALEX 3.0 (a class of patented AtheroEdge™ software) on a low contrast and low resolution image database acquired during an epidemiological study from India. The image contrast was very low with pixel density of 12.7 pixels/mm. Further, to demonstrate the accuracy and reproducibility of the AtheroEdge™ software system we compared it with the manual tracings of a vascular surgeon--considered as a gold standard. METHODS: We automatically measured the IMT value of 885 common carotid arteries in longitudinal B-Mode images. CALEX 3.0 consisted of a stage for the automatic recognition of the carotid artery and an IMT measurement modulus made of a fuzzy K-means classifier. Performance was assessed by measuring the system accuracy and reproducibility against manual tracings by experts. RESULTS: CALEX 3.0 processed all the 885 images of the dataset (100% success). The average automated obtained IMT measurement by CALEX 3.0 was 0.407±0.083 mm compared with 0.429 ± 0.052 mm for the manual tracings, which led to an IMT bias of 0.022±0.081mm. The IMT measurement accuracy (0.022 mm) was comparable to that obtained on high-resolution images and the reproducibility (0.081 mm) was very low and suitable to clinical application. The Figure-of-Merit defined as the percent agreement between the computer-estimated IMT and manually measured IMT for CALEX 3.0 was 94.7%. CONCLUSION: CALEX 3.0 had a 100% success in processing low contrast/low-resolution images. CALEX 3.0 is the first technique, which has led to high accuracy and reproducibility on low-resolution images acquired during an epidemiological study. We propose CALEX 3.0 as a generalized framework for IMT measurement on large datasets.

Evaluation of improvement in quality of life and physical activity after total knee arthroplasty in greek elderly women.

BACKGROUND: The aim of this study was to evaluate the changes in quality of life of patients after total knee arthroplasty and to assess the changes in physical activity by using a self-reported questionnaire and by counting the number of steps 3-6 months after post-operatively. METHODS: Included were fifty two elderly women (age 72.6±65.9 years, mean±SD) with knee osteoarthritis undergoing primary knee arthroplasty. Health-related quality of life, physical activity, pain and function and the number of steps were assessed before, 3 and 6 months post-operatively. We used the Medical Outcomes Study Short Form (SF-36), the Physical Activity Scale for the Elderly (PASE) and the pedometer SW200 Digiwalker of Yamax. RESULTS: Patients showed a significant improvement (p< 0.01, η2 =0.22) in health-related quality of life, particularly in physical function, (p<0 .001) body pain (p< 0.001) and vitality scale (p< 0.001) of SF-36 at 3 and 6 months after the procedure. Physical activity (PASE score) increased at 3 and 6 months after arthroplasty (p< 0.001, η2 =0.74), and the number of steps increased 6 months after, compared to the assessment that took place 3 months after operation (p< 0.001). CONCLUSIONS: Our results suggest that total knee arthroplasty leads to a gradual improvement in quality of life of elderly patients over the first 6 post-operative months.

Plaque area at carotid and common femoral bifurcations and prevalence of clinical cardiovascular disease.

AIM: Different ultrasonic arterial wall measurements have been used as predictors of future myocardial infarction or stroke. The aim of the present study was to determine the relationship of total plaque area (TPA) (the sum of the atherosclerotic plaque area measurements from both carotid and both common femoral arteries) with prevalence of cardiovascular disease in a population-based cross-sectional study and compare it with intima-media thickness (IMT). METHODS: Seven hundred sixty-two individuals (47% male) over the age of 40 were screened for cardiovascular risk factors. RESULTS: Evidence of clinical cardiovascular disease was present in 113 (14.8%). Both carotid and both common femoral bifurcations were scanned with ultrasound. After adjustment for conventional risk factors the association of IMT with prevalence of clinical cardiovascular disease was low (P=0.84, OR of upper IMT quintile 1.36; 95% CI 0.56 to 3.26) and of TPA high (P<0.001, OR of upper TPA quintile 8.38; 95% CI 2.57 to 27.32). TPA greater than 42 mm2 (cut-point derived from ROC curve analysis) identified 266 (34.9%) of the population that contained 87/113 (76.9%) of the clinical events (sensitivity: 77%; specificity: 73%; positive predictive value: 33%; negative predictive value: 94%; positive likelihood ratio of 2.79). In contrast, IMT greater than 0.07 mm had a sensitivity, specificity, positive and negative predictive value and positive likelihood ratio of 68%, 60%, 23%, 91% and 1.69 respectively. CONCLUSION: Total plaque area appears to be more strongly associated with the prevalence of cardiovascular disease than IMT. This finding warrants further prospective studies.

Leukocyte telomere length is associated with measures of subclinical atherosclerosis.

AIMS: Our aim was to test the association of mean leukocyte telomere length (LTL) with ultrasonic measures of subclinical atherosclerosis such as intima-media thickness in the common carotid (IMTcc) and sum of plaque areas (SPA) and with serological markers. METHODS AND RESULTS: Carotid and femoral bifurcations were scanned in 762 general population volunteers (46% men) over 40. Four features were considered: (a) IMTcc, (b) sum plaque areas of carotid plaques (SPAcar), (c) sum plaque area of common femoral plaques (SPAfem) and (d) sum plaque area (SPA--sum of the plaque areas of the largest plaques present in each of both carotid and femoral bifurcations). Mean LTL was determined with a quantitative real-time PCR-based method. IMTcc was strongly associated with mean LTL both before and after correction for traditional risk factors (B=-0.002; 95% CI=-0.004 to -0.00; p=0.014). In sex-specific analysis, the association was stronger in men (p for sex interaction<0.001). SPAfem was associated with LTL in women before and after correction (B=-0.195; 95% CI=-0.38 to -0.01; p=0.037) (p for sex interaction<0.001). LTL was also associated with age and sex-adjusted levels of hsCRP (p=0.012), sCD40L (p=0.042), homocysteine (p=0.006), creatinine (p=0.02), ApoA1 (p=0.01), Lp(a) (p=0.04) and HOMA-IR (p=0.008). CONCLUSIONS: Our results support the telomere hypothesis and highlight potential differences in the biological mechanisms leading to intima-media thickening and/or plaque formation between vascular beds. They may provide insights into a novel treatment of antisenescence to prevent atherosclerosis.

ApoB/ApoA1 ratio and subclinical atherosclerosis.

AIM: It has been demonstrated that an increased apolipoprotein B (ApoB)/apolipoprotein A-I (ApoA1) ratio is associated with atherogenic low density lipoprotein (LDL) particles and the development of clinical cardiovascular disease. The aim of this study was to test the hypothesis that ApoB/ApoA1 ratio is associated with early subclinical atherosclerosis as demonstrated by ultrasonic measurements. METHODS: Both common carotid and common femoral bifurcations have been scanned with high-resolution ultrasound in 767 volunteers over the age of 40. The latter consisted of 95% of the population of two randomly selected areas. IMTcc, IMTmax (including plaques), total plaque thickness (TPT) (the sum of the thickest plaques present at each bifurcation in cm) and black plaque burden (BPB) (TPT means plaque type) using the Widder classification with type 1 being the most hyperechoic and calcified and type 5 the most hypoechoic plaque were recorded. A medical history was taken with emphasis on risk factors present and a fasting lipid profile including ApoB and ApoA1 was determined. RESULTS: In the total population (N.=767) the mean (+/-SD) ApoB/ApoA1 ratio was 0.85 (+/-0.22). In linear regression analysis, the Apob/ApoA1 ratio was significantly associated with all the ultrasonic measurements of early atherosclerosis (intima media thickness, IMTcc, IMTmax, TPT and BPB). These findings remained significant after correcting for age, gender, smoking, hypertension and diabetes (P<0.001 for all). CONCLUSION: The results indicate that a high ApoB/ApoA1 ratio is associated not only with early atherosclerosis but also with hypoechoic (BPB) and by inference unstable plaques.

Media thickness measurement of the common carotid artery.

The intima-media thickness (IMT) of the common carotid artery (CCA) is widely used as an early indicator of the development of cardiovascular disease (CVD). It was proposed but not thoroughly investigated that the media thickness (MT), its composition and texture may be indicative for identifying the risk of stroke and differentiating between patients with high and low risk. In this study we present an automated method for segmentation of the media layer and measurement of its thickness in ultrasound images of the CCA. The snakes segmentation method was used, and was evaluated on 100 images against manual segmentation. The mean +/- standard deviation (sd) for the manual and the automated IMT measurements were 0.71+/-0.17 mm and 0.67+/-0.12 mm, and for the manual and the automated MT measurements were 0.25+/-0.12 mm and 0.25+/-0.11 mm respectively. There was no significant difference between the manual and the automated measurements. Further research for validating the proposed technique is required and for evaluating it in a larger sample of subjects.

Iron enhances endothelial cell activation in response to Cytomegalovirus or Chlamydia pneumoniae infection.

BACKGROUND: Chronic inflammation has been implemented in the pathogenesis of inflammatory diseases like atherosclerosis. Several pathogens like Chlamydia pneumoniae (Cp) and cytomegalovirus (CMV) result in inflammation and thereby are potentially artherogenic. Those infections could trigger endothelial activation, the starting point of the atherogenic inflammatory cascade. Considering the role of iron in a wide range of infection processes, the presence of iron may complicate infection-mediated endothelial activation. MATERIALS AND METHODS: Endothelial intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and endothelial selectin (E-selectin) expression were measured using flow cytometry, as an indication of endothelial activation. Cytotoxicity was monitored using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Immunostaining was applied to measure Cp and CMV infectivity to endothelial cells. RESULTS: An increased number of infected endothelial cells in a monolayer population leads to a raised expression of adhesion molecules of the whole cell population, suggesting paracrine interactions. Iron additively up-regulated Cp-induced VCAM-1 expression, whereas synergistically potentiated Cp-induced ICAM-1 expression. Together with CMV, iron also enhanced ICAM-1 and VCAM-1 expression. These iron effects were observed without modulation of the initial infectivity of both microorganisms. Moreover, the effects of iron could be reversed by intracellular iron chelation or radical scavenging, conforming modulating effects of iron on endothelial activation after infections. CONCLUSIONS: Endothelial response towards chronic infections depends on intracellular iron levels. Iron status in populations positive for Cp or CMV infections should be considered as a potential determinant for the development of atherosclerosis.

Severity of asymptomatic carotid stenosis and risk of ipsilateral hemispheric ischaemic events: results from the ACSRS study.

OBJECTIVES: This study determines the risk of ipsilateral ischaemic neurological events in relation to the degree of asymptomatic carotid stenosis and other risk factors. METHODS: Patients (n=1115) with asymptomatic internal carotid artery (ICA) stenosis greater than 50% in relation to the bulb diameter were followed up for a period of 6-84 (mean 37.1) months. Stenosis was graded using duplex, and clinical and biochemical risk factors were recorded. RESULTS: The relationship between ICA stenosis and event rate is linear when stenosis is expressed by the ECST method, but S-shaped if expressed by the NASCET method. In addition to the ECST grade of stenosis (RR 1.6; 95% CI 1.21-2.15), history of contralateral TIAs (RR 3.0; 95% CI 1.90-4.73) and creatinine in excess of 85 micromol/L (RR 2.1; 95% CI 1.23-3.65) were independent risk predictors. The combination of these three risk factors can identify a high-risk group (7.3% annual event rate and 4.3% annual stroke rate) and a low risk group (2.3% annual event rate and 0.7% annual stroke rate). CONCLUSIONS: Linearity between ECST per cent stenosis and risk makes this method for grading stenosis more amenable to risk prediction without any transformation not only in clinical practice but also when multivariable analysis is to be used. Identification of additional risk factors provides a new approach to risk stratification and should help refine the indications for carotid endarterectomy.

Factors associated with mortality in patients with asymptomatic carotid stenosis: results from the ACSRS Study.

AIM: This study determines the factors associated with mortality in patients with asymptomatic carotid stenosis. METHODS: Patients (n=1,101) with asymptomatic internal carotid artery stenosis greater than 50% in relation to the bulb diameter were followed up for a period of 6 to 84 (median 38) months. Stenosis was graded using duplex scanning and expressed as a percentage of the carotid bulb diameter. Clinical and biochemical risk factors were recorded. The end-points were ipsilateral ischemic stroke, cardiovascular death and all cause mortality. RESULTS: In a Cox multivariate analysis 6 factors emerged as independent predictors of risk. Age, male gender, cardiac failure, left ventricular hypertrophy on electrocardiogram (ECG) and myocardial ischemia on ECG were associated with increased risk. Antiplatelet therapy was associated with decreased risk. Based on these risk factors a high-risk group consisting of one third of the population with a 40% cumulative cardiovascular death rate and a 66% all cause death rate at 7 years could be identified. The remaining 2/3 consisted of a low-risk group with a 10% cumulative cardiovascular death rate and a 21% all cause death rate at 7 years (P<0.0001 compared to the high risk group). There was not any significant difference in the cumulative ipsilateral stroke rate, which was 12% in the low and 13% in the high cardiovascular risk group (Log Rank P>0.05). CONCLUSIONS: The methodology and findings from the ACSRS natural history study need to be applied to randomized controlled trials on the value of carotid endarterectomy or stenting in patients with asymptomatic carotid stenosis. They may help refine the indications for intervention in patients with carotid endarterectomy.

Human immunodeficiency virus type 1 replication inhibition by the bidentate iron chelators CP502 and CP511 is caused by proliferation inhibition and the onset of apoptosis.

BACKGROUND: The iron chelators deferoxamine (DF) and deferiprone (CP20) have been shown to inhibit human immunodeficiency virus type 1 (HIV-1) replication in human peripheral blood lymphocytes (PBL). The orally active bidentate chelators CP502 and CP511, which also belong to the 3-hydroxypyridin-4-one family, but with higher affinities for iron than CP20, were monitored for their antiviral properties by checking for p24 antigen production and nuclear factor (NF)-kappaB activation, and their ability to induce apoptosis. MATERIALS AND METHODS: Human PBLs were isolated from HIV-1 seronegative donors and subsequently infected with HIV-1(Ba-L) for 2 h. After 5 days' incubation, HIV-1 replication was monitored by p24 antigen production. Cellular proliferation as well as caspase-3 activity were monitored in uninfected cells after a period of 5 days and after 1 day infection, respectively. NF-kappaB activity was also monitored by electromobility shift assays (EMSA) performed on nuclear extracts of Jurkat cells treated with the different chelators for 4 h. RESULTS: CP502 and CP511 decrease HIV-1 replication by decreasing cellular proliferation in a similar manner to DF and CP20. CP511 seemed to be more potent than either CP502 or CP20. Due to the reduction in cellular proliferation, there was an increase in caspase-3 activity after 24 h incubation. NF-kappaB activity was not affected by any of the chelators. CONCLUSIONS: Iron chelators with high affinities for iron, which are under development for the treatment of iron overload, could contribute to the reduction of HIV-1 replication in infected patients by cellular proliferation inhibition rather than by a direct antiviral action.

The chemotherapeutic agent bleomycin in a two-drug combination with zidovudine, ritonavir or indinavir synergistically inhibits HIV Type-1 replication in peripheral blood lymphocytes.

It has been suggested that the combination of cancer chemotherapy with antiviral therapy is helpful for the containment of lymphomas in HIV-infected patients. Since we have recently shown that the nucleic acid binding chemotherapeutic agent bleomycin in itself has antiviral properties, we looked to see if there was any possible synergy with current anti-HIV agents. Combinations of zidovudine, indinavir or ritonavir with bleomycin, synergistically inhibited HIV-1(AT) replication in stimulated peripheral blood lymphocytes (combination index at 50% virus inhibition was 0.427, 0.604 and 0.535, respectively) and this synergism was not accompanied by any synergistic effects on cytotoxicity. We conclude from these data that further studies to investigate the clinical efficacy of combinations of antiviral and cancer chemotherapeutic agents are warranted in relation to viral load improvement.

Movement-related potentials in Huntington's disease: movement preparation and execution.

Movement-related potentials (MRPs) reflect increasing cortical activity related to the preparation and execution of voluntary movement. Execution and preparatory components may be separated by comparing MRPs recorded from actual and imagined movement. Imagined movement initiates preparatory processes, but not motor execution activity. MRPs are maximal over the supplementary motor area (SMA), an area of the cortex involved in the planning and preparation of movement. The SMA receives input from the basal ganglia, which are affected in Huntington's disease (HD), a hyperkinetic movement disorder. In order to further elucidate the effects of the disorder upon the cortical activity relating to movement, MRPs were recorded from ten HD patients, and ten age-matched controls, whilst they performed and imagined performing a sequential button-pressing task. HD patients produced MRPs of significantly reduced size both for performed and imagined movement. The component relating to movement execution was obtained by subtracting the MRP for imagined movement from the MRP for performed movement, and was found to be normal in HD. The movement preparation component was found by subtracting the MRP found for a control condition of watching the visual cues from the MRP for imagined movement. This preparation component in HD was reduced in early slope, peak amplitude, and post-peak slope. This study therefore reported abnormal MRPs in HD, particularly in terms of the components relating to movement preparation, and this finding may further explain the movement deficits reported in the disease.

Anti-HIV effect of iron chelators: different mechanisms involved.

BACKGROUND: Drugs for the treatment of AIDS have been directed to specific events in the human immunodeficiency virus (HIV-1) life cycle, aimed to stop viral replication by inhibition of reverse transcriptase or protease activity. Studies showing that oxidative stress and iron may be important in the activation of HIV-1 have focused attention on the potential therapeutic use of iron chelators. OBJECTIVES: The goal of this review is to describe several possibilities as to how iron is involved in the replication of HIV and how iron chelation may interfere in this process. STUDY DESIGN: First some physico-chemical properties of iron concerning solubility, oxidation-reduction potential, catalysis, and chelation will be discussed. In the second part, the role of iron in various biochemical systems is explained. RESULTS: Nuclear factor kappa B (NF-kappaB) activation, regulating proviral transcription, can be influenced by iron through the production of reactive oxygen species. A second route by which iron chelation could influence HIV replication, is by inhibition of DNA synthesis through inactivation of iron-dependent ribonucleotide reductase. Another strategy which can be employed in targeting iron chelators against HIV-1, is direct oxidative viral RNA/DNA attack. This could be achieved by bleomycin, a cytostatic agent with the ability to form a complex with DNA and RNA. CONCLUSION: Chelation may withhold iron from viral metabolism but on the other hand may also favor catalysis of reactive oxygen species directed to viral constituents. In combination with existing antivirals, iron chelation could add to improve the treatment of HIV-disease.