A coronary heart disease risk model for predicting the effect of potent antiretroviral therapy in HIV-1 infected men

BACKGROUND: Many HIV-infected patients on highly active antiretroviral therapy (HAART) experience metabolic complications including dyslipidaemia and insulin resistance, which may increase their coronary heart disease (CHD) risk. We developed a prognostic model for CHD tailored to the changes in risk factors observed in patients starting HAART. METHODS: Data from five cohort studies (British Regional Heart Study, Caerphilly and Speedwell Studies, Framingham Offspring Study, Whitehall II) on 13,100 men aged 40-70 and 114,443 years of follow up were used. CHD was defined as myocardial infarction or death from CHD. Model fit was assessed using the Akaike Information Criterion; generalizability across cohorts was examined using internal-external cross-validation. RESULTS: A parametric model based on the Gompertz distribution generalized best. Variables included in the model were systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, triglyceride, glucose, diabetes mellitus, body mass index and smoking status. Compared with patients not on HAART, the estimated CHD hazard ratio (HR) for patients on HAART was 1.46 (95% CI 1.15-1.86) for moderate and 2.48 (95% CI 1.76-3.51) for severe metabolic complications. CONCLUSIONS: The change in the risk of CHD in HIV-infected men starting HAART can be estimated based on typical changes in risk factors, assuming that HRs estimated using data from non-infected men are applicable to HIV-infected men. Based on this model the risk of CHD is likely to increase, but increases may often be modest, and could be offset by lifestyle changes.

Functional effect of FGF2- and FGF8-expanded ventral mesencephalic precursor cells in a rat model of Parkinson's disease

Ventral mesencephalic (VM) precursor cells are of interest in the search for transplantable dopaminergic neurons for cell therapy in Parkinson's disease (PD). In the present study we investigated the survival and functional capacity of in vitro expanded, primary VM precursor cells after intrastriatal grafting to a rat model of PD. Embryonic day 12 rat VM tissue was mechanically dissociated and cultured for 4 or 8 days in vitro (DIV) in the presence of FGF2 (20 ng/ml), FGF8 (20 ng/ml) or without mitogens (control). Cells were thereafter differentiated for 6 DIV by mitogen withdrawal and addition of serum. After differentiation, significantly more tyrosine hydroxylase-immunoreactive (TH-ir), dopamine-producing neurons were found in FGF2- and FGF8-expanded cultures compared to controls. Moreover, expansion for 4 DIV resulted in significantly more TH-ir cells than expansion for 8 DIV both for FGF2 (2.4 fold; P<0.001) and FGF8 (3.8 fold; P<0.001) treated cultures. The functional potential of the expanded cells (4 DIV) was examined after grafting into striatum of aged 6-hydroxydopamine-lesioned rats. Amphetamine-induced rotations performed 3, 6 and 9 weeks postgrafting revealed that grafts of FGF2-expanded cells induced a significantly faster and better functional recovery than grafts of FGF8-expanded cells or control cells (P<0.05 for both). Grafts of FGF2-expanded cells also contained significantly more TH-ir cells than grafts of FGF8-expanded cells (P<0.05) or control cells (P<0.01). In conclusion, FGF2-mediated pregrafting expansion of primary VM precursor cells considerably improves dopaminergic cell survival and functional restoration in a rat model of PD.

Optimal beam forming for laser beam propagation through random media

Focusing optical beams on a target through random propagation media is very important in many applications such as free space optical communica- tions and laser weapons. Random media effects such as beam spread and scintillation can degrade the optical system's performance severely. Compensation schemes are needed in these applications to overcome these random media effcts. In this research, we investigated the optimal beams for two different optimization criteria: one is to maximize the concentrated received intensity and the other is to minimize the scintillation index at the target plane. In the study of the optimal beam to maximize the weighted integrated intensity, we derive a similarity relationship between pupil-plane phase screen and extended Huygens-Fresnel model, and demonstrate the limited utility of maximizing the average integrated intensity. In the study ofthe optimal beam to minimize the scintillation index, we derive the first- and second-order moments for the integrated intensity of multiple coherent modes. Hermite-Gaussian and Laguerre-Gaussian modes are used as the coherent modes to synthesize an optimal partially coherent beam. The optimal beams demonstrate evident reduction of scintillation index, and prove to be insensitive to the aperture averaging effect.

Adenovirus-mediated transforming growth factor-beta ameliorates ischemic necrosis of epigastric skin flaps in a rat model

BACKGROUND: Gene therapy has been recently introduced as a novel approach to treat ischemic tissues by using the angiogenic potential of certain growth factors. We investigated the effect of adenovirus-mediated gene therapy with transforming growth factor-beta (TGF-beta) delivered into the subdermal space to treat ischemically challenged epigastric skin flaps in a rat model. MATERIAL AND METHODS: A pilot study was conducted in a group of 5 animals pretreated with Ad-GFP and expression of green fluorescent protein in the skin flap sections was demonstrated under fluorescence microscopy at 2, 4, and 7 days after the treatment, indicating a successful transfection of the skin flaps following subdermal gene therapy. Next, 30 male Sprague Dawley rats were divided into 3 groups of 10 rats each. An epigastric skin flap model, based solely on the right inferior epigastric vessels, was used as the model in this study. Rats received subdermal injections of adenovirus encoding TGF-beta (Ad-TGF-beta) or green fluorescent protein (Ad-GFP) as treatment control. The third group (n = 10) received saline and served as a control group. A flap measuring 8 x 8 cm was outlined on the abdominal skin extending from the xiphoid process proximally and the pubic region distally, to the anterior axillary lines bilaterally. Just prior to flap elevation, the injections were given subdermally in the left upper corner of the flap. The flap was then sutured back to its bed. Flap viability was evaluated seven days after the initial operation. Digital images of the epigastric flaps were taken and areas of necrotic zones relative to total flap surface area were measured and expressed as percentages by using a software program. RESULTS: There was a significant increase in mean percent surviving area between the Ad-TGF-beta group and the two other control groups (P < 0.05). (Ad-TGF-beta: 90.3 +/- 4.0% versus Ad-GFP: 82.2 +/- 8.7% and saline group: 82.6 +/- 4.3%.) CONCLUSIONS: In this study, the authors were able to demonstrate that adenovirus-mediated gene therapy using TGF-beta ameliorated ischemic necrosis in an epigastric skin flap model, as confirmed by significant reduction in the necrotic zones of the flap. The results of this study raise the possibility of using adenovirus-mediated TGF-beta gene therapy to promote perfusion in random portion of skin flaps, especially in high-risk patients.

Hierarchical Markov Random Fields Applied to Model Soft Tissue Deformations on Graphics Hardware

Many methodologies dealing with prediction or simulation of soft tissue deformations on medical image data require preprocessing of the data in order to produce a different shape representation that complies with standard methodologies, such as mass–spring networks, finite element method s (FEM). On the other hand, methodologies working directly on the image space normally do not take into account mechanical behavior of tissues and tend to lack physics foundations driving soft tissue deformations. This chapter presents a method to simulate soft tissue deformations based on coupled concepts from image analysis and mechanics theory. The proposed methodology is based on a robust stochastic approach that takes into account material properties retrieved directly from the image, concepts from continuum mechanics and FEM. The optimization framework is solved within a hierarchical Markov random field (HMRF) which is implemented on the graphics processor unit (GPU See Graphics processing unit ).

Effect of vascular targeting agent in rat tumor model: dynamic contrast-enhanced versus diffusion-weighted MR imaging

PURPOSE: To compare dynamic contrast material-enhanced magnetic resonance (MR) imaging and diffusion-weighted MR imaging for noninvasive evaluation of early and late effects of a vascular targeting agent in a rat tumor model. MATERIALS AND METHODS: The study protocol was approved by the local ethics committee for animal care and use. Thirteen rats with one rhabdomyosarcoma in each flank (26 tumors) underwent dynamic contrast-enhanced imaging and diffusion-weighted echo-planar imaging in a 1.5-T MR unit before intraperitoneal injection of combretastatin A4 phosphate and at early (1 and 6 hours) and later (2 and 9 days) follow-up examinations after the injection. Histopathologic examination was performed at each time point. The apparent diffusion coefficient (ADC) of each tumor was calculated separately on the basis of diffusion-weighted images obtained with low b gradient values (ADC(low); b = 0, 50, and 100 sec/mm(2)) and high b gradient values (ADC(high); b = 500, 750, and 1000 sec/mm(2)). The difference between ADC(low) and ADC(high) was used as a surrogate measure of tissue perfusion (ADC(low) - ADC(high) = ADC(perf)). From the dynamic contrast-enhanced MR images, the volume transfer constant k and the initial slope of the contrast enhancement-time curve were calculated. For statistical analyses, a paired two-tailed Student t test and linear regression analysis were used. RESULTS: Early after administration of combretastatin, all perfusion-related parameters (k, initial slope, and ADC(perf)) decreased significantly (P < .001); at 9 days after combretastatin administration, they increased significantly (P < .001). Changes in ADC(perf) were correlated with changes in k (R(2) = 0.46, P < .001) and the initial slope (R(2) = 0.67, P < .001). CONCLUSION: Both dynamic contrast-enhanced MR imaging and diffusion-weighted MR imaging allow monitoring of perfusion changes induced by vascular targeting agents in tumors. Diffusion-weighted imaging provides additional information about intratumoral cell viability versus necrosis after administration of combretastatin.

Effect of pressure-controlled intermittent coronary sinus occlusion (PICSO) on myocardial ischaemia and reperfusion in a closed-chest porcine model

AIMS To investigate a pressure-controlled intermittent coronary sinus occlusion (PICSO) system in an ischaemia/reperfusion model. METHODS AND RESULTS We randomly assigned 18 pigs subjected to 60 minutes ischaemia by left anterior descending (LAD) coronary artery balloon occlusion to PICSO (n=12, groups A and B) or to controls (n=6, group C). PICSO started 10 minutes before (group A), or 10 minutes after (group B) reperfusion and was maintained for 180 minutes. A continuous drop of distal LAD pressure was observed in group C. At 180 minutes of reperfusion, LAD diastolic pressure was significantly lower in group C compared to groups A and B (p=0.02). LAD mean pressure was significantly less than the systemic arterial mean pressure in group C (p=0.02), and the diastolic flow slope was flat, compared to groups A and B (p=0.03). IgG and IgM antibody deposition was significantly higher in ischaemic compared to non-ischaemic tissue in group C (p<0.05). Significantly more haemorrhagic lesions were seen in the ischaemic myocardium of group C, compared to groups A and B (p=0.002). The necrotic area differed non-significantly among groups. CONCLUSIONS PICSO was safe and effective in improving coronary perfusion pressure and reducing antibody deposition consistent with reduced microvascular obstruction and ischaemia/reperfusion injury.

Neuroprotective effect of cathodal transcranial direct current stimulation in a rat stroke model

Experimental focal brain ischemia generates in the penumbra recurrent depolarizations which spread across the injured cortex inducing infarct growth. Transcranial direct current stimulation can induce a lasting, polarity-specific, modulation of cortical excitability. To verify whether cathodal transcranial direct current stimulation could reduce the infarct size and the number of depolarizations, focal ischemia was induced in the rat by the 3 vessels occlusion technique. In the first experiment 12 ischemic rats received cathodal stimulation (alternating 15min on and 15min off) starting 45min after middle cerebral artery occlusion and lasting 4h. In the second experiment 12 ischemic rats received cathodal transcranial direct current stimulation with the same protocol but starting soon after middle cerebral artery occlusion and lasting 6h. In both experiments controls were 12 ischemic rats not receiving stimulation. Cathodal stimulation reduced the infarct volume in the first experiment by 20% (p=0.002) and in the second by 30% (p=0.003). The area of cerebral infarction was smaller in animals receiving cathodal stimulation in both experiments (p=0.005). Cathodal stimulation reduced the number of depolarizations (p=0.023) and infarct volume correlated with the number of depolarizations (p=0.048). Our findings indicate that cathodal transcranial direct current stimulation exert a neuroprotective effect in the acute phase of stroke possibly decreasing the number of spreading depolarizations. These findings may have translational relevance and open a new avenue in neuroprotection of stroke in humans.

Effect of enamel matrix derivative on periodontal wound healing and regeneration in an osteoporotic model.

BACKGROUND Despite the worldwide increased prevalence of osteoporosis, no data are available evaluating the effect of an enamel matrix derivative (EMD) on the healing of periodontal defects in patients with osteoporosis. This study aims to evaluate whether the regenerative potential of EMD may be suitable for osteoporosis-related periodontal defects. METHODS Forty female Wistar rats (mean body weight: 200 g) were used for this study. An osteoporosis animal model was carried out by bilateral ovariectomy (OVX) in 20 animals. Ten weeks after OVX, bilateral fenestration defects were created at the buccal aspect of the first mandibular molar. Animals were randomly assigned to four groups of 10 animals per group: 1) control animals with unfilled periodontal defects; 2) control animals with EMD-treated defects; 3) OVX animals with unfilled defects; and 4) OVX animals with EMD-treated defects. The animals were euthanized 28 days later, and the percentage of defect fill and thickness of newly formed bone and cementum were assessed by histomorphometry and microcomputed tomography (micro-CT) analysis. The number of osteoclasts was determined by tartrate-resistant acid phosphatase (TRAP), and angiogenesis was assessed by analyzing formation of blood vessels. RESULTS OVX animals demonstrated significantly reduced bone volume in unfilled defects compared with control defects (18.9% for OVX animals versus 27.2% for control animals) as assessed by micro-CT. The addition of EMD in both OVX and control animals resulted in significantly higher bone density (52.4% and 69.2%, respectively) and bone width (134 versus 165μm) compared with untreated defects; however, the healing in OVX animals treated with EMD was significantly lower than that in control animals treated with EMD. Animals treated with EMD also demonstrated significantly higher cementum formation in both control and OVX animals. The number of TRAP-positive osteoclasts did not vary between untreated and EMD-treated animals; however, a significant increase was observed in all OVX animals. The number of blood vessels and percentage of new vessel formation was significantly higher in EMD-treated samples. CONCLUSIONS The results from the present study suggest that: 1) an osteoporotic phenotype may decrease periodontal regeneration; and 2) EMD may support greater periodontal regeneration in patients suffering from the disease. Additional clinical studies are necessary to fully elucidate the possible beneficial effect of EMD for periodontal regeneration in patients suffering from osteoporosis.

Effect of Combined Systemic and Local Morpholino Treatment on the Spinal Muscular Atrophy Δ7 Mouse Model Phenotype

BACKGROUND: Spinal muscular atrophy (SMA) is a fatal motor neuron disease of childhood that is caused by mutations in the SMN1 gene. Currently, no effective treatment is available. One possible therapeutic approach is the use of antisense oligos (ASOs) to redirect the splicing of the paralogous gene SMN2, thus increasing functional SMN protein production. Various ASOs with different chemical properties are suitable for these applications, including a morpholino oligomer (MO) variant with a particularly excellent safety and efficacy profile. OBJECTIVE: We investigated a 25-nt MO sequence targeting the negative intronic splicing silencer (ISS-N1) 10 to 34 region. METHODS: We administered a 25-nt MO sequence against the ISS-N1 region of SMN2 (HSMN2Ex7D[-10-34]) in the SMAΔ7 mouse model and evaluated the effect and neuropathologic phenotype. We tested different concentrations (from 2 to 24 nM) and delivery protocols (intracerebroventricular injection, systemic injection, or both). We evaluated the treatment efficacy regarding SMN levels, survival, neuromuscular phenotype, and neuropathologic features. RESULTS: We found that a 25-nt MO sequence against the ISS-N1 region of SMN2 (HSMN2Ex7D[-10-34]) exhibited superior efficacy in transgenic SMAΔ7 mice compared with previously described sequences. In our experiments, the combination of local and systemic administration of MO (bare or conjugated to octaguanidine) was the most effective approach for increasing full-length SMN expression, leading to robust improvement in neuropathologic features and survival. Moreover, we found that several small nuclear RNAs were deregulated in SMA mice and that their levels were restored by MO treatment. CONCLUSION: These results indicate that MO-mediated SMA therapy is efficacious and can result in phenotypic rescue, providing important insights for further development of ASO-based therapeutic strategies in SMA patients.

Effect of surface restoring on subsurface variability in a climate model during 1949–2005

Initializing the ocean for decadal predictability studies is a challenge, as it requires reconstructing the little observed subsurface trajectory of ocean variability. In this study we explore to what extent surface nudging using well-observed sea surface temperature (SST) can reconstruct the deeper ocean variations for the 1949–2005 period. An ensemble made with a nudged version of the IPSLCM5A model and compared to ocean reanalyses and reconstructed datasets. The SST is restored to observations using a physically-based relaxation coefficient, in contrast to earlier studies, which use a much larger value. The assessment is restricted to the regions where the ocean reanalyses agree, i.e. in the upper 500 m of the ocean, although this can be latitude and basin dependent. Significant reconstruction of the subsurface is achieved in specific regions, namely region of subduction in the subtropical Atlantic, below the thermocline in the equatorial Pacific and, in some cases, in the North Atlantic deep convection regions. Beyond the mean correlations, ocean integrals are used to explore the time evolution of the correlation over 20-year windows. Classical fixed depth heat content diagnostics do not exhibit any significant reconstruction between the different existing bservation-based references and can therefore not be used to assess global average time-varying correlations in the nudged simulations. Using the physically based average temperature above an isotherm (14°C) alleviates this issue in the tropics and subtropics and shows significant reconstruction of these quantities in the nudged simulations for several decades. This skill is attributed to the wind stress reconstruction in the tropics, as already demonstrated in a perfect model study using the same model. Thus, we also show here the robustness of this result in an historical and observational context.

Effect sizes and standardization in neighbourhood models of forest stands: potential biases and misinterpretations

Effects of conspecific neighbours on survival and growth of trees have been found to be related to species abundance. Both positive and negative relationships may explain observed abundance patterns. Surprisingly, it is rarely tested whether such relationships could be biased or even spurious due to transforming neighbourhood variables or influences of spatial aggregation, distance decay of neighbour effects and standardization of effect sizes. To investigate potential biases, communities of 20 identical species were simulated with log-series abundances but without species-specific interactions. No relationship of conspecific neighbour effects on survival or growth with species abundance was expected. Survival and growth of individuals was simulated in random and aggregated spatial patterns using no, linear, or squared distance decay of neighbour effects. Regression coefficients of statistical neighbourhood models were unbiased and unrelated to species abundance. However, variation in the number of conspecific neighbours was positively or negatively related to species abundance depending on transformations of neighbourhood variables, spatial pattern and distance decay. Consequently, effect sizes and standardized regression coefficients, often used in model fitting across large numbers of species, were also positively or negatively related to species abundance depending on transformation of neighbourhood variables, spatial pattern and distance decay. Tests using randomized tree positions and identities provide the best benchmarks by which to critically evaluate relationships of effect sizes or standardized regression coefficients with tree species abundance. This will better guard against potential misinterpretations.

Development of a Tumour Growth Inhibition Model to Elucidate the Effects of Ritonavir on Intratumoural Metabolism and Anti-tumour Effect of Docetaxel in a Mouse Model for Hereditary Breast Cancer

In a mouse tumour model for hereditary breast cancer, we previously explored the anti-cancer effects of docetaxel, ritonavir and the combination of both and studied the effect of ritonavir on the intratumoural concentration of docetaxel. The objective of the current study was to apply pharmacokinetic (PK)-pharmacodynamic (PD) modelling on this previous study to further elucidate and quantify the effects of docetaxel when co-administered with ritonavir. PK models of docetaxel and ritonavir in plasma and in tumour were developed. The effect of ritonavir on docetaxel concentration in the systemic circulation of Cyp3a knock-out mice and in the implanted tumour (with inherent Cyp3a expression) was studied, respectively. Subsequently, we designed a tumour growth inhibition model that included the inhibitory effects of both docetaxel and ritonavir. Ritonavir decreased docetaxel systemic clearance with 8% (relative standard error 0.4%) in the co-treated group compared to that in the docetaxel only-treated group. The docetaxel concentration in tumour tissues was significantly increased by ritonavir with mean area under the concentration-time curve 2.5-fold higher when combined with ritonavir. Observed tumour volume profiles in mice could be properly described by the PK/PD model. In the co-treated group, the enhanced anti-tumour effect was mainly due to increased docetaxel tumour concentration; however, we demonstrated a small but significant anti-tumour effect of ritonavir addition (p value <0.001). In conclusion, we showed that the increased anti-tumour effect observed when docetaxel is combined with ritonavir is mainly caused by enhanced docetaxel tumour concentration and to a minor extent by a direct anti-tumour effect of ritonavir.