Interleukin-18 Antagonism Improved Histopathological Conditions of Malaria Infection in Mice

Background: Interleukin 18 (IL-18) exerts pleiotropic roles in many inflammatory-related diseases including parasitic infection. Previous studies have demonstrated the promising therapeutic potential of modulating IL-18 bioactivity in various pathological conditions. However, its involvement during malaria infection has yet to be established. In this study, we demonstrated the effect of modulating IL-18 on the histopathological conditions of malaria infected mice. Methods: Plasmodium berghei ANKA infection in male ICR mice was used as a model for malaria infection. Modulation of IL-18 release was carried out by treatment of malarial mice with recombinant mouse IL-18 (rmIL-18) and recombinant mouse IL-18 Fc chimera (rmIL-18Fc) intravenously. Histopathological study and analysis were performed on major organs including brain, liver, spleen, lungs and kidney. Results: Treatment with rmIL-18Fc resulted in significant improvements on the histopathological conditions of the organs in malaria-infected mice. Conclusion: IL-18 is an important mediator of malaria pathogenesis and targeting IL-18 could prove beneficial in malaria-infected host.Key Words: Malaria, Interleukin-18, Plasmodium berghei, Histopathology     

Risk-Taking in Disorders of Natural and Drug Rewards: Neural Correlates and Effects of Probability,Valence, and Magnitude

Pathological behaviors toward drugs and food rewards have underlying commonalities. Risk-taking has a fourfold pattern varying as a function of probability and valence leading to the nonlinearity of probability weighting with overweighting of small probabilities and underweighting of large probabilities. Here we assess these influences on risk-taking in patients with pathological behaviors toward drug and food rewards and examine structural neural correlates of nonlinearity of probability weighting in healthy volunteers. In the anticipation of rewards, subjects with binge eating disorder show greater risk-taking, similar to substance-use disorders. Methamphetamine-dependent subjects had greater nonlinearity of probability weighting along with impaired subjective discrimination of probability and reward magnitude. Ex-smokers also had lower risk-taking to rewards compared with non-smokers. In the anticipation of losses, obesity without binge eating had a similar pattern to other substance-use disorders. Obese subjects with binge eating also have impaired discrimination of subjective value similar to that of the methamphetamine-dependent subjects. Nonlinearity of probability weighting was associated with lower gray matter volume in dorsolateral and ventromedial prefrontal cortex and orbitofrontal cortex in healthy volunteers. Our findings support a distinct subtype of binge eating disorder in obesity with similarities in risk-taking in the reward domain to substance use disorders. The results dovetail with the current approach of defining mechanistically based dimensional approaches rather than categorical approaches to psychiatric disorders. The relationship to risk probability and valence may underlie the propensity toward pathological behaviors toward different types of rewards.     

The effect of fluvastatin on fibrinolytic factors in patients with hypercholesterolemia

Several studies have shown cardiovascular benefit in treating hypercholesterolemia with HMG-CoA reductase inhibitor. However, in addition to the lowering of cholesterol, the beneficial effects of this inhibitor reflect other pharmacological activities. Whether these beneficial effects are partly mediated by changes in fibrinolytic factors remains to be proven, since clinical studies on the effects of HMG-CoA reductase inhibitors on fibrinolytic factors have not yielded consistent results. The purpose of this study was to evaluate the effects of fluvastatin on fibrinolytic factors in hypercholesterolemic patients. After 6 weeks on a low-fat, low-cholesterol diet, 23 outpatients known to have primary hypercholesterolemia with low density lipoprotein cholesterol (LDL-C) > or = 130 mg/dl with at least 2 risk factors or fasting LDL-C > or = 160 mg/dl were selected for the study. Venous blood samples were collected at baseline and at 8 weeks after fluvastatin therapy (40 mg/day) to measure of tissue plasminogen activator (t-PA), plasminogen activators inhibitor-1 (PAI-1), fibrinogen, D-dimer and lipid profile. After 8 weeks of therapy, fluvastatin reduced serum cholesterol by 11% (261.9 mg/dl vs 233.2 mg/dl, P < 0.01) and LDL-C by 22% (191.9 mg/dl vs 149.3 mg/dl, P < 0.01). D-dimer was significantly decreased (0.38 ng/L vs 0.28 ng/L, P = 0.02) and tPA, PAI-1 and fibrinogen tended to decrease after therapy. Fluvastatin therapy improved fibrinolytic profile; the result of this study may in part explain the benefit of HMG-CoA reductase inhibitor on cardiovascular system other than lipid lowering.     

Dopaminergic function and intertemporal choice

The discounting of delayed rewards, also known as temporal or delay discounting, is intrinsic to everyday decisions and can be impaired in pathological states such as addiction disorders. Preclinical and human studies suggest a role for dopaminergic function in temporal discounting but this relationship has not yet been verified using molecular imaging of the living human brain. Here, we evaluated dopaminergic function in temporal discounting using positron emission tomography (PET) with two different dopaminergic ligands assessing three populations in whom temporal discounting has been shown to be impaired. First, we show using [11C]raclopride PET that in pathological gamblers, greater temporal discounting correlates with decreased ventral striatal binding potential, convergent with translational findings of lower nucleus accumbens D2/D3 receptor density in high-impulsive rodents. Temporal discounting also correlates with lower ventral striatal dopamine release in response to high-reward magnitude suggesting that dopamine-mediated devaluation of larger delayed rewards may drive choice preferences. Second, we show using [18F]fluorodopa PET that in Parkinson''s disease, temporal discounting correlates with greater left caudate dopaminergic terminal function. Finally, in subjects with Parkinson''s disease and dopamine medication-induced behavioral addictions, temporal discounting is further correlated with greater dopaminergic terminal function in the anterior putamen. These findings provide insights into the relationship between striatal dopamine function and temporal discounting, and its potential role in pathological disorders and mechanisms underlying treatment interventions.     

Brachial-ankle pulse wave velocity and systolic time intervals in risk stratification for progression of renal function decline

BackgroundCardiovascular dysfunction was associated with progression of renal function decline. This study was to assess whether combination of brachial-ankle pulse wave velocity (baPWV) and the ratio of brachial pre-ejection period (bPEP) to brachial ejection time (bET) was independently associated with progression of renal function decline.MethodsWe included 363 patients and classified them into four groups according to median values of bPEP/bET and baPWV. Groups 1, 2, 3, and 4 were patients with bPEP/bET and baPWV below the median, bPEP/bET above but baPWV below the median, bPET/bET below but baPWV above the median, and bPET/bET and baPWV above the median, respectively. The decline in renal function was assessed by the estimated glomerular filtration rate (eGFR) slope and the renal end points were defined as commencement of dialysis or ≥25% decline in eGFR. The relative risk of renal end points was analyzed by Cox regression method.ResultsThe eGFR slope was significantly associated with baPWV, bPEP/bET, and patients in groups 2, 3, and 4 (vs. group 1) (P < 0.006). Multivariate forward Cox regression analysis showed that high baPWV, high bPEP/bET, and patients in groups 2, 3, and 4 (vs. group 1) (P ≤ 0.047) were independent predictors of renal end points.ConclusionsOur results demonstrated higher baPWV and bPEP/bET were associated with faster renal function decline and adverse renal end points. Dividing patients into four groups using these two parameters might be useful in risk stratification for progression of renal function decline.American Journal of Hypertension 2012; doi:10.1038/ajh.2012.77.     

Efficacy of MEM 1003, a novel calcium channel blocker, in delay and trace eyeblink conditioning in older rabbits

Eyeblink conditioning is a relatively simple form of associative learning that shows neurobiological and behavioral parallels across several species, including humans. Aged subjects acquire eyeblink conditioning more slowly than young ones. In addition, eyeblink conditioning effectively discriminates patients with Alzheimer's disease from healthy older adults. The present study evaluated the effect of a novel L-type Ca2+ channel antagonist, MEM 1003, on delay and trace eyeblink conditioning in older (mean 33.4 months old) female New Zealand white rabbits. In the delay conditioning paradigm, an 850 ms tone conditioning stimulus (CS) was followed 750 ms after its onset by a 100 ms corneal air puff. Several trace conditioning paradigms were evaluated, with a silent period of 300, 400 or 500 ms between the end of the tone CS and the delivery of the air puff. Learning was more difficult in the longer trace paradigms than in the delay paradigm. MEM 1003, at a dose of 2.0 mg/kg, s.c., given daily 30 min prior to training on each of the 15 training days, enhanced learning compared to vehicle injections in both delay and trace paradigms. However, higher or lower doses were ineffective. These results support previous work demonstrating that modulation of Ca2+ channel activity can reduce age-related cognitive impairments.     

Monocyte chemoattractant protein 3 as a mediator of fibrosis: Overexpression in systemic sclerosis and the type 1 tight-skin mouse

OBJECTIVE: To determine the gene-expression profile in dermal fibroblasts from type 1 tight-skin (Tsk1) mice, and to examine the expression and potential fibrotic activity of monocyte chemoattractant protein 3 (MCP-3) in Tsk1 mouse and human systemic sclerosis (SSc) skin. METHODS: Complementary DNA microarrays (Atlas 1.2) were used to compare Tsk1 fibroblasts with non-Tsk1 littermate cells at 10 days, 6 weeks, and 12 weeks of age. Expression of MCP-3 protein was assessed by Western blotting of fibroblast culture supernatants, and localized in the mouse and human skin biopsy samples by immunohistochemistry. Activation of collagen reporter genes by MCP-3 was explored in transgenic mouse fibroblasts and by transient transfection assays. RESULTS: MCP-3 was highly overexpressed by neonatal Tsk1 fibroblasts and by fibroblasts cultured from the lesional skin of patients with early-stage diffuse cutaneous SSc. Immunolocalization confirmed increased expression of MCP-3 in the dermis of 4 of 5 Tsk1 skin samples and 14 of 28 lesional SSc skin samples, compared with that in matched healthy mice (n = 5) and human controls (n = 11). Proalpha2(I) collagen promoter-reporter gene constructs were activated by MCP-3 in transgenic mice and by transient transfection assays. This response was maximal between 16 and 24 hours of culture and mediated via sequences within the proximal promoter. The effects of MCP-3 could be diminished by a neutralizing antibody to transforming growth factor beta. CONCLUSION: We demonstrate, for the first time, overexpression of MCP-3 in early-stage SSc and in Tsk1 skin, and suggest a novel role for this protein as a fibrotic mediator activating extracellular matrix gene expression in addition to promoting leukocyte trafficking. This chemokine may be an important early member of the cytokine cascade driving the pathogenesis of SSc.     

Partial anomalous pulmonary venous connection draining into superior vena cava--two cases reports

Anomalous pulmonary venous connection is a relatively common associated anomaly in patients with atrial septal defect (ASD), particularly among those with the sinus venosus type. The incidence of partial anomalous pulmonary venous connection (PAPVC) is higher than 0.7% in the general population and 10% in patients with ASD. In this study, we present two cases with initial impression of ASD, the sinus venosus type in one and the secundum type in the other. The one with the sinus venosus type was found to have a PAPVC that drained into SVC, and the other was suspected of having the same problem because an abnormal shunt was found during cardiac catheterization. This speculation could not be proved, however, due to transesophageal echocardiogram failure. Because we feared the possibility of cardiac defects other than ASD, we performed a minimally invasive operation using a small midline incision instead of the submammary incision and did a full median sternotomy on the patient to look for other complicating coexistent cardiac defects. This patient and the former one were both proven intraoperatively to have a PAPVC that drained into SVC with sinus venosus ASD. The operation to correct an ASD is a rudimentary procedure, and it often becomes a common type of minimally invasive operation among young cardiac surgeons with limited experience. A submammary incision under the impression of simple ASD may meet with certain complications. Therefore, after our experience with the latter case, we do the minimally invasive operation using a small midline incision, which can be easily extended if need be.     

Usefulness of Upstroke Time per Cardiac Cycle for Cardiovascular and All-Cause Mortality Prediction in Patients with Normal Ankle-Brachial Index

Aim: Abnormal ankle-brachial index (ABI) is regarded as peripheral artery disease and can be used to predict cardiovascular (CV) outcomes. However, the usefulness of ABI for the prediction of CV outcome in patients with normal ABI is limited. Upstroke time per cardiac cycle (UTCC) is recently reported to be associated with mortality in patients with acute myocardial infarction and the elderly. Therefore, we aimed to evaluate UTCC, left ventricular ejection fraction (LVEF), brachial-ankle pulse wave velocity (baPWV), and ABI for the prediction of mortality in patients with normal ABI. Methods: Patients arranged for echocardiographic examinations were enrolled, and 1076 patients with normal ABI were included. ABI, baPWV, and UTCC were measured by an ABI-form device. Results: The median follow-up to mortality was 95 months. There were 88 CV and 244 all-cause deaths. After multivariate analysis, UTCC was associated with increased CV and all-cause mortality ( P ≤ 0.004). Age, diabetes, heart failure, left ventricular hypertrophy, baPWV, and LVEF were also independent predictors of CV and all-cause mortality, but ABI was not. Furthermore, UTCC had a better additive predictive value than ABI, baPWV, and LVEF for CV mortality ( P ≤ 0.012). It also had a better additive predictive value than ABI and LVEF for all-cause mortality ( P ≤ 0.013). Conclusions: UTCC is an independent predictor for CV and all-cause mortality in patients with normal ABI. It also has a better additive predictive value of CV and all-cause mortality than ABI and LVEF. Therefore, UTCC is a simple, novel, and useful parameter for identifying high-risk patients with normal ABI.