Novel approach to analysis of the immune system using an ungated model of immune surface marker abundance to predict health outcomes.

Traditionally, the immune system is understood to be divided into discrete cell types that are identified via surface markers. While some cell type distinctions are no doubt discrete, others may in fact vary on a continum, and even within discrete types, differences in surface marker abundance could have functional implications. Here we propose a new way of looking at immune data, which is by looking directly at the values of the surface markers without dividing the cells into different subtypes. To assess the merit of this approach, we compared it with manual gating using cytometry data from the Singapore Longitudinal Aging Study (SLAS) database. We used two different neural networks (one for each method) to predict the presence of several health conditions. We found that the model built using raw surface marker abundance outperformed the manual gating one and we were able to identify some markers that contributed more to the predictions. This study is intended as a brief proof-of-concept and was not designed to predict health outcomes in an applied setting; nonetheless, it demonstrates that alternative methods to understand the structure of immune variation hold substantial progress.

Comparative effectiveness and safety of antipsychotic drugs in schizophrenia treatment: a real-world observational study.

OBJECTIVE: The objective was to compare, in a real-world setting, the risk of mental and physical health events associated with different antipsychotic drugs (clozapine, olanzapine, risperidone, quetiapine and first-generation antipsychotics) in patients with SZ. METHODS: This is a retrospective cohort study using administrative data. Outcome measures included any mental health event (suicide, hospitalization or emergency visit for mental disorders) and physical health event (death other than suicide, hospitalization or emergency visit for physical disorders). Cox proportional hazard models were used to estimate the hazard ratios of the events associated with the use of the different antipsychotic drugs. RESULTS: The cohort included 18 869 adult patients living in the province of Quebec (Canada) with SZ and starting antipsychotic drugs between January 1998 and December 2005. Results show that quetiapine and not using any antipsychotics were associated with an increased risk of mental and physical health events as compared to other drugs. The second finding is the confirmation of better performance of clozapine. The results were robust across sensitivity analyses. CONCLUSION: Both findings call for an international public health and drug agencies surveillance of 'real-world' antipsychotic medication to ensure the optimal choices in treatment guidelines for SZ.

Immunology of Aging: the Birth of Inflammaging.

The inflammaging concept was introduced in 2000 by Prof. Franceschi. This was an evolutionary or rather a revolutionary conceptualization of the immune changes in response to a lifelong stress. This conceptualization permitted to consider the lifelong proinflammatory process as an adaptation which could eventually lead to either beneficial or detrimental consequences. This dichotomy is influenced by both the genetics and the environment. Depending on which way prevails in an individual, the outcome may be healthy longevity or pathological aging burdened with aging-related diseases. The concept of inflammaging has also revealed the complex, systemic nature of aging. Thus, this conceptualization opens the way to consider age-related processes in their complexity, meaning that not only the process but also all counter-processes should be considered. It has also opened the way to add new concepts to the original one, leading to better understanding of the nature of inflammaging and of aging itself. Finally, it showed the way towards potential multimodal interventions involving a holistic approach to optimize the aging process towards a healthy longevity.

Immunosenescence is both functional/adaptive and dysfunctional/maladaptive.

Alterations in the immune system with aging are considered to underlie many age-related diseases. However, many elderly individuals remain healthy until even a very advanced age. There is also an increase in numbers of centenarians and their apparent fitness. We should therefore change our unilaterally detrimental consideration of age-related immune changes. Recent data taking into consideration the immunobiography concept may allow for meaningful distinctions among various aging trajectories. This implies that the aging immune system has a homeodynamic characteristic balanced between adaptive and maladaptive aspects. The survival and health of an individual depends from the equilibrium of this balance. In this article, we highlight which parts of the aging of the immune system may be considered adaptive in contrast to those that may be maladaptive.

A theoretical model of the evolution of actuarial senescence under environmental stress.

Free-living organisms are exposed to a wide range of stressors, all of which can disrupt components of stress-related and detoxification physiology. The subsequent accumulation of somatic damage is widely believed to play a major role in the evolution of senescence. Organisms have evolved sophisticated physiological regulatory mechanisms to maintain homeostasis in response to environmental perturbations, but these systems are likely to be constrained in their ability to optimise robustness to multiple stressors due to functional correlations among related traits. While evolutionary change can accelerate due to human ecological impacts, it remains to be understood how exposure to multiple environmental stressors could affect senescence rates and subsequently population dynamics and fitness. We used a theoretical evolutionary framework to quantify the potential consequences for the evolution of actuarial senescence in response to exposure to simultaneous physiological stressors--one versus multiple and additive versus synergistic--in a hypothetical population of avian "urban adapters". In a model in which multiple stressors have additive effects on physiology, species may retain greater capacity to recover, or respond adaptively, to environmental challenges. However, in the presence of high synergy, physiological dysregulation suddenly occurs, leading to a rapid increase in age-dependent mortality and subsequent population collapse. Our results suggest that, if the synergistic model is correct, population crashes in environmentally-stressed species could happen quickly and with little warning, as physiological thresholds of stress resistance are overcome.

Hemodynamic effects of guanfacine in essential hypertension.

Hemodynamic evaluation of three men and eight women aged 20 to 58 years (mean, 44 years) with essential hypertension was performed before and after a single dose of guanfacine and before and after long-term administration of the drug, which is a stimulant of central alpha-adrenergic receptors. Mean (+/- SE) recordings of blood pressure before catheterization were 168/115 +/- 6/3 mmHg when supine and 168/112 +/- 8/4 mmHg when standing. Within two hours of oral administration of 3 mg of guanfacine, the heart rate decreased from a mean of 77 +/- 2 to 69 +/- 3 beats/min (P less than 0.05), and the pulmonary capillary wedge pressure (PCWP) decreased from a mean of 9 +/- 1 to 6 +/- 1 mmHg (P less than 0.02). The mean readings of pulmonary arterial pressure also decreased, as follows: systolic, from 22 +/- 2 to 18 +/- 0.14 mmHg (P less than 0.05); diastolic, from 9 +/- 1 to 7 +/- 1 mmHg (P less than 0.05); and mean, from 15 +/- 1 to 12 +/- 2 mmHg (P less than 0.05). No changes were observed in systemic blood pressure, the cardiac index, systemic vascular resistance, or total pulmonary vascular resistance. After a six-week course (mean dosage, 3.9 +/- 0.57 mg/day), the following variables decreased significantly: systemic blood pressure--systolic, diastolic, and mean, both supine and standing (P less than 0.001); heart rate (P less than 0.001); and systemic vascular resistance (P less than 0.01). The PCWP reached values similar to those measured during the control phase. Increases were noted in pulmonary artery systolic pressure (P less than 0.05), mean right atrial pressure (P less than 0.01), and in the stroke volume index (P less than 0.05). It is likely that the main hemodynamic mechanism underlying the long-term antihypertensive effect of guanfacine is a decrease in systemic vascular resistance.

Dynamic proteomics of individual cancer cells in response to a drug.

Why do seemingly identical cells respond differently to a drug? To address this, we studied the dynamics and variability of the protein response of human cancer cells to a chemotherapy drug, camptothecin. We present a dynamic-proteomics approach that measures the levels and locations of nearly 1000 different endogenously tagged proteins in individual living cells at high temporal resolution. All cells show rapid translocation of proteins specific to the drug mechanism, including the drug target (topoisomerase-1), and slower, wide-ranging temporal waves of protein degradation and accumulation. However, the cells differ in the behavior of a subset of proteins. We identify proteins whose dynamics differ widely between cells, in a way that corresponds to the outcomes-cell death or survival. This opens the way to understanding molecular responses to drugs in individual cells.

Structure design: an artificial intelligence-based method for the design of molecules under geometrical constraints.

This study presents an algorithm that implements artificial-intelligence techniques for automated, and site-directed drug design. The aim of the method is to link two or more predetermined functional groups into a sensible molecular structure. The proposed designing process mimics the classical manual design method, in which the drug designer sits in front of the computer screen and with the aid of computer graphics attempts to design the new drug. Therefore, the key principle of the algorithm is the parameterization of some criteria that affect the decision-making process carried out by the drug designer. This parameterization is based on the generation of weighting factors that reflect the knowledge and knowledge-based intuition of the drug designer, and thus add further rationalization to the drug design process. The proposed algorithm has been shown to yield a large variety of different structures, of which the drug designer may choose the most sensible. Performance tests indicate that with the proper set of parameters, the method generates a new structure within a short time.

Hemodynamic effects of intravenous flecainide in acute noncomplicated myocardial infarction.

Hemodynamic and ECG effects of intravenous flecainide were assessed in 10 patients with acute myocardial infarction and no symptoms or signs of heart failure. The dose was 2 mg/kg injected over a 15-minute period. R-R interval did not change, but PR interval and QRS increased significantly, 28% (p less than 0.0005) and 20% (p less than 0.05), respectively. Duration of P wave also increased significantly, 15% (p less than 0.02). Pulmonary wedge pressure increased 29% (p less than 0.005) and cardiac index and left ventricular stroke work index decreased 9% (p less than 0.05) and 20% (p less than 0.05), respectively. No significant change in mean aortic pressure and systemic vascular resistance occurred. Thus, intravenous flecainide has a mild and transient negative inotropic effect in patients with noncomplicated acute myocardial infarction. It did not induce ventricular failure in this group of patients but should be administered cautiously to patients with overt heart failure or severe conduction defects.