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Background: Obesity is an increasingly recognized modifiable risk factor for Alzheimer’s disease (AD). Increased body mass index (BMI) is related to distinct changes in white matter (WM) fiber density and connectivity. Objective: We investigated whether sex differentially affects the relationship between BMI and WM structural connectivity. Methods: A cross-sectional sample of 231 cognitively normal participants were enrolled from the Knight Alzheimer Disease Research Center. Connectome analyses were done with diffusion data reconstructed using q-space diffeomorphic reconstruction to obtain the spin distribution function and tracts were selected using a deterministic fiber tracking algorithm. Results: We identified an inverse relationship between higher BMI and lower connectivity in the associational fibers of the temporal lobe in overweight and obese men. Normal to overweight women showed a significant positive association between BMI and connectivity in a wide array of WM fibers, an association that reversed in obese and morbidly obese women. Interaction analyses revealed that with increasing BMI, women showed higher WM connectivity in the bilateral frontoparietal and parahippocampal parts of the cingulum, while men showed lower connectivity in right sided corticostriatal and corticopontine tracts. Subgroup analyses demonstrated comparable results in participants with and without positron emission tomography or cerebrospinal fluid evidence of brain amyloidosis, indicating that the relationship between BMI and structural connectivity in men and women is independent of AD biomarker status. Conclusion: BMI influences structural connectivity of WM differently in men and women across BMI categories and this relationship does not vary as a function of preclinical AD.

Label propagation algorithm is widely used for community detection in a network due to its linear time complexity. It also does not need any predefined information such as the number of communities. However, the results of this algorithm are not stable because of the randomness strategy used in its propagation process. In this paper, a modification on label propagation strategy is proposed in which labels are propagated based on nodes importance defined by their positions and popularity among neighbors. The proposed strategy is an updating process which reduces the instability of the label propagation algorithm. Experiments on real-world and synthetic networks show that the proposed method improves accuracy in terms of modularity, NMI and ARI. Also, the method has an acceptable execution time.

Purpose This paper aims to present a hierarchal and operational model of coding knowledge towards facilitating the transformation of knowledge in organizations. Design/methodology/approach The methodology used, is based on collaborative participation in knowledge coding that is widely used in large settings such as Wikipedia. Findings Knowledge coding means the transfer of knowledge into a model which can be stored and shared. According to this definition, Knowledge can be accepted as a set of facts and the relationships among them. Through the suggested hierarchical model, primarily facts and initial entities are determined and knowledge record begins with the start of recording routines. In general, each routine is made up of simpler routines and facts. Thus the final model, which is a set of compound and complicated routines, can encode different levels of knowledge with different complexities. The suggested model in the explained processes is a conceptual model and a descriptive model in explaining facts. Research limitations/implications Due to high-level programming expertise, in this paper, only the method of implementation of the proposed operational model has been explained. The proposed method maintains various advantages such as applicability, comprehensibility by different people in an organization, the possibility of knowledge coding at different levels, supporting abstract concepts besides operational ones and finally the possibility of implementing it by existing tools. Practical implications The suggested model can be used for a variety of needs. For instance, in this paper, the first modelling example referred to a software concept, while the other referred to the implementation of an organizational process. Due to a hierarchy in describing knowledge, the suggested model can be used by any user with any level of knowledge (either user or registrar). Social implications This method can create a change in social media and make it possible for anyone in any society with any level of information to share their knowledge at their own level and use the knowledge of others at the same level. Originality/value The strength of the proposed model stems from its hierarchical nature which is considered for knowledge coding at different levels and includes advantages such as comprehensibility for different people in an organization, the possibility of knowledge coding at different levels and supporting abstract concepts in addition to operational ones.

Accumulation of misfolded tau, amyloid β (Aβ), and alpha-synuclein (α-syn) proteins is the fundamental contributor to many neurodegenerative diseases, namely Parkinson's (PD) and AD. Such protein aggregations trigger activation of immune mechanisms in neuronal and glial, mainly M1-type microglia cells, leading to release of pro-inflammatory mediators, and subsequent neuronal dysfunction and apoptosis. Despite the described neurotoxic features for glial cells, recruitment of peripheral leukocytes to the brain and their conversion to neuroprotective M2-type microglia can mitigate neurodegeneration by clearing extracellular protein accumulations or residues. Based on these observations, it was speculated that Dendritic cell (DC)-based vaccination, by making use of DCs as natural adjuvants, could be used for treatment of neurodegenerative disorders. DCs potentiated by disease-specific antigens can also enhance T helper 2 (Th2)-specific immune response and by production of specific antibodies contribute to clearance of intracellular aggregations, as well as enhancing regulatory T cell response. Thus, enhancement of immune response by DC vaccine therapy can potentially augment glial polarization into the neuroprotective phenotype, enhance antibody production, and at the same time balance neuronal cells' repair, renewal, and protection. The characteristic feature of this method of treatment is to maintain the equilibrium in the immune response rather than targeting a single mediator in the disease and their application in other neurodegenerative diseases should be addressed. However, the safety of these methods should be investigated by clinical trials.

BACKGROUND AND PURPOSE: Clinical and imaging manifestations of idiopathic intracranial hypertension should prompt early diagnosis and treatment to avoid complications. Multiple diagnostic imaging criteria are reported to suggest the diagnosis of idiopathic intracranial hypertension with questionable sensitivity and/or specificity. Increased intracranial pressure results in dilation of the perineural cisternal spaces such as the optic nerve sheaths and the Meckel cave. It may also cause protrusion of cisternal structures of the Meckel cave through the skull base foramina, which could result in indentation or a bilobed appearance of the Meckel cave. We investigated the changes in the Meckel cave in patients with proved idiopathic intracranial hypertension versus healthy controls. MATERIALS AND METHODS: We studied 75 patients with a diagnosis of idiopathic intracranial hypertension and 75 age-and sex-matched healthy controls. The transverse diameter of Meckel cave was measured in the axial and coronal planes of T2-weighted MR imaging sequences, and comparison was made between the 2 groups. RESULTS: The mean diameters of the Meckel cave on the coronal T2 plane in patients with idiopathic intracranial hypertension were 5.21 ± 1.22 mm on the right side and 5.16 ± 0.90 mm on the left side, while in the control group, they measured 3.89 ± 0.62 mm and 4.09 ± 0.68 mm, respectively (P value < .001). Of 75 patients with an approved diagnosis of idiopathic intracranial hypertension, 57 (76%) showed an indented Meckel cave as opposed to 21 (28%) in the control group. CONCLUSIONS: Our results confirm for the first time that the shape and size of the Meckel cave can be used as sensitive and specific diagnostic imaging markers for the diagnosis of idiopathic intracranial hypertension.

Eukaryotic initiation factor 2 (eIF2α) pathway is overactivated in Alzheimer disease and is probably associated with synaptic and memory deficiencies. EIF2α protein is principally in charge of the regulation of protein synthesis in eukaryotic cells. Four kinases responsible for eIF2α phosphorylation at ser-51 are: General control non-derepressible-2 kinase (GCN2), double-stranded RNA-activated protein kinase (PKR), PKR-like endoplasmic reticulum kinase (PERK), and heme-regulated inhibitor kinase (HRI) are the four kinases. They lead to reduced levels of general translation and paradoxical increase of stress-responsive mRNAs expression including the B-secretase (BACE1) and the transcriptional modulator activating transcription factor 4 (ATF4), which in turn accelerates the beta-amyloidogenesis, tau phosphorylation, proapoptotic pathway induction and autophagy elements formation leading to the main pathological hallmarks of AD. Findings suggest that genetic or pharmacological inhibition of correspondent kinases can restore memory and prevent neurodegeneration. This implies that inhibition of eIF2α phosphorylation through respondent kinases is indeed a feasible prospect of clinical application. This review discusses recent therapeutic approaches targeting eIF2α pathway and provides an overview of the links between correspondent kinases overactivation with neurodegeneration in AD.

We describe a cohort of 25 Iranian patients with infantile inflammatory bowel disease (IBD), 14 (56%) of whom had monogenic defects. After proper screening, patients were referred for whole exome sequencing (WES). Four patients had missense mutations in the

Multiple studies have investigated the disruptions in structural and functional connectivity in aging, dementia and Alzheimer’s disease (AD). The study of metabolic connectivity between brain regions using fluorodeoxyglucose positron emission tomography (FDG-PET) however, is a new focus of interest. Several methodological approaches, including seed-based correlation, independent and principal component analysis, and graph-theoretical approaches have been employed to study the metabolic disconnectivity in AD. We conducted a systematic search of the literature using the keywords metabolic connectivity and Alzheimer disease, up to the date of last submission and included 15 original articles as relevant. Existing literature implies a generalized metabolic disconnectivity in the brain which closely follow findings from functional studies. In the following review, we introduce the concept of metabolic disconnectivity and discuss the alterations in metabolic connectivity in AD and the potential underlying mechanisms. We find it imperative for future studies to investigate alterations in metabolic and functional connectome of AD and mild cognitive disorder through simultaneous acquisition of FDD-PET, functional and structural scans.

Background Intracranial internal carotid artery (ICA) calcification is a common incidental finding in non-contrast head CT. We evaluated the predictive value of ICAC (ICAC) for future risk of cognitive decline and compared the results with conventional imaging biomarkers of dementia. Methods In a retrospective observational cohort, we included 230 participants with a PET-CT scan within 18 months of a baseline clinical assessment and longitudinal imaging assessments. Intracranial ICAC was quantified on baseline CT scans using the Agatson calcium score, and the association between baseline ICA calcium scores and the risk of conversion from a CDR of zero in baseline to a persistent CDR > 0 at any follow-up visit, as well as longitudinal changes in cognitive scores, were evaluated through linear and mixed regression models. We also evaluated the association of conventional imaging biomarkers of dementia with longitudinal changes in cognitive scores and a potential indirect effect of ICAC on cognition through these biomarkers. Results Baseline ICA calcium score could not distinguish participants who converted to CDR > 0. ICA calcium score was also unable to predict longitudinal changes in cognitive scores, imaging biomarkers of small vessel disease such as white matter hyperintensities (WMH) volume, or AD such as hippocampal volume, AD cortical signature thickness, and amyloid burden. Severity of intracranial ICAC increased with age and in men. Higher WMH volume and amyloid burden as well as lower hippocampal volume and AD cortical signature thickness at baseline predicted lower Mini-Mental State Exam scores at longitudinal follow-up. Baseline ICAC was indirectly associated with longitudinal cognitive decline, fully mediated through WMH volume. Conclusions In elderly and preclinical AD populations, atherosclerosis of large intracranial vessels as demonstrated through ICAC is not directly associated with a future risk of cognitive impairment, or progression of imaging biomarkers of AD or small vessel disease.

Purpose Alzheimer’s disease (AD) and mild cognitive impairment (MCI) are characterized by both aberrant regional neural activity and disrupted inter-regional functional connectivity (FC). However, the effect of AD/MCI on the coupling between regional neural activity (measured by regional fluorodeoxyglucose imaging (rFDG)) and inter-regional FC (measured by resting-state functional magnetic resonance imaging (rs-fMRI)) is poorly understood. Methods We scanned 19 patients with MCI, 33 patients with AD, and 26 healthy individuals by simultaneous FDG-PET/rs-fMRI and assessed rFDG and inter-regional FC metrics (i.e., clustering coefficient and degree centrality). Next, we examined the potential moderating effect of disease status (MCI or AD) on the link between rFDG and inter-regional FC metrics using hierarchical moderated multiple regression analysis. We also tested this effect by considering interaction between disease status and inter-regional FC metrics, as well as interaction between disease status and rFDG. Results Our findings revealed that both rFDG and inter-regional FC metrics were disrupted in MCI and AD. Moreover, AD altered the relationship between rFDG and inter-regional FC metrics. In particular, we found that AD moderated the effect of inter-regional FC metrics of the caudate, parahippocampal gyrus, angular gyrus, supramarginal gyrus, frontal pole, inferior temporal gyrus, middle frontal, lateral occipital, supramarginal gyrus, precuneus, and thalamus on predicting their rFDG. On the other hand, AD moderated the effect of rFDG of the parietal operculum on predicting its inter-regional FC metric. Conclusion Our findings demonstrated that AD decoupled the link between regional neural activity and functional segregation and global connectivity across particular brain regions.

The brain-derived neurotrophic factor (BDNF) mediates the plasticity-related changes that associate with memory processing during sleep. Sleep deprivation and chronic stress are associated with propensity to depression, anxiety, and insomnia. We propose a model by which explain alterations in the CNS and serum expression of BDNF associated with chronic sleep deprivation, depression, and insomnia. Mild sleep deprivation activates the cerebral cortex and brainstem to generate the physiologic drive for non-rapid eye movement (NREM) and rapid eye movement (REM) sleep drive respectively, associated with BDNF upregulation in these regions. This physiological response loses effectiveness with longer episodes or during chronic of total or selective REM sleep loss, which are associated with impaired hippocampal BDNF expression, impaired memory and cognition. Chronic sleep deprivation and insomnia can act as an external stressors and result in depression, characterized by hippocampal BDNF downregulation along with disrupted frontal cortical BDNF expression, as well as reduced levels and impaired diurnal alterations in serum BDNF expression. Acute REM sleep deprivation breaks the cycle by restoration of hippocampal, and possibly restoration of cortical and serum expression of BDNF. The BDNF Val66Met polymorphism alters susceptibility to depression, anxiety, and insomnia by altering availability and expression of BDNF in brain and blood. The proposed model is testable and implies that low levels and low variability in serum BDNF are associated with poor response to anti-depressive medications, electroconvulsive therapy, and REM sleep deprivation, in patients with depression. Our mode is also backed up by the existing clinical evidence but is yet to be investigated.

Aim To determine whether serum ferritin, liver transaminases, and regularity and type of iron chelation protocol can be used to predict liver iron load as assessed by T2* magnetic resonance imaging (MRI) in patients with beta thalassemia major (TM). Methods This cross-sectional study, conducted from March 1, 2014 to March 1, 2015, involved 90 patients with beta TM on regular packed red blood cell transfusion. Liver and cardiac iron load were evaluated with T2* MRI. Compliance with iron-chelating agents, deferoxamine or deferasirox, and regularity of their use, as well as serum ferritin and liver transaminase levels were assessed. Results Patients with high serum ferritin were 2.068 times (95% confidence interval 1.26-3.37) more likely to have higher liver or cardiac iron load. High serum aspartate aminotransferases and irregular use of iron chelating agents, but not their type, predicted higher cardiac iron load. In a multiple regression model, serum ferritin level was the only significant predictor of liver and myocardial iron load. Conclusions Higher serum ferritin strongly predicted the severity of cardiac and liver iron load. Irregular use of chelator drugs was associated with a higher risk of cardiac and liver iron load, regardless of the type of chelating agent.

Neurofilament light chain (NFL) has been recently introduced as a biomarker of early dementia. 18-Fluorodeoxyglucose positron emission tomography (18F-FDG-PET) is a proxy for regional hypometabolism in Alzheimer disease (AD). Globally normalized 18F-FDG-PET values and levels of NFL and tau were obtained from 149 patients with mild cognitive impairment (MCI) from the baseline cohort of the Alzheimer’s Disease Neuroimaging Initiative database. We adopted a stepwise partial correlation model using plasma NFL, plasma tau, CSF NFL, and regional cerebral metabolic rate of glucose (CMRGlc) as main variables, and age, sex, and Alzheimer’s Disease Rating Scale (ADAS) as covariates. Significant regions were entered into a stepwise multiple regression analysis to investigate the independent correlation of each biomarker to baseline regional CMRGlc and its progression in patients with MCI. Higher baseline CSF NFL levels correlated with hypometabolism in bilateral precuneal and posterior cingulate cortex. After correction for age, sex, and ADAS score, plasma NFL levels correlated with hypometabolism in bilateral parahippocampal and middle temporal gyri. Cortical hypometabolism in bilateral parahippocampal gyri and right fusiform and middle temporal gyri was independently predicted by higher baseline plasma NFL levels in a multiple regression model. Plasma NFL promises to be an early biomarker of cortical hypometabolism in MCI and for MCI progression to AD.

Levodopa remains to be the mainstay for treatment of Parkinson disease (PD). Long-term levodopa treatment bears a risk for developing levodopa-induced dyskinesia (LID). LID significantly overshadows patients' quality of life and therapeutic efficacy of levodopa. Pre- and post-synaptic changes in dopamine secretion and signaling, along with altered glutamate receptor expression and glutamatergic signaling in striatal neurons, and the resulting disinhibition-like changes in the corticostriatal circuitry, lead to aberrant activity of motor cortex and formation of LID. Research has highlighted the role of group I metabotropic glutamate receptors especially the metabotropic glutamate receptor 5 (mGlu5) in formation of LID through potentiating of ionotropic glutamate NMDA receptors and dopamine D1/D5 receptors in direct pathway. Accordingly, MTEP and MPEP were the first mGlu5 receptor antagonists which were shown to attenuate LID in animal models through suppression of downstream signaling cascades involving mitogen-activated protein kinase (MAPK) and FosB/delta FosB activation, as well as modulation of prodynorphinegic, preproenkephalinergic, and GABA-ergic neurotransmission systems. Beneficial effects of other mGlu5 receptor antagonists such as AFQ056/mavoglurant and ADX48621/dipraglurant in amelioration of LID has been shown not only in animal models but also in clinical trials. Considering the presence of mGlu receptor dysregulation in rapid eye movement (REM) sleep behavior disorder and depression, which are prodromal signs of PD, along with the neuroprotective effects of mGlu receptor antagonists, and their cognitive benefits, potential effectiveness of mGlu receptor antagonists in early prevention of PD remains to be investigated.

Medial temporal lobe epilepsy (mTLE) has been associated with widespread white mater (WM) alternations in addition to mesial temporal sclerosis (MTS). Herein, we aimed to investigate the correlation between disease duration and WM structural abnormalities in mTLE using diffusion MRI (DMRI) connectometry approach. DMRI connectometry was conducted on 24 patients with mTLE. A multiple regression model was used to investigate white matter tracts with microstructural correlates to disease duration, controlling for age and sex. DMRI data were processed in the MNI space using q-space diffeomorphic reconstruction to obtain the spin distribution function (SDF). The SDF values were converted to quantitative anisotropy (QA) and used in further analyses. Connectometry analysis identified impaired white matter QA of the following fibers to be correlated with disease duration: bilateral retrosplenial cingulum, bilateral fornix, right inferior longitudinal fasciculus (ILF), and genu of corpus callosum (CC) (FDR = 0.009). Our results were obtained from DMRI connectometry, which indicates the connectivity and the level of diffusion in nerve fibers rather just the direction of diffusion. Compared to previous studies investigating the correlation between duration of epilepsy and white matter integrity in mTLE patients, we detected broader and somewhat different associations in midline structures and component of limbic system. However, further studies with larger sample sizes are required to elucidate previous and current results.

Background Brain-derived neurotrophic factor (BDNF) is an abundant neurotrophin in the adult brain. Serum BDNF levels might be used as a proxy for its central expression. Considering conflicting reports, we aimed to answer “How do serum/CSF levels of BDNF change in patients with PD?”. Methods We conducted a comprehensive search in MEDLINE, EMBASE and SCOPUS databases including 12 eligible studies. Five studies compared BDNF in serum of PD patients versus healthy controls (HC) and 3 studies provided BDNF levels in sera of non-depressed and depressed PD patients (NDPD and DPD). Review Manager and Software version 3.0 were used for meta-analysis and meta-regressions. Mean difference (MD) was used for measurement of effect size. Results PD patients had reduced serum BDNF levels compared to HC (MD = - 2.99 ng/mL). Serum BDNF was highest in DPD patients compared to HC (MD = - 4.83 ng/mL), with no difference between DPD and NDPD patients in serum BDNF levels. Among co-variates that were eligible for meta-regression, age, sex, and Hoehn and Yahr (H&Y) motor stage had significant positive associations with the effect size in the difference of serum BDNF between patients and HC. Conclusions PD patients had reduced serum BDNF levels compared to HC, regardless of presence of co-morbid depression. PD is at least equally effective in reducing serum BDNF levels as depression. Motor progression predicts serum BDNF downregulation in PD. Acute exercise improves motor function and depressive symptoms in PD probably via BDNF upregulation. The paradoxical rise in serum BDNF in advance PD is probably compensatory in nature.

PURPOSE: Mesial temporal lobe epilepsy (mTLE) is a chronic focal epileptic disorder characterized by recalcitrant seizures often necessitating surgical intervention. Identifying the laterality of seizure focus is crucial for pre-surgical planning. We implemented diffusion MRI (DMRI) connectometry to identify differences in white matter connectivity in patients with left and right mTLE relative to healthy control subjects. METHOD: We enrolled 12 patients with right mTLE, 12 patients with left mTLE, and 12 age/sex matched healthy controls (HCs). We used DMRI connectometry to identify local connectivity patterns of white matter tracts, based on quantitative anisotropy (QA). We compared QA of white matter to reconstruct tracts with significant difference in connectivity between patients and HCs and then between patients with left and right mTLE. RESULTS: Right mTLE patients show higher anisotropy in left inferior longitudinal fasciculus (ILF) and forceps minor and lower QA in genu of corpus callosum (CC), bilateral corticospinal tracts (CSTs), and bilateral middle cerebellar peduncles (MCPs) compared to HCs. Left mTLE patients show higher anisotropy in genu of CC, bilateral CSTs, and right MCP and decreased anisotropy in forceps minor compared to HCs. Compared to patients with right mTLE, left mTLE patients showed increased and decreased connectivity in some major tracts. CONCLUSIONS: Our study showed the pattern of microstructural disintegrity in mTLE patients relative to HCs. We demonstrated that left and right mTLE patients have discrepant alternations in their white matter microstructure. These results may indicate that left and right mTLE have different underlying pathologic mechanisms.

A myriad of environmental and genetic factors, as well as the physiologic process of aging, contribute to Alzheimer’s disease (AD) pathology. Neuroinflammation is and has been a focus of interest, as a common gateway for initiation of many of the underlying pathologies of AD. Amyloid beta (Aβ) toxicity, increasing RAGE expression, tau hyperphosphorylation, induction of apoptosis, and deregulated autophagy are among other mechanisms, partly entangled and being explained by activation of mitogen-activated protein kinase (MAPK) and MAPK signaling. p38 MAPK is the most essential regulator of Aβ induced toxicity from this family. p38 induces NF-κB activation, glutamate excitotoxicity, and disruption of synaptic plasticity, which are other implications of all justifying the p38 MAPK as a potential target to break the vicious Aβ toxicity cycle. Until recently, manyin vivoandin vitrostudies have investigated the effects of p38 MAPK inhibitors in AD. The pyridinyl imidazole compoundsSB202190andSB203580have shown promising anti-apoptotic resultsin vivo. MW108inhibits activation of p38 and is able to postpone cognitive decline in animal models. ThePD169316, with anti-inflammatory, anti-oxidative, and anti-apoptotic features, has improved spatial memoryin vivo. Natural compounds fromCamellia sinensis(green tea), polyphenols from olive oil, pinocembrin from propolis, and the puerarine extract isoflavones, have shown strong anti-apoptotic features, mediated by p38 MAPK inhibition. Use of these drug targets is limited due to central nervous system side effects or cross-reactivity with other kinases, predicting the low efficacy of these drugs in clinical trials.

Understanding the etiology and treatment approaches in schizophrenia is challenged in part by the heterogeneity of this disorder. One encouraging progress is the growing evidence that there are subtypes of schizophrenia that may relate to disease duration and premorbid severity. Recent in vitro findings of messenger ribonucleic acid (mRNA) gene expression on postmortem dorsolateral prefrontal cortex (DLPFC) showed that schizophrenia has two subtypes, those with a relatively normal DLPFC transcriptome (Type 1) and those with differentially expressed genes (Type 2). Sphingosine-1-phosphate receptor-1 (S1PR1) is one of the genes that was highly upregulated in Type 2 compared to Type 1 and controls. The impact of that finding is limited because it only can be confirmed through analysis of autopsy tissue, and the clinical characteristics such as symptoms severity or illness duration was not available from that Medical Examiner based autopsy study. However, S1PR1 has great potential because it is a target gene that can be accessed via positron emission tomography (PET) in vivo using specific radioligands (starting with [11C]CS1P1) successfully developed at our center in human brain imaging. As a preliminary study to validate this PET target in schizophrenia, S1PR1 protein expression was assessed by receptor autoradiography (ARG) using [3H]CS1P1 and immunohistochemistry (IHC) in the DLPFC from patients with schizophrenia classified as Type 1 or Type 2 based on their DLPFC transcriptomes and from controls. Our analyses demonstrate that ARG S1PR1 protein expression is significantly higher in Type 2 compared to Type 1 (p < 0.05) and controls (p < 0.05), which was consistent with previous mRNA S1PR1. These findings support the possibility that PET S1PR1 can be used as a future imaging biomarker to distinguish these subgroups of schizophrenic patients during life with obvious implications for both patient management and the design of clinical trials to validate novel pharmacologic therapies.