Clinical, cognitive and anatomical evolution from nonfluent progressive aphasia to corticobasal syndrome: a case report

Recent clinical and pathological studies have suggested that frontotemporal lobar degeneration (FTLD) and corticobasal syndrome (CBS) show clinical and pathological overlap. We present four years of longitudinal clinical, cognitive and anatomical data in the case of a 56-year-old woman, AS, whose clinical picture evolved from FTLD to CBS. For the first three years, AS showed a progressive speech and language disorder compatible with a diagnosis of the nonfluent aphasia variant of FTLD. At year four, 10 years after her first symptom, AS developed the classical clinical signs of CBS, including alien limb phenomenon and dystonia. Voxel-based morphometry (VBM) applied to AS's four annual scans showed progression of atrophy from the inferior posterior frontal gyrus, to the left insula and finally to the medial frontal lobe. This case demonstrates the clinical overlap between FTLD and CBS and shows that the two can appear in the same patient at different stages of the disease in relation to the progression of anatomical damage.     

Understanding the human salivary metabolome

Saliva is a readily accessible biofluid that is important for the overall health, aiding in the chewing, swallowing, and tasting of food as well as the regulation mouth flora. As a first step to determining and understanding the human saliva metabolome, we have measured salivary metabolite concentrations under a variety of conditions in a healthy population with reasonably good oral hygiene. Using ¹H NMR spectroscopy, metabolite concentrations were measured in resting (basal) and stimulated saliva from the same subject and compared in a cohort of healthy male non‐smoking subjects (n = 62). Almost all metabolites were higher in the unstimulated saliva when compared to the stimulated saliva. Comparison of the salivary metabolite profile of male smokers and non‐smokers (n = 46) revealed citrate, lactate, pyruvate, and sucrose to be higher and formate to be lower in concentration in smokers compared with non‐smokers (p < 0.05). Gender differences were also investigated (n = 40), and acetate, formate, glycine, lactate, methanol, propionate, propylene glycol, pyruvate, succinate, and taurine were significantly higher in concentration in male saliva compared to female saliva (p < 0.05). These results show that differences between male and female, stimulated and unstimulated, as well as smoking status may be observed in the salivary metabolome. Copyright © 2009 John Wiley & Sons, Ltd.     

Stimulation of inflammatory responses in vitro and in vivo by lipophilic HMG-CoA reductase inhibitors

The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase catalyses the rate limiting step in cholesterol biosynthesis and is markedly inhibited by the statin family of drugs. The effect of statins on lipid lowering is clearly defined, but the ability of the drugs to directly regulate inflammatory functions has not been well explored. In this report, we show that there are differences among the statins in their capacity to induce proinflammatory responses both in human monocytes in vitro, and in leukocytes in mice in vivo. Treatment of human monocytes with lipophilic statins alone stimulated the production of MCP-1, IL-8, TNF-alpha and IL-1 beta and markedly sensitized the cells to subsequent challenge with inflammatory agents. Lipophilic statins also increased the production of reactive oxygen species in monocytes. In contrast, pretreatment of cells with the hydrophilic pravastatin did not induce these heightened inflammatory responses. Furthermore, treatment of mice with lipophilic statins caused a markedly higher influx of leukocytes into the inflamed peritoneal cavity following challenge with thioglycollate. Overall, these results demonstrate that the lipophilic statins influence a regulatory pathway in monocytes that controls cytokine production and that the statins induce different pro-inflammatory responses both in vitro and in vivo.     

Left ventricular shape variation in asymptomatic populations: the multi-ethnic study of atherosclerosis

Background

Although left ventricular cardiac geometric indices such as size and sphericity characterize adverse remodeling and have prognostic value in symptomatic patients, little is known of shape distributions in subclinical populations. We sought to quantify shape variation across a large number of asymptomatic volunteers, and examine differences among sub-cohorts.

Methods

An atlas was constructed comprising 1,991 cardiovascular magnetic resonance (CMR) cases contributed from the Multi-Ethnic Study of Atherosclerosis baseline examination. A mathematical model describing regional wall motion and shape was used to establish a coordinate map registered to the cardiac anatomy. The model was automatically customized to left ventricular contours and anatomical landmarks, corrected for breath-hold mis-registration between image slices. Mathematical techniques were used to characterize global shape distributions, after removal of translations, rotations, and scale due to height. Differences were quantified among ethnicity, sex, smoking, hypertension and diabetes sub-cohorts.

Results

The atlas construction process yielded accurate representations of global shape (errors between manual and automatic surface points in 244 validation cases were less than the image pixel size). After correction for height, the dominant shape component was associated with heart size, explaining 32% of the total shape variance at end-diastole and 29% at end-systole. After size, the second dominant shape component was sphericity at end-diastole (13%), and concentricity at end-systole (10%). The resulting shape components distinguished differences due to ethnicity and risk factors with greater statistical power than traditional mass and volume indices.

Conclusions

We have quantified the dominant components of global shape variation in the adult asymptomatic population. The data and results are available at cardiacatlas.org. Shape distributions were principally explained by size, sphericity and concentricity, which are known correlates of adverse outcomes. Atlas-based global shape analysis provides a powerful method for quantifying left ventricular shape differences in asymptomatic populations.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00005487","term_id":"NCT00005487"}}NCT00005487     

Mechanisms of termination and prevention of atrial fibrillation by drug therapy

Atrial fibrillation (AF) is a disorder of the rhythm of electrical activation of the cardiac atria. It is the most common cardiac arrhythmia, has multiple aetiologies, and increases the risk of death from stroke. Pharmacological therapy is the mainstay of treatment for AF, but currently available anti-arrhythmic drugs have limited efficacy and safety. An improved understanding of how anti-arrhythmic drugs affect the electrophysiological mechanisms of AF initiation and maintenance, in the setting of the different cardiac diseases that predispose to AF, is therefore required. A variety of animal models of AF has been developed, to represent and control the pathophysiological causes and risk factors of AF, and to permit the measurement of detailed and invasive parameters relating to the associated electrophysiological mechanisms of AF. The purpose of this review is to examine, consolidate and compare available relevant data on in-vivo electrophysiological mechanisms of AF suppression by currently approved and investigational anti-arrhythmic drugs in such models. These include the Vaughan Williams class I-IV drugs, namely Na⁺ channel blockers, β-adrenoceptor antagonists, action potential prolonging drugs, and Ca²⁺ channel blockers; the “upstream therapies”, e.g., angiotensin converting enzyme inhibitors, statins and fish oils; and a variety of investigational drugs such as “atrial-selective” multiple ion channel blockers, gap junction-enhancers, and intracellular Ca²⁺-handling modulators. It is hoped that this will help to clarify the main electrophysiological mechanisms of action of different and related drug types in different disease settings, and the likely clinical significance and potential future exploitation of such mechanisms.