Higher midlife CAIDE score is associated with increased brain atrophy in a cohort of cognitively healthy middle-aged individuals

Journal of Neurology - Structural brain changes associated with Alzheimer’s disease (AD) can occur decades before the onset of symptoms. The Cardiovascular Risk Factors, Aging, and Dementia...     

Effect of Moderate Wine Consumption on Oxidative Stress Markers in Coronary Heart Disease Patients

Evidence from research studies reports that wine consumption is associated with lower cardiovascular disease risk, partly through the amelioration of oxidative stress. The aim of the present study was to examine the effect of regular light to moderate wine consumption from coronary heart disease (CHD) patients compared to the effect induced by alcohol intake without the presence of wine microconstituents, on oxidation-induced macromolecular damage as well as on endogenous antioxidant enzyme activity. A randomized, single-blind, controlled, three-arm parallel intervention was carried out, in which 64 CHD patients were allocated to three intervention groups. Group A consumed no alcohol, and Group B (wine) and Group C (ethanol) consumed 27 g of alcohol/day for 8 weeks. Blood and urine samples were collected at baseline and at 4 and 8 weeks. Urine oxidized guanine species levels, protein carbonyls, thiobarbituric acid substances (TBARS) levels, as well as superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, were measured. Oxidized guanine species and protein carbonyl levels were significantly increased in the ethanol group during the intervention and were significantly decreased in the wine group. These results support the idea that wine’s bioactive compounds may exert antioxidant actions that counteract the macromolecular oxidative damage induced by alcohol in CHD patients.     

An effort to understand the molecular basis of hypertension through the study of conformational analysis of losartan and sarmesin using a combination of nuclear magnetic resonance spectroscopy and theoretical calculations.

Losartan is the first recently approved drug against hypertension disease that competes with the biological action of angiotensin II (AII) at the AT1 receptor. Its design was based on the mimicry of the C-terminal segment of AII. Due to the biological significance of Losartan, its structure elucidation and conformational properties are reported as determined by NMR spectroscopy and computational analysis. In addition, molecular modeling of the peptide Sarmesin [Sar1Tyr(OMe)4AII], a competitive antagonist of AII, was also developed based on NMR and computational analysis data. Sarmesin's C-terminal was used as a template for superimposition with specific molecular features of interest in the structure of Losartan such as the conformation of biphenyltetrazole, the n-butyl chain, and the orientation of hydroxymethylimidazole relative to the biphenyl template. The major conclusions derived from this study are the following: (a) Sarmesin, like the AII superagonist [Sar1]AII, adopts a conformation which keeps in close proximity the key amino acids Sar1 (or Arg2)-Tyr(OMe)4-His6-Phe8. (b) Losartan favors a low-energy conformation in which imidazole and tetrazole rings are placed in the opposite site relative to the spacer phenyl ring plane; the hydroxymethyl group is placed away from the spacer phenyl ring, the alkyl chain is oriented above the spacer phenyl ring, and the two phenyl rings deviate approximately 60 degrees from being coplanar. (c) Overlay of the C-terminal region of Sarmesin with Losartan using equivalent groups revealed an excellent match. (d) Interestingly, the matching between enantiomeric structures of Losartan was not equivalent, proposing that the chirality of this molecule is significant in order to exert its biological activity. These findings open a new avenue for synthetic chemists to design and synthesize peptidomimetic drugs based on the C-terminal segment of the proposed model of Sarmesin. The new candidate drug molecules are not restricted to structurally resemble Losartan as the design is hitherto focused.     

Detection of L265P MYD‐88 mutation in a series of clonal B‐cell lymphocytosis of marginal zone origin (CBL‐MZ)

Clonal B‐cell lymphocytosis of marginal zone origin (CBL‐MZ) is a recently described entity characterized by the presence of clonal B cells in the blood and/or bone marrow (BM) with morphologic and immunophenotypic features consistent with marginal zone derivation in otherwise healthy individuals. CBL‐MZ is commonly associated with paraproteinemia, usually immunoglobulin M (IgM), raising diagnostic difficulties from Waldenstrom macroglobulinemia (WM). The aim of the present study was to determine the presence of MYD‐88 L265P mutation in a well‐characterized series of CBL‐MZ to identify cases that may in fact represent WM. Fifty‐three CBL‐MZ cases were retrospectively evaluated. MYD‐88 L265P mutation was determined by allele‐specific polymerase chain reaction in blood and/or BM mononuclear cells. Almost half of the CBL‐MZ cases (49%) were associated with paraproteinemia mainly of the IgM type (65%). MYD‐88 L265P mutation was identified in 10 cases (19%). These cases may truly represent WM, whereas 43 cases (81%) are still classified as CBL‐MZ. Mutated cases were all associated with paraproteinemia compared with 37% of the nonmutated ones (P < .0001). In addition, mutated cases displayed more frequently CD38 and CD25 positivity (P = .002 and P = .005, respectively). Moreover, cases without paraproteinemia presented more frequently with lymphocytosis, irrespective of the presence of the MYD‐88 mutation (P = .02). The present study demonstrates that MYD‐88 L265P mutation may represent the only sensitive marker for the differentiation of CBL‐MZ from probable WM. However, further studies are warranted to better define the biological significance of MYD‐88 L265P mutation and to clarify whether the presence of the mutation establishes WM diagnosis or that it can also be present in borderline cases associated with paraproteinemia.     

Sleep-Disordered Breathing and Excessive Daytime Sleepiness in Chronic Kidney Disease and Hemodialysis

Summary

Background and objectives

Sleep-disordered breathing (SDB) and excessive daytime sleepiness (EDS) are highly prevalent among hemodialysis (HD) patients. It is unclear to what extent SDB is associated with advanced chronic kidney disease (CKD; stages 4 to 5). This paper describes and compares the prevalence, severity, and patterns of SDB and EDS among patients with advanced CKD, HD-dependent patients, and community individuals without known renal disease.

Design, setting, participants, & measurements

Eighty-nine CKD and 75 HD patients were compared with 224 participants from the Sleep-Strategies Concentrating on Risk Evaluation Sleep-SCORE study of sleep and cardiovascular risk. Participants had in-home unattended polysomnography for quantifying SDB. EDS was defined by a score ≥10 on the Epworth Sleepiness Scale.

Results

The sample had a median age 58.1 years, was predominantly male (57.4%) and white (62.5%), and had a median body mass index of 28.1 kg/m². Controls and Sleep-SCORE Study CKD patients had significantly higher median total sleep time and sleep efficiency compared with HD patients. The adjusted odds of severe SDB were higher for CKD and HD groups compared with the controls. Nocturnal hypoxemia was significantly elevated in the HD group compared with the CKD group. There were similar proportions of participants with EDS between the controls (33%), the CKD patients (29.3%), and the HD patients (40.6%).

Conclusions

Severe SDB (predominantly obstructive) and EDS are common among advanced CKD and HD patients. EDS correlated modestly with severe SDB and its obstructive and mixed patterns in the HD group.     

CD14 and TRIF govern distinct responsiveness and responses in mouse microglial TLR4 challenges by structural variants of LPS

Toll-like receptor (TLR) 4 responds to a range of agonists in infection and injury, but is best known for the recognition of bacterial lipopolysaccharides (LPS). Assembly in heterologous receptor complexes as well as signaling through both MyD88 and TRIF adaptor proteins, as unmatched by other TLRs, could underlie its versatile response options, probably also in a cell type-dependent manner. We show that microglia, the CNS macrophages, react to diverse LPS variants, including smooth (S) and rough (R) LPS chemotypes, with cytokine/chemokine induction, MHC I expression and suppression of myelin phagocytosis. The TLR4 co-receptor CD14 was shown in peritoneal macrophages to be essential for S-LPS effects and the link of both S- and R-LPS to TRIF signaling. In contrast, cd14^−/− microglia readily respond to S- and R-LPS, suggesting an a priori high(er) sensitivity to both chemotypes, while CD14 confers increased S- and R-LPS potencies and compensates for their differences. Importantly, CD14 controls the magnitude and shapes the profile of cyto/chemokine production, this influence being itself regulated by critical LPS concentrations. Comparing reactive phenotypes of microglia with deficiencies in CD14, MyD88 and TRIF (cd14^−/−, myd88^−/−, and trif^lps2), we found that distinct signaling routes organize for individual functions in either concerted or non-redundant fashion and that CD14 has contributions beyond the link to TRIF. Modulation of response profiles by key cytokines finally reveals that the microglial TLR4 can differentiate between the class of LPS structures and a self-derived agonist, fibronectin. It thus proves as a sophisticated decision maker in infectious and non-infectious CNS challenges.