Plasma dilution improves cognition and attenuates neuroinflammation in old mice

Our recent study has established that young blood factors are not causal, nor necessary, for the systemic rejuvenation of mammalian tissues. Instead, a procedure referred to as neutral blood exchange (NBE) that resets signaling milieu to a pro-regenerative state through dilution of old plasma, enhanced the health and repair of the muscle and liver, and promoted better hippocampal neurogenesis in 2-year-old mice (Mehdipour et al., Aging 12:8790–8819, 2020). Here we expand the rejuvenative phenotypes of NBE, focusing on the brain. Namely, our results demonstrate that old mice perform much better in novel object and novel texture (whisker discrimination) tests after a single NBE, which is accompanied by reduced neuroinflammation (less-activated CD68⁺ microglia). Evidence against attenuation/dilution of peripheral senescence-associated secretory phenotype (SASP) as the main mechanism behind NBE was that the senolytic ABT 263 had limited effects on neuroinflammation and did not enhance hippocampal neurogenesis in the old mice. Interestingly, peripherally acting ABT 263 and NBE both diminished SA-βGal signal in the old brain, demonstrating that peripheral senescence propagates to the brain, but NBE was more robustly rejuvenative than ABT 263, suggesting that rejuvenation was not simply by reducing senescence. Explaining the mechanism of the positive effects of NBE on the brain, our comparative proteomics analysis demonstrated that dilution of old blood plasma yields an increase in the determinants of brain maintenance and repair in mice and in people. These findings confirm the paradigm of rejuvenation through dilution of age-elevated systemic factors and extrapolate it to brain health and function.

     

New antiarrhythmic drugs for atrial fibrillation: Focus on dronedarone and vernakalant

The prevalence of atrial fibrillation (AF) is forecast to rise to 2–5% of the general population by 2050. Of the two fundamental treatment strategies for AF management, rhythm control is the approach which is generally preferred for active, symptomatic, and/or younger patients, whereas rate control is all that is found necessary in the more elderly, sedentary, asymptomatic individual. In many cases, at neither extreme, there remains a genuine choice of therapy, and for those patients, antiarrhythmic strategies would be preferred if effective and safe antiarrhythmic medications were available. Many new antiarrhythmic agents exploiting new mechanisms of action or novel combinations of established antiarrhythmic activity are currently being investigated. Agents which selectively inhibit ion channels specifically involved in atrial repolarization, so-called atrial repolarization delaying agents, are widely acknowledged as potentially ideal antiarrhythmic treatments, as they will probably be both effective and safe, at the very least (free of pro-arrhythmic effects at the ventricular level). Modified analogues of traditional antiarrhythmic drugs with different combinations of ion channel and receptor blocking effects, novel mechanisms of action, and less complicated metabolic profiles are also under development. Completely innovative antiarrhythmic agents with new antiarrhythmic mechanisms, such as stretch receptor antagonism, sodium calcium exchanger blockade, late sodium channel inhibition, and gap junction modulation are also being explored. In addition, there is increasing evidence in support of the antiarrhythmic action of non-antiarrhythmic drugs. Treatments with statins, omega-3 fatty acids, angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and aldosterone antagonists are all potentially valuable, over and above any effect related to the treatment of underlying heart disease. Professor A. John Camm is a consultant to AstraZeneca, Cardiome, sanofi aventis, and Xention.     

Effects of Q/N-rich, polyQ, and non-polyQ amyloids on the de novo formation of the [PSI+] prion in yeast and aggregation of Sup35 in vitro

Prions are infectious protein conformations that are generally ordered protein aggregates. In the absence of prions, newly synthesized molecules of these same proteins usually maintain a conventional soluble conformation. However, prions occasionally arise even without a homologous prion template. The conformational switch that results in the de novo appearance of yeast prions with glutamine/aspargine (Q/N)-rich prion domains (e.g., [PSI+]), is promoted by heterologous prions with a similar domain (e.g., [RNQ+], also known as [PIN+]), or by overexpression of proteins with prion-like Q-, N-, or Q/N-rich domains. This finding led to the hypothesis that aggregates of heterologous proteins provide an imperfect template on which the new prion is seeded. Indeed, we show that newly forming Sup35 and preexisting Rnq1 aggregates always colocalize when [PSI+] appearance is facilitated by the [RNQ+] prion, and that Rnq1 fibers enhance the in vitro formation of fibers by the prion domain of Sup35 (NM). The proteins do not however form mixed, interdigitated aggregates. We also demonstrate that aggregating variants of the polyQ-containing domain of huntingtin promote the de novo conversion of Sup35 into [PSI+]; whereas nonaggregating variants of huntingtin and aggregates of non-polyQ amyloidogenic proteins, transthyretin, alpha-synuclein, and synphilin do not. Furthermore, transthyretin and alpha-synuclein amyloids do not facilitate NM aggregation in vitro, even though in [PSI+] cells NM and transthyretin aggregates also occasionally colocalize. Our data, especially the in vitro reproduction of the highly specific heterologous seeding effect, provide strong support for the hypothesis of cross-seeding in the spontaneous initiation of prion states.     

Energetics and Mechanism of Conformational Transitions of Protein‐Like NIPAM‐Sodium Styrene Sulfonate Copolymers in Aqueous Solutions

Protein‐like and random NIPAM‐sodium styrene sulfonate copolymers of similar composition have been prepared by radical polymerization in water at temperatures above and below the LCST of PNIPAM, respectively. Thermal transitions of the copolymers in aqueous solutions have been studied by means of dynamic light scattering, viscometry, and high‐sensitivity differential scanning calorimetry. The phase separation or cooperative conformational transitions without phase separation were observed for the random or the protein‐like copolymers, respectively. Transition temperature, enthalpy, and heat capacity increment of the protein‐like copolymer differed insignificantly from those of the random copolymer of similar composition. The transition heat capacity increments of the protein‐like copolymers revealed that only 10–20% of their NIPAM links participate in the formation of a dense water‐free globule core. The coil–globule transitions of the protein‐like copolymers were described by the thermodynamic three‐state model according to the scheme “random coil?condensed coil?globule”, which is known to simulate the folding mechanism of globular proteins.

     

Serotype 10A in Case Patients with Invasive Pneumococcal Disease: A Pilot Study of PCR-Based Serotyping in New Jersey

In 2008, the New Jersey Department of Health (NJDOH) identified a 21.1% increase in reported invasive pneumococcal disease (IPD). In 2009, NJDOH piloted nucleic acid-based serotyping to characterize serotypes causing IPD. From April through September, NJDOH received specimens from 149 of 302 (49%) case patients meeting our case definition. An uncommon serotype, 10A, accounted for 25.2% of IPD overall and was identified in 12 counties, but it was associated with one county (rate ratio = 5.4, 95% confidence interval [CI] 2.1, 11.8). NJDOH subsequently conducted a case-control study to assess the presentation of and clinical risk factors for 10A IPD. Case patients with 10A IPD were more likely to have had immunosuppression, asthma, and multiple chronic medical conditions than control subjects had (odds ratio [OR] = 2.6, 95% CI 1.1, 6.3; OR=4.7, 95% CI 1.7, 13.2; and OR=2.3, 95% CI 1.0, 5.2, respectively). State-based pneumococcal serotype testing identified an uncommon serotype in New Jersey. Continued pneumococcal serotype surveillance might help the NJDOH identify and respond to future serotype-specific increases.Streptococcus pneumoniae (S. pneumoniae) is a leading cause of bacterial pneumonia, bacteremia, and meningitis. In 2008, the New Jersey Department of Health (NJDOH) observed a 21.1% increase in reported invasive pneumococcal disease (IPD) compared with IPD cases reported in 2007 (95% confidence interval [CI] 8.6, 35.2, 8.33 cases/100,000 population in 2008 vs. 6.88 cases/100,000 population in 2007), including increases in four counties. In response, in 2009, NJDOH began a pilot project to characterize the serotypes causing IPD and to determine if serotypes not included in current vaccines contributed to these increases. When our investigation identified an unusual serotype, 10A, NJDOH conducted a case-control study to assess the presentation of and clinical risk factors for 10A IPD.     

Computer‐Based Malnutrition Risk Calculation May Enhance the Ability to Identify Pediatric Patients at Malnutrition‐Related Risk for Unfavorable Outcome

Background: The study aimed to test the hypothesis that computer‐based calculation of malnutrition risk may enhance the ability to identify pediatric patients at malnutrition‐related risk for an unfavorable outcome. The Pediatric Digital Scaled MAlnutrition Risk screening Tool (PeDiSMART), incorporating the World Health Organization (WHO) growth reference data and malnutrition‐related parameters, was used. Materials and Methods: This was a prospective cohort study of 500 pediatric patients aged 1 month to 17 years. Upon admission, the PeDiSMART score was calculated and anthropometry was performed. Pediatric Yorkhill Malnutrition Score (PYMS), Screening Tool Risk on Nutritional Status and Growth (STRONGkids), and Screening Tool for the Assessment of Malnutrition in Pediatrics (STAMP) malnutrition screening tools were also applied. PeDiSMART's association with the clinical outcome measures (weight loss/nutrition support and hospitalization duration) was assessed and compared with the other screening tools. Results: The PeDiSMART score was inversely correlated with anthropometry and bioelectrical impedance phase angle (BIA PhA). The score's grading scale was based on BIA Pha quartiles. Weight loss/nutrition support during hospitalization was significantly independently associated with the malnutrition risk group allocation on admission, after controlling for anthropometric parameters and age. Receiver operating characteristic curve analysis showed a sensitivity of 87% and a specificity of 75% and a significant area under the curve, which differed significantly from that of STRONGkids and STAMP. In the subgroups of patients with PeDiSMART‐based risk allocation different from that based on the other tools, PeDiSMART allocation was more closely related to outcome measures. Conclusion: PeDiSMART, applicable to the full age range of patients hospitalized in pediatric departments, graded according to BIA PhA, and embeddable in medical electronic records, enhances efficacy and reproducibility in identifying pediatric patients at malnutrition‐related risk for an unfavorable outcome. Patient allocation according to the PeDiSMART score on admission is associated with clinical outcome measures.