Mitochondrial function and mitochondrial DNA maintenance with advancing age

We review the impact of mitochondrial DNA (mtDNA) maintenance and mitochondrial function on the aging process. Mitochondrial function and mtDNA integrity are closely related. In order to create a protective barrier against reactive oxygen and nitrogen species (RONS) attacks and ensure mtDNA integrity, multiple cellular mtDNA copies are packaged together with various proteins in nucleoids. Regulation of antioxidant and RONS balance, DNA base excision repair, and selective degradation of damaged mtDNA copies preserves normal mtDNA quantities. Oxidative damage to mtDNA molecules does not substantially contribute to increased mtDNA mutation frequency; rather, mtDNA replication errors of DNA PolG are the main source of mtDNA mutations. Mitochondrial turnover is the major contributor to maintenance of mtDNA and functionally active mitochondria. Mitochondrial turnover involves mitochondrial biogenesis, mitochondrial dynamics, and selective autophagic removal of dysfunctional mitochondria (i.e., mitophagy). All of these processes exhibit decreased activity during aging and fall under greater nuclear genome control, possibly coincident with the emergence of nuclear genome instability. We suggest that the age-dependent accumulation of mutated mtDNA copies and dysfunctional mitochondria is associated primarily with decreased cellular autophagic and mitophagic activity.     

Implicit versus explicit measures of self-concept of self-control and their differential predictive power for spontaneous trait-relevant behaviors

Background and objectives

Low trait self-control constitutes a core criterion in various psychiatric disorders. Personality traits such as low self-control are mostly indexed by self-report measures. However, several theorists emphasized the importance of differentiating between explicit and implicit indices of personality traits, Therefore, the present study examined the unique predictive validity of an implicit measure of trait self-control for spontaneous dysfunctional behavior.

Methods

As a measure of implicit trait self-control, we used an irrelevant feature task: a speeded reaction time task comprising a task-relevant stimulus feature (i.e., capital vs. lower case letter type) and a task-irrelevant feature (high vs. low self-control word type). The irrelevant feature had to be ignored, while participants (n = 34) responded to the relevant stimulus feature. However, their response was either congruent or incongruent with the irrelevant stimulus feature, resulting in facilitated or deteriorated task performance. As indicators of trait-related spontaneous dysfunctional behavior, we included indices of frustration tolerance and the preference for short-term reward over meeting long-term goals. We also included two explicit measures of trait self-control: a self-report questionnaire and an explicit self-relevance rating of the implicit task stimuli.

Results

Specifically the implicit measure of trait self-control showed predictive validity for the target self-control behaviors.

Limitations

The predictive validity of implicit measures of personality traits requires further study in larger, non-student samples.

Conclusions

As predicted, the implicit measure of trait self-control showed superior predictive power for spontaneous trait-related behavior. This finding points to the relevance of complementing the routinely used self-report measures with implicit measures of trait self-control.     

Can Mental Health Be Viewed as a Public Social Problem?

We can define the concept of mental health not just as a health phenomenon, but also as a social and psychological one. Defining mental health separately from mental illness places it into the concept of public health, which exceeds the medical definition of the determination of a "mental illness." The anthropology of health defines the medical treatment as a social practice, which takes into consideration a person's social context, the differences between genders, and the connection between personal and social. It accents the characteristics of social systems, values, and manifestations of social crises through basic concepts and discourses, such as gender and culture. Besides the consideration of health and disease, it also enables the consideration of a person in a highly industrialized society and of a culture as a totality. The phenomenon of destructive ways of manifesting psychic crises (within the presented case study research) implies that mental health should be seen as a social problem.     

The proteasomal subunit Rpn6 is a molecular clamp holding the core and regulatory subcomplexes together

Proteasomes execute the degradation of most cellular proteins. Although the 20S core particle (CP) has been studied in great detail, the structure of the 19S regulatory particle (RP), which prepares ubiquitylated substrates for degradation, has remained elusive. Here, we report the crystal structure of one of the RP subunits, Rpn6, and we describe its integration into the cryo-EM density map of the 26S holocomplex at 9.1?? resolution. Rpn6 consists of an α-solenoid-like fold and a proteasome COP9/signalosome eIF3 (PCI) module in a right-handed suprahelical configuration. Highly conserved surface areas of Rpn6 interact with the conserved surfaces of the Pre8 (alpha2) and Rpt6 subunits from the alpha and ATPase rings, respectively. The structure suggests that Rpn6 has a pivotal role in stabilizing the otherwise weak interaction between the CP and the RP.     

Dicyanovinylnaphthalenes for neuroimaging of amyloids and relationships of electronic structures and geometries to binding affinities

The positron-emission tomography (PET) probe 2-(1-[6-[(2-fluoroethyl)(methyl)amino]-2-naphthyl]ethylidene) (FDDNP) is used for the noninvasive brain imaging of amyloid-β (Aβ) and other amyloid aggregates present in Alzheimer’s disease and other neurodegenerative diseases. A series of FDDNP analogs has been synthesized and characterized using spectroscopic and computational methods. The binding affinities of these molecules have been measured experimentally and explained through the use of a computational model. The analogs were created by systematically modifying the donor and the acceptor sides of FDDNP to learn the structural requirements for optimal binding to Aβ aggregates. FDDNP and its analogs are neutral, environmentally sensitive, fluorescent molecules with high dipole moments, as evidenced by their spectroscopic properties and dipole moment calculations. The preferred solution-state conformation of these compounds is directly related to the binding affinities. The extreme cases were a nonplanar analog t-butyl-FDDNP, which shows low binding affinity for Aβ aggregates (520 nM K_i) in vitro and a nearly planar tricyclic analog cDDNP, which displayed the highest binding affinity (10 pM K_i). Using a previously published X-ray crystallographic model of 1,1-dicyano-2-[6-(dimethylamino)naphthalen-2-yl]propene (DDNP) bound to an amyloidogenic Aβ peptide model, we show that the binding affinity is inversely related to the distortion energy necessary to avoid steric clashes along the internal surface of the binding channel.     

Multicentre analysis of 178,992 type 2 diabetes patients revealed better metabolic control despite higher rates of hypertension,stroke, dementia and repeated inpatient care in patients with comorbid Parkinson's disease

BackgroundEspecially in older people, physicians are faced with the coexistence of type 2 diabetes mellitus (T2DM) and Parkinson's disease (PD). Therefore, this research aimed to compare diabetes endpoints between T2DM with and without PD.MethodsBased on the standardized, multicenter, prospective DPV database, 178,992 T2DM patients (≥40 years) were analyzed. 1579 were diagnosed with PD and/or received specific treatment. Hierarchical multivariable regression models were used for group comparisons; adjusted estimates based on observed marginal frequencies were calculated.ResultsPD patients were significantly older (77.9 vs. 70.0 years; p < 0.0001) and had a longer diabetes duration (10.3 vs. 8.4 years; p < 0.0001). In young PD patients (<50 years), percentage of females was significantly higher compared to age-matched T2DM patients without PD or people of the German population (66.7 vs. 38.1 vs. 49.0%; p < 0.0001, p < 0.02).After demographic adjustment, T2DM patients with PD showed a significantly lower HbA1c (58.0 vs. 60.3 mmol/mol; p < 0.0001), OAD/GLP-1 treatment (41.9 vs. 45.9%; p < 0.01) and frequency of dyslipidemia (62.0 vs. 64.5%; p < 0.05). In contrast, rates of insulin therapy (57.8 vs. 54.8%; p < 0.05), hypertension (73.3 vs. 68.6%; p < 0.001), antihypertensive medication (60.4 vs. 56.1%; p < 0.01), stroke (12.0 vs. 7.3%; p < 0.0001), dementia (9.2 vs. 2.6%; p < 0.0001) and repeated inpatient care (15.7 vs. 12.0%; p < 0.0001) were significantly higher and duration of hospital stay (6.2 vs. 4.7 days; p < 0.0001) was significantly longer in T2DM with PD.ConclusionClear demographic and clinical differences were observed between T2DM with and without PD. In PD patients, metabolic control is better, potentially due to more intensive medical care.     

Accurate and early diagnosis of orthopedic device‐related infection by microbial heat production and sonication

Proper and rapid diagnosis of orthopedic device‐related infection is important for successful treatment. Sonication has been shown to improve the diagnostic performance. We hypothesized that the combination of sonication with a novel method called microcalorimetry will further improve and accelerate the diagnosis of implant infection. We prospectively included 39 consecutive patients (mean age 59 years, 62% males) at our institution from whom 29 orthopedic prostheses and 10 osteosynthesis material were explanted. The explanted device was sonicated. The resulting sonication fluid was analyzed using microcalorimetry. Using standardized criteria to define orthopedic device‐related infection, 12 cases (31%) were defined as infected. In all, positive periprosthetic tissue cultures were found. The sensitivity and specificity of microcalorimetry of sonication fluid were 100% and 97%, respectively. Mean time to detection, defined as time to reach a rising heat flow signal of 20 µW measured after equilibiration needed to get accurate measurement, was 10.9 h. In summary, microcalorimetry of sonication fluid is a reliable and a fast method in detecting the presence of microorganisms in orthopedic device‐related infection. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:1700–1703, 2013     

Impact of cyclosporine versus tacrolimus on the incidence of de novo malignancy following liver transplantation: a single center experience with 609 patients

De novo malignancies are a major cause of late death after liver transplantation. Aim of the present study was to determine whether use of cyclosporine versus tacrolimus affects long‐term tumor incidence considering potential confounders. De novo malignancies in 609 liver transplant recipients at Munich Transplant Centre between 1985 and 2007 were registered. In 1996, the standard immunosuppressive regimen was changed from cyclosporine to tacrolimus. Different effects of those drugs on long‐term tumor incidence were analyzed in multivariate analysis. During 3765 patient years of follow‐up (median 4.78 years), 87 de novo malignancies occurred in 71 patients (mean age 47.5 ± 13.3 years, mean time after liver transplantation 5.7 ± 3.7 years). The cumulative incidence of de novo malignancies was 34.7% for all tumor entities after 15 years as compared to 8.9% for a nontransplanted population. The most frequent tumors observed were nonmelanoma skin cancers (44.83%). Moreover, post‐transplant lymphoid disease, oropharyngeal cancer (n = 6, 6.9%), upper gastrointestinal tract cancer (n = 4, 4.6%), lung cancer (n = 4, 4.6%), gynecological malignancies (n = 4, 4.6%), and kidney cancer (n = 3, 3.45%) were detected. Multivariate analysis revealed recipient age [hazards ratio (HR) 1.06], male gender (HR 1.73), and tacrolimus‐based immunosuppression (HR 2.06) as significant risk factors. Based on those results, a tacrolimus‐based immunosuppression should be discussed especially in older male patients. Whether reducing tacrolimus target levels may reduce the risk for de novo malignancies has yet to be determined in prospective trials.