Metabolic syndrome in the offspring of centenarians: focus on prevalence,components, and adipokines

With aging, an increased prevalence of a clustering of metabolic abnormalities has been observed. These abnormalities include obesity, dyslipidemia, hypertension, and insulin resistance and are collectively known as metabolic syndrome (MetS), a low-grade, systemic, inflammatory condition associated with an increased risk of cardiovascular disease, diabetes, and other adverse health outcomes. A number of studies have demonstrated that centenarians’ offspring have a significant survival advantage and a lower risk of developing the most important age-related diseases. They therefore represent one of the best models with which to study the familiar component of human longevity. The aim of this study was to determine if the offspring of centenarians (n = 265 subjects) showed a different prevalence of MetS in comparison to the offspring of non-long-lived parents (controls, n = 101 subjects). In addition, we assessed whether centenarians’ offspring showed particular features of MetS and a distinct regulation of circulating adipokines, cytokines, and metabolic mediators. Although the prevalence of MetS was quite similar both in the offspring of centenarians and the controls, MetS-affected centenarians’ offspring seemed healthier, more functionally fit, and had lower resistin levels. MetS prevalence did not change in centenarians’ offspring across resistin, IGF-1, and resistin/IGF-1 ratio tertiles. On the other hand, in controls, MetS prevalence strongly increased across resistin tertiles and in the third resistin/IGF-1 ratio tertile, indicating a dramatic increase in MetS prevalence when the ratio between these two factors is unbalanced, with high levels of resistin and low levels of IGF-1.     

Investigation of the effect of active efflux at the blood–brain barrier on the distribution of nonsteroidal aromatase inhibitors in the central nervous system

The brain distribution of nonsteroidal aromatase inhibitors was investigated in mice to understand their interactions with brain aromatase. The brain-to-plasma ratio (K_p,brain, mL/g brain) of anastrozole was 0.0299 ± 0.0068, which was lower than that of letrozole (0.383 ± 0.048) and vorozole (0.185 ± 0.031) despite their similar physicochemical properties. The brain-to-plasma unbound concentration ratio of anastrozole, measured using microdialysis, was 0.118 ± 0.037 mL/g brain. In situ mouse brain perfusion also demonstrated that the uptake clearance [mL/(min·g brain)] of anastrozole by the brain (0.108 ± 0.018) was lower than that for letrozole and vorozole (0.422 ± 0.068 and 0.910 ± 0.152, respectively). Anastrozole and vorozole were transported by P-glycoprotein (P-gp) in vitro, whereas none of the compounds were transported by breast cancer resistance protein (BCRP). The K_p,brain of anastrozole and vorozole were increased by 12- and 3.3-fold, respectively, in Mdr1a/b/Bcrp(?/?) mice. IC₅₀ (nM) of anastrozole and letrozole against human aromatase was 12.9 ± 0.7 and 3.59 ± 0.75, respectively. Taken together, these results suggest that active efflux mediated by P-gp at the blood–brain barrier limits the effect of anastrozole in the central nervous system, whereas vorozole and letrozole easily traverse the barrier.     

Comparison of select cancer biomarkers in human circulating and bulk tumor cells using magnetic nanoparticles and a miniaturized micro-NMR system

Circulating tumor cells (CTC) harvested from peripheral blood have received significant interest as sources for serial sampling to gauge treatment efficacy. Nanotechnology and microfluidic based approaches are emerging to facilitate such analyses. While of considerable clinical importance, there is little information on how similar or different CTCs are from their shedding bulk tumors. In this clinical study, paired tumor fine needle aspirate and peripheral blood samples were obtained from cancer patients during image-guided biopsy. Using targeted magnetic nanoparticles and a point-of-care micro-NMR system, we compared selected biomarkers (EpCAM, EGFR, HER-2 and vimentin) in both CTC and fine needle biopsies of solid epithelial cancers. We show a weak correlation between each paired sample, suggesting that use of CTC as “liquid biopsies” and proxies to metastatic solid lesions could be misleading.From the Clinical EditorIn this clinical study, paired tumor fine needle aspirate and peripheral blood samples were obtained from patients with solid epithelial cancers during image-guided biopsy. Using targeted magnetic nanoparticles and a point-of-care micro-NMR system, the authors compared selected biomarkers in both circulating tumor cells (CTC) and fine needle biopsies, demonstrating a weak correlation between each paired sample, suggesting that use of CTC could be misleading in this context.     

Quality KPIs in Pharmaceutical and Food Industry

Purpose

This study aims to investigate what type of quality key performance indicators (KPIs) companies use and how they utilize the results of these KPIs.

Methods

This e-mail survey is aimed at the personnel in the pharmaceutical and the food industries of Finland responsible for quality.

Results

Quality KPIs were similar for both the pharmaceutical and food industries with some differences existing in their usage and reporting. In the pharmaceutical industry, the most common quality KPI was rejected batches followed by the number of complaints, product defects, and deviations. The number of complaints was the most common quality KPI for the food industry. The next most common KPIs were the loss during process and the number of deviations. Respondents in both the pharmaceutical and food industries thought that it is important to follow the indicators that describe the quality of a product and operation. Food companies shared their KPIs and their results with their partners and relevant authorities more often than did pharmaceutical companies.

Conclusions

The results of this study showed that the food industry was slightly more advanced than the pharmaceutical industry in the utilization of the quality indicators. However, statistical significant differences exist between the pharmaceutical and food industries with regard to one quality indicator, namely, rejected batches on the one hand and in the opinion of respondents on how well quality indicators will help direct operations in the right direction on the other.     

Can vergence training improve reading in dyslexics?

Background: Dyslexia affects 5%–8% of the population of the Western world. While reading, different eye movements are required. Compared to other persons, dyslexics have more and longer fixations, shorter saccade amplitude, a higher percentage of regression, and more fixation disparity when reading. In non-reading situations, dyslexics do not have more binocular problems than others. The aim of the present study was to investigate whether computerized orthoptic vergence training could improve reading ability for dyslexic children.

Methods: The study was conducted at Ängkärrskolan, Solna, an elementary school exclusively for dyslexic children. Twelve subjects, aged 13–14 years, were trained with RetCorr, a computerized vergence training program. Reading speed was assessed before and after treatment. The results were compared with an age-matched control group.

Results: The dyslexic subjects conducted on average 11.75 sessions (±2.53 SD) of orthoptic training over a 5-week period. On average, the number of words read per minute before training were 87.83 (±16.80 SD) and after training 95.58 words (±18.08 SD). The difference was statistically significant (p?=?0.0066). In the control group, the change was from 85.00 (±19.68 SD) words to 89.37 words (±19.71 SD) over the same time period. This difference was not significant (p?=?0.1235).

Discussion: Most scientists agree that dyslexia is mainly a phonological impairment. Nevertheless, the results show that vergence treatment might help dyslexics. Larger studies are required to provide guidance in this area.     

Overexpression of pro-inflammatory genes and down-regulation of SOCS-1 in human PTC and in hypoxic BCPAP cells

Hypoxia-inducible factor-1α (HIF-1α) is frequently overexpressed and activated in many cancer types. However, its regulation and function in thyroid carcinomas are only partially known. Aim of our study was to demonstrate that adaptation to the hypoxic micro-environment by human papillary thyroid carcinoma (PTC) cells, in the absence of leukocyte infiltrate, induces a “molecular inflammation” process characterized by the expression of a large set of genes normally involved in inflammation. To address this, tumor, peritumor or normal host tissue from eleven human PTC surgical samples, were separated by laser capture microdissection (LCMD) and studied by real-time quantitative PCR and Western blot. In such condition, we observed an increased expression and activation of HIF-1α, NF-kB and pro-inflammatory genes only in tumor tissues. Importantly, an anti-inflammatory gene such as SOCS-1 was markedly down-regulated in tumor tissue compared to surrounding normal host tissue. Similar results were found in fine-needle aspiration biopsy (FNAB)-derived specimens from PTC and in hypoxic human papillary thyroid tumor cell line, BCPAP. Moreover, we also detected an elevated expression of metalloproteinase-9 (MMP9) both in solid tumor and in hypoxic-treated BCPAP cells. Our findings reveal that, in human PTC tumor, hypoxic conditions are accompanied by up-regulation of pro-inflammatory genes, down-regulation of anti-inflammatory genes and increased expression of MMP9. We propose that a better understanding of the pro- and anti-inflammatory pathways involved in the “molecular inflammation” process even in the absence of leukocyte, may help to clarify progression toward malignancy and may prove useful for new anti-tumor strategy.     

Progression of phosphorylated α‐synuclein in Macaca fuscata

Prion‐like spreading of abnormal proteins is proposed to occur in neurodegenerative diseases, and the progression of α‐synuclein (α‐syn) deposits has been reported in the brains of animal models injected with synthetic α‐syn fibrils or pathological α‐syn prepared from patients with Parkinson''s disease (PD) and dementia with Lewy bodies (DLB). However, α‐syn transmission in nonhuman primates, which are more similar to humans, has not been fully clarified. Here, we injected synthetic human α‐syn fibrils into the left striatum of a macaque monkey (Macaca fuscata). At 3 months after the injection, we examined neurodegeneration and α‐syn pathology in the brain using α‐syn epitope‐specific antibodies, antiphosphorylated α‐syn antibodies (pSyn#64 and pSer129), anti‐ubiquitin antibodies, and anti‐p62 antibodies. Immunohistochemical examination with pSyn#64, pSer129, and α‐syn epitope‐specific antibodies revealed Lewy bodies, massive α‐syn‐positive neuronal intracytoplasmic inclusions (NCIs), and neurites in the left putamen. These inclusions were also positive for ubiquitin and p62. LB509, a human‐specific α‐syn antibody targeting amino acid residues 115–122, showed limited immunoreactivity around the injection site. The left substantia nigra (SN) and the bilateral frontal cortex also contained some NCIs and neurites. The left hemisphere, including parietal/temporal cortex presented sparse α‐syn pathology, and no immunoreactivity was seen in olfactory nerves, amygdala, hippocampus, or right parietal/temporal cortex. Neuronal loss and gliosis in regions with α‐syn pathology were mild, except for the left striatum and SN. Our results indicate that abnormal α‐syn fibrils propagate throughout the brain of M. fuscata via projection, association, and commissural fibers, though the progression of α‐syn pathology is limited.