A cell-based multifactorial approach to angiogenesis

We here propose an alternative cell therapy approach to induce angiogenesis. We prepared small organ fragments whose geometry allows preservation of the natural epithelial/mesenchymal interactions and ensures appropriate diffusion of nutrients and gases to all cells. Fragments derived from lung are shown to behave as fairly independent units, to undergo a marked upregulation of angiogenic factors and to continue to function for several weeks in vitro in serum-free media. When implanted into hosts, they transcribe a similar array of angiogenic factors that specifically induce the formation of a potent vascular network. The angiogenic induction capacity of these fragments was also tested in a mouse and rat model of limb ischemia. We report that such fragments, when implanted in the vicinity of the ischaemic area, induce an angiogenic response which can rescue the ischaemia-induced damage. The approach presented differs from single factor application, gene therapy and other cell therapy methods in that it exploits the complex behaviour of autologous cells in their near to normal environment in order to achieve secretion of a whole range of angiogenic stimuli continuously and in an apparently coordinated fashion.     

Views on aging: older adults’ self-perceptions of age and of health

Perceptions of age and perceptions of health have each been found to predict future health and well-being, yet surprisingly, studies typically focused on one or the other. Studies on perceived age suggested that its effects on longevity may be mediated by perceived health. Within each of these lines of research, the constructs have not been consistently operationalized, making it difficult to generalize across studies. We aimed to investigate the associations of different measures of perceptions of age and of health with one another and with longevity. Data collected at baseline from the 851 participants of the Rutgers Aging and Health longitudinal study (mean age 73) included perceptions of age and health, each assessed with four different single-item measures, sociodemographic, and health measures. Mortality was followed-up for 10 years. All four health perceptions and two of the age perceptions (Age-group identity and nearness-to-death) were associated with survival time. Age and health perceptions had similar independent effects in models that included measures of both types, controlling for demographics and chronic conditions, though not after controlling for age. In contrast with our hypothesis, health perceptions did not mediate the association between age perceptions and mortality. Findings regarding health perceptions were generally consistent across measures, whereas age perception measures differed in their associations with various outcomes, indicating that they assess different subjective age constructs. The findings correspond with proposed explanations for the predictive effect of age and health perceptions and support the significant though weaker independent effects of age perceptions compared with health perceptions.     

Pituitary function in children following infectious diseases of the central nervous system

Recent studies in adults suggest that pituitary deficiencies develop in a considerable proportion of patients who recover from infectious meningitis. The aim of this study was to evaluate pituitary function of children with a history of meningitis. Seventy-nine children were admitted to the Safra Children’s Hospital due to meningitis between 2007 and 2010. Twenty-four families were lost for follow-up, 55 were interviewed by phone and 14 (9 males) participated in the study. Evaluation included medical history, physical examination, auxological measurements and basal levels of TSH, fT4, cortisol and IGF1. Children with abnormal results were followed for a year and dynamic testing was performed when indicated. Mean age at time of infectious meningitis was 3.8 ± 5.4 years (range 0.03–15.8), and at clinical evaluation 6.4 ± 6.4 (range 1.2–20). The interval between the acute event and evaluation was 2.7 ± 1.2 years. Thyroid function tests and basal cortisol levels were normal for all children. Three children had low IGF1 levels; however over a year of follow-up two of them had normal height and growth velocity, making growth hormone deficiency unlikely. One child had low height SDS, but exhibited a normal response to a growth hormone stimulation test. Pituitary dysfunction with overt clinical symptoms is not a frequent consequence of acute meningitis in children. Follow-up of growth and puberty of children post-meningitis by the primary care physician is probably sufficient. Invasive assessments should be reserved for selected cases where there is slow growth or other clinical suspicion of hypopituitarism.     

Pathogenic Bacterial Species Associated with Endodontic Infection Evade Innate Immune Control by Disabling Neutrophils

Endodontic infections, in which oral bacteria access the tooth pulp chamber, are common and do not resolve once established. To investigate the effects of these infections on the innate immune response, we established a mouse subcutaneous chamber model, where a mixture of four oral pathogens commonly associated with these infections (endodontic pathogens [EP]), i.e., Fusobacterium nucleatum, Streptococcus intermedius, Parvimonas micra, and Prevotella intermedia, was inoculated into subcutaneously implanted titanium chambers. Cells that infiltrated the chamber after these infections were primarily neutrophils; however, these neutrophils were unable to control the infection. Infection with a nonpathogenic oral bacterial species, Streptococcus mitis, resulted in well-controlled infection, with bacterial numbers reduced by 4 to 5 log units after 7 days. Propidium iodide (PI) staining of the chamber neutrophils identified three distinct populations: neutrophils from EP-infected chambers were intermediate in PI staining, while cells in chambers from mice infected with S. mitis were PI positive (apoptotic) or negative (live). Strikingly, neutrophils from EP-infected chambers were severely impaired in their ability to phagocytose and to generate reactive oxygen species in vitro after removal from the chamber compared to cells from S. mitis-infected chambers. The mechanism of neutrophil impairment was necrotic cell death as determined by morphological analyses. P. intermedia alone could induce a similar neutrophil phenotype. We conclude that the endodontic pathogens, particularly P. intermedia, can efficiently disable and kill infiltrating neutrophils, allowing these infections to become established. These results can help explain the persistence of endodontic infections and demonstrate a new virulence mechanism associated with P. intermedia.     

The association between systolic blood pressure reduction during clonidine suppression testing and the decrease in plasma catecholamines and metanephrines

Borderline isolated norepinephrine (NE) and normetanephrine (NMT) elevation is common among patients with suspected pheochromocytoma and paraganglioma (PPGL). The clonidine suppression test (CST) may help establish the etiology in these cases. Prolonged laboratory processing and/or paucity of reliable biochemical assays may limit the utility of CST. The aim of this study was to evaluate whether blood pressure (BP) reduction during CST is associated with alterations in plasma NMT/NE, thereby potentially providing an immediate indication of CST results. In this cross‐sectional study, the authors included all consecutive patients with suspected PPGL who underwent CST from January 1, 2014, to December 31, 2019. Linear regression models were conducted to evaluate the association between BP reduction and decrease in plasma NMT/NE. The final analysis included 36 patients (17 males). The decrease in systolic BP (SBP) 90 minutes postclonidine was associated with a decrease in plasma NMT (R = 0.668, P = .025) and NE (R = 0.562, P = .005). A 40% decrease in NMT and NE correlated with a 9.74% and 7.16% decrease in SBP, respectively. Subgroup analyses demonstrated that the association between SBP reduction and the decrease in plasma NMT (R = 0.764, P = .046) and NE (R = 0.714, P = .003) strengthens among patients with hypertension and among those with diabetes mellitus (R = 0.974, P = .026 for NMT). In conclusion, SBP reduction during CST is associated with plasma NMT and NE decrease. Therefore, the decrease in SBP 90 minutes postclonidine may serve as an immediate complementary clinical tool for PPGL diagnosis.     

Nicotinamide, a SIRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow homing and engraftment

Strategies that increase homing to the bone marrow and engraftment efficacy of ex?vivo expended CD34(+) cells are expected to enhance their clinical utility. Here we report that nicotinamide (NAM), a form of vitamin B-3, delayed differentiation and increased engraftment efficacy of cord blood-derived human CD34(+) cells cultured with cytokines. In the presence of NAM, the fraction of CD34(+)CD38(-) cells increased and the fraction of differentiated cells (CD14(+), CD11b(+), and CD11c(+)) decreased. CD34(+) cells cultured with NAM displayed increased migration toward stromal cell derived factor-1 and homed to the bone marrow with higher efficacy, thus contributing to their increased engraftment efficacy, which was maintained in competitive transplants with noncultured competitor cells. NAM is a known potent inhibitor of several classes of ribosylase enzymes that require NAD for their activity, as well as sirtuin (SIRT1), class III NAD(+)-dependent-histone-deacetylase. We demonstrated that EX-527, a specific inhibitor of SIRT1 catalytic activity, inhibited differentiation of CD34(+) cells similar to NAM, while specific inhibitors of NAD-ribosylase enzymes did not?inhibit differentiation, suggesting that the NAM effect is SIRT1-specific. Our findings suggest?a critical function of SIRT1 in the regulation of hematopoietic stem cell activity and imply the?clinical utility of NAM for ex?vivo expansion of functional CD34(+) cells.