We evaluated the association of diabetes and insulin resistance with the response to cell therapy in patients with nonischemic dilated cardiomyopathy (DCM). CD34[sup]+ cells were collected by apheresis and injected transendocardially. Twelve patients had diabetes mellitus (DM group), 17 had insulin resistance (IR group), and 16 displayed normal glucose metabolism (no-IR group). After stimulation, we found higher numbers of CD34[sup]+ cells in the IR group (94+-73x10[sup]6 cells per liter) than in the no-IR group (54 +- 35 x 10[sup]6 cells per liter) or DM group (31 +- 20 x 10[sup]6 cells per liter; p = .005). Similarly, apheresis yielded the highest numbers of CD34[sup]+ cells in the IR group (IR group, 216+-110x10[sup]6 cells; no-IR group, 127+-82x10[sup]6 cells; DMgroup, 77+-83x10[sup]6 cells; p = .002). Six months after cell therapy, we found an increase in left ventricular ejection fraction in the IR group (+5.6%+-6.9%) and the no-IR group (+4.4% + 7.2%) but not in the DM group (-0.9% +- 5.4%; p = .035). The N-terminal probrain natriuretic peptide levels decreased in the IR and no-IR groups, but not in the DMgroup (-606+- 850 pg/ml; -698 +- 1,105 pg/ml; and +238 +- 963 pg/ml, respectively; p = .034). Transendocardial CD34+ cell therapy appears to be ineffective in DCM patients with diabetes. IR was associated with improved CD34+ stem cell mobilization and a preserved clinical response to cell therapy.
COBISS.SI-ID: 32541145
Therapeutic hypothermia (HT) is standard care for moderate and severe neonatal hypoxic-ischaemic encephalopathy (HIE), the leading cause of permanent brain injury in term newborns. However, the optimal temperature for HT is still unknown, and few preclinical studies have compared multiple HT treatment temperatures. Additionally, HT may not benefit infants with severe encephalopathy. In a neonatal rat model of unilateral hypoxia-ischaemia (HI), the effect of five different HT temperatures was investigated after either moderate or severe injury. One week after treatment, neuropathological analysis of hemispheric and hippocampal area loss, and CA1 hippocampal pyramidal neuron count, was performed. After moderate injury, a significant reduction in hemispheric and hippocampal loss on the injured side, and preservation of CA1 pyramidal neurons, was seen in the 33.5°C, 32°C, and 30°C groups. Cooling below 33.5°C did not provide additional neuroprotection. Regardless of treatment temperature, HT was not neuroprotective in the severe HI model. Based on these findings, and previous experience translating preclinical studies into clinical application, we propose that milder cooling should be considered for future clinical trials.
COBISS.SI-ID: 32562905
Background: Therapeutic hypothermia (TH) is standard treatment following perinatal asphyxia in newborn infants. Experimentally, TH is neuroprotective after moderate hypoxia-ischemia (HI) in seven-day-old (P7) rats. However, TH is not neuroprotective after severe HI. After a moderate HI insult in newborn brain injury models, the anesthetic gas xenon (Xe) doubles TH neuroprotection. The aim of this study was to examine whether combining Xe and TH is neuroprotective as applied in a P7 rat model of severe HI. Following the HI insult, median (interquartile range, IQR) hemispheric brain area loss was similar in all groups: 63.5% (55.5-75.0) for NT-37 group, 65.0% (57.0-65.0) for TH-32 group, and 66.5% (59.0-72.0) for TH-32+Xe50% group (not significant). Correspondingly, there was no difference in neuronal cell count (NeuN marker) in the subventricular zone across the three treatment groups. Conclusions: Immediate therapeutic hypothermia with or without additional 50% inhaled Xe, does not provide neuroprotection one week after severe HI brain injury in the P7 neonatal rat. This model aims to mimic the clinical situation in severely asphyxiated neonates and treatment these newborns remains an ongoing challenge.
COBISS.SI-ID: 32688089
Oxidative stress and decreased DNA damage repair in vertebrates increase with age also due to lowered cellular NAD+. NAD+ depletion may play a major role in the aging process at the cellular level by limiting (1) energy production, (2) DNA repair, and (3) genomic signaling. In this study, we hypothesize that it is not NAD+ as a cofactor in redox reactions and coenzyme in metabolic processes that has the ultimate role in aging, but rather the role of NAD+ in cellular signaling when used as substrate for sirtuins (SIRT1-7 in mammals) and PARPs [Poly(ADP-ribose) polymerases]. Both sirtuins and PARPs influence many transcription factors and can affect gene expression. As a signaling molecule, NAD+ is consumed in the reaction donating ADP-ribose and releasing nicotinamide (NAM) as a by-product. It seems that aging at the cellular level is associated with a decline of NAD+ and that NAD+ restoration can reverse phenotypes of aging by inducing cellular repair and stress resistance. Adequate intracellular NAD+ concentrations may be an important longevity assurance factor, while lowered cellular NAD+ concentration may negatively influence the life span.
COBISS.SI-ID: 5019243
In astrocytes, carbon monoxide (CO) poisoning causes oxidative stress and mitochondrial dysfunction accompanied by caspase and calpain activation. Impairment in astrocyte function can be time-dependently reduced by hyperbaric (3 bar) oxygen (HBO). Due to the central role of astrocytes in maintaining neuronal function by offering neurotrophic support we investigated the hypothesis that HBO therapy may exert beneficial effect on acute CO poisoning-induced impairment in intrinsic neurotrophic activity. Exposure to 3000 ppm CO in air followed by 24-72 h of normoxia caused a progressive decline of gene expression, synthesis and secretion of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) to different extent. 1 h treatment with 100%hyperbaric oxygen disclosed a pressure- and time-dependent efficacy in preserving astrocytic neurotrophic support. Normo-baric oxygen was not effective. The beneficial effect was most evident when the astrocytes were exposed to HBO 1-5 h after exposure to CO. The results further support an active role of hyperbaric, not normobaric, oxygenation in reducing dysfunction of astrocytes after acute CO poisoning. By preserving endogenous neurotrophic activity HBO therapy might promote neuronal protection and thus prevent the occurrence of late neuropsychological sequelae.
COBISS.SI-ID: 32604633