The potential of non-myeloablative heterochronous autologous hematopoietic stem cell transplantation for extending a healthy life span

Aging is a complex multifactorial process, a prominent component being the senescence of the immune system. Consequently, immune-related diseases develop, including atherosclerosis, cancer, and life-threatening infections, which impact on health and longevity. Rejuvenating the aged immune system could mitigate these diseases, thereby contributing to longevity and health. Currently, an appealing option for rejuvenating the immune system is heterochronous autologous hematopoietic stem cell transplantation (haHSCT), where healthy autologous bone marrow/peripheral blood stem cells are collected during the youth of an individual, cryopreserved, and re-infused when he or she has reached an older age. After infusion, young hematopoietic stem cells can reconstitute the compromised immune system and improve immune function. Several studies using animal models have achieved substantial extension of the life span of animals treated with haHSCT. Therefore, haHSCT could be regarded as a potential procedure for preventing age-related immune defects and extending healthy longevity. In this review, the pros, cons, and future feasibility of this approach are discussed.     

Priming of the vascular endothelial growth factor signaling pathway by thrombospondin-1, CD36, and spleen tyrosine kinase

CD36 plays a critical role in the inhibition of angiogenesis through binding to the type 1 repeats of thrombospondin-1 (TSP-1) and activating Fyn tyrosine kinase and MAPK pathways. Here, we reveal a novel association of CD36 with VEGFR-2 and spleen tyrosine kinase (Syk). We also address the correlation between the expression of CD36 and Syk by demonstrating that overexpression of CD36 in HUVECs up-regulates endogenous Syk expression. We also define a new role for TSP-1 and CD36 in the activation of the VEGFR-2 signaling pathway that requires Syk. Our findings also identify a role for Syk as a stimulator of VEGF-A-induced angiogenesis by increasing phosphorylation of Y1175 in VEGFR-2, which is a major tyrosine for promoting VEGF-A-induced endothelial cell migration. Together, these studies introduce a new signaling pathway for TSP-1, CD36, and Syk, and address the role of these proteins in regulating the angiogenic switch.     

Effect of verapamil, a calcium antagonist, on the gastric secretion stimulated by histamine or sham-feeding

While "in vitro" studies suggest that cholinergic but not histamine stimulation of the parietal cell is closely related to the flow of extracellular Ca++ into the cell, human studies show a great deal of discrepancy. We evaluated the effects of verapamil, a Ca++ channel antagonist, on gastric secretion stimulated by histamine and sham feeding in 19 patients with duodenal ulcers. Verapamil (200 mcg/kg/h in continuous perfusion) had no effect either on acid production or the volume of secretion in 10 duodenal ulcer patients during simultaneous perfusion of three progressive doses of histamine. However, it significantly inhibited both SAO (51.83%; p less than 0.01) and the volume of secretion in the sham feeding period (28.39%; p less than 600.05), in a group of nine duodenal ulcer patients. These findings suggest that the Ca++ acts as an intracellular mediator in the stimulation/secretion relationship for cholinergic but not histaminergic stimulation in humans.     

A survey of nine years heart transplantation at Erasme Hospital, University of Brussels.

Between March 1982 and March 1991, 225 heart transplantations (HTx) have been performed in 220 patients suffering end stage cardiac disease. Thirteen percent were females and 87% were males. Age range was from 5 to 68 years. The underlying cardiac disease was ischemic cardiopathy in 51.5%, congestive dilated cardiomyopathy in 42%, valvular cardiomyopathy in 3.5%, toxic myocarditis (post-adriamycin) in 1.5% and chronic rejection in 2.5% (retransplantation). Selection of the recipients was done following the currently well established criteria also taking into account the absolute major contraindications for HTx. Due to the still increasing demand of donor organs, currently donor age has been extended up to 50 years for male and 55 years for female donors. One quarter of the grafts were harvested on site in our institution, two other quarters were harvested somewhere else in Belgium and the last quarter provided by other countries cooperating with Eurotransplant. All patients have undergone orthotopic cardiac transplantation using the standard Lower and Shumway technique. Immunosuppression protocols have changed four times throughout the years. Nevertheless all were based on the use of Ciclosporine variously combined with other current immunosuppressive drugs. Rejection monitoring relied on routine endocardiac biopsy and was diagnosed according to the Billingham criteria. The in-hospital mortality is currently 11%. Infection, early right heart graft failure and acute rejection were the leading causes of death. The major causes of early morbidity were several curable infections, reversible rejection episodes, transient acute renal failure and controllable arterial hypertension. Among the survivors followed for at least one month up to nine years, half of late mortality was caused by chronic rejection followed by infection, sudden death, metabolic disorders, stroke and malignancy. Late morbidity involves cases of mild coronary graft diseases, biological renal insufficiency, some degree of arterial hypertension, dislipidemia. Current actuarial survival rate is 87% at one year, 76% at 5 years up to 9 years. Our experience confirms that HTx represents today and effective therapy for selected patients suffering end stage cardiac disease.     

A pharmacological study of Araujia sericifera B. extracts in rodents

The present study analyses the pharmacological activity in in vitro and in vivo models of different extracts obtained from Araujia sericifera. The hexane extract of fruits lacked toxicity, but exhibited an analgesic effect in models of chemical and thermal stimulation. Such an extract was the only one which exhibited antiinflammatory actions. The intrinsic effect on arterial blood pressure was biphasic: at low doses it significantly increased blood pressure, whereas at high doses it exerted the opposite effect. On isolated organs it produced a marked decrease in the maximum effect of histamine and acetylcholine. The dichloromethanol extract of fruits decreased arterial pressure and the maximum effect of histamine. The methanol extract of fruits slightly depressed the CNS. An analgesic effect was noted following chemical stimulation; the maximum effect of serotonin was significantly decreased. The dichloromethanol extract of seeds markedly decreased arterial pressure and the maximum effect of acetylcholine and serotonin. The methanol extract of seeds exerted an analgesic effect after chemical stimulation and modified the maximum effect of noradrenaline and serotonin.     

Pharmacological evaluation of the dichloromethanol extract from Inula crithmoides L.

The pharmacological effect of the dichloromethanol extract of Inula crithmoides L. was analysed in in vitro and in vivo models. The extract dose-dependently decreased arterial blood pressure and furthermore it showed low acute toxicity, CNS depressor activity and analgesic and antiinflammatory effects. Preincubation of the guineapig ileum and rat duodenum (100 μg/mL) produced a significant reduction in the contractile effects of histamine and acetylcholine and a concentration-related inhibition of the effects of serotonin. Following further fractionation the methylene chloride/acetone (50/50) fraction caused a significant decrease in motor activity and significantly reduced the threshold of pain chemical stimulus.     

Concurrent chemoradiation strategies in the management of unresectable stage III non-small-cell lung cancer

Locally advanced or unresectable stage III non-small-cell lung cancer (NSCLC) patients treated with combined-modality therapy with chemotherapy plus thoracic radiation have improved survival compared to those treated with radiotherapy alone. Furthermore, recent studies in good performance status, stage III patients have shown that concurrent chemoradiotherapy improves survival compared to sequential chemoradiotherapy. However, the optimal chemoradiation approach continues to evolve and is the subject of this review. Since the majority of patients completing chemoradiotherapy will succumb to distant metastatic disease, active systemic agents targeting this tumor compartment are required. Recent data suggest that full-dose chemotherapy designed to eradicate distant micrometastases given either as induction or consolidation has the potential to yield improved patient outcomes. Many of these chemotherapeutic agents are also potent radiosensitizers, hence providing enhanced local control. The integration of these chemotherapeutic agents into chemoradiotherapy programs in stage III NSCLC is the focus of current trials. Ongoing research with novel therapeutic agents with activity against distant micrometastases, refined radiation techniques, and enhanced imaging methodologies to aid in accurate staging are being pursued and should lead to improved survival and toxicity outcomes in this disease.