Induced Coma, Death, and Organ Transplantation: A Physiologic, Genetic, and Theological Perspective.

In the clinic, the death certificate is issued if brain electrical activity is no longer detectable. However, recent research has shown that in model organisms and humans, gene activity continues for at least 96 h postmortem. The discovery that many genes are still working up to 48 h after death questions our definition of death and has implications for organ transplants and forensics. If genes can be active up to 48 h after death, is the person technically still alive at that point? We discovered a very interesting parallel between genes that were upregulated in the brain after death and genes upregulated in the brains that were subjected to medically-induced coma, including transcripts involved in neurotransmission, proteasomal degradation, apoptosis, inflammation, and most interestingly, cancer. Since these genes are involved in cellular proliferation, their activation after death could represent the cellular reaction to escape mortality and raises the question of organ viability and genetics used for transplantation after death. One factor limiting the organ availability for transplantation is religious belief. However, more recently, organ donation for the benefit of humans in need has been seen as "posthumous giving of organs and tissues can be a manifestation of love spreading also to the other side of death".

Present Status and Future Challenges of New Therapeutic Targets in Preclinical Models of Stroke in Aged Animals with/without Comorbidities.

The aging process, comorbidities, and age-associated diseases are closely dependent on each other. Cerebral ischemia impacts a wide range of systems in an age-dependent manner. However, the aging process has many facets which are influenced by the genetic background and epigenetic or environmental factors, which can explain why some people age differently than others. Therefore, there is an urgent need to identify age-related changes in body functions or structures that increase the risk for stroke and which are associated with a poor outcome. Multimodal imaging, electrophysiology, cell biology, proteomics, and transcriptomics, offer a useful approach to link structural and functional changes in the aging brain, with or without comorbidities, to post-stroke rehabilitation. This can help us to improve our knowledge about senescence firstly, and in this context, aids in elucidating the pathophysiology of age-related diseases that allows us to develop therapeutic strategies or prevent diseases. These processes, including potential therapeutical interventions, need to be studied first in relevant preclinical models using aged animals, with and without comorbidities. Therefore, preclinical research on ischemic stroke should consider age as the most important risk factor for cerebral ischemia. Furthermore, the identification of effective therapeutic strategies, corroborated with successful translational studies, will have a dramatic impact on the lives of millions of people with cerebrovascular diseases.

Stem Cell Treatments in Preclinical Relevant Stroke Models.

Since stroke has limited treatment options, an active search for new therapeutic approaches is required. Initial excitement of using cell-based therapies to stimulate recovery processes in the ischemic brain turned into a more measured perspective, acknowledging obstacles related to the unfavorable environments associated in part with aging. Given the predominance of stroke in older populations, evaluating the effectiveness of cell therapies in aged brain environments is essential and clinically relevant. Despite a common perception of the aged brain being resistant to regeneration, recent research with neural precursor cells and bone marrow-derived mesenchymal stem cells indicates that cell-based therapy can promote plasticity and remodeling in the aged rat brain. However, significant differences in the aged brain compared to the young brain, such as expedited progression of ischemic injury to brain infarction, decreased rate of endogenous neurogenesis, and delayed onset of neurological recovery, must be noted. The effectiveness of cell-based therapies may further be connected to age-related comorbidities such as diabetes or hyperlipidemia, potentially leading to maladaptive or impaired brain remodeling. These age-related factors need careful consideration in the clinical application of restorative therapies for stroke.

Toxicity and health impact of nanoparticles. Basic biology and clinical perspective.

Stroke has limited restorative treatment options. In search of new therapeutic strategies for the ischemic brain, cell-based therapies offered new hope, which has been, in the meanwhile, converted into a more realistic approach recognizing difficulties related to unfavorable environments causing low survival rates of transplanted neuronal precursors. Stem cell therapies are based on the transplantation of neuronal precursor cells (NPCs), adult stem cells propagated in cell culture or inducible pluripotent cells (iPSCs) obtained from patients and trans-differentiated into neural cells. Of these, autologous iPSCs have the advantage to be used in stroke patients because they do not raise ethical concerns and the risk of graft rejection is low. However, the use of stem cells for stroke therapy in humans has to take into account many factors including, dosage, route of administration, toxicity and side effects. For example, nanoparticles (NPs) may increase the efficacy of drugs and therapeutic cells delivery to the diseased brain. Medication dosages are generally determined by clinical trials done in relatively young, healthy people. However, in vivo and clinical data evaluating the toxic effects of NPs on neural cells are still scarce especially in the aged brain, which has a decreased homeostatic capacity and a reduced ability to cope with internal and environmental stress, as compared to the young brain. Previous studies in rodents indicate that aging along with neurodegenerative diseases may promote a proinflammatory state and leads to the development of gliosis in the aged brains. On the other hand, the nonspecific interaction between the shell of NPs and brain proteins leads to the adsorption of opsonins on their surface, forming the so-called "corona", thereby becoming ideal candidates to attract phagocytic microglia resulting in NPs engulfment and thus exacerbating neuronal death. Therefore, when designing NPs for clinical use, it should be considered that their systemic administration is associated with potential risks, especially in the aged subjects. Recently, NPs have been shown in recent years to play a crucial role in cell signaling processes involved in stroke recovery. Extracellular vesicles (EVs) are secreted by virtually all type of cells in the body and have been shown to reflect the physiological and metabolic status of the host cells. Thus, understanding the disease-specific contents of EVs would enable the discovery of novel predictive biomarkers.

Autophagy in aging and disease.

Autophagy is a catabolic degradation system used to destroy and recycle the unnecessary or damaged components of a cell. Autophagy is present at a basal level in all mammals and is regulated by some conditions, such as oxidative stress, starvation or hypoxia. In aged tissues, increased but also decreased expression of autophagy-specific proteins, Beclin 1, LC3, Atg5 and Atg7 has been reported. Likewise, it could be shown that the lifespan of yeast, nematodes and flies is prolonged by pharmacologically stimulated autophagy using exogenous administered spermidine. Autophagy is potentially implicated in acute lung injury and sepsis, two main causes of morbidity and mortality worldwide. Finally, a quite recent study supports the hypothesis that autophagy might be useful in vascular disease prevention by stimulating cholesterol efflux, which leads to inhibition of necrotic core formation and lipid accumulation. Since autophagy is also implicated in neuro-protection, in Alzheimer's and Huntington's disease animal models and many others normal and pathological states, including immunity, diabetes mellitus, different kind of tumors, colorectal cancer, different inflammations, lung diseases, neurodegenerative diseases, autophagy is of interest to many biomedical researchers.

RETINAL ANGIOMATOUS PROLIFERATION CASE REPORT.

The diagnosis of RAP is similar with the diagnosis of the AMD, but PED, exudate and superficial hemorrhages are more common in RAP. A 75-year-old male presented himself at the Ophthalmology Department of the Emergency County Hospital in Craiova in January 2015, with a 4 months history of vision loss. In his right eye the visual acuity was 4/50 eye non-optical correctable and 5/5 with optical correction in the left eye. According to the FA and OCT that were performed in both eyes, in the right eye was found intraretinal neovascularization and sub and intraretinal fluid. A normal aspect was found in the left eye. After the investigations we decided to start the treatment consisting in one single intravitreal injection with Triamcinolone Acetonide (IVTA) in the right eye. The VA improved 1 week after the treatment from 4/50 to 5/30. In comparison with the improved VA, the macular edema gradually resorbed 1 month after the IVTA injection. In spite of the late presentation of the patient in the Ophthalmology Department, the VA and OCT outcome after a single dose of IVTA injection was very good.