Topical Cellular/Tissue and Molecular Aspects Regarding Nonpharmacological Interventions in Alzheimer's Disease-A Systematic Review.

One of the most complex and challenging developments at the beginning of the third millennium is the alarming increase in demographic aging, mainly-but not exclusively-affecting developed countries. This reality results in one of the harsh medical, social, and economic consequences: the continuously increasing number of people with dementia, including Alzheimer's disease (AD), which accounts for up to 80% of all such types of pathology. Its large and progressive disabling potential, which eventually leads to death, therefore represents an important public health matter, especially because there is no known cure for this disease. Consequently, periodic reappraisals of different therapeutic possibilities are necessary. For this purpose, we conducted this systematic literature review investigating nonpharmacological interventions for AD, including their currently known cellular and molecular action bases. This endeavor was based on the PRISMA method, by which we selected 116 eligible articles published during the last year. Because of the unfortunate lack of effective treatments for AD, it is necessary to enhance efforts toward identifying and improving various therapeutic and rehabilitative approaches, as well as related prophylactic measures.

Lithium Biological Action Mechanisms after Ischemic Stroke.

Lithium is a source of great scientific interest because although it has such a simple structure, relatively easy-to-analyze chemistry, and well-established physical properties, the plethora of effects on biological systems-which influence numerous cellular and molecular processes through not entirely explained mechanisms of action-generate a mystery that modern science is still trying to decipher. Lithium has multiple effects on neurotransmitter-mediated receptor signaling, ion transport, signaling cascades, hormonal regulation, circadian rhythm, and gene expression. The biochemical mechanisms of lithium action appear to be multifactorial and interrelated with the functioning of several enzymes, hormones, vitamins, and growth and transformation factors. The widespread and chaotic marketing of lithium salts in potions and mineral waters, always at inadequate concentrations for various diseases, has contributed to the general disillusionment with empirical medical hypotheses about the therapeutic role of lithium. Lithium salts were first used therapeutically in 1850 to relieve the symptoms of gout, rheumatism, and kidney stones. In 1949, Cade was credited with discovering the sedative effect of lithium salts in the state of manic agitation, but frequent cases of intoxication accompanied the therapy. In the 1960s, lithium was shown to prevent manic and also depressive recurrences. This prophylactic effect was first demonstrated in an open-label study using the "mirror" method and was later (after 1970) confirmed by several placebo-controlled double-blind studies. Lithium prophylaxis was similarly effective in bipolar and also unipolar patients. In 1967, the therapeutic value of lithemia was determined, included in the range of 0.5-1.5 mEq/L. Recently, new therapeutic perspectives on lithium are connected with improved neurological outcomes after ischemic stroke. The effects of lithium on the development and maintenance of neuroprotection can be divided into two categories: short-term effects and long-term effects. Unfortunately, the existing studies do not fully explain the lithium biological action mechanisms after ischemic stroke.

Main Cations and Cellular Biology of Traumatic Spinal Cord Injury.

Traumatic spinal cord injury is a life-changing condition with a significant socio-economic impact on patients, their relatives, their caregivers, and even the community. Despite considerable medical advances, there is still a lack of options for the effective treatment of these patients. The major complexity and significant disabling potential of the pathophysiology that spinal cord trauma triggers are the main factors that have led to incremental scientific research on this topic, including trying to describe the molecular and cellular mechanisms that regulate spinal cord repair and regeneration. Scientists have identified various practical approaches to promote cell growth and survival, remyelination, and neuroplasticity in this part of the central nervous system. This review focuses on specific detailed aspects of the involvement of cations in the cell biology of such pathology and on the possibility of repairing damaged spinal cord tissue. In this context, the cellular biology of sodium, potassium, lithium, calcium, and magnesium is essential for understanding the related pathophysiology and also the possibilities to counteract the harmful effects of traumatic events. Lithium, sodium, potassium-monovalent cations-and calcium and magnesium-bivalent cations-can influence many protein-protein interactions, gene transcription, ion channel functions, cellular energy processes-phosphorylation, oxidation-inflammation, etc. For data systematization and synthesis, we used the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) methodology, trying to make, as far as possible, some order in seeing the "big forest" instead of "trees". Although we would have expected a large number of articles to address the topic, we were still surprised to find only 51 unique articles after removing duplicates from the 207 articles initially identified. Our article integrates data on many biochemical processes influenced by cations at the molecular level to understand the real possibilities of therapeutic intervention-which must maintain a very narrow balance in cell ion concentrations. Multimolecular, multi-cellular: neuronal cells, glial cells, non-neuronal cells, but also multi-ionic interactions play an important role in the balance between neuro-degenerative pathophysiological processes and the development of effective neuroprotective strategies. This article emphasizes the need for studying cation dynamics as an important future direction.

Recent Advances in Molecular Research on Hydrogen Sulfide (H2S) Role in Diabetes Mellitus (DM)-A Systematic Review.

Abundant experimental data suggest that hydrogen sulfide (H2S) is related to the pathophysiology of Diabetes Mellitus (DM). Multiple molecular mechanisms, including receptors, membrane ion channels, signalingmolecules, enzymes, and transcription factors, are known to be responsible for the H2S biological actions; however, H2S is not fully documented as a gaseous signaling molecule interfering with DM and vascular-linked pathology. In recent decades, multiple approaches regarding therapeutic exploitation of H2S have been identified, either based on H2S exogenous apport or on its modulated endogenous biosynthesis. This paper aims to synthesize and systematize, as comprehensively as possible, the recent literature-related data regarding the therapeutic/rehabilitative role of H2S in DM. This review was conducted following the "Preferred reporting items for systematic reviews and meta-analyses" (PRISMA) methodology, interrogating five international medically renowned databases by specific keyword combinations/"syntaxes" used contextually, over the last five years (2017-2021). The respective search/filtered and selection methodology we applied has identified, in the first step, 212 articles. After deploying the next specific quest steps, 51 unique published papers qualified for minute analysis resulted. To these bibliographic resources obtained through the PRISMA methodology, in order to have the best available information coverage, we added 86 papers that were freely found by a direct internet search. Finally, we selected for a connected meta-analysis eight relevant reports that included 1237 human subjects elicited from clinical trial registration platforms. Numerous H2S releasing/stimulating compounds have been produced, some being used in experimental models. However, very few of them were further advanced in clinical studies, indicating that the development of H2S as a therapeutic agent is still at the beginning.

Cellular and Molecular Targets for Non-Invasive, Non-Pharmacological Therapeutic/Rehabilitative Interventions in Acute Ischemic Stroke.

BACKGROUND: Cerebral circulation delivers the blood flow to the brain through a dedicated network of sanguine vessels. A healthy human brain can regulate cerebral blood flow (CBF) according to any physiological or pathological challenges. The brain is protected by its self-regulatory mechanisms, which are dependent on neuronal and support cellular populations, including endothelial ones, as well as metabolic, and even myogenic factors. OBJECTIVES: Accumulating data suggest that "non-pharmacological" approaches might provide new opportunities for stroke therapy, such as electro-/acupuncture, hyperbaric oxygen therapy, hypothermia/cooling, photobiomodulation, therapeutic gases, transcranial direct current stimulations, or transcranial magnetic stimulations. We reviewed the recent data on the mechanisms and clinical implications of these non-pharmaceutical treatments. METHODS: To present the state-of-the-art for currently available non-invasive, non-pharmacological-related interventions in acute ischemic stroke, we accomplished this synthetic and systematic literature review based on the Preferred Reporting Items for Systematic Principles Reviews and Meta-Analyses (PRISMA). RESULTS: The initial number of obtained articles was 313. After fulfilling the five steps in the filtering/selection methodology, 54 fully eligible papers were selected for synthetic review. We enhanced our documentation with other bibliographic resources connected to our subject, identified in the literature within a non-standardized search, to fill the knowledge gaps. Fifteen clinical trials were also identified. DISCUSSION: Non-invasive, non-pharmacological therapeutic/rehabilitative interventions for acute ischemic stroke are mainly holistic therapies. Therefore, most of them are not yet routinely used in clinical practice, despite some possible beneficial effects, which have yet to be supplementarily proven in more related studies. Moreover, few of the identified clinical trials are already completed and most do not have final results. CONCLUSIONS: This review synthesizes the current findings on acute ischemic stroke therapeutic/rehabilitative interventions, described as non-invasive and non-pharmacological.

Translation of the Fugl-Meyer assessment into Romanian: Transcultural and semantic-linguistic adaptations and clinical validation.

Purpose: The Fugl-Meyer Assessment (FMA) scale, which is widely used and highly recommended, is an appropriate tool for evaluating poststroke sensorimotor and other possible somatic deficits. It is also well-suited for capturing a dynamic rehabilitation process. The aim of this study was to first translate the entire sensorimotor FMA scale into Romanian using the transcultural and semantic-linguistic adaptations of its official afferent protocols and to then validate it using the preliminary clinical evaluation of inter- and intra-rater reliability and relevant concurrent validity. Methods: Through three main steps, we completed a standardized procedure for translating FMA's official afferent evaluation protocols into Romanian and their transcultural and semantic-linguistic adaptation for both the upper and lower extremities. For relevant clinical validation, we evaluated 10 patients after a stroke two times: on days 1 and 2. All patients were evaluated simultaneously by two kinesi-physiotherapists (generically referred to as KFT1 and KFT2) over the course of 2 consecutive days, taking turns in the roles of an examiner and observer, and vice versa (inter-rater). Two scores were therefore obtained and compared for the same patient, i.e., being afferent to an inter-rater assay by comparing the assessment outcomes obtained by the two kinesi-physiotherapists, in between, and respectively, to the intra-rater assay: based on the evaluations of the same kinesi-physiotherapist, in two consecutive days, using a rank-based method (Svensson) for statistical analysis. We also compared our final Romanian version of FMA's official protocols for concurrent validity (Spearman's rank correlation statistical method) to both of the widely available assessment instruments: the Barthel Index (BI) and the modified Rankin scale (mRS). Results: Svensson's method confirmed overall good inter- and intra-rater results for the main parts of the final Romanian version of FMA's evaluation protocols, regarding the percentage of agreement (≥80% on average) and for disagreement: relative position [RP; values outside the interval of (-0.1, 0.1) in only two measurements out of the 56 comparisons we did], relative concentration [RC; values outside the interval of (-0.1, 0.1) in only nine measurements out of the same 56 comparisons done], and relative rank variation [RV; all values within an interval of (0, 0.1) in only five measurements out of the 56 comparisons done]. High correlation values were obtained between the final Romanian version of FMA's evaluation protocols and the BI (ρ = 0.9167; p = 0.0002) for FMA-upper extremity (FMA-UE) total A-D (motor function) with ρ = 0.6319 and for FMA-lower extremity (FMA-LE) total E-F (motor function) with p = 0.0499, and close to the limit, with the mRS (ρ = -0.5937; p = 0.0704) for FMA-UE total A-D (motor function) and (ρ = -0.6615; p = 0.0372) for FMA-LE total E-F (motor function). Conclusions: The final Romanian version of FMA's official evaluation protocols showed good preliminary reliability and validity, which could be thus recommended for use and expected to help improve the standardization of this assessment scale for patients after a stroke in Romania. Furthermore, this endeavor could be added to similar international translation and cross-cultural adaptations, thereby facilitating a more appropriate comparison of the evaluation and outcomes in the management of stroke worldwide.

Non-invasive, non-pharmacological/bio-technological interventions towards neurorestoration upshot after ischemic stroke, in adults-systematic, synthetic, literature review.

Considering its marked life-threatening and (not seldom: severe and/or permanent) disabling, potential, plus the overall medico-psycho-socio-economic tough burden it represents for the affected persons, their families and the community, the cerebrovascular accident (CVA)-including with the, by far more frequent, ischemic type-is subject to considerable scientific research efforts that aim (if possible) at eliminating the stroke induced lesions, and consist, as well, in ambitious-but still poorly transferable into medical practice-goals such as brain neuroregeneration and/or repair, within related corollary/upshot of neurorestoration. We have conducted, in this respect, a systematic and synthetic literature review, following the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)" concept. Accordingly, we have interrogated five internationally renowned medical data bases: Elsevier, NCBI/PubMed, NCBI/PMC, PEDro, and ISI Web of Knowledge/Science (the last one to check whether the initially identified articles are published in ISI indexed journals), based on a large (details in the body text) number of most appropriate, to our knowledge, key word combinations/"syntaxes"-used contextually-and subsequently fulfilling the related, on five steps, filtering/selection methodology. We have thereby selected 114 fully eligible (of which contributive: 83-see further) papers; at the same time, additionally, we have enhanced our documentation-basically, but not exclusively, for the introductive part of this work (see further)-with bibliographic resources, overall connected to our subject, identified in the literature within a non-standardized search. It appears that the opportunity window for morph-functional recovery after stroke is larger than previously thought, actually being considered that brain neurorestoration/repair could occur, and therefore be expected, in later stages than in earlier ones, although, in this context, the number of cases possibly benefitting (for instance after physical and/or cognitive rehabilitation-including with magnetic or direct current transcranial stimulation) is quite small and with more or less conflicting, related outcomes, in the literature. Moreover, applying especially high intense, solicitating, rehabilitation interventions, in early stages post (including ischemic) stroke could even worsen the functional evolution. Accordingly, for clarifications and validation of more unitary points of view, continuing and boosting research efforts in this complex, interdisciplinary domain, is necessary. Until finding (if ever) effective modalities to cure the lesions of the central nervous system (CNS)-including post ischemic stroke-it is reasonable and recommendable-based on rigorous methodologies-the avail of combined ways: physiatric, pharmacologic, possibly also bio-technologic. On a different note, but however connected to our subject: periodic related systematic, synthetic literature reviews reappraisals are warranted and welcome.

Modulated Neuroprotection in Unresponsive Wakefulness Syndrome after Severe Traumatic Brain Injury.

BACKGROUND: We aimed to assess the effects of modulated neuroprotection with intermittent administration in patients with unresponsive wakefulness syndrome (UWS) after severe traumatic brain injury (TBI). METHODS: Retrospective analysis of 60 patients divided into two groups, with and without neuroprotective treatment with Actovegin, Cerebrolysin, pyritinol, L-phosphothreonine, L-glutamine, hydroxocobalamin, alpha-lipoic acid, carotene, DL-α-tocopherol, ascorbic acid, thiamine, pyridoxine, cyanocobalamin, Q 10 coenzyme, and L-carnitine alongside standard treatment. MAIN OUTCOME MEASURES: Glasgow Coma Scale (GCS) after TBI, Extended Glasgow Coma Scale (GOS E), Disability Rankin Scale (DRS), Functional Independence Measurement (FIM), and Montreal Cognitive Assessment (MOCA), all assessed at 1, 3, 6, 12, and 24 months after TBI. RESULTS: Patients receiving neuroprotective treatment recovered more rapidly from UWS than controls (p = 0.007) passing through a state of minimal consciousness and gradually progressing until the final evaluation (p = 0.000), towards a high cognitive level MOCA = 22 ± 6 points, upper moderate disability GOS-E = 6 ± 1, DRS = 6 ± 4, and an assisted gait, FIM =101 ± 25. The improvement in cognitive and physical functioning was strongly correlated with lower UWS duration (-0.8532) and higher GCS score (0.9803). CONCLUSION: Modulated long-term neuroprotection may be the therapeutic key for patients to overcome UWS after severe TBI.

Mobile Mechatronic/Robotic Orthotic Devices to Assist-Rehabilitate Neuromotor Impairments in the Upper Limb: A Systematic and Synthetic Review.

This paper overviews the state-of-the-art in upper limb robot-supported approaches, focusing on advancements in the related mechatronic devices for the patients' rehabilitation and/or assistance. Dedicated to the technical, comprehensively methodological and global effectiveness and improvement in this inter-disciplinary field of research, it includes information beyond the therapy administrated in clinical settings-but with no diminished safety requirements. Our systematic review, based on PRISMA guidelines, searched articles published between January 2001 and November 2017 from the following databases: Cochrane, Medline/PubMed, PMC, Elsevier, PEDro, and ISI Web of Knowledge/Science. Then we have applied a new innovative PEDro-inspired technique to classify the relevant articles. The article focuses on the main indications, current technologies, categories of intervention and outcome assessment modalities. It includes also, in tabular form, the main characteristics of the most relevant mobile (wearable and/or portable) mechatronic/robotic orthoses/exoskeletons prototype devices used to assist-rehabilitate neuromotor impairments in the upper limb.