In a phase I/II study, Stathopoulos GP et al evaluated the maximum tolerated dose of lipoplatin in combination with gemcitabine in patients with previously treated advanced pancreatic cancer (25). Lipoplatin was given as an 8-hour infusion followed by 60

minutes infusion of 1,000 mg/m2 of gemcitabine at day 1 and 15 every 28 days. The dose of lipoplatin was stepwise escalated from 25 mg/m2 to 125 mg/m2. Of the 24 enrolled patients, two of four patients at 125 mg/m2 experienced grade 3-4 neutropenia. Therefore, the MTD of lipoplatin in this combination was determined to be 100 mg/m2. In this dose escalating study, there were two (8.3%) partial responders Inhibitors,research,lifescience,medical and 14 (58.3%) disease stabilizers, and the median overall survival was 4 month. Further randomized phase II/III trial

against gemcitabine monotherapy is under evaluation. Liposome-entrapped cis-bisneodecanoato-trans-R,R-1,2-diaminocyclohexane Inhibitors,research,lifescience,medical (DACH) platinum(II) (L-NDDP, Aroplatin™) is a lipophilic cisplatin analog that has been formulated in relatively large-size Inhibitors,research,lifescience,medical multi-lamellar liposomes measuring from 1 to 3 µm in diameter. L-NDDP has been Tariquidar demonstrated to be non–cross-resistant with cisplatin in cisplatin-resistant Lovo DDP 3.0 (human colon cancer cells) and L1210/PPD (human leukemia cells) both in vitro and in vivo models. In a phase I study, L-NDDP was given intravenously once every 4 weeks, ranging from 7.5 mg/m2 to 390 mg/m2 (26). The infusion rate was set at 4 mg NDDP per minute for all cases. In this particular study, intra-patient dose escalation was allowed. Inhibitors,research,lifescience,medical Grade 1-2 nausea/vomiting, diarrhea and fever were frequently observed in patients receiving

100 mg/m2 or higher dose of L-NDDP. Six out of the 10 patients who had 390 mg/m2 experienced grade 4 hematological toxicities manifesting as thrombocytopenia, granulocytopenia or both. The MTD of Inhibitors,research,lifescience,medical intravenous L-NDDP every 4 weeks was determined as 300 mg/m2. In 2004, Aronex Pharmaceuticals had registered a phase I/II study of L-NDDP and gemcitabine combination in patients with advanced pancreatic cancer resistant to standard therapy in a public clinical trial registration website, the clinicaltrials.gov, with an indentifier of NCT00081549. Unfortunately, the latest trial information was updated in June 2005, and no further publication on this trial can be found. Liposomal STK38 Irinotecan (Nanoliposomal CPT-11, PEP02, MM-398) Irinotecan hydrochloride (CPT-11) is a water-soluble semi-synthetic derivative of camptothecin targeting topoisomerase I, and has been an approved agent for the treatment of metastatic colorectal cancer worldwide, and also for gastric cancer (Japan and Korea), non-small cell lung cancer, small cell lung cancer, cervical cancer, and non-Hodgkin’s lymphoma in Japan.

Levels of follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone were assessed by electrohemiluminiscence immunoassay. Normal learn more values of our laboratory are 1.5-12.4 mlU/l for FSH, 1.7-8.6 mlU/l for LH and 8.64-29.0 nmol/l for testosterone. Regarding interstitial testicular function, patients with normal values of LH and testosterone were classified as eugonadic, those with increased LH and normal testosterone had compensated hypogonadism and those with Inhibitors,research,lifescience,medical increased LH and decreased testosterone had primary hypogonadism. Increased level of FSH indicated tubular failure of testicles. All patients completed Serbian version

of the SF-36 questionnaire as a measure of health-related QoL (12). The SF-36 is a generic instrument that measures eight general health concepts: physical functioning (PF), role physical (RP), bodily pain (BP), general health Inhibitors,research,lifescience,medical (GH), vitality (VT), social functioning (SF), role emotional (RE) and mental health (MH). Two main scores are available to summarize these scales: physical composite

score (PCS) and mental composite score (MCS), as well Inhibitors,research,lifescience,medical as total SF- 36 score. All these scores fall within a 0-100 scale. Higher scores reflect better HRQoL. Methods of descriptive statistic, χ2 test for comparisons between nominal and ordinal variables and Mann- Withney U test for comparisons between continous nonparametric variables were used. In all analyses, Inhibitors,research,lifescience,medical significant testing was two-sided, with alpha set at 0.05 for statistical significance and 0.01 for high statistical significance. Results Demographic and clinical characteristics of the patients are shown in Table 1. Table 1. Demographic and clinical features of investigated men with DM1 (n = 25). Mean IIEF-5 score was 16.4 ± 6.2. Eighteen (72%) patients had ED. Mild ED was Inhibitors,research,lifescience,medical detected in 8 patients (32%), mild to moderate in 4 (16%), moderate in 3 (12%) and severe ED in 3 patient (12%). Mean testosterone level in our DM1 patients was within normal range (16.8

± 6.5 nmol/l), while mean LH and FSH levels were increased (11.5 ± 4.4 mlU/l and 22.7 ± 14.7 mlU/l, respectively). Seven (28%) patients were eugonadic, 16 (64%) had compensated hypogonadism and 2 (8%) patients had primary hypogonadism. Increased FSH, index of tubular Vasopressin Receptor dysfunction, was registered in 15 (60%) patients and it was more frequent in DM1 men with androgenic dysfunction (88% vs. 20%, p < 0.01). Comparisons of different demographic and clinical features between patients with and without ED are presented in Table 2. Presence of ED was not in association with age at the onset of disease, age at the moment of investigation, duration of disease, number of CTG repeats and degree of muscle weakness. Difference in the hormones levels was not observed between patients with and without ED.

It has to be taken into consideration, however, that it was not always possible to differentiate between the side effects attributable to the psychostimulants and those attributable to the antidepressants. None of the depressed RAD001 supplier patients developed drug dependency or addictive behavior. To test for this possibility, psychostimulant, treatment was withdrawn, in most patients, at least once during the course of treatment for a period of 2 days, during

which the patients experienced apathy and tiredness, but without, developing any craving for psychostimulant or signs of withdrawal. In the 38 patients who experienced Inhibitors,research,lifescience,medical a beneficial effect from treatment with psychostimulants, 35 patients reported an improvement, in energy, 26 in mood, 26 in motor activity, 15 in symptoms of psychomotor retardation, 11 in vigilance, and 7 in social interactions. Negative symptoms did not improve in the 4 patients with schizoaffective disorders. Inhibitors,research,lifescience,medical Discussion Our study highlights the benefit of the administration of psychostimulants in addition to conventional antidepressants in patients Inhibitors,research,lifescience,medical with treatment-resistant depression. These findings are concordant

with those of the majority of open studies (see the review of the literature in the first part of this paper). There were no severe side effects and only a low incidence of mild and moderate side effects in the patient population we studied, in agreement with the findings described in the literature. Unlike Kramer et al3 and Edison,36 we found no evidence of drug dependency in our patients. Some of our patients Inhibitors,research,lifescience,medical were suffering from concomitant.

somatic illnesses. These patients probably benefited from the treatment, with psychostimulants, as reported by Woods et al22 in their sample of patients with depressive disorders secondary to somatic illnesses. There were no severe cardiovascular disturbances in our patients. In several Inhibitors,research,lifescience,medical studies in the literature, psychostimulants Linifanib (ABT-869) were used preferentially in elderly persons. In our study, both elderly and younger patients were treated with psychostimulants, with the same positive effect. No psychoses (as opposed to Lucas and Weiss27) were observed in any of our patients treated with psychostimulants. Some of the patients of our study (6 out of responded positively to combined treatment with (reversible) MAO-A inhibitors (like moclobemide) and psychostimulants, even though this particular combination is regarded as controversial. The positive effect, of a combination of psychostimulants with tricyclic antidepressants (as recommended by Spencer69 and Woggon70) was confirmed in our study (30 of 48 patients treated with tricyclics and psychostimulants showed improvement).

4 Remarkably, for each of these genes a majority of studies have reported significant associations with markers and/or marker combinations (haplotypes). However, the associated markers and haplotypes vary across studies for all three genes. Caveats to current claims for susceptibility genes for schizophrenia The confidence in these three claims is, however, limited for the following this website reasons: The fact that the reported at-risk haplotypes in the different

studies/samples are not overlapping, and do not include a common denominator allele or core haplotype for any of the claimed susceptibility genes. Poor reproducibility of Inhibitors,research,lifescience,medical the identical at-risk haplotype in different samples, although for each of the claimed susceptibility genes the vast majority of published inquiries found alleles and haplotypes. Absence of demonstrated function of any of the extracted at-risk haplotypes. No expressed exonic DNA-sequence variants can explain the reported associations,

Inhibitors,research,lifescience,medical ie, neither of these claimed susceptibility genes contains DNA-sequence variants that might: – result in change of the amino-acid sequence in the expressed protein; – account for any of the reported genetic associations with schizophrenia. The failure Inhibitors,research,lifescience,medical to identify one or more susceptibility variants in any of the claimed susceptibility genes directly influencing the etiology of schizophrenia. Thus, there

is a set of consistencies and inconsistencies which are difficult to understand in combination. What is the meaning of Inhibitors,research,lifescience,medical these finding? Given the variation of associated markers/haplotypes across studies and small relative risks, the reported findings might reflect false-positives. This possibility, however, is very unlikely. For example, let us look at NRG1: The proportion of reports with significant, associations in a 300 kb region around the exon 1 is too high to be due to chance (12 out of 14). In addition, the strong association of the originally identified at-risk haplotypes was independently replicated, Inhibitors,research,lifescience,medical and several subsequent studies did not use this marker combination; furthermore, this lack of association those of original haplotypes occurred in Asian populations, due to its very low frequency, whereas more common variants at the same loci were associated with schizophrenia.5 Taking the findings for all the abovementioned genes together, a general pattern can be recognized: Several genes impact on the manifestation of schizophrenia; causal genes can be excluded; the absence of strong linkages to any locus across all genome-wide linkage scans. All susceptibility genes only contribute by a small or, maximally, moderate effect; the relative risks are small in outbred populations (OR 1.5-2.5). The mode of interaction between genes coding for schizophrenia remains obscure.

In addition, LQ treatment reverses ongoing motor deficit as measured using standard EAE clinical scoring and rotorod motor performance. While many reports focus on the prevention or inhibition of early EAE symptoms using LQ, ours is the first study to show distinct improvement in axon myelination, axon conduction, and motor function as a result of LQ treatment in pre (day 0), early post (day 8), and peak (~day 21) EAE mice. We took advantage of PLP_EGFP and Thy1-YFP transgenic mice to study the direct effects Inhibitors,research,lifescience,medical of LQ treatment

on neurodegeneration and demyelination in EAE. LQ treatment significantly attenuated the loss of GFP fluorescence in neurons, axons, and OLs of the CNS. Most remarkable was the increased axon remyelination, axon conduction, and Inhibitors,research,lifescience,medical the significant recovery in proliferating and mature OL numbers of EAE animals

treated with LQ after peak disease. This recovery correlated with LQ-mediated suppression of cytokine production and reduction in infiltrating immune cells in the CNS. Previous studies have also shown LQ-induced neuroprotection in EAE CNS (Ruffini et al. 2012), which correlates with suppression of cytokine production and reduction in infiltrating immune cells (Yang et al. 2004; Wegner et al. 2010; Aharoni et al. 2012; Bruck et al. 2012). In the present study, peripheral Inhibitors,research,lifescience,medical cytokine PI3K inhibitor levels determined after post-immunization day 30 of EAE following 25 mg/kg LQ treatment were similar to levels observed at day 13 (i.e., downregulation of pro-inflammatory cytokines IL-13, Inhibitors,research,lifescience,medical IL-17, IFN-γ, and TNF-α (Wegner et al. 2010). In addition, there was a significant decrease in IL-4, IL-5, and IL-6 cytokines. Our findings of LQ-induced reduction in IL-10 levels in EAE mice are similar to Wegner et al. (2010) and contrast the increase in IL-10 levels reported by Yang et al. (2004). MMP have a crucial function in the migration of peripheral inflammatory cells into the CNS and levels of MMP-9 are elevated in MS and EAE.

Inhibitors,research,lifescience,medical The 25 mg/kg LQ treatment during pre-EAE and peak EAE significantly decreased MMP-9 levels. Taken together, our findings suggest that LQ protects myelin and axons by decreasing pro-inflammatory cytokines and Suplatast tosilate impairing the migratory capacity of inflammatory cells. Reactive astrogliosis is a prominent feature of the chronic and widespread adaptive immune inflammation of the CNS that occurs during EAE and MS (Eng 1985). Reactive astrocytes are responsible for the production of pro-inflammatory molecules (e.g., cytokines, chemokines, growth factors, nitric oxide), growth-inhibitory molecules, and increased production of NFκB-dependent pro-inflammatory molecules. These molecules are detrimental to oligodendrocyte survival, remyelination, and functional recovery (Brambilla et al. 2009; Chang et al. 2012).

5,6 The classical definition of AD, restricted to the concept of dementia, was mainly justified by the fact that the diagnosis was more difficult to make in the early, predementia phase in the last decades: and this was the reason for considering

it a stage of MCI. However, the emerging literature on MCI has emphasized an intrinsic etiological heterogeneity and a diversity of outcomes within research Inhibitors,research,lifescience,medical studies. Efforts to address these issues have not succeeded, and the limitations of MCI are apparent. Hie risk of intervening on an etiologically heterogeneous sample of MCI subjects will include running the risk of “diluting” a significant treatment effect.6 Recently, research has begun to focus on developing new tools, such as neuroimaging and cerebrospinal fluid (CSF) biomarkers, that could increase the specificity of the prodromal AD diagnosis.7 Before using such invasive or expensive tools, it is necessary to screen patients Inhibitors,research,lifescience,medical in memory clinics with neurological exams and find more neuropsychological assessment. The most prominent feature of AD is the decline in cognitive function. Memory impairment of recent events, Inhibitors,research,lifescience,medical unusual repeated omissions, and difficulty learning new information characterize the first clinical signs.8,9 This progression of cognitive deficits

is related to the progression of the underlying cerebral lesions, as established by Braak and Braak.10 In the early

stages of AD (Braak I-III), critical areas for episodic memory are already Inhibitors,research,lifescience,medical affected by neuropathological changes (neurofibrillary degeneration) in medial temporal regions (hippocampal formations, parahippocampal gyrus, and entorhinal cortex) and, consequently, episodic memory deficit Inhibitors,research,lifescience,medical is the initial and reliable neuropsychological marker of AD. As the condition progresses, deficits occur in instrumental functions (language, praxis, visuospatial capacities), which are consistent with the extension of lesions into the crotamiton neocortical associative areas (Braak V). The situation faced by clinicians is easy to summarize: i) memory disorders are the most reliable sign of prodromal AD; ii) unfortunately, memory disorders are a verycommon sign, observed in many disorders: for example in depression, anxiety, sleep disorders, brain vascular lesions, frontal lobe dysfunction, and even in normal aging. Is it possible, therefore, to identify the memory disorders of AD? Here again, the answer is yes, because the memory disorders of AD are not like other memory disorders: there are very specific because they result from a hippocampal dysfunction. This is why the neuropsychological evaluation is crucial at the prodromal stage, for establishing the nature of memory impairment.

demented.10 The diagnostic criteria for MCI are the following: (i) presence of memory complaint; (ii) normal activities of daily living; (iii) normal general learn more cognitive function; (iv) abnormal memory for age; and (v) absence of clinical dementia.11 Petersen et al11 demonstrated that, about 12% of individuals with MCI may progress to Alzheimer’s disease (AD), but a large proportion of MCI individuals will never convert, to dementia. Quantitative measurements of brain atrophy and activation studies with functional magnetic resonance Inhibitors,research,lifescience,medical imaging (MRI) have separated MCI decliners

fromnondecliners (see reference 12 for a comprehensive review). Other authors13 suggested that most individuals with MCI may eventually develop the neuropathology of AD, and question the usefulness of the definition MCI. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)14 includes the Inhibitors,research,lifescience,medical category of age-related cognitive decline, which may be used whenever a decline in cognitive functions, as identified with specific neuropsychological instruments, lies ”within normal limits given the person’s age,“ with the provision that the cognitive impairment, should not be caused by a psychiatric disorder (eg, depression) or a neurological condition (eg, AD). The DSM-IV also includes criteria

Inhibitors,research,lifescience,medical for mild neurocognitive disorder with the provision that, these criteria are subject, to further study. The main feature of this syndrome is that the cognitive deficit should be the result, of a medical condition (Table II). The cognitive disorder is characterized by deficits in at least two cognitive domains, which may be confirmed through neuropsychological testing. The severity of the disorder Inhibitors,research,lifescience,medical is mild by definition, but. should be severe enough

to interfere with the patient’s social and/or workplace functioning. The main differential diagnoses of mild ncurocognitivc disorder are dementia (with relatively more severe cognitive deficits and more severe impairments in activities of daily living), Inhibitors,research,lifescience,medical a slowly evolving delirium, a postconcussion disorder, and cognitive deficits due to substance abuse or medications. The International Classification of Diseases-! Oth revision (ICD-10) Classification of Mental and Behavioral Disorders* Terminal deoxynucleotidyl transferase includes the category of mild cognitive disorder with the cautionary note that this construct is still under consideration (Table III). Table II Research criteria for mild neurocognitive disorder. Adapted from reference 14 with permission: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (4th edition) (DSM-IV). Washington, DC: American Psychiatric Press; … Table III Mild cognitive disorder. Adapted from reference 15 with permission: World Health Association. International Statistical Classification of Disease, and Related Health Problems- 10th revision. The iCD- 10 Classification of Mental and Behavioral Disorders. …

This review has focused on LNPs and particularly on those that conform to the ABCD nanoparticle structural paradigm. There is plenty enough good reason for this focus given prospects for LNPs that conform to this paradigm in vivo, in pre-clinical studies and even in clinic. However, nanoparticles now come in many shapes and sizes ranging from polymer-based nanoparticles (PNPs) to hard, inorganic nanoparticle structures, such as the highly novel and advanced targeted 2T2NP system mentioned above. However, in general, although many such systems are showing promise in vivo, few PNPs or Inhibitors,research,lifescience,medical inorganic nanoparticle

structures have advanced significantly towards clinical applications. My own view is that many of these technologies may induce significant toxicologies in humans, not seen with LNP systems; therefore, substantial preclinical evaluation would be essential and clinical trials would need to be performed with extreme caution in these cases. Accordingly, my expectation is that LNPs should be the first nanoparticle systems to make a substantial impact on cancer Inhibitors,research,lifescience,medical nanotechnology going forward and on the management of cancers in general. Therefore,

Doxil nanoparticles should be seen as just the first of a wave of exciting new LNP-mediated drug delivery products that could have a truly transformational impact on anticancer therapeutics and diagnostics in the years to come. Conflict of Interests Inhibitors,research,lifescience,medical Professor Andrew D. Miller is chief executive and chief science officer of GlobalAcorn Ltd. and is also a shareholder in this company.
Oral administration is the most commonly preferred route for drug delivery Inhibitors,research,lifescience,medical because of its simplicity, convenience, and Selleck Alvocidib patient acceptance, especially in the case of repeated dosing for chronic therapy [1–3]. In contrast

to the intravenous administration, which probably results in toxic blood level after injection and sometimes an under concentration of the desired threshold towards the end of the dosing interval, oral chemotherapy can provide a prolonged and continuous exposure to a relatively Inhibitors,research,lifescience,medical lower and thus safer concentration [2]. Now, more than 60% of marketed drugs are used as oral products [4]. However, it is intricate to formulate a therapeutic agent for oral administration. The bioavailability of oral drugs is strongly influenced by two important out parameters, solubility and permeability [3]. Based on that, the Biopharmaceutic Classification System (BCS) defines four categories of drugs [5]. Many existing and new therapeutic entities are characterized as BCS class II (low solubility and high permeability) or BCS class IV (low solubility and low permeability). Poorly water-soluble drug candidates encountered in drug discovery cause increasing problems of poor and variable bioavailability. It is estimated that approximately 70% of new chemical entities are poorly soluble in aqueous medium and many even in organic medium.

For all non-responders, two weeks following the reminder e-mail, a paper version of the survey will be mailed, with addressed stamped envelopes. The data from the paper surveys will be reconciled with the data from the electronic surveys. Study population There are currently 23 medical dispatch centres in Ontario that employ approximately 850 call takers [personal communication, Ontario Ministry of Health and Long-Term Care, [8]. We will approach managers of the selected medical dispatch centres and ask for their assistance in recruiting call takers to participate in Phase One (iterative

surveys) and Phase Three (survey). Inhibitors,research,lifescience,medical In Phase Three, the finalized survey will Inhibitors,research,lifescience,medical be circulated to our PF-02341066 datasheet target population – all 9-1-1 call takers in the province of Ontario. Sample Size Power calculations for multiple regression analysis of Phase Three survey will depend on the number of cases per predictor variable. A minimum sample size of 50 + 8 m, where m is the number of predictor variables, is recommended for testing the multiple correlation, and 100

+ 8 m for testing Inhibitors,research,lifescience,medical individual predictors [37,38]. The survey will be organized using the theoretical constructs of the theory of planned behaviour which measure: behavioural intentions, attitudes, subjective norms, and perceived behavioural control. Assessments for each of the four theoretical constructs for both behaviours under study will include direct and indirect belief-based measures; each measure

Inhibitors,research,lifescience,medical will use a minimum of three items on a 7-point Likert scale. Our survey should measure approximately 10–12 items, requiring a minimum sample size of 146 to test the multiple correlation, or 196 to test individual predictors. Methods of measurement For Phase One, the audio-tapes of the interviews will be transcribed verbatim and verified by the interviewer prior Inhibitors,research,lifescience,medical to analysis. Data will be analyzed to identify themes and codes, including intentions to perform the behaviour, attitudes, subjective norms and perceived behavioural control of the behaviour. Two researchers will independently analyse the content of the responses, identify themes, and list them in order of frequency Histone demethylase [39-42]. In Phase Two and Three, the survey data will be entered into a secure database developed by the Data Methods Centre at the Ottawa Hospital Research Institute. Upper and lower limits will be set for each variable and logical and range errors will be detected immediately by the program and highlighted for correction. Ten percent of case records, randomly selected, will be re-entered to assess data entry accuracy.

Of these drug delivery systems, liposome-based agents will have the greatest impact in neurology. Current liposomal drugs evolve from a number of design strategies for the improvement in biodistribution over free drugs. Reticuloendothelial system-targeted formulations significantly reduce systemic exposure to high peak levels of free drug but do not facilitate targeting to brain. Passive or physiologic targeting of drugs to brain regions is achievable Inhibitors,research,lifescience,medical using long-circulating liposomes, including pure lipid systems as well as surface-modified

formulations designed to resist recognition and uptake by reticuloendothelial system cells. The neurodegeneration of the Alzheimer’s disease and Parkinson’s disease has not been beneficially treated by classical oral therapy. Levodopa for Parkinson’s disease and rivastigmine for Alzheimer’s disease remain the gold standard for the therapy. The design and development Inhibitors,research,lifescience,medical of an alternative drug based on new technologies will have a key role in the systemic application of new drugs, such as, growth factors, peptides or hormones. Nowadays is impossible to treat correctly many diseases mainly for the localization of damaged tissue Inhibitors,research,lifescience,medical or the complexity of tissue this website affected. The complexity of the disease and, many times, the localization of the tissue damage, difficult the possible treatment, for example,

the brain is isolated by the BBB. It is well demonstrated that the application of neurotrophic factors is able to modulate neuronal survival and synaptic connectivity, and it

is a promising therapeutic approach for these neurodegenerative diseases. Although, it is very difficult to ensure long-term administration into the brain, liposome technology Inhibitors,research,lifescience,medical allows us to facilitate transport across the BBB. Liposomes have been used clinically as delivery systems for therapeutic drug delivery of chemotherapeutic agents, antibiotics, and antifungals. This is because liposomal preparations have been shown to increase the margin of safety of many drugs and also their efficacy. Among all the applications Inhibitors,research,lifescience,medical of liposomal technology, the development of a suitable liposomal carrier to encapsulate neuroactive Parvulin compounds is very promising. These liposomes are stable enough to be carried to the brain across the BBB, with the appropriate surface characteristics for an effective targeting and for an active membrane transport. Improvements and adjustments to the liposomal formulation are constantly being explored through the addition of different lipids and targeting molecules. For example, in liposomes lacking cholesterol, high-density lipoprotein can cause disintegration of the liposome, or in liposomes which do contain too much cholesterol, high-density lipoprotein can also cause leakage of contents. The development of novel therapeutic strategies for neurodegenerative and neurological diseases represents one of the biggest unmet medical needs today.