copper, I am sorry that I posted the NAC paper by Bush. He is a psychiatrist and interested not only AD and other neurological diseases but also real difficult psychiatric disoders.
To me it is interesting that the efficacy was measured only by subjective and clinical examination and no imaging or other biomarkers. If that will be the case also when studing PBT434 it perhaps is more simple than to deal with PET scans, MRI and other surrogate biomarkers. I think Prana will placebos as comparison, however.
The genome-wide significance level was defined as meta P=1.8×10-6 (0.05/number of genes in human genome = 0.05/28,517). ZNF628, which is located at chromosome 19q13.42, showed a genome-wide significant association with AD. The association of ZNF628 with AD was not dependent on APOE ε4. APOE and TREM2 were also significantly associated with AD, although not at genome-wide significance levels. Other genes identified by targeting common alleles could not be replicated in our gene-based rare allele analysis. We identified that rare variants in ZNF628 are associated with AD. The protein encoded by ZNF628 is known as a transcription factor. Furthermore, the associations of APOE and TREM2 with AD were highly significant, even in gene-based rare allele analysis, which implies that further deep sequencing of these genes is required in AD heritability studies.
So IMO now there is a gene mutation related to metal balance !!!!! If there is a mutaion of this protein it perhaps will not contact with Zn or other metals in the right way.
This protein belongs to zinc fingers, and they are in contact with zinc and other metals when proteins are folding into their shape (?)
PLoS One. 2014 Oct 20;9(10):e107983. doi: 10.1371/journal.pone.0107983. eCollection 2014.
Gene-Based Rare Allele Analysis Identified a Risk Gene of Alzheimer's Disease.
Kim JH1, Song P2, Lim H3, Lee JH4, Lee JH1, Park SA5; for the Alzheimer’s Disease Neuroimaging Initiative.
Alzheimer's disease (AD) has a strong propensity to run in families. However, the known risk genes excluding APOE are not clinically useful. In various complex diseases, gene studies have targeted rare alleles for unsolved heritability. Our study aims to elucidate previously unknown risk genes for AD by targeting rare alleles. We used data from five publicly available genetic studies from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the database of Genotypes and Phenotypes (dbGaP). A total of 4,171 cases and 9,358 controls were included. The genotype information of rare alleles was imputed using 1,000 genomes. We performed gene-based analysis of rare alleles (minor allele frequency≤3%). The genome-wide significance level was defined as meta P
A paper by Bush et al about schizophrenia treatment:
Prog Neuropsychopharmacol Biol Psychiatry. 2014 Oct 11. pii: S0278-5846(14)00192-4. doi: 10.1016/j.pnpbp.2014.10.002. [Epub ahead of print]
Towards stage specific treatments: Effects of duration of illness on therapeutic response to adjunctive treatment with N-acetyl cysteine in schizophrenia.
Rapado-Castro M1, Berk M2, Venugopal K3, Bush AI4, Dodd S3, Dean OM5.
Schizophrenia is a chronic and often debilitating disorder in which stage of illness appears to influence course, outcome, prognosis and treatment response. Current evidence suggests roles for oxidative, neuroinflammatory, neurotrophic, apoptotic, mitochondrial and glutamatergic systems in the disorder; all targets of N-acetyl cysteine (NAC). A double blind, placebo controlled trial suggested NAC to be beneficial to those diagnosed with schizophrenia. The current manuscript aims to investigate duration of the illness as a key factor that may be modulating the response to NAC in the participants who took part in the study. A sample of 121 participants were randomized in a double fashion to 24weeks (placebo=62; NAC=59). Clinical and functional variables were collected over the treatment period. Duration of the illness at baseline was grouped into 20years. Mixed Model Repeated Measures Analysis was used to explore the effect of illness duration on response to treatment with NAC. A significant interaction between duration of the illness and response to treatment with NAC was consistently found for positive symptoms and functional variables, but not for negative or general symptoms or for side effects related outcomes. The pattern of changes suggests this mediator effect of duration of illness in response to treatment is more evident in those participants with 20years or more of illness duration. Our results suggest a potential advantage of adjunctive NAC over placebo on functioning and positi
I just hope that Prana will consult ( and sure it will) marketing specialists to get the best method possible. We have many diabetic, hypertonic, high cholesterol patients without diagnosis and treatment and I think that we have also many HD patients without diagnosis. If there will be a disease modifying drug it will be a big task to convince doctors, family members and patients to get and prescribe the new drug treatment. But there will be also patients who want to get it immediately.
Thank you all about the examples. Dr. Reddy's will be the manufacturer, I suppose and perhaps the distributor where ever PBT2 can be sold ?? Perhaps I thought that a partner would invest much more to the marketing than a distributor would like to do. Distributor will get the drug to the pharmacy but special marketing effort is needed to get patients to buy it, doctors to presrcibe it and doctors to known about it.
Do you have any examples of "only distributor" deals by such a small company as Prana?
I have still big concerns if Prana could ever be able to go to the market on it's own.
Your prediction when Prana's IND (investigational New Drug) program of PBT2 for HD will be changed to NDA ? Now it is some 6 weeks since orphan status was approved.
The annual report told that Prana is now preparing a submission to Europe for Orphan designation and also considering submission to other territories. The rules are everywhere different and so it could be that the first territory for PBT2 is perhaps not the USA .
When you look at the home page of Arthrex anybody can understand that there are a lot of synergies between these 2 companies. To me this is a win- win deal !
pps of osir is totally controlled by shorts. Over 3.5M shares shorted. Today is typical, started up some 5% and now down 2% with low vol. all after positive news !
Without knowing why to partner with Arthrex I would assume that the teaching facility Arthrex has in Florida is one important factor. Osiris does not have one, but it is needed when you want surgeons to use your products. It is not a prescription, it is much more than a drug. Without that knowhow your products will not sell.
Meta-analysis of the 26 SNPs using the 4 independent replication cohorts found SNPs rs9321334 and rs6902875 to be nominally significantly associated with episodic memory (P = .009 and P = .013, respectively). With meta-analysis restricted to individuals lacking an APOE ε4 allele, SNP rs6902875 became statistically significant (meta-analysis, P = 6.7 × 10-5). Haplotype analysis incorporating the 2 SNPs flanking rs6902875 (rs9321334 and rs4897574) revealed that the A-A-C haplotype was significantly associated with episodic memory performance (P = 2.4 × 10-5). This genomic region harbors monooxygenase dopamine β-hydroxylase-like 1 gene (MOXD1), implicated in the biosynthesis of norepinephrine, which is prominently involved in cognitive functions.
Conclusions and Relevance:
The results provide strong evidence for potential candidate genes related to EEM on 6q24. Identifying the genes will help in understanding the biological basis of memory performance and allow interventions for enhancement of cognitive function.
JAMA Neurol. 2014 Oct 13. doi: 10.1001/jamaneurol.2014.1663. [Epub ahead of print]
Common Genetic Variants on 6q24 Associated With Exceptional Episodic Memory Performance in the Elderly.
Barral S1, Cosentino S1, Christensen K2, Newman AB3, Perls TT4, Province MA5, Mayeux R1; for the Long Life Family Study.
There are genetic influences on memory ability as we age, but no specific genes have been identified.
To use a cognitive endophenotype, exceptional episodic memory (EEM) performance, derived from nondemented offspring from the Long Life Family Study (LLFS) to identify genetic variants that may be responsible for the high cognitive performance of LLFS participants and further replicate these variants using an additional 4006 nondemented individuals from 4 independent elderly cohorts.
Design, Setting, and Participants:
A total of 467 LLFS participants from 18 families with 2 or more offspring that exhibited exceptional memory performance were used for genome-wide linkage analysis. Adjusted multivariate linear analyses in the 40-megabase region encompassing the linkage peak were conducted using 4 independent replication data sets that included 4006 nondemented elderly individuals. Results of the individual replication cohorts were combined by meta-analysis.
Main Outcome Measure:
Episodic memory scores computed as the mean of the 2 standardized measures of Logical Memory IA and IIA.
Heritability estimates indicated a significant genetic component for EEM (h2 = 0.21; SE = 0.09). Genome-wide linkage analysis revealed that EEM was linked to the 6q24 region (maximum logarithm of odds score, 3.64). Association analysis in LLFS families identified single-nucleotide polymorphisms (SNPs) nominally associated with EEM in the 40-megabase window encompassing the linkage peak. Replication in one cohort identified a set of 26 SNPs associated with episodic memory (P ≤ .05). Meta-analysis of
Lab Chip. 2014 Oct 15. [Epub ahead of print]
Three-dimensional brain-on-a-chip with an interstitial level of flow and its application as an in vitro model of Alzheimer's disease.
Park J1, Lee BK, Jeong GS, Hyun JK, Lee CJ, Lee SH.
There has been a growing need for in vitro models of neurodegenerative diseases such as Alzheimer's disease that would enable a better understanding of etiology and faster development of treatment strategies. However, meeting this demand has been held back by the limited ability to mimic the in vivo microenvironment in an in vitro system. Here, we developed a microfluidic chip based on three-dimensional (3D) neurospheroids that more closely mimics the in vivo brain microenvironment by providing a constant flow of fluid that is readily observed in the interstitial space of the brain. Uniform neurospheroids, with cell-cell interactions and contacts in all directions, were formed in concave microwell arrays, and a slow interstitial level of flow was maintained using an osmotic micropump system. Using this platform, we investigated the effect of flow on neurospheroid size, neural network, and neural differentiation. Neurospheroids cultured with flow were larger and formed more robust and complex neural networks than those cultured under static conditions, suggesting an effect of the interstitial level of slow and diffusion-dominant flow on continuous nutrient, oxygen, and cytokine transport and removal of metabolic wastes. We also tested the toxic effects of amyloid-β, which is generally considered to be the major contributor in Alzheimer's disease. Amyloid-β treatment via an osmotic micropump significantly reduced the viability of neurospheroids and caused a significantly more destruction of neural networks, compared to the amyloid-β treatment under static conditions. By adding in vivo-like microenvironme