Peripheral Sensory Neuropathy Associates With Micro- or Macroangiopathy: Results from a population-based study of type 2 diabetic patients in Sweden

OBJECTIVE—To assess associations between peripheral sensory neuropathy (PSN) and other diabetes-related complications

A comparative analysis of the information content in long and short SAGE libraries

BACKGROUND: Serial Analysis of Gene Expression (SAGE) is a powerful tool to determine gene expression profiles. Two types of SAGE libraries, ShortSAGE and LongSAGE, are classified based on the length of the SAGE tag (10 vs. 17 basepairs). LongSAGE libraries are thought to be more useful than ShortSAGE libraries, but their information content has not been widely compared. To dissect the differences between these two types of libraries, we utilized four libraries (two LongSAGE and two ShortSAGE libraries) generated from the hippocampus of Alzheimer and control samples. In addition, we generated two additional short SAGE libraries, the truncated long SAGE libraries (tSAGE), from LongSAGE libraries by deleting seven 5' basepairs from each LongSAGE tag. RESULTS: One problem that occurred in the SAGE study is that individual tags may have matched to multiple different genes – due to the short length of a tag. We found that the LongSAGE tag maps up to 15 UniGene clusters, while the ShortSAGE and tSAGE tags map up to 279 UniGene clusters. Both long and short SAGE libraries exhibit a large number of orphan tags (no gene information in UniGene), implying the limitation of the UniGene database. Among 100 orphan LongSAGE tags, the complete sequences (17 basepairs) of nine orphan tags match to 17 genomic sequences; four of the orphan tags match to a single genomic sequence. Our data show the potential to resolve 4–9% of orphan LongSAGE tags. Finally, among 400 tSAGE tags showing significant differential expression between AD and control, 79 tags (19.8%) were derived from multiple non-significant LongSAGE tags, implying the false positive results. CONCLUSION: Our data show that LongSAGE tags have high specificity in gene mapping compared to ShortSAGE tags. LongSAGE tags show an advantage over ShortSAGE in identifying novel genes by BLAST analysis. Most importantly, the chances of obtaining false positive results are higher for ShortSAGE than LongSAGE libraries due to their specificity in gene mapping. Therefore, it is recommended that the number of corresponding UniGene clusters (gene or ESTs) of a tag for prioritizing the significant results be considered

Izloženost alergenima plijesni u unutarnjem okolišu

Humid indoor environments may be colonised by allergenic fi lamentous microfungi (moulds), Aspergillus spp., Penicillium spp., Cladosporium spp., and Alternaria spp. in particular. Mould-induced respiratory diseases are a worldwide problem. In the last two decades, mould allergens and glucans have been used as markers of indoor exposure to moulds. Recently, mould allergens Alt a 1 (Alternaria alternata) and Asp f 1 (Aspergillus fumigatus) have been analysed in various environments (residential and occupational) with enzyme-linked immunosorbent assays, which use monoclonal or polyclonal antibodies. Household Alt a 1 and Asp f 1 levels were usually under the limit of the method detection. By contrast, higher levels of mould allergens were found in environments with high levels of bioaerosols such as poultry farms and sawmills. Data on allergen Alt a 1 and Asp f 1 levels in agricultural settings may provide information on possible colonisation of respective moulds and point out to mould-related diseases in occupants.Vlažni, unutarnji prostori mogu biti kolonizirani alergogenim, filamentoznim mikrogljivicama (plijesni) uglavnom rodova Aspergillus, Penicillium, Cladosporium i Alternaria. Respiratorne bolesti uzrokovane plijesnima zdravstveni su problem diljem svijeta. U posljednja dva desetljeća, neki sastavni dijelovi plijesni kao alergeni i glukan rabe se kao pokazatelji izloženosti plijesni u unutarnjem okolišu. Nedavno su alergeni plijesni Alt a 1 (Alternaria alternata) i Asp f 1 (Aspergillus fumigatus) određivani u različitom okolišu (kućnom i profesionalnom) enzim-imunokemijskom metodom koja rabi monoklonska ili poliklonska antitijela. Razina Alt a 1 i Asp f 1 u kućnoj prašini ispod je granice detekcije. Nasuprot tomu, alergeni plijesni su određeni u okolišu s visokom razinom bioaerosola kao peradarnici i pilane. Razine alergena Alt a 1 i Asp f 1 u nekim poljoprivrednim objektima pružaju informaciju o mogućoj kolonizaciji plijesnima, što upućuje na moguće zdravstvene učinke kod zaposlenika

Generation of NSE-MerCreMer Transgenic Mice with Tamoxifen Inducible Cre Activity in Neurons

To establish a genetic tool for conditional deletion or expression of gene in neurons in a temporally controlled manner, we generated a transgenic mouse (NSE-MerCreMer), which expressed a tamoxifen inducible type of Cre recombinase specifically in neurons. The tamoxifen inducible Cre recombinase (MerCreMer) is a fusion protein containing Cre recombinase with two modified estrogen receptor ligand binding domains at both ends, and is driven by the neural-specific rat neural specific enolase (NSE) promoter. A total of two transgenic lines were established, and expression of MerCreMer in neurons of the central and enteric nervous systems was confirmed. Transcript of MerCreMer was detected in several non-neural tissues such as heart, liver, and kidney in these lines. In the background of the Cre reporter mouse strain Rosa26R, Cre recombinase activity was inducible in neurons of adult NSE-MerCreMer mice treated with tamoxifen by intragastric gavage, but not in those fed with corn oil only. We conclude that NSE-MerCreMer lines will be useful for studying gene functions in neurons for the conditions that Cre-mediated recombination resulting in embryonic lethality, which precludes investigation of gene functions in neurons through later stages of development and in adult

Biomarkers of Therapeutic Response in the IL-23 Pathway in Inflammatory Bowel Disease

OBJECTIVES: Interleukin-23 (IL-23) has emerged as a new therapeutic target for the treatment of inflammatory bowel disease (IBD). As biomarkers of disease state and treatment efficacy are becoming increasingly important in drug development, we sought to identify efficacy biomarkers for anti-IL-23 therapy in Crohn's disease (CD). METHODS: Candidate IL-23 biomarkers, downstream of IL-23 signaling, were identified using shotgun proteomic analysis of feces and colon lavages obtained from a short-term mouse IBD model (anti-CD40 Rag2(-/-)) treated preventively with monoclonal antibodies (mAbs) to the IL-23 receptor (IL-23R). The biomarkers were then measured in an IBD T-cell transfer model treated therapeutically with a mAb to IL-23 (p19), confirming their association with IBD. To assess the clinical relevance of these markers, we assessed their concentrations in clinical serum, colon tissue, and feces from CD patients. RESULTS: We identified 57 proteins up or downregulated in diseased animals that returned to control values when the mice were treated with mAbs to IL-23R. Among those, S100A8, S100A9, regenerating protein 3β (REG), REG3γ, lipocalin 2 (LCN2), deleted in malignant tumor 1 (DMBT1), and macrophage migration inhibitory factor (MIF) mRNA levels correlated with disease score and dose titration of mAbs to IL-23R or IL-23(p19). All biomarkers, except DMBT1, were also downregulated after therapeutic administration of mAbs to IL-23(p19) in a T-cell transfer IBD mouse model. In sera from CD patients, we confirmed a significant upregulation of S100A8/A9 (43%), MIF (138%), pancreatitis-associated protein (PAP, human homolog of REG3β/γ; 49%), LCN2 (520%), and CCL20 (1280%), compared with control samples, as well as a significant upregulation of S100A8/A9 (887%), PAP (401%), and LCN2 (783%) in human feces from CD patients compared with normal controls. CONCLUSIONS: These studies identify multiple protein biomarkers downstream of IL-23 that could be valuable tools to assess the efficacy of this new therapeutic agent.Clinical and Translational Gastroenterology (2012) 3, e10; doi:10.1038/ctg.2012.2; published online 16 February 2012

Association of plasma and cortical beta-amyloid is modulated by APOE ε4 status.

Background: APOE ε4’s role as a modulator of the relationship between soluble plasma beta-amyloid (Aβ) and fibrillar brain Aβ measured by Pittsburgh Compound-B positron emission tomography ([11C]PiB PET) has not been assessed. Methods: Ninety-six Alzheimer’s Disease Neuroimaging Initiative participants with [11C]PiB scans and plasma Aβ1-40 and Aβ1-42 measurements at time of scan were included. Regional and voxel-wise analyses of [11C]PiB data were used to determine the influence of APOE ε4 on association of plasma Aβ1-40, Aβ1-42, and Aβ1-40/Aβ1-42 with [11C]PiB uptake. Results: In APOE ε4− but not ε4+ participants, positive relationships between plasma Aβ1-40/Aβ1-42 and [11C]PiB uptake were observed. Modeling the interaction of APOE and plasma Aβ1-40/Aβ1-42 improved the explained variance in [11C]PiB binding compared to using APOE and plasma Aβ1-40/Aβ1-42 as separate terms. Conclusions: The results suggest that plasma Aβ is a potential Alzheimer’s disease biomarker and highlight the importance of genetic variation in interpretation of plasma Aβ levels

Nuclear Progesterone Receptors Are Up-Regulated by Estrogens in Neurons and Radial Glial Progenitors in the Brain of Zebrafish

In rodents, there is increasing evidence that nuclear progesterone receptors are transiently expressed in many regions of the developing brain, notably outside the hypothalamus. This suggests that progesterone and/or its metabolites could be involved in functions not related to reproduction, particularly in neurodevelopment. In this context, the adult fish brain is of particular interest, as it exhibits constant growth and high neurogenic activity that is supported by radial glia progenitors. However, although synthesis of neuroprogestagens has been documented recently in the brain of zebrafish, information on the presence of progesterone receptors is very limited. In zebrafish, a single nuclear progesterone receptor (pgr) has been cloned and characterized. Here, we demonstrate that this pgr is widely distributed in all regions of the zebrafish brain. Interestingly, we show that Pgr is strongly expressed in radial glial cells and more weakly in neurons. Finally, we present evidence, based on quantitative PCR and immunohistochemistry, that nuclear progesterone receptor mRNA and proteins are upregulated by estrogens in the brain of adult zebrafish. These data document for the first time the finding that radial glial cells are preferential targets for peripheral progestagens and/or neuroprogestagens. Given the crucial roles of radial glial cells in adult neurogenesis, the potential effects of progestagens on their activity and the fate of daughter cells require thorough investigation

What People Believe about How Memory Works: A Representative Survey of the U.S. Population

Incorrect beliefs about the properties of memory have broad implications: The media conflate normal forgetting and inadvertent memory distortion with intentional deceit, juries issue verdicts based on flawed intuitions about the accuracy and confidence of testimony, and students misunderstand the role of memory in learning. We conducted a large representative telephone survey of the U.S. population to assess common beliefs about the properties of memory. Substantial numbers of respondents agreed with propositions that conflict with expert consensus: Amnesia results in the inability to remember one's own identity (83% of respondents agreed), unexpected objects generally grab attention (78%), memory works like a video camera (63%), memory can be enhanced through hypnosis (55%), memory is permanent (48%), and the testimony of a single confident eyewitness should be enough to convict a criminal defendant (37%). This discrepancy between popular belief and scientific consensus has implications from the classroom to the courtroom

Preventing β-amyloid fibrillization and deposition: β-sheet breakers and pathological chaperone inhibitors

Central to the pathogenesis of Alzheimer's disease (AD) is the conversion of normal, soluble β-amyloid (sAβ) to oligomeric, fibrillar Aβ. This process of conformational conversion can be influenced by interactions with other proteins that can stabilize the disease-associated state; these proteins have been termed 'pathological chaperones'. In a number of AD models, intervention that block soluble Aβ aggregation, including β-sheet breakers, and compounds that block interactions with pathological chaperones, have been shown to be highly effective. When combined with early pathology detection, these therapeutic strategies hold great promise as effective and relatively toxicity free methods of preventing AD related pathology