Intranasal “painless” Human Nerve Growth Factors Slows Amyloid Neurodegeneration and Prevents Memory Deficits in App X PS1 Mice

Nerve Growth Factor (NGF) is being considered as a therapeutic candidate for Alzheimer's disease (AD) treatment but the clinical application is hindered by its potent pro-nociceptive activity. Thus, to reduce systemic exposure that would induce pain, in recent clinical studies NGF was administered through an invasive intracerebral gene-therapy approach. Our group demonstrated the feasibility of a non-invasive intranasal delivery of NGF in a mouse model of neurodegeneration. NGF therapeutic window could be further increased if its nociceptive effects could be avoided altogether. In this study we exploit forms of NGF, mutated at residue R100, inspired by the human genetic disease HSAN V (Hereditary Sensory Autonomic Neuropathy Type V), which would allow increasing the dose of NGF without triggering pain. We show that “painless” hNGF displays full neurotrophic and anti-amyloidogenic activities in neuronal cultures, and a reduced nociceptive activity in vivo. When administered intranasally to APPxPS1 mice ( n = 8), hNGFP61S/R100E prevents the progress of neurodegeneration and of behavioral deficits. These results demonstrate the in vivo neuroprotective and anti-amyloidogenic properties of hNGFR100 mutants and provide a rational basis for the development of “painless” hNGF variants as a new generation of therapeutics for neurodegenerative diseases

Intact memory in TGF-β1 transgenic mice featuring chronic cerebrovascular deficit: recovery with pioglitazone

The roles of chronic brain hypoperfusion and transforming growth factor-beta 1 (TGF-β1) in Alzheimer's disease (AD) are unresolved. We investigated the interplay between TGF-β1, cerebrovascular function, and cognition using transgenic TGF mice featuring astrocytic TGF-β1 overexpression. We further assessed the impact of short, late therapy in elderly animals with the antioxidant N-acetyl--cysteine (NAC) or the peroxisome proliferator-activated receptor-γ agonist pioglitazone. The latter was also administered to pups as a prophylactic 1-year treatment. Elderly TGF mice featured cerebrovascular dysfunction that was not remedied with NAC. In contrast, pioglitazone prevented or reversed this deficit, and rescued the impaired neurovascular coupling response to whisker stimulation, although it failed to normalize the vascular structure. In aged TGF mice, neuronal and cognitive indices—the stimulus-evoked neurometabolic response, cortical cholinergic innervation, and spatial memory in the Morris water maze—were intact. Our findings show that impaired brain hemodynamics and cerebrovascular function are not accompanied by memory impairment in this model. Conceivably in AD, they constitute aggravating factors against a background of aging and underlying pathology. Our data further highlight the ability of pioglitazone to protect the cerebrovasculature marked by TGF-β1 increase, aging, fibrosis, and antioxidant resistance, thus of high relevance for AD patients

Isovalent Substitution and Heat Treatments Control of Tc, Chain Oxygen Disorder and Structural Phase Transition in High Tc Superconductors (Y1-xNdx)SrBaCu3O6+z

We report here on the preparation, X-ray diffraction with Rietveld refinement, AC magnetic susceptibility measurements and effect of heat treatments in (Y1−xNdx )SrBaCu3O6+z. Each sample was subject to two types of heat treatment: oxygen annealing [O] and argon annealing followed by oxygen annealing [AO]. For each x, the [AO] heat treatment increases the orthorhombicity ! = (b − a)/(b + a) (for 0 "x 0.2) and the distance d[Cu(1) (Sr/Ba)] (decrease Tc) for x 0.25. When x increase from 0 to 1, ! decreases to 0 with transition from orthorhombic to tetragonal structure. ![O] decreases with Tc[O]. However, Tc[AO] decreases with ![AO] until x = 0.2, increases for x = 0.4 and after it decreases by 9.8 K to 77.2 K for x = 1 [AO]. Remarkable correlations were observed between Tc(x) and the volume of the unit cell V (x); and between "Tc(x) = Tc[AO]−Tc[O] and "!(x). A combination of several factors such as decrease in d[Cu(1) (Sr/Ba)]; increase in cationic and chain oxygen ordering; the number psh(x) of holes by Cu(2) O2 superconducting plans and in-phase purity for the [AO] samples may account for the observed data.Morghi, R.; Nafidi, A.; Aboulkassim, A.; Chaib, H.; Charafi, H.; Ait Taleb, T.; Marí Soucase, B.... (2012). Isovalent Substitution and Heat Treatments Control of Tc, Chain Oxygen Disorder and Structural Phase Transition in High Tc Superconductors (Y1-xNdx)SrBaCu3O6+z. Journal of Low Temperature Physics. 1-10. doi:10.1007/s10909-012-0834-xS110Y. Tokura, H. Takagi, S. Uchida, A superconducting copper oxide compound with electrons as the charge carriers. Nature 337, 345–347 (1989)R.J. Cava, Structural chemistry and the local charge picture of copper oxide superconductors. Science 247, 656–662 (1990)B. Raveau, C. Michel, M. Hervieu, D. Grout, Crystal Chemistry of High-T c Superconducting Copper Oxides (Springer, Berlin, 1991), Chap. 1-3T. Wada, N. Suzuki, A. Maeda, T. Yabe, K. Uchinokura, S. Uchida, S. Tanaka, Preparation and properties of superconducting La1+x Ba2−x Cu3O y (0≤x≤0.5) ceramics sintered in N2 gas atmosphere. Phys. Rev. B 39(13), 9126–9138 (1989)M. Izumi, T. Yabe, T. Wada, A. Maeda, K. Uchinokura, S. Tanaka, H. Asano, Structural properties of the superconductor LaBa2Cu3−y O7−z in the solid solution system La1+x Ba2−x Cu3−y O7−z . Phys. Rev. B 40(10), 6771–6786 (1989)H.M. Rietveld, A profile refinement method for nuclear and magnetic structures. J. Appl. Crystallogr. 2, 65–71 (1969)A. Nafidi, B. Bouallal, A. El Kaaouachi, H. Chaib, Remarkable influence of heat treatment on the structural and superconducting properties of LnSrBaCu3O6+z . IEEE Trans. Appl. Supercond. 17(02), 2969–2972 (2007)I.D. Brown, D. Altermatt, Bond-valence parameters obtained from a systematic analysis of the inorganic crystal structure database. Acta Crystallogr., B Struct. Crystallogr. Cryst. Chem. 41(4), 244–247 (1985)I. Zelnay, A. Nafidi, C. Greaves, R. Suryanarayanan, Seebeck effect and neutron diffraction of NdSrBaCu3O6+z , effect of argon annealing. Physica C 231, 207–212 (1994

Clinicopathological correlates of Gli1 expression in a population-based cohort of patients with newly diagnosed bladder cancer

INTRODUCTION: Dysregulation of the hedgehog signalling pathway has been linked to the development and progression of a variety of different human tumors including cancers of the skin, brain, colon, prostate, blood, and pancreas. We assessed the clinicopathological factors that are potentially related to expression of Gli1, the transcription factor that is thought to be the most reliable marker of hedgehog pathway activation in bladder cancer. METHODS: Bladder cancer cases were identified from the New Hampshire State Cancer Registry as histologically confirmed primary bladder cancer diagnosed between January 1, 2002, and July 31, 2004. Immunohistochemical analysis was performed on a tissue microarray to detect Gli1 and p53 expression in these bladder tumors. We computed odds ratios (ORs) and their 95% CIs for Gli1 positivity for pathological category using T category (from TNM), invasiveness, and grade with both the World Health Organization 1973 and World Health Organization International Society of Urological Pathology criteria. We calculated hazard ratios and their 95% CI for Gli1 positivity and recurrence for both Ta-category and invasive bladder tumors (T1+). RESULTS: A total of 194 men and 67 women, whose tumors were assessable for Gli1 staining, were included in the study. No appreciable differences in Gli1 staining were noted by sex, age, smoking status, or high-risk occupation. Ta-category tumors were more likely to stain for Gli1 as compared with T1-category tumors (adjusted OR = 0.38, CI: 0.17–0.87). Similarly, low-grade (grades 1–2) tumors were more likely to stain for Gli1 as compared with high-grade tumors (grade 3) (adjusted OR = 0.44, CI: 0.21–0.93). In a Cox proportional hazards regression analysis, non–muscle-invasive bladder tumors expressing Gli1 were less likely to recur (adjusted hazard ratio = 0.48; CI: 0.28–0.82; P < 0.05) than those in which Gli1 was absent. CONCLUSION: Our findings indicate that Gli1 expression may be a marker of low-stage, low-grade bladder tumors and an indicator of a reduced risk of recurrence in this group