Modeling sporadic alzheimer's disease: the insulin resistant brain state generates multiple long-term morphobiological abnormalities inclusive hyperphosphorylated tau protein and amyloid-beta. A Synthesis

Nosologically, Alzheimer's disease (AD) is not a single disorder. Missense gene mutations involved in increased formation of the amyloid-beta protein precursor derivatives amyloid-beta (Abeta)_{1-40} and Abeta_{1-42/43} lead to autosomal dominant familial AD, found in the minority of AD cases. However, millions of subjects suffer from sporadic AD (sAD) of late onset, for which no convincing evidence suggests Abeta as the primary disease-generating compound. Environmental factors operating during pregnancy and postnatally may affect susceptibility genes and stress factors (e.g., cortisol), consequently affecting brain development both structurally and functionally, causing disorders becoming manifest late in life. With aging, a desynchronization of biological systems may result, increasing further brain entropy/declining criticality. In sAD, this desynchronization may involve stress components, cortisol and noradrenaline, reactive oxygen species, and membrane damage as major candidates causing an insulin resistant brain state with decreased glucose/energy metabolism. This further leads to a derangement of ATP-dependent cellular and molecular work, of the cell function in general, as well as derangements in the endoplasmic reticulum/Golgi apparatus, axon, synapses, and membranes, in particular. A self-propagating process is thus generated, including the increased formation of hyperphosphorylated tau-protein and Abeta as abnormal terminal events in sAD rather than causing the disorder, as elaborated in the review

Headache in 25 consecutive patients with atrial septal defects before and after percutaneous closure – a prospective case series

In contrast to patent foramen ovale, that is highly prevalent in the general population, atrial septal defect (ASD) is a rare congenital heart defect. The effect of ASD closure on headache and migraine remains a matter of controversy. The objectives of the study were (i) to determine headache prevalence in consecutive patients with ASD scheduled for percutaneous closure for cardiologic indications, using the classification of the International Headache Society and (ii) to compare headache characteristics before and after closure of ASD. In this observational case series no a priori power analysis was performed. Twenty-five consecutive patients were prospectively included over 27 months. Median duration of follow-up was 12 months, [Interquartile range 0]. Prevalence of active headache seemed to be increased compared to the general population: Any headaches 88% (95% confidence interval 70-96), migraine without aura 28% (14-48), migraine with aura 16% (6-35). After ASD closure, we observed a slightly lower headache frequency (median frequency 1.0 [2.6] vs. 0.3 [1.5] headaches per month; p=0.067). In patients with ongoing headaches, a significant decrease in headache intensity (median VAS 7 [3] vs. 5 [4]; p=0.036) was reported. Three patients with migraine with aura before the intervention reported no migraine with aura attacks at followup, two of them reported ongoing tension-type headache, one migraine without aura. In summary, this prospective observational study confirms the high prevalence of headache, particularly migraine, in ASD patients and suggests a possible small beneficial effect of ASD closure

Study of the 2-d CP(N-1) models at \theta=0 and \pi

We present numerical results for 2-d CP(N-1) models at \theta=0 and \pi obtained in the D-theory formulation. In this formulation we construct an efficient cluster algorithm and we show numerical evidence for a first order transition for CP(N-1\geq 2) models at \theta = \pi. By a finite size scaling analysis, we also discuss the equivalence in the continuum limit of the D-theory formulation of the 2-d CP(N-1) models and the usual lattice definition.Comment: 3 pages, 2 figures. Talk presented at Lattice2004(spin), Fermilab, June 21-26, 200

Microtubule Associated Protein 1b (MAP1B) Is a Marker of the Microtubular Cytoskeleton in Podocytes but Is Not Essential for the Function of the Kidney Filtration Barrier in Mice.

Podocytes are essential for the function of the kidney glomerular filter. A highly differentiated cytoskeleton is requisite for their integrity. Although much knowledge has been gained on the organization of cortical actin networks in podocyte's foot processes, less is known about the molecular organization of the microtubular cytoskeleton in primary processes and the cell body. To gain an insight into the organization of the microtubular cytoskeleton of the podocyte, we systematically analyzed the expression of microtubule associated proteins (Maps), a family of microtubules interacting proteins with known functions as regulator, scaffold and guidance proteins. We identified microtubule associated protein 1b (MAP1B) to be specifically enriched in podocytes in human and rodent kidney. Using immunogold labeling in electron microscopy, we were able to demonstrate an enrichment of MAP1B in primary processes. A similar association of MAP1B with the microtubule cytoskeleton was detected in cultured podocytes. Subcellular distribution of MAP1B HC and LC1 was analyzed using a double fluorescent reporter MAP1B fusion protein. Subsequently we analyzed mice constitutively depleted of MAP1B. Interestingly, MAP1B KO was not associated with any functional or structural alterations pointing towards a redundancy of MAP proteins in podocytes. In summary, we established MAP1B as a specific marker protein of the podocyte microtubular cytoskeleton

Efficient Cluster Algorithm for CP(N-1) Models

Despite several attempts, no efficient cluster algorithm has been constructed for CP(N-1) models in the standard Wilson formulation of lattice field theory. In fact, there is a no-go theorem that prevents the construction of an efficient Wolff-type embedding algorithm. In this paper, we construct an efficient cluster algorithm for ferromagnetic SU(N)-symmetric quantum spin systems. Such systems provide a regularization for CP(N-1) models in the framework of D-theory. We present detailed studies of the autocorrelations and find a dynamical critical exponent that is consistent with z = 0.Comment: 14 pages, 3 figure

Inflammatory Pathways in Parkinson's Disease; A BNE Microarray Study

The aetiology of Parkinson's disease (PD) is yet to be fully understood but it is becoming more and more evident that neuronal cell death may be multifactorial in essence. The main focus of PD research is to better understand substantia nigra homeostasis disruption, particularly in relation to the wide-spread deposition of the aberrant protein α-synuclein. Microarray technology contributed towards PD research with several studies to date and one gene, ALDH1A1 (Aldehyde dehydrogenase 1 family, member A1), consistently reappeared across studies including the present study, highlighting dopamine (DA) metabolism dysfunction resulting in oxidative stress and most probably leading to neuronal cell death. Neuronal cell death leads to increased inflammation through the activation of astrocytes and microglia. Using our dataset, we aimed to isolate some of these pathways so to offer potential novel neuroprotective therapeutic avenues. To that effect our study has focused on the upregulation of P2X7 (purinergic receptor P2X, ligand-gated ion channel, 7) receptor pathway (microglial activation) and on the NOS3 (nitric oxide synthase 3) pathway (angiogenesis). In summary, although the exact initiator of striatal DA neuronal cell death remains to be determined, based on our analysis, this event does not remain without consequence. Extracellular ATP and reactive astrocytes appear to be responsible for the activation of microglia which in turn release proinflammatory cytokines contributing further to the parkinsonian condition. In addition to tackling oxidative stress pathways we also suggest to reduce microglial and endothelial activation to support neuronal outgrowth

Familial neuralgia of occipital and intermedius nerves in a Chinese family

Cranial nerve neuralgia usually occurs sporadically. Nonetheless, familial cases of trigeminal neuralgia are not uncommon with a reported incidence of 1–2%, suggestive of an autosomal dominant inheritance. In contrast, familial occipital neuralgia is rarely reported with only one report in the literature. We present a Chinese family with five cases of occipital and nervus intermedius neuralgia alone or in combination in three generations. All persons afflicted with occipital neuralgia have suffered from paroxysmal ‘electric wave’-like pain for years. In the first generation, the father (index patient) was affected, in the second generation all his three daughters (with two sons spared) and in the third generation a daughter’s male offspring is affected. This familial pattern suggests an X-linked dominant or an autosomal dominant inheritance mode

D-Theory: Field Quantization by Dimensional Reduction of Discrete Variables

D-theory is an alternative non-perturbative approach to quantum field theory formulated in terms of discrete quantized variables instead of classical fields. Classical scalar fields are replaced by generalized quantum spins and classical gauge fields are replaced by quantum links. The classical fields of a d-dimensional quantum field theory reappear as low-energy effective degrees of freedom of the discrete variables, provided the (d+1)-dimensional D-theory is massless. When the extent of the extra Euclidean dimension becomes small in units of the correlation length, an ordinary d-dimensional quantum field theory emerges by dimensional reduction. The D-theory formulation of scalar field theories with various global symmetries and of gauge theories with various gauge groups is constructed explicitly and the mechanism of dimensional reduction is investigated.Comment: 30 pages, no figure