Propagation of TDP-43 proteinopathy in neurodegenerative disorders

Neurodegenerative disorders are characterized by disruptions to neuronal function and circuitry,leading to a variety of clinical syndromes depending on the affected neuroanatomic regions(Geula,1998).Many proteinopathies implicated in neurodegenerative diseases are characterized by the pathologic accumulation of proteins into inclusions that are initially deposited in specific areas of the brain and spread widely with disease progression.     

A suite of multiplexed microsatellite loci for the ground beetle Abax parallelepipedus (Piller and Mitterpacher, 1783) (Coleoptera, Carabidae)

We report two sets of polymorphic, multiplexed microsatellite markers for the ground beetle Abax parallelepipedus. As the species is flightless, restricted to forests and affected by habitat fragmentation it can serve as a model species for landscape and conservation genetics. A complete set of 20 loci can be amplified in five PCR reactions and sequenced in two rounds, and a subset of 14 loci can be analyzed together in one PCR run and one sequencing round. In a scan of 3,432 individuals from across Germany using the 14 loci subset, we found between three and 14 alleles per locus. After accounting for two loci that are apparently sex-linked, no significant deviations from Hardy–Weinberg equilibrium were found. None of the loci showed evidence for the presence of null alleles. No overall linkage disequilibrium was detected. Some of the loci can also be used to study other Abax species.     

‘Isn’t it ironic?’ Beliefs about the unacceptability of emotions and emotional suppression relate to worse outcomes in fibromyalgia

Beliefs about the unacceptability of experiencing and expressing emotions have been found to be related to worse outcomes in people with persistent physical symptoms. The current study tested mediation models regarding emotional suppression, beliefs about emotions, support-seeking and global impact in fibromyalgia. One hundred eighty-two participants took part in an online questionnaire testing potential mechanisms of this relationship using mediation analysis. The model tested emotional suppression and affective distress as serial mediators of the relationship between beliefs about emotions and global impact. In parallel paths, two forms of support-seeking were tested (personal/emotional and symptom-related support-seeking) as mediators. Emotional suppression and affective distress significantly serially mediated the relationship between beliefs about emotions and global impact. Neither support-seeking variable significantly mediated this relationship. Results indicate a potential mechanism through which beliefs about emotions and global impact might relate which might provide a theoretical basis for future research on treatments for fibromyalgia.     

Postremission therapy with two different dose regimens of cytarabine in adults with acute myelogenous leukemia

Sixty-seven out of 105 (64%) adults with de novo acute myelogenous leukemia (AML), achieving complete remission after induction chemotherapy, entered two successive postremission treatment protocols. Between 1987 and 1989, 35 patients received an intermediate dose of cytarabine (IDAC) along with other drugs. Between 1990 and 1993, 32 patients received high dose cytarabine (HIDAC) with similar other drugs. Patients treated with IDAC had a median survival of 13.8 months (95% Cl 11.2–23.1 months) and a 2 year survival of 34.3 ± 8.0%. Patients receiving HIDAC had a median survival of 35.5 months (95% Cl, lower limit 29.8 months) and a 2 year survival of 71.6 ± 9.4% (P < 0.002). The 2 year actuarial leukemia-free survival (LFS) was 17.8 ± 6.6% in the IDAC group and 67.3 ± 10.0% months in the HIDAC group (P = 0.004). The HIDAC group had a significant 2 year survival advantage over the IDAC group only in patients younger than 45 years. The 2 year survival in the first group was 83.3 ± 10.8% versus 23.5 ± 10.3% in the IDAC group (P = 0.0001). In patients older than 45 years, no significant differences in 2 year survival was noticed (52.9 ± 15.78 versus 44.4 ± 11.7, P = 0.8). Censoring the 21 patients who underwent bone marrow transplantation (BMT) at BMT did not change significantly the survival analysis of the patients in each group. This study is consistent with previous reports favoring HIDAC intensification in the postremission treatment of young patients with AML.     

Novel dual inhibitors of AChE and MAO derived from hydroxy aminoindan and phenethylamine as potential treatment for Alzheimer's disease

Carbamate derivatives of N-propargylaminoindans (Series I) and N-propargylphenethylamines (Series II) were synthesized via multistep procedures from the corresponding hydroxy precursors. The respective rasagiline- and selegiline-related series were designed to combine inhibitory activities of both acetylcholine esterase (AChE) and monoamine oxidase (MAO) by virtue of their carbamoyl and propargylamine pharmacophores. Each compound was tested for these activities in vitro in order to find molecules with similar potencies against each enzyme. Compounds with such dual AChE and MAO inhibitory activities are expected to have potential for the treatment of Alzheimer's disease. The observed SAR also offers insight into the requirements of the active sites on these enzymes. A carbamate moiety was found to be essential for AChE inhibition, which was absent in the corresponding hydroxy precursors. The propargyl group caused 2-70-fold decrease in AChE inhibitory activity (depending on the position of the carbamoyl group) of Series I, but had little or no effect in Series II. Thus, the 6- and 7-carbamyloxyphenyls in Series I were either equipotent to, or slightly (2- to 5-fold) less active as AChE inhibitors than, the corresponding compounds in Series II, while the 4-carbamyloxyphenyls were more potent. The presence of the carbamate moiety in 6- and 7-carbamyloxyphenyls of Series I, considerably decreased MAO-A and -B inhibitory activity, compared to that of the parent hydroxy analogues, while the opposite was true for Series II. Thus, the 6- and 7-carbamyloxyphenyls in Series I were 2-3 orders of magnitude weaker MAO inhibitors while the 4- carbamyloxyphenyls were equipotent with the corresponding compounds in Series II. In both series, N-methylation of the propargylamine enhanced the MAO (A and B equally) inhibitory activities and decreased the AChE inhibitory activity. Two candidates belonging to the indan and tetralin ring systems (24c, 27b) and one phenethylamine (53d) were identified as possible leads for further development based on the following criteria: (a) comparable AChE and MAO-B inhibitory activities, (b) good to moderate AChE inhibitory activity, and (c) lack of strong MAO-A selectivity. However, it is likely that these compounds will be metabolized to the corresponding phenols, with inhibitory activities against AChE and/or MAO-A or -B, different from those of the parent carbamates. Thus, the apparent enzyme inhibition will be a result of the combined inhibition of all of these individual metabolites. The results of our ongoing in vivo screening programs will be published elsewhere.     

Peripheral nerve ischemia: apolipoprotein E deficiency results in impaired functional recovery and reduction of associated intraneural angiogenic response

Apolipoprotein E-knockout (apoE KO) mice have peripheral sensory nerve defects, reduced and delayed response to noxious thermal stimuli, abnormal morphology of unmyelinated fibers, and impaired blood-nerve and blood-brain barriers. In this study, we show that, compared to wild-type mice, peripheral nerves of apoE KO mice have impaired ability to respond to ischemia, as demonstrated by measurement of motor and sensory conduction velocity. In addition, mice lacking apoE exhibit a deficit of reinnervation of ischemic epidermis, evaluated by immunofluorescent staining for the pan-neuronal marker PGP 9.5. Also regional nerve blood flow, measured by laser Doppler, and intraneural angiogenesis after ischemia are significantly compromised in apoE-deficient mice. Finally, upregulation of the angiogenic cytokine vascular endothelial growth factor (VEGF), which physiologically occurs after ischemia in the peripheral nerve of wild-type mice, is severely impaired in apoE KO mice. Among the several neural defects that have already been described in mice lacking apoE, this is the first demonstration that functional recovery to ischemia is impaired in the peripheral nerves of these animals. This deficit is mirrored by the inability of upregulating VEGF and mounting an appropriate intraneural angiogenic response following injury. These findings provide new evidence of possible interdependent relationships between VEGF, angiogenesis, and nerve function and regeneration and may provide new important information on the role of apoE in the nervous system.