Mitochondrial Dysfunction—A Pharmacological Target in Alzheimer's Disease

Increasing evidences suggest that mitochondrial dysfunction plays an important role in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD). Alterations of mitochondrial efficiency and function are mainly related to alterations in mitochondrial content, amount of respiratory enzymes, or changes in enzyme activities leading to oxidative stress, mitochondrial permeability transition pore opening, and enhanced apoptosis. More recently, structural changes of the network are related to bioenergetic function, and its consequences are a matter of intensive research. Several mitochondria-targeting compounds with potential efficacy in AD including dimebon, methylene blue, piracetam, simvastatin, Ginkgo biloba, curcumin, and omega-3 polyunsaturated fatty acids have been identified. The majority of preclinical data indicate beneficial effects, whereas most controlled clinical trials did not meet the expectations. Since mitochondrial dysfunction represents an early event in disease progression, one reason for the disappointing clinical results could be that pharmacological interventions might came too late. Thus, more studies are needed that focus on therapeutic strategies starting before severe disease progress.     

Pilot study: potential transcription markers for adult attention-deficit hyperactivity disorder in whole blood

Attention-deficit hyperactivity disorder (ADHD) is a common behavioural disorder that affects not only children and adolescents but also adults; however, diagnosis of adult ADHD is difficult because patients seem to have reduced externalized behaviour. ADHD is a multifactorial disorder in which many genes, all with small effects, are thought to cause the disorder in the presence of unfavourable environmental conditions. Therefore, in this pilot study, we explored the expression profile of a list of previously established candidate genes in peripheral blood samples from adult ADHD subjects (n = 108) and compared these results with those of healthy controls (n = 35). We demonstrate that combining the gene expression levels of dopamine transporter (SLC6A3), dopamine D5 receptor, tryptophan hydroxylase-1, and SNAP25 as predictors in a regression model resulted in sensitivity and specificity of over 80 % (ROC: max R(2) = 0.587, AUC = 0.917, P < 0.001, 95 % CI: 0.900-0.985). In conclusion, the combination of these four genes could represent a potential method for estimating risk and could be of diagnostic value for ADHD. Nevertheless, further investigation in a larger independent population including different subtypes of ADHD (inattentive, hyperactive, or combined type) patients is required to obtain more specific sets of biomarkers for each subtype as well as to differentiate between child, adolescent, and adulthood forms.     

First human rabies case in French Guiana, 2008: epidemiological investigation and control

Background

Until 2008, human rabies had never been reported in French Guiana. On 28 May 2008, the French National Reference Center for Rabies (Institut Pasteur, Paris) confirmed the rabies diagnosis, based on hemi-nested polymerase chain reaction on skin biopsy and saliva specimens from a Guianan, who had never travelled overseas and died in Cayenne after presenting clinically typical meningoencephalitis.

Methodology/Principal Findings

Molecular typing of the virus identified a Lyssavirus (Rabies virus species), closely related to those circulating in hematophagous bats (mainly Desmodus rotundus) in Latin America. A multidisciplinary Crisis Unit was activated. Its objectives were to implement an epidemiological investigation and a veterinary survey, to provide control measures and establish a communications program. The origin of the contamination was not formally established, but was probably linked to a bat bite based on the virus type isolated. After confirming exposure of 90 persons, they were vaccinated against rabies: 42 from the case''s entourage and 48 healthcare workers. To handle that emergence and the local population''s increased demand to be vaccinated, a specific communications program was established using several media: television, newspaper, radio.

Conclusion/Significance

This episode, occurring in the context of a Department far from continental France, strongly affected the local population, healthcare workers and authorities, and the management team faced intense pressure. This observation confirms that the risk of contracting rabies in French Guiana is real, with consequences for population educational program, control measures, medical diagnosis and post-exposure prophylaxis.     

Time Course,Distribution and Cell Types of Induction of Transforming Growth Factor Betas following Middle Cerebral Artery Occlusion in the Rat Brain

Transforming growth factor-βs (TGF-β1–3) are cytokines that regulate the proliferation, differentiation, and survival of various cell types. The present study describes the induction of TGF-β1–3 in the rat after focal ischemia at 3 h, 24 h, 72 h and 1 month after transient (1 h) or permanent (24 h) middle cerebral artery occlusion (MCAO) using in situ hybridization histochemistry and quantitative analysis. Double labeling with different markers was used to identify the localization of TGF-β mRNA relative to the penumbra and glial scar, and the types of cells expressing TGF-βs. TGF-β1 expression increased 3 h after MCAO in the penumbra and was further elevated 24 h after MCAO. TGF-β1 was present mostly in microglial cells but also in some astrocytes. By 72 h and 1 month after the occlusion, TGF-β1 mRNA-expressing cells also appeared in microglia within the ischemic core and in the glial scar. In contrast, TGF-β2 mRNA level was increased in neurons but not in astrocytes or microglial cells in layers II, III, and V of the ipsilateral cerebral cortex 24 h after MCAO. TGF-β3 was not induced in cells around the penumbra. Its expression increased in only a few cells in layer II of the cerebral cortex 24 h after MCAO. The levels of TGF-β2 and -β3 decreased at subsequent time points. Permanent MCAO further elevated the levels of all 3 subtypes of TGF-βs suggesting that reperfusion is not a major factor in their induction. TGF-β1 did not co-localize with either Fos or ATF-3, while the co-localization of TGF-β2 with Fos but not with ATF-3 suggests that cortical spreading depolarization, but not damage to neural processes, might be the mechanism of induction for TGF-β2. The results imply that endogenous TGF-βs are induced by different mechanisms following an ischemic attack in the brain suggesting that they are involved in distinct spatially and temporally regulated inflammatory and neuroprotective processes.     

Analysis of functional germline polymorphisms for prediction of response to anthracycline-based neoadjuvant chemotherapy in breast cancer

To elucidate the role of predictive factors on individual's drug response, based on genetic variation, we examined the association between eight germline polymorphisms in genes involved in protection against oxidative stress, apoptosis, oncogenic transformation, proliferation, immune response and DNA repair (TP53, NQO1, IL6, TLR4 and XRCC1) and the pathological response to anthracycline-based neoadjuvant chemotherapy in 70 patients with breast cancer. The DNA was genotyped for eight polymorphisms in five genes (TP53, NQO1, IL6, TLR4 and XRCC1) by 5'-exonuclease (TaqMan?) technology. Fisher's exact test was used to evaluate the association between genotype, clinicopathological parameters and pathological response. A good pathological response, defined as a pathological complete response or residual isolated invasive tumor cells, was found significantly more frequently for estrogen (ER) and progesterone receptor (PR) negative breast carcinomas compared to ER and PR positive and ER or PR positive carcinomas, respectively (43.5 vs. 37.5 and 10.3?%, p?=?0.006), and was significantly associated with high tumor grade (G3) (p?=?0.002). A non-significant trend towards a good pathological response was shown in patients carrying the Arg/Arg or Arg/Pro TP53 codon 72 gene variant compared to those harboring the Pro/Pro variant (17.6 or 37.9?% vs. 0; p?=?0.071). No association was found between NQO1 Pro187Ser, IL6 -174G>C, TLR4 Asp299Gly and Thr399Ile, and XRCC1 Arg194Trp, Arg399Gln and Arg280His and pathological response. The present study shows hormone receptor status and tumor grade as predictors for pathological response to neoadjuvant anthracycline-based chemotherapy. Among various functional germline polymorphisms, a potential predictive value was only found for the TP53 Arg72Pro gene variant.     

TIMING DEEP DIVERGENCE EVENTS IN CALCAREOUS DINOFLAGELLATES1

Based on morphological and molecular data, calcareous dinoflagellates (Thoracosphaeraceae, Peridiniales) are a monophyletic group comprising the three major clades Ensiculifera/Pentapharsodinium, Thoracosphaera/Pfiesteria, and Scrippsiella sensu lato. We used stratigraphically well‐documented first occurrences of particular archeopyle types to constrain relaxed Bayesian molecular clocks applied to nuclear rRNA sequences of 18 representatives of the three main clades. By comparing divergence estimates obtained in differently calibrated clocks with first stratigraphic occurrences of taxa not themselves used as constraints, we identified plausible divergence times for several subclades of calcareous dinoflagellates. The initial diversification of extant calcareous dinoflagellates probably took place in the Late Jurassic, with the three main clades all established by the Cretaceous. The two mesoepicystal operculum types observed in calcareous dinoflagellates probably evolved independently from simple apical archeopyles. Based on our taxon sample, the K/T boundary had relatively little effect on the diversity of the group, with several lineages dating to before 65 mya (million years ago). The first stratigraphic occurrences of key taxa, such as Thoracosphaera and Calciodinellum (not themselves used as constraints), are in agreement with the molecular time estimates. Conflicts that involve “Calciodinellum”levantinum, Leonella, Pentapharsodinium, Pernambugia, and the Scrippsiella trochoidea species complex may be due to inaccurate assignment of fossils because of high morphological homoplasy and insufficient knowledge of the extant diversity of calcareous dinoflagellates.     

The challenge of CT and MRI imaging of obese individuals who present to the emergency department: a national survey

The objective of this study was to estimate the availability of large weight capacity computed tomography (CT) and magnetic resonance imaging (MRI) equipment in US hospitals with emergency departments (EDs) and to evaluate animal facilities as alternate sources of imaging. We conducted a telephone survey of radiology technicians from a random sample of all the US hospitals with EDs (n = 262) and all 136 primary hospitals of academic EDs, 145 zoos, and 28 veterinary schools. We measured the prevalence of large weight capacity (>450 lb) CT and MRI, stratified by hospital characteristics. Response rates were 94-100% across samples. Nationally, 10% (95% confidence interval, 7-15) of hospitals with EDs had large weight capacity CT and 8% (95% confidence interval, 5-13) had large weight capacity MRI. In academic hospitals, access to large capacity equipment was better for CT (28%), but similar for MRI (10%) (P < 0.001 and 0.51, respectively). Few rural (5%) and critical-access hospitals (3%) had large capacity CT. In addition, 34% of trauma centers, 23% of stroke centers, and 21% of bariatric surgery centers of excellence had large capacity CT. Only two zoos (1%) had CT scanners; both would not image human patients. Among veterinary schools, 16 (57%) had large weight capacity CT equipment, but only 4 (14%) would consider imaging human patients. Further, 23 (82%) veterinary schools reported policies that specifically prohibited imaging humans. For patients who weigh >450 lb, access to emergent CT and MRI is limited, even at academic and bariatric surgery centers. Animal facilities are not a viable alternative for diagnostic imaging of human patients.     

Molecular dynamics of postsynaptic receptors and scaffold proteins

The activity of neurotransmitter receptors determines the strength of synaptic transmission. Therefore, the clustering of receptors at synapses is an important mechanism underlying synaptic plasticity. The dynamic exchange of receptors between synaptic and extrasynaptic membranes is dependent on their interaction with synaptic scaffold proteins. Here, we review the recent advances and emerging concepts related to the dynamics of synaptic proteins at inhibitory and excitatory synapses. These include the imaging techniques that enable the study of protein dynamics in cells, the differences and similarities of receptor dynamics at excitatory and inhibitory synapses, the relationship between the exchange of receptor and scaffold proteins, as well as the role of receptor fluxes in the modulation of synaptic strength.     

Interleukin-12 increases bispecific-antibody-mediated natural killer cell cytotoxicity against human tumors

 The combination of CD16/CD30 bispecific monoclonal antibodies (bi-mAb) and unstimulated human resting natural killer (NK) cells can cure about 50% of mice with severe combined immunodeficiency (SCID) bearing subcutaneously growing established Hodgkin’s lymphoma. As interleukin-2 (IL-2) and IL-12 have been shown to increase NK cell activity, we tested the capacity of these cytokines to increase bi-mAb-mediated NK cell cytotoxicity against two types of human tumors (Hodgkin’s disease and colorectal carcinoma). Unstimulated NK cells needed a three- to five-times higher antibody concentration than cytokine-stimulated NK cells to exert similar levels of bi-mAb-mediated cytotoxicity. The augmented tumor cell lysis was achieved with IL-12 at considerably lower concentrations than with IL-2 and was associated with a significantly increased bi-mAb-mediated intracellular Ca²⁺ mobilization. The efficiency of IL-12 in this setting together with its low toxicity make it the ideal candidate for a combination therapy with NK-cell-activating bi-mAb in human tumors that are resistant to standard treatment. Received: 26 July 1995 / Accepted: 16 November 1995