Cognitive comorbidities of experimental absence seizures are independent of anxiety.

Typical absence seizures (ASs) are brief periods of lack of consciousness, associated with 2.5-4 Hz spike-wave discharges (SWDs) in the EEG, which are highly prevalent in children and teenagers. The majority of probands in these young epileptic cohorts show neuropsychological comorbidities, including cognitive, memory and mood impairments, even after the seizures are pharmacologically controlled. Similar cognition and memory deficits have been reported in different, but not all, genetic animal models of ASs. However, since these impairments are subtle and highly task-specific their presence may be confounded by an anxiety-like phenotype and no study has tested anxiety and memory in the same animals. Moreover, the majority of studies used non-epileptic inbred animals as the only control strain and this may have contributed to a misinterpretation of these behavioural results. To overcome these issues, here we used a battery of behavioural tests to compare anxiety and memory in the same animals from the well-established inbred model of Genetic Absence Epilepsy Rats from Strasbourg (GAERS), their inbred strain of Non-Epileptic Control (NEC) strain (that lack ASs) and normal outbred Wistar rats. We found that GAERS do not exhibit increased anxiety-like behavior and neophobia compared to both NEC and Wistar rats. In contrast, GAERS show decreased spontaneous alternation, spatial working memory and cross-modal object recognition compared to both NEC and Wistar rats. Furthermore, GAERS preferentially used egocentric strategies to perform spatial memory tasks. In summary, these results provide solid evidence of memory deficits in GAERS rats that do not depend on an anxiety or neophobic phenotype. Moreover, the presence of differences between NEC and Wistar rats stresses the need of using both outbred and inbred control rats in behavioural studies involving genetic models of ASs.

Accentuated 123ImIBG uptake by the left lobe of the liver - A clue to nowhere.

A 57-year-old male was imaged with 123I mIBG for left sided suprarenal mass. The planar and SPECT-CT acquisitions revealed features consistent with a left sided pheochromocytoma. There was physiological and high uptake in the hypertrophied left lobe of the liver which was normal at both MRI and non-contrast CT. Asymmetrical increased 123I mIBG uptake in the left lobe of the liver as compared to the right lobe is a known physiological finding with no obvious cause or significance.

Neuroendocrine liver metastases - 'doughnut box sign' on SPECT/CT.

A 76 year old patient was referred for Indium111 Octreotide scan to look for primary tumour and extent of neuroendocrine metastases. Indium 111 Octreotide scan showed a liver packed with centrally necrotic metastases like doughnuts packed in a box. No primary lesion was identified in this scan.

Recovery of Depleted miR-146a in ALS Cortical Astrocytes Reverts Cell Aberrancies and Prevents Paracrine Pathogenicity on Microglia and Motor Neurons.

Reactive astrocytes in Amyotrophic Lateral Sclerosis (ALS) change their molecular expression pattern and release toxic factors that contribute to neurodegeneration and microglial activation. We and others identified a dysregulated inflammatory miRNA profile in ALS patients and in mice models suggesting that they represent potential targets for therapeutic intervention. Such cellular miRNAs are known to be released into the secretome and to be carried by small extracellular vesicles (sEVs), which may be harmful to recipient cells. Thus, ALS astrocyte secretome may disrupt cell homeostasis and impact on ALS pathogenesis. Previously, we identified a specific aberrant signature in the cortical brain of symptomatic SOD1-G93A (mSOD1) mice, as well as in astrocytes isolated from the same region of 7-day-old mSOD1 mice, with upregulated S100B/HMGB1/Cx43/vimentin and downregulated GFAP. The presence of downregulated miR-146a on both cases suggests that it can be a promising target for modulation in ALS. Here, we upregulated miR-146a with pre-miR-146a, and tested glycoursodeoxycholic acid (GUDCA) and dipeptidyl vinyl sulfone (VS) for their immunoregulatory properties. VS was more effective in restoring astrocytic miR-146a, GFAP, S100B, HMGB1, Cx43, and vimentin levels than GUDCA, which only recovered Cx43 and vimentin mRNA. The miR-146a inhibitor generated typical ALS aberrancies in wild type astrocytes that were abolished by VS. Similarly, pre-miR-146a transfection into the mSOD1 astrocytes abrogated aberrant markers and intracellular Ca2+ overload. Such treatment counteracted miR-146a depletion in sEVs and led to secretome-mediated miR-146a enhancement in NSC-34-motor neurons (MNs) and N9-microglia. Secretome from mSOD1 astrocytes increased early/late apoptosis and FGFR3 mRNA in MNs and microglia, but not when derived from pre-miR-146a or VS-treated cells. These last strategies prevented the impairment of axonal transport and synaptic dynamics by the pathological secretome, while also averted microglia activation through either secretome, or their isolated sEVs. Proteomic analysis of the target cells indicated that pre-miR-146a regulates mitochondria and inflammation via paracrine signaling. We demonstrate that replenishment of miR-146a in mSOD1 cortical astrocytes with pre-miR-146a or by VS abrogates their phenotypic aberrancies and paracrine deleterious consequences to MNs and microglia. These results propose miR-146a as a new causal and emerging therapeutic target for astrocyte pathogenic processes in ALS.

Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases.

Excitotoxicity is a phenomenon that describes the toxic actions of excitatory neurotransmitters, primarily glutamate, where the exacerbated or prolonged activation of glutamate receptors starts a cascade of neurotoxicity that ultimately leads to the loss of neuronal function and cell death. In this process, the shift between normal physiological function and excitotoxicity is largely controlled by astrocytes since they can control the levels of glutamate on the synaptic cleft. This control is achieved through glutamate clearance from the synaptic cleft and its underlying recycling through the glutamate-glutamine cycle. The molecular mechanism that triggers excitotoxicity involves alterations in glutamate and calcium metabolism, dysfunction of glutamate transporters, and malfunction of glutamate receptors, particularly N-methyl-D-aspartic acid receptors (NMDAR). On the other hand, excitotoxicity can be regarded as a consequence of other cellular phenomena, such as mitochondrial dysfunction, physical neuronal damage, and oxidative stress. Regardless, it is known that the excessive activation of NMDAR results in the sustained influx of calcium into neurons and leads to several deleterious consequences, including mitochondrial dysfunction, reactive oxygen species (ROS) overproduction, impairment of calcium buffering, the release of pro-apoptotic factors, among others, that inevitably contribute to neuronal loss. A large body of evidence implicates NMDAR-mediated excitotoxicity as a central mechanism in the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and epilepsy. In this review article, we explore different causes and consequences of excitotoxicity, discuss the involvement of NMDAR-mediated excitotoxicity and its downstream effects on several neurodegenerative disorders, and identify possible strategies to study new aspects of these diseases that may lead to the discovery of new therapeutic approaches. With the understanding that excitotoxicity is a common denominator in neurodegenerative diseases and other disorders, a new perspective on therapy can be considered, where the targets are not specific symptoms, but the underlying cellular phenomena of the disease.

Glutamate Transporters in Hippocampal LTD/LTP: Not Just Prevention of Excitotoxicity.

Glutamate uptake is a process mediated by sodium-dependent glutamate transporters, preventing glutamate spillover from the synapse. Typically, astrocytes express higher amounts of glutamate transporters, thus being responsible for most of the glutamate uptake; nevertheless, neurons can also express these transporters, albeit in smaller concentrations. When not regulated, glutamate uptake can lead to neuronal death. Indeed, the majority of the studies regarding glutamate transporters have focused on excitotoxicity and the subsequent neuronal loss. However, later studies have found that glutamate uptake is not a static process, evincing a possible correlation between this phenomenon and the efficiency of synaptic transmission and plasticity. In this review, we will focus on the role of the increase in glutamate uptake that occurs during long-term potentiation (LTP) in the hippocampus, as well as on the impairment of long-term depression (LTD) under the same conditions. The mechanism underpinning the modulatory effect of glutamate transporters over synaptic plasticity still remains unascertained; yet, it appears to have a more prominent effect over the N-methyl-D-aspartate receptor (NMDAR), despite changes in other glutamate receptors may also occur.

Poor quality male latex condoms found in Dominican Republic: Quality assurance evaluation and public health impact.

Male condoms are important to prevent transmission of HIV (and other STIs) and unwanted pregnancies. Research was conducted to evaluate the quality of male condoms available in the Dominican Republic market based on preliminary concerns of suspect product. Based on international testing standards (ISO 4074 and ASTM D 3492-08), condoms were sampled across ten prominent brands within the market and evaluated for airburst pressure / volume, freedom from holes, visual defects, package seal integrity, packaging and marking, lubricant quantity, and dimensions. Five of the brands were found to have extensive quality problems, where holes were found in 5.7% to 17.5% of the condoms (depending on the brand). Between 5.1% and 30.5% of these condoms failed to meet the requirements for airburst properties, and violations in regulatory labeling where observed. Three additional brands were compliant for the other tests, but were found to have the same challenges with labeling violations as the previous five brands. Two brands were found to be fully compliant with all aspects of the evaluation. The level of defects observed in these samples would greatly increase the risk of HIV transmission (and other STIs) and unwanted pregnancies. When projected on the annual market of male condoms sold in the Dominican Republic (~26 million), potentially over 1 million condoms could be estimated to adversely impact the health risk of the end-user. These results prompted action by the Dominican Republic regulatory authorities to investigate and remove poor quality product from the market. This research study emphasizes the need for continued vigilance towards increased regulatory and market surveillance efforts to better protect public health interests.

Occupational exposure to formaldehyde: genotoxic risk evaluation by comet assay and micronucleus test using human peripheral lymphocytes.

Formaldehyde (FA) is a world high-production compound with numerous applications ranging from production of resins to medicines. Due to its sensitizing properties, irritating effects and potential cancer hazard FA is of great environmental health concern. Numerous studies in humans and experimental animals demonstrated that inhaled FA produced toxicity, genotoxicity, and cancer at distal sites. IARC, based on sufficient data, reclassified FA as a human carcinogen. The highest level of human exposure to this aldehyde occurs in occupational settings, namely, in pathology and anatomy laboratories, where FA is commonly used as a fixative and tissue preservative. Several studies consistently showed that the levels of airborne FA in anatomy laboratories exceeded recommended exposure criteria. In order to assess the genotoxic effects of chronic occupational exposure to FA, a group of pathology/anatomy workers was assessed using a micronucleus (MN) test and comet assay. The level of exposure to FA was also determined and the time-weighted average (TWA) of exposure was calculated for each subject. The TWA mean value for FA exposed workers was 0.43 ± 0.06 ppm, exceeding national and international recommended limit levels of 0.3 ppm. Both MN frequency and comet assay parameters were significantly higher in exposed subjects. Data obtained confirm a correlation between genetic damage and occupational exposure to FA. These data, along with recent implications of human carcinogenicity, point out the need for close monitoring of occupational exposure to FA. Implementation of security and hygiene measures as well as good practices campaigns may be crucial to decrease risk.