Robust chronic convulsive seizures, high frequency oscillations, and human seizure onset patterns in an intrahippocampal kainic acid model in mice

Intrahippocampal kainic acid (IHKA) has been widely implemented to simulate temporal lobe epilepsy (TLE), but evidence of robust seizures is usually limited. To resolve this ambiguity, we slightly modified previous methods and employed continuous wideband video-EEG monitoring from 4 recording sites to best detect and characterize chronic epilepsy outcomes in both male and female mice. We found many more convulsive seizures than most studies have reported. Mortality was low. Analysis of convulsive seizures at 2-4 and 10-12 wks post-IHKA showed a robust frequency (2-4 per day on average) and duration (typically 20-30 sec) at each time. Comparison of the two timepoints showed that seizure burden became more severe in approximately 50% of the animals. We show that almost all convulsive seizures could be characterized as either low-voltage fast or hypersynchronous onset seizures, which has not been reported in a mouse model of epilepsy and is important because these seizure types are found in humans. In addition, we report that high frequency oscillations (>250 Hz) occur, resembling findings from IHKA in rats and TLE patients. Pathology in the hippocampus at the site of IHKA injection was similar to mesial temporal lobe sclerosis and reduced contralaterally. In summary, our methods produce a model of TLE in mice with robust convulsive seizures, and there is variable progression. HFOs are robust also, and seizures have onset patterns and pathology like human TLE.

Pleural Involvement in Pulmonary Sarcoidosis: A Case Report and Review of the Literature

Background: Sarcoidosis is a chronic, multisystemic granulomatosis of unknown origin that can affect multiple organs throughout the body with variable progression and prognosis. Although the lungs and mediastinal lymph nodes are almost always affected in sarcoidosis, involvement of the pleura remains uncommon.Case presentation: A 69-year-old female presented with dry cough, dyspnea on exertion and fatigue. She was diagnosed with pleural sarcoidosis based on the histological examination of the pleural biopsy and was treated with oral prednisone. Her complaints regressed two weeks later and the left pleural effusion almost disappeared four weeks later.Conclusions: Pleural involvements in sarcoidosis should be considered in the differential diagnosis of pleural effusion and pleural nodules.

Making sense of missense variants in TTN-related congenital myopathies

Mutations in the sarcomeric protein titin, encoded by TTN, are emerging as a common cause of myopathies. The diagnosis of a TTN-related myopathy is, however, often not straightforward due to clinico-pathological overlap with other myopathies and the prevalence of TTN variants in control populations. Here, we present a combined clinico-pathological, genetic and biophysical approach to the diagnosis of TTN-related myopathies and the pathogenicity ascertainment of TTN missense variants. We identified 30 patients with a primary TTN-related congenital myopathy (CM) and two truncating variants, or one truncating and one missense TTN variant, or homozygous for one TTN missense variant. We found that TTN-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of certain clinico-pathological features. Presentation was typically at birth with the clinical course characterized by variable progression of weakness, contractures, scoliosis and respiratory symptoms but sparing of extraocular muscles. Cardiac involvement depended on the variant position. Our biophysical analyses demonstrated that missense mutations associated with CMs are strongly destabilizing and exert their effect when expressed on a truncating background or in homozygosity. We hypothesise that destabilizing TTN missense mutations phenocopy truncating variants and are a key pathogenic feature of recessive titinopathies that might be amenable to therapeutic intervention.

Tourism as a Complex System

The last chapter examined Butler’s and Plog’s lifecycle models. They suggest that tourism works as a linear, predictable manner, moving logically through a pre-determined lifecycle. While the speed of change may be variable, progression through the stages up to and possibly including decline seems inevitable. These models and the models identified earlier in this book share a number of features in common. They recognize that any tourism system begins with the tourist and that also any system needs some destination features and a linkage between the tourist and the destination. The models all have a number of advantages helping us to understand the constituent parts of tourism and some of the simple linkages between elements. They are also deficient in a number of areas, though, for they do not work in practice. This chapter takes an alternative view to the organization and evolution of tourism by looking at tourism from the perspective of complexity theory. In the last 20 years, complexity theory has made strong inroads into management disciplines, but has only recently gained limited interest in the tourism sector, notably from Rodolfo Baggio (Baggio, 2008; Scott, Baggio and Cooper, 2008; Sainaghi and Baggio, 2017).

The contribution of hippocampal subfields to the progression of neurodegeneration

Mild cognitive impairment (MCI) is often considered the precursor of Alzheimer’s disease. However, MCI is associated with substantially variable progression rates, which are not well understood. Attempts to identify the mechanisms that underlie MCI progression have often focused on the hippocampus, but have mostly overlooked its intricate structure and subdivisions. Here, we utilized deep learning to delineate the contribution of hippocampal subfields to MCI progression using a total sample of 1157 subjects (349 in the training set, 427 in a validation set and 381 in the testing set). We propose a dense convolutional neural network architecture that differentiates stable and progressive MCI based on hippocampal morphometry. The proposed deep learning model predicted MCI progression with an accuracy of 75.85%. A novel implementation of occlusion analysis revealed marked differences in the contribution of hippocampal subfields to the performance of the model, with presubiculum, CA1, subiculum, and molecular layer showing the most central role. Moreover, the analysis reveals that 10.5% of the volume of the hippocampus was redundant in the differentiation between stable and progressive MCI. Our predictive model uncovers pronounced differences in the contribution of hippocampal subfields to the progression of MCI. The results may reflect the sparing of hippocampal structure in individuals with a slower progression of neurodegeneration.

Deletion, insertion and stop codon mutations in vif genes of HIV-1 infecting slow progressor patients

Background: Variable progression towards AIDS has been described and has been related to viral and host factors. Around 10% of the HIV-1 infected patients are slow progressors (SP), not presenting with AIDS disease signs even after more than 10 years of infection. Viral gene defects have been associated with the disease progression but more studies are still needed. Methodology: The sequence of vif and nef were analyzed for HIV-1 infecting 14 SP and 46 normal progressors (NP) patients. Results: Co-circulation of a strain carrying vif deleted gene with the wild type strain was detected in an SP patient with more than 10 years of infection. Other mutations (insertion in aa 63 in one strain, two premature stop codons in another one) were found in viruses infecting two other patients. Except for the SP8 strain, which exhibited a premature stop codon in nef, no gross deletions or insertions were observed in nef genes of both NPs and SPs strains analyzed. Conclusions: Different kind of mutation: deletion, insertion and stop codon, were detected in 3/14 samples from SP, with co-circulation of a 195 bp vif deletion virus with a wild type in one of these patients. Although vif defects do not seem to be a frequent feature in SPs, this study illustrates the importance of analysing this gene, in addition to the multiple factors associated with the long-term non progression to AIDS.