The fourth genus in the Orthomyxoviridae: sequence analyses of two Thogoto virus polymerase proteins and comparison with influenza viruses

The tick-borne Thogoto virus (THOV) is the type species of a newly recognized fourth genus, Thogotovirus, in the family Orthomyxoviridae. Because of the distant relationship of THOV with the influenza viruses, determination of its genomic information can potentially be used to identify important domains in influenza virus proteins. We have determined the complete nucleotide sequence of the second longest RNA segment of THOV. The molecule comprises 2212 nucleotides with a single large open reading frame encoding a protein of 710 amino acids, estimated M_r 81 284. The protein shares 77% amino acid similarity with the PB1-like protein of Dhori virus, a related tick-borne virus, and 50–53% with the PB1 polymerase proteins of influenza virus A, B and C. All the motifs characteristic of RNA-dependent polymerases were identified including the SSDD motif common to all RNA-dependant RNA polymerases, indicating that the THOV protein is functionally analogous to the influenza virus PB1 proteins and involved in chain elongation. We also report the corrected sequence of the third longest RNA segment of THOV, encoding a protein which shares 44–47% amino acid similarity with the PA-like polymerase proteins of influenza virus A, B and C. The biological significance of conserved domains in these orthomyxovirid proteins is discussed.     

Inhibition of Dugbe nairovirus replication by human MxA protein

Sensitivity to the interferon-induced protein, MxA, has previously been demonstrated for viruses belonging to the Orthobunyavirus, Hantavirus and Phlebovirus genera of the Bunyaviridae family. We have extended these findings to a member of the fourth and remaining genus containing viruses that infect man and other animals, the nairovirus Dugbe virus (DUGV). Indirect immunofluorescence experiments using VA9 cells (Vero cells permanently transfected with MxA cDNA) revealed strongly reduced DUGV antigen expression, suggesting that MxA inhibited DUGV replication. Western and Northern blot analyses showed significantly lower DUGV nucleocapsid (N) protein expression and DUGV genomic RNA, respectively, in the presence of MxA. Viral titres were also reduced by more than two orders of magnitude in VA9 cells compared with control VN36 cells. This finding may have application to nairovirus therapeutics.     

Word-specific cortical activity as revealed by the mismatch negativity

Neurophysiological brain activity evoked by individual spoken words and pseudowords was recorded and the mismatch negativity (MMN), an automatic index of experience-dependent auditory memory traces, was calculated. Consistent with earlier reported results, the MMN response to word-final syllables was enhanced compared with that elicited by the same syllables placed in a pseudoword context. Here we now demonstrate that the enhancement of the MMN elicited by two individual words showed different scalp topographies. The early word-specific brain activity is consistent with the assumption that the memory traces activated by individual words are carried by large neuronal ensembles that differ in their distributions over the cortex. Current source estimates localized the between-word differences in the right hemisphere and in parieto-occipital left-hemispheric areas. The differential brain responses to individual words appeared as early as ∼100 ms after the recognition points of the words, suggesting that their specific memory traces become active almost immediately after the information in the acoustic input is sufficient for word identification.     

Involvement of E-cadherin and beta-catenin in germ cell tumours and in normal male fetal germ cell development

Intercellular contacts, mediated by E-cadherin, are essential for germ cell migration and maturation. Furthermore, it has been suggested that decrease or loss of E-cadherin correlates with tumour progression and invasive behaviour. beta-catenin is involved in a number of different processes, including cell--cell interaction when bound to cadherins, and determination of cell fate in pluripotent cells when activated via the Wnt signal-transduction pathway. To shed more light on the role of these factors in normal fetal germ cell development and the pathogenesis of germ cell tumours (GCTs), the present study investigated the presence and localization of E-cadherin and beta-catenin by immunohistochemistry. E-cadherin was only weakly expressed in or absent from fetal germ cells of the second and third trimesters, and was not expressed in carcinoma in situ/intratubular germ cell neoplasia unclassified (CIS/ITGCNU) and gonadoblastoma, the precursor of an invasive GCT in dysgenetic gonads. In GCTs, it was generally not expressed in seminoma and dysgerminoma, but was found in the vast majority of non-seminoma cells. beta-catenin was found in the cytoplasm of fetal germ cells at all gestational ages and in spermatogenesis in post-pubertal testes. It was also present in CIS/ITGCNU and gonadoblastoma. Whereas seminomas and dysgerminoma were negative, non-seminoma cells were frequently found to express beta-catenin. Expression of both factors therefore reflects the degree of differentiation of these tumours. No differences for either E-cadherin or beta-catenin were observed between samples of tumours resistant or sensitive to chemotherapy, and E-cadherin expression did not correlate with vascular invasion. E-cadherin and beta-catenin therefore play a role in both normal and malignant germ cell development and differentiation that warrants further investigation, but they seem to be of limited value as predictive or prognostic factors in GCTs.     

Analysis of outcome for elderly patients after microvascular flap surgery: a monocentric retrospective cohort study

Objectives

Increasingly, aging societies pose a challenge, particularly in the most developed countries. This trend leads to an increasing group of old and very old patients presenting unique requirements and challenges. One of these challenges consists in reassessment and adaption of established treatment strategies for the elderly patients. There is an ongoing discussion taking place among cranio-maxillo-facial surgeons about the appropriate extent of reconstructive flap surgery for old patients.

Materials and methods

This monocentric retrospective cohort study investigated 281 reconstructions with microvascular flaps by comparing the risk for a negative outcome, which was defined as revision, flap loss, and patient death, between three subgroups of elderly patients and younger patients. The three subgroups of elderly patients were defined as—1: young old (65–74 years), 2: old (75–84 years), and 3: oldest old (≥ 85 years). The group of the younger patients was defined by age between 50 and 64 years. Data were obtained within a defined period of 42 months.

Results

Significant correlations with a negative outcome were found for the variables stay on IMC/ICU, multiple flaps, and radiotherapy prior surgery. Our data showed no significant correlation between age and a higher risk for a negative outcome.

Conclusion

Defect reconstruction with microvascular flaps in old patients is not related with a higher risk for a negative outcome.

Clinical relevance

Independently of age, treatment with microvascular flaps is an option for all operable patients, with an indication for oncologic surgery. For optimal therapy planning, individual patient resources and preferences should be considered instead of chronologic age.

     

Treatment of sleep disorders may improve fatigue in multiple sclerosis

Objective

In a previous polysomnographic cross-sectional study we found a significant relationship between sleep disorders and multiple sclerosis (MS) related fatigue. The purpose of this open follow-up observation was to compare the impact of treatment of sleep disorders on MS related fatigue measured with the Modified Fatigue Impact Scale (MFIS).

Methods

Non-randomized follow-up observation: treated versus untreated patients, subgroups according to compliance with sleep medical treatment recommendations (univariate, multivariate analysis, multiple logistic regression). 66 MS patients were followed after polysomnography, 49 patients with relevant sleep disorders and 17 without.

Results

Mean MFIS scores decreased from 41.2 to 26.2 (p = 0.025) in patients with good compliance (GC; n = 18), from 42.4 to 32.1 (p = 0.12) in patients with moderate compliance (MC; n = 12), and from 41.6 to 35.5 (p = 0.17) in non-compliant patients (NC; n = 17). Mean MFIS values increased in patients without sleep disorders from 22.9 to 25.4 (NSD; n = 12, p = 0.56). In multiple logistic regression, treatment of sleep disorders predicted decrease of MFIS-values (GC versus NSD odds ratio 13.4; p = 0.015; 95% confidence interval (CI) 1.7–107.2, MC versus NSD odds ratio 13.8; p = 0.028; 95% CI 1.3–143.3).

Conclusions

Sleep medical treatment may improve MS related fatigue when patients adhere to treatment recommendations.     

Androgen receptor aberrations in the era of abiraterone and enzalutamide

Prostate cancer is the most prevalent non-skin cancer and the second leading cause of cancer death in men of the western world. As growth and differentiation of prostate cancer largely depend on androgens, inhibition of the androgen/androgen receptor signaling axis is the main treatment for locally advanced and/or metastatic tumors. Although first-line androgen deprivation therapies like chemical/surgical castration and/or administration of anti-androgens are able to control the disease for several years, prostate cancer almost invariably recurs as castration-resistant prostate cancer. This stage of the disease is characterized by a sustained AR-signaling despite castrate levels of circulating androgens. Various molecular mechanisms were shown to induce castration resistance. This review will discuss the most recent and relevant experimental findings on AR-signaling in castration-resistant prostate cancer in order to provide a comprehensive interpretation of the clinical behavior of this tumor entity following treatments with abiraterone, enzalutamide, ARN-509 or taxanes.