Krabbe's disease is an infantile neurodegenerative disease, which is affected by mutations in the lysosomal enzyme galactocerebrosidase, leading to the accumulation of its metabolite psychosine. We have shown previously that the S1P receptor agonist fingolimod (FTY720) attenuates psychosine-induced glial cell death and demyelination both in vitro and ex vivo models. These data, together with a lack of therapies for Krabbe's disease, prompted the current preclinical study examining the effects of fingolimod in twitcher mice, a murine model of Krabbe's disease. Twitcher mice, both male and female, carrying a natural mutation in the galc gene were given fingolimod via drinking water (1 mg/kg/d). The direct impact of fingolimod administration was assessed via histochemical and biochemical analysis using markers of myelin, astrocytes, microglia, neurons, globoid cells, and immune cells. The effects of fingolimod on twitching behavior and life span were also demonstrated. Our results show that treatment of twitcher mice with fingolimod significantly rescued myelin levels compared with vehicle-treated animals and also regulated astrocyte and microglial reactivity. Furthermore, nonphosphorylated neurofilament levels were decreased, indicating neuroprotective and neurorestorative processes. These protective effects of fingolimod on twitcher mice brain pathology was reflected by an increased life span of fingolimod-treated twitcher mice. These in vivo findings corroborate initial in vitro studies and highlight the potential use of S1P receptors as drug targets for treatment of Krabbe's disease.

Temporomandibular disorders (TMDs) are the most frequent non-dental orofacial pain disorders and may be associated with rheumatoid arthritis (RA), resulting in oropharyngeal dysphagia (OD). However, clinicians' understanding of involvement with OD caused by RA-related TMDs is limited and the methodological quality of research in this field has been criticised. Therefore, the aim of this study was to systematically review the prevalence of oral preparatory and oral stage signs and symptoms of OD in adults presenting with TMDs associated with RA. A systematic review of the literature was completed. The following electronic databases were searched from inception to February 2016, with no date/language restriction: EMBASE, PubMed, CINAHL, Web of Science, Elsevier Scopus, Science Direct, AMED, The Cochrane Database of Systematic Reviews, and ProQuest Dissertations and Theses A & I. Grey literature and reference lists of the included studies were also searched. Studies reporting the frequency of OD in adults presenting with TMD and RA were included. Study eligibility and quality were assessed by three independent reviewers. Methodological quality was assessed using the Down's and Black tool. The search yielded 19 eligible studies. Typical difficulties experienced by RA patients included impaired swallowing (24.63%), impaired masticatory ability (30.69%), masticatory pain (35.58%), and masticatory fatigue (21.26%). No eligible studies reported figures relating to the prevalence of weight loss. Eligible studies were deemed on average to be of moderate quality. Study limitations included the small number of studies which met the inclusion criteria and the limited amount of studies utilising objective assessments. Valid and reliable prospective research is urgently required to address the assessment and treatment of swallowing difficulties in RA as TMJ involvement may produce signs and symptoms of OD.

Oropharyngeal aspiration (OPA) is a common occurrence in patients with tracheostomy. The modified Evan's blue dye test (MEBDT) is an easily administered bedside procedure for the assessment of tracheostomised patients. However, studies evaluating the diagnostic accuracy of the MEBDT reach conflicting results. Therefore, we conducted a systematic review to determine the overall accuracy of the MEBDT in detecting OPA in adults with tracheostomy. The search strategy incorporated searching electronic databases, checking reference lists and citations and retrieving unpublished data. Data of primary studies were extracted and examined by three independent reviewers. The assessment of the methodological quality of included studies was performed using the QUADAS-2 tool. Six studies met the inclusion criteria for this systematic review. The studies presented significant disparities in study design and patient characteristics. Furthermore, high discrepancies in the administration of MEBDT across studies were noted. Therefore, a meta-analysis was not considered appropriate. Sensitivity estimates varied widely across the studies (38-95 %), indicating that the MEBDT is unreliable in detecting OPA. However, the studies emerge with overall high specificity values, ranging from 79 to 100 %. This true negative rate suggests that the MEBDT correctly identifies patients without OPA. This review highlights the need for further research studies assessing the accuracy of the MEBDT in detecting aspiration in patients with tracheostomy, using a standardised and reliable procedure. Outcomes from such studies will update the current level of evidence in relation to the MEBDT and consequently define best clinical practice.

Therapeutic strategies for Alzheimer’s disease (AD) have largely focused on the regulation of amyloid pathology while those targeting tau pathology, and inflammatory mechanisms are less explored. In this regard, drugs with multimodal and concurrent targeting of Aβ, tau, and inflammatory processes may offer advantages. Here, we investigate one such candidate drug in the triple transgenic 3xTg-AD mouse model of AD, namely the disease-modifying oral neuroimmunomodulatory therapeutic used in patients with multiple sclerosis, called fingolimod. In this study, administration of fingolimod was initiated after behavioral symptoms are known to emerge, at 6 months of age. Treatment continued to 12 months when behavioral tests were performed and thereafter histological and biochemical analysis was conducted on postmortem tissue. The results demonstrate that fingolimod reverses deficits in spatial working memory at 8 and 12 months of age as measured by novel object location and Morris water maze tests. Inflammation in the brain is alleviated as demonstrated by reduced Iba1-positive and CD3-positive cell number, less ramified microglial morphology, and improved cytokine profile. Finally, treatment with fingolimod was shown to reduce phosphorylated tau and APP levels in the hippocampus and cortex. These results highlight the potential of fingolimod as a multimodal therapeutic for the treatment of AD.

This search yielded 20 eligible studies. Swallowing itself was impaired in only 9.3% of patients with TMDs. A range of additional OD signs and symptoms were also commonly reported (e.g. masticatory pain (87.4%) and fatigue (62%)). Study limitations included the small number of studies which were eligible for inclusion. As signs and symptoms of OD are frequently reported by patients with TMDs, psychometrically robust prospective research is warranted to determine current and optimal management of this condition.