Despite the availability of a variety of treatment options, many asthma patients have poorly controlled disease with frequent exacerbations. Proteinase-activated receptor-2 (PAR2) has been identified in preclinical animal models as important to asthma initiation and progression following allergen exposure. Proteinase activation of PAR2 raises intracellular Ca

, inducing MAPK and β-arrestin signalling in the airway, leading to inflammatory and protective effects. We have developed C391, a potent PAR2 antagonist effective in blocking peptidomimetic- and trypsin-induced PAR2 signalling in vitro as well as reducing inflammatory PAR2-associated pain in vivo. We hypothesized that PAR2 antagonism by C391 would attenuate allergen-induced acutely expressed asthma indicators in murine models.

We evaluated the ability of C391 to alter Alternaria alternata-induced PAR2 signalling pathways in vitro using a human airway epithelial cell line that naturally expresses PAR2 (16HBE14o-) and a transfected embryonic cell line (HEK 293). We next evaluated the ability for C391 to reduce A.alternata-induced acutely expressed asthma indicators in vivo in two murine strains.

C391 blocked A.alternata-induced, PAR2-dependent Ca

and MAPK signalling in 16HBE14o- cells, as well as β-arrestin recruitment in HEK 293 cells. C391 effectively attenuated A.alternata-induced inflammation, mucus production, mucus cell hyperplasia and airway hyperresponsiveness in acute allergen-challenged murine models.

To our best knowledge, this is the first demonstration of pharmacological intervention of PAR2 to reduce allergen-induced asthma indicators in vivo. These data support further development of PAR2 antagonists as potential first-in-class allergic asthma drugs.

To our best knowledge, this is the first demonstration of pharmacological intervention of PAR2 to reduce allergen-induced asthma indicators in vivo. These data support further development of PAR2 antagonists as potential first-in-class allergic asthma drugs.Gold core silica shell (AuMSS) nanorods present excellent physicochemical properties that allow their application as photothermal and drug delivery agents. Herein, AuMSS nanorods were dual-functionalized with Polyethylene glycol methyl ether (PEG-CH3 ) and Gelatin (GEL) to enhance both the colloidal stability and uptake by HeLa cancer cells. Additionally, the AuMSS nanorods were combined for the first time with IR780 (a heptamethine cyanine molecule) and its photothermal and photodynamic capacities were determined. The obtained results reveal that the encapsulation of IR780 (65 µg per AuMSS mg) increases the photothermal conversion efficiency of AuMSS nanorods by 10%, and this enhanced heat generation was maintained even after three irradiation cycles with a NIR (808 nm) laser. Moreover, the IR780-loaded AuMSS/T-PEG-CH3 /T-GEL presented ≈2-times higher uptake in HeLa cells, when compared to the non-coated counterparts, and successfully mediated the light-triggered generation of reactive oxygen species. Overall, the combination of photodynamic and photothermal therapy mediated by IR780-loaded AuMSS/T-PEG-CH3 /T-GEL nanorods effectively promoted the ablation of HeLa cancer cells.

Recently, TANK binding kinase 1 (TBK1) mutation has been reported as a causative gene for overlap frontotemporal dementia (FTD)-amyotrophic lateral sclerosis (ALS) syndrome. However, there are no reports from families of South Asian ethnicity.

To report a case study of a family with the proband having overlap FTD-ALS syndrome caused by a novel TBK1 variant.

Clinical, brain imaging, genetic analysis and laboratory data of the patient with FTD-ALS were performed. In addition, family-based segregation analysis of identified novel variants was also done.

This study pertains to genetic analysis in 11members in a family with only one member affected with overlap FTD-ALS syndrome. The whole-exome sequencing analysis in the symptomatic member showed a novel loss-of-function (LoF) variant c.1810G>T(p.E604X) in the TBK1gene. Neuroimaging showed a pattern of asymmetric frontotemporal atrophy and hypometabolism. Segregation analysis of the variation demonstrated its presence in several family members, althoughd be considered when encountering overlap FTD syndromes.The evolutionary history of archosaurs and their closest relatives is characterized by a wide diversity of locomotor modes, which has even been suggested as a pivotal aspect underlying the evolutionary success of dinosaurs vs. pseudosuchians across the Triassic-Jurassic transition. selleckchem This locomotor diversity (e.g., more sprawling/erect; crouched/upright; quadrupedal/bipedal) led to several morphofunctional specializations of archosauriform limb bones that have been studied qualitatively as well as quantitatively through various linear morphometric studies. However, differences in locomotor habits have never been studied across the Triassic-Jurassic transition using 3D geometric morphometrics, which can relate how morphological features vary according to biological factors such as locomotor habit and body mass. Herein, we investigate morphological variation across a dataset of 72 femora from 36 different species of archosauriforms. First, we identify femoral head rotation, distal slope of the fourth trochanter, ral morphology in early archosauriforms was functionally constrained by locomotor habit and body size, which should aid ongoing discussions about the early evolution of dinosaurs and the nature of their evolutionary “success” over pseudosuchians.

Prioritising normal birth has led to harm in some instances in the United Kingdom. While Australian organisations also promote normal birth, its negative impact is less well understood here.

This study explores the problems that may arise from the promotion of normal birth and the quality of clinical incident investigations.

This study uses a survey-based research design and has received 1278 responses. The main outcome measures include perceptions on bias against interventions, delays in interventions, systemic attempts to reduce caesarean rates, and clinical incident investigations.

The perception among both obstetric and midwifery cohorts is that the promotion of normal birth may sometimes or frequently lead to bias against intervention for women (93.8% vs 63.2%), bias against intervention for clinicians (81.1% vs 53.1%), delays in interventions (86.8% vs 37.4%), maternal request caesarean sections being discouraged (81.2% vs 66.9%), an increased emphasis on vaginal birth after caesarean (88.1% vs ound informed consent.

Anti-dipeptidyl-peptidase-like protein 6 (DPPX) encephalitis is a rare but treatable autoimmune disorder, characterized by gastrointestinal symptoms, cognitive dysfunction, and central nervous system hyperexcitability.

Herein, we report a case of an 80-year-old male patient who presented with unexplained diarrhea, weight loss, rapidly progressive dementia, tremors, and myoclonus. His serum tested positive for anti-DPPX antibodies. He was treated with plasma exchange, oral prednisolone, and azathioprine. All his symptoms improved substantially after treatment.

Early recognition of anti-DPPX encephalitis is important because it can be treated with immunotherapy. To the best of our knowledge, this is the first reported case of anti-DPPX encephalitis in Taiwan.

Early recognition of anti-DPPX encephalitis is important because it can be treated with immunotherapy. To the best of our knowledge, this is the first reported case of anti-DPPX encephalitis in Taiwan.

Early distal muscle weakness and myotonia are typical clinical presentations in type I myotonic dystrophy (DM1). We present a DM1 case with unusual predominant proximal weakness without action myotonia.

The chief complaint of this 48-year-old female was difficulty in raising her arms and frequent falling in recent years. On neurological examination, proximal muscle weakness was more pronounced than the distal muscle groups, in addition to facial involvement. Although she did not experience any action myotonia throughout her life, hand and tongue myotonia were readily inducible by percussion during neurological examination. The diagnosis of DM1 was later supported by electromyography and neuropathological studies, and confirmed by molecular testing. The pathological findings in this patient and the characteristic features in typical DM1 patients were briefly reviewed.

The unusual presentation of this DM1 patient suggests the importance of comprehensive neurological examination including percussion of thenar and tongue muscles, even in a patient with atypical distribution of muscle weakness and without a clear personal and family history of myotonia. In addition to molecular testing, muscle biopsy remains supportive in making the diagnosis.

The unusual presentation of this DM1 patient suggests the importance of comprehensive neurological examination including percussion of thenar and tongue muscles, even in a patient with atypical distribution of muscle weakness and without a clear personal and family history of myotonia. In addition to molecular testing, muscle biopsy remains supportive in making the diagnosis.

Neuromyelitis optica (NMO) spectrum disorder and multiple sclerosis (MS) have similar clinical presentations which may make a diagnostic difficulty, especially when the data of aquaporin-4 (AQP4) antibody is not available. We reported the diagnostic and therapeutic dilemma of a woman with a delayed diagnosis of NMO spectrum disorder for more than 20 years.

The patient was a 51 years old woman who suffered from several episodes of relapsing and remission of limbs weakness, visual impairment and gait disturbance since 29 years old. She was diagnosed as a case of MS and received treatment accordingly. Treatment with the use of Rebif was started since 2008-2012, and was then shifted to Fingolimod due to several minor attacks were still noted during this period. Serum AQP4-IgG was checked before the use of Fingolimod by using Enzyme-linked immunosorbent assay (ELISA) and the result showed sero-negative for this Ab. However, occasional minor attacks were still noted. In May 2018, severe relapsing developed and brain magnetic resonance imaging (MRI) showed marked progression of the brain lesion. Initially, progressive multifocal leukoencephalopathy was suspected, but both cerebrospinal fluid and serologic study for John Cunningham virus (JCV) were negative. AQP4-IgG was rechecked by using cell-based assay (CBA), and the result showed positive finding. Thereafter, her therapy was changed to NMO spectrum disorder regimen.

It is worthwhile to recheck the serum AQP4-IgG if the initial study showed negative result by using ELISA since CBA has higher sensitivity than previous study method.

It is worthwhile to recheck the serum AQP4-IgG if the initial study showed negative result by using ELISA since CBA has higher sensitivity than previous study method.There is great interest in crosstalk between the gastrointestinal and immune systems. Small intestinal bacterial overgrowth (SIBO) is a bowel disorder prevalent among patients with Parkinson’s disease; SIBO treatment has been shown to modulate neurological inflammation, motor and cognitive outcomes there. However, to date, no link between Alzheimer’s dementia and SIBO has been established. This pilot study sought to estimate the prevalence of SIBO in Alzheimer’s dementia in the outpatient setting in Singapore General Hospital. It entailed performing a hydrogen breath test and objectively scoring gastrointestinal symptoms and their severity in 48 patients, comparing symptom scores and mean breath test values in those with mild to moderate Alzheimer’s against age- and sex-matched controls that did not fulfill DSM-V criteria for probable Alzheimer’s. Here, the prevalence of positive breath tests and symptoms of SIBO were no greater among Alzheimer’s patients than in controls. This suggests that the gut microbiome changes and increased bowel inflammation seen in previous studies on Alzheimer’s patients are likely effected through pathways other than SIBO, and are likely more complex than a mere increase in small bowel bacterial volume.