Patterns of urgent hoarseness referrals to ENT – When should we be suspicious of cancer?

Background: Current UK referral criteria stipulate that hoarseness should be persistent to merit 2 week wait (2WW) or urgent suspicion of cancer (USOC) referral. This study delineates patterns of hoarseness presentation with a view to assisting referral pathways, and whereby reassurance could be provided. Methods: A pre-existing database of patients referred with hoarseness under the urgent suspicion of cancer (USOC) category was analysed. Univariate and multivariate analyses were performed on a variety of demographic and comorbid features to produce odds ratios (OR) of features either related or not related to laryngeal cancer. Results: Of 698 consecutive hoarseness referrals were studied. In these referrals there were 506(73%) with persistent hoarseness and 192(27%) with intermittent hoarseness. The most significant patient variables related to laryngeal cancer were persistent hoarseness (OR 4.97), recreational drug use (OR 4.94), male gender (OR 4.01) and weight loss (OR 3.75). Significant patient variables present not related to laryngeal cancer diagnosis were intermittent hoarseness (OR 0.2), the presence of cough (OR 0.2), globus sensation (OR 0.25) and recent viral infection (OR 0.29). Conclusion: The strongest association with cancer is seen in patients that are persistently hoarse. Patients with fluctuating hoarseness do not need an “urgent suspicion of cancer” referral. Additional demographic referral information could help to streamline the referral of these patients, and reassure others

Minocycline inhibits glial proliferation in the H-Tx rat model of congenital hydrocephalus

<p>Abstract</p> <p>Background</p> <p>Reactive astrocytosis and microgliosis are important features of the pathophysiology of hydrocephalus, and persistent glial "scars" that form could exacerbate neuroinflammation, impair cerebral perfusion, impede neuronal regeneration, and alter biomechanical properties. The purpose of this study was to determine the efficacy of minocycline, an antibiotic known for its anti-inflammatory properties, to reduce gliosis in the H-Tx rat model of congenital hydrocephalus.</p> <p>Methods</p> <p>Minocycline (45 mg/kg/day i.p. in 5% sucrose at a concentration of 5-10 mg/ml) was administered to hydrocephalic H-Tx rats from postnatal day 15 to day 21, when ventriculomegaly had reached moderate to severe stages. Treated animals were compared to age-matched non-hydrocephalic and untreated hydrocephalic littermates. The cerebral cortex (both gray matter laminae and white matter) was processed for immunohistochemistry (glial fibrillary acidic protein, GFAP, for astrocytes and ionized calcium binding adaptor molecule, Iba-1, for microglia) and analyzed by qualitative and quantitative light microscopy.</p> <p>Results</p> <p>The mean number of GFAP-immunoreactive astrocytes was significantly higher in untreated hydrocephalic animals compared to both types of controls (<it>p </it>< 0.001). Minocycline treatment of hydrocephalic animals reduced the number of GFAP immunoreactive cells significantly (<it>p </it>< 0.001). Likewise, the mean number of Iba-1 immunoreactive microglia was significantly higher in untreated hydrocephalic animals compared to both types of controls (<it>p </it>< 0.001). Furthermore, no differences in the numbers of GFAP-positive astrocytes or Iba-1-positive microglia were noted between control animals receiving no minocycline and control animals receiving minocycline, suggesting that minocycline does not produce an effect under non-injury conditions. Additionally, in six out of nine regions sampled, hydrocephalic animals that received minocycline injections had significantly thicker cortices when compared to their untreated hydrocephalic littermates.</p> <p>Conclusions</p> <p>Overall, these data suggest that minocycline treatment is effective in reducing the gliosis that accompanies hydrocephalus, and thus may provide an added benefit when used as a supplement to ventricular shunting.</p

Comparative proteomic profiling reveals mechanisms for early spinal cord vulnerability in CLN1 disease

CLN1 disease is a fatal inherited neurodegenerative lysosomal storage disease of early childhood, caused by mutations in the CLN1 gene, which encodes the enzyme Palmitoyl protein thioesterase-1 (PPT-1). We recently found significant spinal pathology in Ppt1-deficient (Ppt1−/−) mice and human CLN1 disease that contributes to clinical outcome and precedes the onset of brain pathology. Here, we quantified this spinal pathology at 3 and 7 months of age revealing significant and progressive glial activation and vulnerability of spinal interneurons. Tandem mass tagged proteomic analysis of the spinal cord of Ppt1−/−and control mice at these timepoints revealed a significant neuroimmune response and changes in mitochondrial function, cell-signalling pathways and developmental processes. Comparing proteomic changes in the spinal cord and cortex at 3 months revealed many similarly affected processes, except the inflammatory response. These proteomic and pathological data from this largely unexplored region of the CNS may help explain the limited success of previous brain-directed therapies. These data also fundamentally change our understanding of the progressive, site-specific nature of CLN1 disease pathogenesis, and highlight the importance of the neuroimmune response. This should greatly impact our approach to the timing and targeting of future therapeutic trials for this and similar disorders

Crosstalk between Spinal Astrocytes and Neurons in Nerve Injury-Induced Neuropathic Pain

Emerging research implicates the participation of spinal dorsal horn (SDH) neurons and astrocytes in nerve injury-induced neuropathic pain. However, the crosstalk between spinal astrocytes and neurons in neuropathic pain is not clear. Using a lumbar 5 (L5) spinal nerve ligation (SNL) pain model, we testified our hypothesis that SDH neurons and astrocytes reciprocally regulate each other to maintain the persistent neuropathic pain states. Glial fibrillary acidic protein (GFAP) was used as the astrocytic specific marker and Fos, protein of the protooncogene c-fos, was used as a marker for activated neurons. SNL induced a significant mechanical allodynia as well as activated SDH neurons indicated by the Fos expression at the early phase and activated astrocytes with the increased expression of GFAP during the late phase of pain, respectively. Intrathecal administration of c-fos antisense oligodeoxynucleotides (ASO) or astroglial toxin L-α-aminoadipate (L-AA) reversed the mechanical allodynia, respectively. Immunofluorescent histochemistry revealed that intrathecal administration of c-fos ASO significantly suppressed activation of not only neurons but also astrocytes induced by SNL. Meanwhile, L-AA shortened the duration of neuronal activation by SNL. Our data offers evidence that neuronal and astrocytic activations are closely related with the maintenance of neuropathic pain through a reciprocal “crosstalk”. The current study suggests that neuronal and non-neuronal elements should be taken integrally into consideration for nociceptive transmission, and that the intervention of such interaction may offer some novel pain therapeutic strategies

Abrogated Inflammatory Response Promotes Neurogenesis in a Murine Model of Japanese Encephalitis

Japanese encephalitis virus (JEV) induces neuroinflammation with typical features of viral encephalitis, including inflammatory cell infiltration, activation of microglia, and neuronal degeneration. The detrimental effects of inflammation on neurogenesis have been reported in various models of acute and chronic inflammation. We investigated whether JEV-induced inflammation has similar adverse effects on neurogenesis and whether those effects can be reversed using an anti-inflammatory compound minocycline.Here, using in vitro studies and mouse models, we observed that an acute inflammatory milieu is created in the subventricular neurogenic niche following Japanese encephalitis (JE) and a resultant impairment in neurogenesis occurs, which can be reversed with minocycline treatment. Immunohistological studies showed that proliferating cells were replenished and the population of migrating neuroblasts was restored in the niche following minocycline treatment. In vitro, we checked for the efficacy of minocycline as an anti-inflammatory compound and cytokine bead array showed that production of cyto/chemokines decreased in JEV-activated BV2 cells. Furthermore, mouse neurospheres grown in the conditioned media from JEV-activated microglia exhibit arrest in both proliferation and differentiation of the spheres compared to conditioned media from control microglia. These effects were completely reversed when conditioned media from JEV-activated and minocycline treated microglia was used.This study provides conclusive evidence that JEV-activated microglia and the resultant inflammatory molecules are anti-proliferative and anti-neurogenic for NSPCs growth and development, and therefore contribute to the viral neuropathogenesis. The role of minocycline in restoring neurogenesis may implicate enhanced neuronal repair and attenuation of the neuropsychiatric sequelae in JE survivors

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe