Background Psychiatric disorders such as schizophrenia are worsened by stress, and working memory deficits are often a central feature of illness. Working memory is mediated by the persistent firing of prefrontal cortical (PFC) pyramidal neurons. Stress impairs working memory via high levels of dopamine D1 receptor (D1R) activation of cAMP signaling, which reduces PFC neuronal firing. The current study examined whether D1R-cAMP signaling reduces neuronal firing and impairs working memory by increasing the open state of hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels, which are concentrated on dendritic spines where PFC pyramidal neurons interconnect. Methods A variety of methods were employed to test this hypothesis: dual immunoelectron microscopy localized D1R and HCN channels, in vitro recordings tested for D1R actions on HCN channel current (Ih), while recordings in monkeys performing a working memory task tested for D1R-HCN channel interactions in vivo. Finally, cognitive assessments following intra-PFC infusions of drugs examined D1R-HCN channel interactions on working memory performance. Results Immunoelectron microscopy confirmed D1R colocalization with HCN channels near excitatory-like synapses on dendritic spines in primate PFC. Mouse PFC slice recordings demonstrated that D1R stimulation increased Ih, while local HCN channel blockade in primate PFC protected task-related firing from D1R-mediated suppression. D1R stimulation in rat or monkey PFC impaired working memory performance, while HCN channel blockade in PFC prevented this impairment in rats exposed to either stress or D1R stimulation. Conclusions These findings suggest that D1R stimulation or stress weakens PFC function via opening of HCN channels at network synapses.
Recent genetic studies have linked mental illness to alterations in disrupted in schizophrenia 1 (DISC1), a multifunctional scaffolding protein that regulates cyclic adenosine monophosphate (cAMP) signaling via interactions with phosphodiesterase 4 (PDE4). High levels of cAMP during stress exposure impair function of the prefrontal cortex (PFC), a region gravely afflicted in mental illness. As stress can aggravate mental illness, genetic insults to DISC1 may worsen symptoms by increasing cAMP levels. The current study examined whether viral knockdown (KD) of the Disc1 gene in rat PFC increases susceptibility to stress-induced PFC dysfunction. Rats were trained in a spatial working memory task before receiving infusions of (a) an active viral construct that knocked down Disc1 in PFC (DISC1 KD group), (b) a ‘scrambled' construct that had no effect on Disc1 (Scrambled group), or (c) an active construct that reduced DISC1 expression dorsal to PFC (Anatomical Control group). Data were compared with an unoperated Control group. Cognitive performance was assessed following mild restraint stress that had no effect on normal animals. DISC1 KD rats were impaired by 1 h restraint stress, whereas Scrambled, Control, and Anatomical Control groups were unaffected. Thus, knocking down Disc1 in PFC reduced the threshold for stress-induced cognitive dysfunction, possibly through disinhibited cAMP signaling at neuronal network synapses. These findings may explain why patients with DISC1 mutations may be especially vulnerable to the effects of stress.
Objectives/Hypothesis: Head and neck squamous cell carcinoma represents the sixth most common cancer. As a result of field cancerization, second primaries and recurrences are high. Hence, research has focused on chemoprevention. Curcumin, a polyphenol compound with anticarcinogenic properties, is one such promising nutraceutical. As poor bioavailability limits curcumin's use, a novel gum formulation was tested allowing for direct mucosal absorption into the bloodstream. This preliminary study validates curcumin gum efficacy by assessing release and transmucosal absorption, along with measuring its effects on serum cytokine levels.Study Design: Clinical trial.Methods: Protocols consisting of initial chew (chewing gum for 30 minutes) and revised chew (alternating chewing and parking gum against buccal mucosa for 30 minutes) were tested in healthy volunteers. High-performance liquid chromatography measured remnant curcumin in chewed gum, serum, and saliva. Serum levels were assayed for 15 proinflammatory cytokines via multiplex analysis.Results: Revised chew samples demonstrated significantly higher curcumin release and absorption (P = .0078). Curcumin serum levels were significantly higher at 4 hours in samples > 2.0 g of curcumin release (P = .01). As saliva levels decreased, a concurrent increase in serum levels was observed, with no significance in the inverse relationship (P = .1423). When evaluating differences between gender, race, and age, the Asian population showed significantly lower curcumin release and serum levels (P = .009). CXCL1 (GRO-α) and TNF-α were significantly decreased in serum after chewing the gum (P = .036, P < .001, respectively).Conclusions: Enhanced mucosal contact appears critical in improving curcumin release and absorption. CXCL1 and TNFα both represent potential biomarkers for the future study of curcumin chemoprevention.
Abnormalities of the inner and intermediate retinal structures in patients with amyotrophic lateral sclerosis (ALS) have been described using optical coherence tomography and histopathology. Colour vision is a potential marker of these structural changes. The purpose of this study is to test the hypothesis that colour vision impairment is associated with ALS. Monocular (right eye) colour vision was assessed in subjects with definite or probable ALS ( = 25, aged 50-80 years) and control ( = 21, aged 46-89 years) subjects with corrected near visual acuity of at least 20/40 using the L'Anthony D15 color test (desaturated), scored by c-index, a measure of diffuse colour discrimination. Of ALS subjects, 16/25 (64%) had impaired colour vision (c-index >1.8). Comparing with our normal subjects and accounting for age, 72% ( = 18) of ALS subjects had colour vision below the 50th percentile, 52% ( = 13) had colour vision below the 25th percentile, 24% ( = 6) had colour vision below the 10th percentile, and 8% ( = 2) had colour vision below the 2nd percentile. In multivariate models of ln(c-index) and age, the intercept was higher and the slope was flatter in ALS subjects, suggesting that colour vision deficits are more prominent in younger ALS patients. Diffuse colour discrimination deficits are detected in ALS subjects at younger ages than in control subjects. Further study is needed to confirm these findings and to determine if the ALS colour discrimination abnormalities correlate with structural markers of retinal involvement and ALS disease severity.
High- and low-contrast visual acuity (HCVA, LCVA) are potential quantitative markers of neurological dysfunction in amyotrophic lateral sclerosis (ALS). The complex nature and duration of gold standard (GS) protocols precludes widespread use in neurology settings. This study compares simplified to GS visual acuity (VA) protocols. Monocular HCVA and LCVA were measured in ALS ( = 10) and control ( = 4) subjects using six protocols, varying by two chart and three refraction methods. Intraclass correlation coefficients between simplified and GS protocols ranged from 0.83 to 0.98 (HCVA, excellent agreement) and 0.56 to 0.75 (LCVA, moderate agreement). Differences between LCVA and GS protocols exceeded test-retest reliability. Simplified HCVA protocols using LCD (liquid crystal display) tablet charts and/or pinhole correction produced valid measurements. None of the modified LCVA testing protocols produced valid measurements.
Expression of mutant Kras is observed and often implicated in both pancreatitis and pancreatic cancer. Yet, the means by which inflammation occurs is relatively unexplored, although a previous report supports that induction of inflammation in the presence of oncogenic Kras initiates an NF-κB–mediated positive feedback loop that incorporates Cox-2 and production of PGE2 which further amplify mutant Kras. The involvement of PGE2 is interesting, as recent data suggests diets rich in ω6 fatty acids promote Kras induced pancreatic inflammation and neoplastic lesions. However, the precise mechanism and role of epigenetic events derived from diets rich in fatty acids have yet to be completely resolved. In this work, we demonstrate that a key step in this process is the induction and accumulation of NF-κB in pancreatic epithelia, a factor sufficient to promote chronic inflammation and progression to pancreatic adenocarcinoma. In HPDE cells, inhibition of NF-κB shows promise, as treatment with the IKK inhibitor Bay11-7085 noticeably reduced levels of the pro-proliferative factor pAkt. In EL-Kras mice fed a diet rich in ω6 fatty acids, NF-kB is upregulated in the pancreas, predominantly in metaplastic lesions. Conversely, these transgenic mice fed an ω3 fatty acid diet show little, if any, NF-kB expression, which is similar to the response in mice fed an intermediate, isocaloric high fat diet. pAkt is known to act upstream of NF-κB, implicating that NF-κB may be involved in a positive feedback loop with a variety of Kras effectors culminating in pancreatitis and eventually pancreatic neoplasia/adenocarcinoma. It has also been demonstrated that the ω6 Cox2-metabolite PGE2 is mediating this response, though in cultured human pancreatic epithelia, Cox-2 inhibition showed no significant change on levels of NF-κB. Yet, Cox2 inhibition in the stroma may be synergistic with epithelial inhibition of NF-κB, offering protection against the progression from inflammation to cancer. This data provides support to multiple targets of chemoprevention and therapy, including Ras and IKK/NF-κB, for pancreatic neoplasia and cancer. Citation Format: Daniel R. Principe, Windel Emman T. Mascarinas, Chintan Chheda, Kevin Adrian, Riley Mangan, Lindsay C. Boven, Paul J. Grippo. ω3 rich diet protects against Kras-induced metaplasia via repression of NF-κB. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A84.
Objectives: Metal hypersensitivity reaction to surgical implants is a well- known phenomenon that is associated with pain, swelling, inflammation, and decreased efficacy of the implant. We present a unique case of a patient with placement a metal Jackson tracheostomy tube that led to expeditious total subglottic stenosis. Methods: The patient was a 33-year old, severely atopic woman with history of asthma exacerbations requiring several intubations for acute respiratory failure with several subsequent tracheal dilations with steroid injections, and eventual tracheostomy placement with a metal Jackson tracheostomy tube that led to expeditious total subglottic stenosis. Results: Initial intervention included performing an airway evaluation, CO2 laser, and steroid injection of the area of complete subglottic stenosis. Follow up several months later revealed little improvement in level of tracheal narrowing proximal to the tracheostomy tube. Patient did not have shortness of breath but continued to be aphonic. Cricotracheal versus tracheal resection have been proposed but surgical morbidity was deemed too high due to patient’s obesity. Conclusions: Metal hypersensitivity reactions are well known phenomena as it relates to surgical implants in other surgical specialties but are seldom reported within the ear, nose and throat literature. Oftentimes, it takes astute observation to diagnose and establish a connection. Prompt recognition and treatment can be acquired from interdisciplinary collaboration with allergy.
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