Declining Use of Corticosteroids for Crohn's Disease Has Implications for Study Recruitment: Results of a Pilot Randomized Controlled Trial.

BACKGROUND: Corticosteroids (CS) have been used extensively to induce remission in Crohn's disease (CD); however, they are associated with severe side effects. We hypothesized that the administration of an exclusive enteral nutrition (EEN) formula to CS would lead to increased CD remission rates and to decreased CS-related adverse events. We proposed to undertake a pilot study comparing EEN and CS therapy to CS alone to assess decrease symptoms and inflammatory markers over 6 weeks. AIM: The overall aim was to assess study feasibility based on recruitment rates and acceptability of treatment in arms involving EEN. METHODS: The pilot study intended to recruit 100 adult patients with active CD who had been prescribed CS to induce remission as part of their care. The patients were randomized to one of three arms: (i) standard-dose CS; (ii) standard-dose CS plus EEN (Modulen 1.5 kcal); or (iii) short-course CS plus EEN. RESULTS: A total of 2009 CD patients attending gastroenterology clinics were screened from October 2018 to November 2019. Prednisone was prescribed to only 6.8% (27/399) of patients with active CD attending outpatient clinics. Of the remaining 372 patients with active CD, 34.8% (139/399) started or escalated immunosuppressant or biologics, 49.6% (198/399) underwent further investigation and 8.8% (35/399) were offered an alternative treatment (e.g., antibiotics, surgery or investigational agents in clinical trials). Only three patients were enrolled in the study (recruitment rate 11%; 3/27), and the study was terminated for poor recruitment. CONCLUSION: The apparent decline in use of CS for treatment of CD has implications for CS use as an entry criterion for clinical trials.

Neurotrophin receptor activation rescues cognitive and synaptic abnormalities caused by hemizygosity of the psychiatric risk gene Cacna1c.

Genetic variation in CACNA1C, which encodes the alpha-1 subunit of CaV1.2 L-type voltage-gated calcium channels, is strongly linked to risk for psychiatric disorders including schizophrenia and bipolar disorder. To translate genetics to neurobiological mechanisms and rational therapeutic targets, we investigated the impact of mutations of one copy of Cacna1c on rat cognitive, synaptic and circuit phenotypes implicated by patient studies. We show that rats hemizygous for Cacna1c harbour marked impairments in learning to disregard non-salient stimuli, a behavioural change previously associated with psychosis. This behavioural deficit is accompanied by dys-coordinated network oscillations during learning, pathway-selective disruption of hippocampal synaptic plasticity, attenuated Ca2+ signalling in dendritic spines and decreased signalling through the Extracellular-signal Regulated Kinase (ERK) pathway. Activation of the ERK pathway by a small-molecule agonist of TrkB/TrkC neurotrophin receptors rescued both behavioural and synaptic plasticity deficits in Cacna1c+/- rats. These results map a route through which genetic variation in CACNA1C can disrupt experience-dependent synaptic signalling and circuit activity, culminating in cognitive alterations associated with psychiatric disorders. Our findings highlight targeted activation of neurotrophin signalling pathways with BDNF mimetic drugs as a genetically informed therapeutic approach for rescuing behavioural abnormalities in psychiatric disorder.

Cyfip1 haploinsufficient rats show white matter changes, myelin thinning, abnormal oligodendrocytes and behavioural inflexibility.

The biological basis of the increased risk for psychiatric disorders seen in 15q11.2 copy number deletion is unknown. Previous work has shown disturbances in white matter tracts in human carriers of the deletion. Here, in a novel rat model, we recapitulated low dosage of the candidate risk gene CYFIP1 present within the 15q11.2 interval. Using diffusion tensor imaging, we first showed extensive white matter changes in Cyfip1 mutant rats, which were most pronounced in the corpus callosum and external capsule. Transmission electron microscopy showed that these changes were associated with thinning of the myelin sheath in the corpus callosum. Myelin thinning was independent of changes in axon number or diameter but was associated with effects on mature oligodendrocytes, including aberrant intracellular distribution of myelin basic protein. Finally, we demonstrated effects on cognitive phenotypes sensitive to both disruptions in myelin and callosal circuitry.

Genetic Variation in the Psychiatric Risk Gene CACNA1C Modulates Reversal Learning Across Species.

Genetic variation in CACNA1C, which encodes the alpha-1 subunit of Cav1.2 L-type voltage-gated calcium channels (VGCCs), has been strongly linked to risk for psychiatric disorders including schizophrenia and bipolar disorder. How genetic variation in CACNA1C contributes to risk for these disorders is however not fully known. Both schizophrenia and bipolar disorder are associated with impairments in reversal learning (RL), which may contribute to symptoms seen in these conditions. We used a translational RL paradigm to investigate whether genetic variation in CACNA1C affects RL in both humans and transgenic rats. Associated changes in gene expression were explored using in situ hybridization and quantitative PCR in rats and the BRAINEAC online human database. Risk-associated genetic variation in CACNA1C in healthy human participants was associated with impairments in RL. Consistent with this finding, rats bearing a heterozygous deletion of Cacna1c were impaired in an analogous touchscreen RL task. We investigated the possible molecular mechanism underlying this impairment and found that Cacna1c +/- rats show decreased expression of Bdnf in prefrontal cortex. Examination of BRAINEAC data showed that human risk-associated genetic variation in CACNA1C is also associated with altered expression of brain-derived neurotrophic factor (BDNF) in the prefrontal cortex in humans. These results indicate that genetic variation in CACNA1C may contribute to risk for schizophrenia and bipolar disorder by impacting behavioral flexibility, potentially through altered regulation of BDNF expression in the prefrontal cortex. Tests of RL may be useful for translational studies and in the development of therapies targeting VGCCs.

Conditioning with spatio-temporal patterns: Constraining the contribution of the hippocampus to configural learning.

The conditions under which the hippocampus contributes to learning about spatio-temporal configural patterns are not fully established. The aim of Experiments 1-4 was to investigate the impact of hippocampal lesions on learning about where or when a reinforcer would be delivered. In each experiment, the rats received exposure to an identical set of patterns (i.e., spotted+morning, checked+morning, spotted+afternoon and checked+afternoon); and the contexts (Experiment 1), times of day (Experiment 2), or their configuration (Experiments 3 and 4) signalled whether or not a reinforcer would be delivered. The fact that hippocampal damage did not disrupt the formation of simple or configural associations involving spatio-temporal patterns is surprising, and suggests that the contribution of the hippocampus is restricted to mediated learning (or updating) involving spatio-temporal configurations.

Mediated configural learning in rats.

Three experiments investigated mediated configural learning in male rats. In Experiment 1, after exposure to audio-visual compounds AX and BY, rats received trials where X was paired with shock, and Y was not. The idea that conditioning with X enables the evoked configural representation of AX to be linked to shock received support from the facts that while AX provoked more fear than BX, there was no difference between BY and AY. Similarly, Experiment 2 showed that after exposure to AX and BY, separate pairings of X and Y with shock resulted in more fear to AX and BY than AY and BX. In Experiment 3, rats in group consistent received separate exposures to A and X in Context C, and B and Y in D, while those in group inconsistent received A and X (and B and Y) in both C and D. After rats had received shocks in both C and D, rats in group consistent showed more fear to AX and BY than to BX and AY, but this was not the case in group inconsistent. These results indicate that configural representations, formed either by presenting auditory and visual stimuli as parts of a compound or in a shared context, are subject to a process of mediated learning.

Reliability of diagnosis from Mohs slides: interpersonal and intrapersonal agreement on basal cell carcinoma presence and histological subtype.

BACKGROUND: The success of Mohs micrographic surgery (MMS) depends partly on the correct diagnosis of slides. OBJECTIVES: To determine reliability of diagnosis from Mohs slides. METHODS: This was a prospective study evaluating the reliability of diagnosis from Mohs slides of basal cell carcinoma (BCC) presence, BCC location on the slide and BCC subtype among six raters who independently assessed 50 Mohs slides twice with a 2-month interval. Slides were randomly selected whereby difficult-to-diagnose slides were oversampled. For each slide, a reference diagnosis was established by an expert panel. Cohen's kappa (κ) was calculated to determine levels of agreement interpersonally (rater vs. reference diagnosis) and intrapersonally (rater at T1 vs. T2). Multivariable logistic regression was used to determine independent risk factors for slides with interpersonal discordant diagnosis. The variables studied were BCC presence, whether a slide was scored as easy or difficult to diagnose, review duration of the 50 slides, profession and years of experience in diagnosis from Mohs slides. RESULTS: Interpersonal and intrapersonal agreement were substantial on BCC presence (κ = 0·66 and 0·68) and moderate on BCC subtype (κ = 0·45 and 0·55). Slides that were scored as difficult to diagnose were an independent risk factor for interpersonal discordant diagnosis on BCC presence (odds ratio 3·54, 95% confidence interval 1·81-6·84). CONCLUSIONS: Reliability of diagnosis from Mohs slides was substantial on BCC presence and moderate on BCC subtype. For slides that are scored difficult to diagnose, a second opinion is recommended to prevent misinterpretation and thereby recurrence of skin cancer.

Novel sensory preconditioning procedures identify a specific role for the hippocampus in pattern completion.

Successful retrieval of a memory for an entire pattern of stimulation by the presentation of a fragment of that pattern is a critical facet of memory function. We examined processes of pattern completion using novel sensory preconditioning procedures in rats that had either received sham lesions (group Sham) or lesions of the hippocampus (group HPC). After exposure to two audio-visual patterns (AX and BY) rats received fear conditioning with X (but not Y). Subsequent tests assessed fear to stimulus compounds (e.g., AX versus BX; Experiment 1) or elements (A versus B; Experiment 2). There was more fear to AX than BX in group Sham but not group HPC, while there was more fear to A than B in group HPC, but not in group Sham. This double dissociation suggests that pattern completion can be based upon separable processes that differ in their reliance on the hippocampus.

Degree of Collaterals and Not Time Is the Determining Factor of Core Infarct Volume within 6 Hours of Stroke Onset.

BACKGROUND AND PURPOSE: Growth of the core infarct during the first hours of ischemia onset is not well-understood. We hypothesized that factors other than time from onset of ischemia contribute to core infarct volume as measured by MR imaging. MATERIALS AND METHODS: Prospectively collected clinical and imaging data of consecutive patients with stroke presenting between March 2008 and April 2013 with anterior circulation large-vessel occlusion and MR imaging performed within 6 hours from the time of onset were reviewed. The association of time from onset, clinical, and radiographic features with DWI volume was assessed by using χ(2) and Mann-Whitney U tests. RESULTS: Of 91 patients, 21 (23%) underwent MR imaging within 0-3 hours from onset, and 70 (76%), within 3-6 hours. Median MR imaging infarct volume was similar in both timeframes, (24.7 versus 29.4 mL, P = .906), and there was no difference in the proportion of patients with large infarct volumes (≥70 mL, 23.8% versus 22.8%, P = .928). Using receiver operating characteristic analysis, we detected no association between the time from onset and MR imaging infarct volume (area under the curve = 0.509). In multivariate analysis, CTA collaterals (>50% of the territory) (adjusted OR, 0.192; 95% CI, 0.04-0.9; P = .046), CTA ASPECTS (adjusted OR, 0.464; 95% CI, 0.3-0.8; P = .003), and a history of hyperlipidemia (adjusted OR, 11.0; 95% CI, 1.4-88.0; P = .023) (but not time from stroke onset to imaging) were independent predictors of MR imaging infarct volume. CONCLUSIONS: Collateral status but not time from stroke onset to imaging was a predictor of the size of core infarct in patients with anterior circulation large-vessel occlusion presenting within 6 hours from onset.

Prodromal psychosis: a case series of ten symptomatic patients.

This case series provides an account of 10 patients with prodromal psychosis in Hong Kong over the course of 12 months between 2012 and 2014. Patterns of symptoms and functioning levels were noted each month and overall presentation was classified into 4 categories. Four patients' conditions were classified as fluctuating, 3 patients as improved, 2 patients as no change, and 1 patient as transition into psychosis. The noted observations were compared to the current conceptualisation of prodromal psychosis according to the clinical staging model of McGorry and colleagues. This case series provides insights into the condition in an Asian population and provides background data to inform future clinical research and mental health services.

Configural integration of temporal and contextual information in rats: Automated measurement in appetitive and aversive preparations.

Two experiments investigated the capacity of rats to learn configural discriminations requiring integration of contextual (where) with temporal (when) information. In Experiment 1, during morning training sessions, food was delivered in context A and not in context B, whereas during afternoon sessions food was delivered in context B and not in context A. Rats acquired this discrimination over the course of 20 days. Experiment 2 employed a directly analogous aversive conditioning procedure in which footshock served in place of food. This procedure allowed the acquisition of the discrimination to be assessed through changes in activity to the contextual + temporal configurations (i.e., inactivity or freezing) and modulation of the immediate impact of footshock presentations (i.e., post-shock activity bursts). Both measures provided evidence of configural learning over the course of 12 days, with a final test showing that the presentation of footshock resulted in more post-shock activity in the nonreinforced than reinforced configurations. These behavioral effects reveal important parallels between (i) configural discrimination learning involving components allied to episodic memory and (ii) simple conditioning.

Neuropathological changes in the substantia nigra in schizophrenia but not depression.

Schizophrenia is a chronic, disabling neuropsychiatric disorder characterised by positive, negative and cognitive symptoms. The aetiology is not known, although genetic, imaging and pathological studies have implicated both neurodevelopmental and neurodegenerative processes. The substantia nigra is a basal ganglia nucleus responsible for the production of dopamine and projection of dopaminergic neurons to the striatum. The substantia nigra is implicated in schizophrenia as dopamine has been heavily implicated in the dopamine hypothesis of schizophrenia and the prevalent psychotic symptoms and the monoamine theory of depression, and is a target for the development of new therapies. Studies into the major dopamine delivery pathways in the brain will therefore provide a strong base in improving knowledge of these psychiatric disorders. This post-mortem study examines the cytoarchitecture of dopaminergic neurons of the substantia nigra in schizophrenia (n = 12) and depression (n = 13) compared to matched controls (n = 13). Measures of nucleolar volume, nuclear length and nuclear area were taken in patients with chronic schizophrenia and major depressive disorder against matched controls. Astrocyte density was decreased in schizophrenia compared to controls (p = 0.030), with no change in oligodendrocyte density observed. Significantly increased nuclear cross-sectional area (p = 0.017) and length (p = 0.021), and increased nucleolar volume (p = 0.037) in dopaminergic neurons were observed in schizophrenia patients compared with controls, suggesting nuclear pleomorphic changes. No changes were observed in depression cases compared to control group. These changes may reflect pathological alterations in gene expression, neuronal structure and function in schizophrenia.

Assessing the encoding specificity of associations with sensory preconditioning procedures.

Three experiments examined the encoding specificity of associations using sensory preconditioning procedures in rats. In Experiment 1a, after exposure to two compounds (AX and BY), X (but not Y) was either followed by shock after a trace interval (Group Trace) or immediately followed by shock (Group Immediate). AX elicited less activity than BX (i.e., more fear) in Group Trace, but equivalent activity levels in Group Immediate. These results, replicated using a within-subjects design in Experiment 1b, indicate that the presence of A (on AX trials) generates fear because it associatively evokes X's memory into the same state as it was associated with the shock during (trace) conditioning. In Experiment 2, after exposure to AX and BY, X (but not Y) was immediately followed by shock. As in Experiment 1a, presentations of AX and BX elicited equivalent levels of fear, but there was more fear in the trace period after AX than in the trace period after BX. This finding suggests that during aversive conditioning, the associatively provoked memory of A was part of the conditioned complex, and that the trace of AX was more likely to activate this memory than was the trace of BX.

Evidence that the rat hippocampus has contrasting roles in object recognition memory and object recency memory.

Adult rats with extensive, bilateral neurotoxic lesions of the hippocampus showed normal forgetting curves for object recognition memory, yet were impaired on closely related tests of object recency memory. The present findings point to specific mechanisms for temporal order information (recency) that are dependent on the hippocampus and do not involve object recognition memory. The object recognition tests measured rats exploring simultaneously presented objects, one novel and the other familiar. Task difficulty was varied by altering the retention delays after presentation of the familiar object, so creating a forgetting curve. Hippocampal lesions had no apparent effect, despite using an apparatus (bow-tie maze) where it was possible to give lists of objects that might be expected to increase stimulus interference. In contrast, the same hippocampal lesions impaired the normal preference for an older (less recent) familiar object over a more recent, familiar object. A correlation was found between the loss of septal hippocampal tissue and this impairment in recency memory. The dissociation in the present study between recognition memory (spared) and recency memory (impaired) was unusually compelling, because it was possible to test the same objects for both forms of memory within the same session and within the same apparatus. The object recency deficit is of additional interest as it provides an example of a nonspatial memory deficit following hippocampal damage.

Encoding specific associative memory: evidence from behavioral and neural manipulations.

Within-subjects procedures with rats assessed the associative structures acquired during conditioning trials in which the interval between the stimuli and food was either short or long (i.e., A-10 s→food and B-40 s→food). In Experiments 1 and 2, after these conditioning trials, A and B served as second-order reinforcers for 2 further stimuli (i.e., X→A and Y→B); whereas Experiment 3 used a sensory preconditioning procedure in which X→A and Y→B trials occurred before the conditioning trials, and rats were finally tested with X and Y. In each experiment, Y elicited greater responding at test than did X. This finding supports the contention that the long-lived trace of B (associated with food on B-40 s→food trials) is more similar to the memory of B that was associatively provoked by Y, than is the short-lived trace of A (associated with food on A-10 s→food trials) to the memory of A that was associatively provoked by X. These conclusions were reinforced by the effects of a neural manipulation that disrupted discrimination learning involving the short traces of stimuli but not the long traces of the same stimuli.

Analysis of the content of configural representations: the role of associatively evoked and trace memories.

Two experiments examined the content of configural learning in rats. In Experiment 1, after simple pre-exposure to two hybrid contexts (AB and CD), rats acquired a configural discrimination involving two of the contexts (A and C) and two auditory stimuli (X and Y; AX→food, AY→no food, CX→no food, and CY→food). When rats were then placed in context B, they were more likely to respond to X than Y, and when they were placed in context D the reverse was the case. Experiment 2 demonstrated that rats can acquire a configural discrimination involving the presence of context (A) and its memory trace (a; AX→food, AY→no food, aX→no food, and aY→food). These results show that associatively provoked memories (Experiment 1) and memory traces (Experiment 2) can participate in configural discriminations.

Endovascular treatment of carotid embolic occlusions has a higher recanalization rate compared with cardioembolic occlusions.

BACKGROUND AND PURPOSE: Treatment of large artery cerebral occlusions is rapidly evolving. We hypothesized that patients with intracranial embolic occlusions secondary to an extracranial carotid artery stenosis or occlusion have a higher probability of successful endovascular recanalization compared with those with cardioembolic occlusions. METHODS: We retrospectively reviewed the databases of three institutions (University of Pittsburgh Medical Center (UPMC), Michigan State University (MSU) and Cleveland Clinic Foundation (CCF)) for acute anterior circulation ischemic strokes treated with endovascular therapies from January 2006 to July 2008. After collection of demographic, radiographic and angiographic variables, two groups were identified: artery to artery embolic occlusions and cardioembolic/cryptogenic intracranial occlusions. We defined recanalization as TIMI 2 or 3 flow. A binary logistic regression model was constructed to determine which characteristics were unique to patients with carotid embolic occlusions. RESULTS: A total of 207 patients were identified (UPMC=100, CCF=71, MSU=36) with a mean age of 69±11 years and mean NIHSS of 17±5. Of these, 157 (75%) were due to a cardiac or cryptogenic source and 50 (25%) were from a carotid embolic source. The use of multimodal therapy (OR 2.6 (1.2-5.6), p<0.009) and the presence of a carotid embolic intracranial occlusion (OR 3.6 (1.2-7.1), p<0.012) were associated with successful recanalization, while carotid terminus occlusions were associated with unsuccessful recanalization (OR 0.35 (0.18-0.68), p<0.002). CONCLUSIONS: Patients with intracranial occlusions secondary to an extracranial carotid stenosis or total occlusion appear to have more successful recanalization rates when treated with endovascular therapy compared with those with cardioembolic occlusions.

Meta-analysis: yield of diagnostic tests for coeliac disease in dyspepsia.

BACKGROUND: The prevalence of coeliac disease (CD) may be increased in individuals with dyspepsia, but evidence is conflicting. AIMS: To conduct a systematic review and meta-analysis of studies reporting prevalence of CD in dyspepsia. METHODS: MEDLINE, EMBASE, and CINAHL were searched up to February 2009. Case series and case-control studies applying serological tests and/or distal duodenal biopsy for CD to unselected adults with dyspepsia were eligible. Prevalence of positive coeliac serology and biopsy-proven CD were pooled for all studies and compared between cases and controls using an odds ratio (OR) and 95% confidence interval (CI). RESULTS: Fifteen studies were identified. Prevalence of positive coeliac serology was higher in cases with dyspepsia (7.9%) compared with controls (3.9%), but not significantly so (OR for positive endomysial antibodies or tissue transglutaminase 1.89; 95% CI 0.90-3.99). Prevalence of biopsy-proven CD following positive serology was also higher (3.2% in cases vs. 1.3% in controls), but again this was not statistically significant (OR 2.85; 95% CI 0.60-13.38). Prevalence of biopsy-proven CD was 1% in ten studies performing duodenal biopsy first-line. CONCLUSION: Prevalence of biopsy-proven CD in subjects with dyspepsia was 1% and was higher than in controls, although this difference was not statistically significant.

Single mode, polarization-independent submicron silicon waveguides based on geometrical adjustments.

In this work, we demonstrate via computer simulation the single mode and zero birefringence conditions for photonic wires with height and width less than 600 nm. We report on the simulation conditions for both single mode and zero birefringence in silicon-on-insulator photonic wires and sub-micron rib waveguides using a 3-dimensional imaginary beam propagation method. The results show that operation in both single mode and zero birefringence is possible under certain circumstances and that the conditions are restricted by fabrication processes where birefringence is strongly dependent upon waveguide dimensions. A matrix of waveguide parameters has been identified at both operating wavelengths of 1310 nm and 1550 nm, which can satisfy single mode and zero birefringence conditions simultaneously. This is to provide a general design rule for waveguides in small dimensions on the order of hundreds of nanometres.

Flat spectral response silicon arrayed waveguide gratings via ion implantation.

A flat spectral response has long been a requirement in photonic networking. In order to find a low cost alternative compared to some other technologies, a novel method is demonstrated to achieve such a response in silicon-on-insulator arrayed waveguide gratings (AWG) through free carrier absorption, implemented by ion implantation of dopant species. The AWG is designed using 1.5mum Si-overlayer on an SOI wafer utilising rib waveguides with a width of 1.1mum and an etch-depth of 0.88mum to facilitate the single-mode, birefringence-free operation. It is also essential to achieve a uniform dopant concentration throughout the guiding region to avoid any phase errors resulting from the free carriers. This can be achieved using multiple ion implantation steps. Both n and p type dopants are investigated and results showed significant reduction of doping length is achieved by using n-type dopant as compared to a p-type dopants. The broadened passband is measured to be 0.5nm, a 5 times broadening from the Gaussian peak.