Phosphorylation of NMDA NR1 subunits in the myenteric plexus during TNBS induced colitis

N-Methyl- d-aspartic acid (NMDA) receptors are known to function in the mediation of pain and have a significant role in the development of hyperalgesia following inflammation. Serine phosphorylation regulation of NMDA receptor function occurs in a variety of conditions. No studies have demonstrated a change in phosphorylation of enteric NMDA receptors following colonic inflammation. We examined the levels of NMDA NR1 phosphorylation in trinitrobenzene sulfonic acid (TNBS) induced colitis in rats and compared it to protein translation and the development of visceral hypersensitivity. We have previously, demonstrated an increase in the C1 cassette of NR1 mRNA expression at 14, 21, and 28 days following TNBS administration. In this study, we examined the NR1 serine phosphorylation at 14 days following TNBS injection. Male Sprague–Dawley rats (200–250 g) were treated with TNBS (20 mg per rat) diluted in 50% ethanol ( n = 3) and vehicle controls of 50% ethanol ( n = 3). TNBS and vehicle controls were administered with a 24 gauge catheter inserted into the lumen of the rat colon. The animals were sacrificed at 14 days after induction of the colitis and their distal colon was retrieved for two-dimensional (2D) western blot analysis. Serine phosphorylation of the NR1 subunit with C1 cassette appears at 14 days after TNBS injection. In contrast, there was no NR1–C1 expression in the vehicle controls and untreated normal controls. These results suggest a role for colonic-NMDA receptor phosphorylation in the development of neuronal plasticity following colonic inflammation. Phosphorylation of NR1 may partially explain visceral hypersensitivity present during colonic inflammation

Cognitive errors, symptom severity, and response to cognitive behavior therapy in older adults with generalized anxiety disorder

OBJECTIVE: Recent research by Wetherell et al. investigating the differential response to group-administered cognitive behavior therapy (CBT) for generalized anxiety disorder (GAD) in older adults found that GAD severity, homework adherence, and psychiatric comorbidity predicted statistically significant improvement. The current study investigated whether the presence/absence of cognitive errors on separate domains of the Mini-Mental State Exam (MMSE) predicted baseline differences in symptom severity and improvement following CBT, above and beyond already established predictors. METHODS: Baseline characteristics were investigated in a sample of 208 older patients diagnosed with GAD. Predictors of treatment response were examined in a subsample of 65 patients who completed CBT and were included in a prior study by Wetherell et al. of response predictors. RESULTS: Results from the baseline sample indicated that only subjects who committed an error on the MMSE Working Memory domain exhibited increased severity in anxiety and depressive symptoms. Results from the treatment sample indicated that an error on the MMSE Orientation domain was a significant predictor of outcome at 6-month follow-up, while controlling for previously established predictors. Patients who committed at least one error in this domain showed decreased response relative to patients who committed no errors. CONCLUSION: In this sample of older adults diagnosed with GAD, poor performance on the MMSE Working Memory domain was associated with increased baseline anxiety and depression, while baseline performance differences on the MMSE Orientation domain predicted outcome six months after CBT intervention. © 2007 American Association for Geriatric Psychiatry

Impact of neoadjuvant therapy on eligibility for and frequency of breast conservation in stage II–III HER2-positive breast cancer: surgical results of CALGB 40601 (Alliance)

OBJECTIVE: It had been previously shown that patients who receive neoadjuvant systemic therapy (NST) are more likely to undergo breast-conserving therapy (BCT) than those who have primary surgery. However, the frequency with which patients who are not BCT-eligible prior to NST convert to BCT-eligible with treatment is unknown. To document this conversion rate in a subset of patients expected to have a high clinical response rate to NST, we studied surgical assessment and management of patients enrolled on a randomized neoadjuvant trial for stage II–III HER2-positive breast cancer (HER2 + BC)(CALGB 40601). METHODS: The treating surgeon assessed BCT candidacy based on clinico-radiographic criteria both before and after NST. Definitive breast surgical management was at surgeon and patient discretion. We sought to determine (1) the conversion rate from BCT-ineligible to BCT-eligible (2) the percentage of BCT-eligible patients who chose breast conservation, and (3) the rate of successful BCT. We also evaluated surgeon-determined factors for BCT-ineligibility and the correlation between BCT eligibility and pathologic complete response (pCR). RESULTS: Of 292 patients with pre- and post-NST surgical assessments, 59 % were non-BCT candidates at baseline. Of the 43 % of these patients who converted with NST, 67 % opted for BCT, with an 80 % success rate. NST increased the BCT-eligible rate from 41 to 64 %. Common factors cited for BCT-ineligibility prior to NST including tumor size (56 %) and probable poor cosmetic outcome (26 %) were reduced by 67 and 75 %, respectively, with treatment, while multicentricity, the second most common factor (33 %), fell by only 16 %. Since 23 % of the BCT-eligible patients chose mastectomy, BCT was the final surgical procedure in just 40 % of the patients. Patients considered BCT-eligible both at baseline and after NST had a pCR rate of 55 %, while patients who were BCT-ineligible prior to NST had the same pCR rate (44 %) whether they converted to BCT-eligible or not. CONCLUSIONS: Many patients with HER2 + BC deemed ineligible for BCT at baseline can be converted to BCT-eligible with NST; excluding patients with multicentric disease substantially increases that percentage. In converted patients who opt for BCT, the success rate is similar to that of patients considered BCT-eligible at baseline. Whether a BCT-ineligible patient converts to BCT eligibility or not does not appear to affect the likelihood of achieving a pCR. Despite the efficacy of NST in this patient cohort, only 40 % of patients had successful BCT; further research into why BCT-eligible patients often opt for mastectomy is needed