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Adaptive reward-related decision making often requires accurate and detailed representation of potential available rewards. Environmental reward-predictive stimuli can facilitate these representations, allowing one to infer which specific rewards might be available and choose accordingly. This process relies on encoded relationships between the cues and the sensory-specific details of the rewards they predict. Here, we interrogated the function of the basolateral amygdala (BLA) and its interaction with the lateral orbitofrontal cortex (lOFC) in the ability to learn such stimulus-outcome associations and use these memories to guide decision making. Using optical recording and inhibition approaches, Pavlovian cue-reward conditioning, and the outcome-selective Pavlovian-to-instrumental transfer (PIT) test in male rats, we found that the BLA is robustly activated at the time of stimulus-outcome learning and that this activity is necessary for sensory-specific stimulus-outcome memories to be encoded, so they can subsequently influence reward choices. Direct input from the lOFC was found to support the BLA in this function. Based on prior work, activity in BLA projections back to the lOFC was known to support the use of stimulus-outcome memories to influence decision making. By multiplexing optogenetic and chemogenetic inhibition we performed a serial circuit disconnection and found that the lOFC→BLA and BLA→lOFC pathways form a functional circuit regulating the encoding (lOFC→BLA) and subsequent use (BLA→lOFC) of the stimulus-dependent, sensory-specific reward memories that are critical for adaptive, appetitive decision making.

Summary The roles of the microbiome and innate immunity in the pathogenesis of multiple sclerosis (MS) remain unclear. We have previously documented abnormally low levels of a microbiome-derived Toll-like receptor (TLR)2-stimulating bacterial lipid in the blood of MS patients and postulated that this is indicative of a deficiency in the innate immune regulating function of the microbiome in MS. We postulated further that the resulting enhanced TLR2 responsiveness plays a critical role in the pathogenesis of MS. As proof-of-concept, we reported that decreasing systemic TLR2 responsiveness by administering very low-dose TLR2 ligands attenuated significantly the mouse model of MS, experimental autoimmune encephalomyelitis. Studies of Toll-like receptor responses in patients with MS have been conflicting. Importantly, most of these investigations have focused on the response to TLR4 ligation and few have characterized TLR2 responses in MS. In the present study, our goal was to characterize TLR2 responses of MS patients using multiple approaches. Studying a total of 26 MS patients and 32 healthy controls, we now document for the first time that a large fraction of MS patients (50%) demonstrate enhanced responsiveness to TLR2 stimulation. Interestingly, the enhanced TLR2 responders include a significant fraction of those with progressive forms of MS, a subset of patients considered unresponsive to adaptive immune system-targeting therapies. Our results suggest the presence of a pathologically relevant TLR2 related innate immune abnormality in patients with both relapsing–remitting and progressive MS. These findings may have significant implications for understanding the role of innate immunity in the pathogenesis of MS.

BACKGROUND. We conducted a phase 2, multicenter, open-label study of erlotinib plus bevacizumab in patients with malignant pleural mesothelioma who had previously received 1 prior chemotherapy regimen. These agents have activity in non–small cell lung cancer, but their role in mesothelioma is unclear. The primary endpoint is response rate. Secondary endpoints include time to progression, survival, and toxicity. METHODS. Eligible patients with mesothelioma who had previously received 1 chemotherapy regimen were treated with erlotinib 150 mg per os daily and bevacizumab 15 mg/kg administered intravenously on Day 1 of a 21-day cycle. Treatment continued until disease progression or development of significant toxicity. Tumor response was assessed after every 2 cycles using previously established mesothelioma response criteria from Byrne and Nowak. RESULTS. Twenty-four eligible patients initiated therapy with erlotinib and bevacizumab between February 2004 and October 2006. There were no complete or partial responses, although 12 patients achieved stable disease for at least 2 cycles of treatment. The median time to progression was 2.2 months (95% confidence interval [CI], 1.4 months-5.9 months). The median survival was 5.8 months (95% CI, 2.8 months-10.1 months). The most common toxicities were rash and diarrhea. There were no treatment-related deaths, intracranial bleeding, or hemoptysis. CONCLUSIONS. The combination of erlotinib and bevacizumab was tolerated reasonably well, but there was no evidence of radiographic response. This study demonstrates the feasibility of conducting trials in mesothelioma patients who have failed first-line therapy. More therapeutic studies with effective agents are needed for these patients. Cancer 2008. © 2008 American Cancer Society.

This paper reports on a qualitative, critical study into the lives of relatives and partners of people living with enduring effects of schizophrenia. A review of the literature showed that caregivers and relatives of sufferers were seldom asked about their experiences, instead they were subject to blame or criticism regarding their parental or caregiving practices. Caregivers of people with schizophrenia were interviewed in order to reveal their experience of caring for their kin after a medication change to atypical neuroleptics. The interview analysis was compared with mental health professional literature, using a Foucauldian approach to reveal the operation of language and power in the positioning of caregivers. This analysis was then compared to the talk of the caregivers. Similarities and differences in their ways of talking about caring were identified. Caregivers spoke of protracted periods of time before the establishment of a definite diagnosis, ambivalence about medication and 'never giving up'. The paper concludes that life for caregivers is constituted as doubly problematic, experiencing stigma personally and vicariously through their kin.

// David M. Jackman 1, 2, * , Leigh A. Cioffredi 4 , Lorraine Jacobs 5 , Farhana Sharmeen 1 , Linda K. Morse 1 , Joan Lucca 1 , Scott R. Plotkin 2, 6 , Paul J. Marcoux 1, 2 , Michael S. Rabin 1, 2 , Thomas J. Lynch 7, 8 , Bruce E. Johnson 1, 2 , Santosh Kesari 3, * 1 Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA 2 Harvard Medical School, Boston, MA, USA 3 Department of Neurosciences, Translational Neuro-Oncology Laboratories, Moores UCSD Cancer Center, University of California, San Diego, La Jolla CA, USA 4 Georgetown University School of Medicine, Washington, DC, USA 5 Eurofins Medinet B.V., Breda, The Netherlands 6 Stephen E. & Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA 7 Smilow Cancer Hospital at Yale-New Haven, Yale Cancer Center, New Haven, CT, USA 8 Yale University, New Haven, CT, USA * These authors have contributed equally to this work Correspondence to: David M. Jackman, e-mail: djackman@partners.org Santosh Kesari, e-mail: skesari@ucsd.edu Keywords: non-small cell lung carcinoma, epidermal growth factor receptor, meningeal carcinomatosis, kinase inhibitors Received: September 20, 2014 Accepted: December 09, 2014 Published: February 25, 2015 ABSTRACT Introduction: There are few effective treatment options for leptomeningeal metastasis (LM) in non-small-cell lung cancer (NSCLC). This study assessed the feasibility of high-dose gefitinib in patients with LM from NSCLC harboring EGFR mutations or prior systemic response to EGFR-TKI. Methods: This phase I open-label trial of a novel gefitinib dosing schedule employed a 3+3 design. Eligible NSCLC patients with LM had known EGFR mutations and/or prior response to EGFR-TKI. Patients alternated 2 weeks of high-dose daily gefitinib (dose levels: 750 mg, 1000 mg, 1250 mg) with 2 weeks of maintenance therapy (500 mg daily). Primary endpoints were safety and toxicity. Secondary endpoints included overall survival (OS), neurological progression-free survival, radiological response, and cytological response in cerebrospinal fluid (CSF). Results: Seven patients were treated: 3 at 750 mg dose level, 4 at 1000 mg dose level. There were no DLTs at the 750 mg dose level, and one DLT (toxic epidermal necrolysis) at the 1000 mg dose level. The study was closed due to slow accrual. Median neurological PFS was 2.3months (range 1.6–4.0 months); median OS was 3.5months (range 1.6–5.1months). Though there were no radiologically documented remissions of LM disease, four patients had improvement in neurological symptoms. One patient cleared their CSF of NSCLC cells, while 2 others had decrease in malignant cells in CSF. Conclusion: Although the MTD was not defined due to slow accrual, this study provides important information about the tolerability and CSF penetration of high-dose gefitinib as a therapeutic option for modest palliation for NSCLC patients with LM and a known EGFR mutation.

It is often asserted that older people are more variable than younger people; however, the published data do not always support this statement. To examine directly the applicability of the assertion, measures of reaction time (RT), memory, and intelligence from studies published in Psychology and Aging and the Journal of Gerontology from 1986 to 1990 were examined. The coefficients of variability calculated from data published in studies in which a group of younger people was compared with a group of older people indicated that variability was greater among older participants on measures of RT, memory, and fluid intelligence but not crystallized intelligence. Further examination of data bearing on relative variability is indicated.

The mediation of lesion-induced sprouting in the nervous system is a complex interaction of local membrane factors and circulating hormones. This series of studies examines the reactivity of the sprouting response of both male and female subjects under different hormonal conditions. Young adult male and female Sprague-Dawley rats which were gonadectomized (GDX) and adrenalectomized (ADX) underwent a unilateral entorhinal cortex lesion, which partially denervates the molecular layer of the ipsilateral hippocampal denate gyrus. At the time of the lesion, each animal received hormonal therapy. Fifteen days post-ERC-ablation the brains were analyzed for changes in reactive fiber outgrowth in the hippocampal commissural/associational afferents. Fiber outgrowth in females in the "asteroidal" (GDX/ADX) condition was unaffected. Asteroidal males demonstrated a decreased response. Gonadal steroid replacement, estrogen or testosterone, enhanced outgrowth in both asteroidal males and females. Glucocorticoid replacement suppressed outgrowth in both asteroidal males and females. Gonadal steroids clearly have neurotrophic activity which is interactive with glucocorticoid activity. Glucocorticoids under the GDX/ADX conditions in vivo have a negative impact on fiber outgrowth in both sexes. The effect of glucocorticoids is most dramatic when compared to the outgrowth of asteroidal animals without additional hormonal supplementation.

Adrenalectomy protects hippocampal pyramidal cells from transient ischemia in rats. We hypothesized that this effect of adrenalectomy could be generalized to the gerbil. We determined the effect of glucocorticoid manipulation on hippocampal CA1 cell death following transient forebrain ischemia in the gerbil. Adrenalectomy diminished hippocampal damage when performed immediately following transient forebrain ischemia, as in the rat, while glucocorticoid administration resulted in an increase in CA1 pyramidal cell damage. Furthermore adrenalectomy 24 h after the ischemic injury diminished hippocampal damage to roughly the same extent as immediate adrenalectomy. However, if gerbils were examined at longer survival periods after ischemia, the difference in hippocampal damage between adrenalectomized and sham-adrenalectomized was lost. These findings suggest that glucocorticoids influence the rate of hippocampal pyramidal cell disappearance following ischemia. Manipulation of glucocorticoids could be an important adjunct to therapy for preventing ischemic brain damage.

Young adult Sprague-Dawley rats of either sex were randomly assigned to be gonadectomized or left intact. Capsules containing either testosterone or estrogen were implanted in animals in both categories. Fifteen days after removal of the entorhinal cortex, the brains were analyzed for changes in reactive outgrowth of the commissural-associational afferent fibers in the hippocampal dentate gyrus. Both male and female control subjects showed identical sprouting responses. Only female subjects were significantly affected by gonadectomy, resulting in significant decreases in reactive fiber outgrowth. Hormone replacement therapy resulted in a return to control values in castrated females but had no affect on castrated males. The results suggest that sex hormones may regulate axon sprouting in the mature central nervous system.

Young adult male and female Sprague-Dawley rats were randomly assigned to be gonadectomized (GDX), adrenalectomized (ADX), gonadectomized and adrenalectomized (GDX/ADX) or left intact. One week following initial surgery all animals were subjected to a lesion of the entorhinal cortex (ERC) which partially denervates the ipsilateral hippocampal dentate gyrus. Fifteen days after the ERC ablation, the brains were analyzed for changes in reactive outgrowth of the hippocampal commissural-associational (C-A) afferents. Under intact conditions there were no differences between male and female subjects. Female subjects demonstrated a suppression of sprouting following GDX alone and an enhancement of growth following ADX alone. Reactive growth in male subjects was unaffected by GDX or ADX alone. When placed in the ‘asteroidal’ (GDX/ADX) condition, reactive outgrowth of male subjects in significantly impaired as compared to female subjects. The results suggest a complex inter-relationship between the gonadal and adrenal hormones and a possible neurotrophic effect for the gonadal steroids.

Hydrocortisone was administered to young adult male or female rats after removal of the entorhinal cortex. Lesion-induced outgrowth of the commissural-associational afferent fibers in the hippocampus was quantitated. The glucocorticoids caused a significant decline in axon sprouting in the male subjects and a significant increase in outgrowth in female subjects. Depending on the sex, the hormonal effects on lesion-induced axonal growth are markedly different in the rat.