Exposure to psychostimulants results in structural and synaptic plasticity in striatal medium spiny neurons (MSNs). These cellular adaptations arise from alterations in genes that are highly implicated in the rearrangement of the actin-cytoskeleton, such as T-lymphoma invasion and metastasis 1 (Tiam1). Previous studies have demonstrated a crucial role for dopamine receptor 1 (D1)-containing striatal MSNs in mediating psychostimulant induced plasticity changes. These D1-MSNs in the nucleus accumbens (NAc) positively regulate drug seeking, reward, and locomotor behavioral effects as well as the morphological adaptations of psychostimulant drugs. Here, we demonstrate that rats that actively self-administer cocaine display reduced levels of Tiam1 in the NAc. To further examine the cell type-specific contribution to these changes in Tiam1 we used optogenetics to selectively manipulate NAc D1-MSNs or dopamine receptor 2 (D2) expressing MSNs. We find that repeated channelrhodopsin-2 activation of D1-MSNs but not D2-MSNs caused a down-regulation of Tiam1 levels similar to the effects of cocaine. Further, activation of D2-MSNs, which caused a late blunted cocaine-mediated locomotor behavioral response, did not alter Tiam1 levels. We then examined the contribution of D1-MSNs to the cocaine-mediated decrease of Tiam1. Using the light activated chloride pump, eNpHR3.0 (enhanced Natronomonas pharaonis halorhodopsin 3.0), we selectively inhibited D1-MSNs during cocaine exposure, which resulted in a behavioral blockade of cocaine-induced locomotor sensitization. Moreover, inhibiting these NAc D1-MSNs during cocaine exposure reversed the down-regulation of Tiam1 gene expression and protein levels. These data demonstrate that altering activity in specific neural circuits with optogenetics can impact the underlying molecular substrates of psychostimulant-mediated behavior and function.
Tumour deposits in the head and neck region were treated with hyperthermia using 915 MHz external microwave applicators and radiation therapy between 1986 and 1990. The mean (± SE) radiation dose was 47 ± 2 Gy (range 21–77 Gy). All but four patients had failed previous therapy. Mean tumour volume was 40 ± 10 cm3 (range 0·3–276 cm3). Hyperthermia was administered biweekly in 80% of the patients in 6·0 ± 0·4 sessions (range 1–10); thermometry involved 3·6 ± 0·4 catheters (range 1–9) and 5·7 ± 0·4 sensors (range 1–12) per tumour. Of the 50 lesions evaluable for response, 29 had a complete response (58%), and 20 had a partial response (40%). Lesions were stratified by depth. In tumours considered potentially heatable (i.e. depth ≤ 3 cm and lateral dimensions at least 2 cm less than boundary of applicator), the complete response rate was 81% (26/32, 47 ± 2 Gy, 15 ± 3 cm3); whereas for patients with tumours deeper than 3 cm, the complete response rate was 17% (3/18, 48 ± 3 Gy, 110 ± 21 cm3), p = 0·0001. Among lesions ≤ 3 cm depth that exhibited a complete response, six recurred (24%, 5·8 ± 1·8 months) while 20 lesions were recurrence free at last follow-up of 11·9 ± 1·2 months. The overall survival of patients with lesions ≤ 3 cm depth was 11·5 ± 1·3 months (range 2·4–32·3 months) while for patients with lesions > 3 cm depth survival was 6·7 ± 0·9 months (range 2·1–18·6 months), p=0·01. In superficial lesions with depth ≤ 3 cm, multivariate logistic regression analysis indicated that the model best correlating with complete response included radiation dose (p=0·08) and tumour volume (p=0·08, model p=0·004). Multivariate proportional hazard analysis indicated that the model best correlating with duration of local control included tumour depth (p=0·03) and previous radiation therapy (p=0·08, model p=0·006). Twenty-two fields were treated without any skin reactions (39%), 23 evidenced erythema (40%) and eight thermal blistering (14%). Ulceration occurred in 11 treatment fields but in all but one of these cases the ulceration may have been due to tumour breakdown as there was direct invasion of the skin by tumour prior to the initiation of treatment. The maximal skin temperature was the best predictor of morbidity although the correlation was not statistically significant (p=0·19).
Successful delivery of new airport capacity projects (including new runways and runway extensions, airspace improvements, terminal expansion, and ground access improvements) can take many years. Such projects are most likely to succeed with steady support from airport sponsors, political constituencies, airport users, interest groups, regulatory agencies, and nearby communities. Many airports need guidance to help them identify, mobilize, maintain, and broaden support, and to deal constructively with project opposition. This report provides guidance to help airport sponsors respond to the many challenges they face when undertaking a significant capacity improvement project. The guidance recognizes that building support must occur early in the process and that, just as importantly, maintaining support is also key to successful implementation, since large capital projects can take many years to accomplish. The guidebook is designed for quick reference, with each chapter featuring a “Key Takeaways” section.
Aim: The need for resection of the primary tumour in stage IV minimally symptomatic rectal cancer (RC) is controversial.
Method: An IRB‐approved cancer database and billing records were queried to identify stage IV rectal cancer patients with a minimally‐symptomatic primary tumour (no obstruction, perforation, or massive bleeding) between 1980 and 2013. Patients who underwent initial resection of the primary tumour (Group I) were case‐matched with patients who underwent treatment without initial resection (Group II) according to age, sex, ASA classification, and number of organs involved with metastatic disease.
Results: Ninety six patients were matched from a total cohort of 249 patients (215 Group I, 34 Group II) with stage IV RC. 54% were male and the mean age was 60.3 ± 11.2 years. Median survival times for Group I and Group II were 15 (range 11–20) and 20.5 (6–29) months respectively (P = 0.54). Within group I, 49 (73%) patients underwent anterior proctosigmoidectomy, 14 (21%) underwent abdominoperineal resection, 2 (3%) underwent Hartmann's procedure, and 2 (3%) underwent total proctocolectomy with end ileostomy. Treatment related mortality rate was 3% in Group I and 0% in Group II. In Group I, post operative morbidity rate was 48% (32 of 67 patients). In Group II, complications related to the unresected primary tumour occurred in 2 patients: acute bowel obstruction requiring endoscopic stenting (1) and rectovaginal fistula requiring stoma diversion (1). 4 patients in Group II required palliative radiotherapy during the course of treatment due to pelvic pain. The median number of in‐hospital days during the course of treatment was 10 (8–13) days in Group I and 1 (0–15) days in Group II (P < 0.001).
Conclusion: In patients presenting with minimally symptomatic Stage IV RC, a treatment strategy of chemotherapy without resection of the primary tumour may minimize treatment‐related morbidity, mortality, and days spent in‐hospital without adversely affecting survival. This may have important implications for quality of life in these patients with limited life expectancy.
Regulating Opioid Responses Different drugs of abuse are thought to highjack similar reward systems in the brain using common mechanisms. However, Koo et al. (p. 124 ) now observe that some of the neural mechanisms that regulate opiate reward can be both different and even opposite to those that regulate reward by stimulant drugs. While knockdown of brain-derived neurotrophic factor (BDNF) in the ventral tegmental area in mice antagonized the response to cocaine, the same manipulation strengthened the potential of opiates to increase dopamine neuron excitability. Optogenetic stimulation of dopaminergic terminals in the nucleus accumbens could counteract the effects of BDNF on morphine reward blockade.
Choice behavior requires animals to evaluate both short- and long-term advantages and disadvantages of all potential alternatives. Impulsive choice is traditionally measured in laboratory tasks by utilizing delay discounting (DD), a paradigm that offers a choice between a smaller immediate reward, or a larger more delayed reward. This study tested a large sample of Heterogeneous Stock (HS) male (n = 896) and female (n = 898) rats, part of a larger genetic study, to investigate whether measures of reward maximization overlapped with traditional models of delay discounting via the patch depletion model using a Sequential Patch Depletion procedure. In this task, rats were offered a concurrent choice between two water "patches" and could elect to "stay" in the current patch or "leave" for an alternative patch. Staying in the current patch resulted in decreasing subsequent reward magnitudes, whereas the choice to leave a patch was followed by a delay and a resetting to the maximum reward magnitude. Based on the delay in a given session, different visit durations were necessary to obtain the maximum number of rewards. Visit duration may be analogous to an indifference point in traditional DD tasks. Males and females did not significantly differ on traditional measures of DD (e.g. delay gradient; AUC). When examining measures of patch utilization, females made fewer patch changes at all delays and spent more time in the patch before leaving for the alternative patch compared to males. Consistent with this, there was some evidence that females deviated from reward maximization more than males. However, when controlling for body weight, females had a higher normalized rate of reinforcement than males. Measures of reward maximization were only weakly associated with traditional DD measures and may represent distinctive underlying processes. Taken together, females performance differed from males with regard to reward maximization that were not observed utilizing traditional measures of DD, suggesting that the patch depletion model was more sensitive to modest sex differences when compared to traditional DD measures in a large sample of HS rats.
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