Therapeutics for dementia and Alzheimer's disease: New directions for precision medicine.

LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.

mGluR7 facilitates extinction of aversive memories and controls amygdala plasticity.

Formation and extinction of aversive memories in the mammalian brain are insufficiently understood at the cellular and molecular levels. Using the novel metabotropic glutamate receptor 7 (mGluR7) agonist AMN082, we demonstrate that mGluR7 activation facilitates the extinction of aversive memories in two different amygdala-dependent tasks. Conversely, mGluR7 knockdown using short interfering RNA attenuated the extinction of learned aversion. mGluR7 activation also blocked the acquisition of Pavlovian fear learning and its electrophysiological correlate long-term potentiation in the amygdala. The finding that mGluR7 critically regulates extinction, in addition to acquisition of aversive memories, demonstrates that this receptor may be relevant for the manifestation and treatment of anxiety disorders.

Feeling strained? Influence of genetic background on depression-related behavior in mice: a review.

Depression is a growing pandemic in developed societies. The use of inbred mouse strains in pre-clinical psychiatric research has proven to be a valuable resource. Firstly, they provide the background for genetic manipulations that aid in the discovery of molecular pathways that may be involved in major depression. Further, inbred mouse strains are also being used in the determination of genetic and environmental influences that may pre-dispose or trigger depression-related behavior. This review aims to highlight the utility of inbred mouse strains in depression research, while providing an overview of the current state of research into behavioral differences between strains in paradigms commonly used in the field. Neurochemical differences that may underlie strain differences are examined, and some caveats and cautions associated with the use of inbred strains are highlighted.

A genetic upper limit to whole-body protein deposition in a strain of growing pigs.

The genetic upper limit to daily whole-body protein deposition (Pdmax) is an important constraint on pig growth. The Pdmax was determined for a specified pig genotype using N balance and serial slaughter techniques. A traditional N-balance study, involving 36 and 90 kg of BW Large White x (Landrace x Large White) entire male pigs, was first conducted to demonstrate that a highly digestible, nutrient-dense diet (1.54% Lys; 18 MJ of DE/kg, air-dried basis) was able to support the attainment of Pdmax within the constraints of pig appetite. Animals were allocated to set levels of feed intake [set proportions of ad libitum DE intake (DEi), 50 to 100%]. Nitrogen retention increased linearly with DEi up to 25.3 and 35.2 MJ of DE/d for the 36 and 90 kg of BW pigs, respectively, then showed a departure (P < 0.05) from linearity. For DEi of the experimental diet above the latter intakes, which were approximately 80% of a determined ad libitum DEi, the pigs deposited protein at a rate approaching Pdmax. When a linear plateau response model (accepted a priori) was fitted, Pdmax values of 189.9 g/d at a DEi breakpoint of 28.3 MJ of DE/d at 36 kg of BW and 186.4 g/d at a DEi breakpoint of 37.3 MJ of DE/d at 90 kg of BW were found. In the serial slaughter study, 18 female and 18 entire male pigs were allocated to 5 slaughter BW (25, 45, 65, 85, and 110 kg) such that there were 5, 3, 3, 3, and 4 animals of each sex at each slaughter weight, respectively. Animals were fed the experimental diet ad libitum, and whole-body protein was determined at slaughter. Growth data were analyzed by differentiating and combining continuous mathematical functions for BW and body composition. The ad libitum DEi were 27.4 and 50.7 MJ/d at 36 and 90 kg of BW for the entire males and were assumed, based on the N-balance results, sufficiently high to allow expression of Pdmax. There was an effect (P < 0.05) of sex on Pdmax vs. time (days on trial). Over the BW range of 25 to 85 kg, Pdmax was constant for the entire male and female pigs at 170 and 147 g/d, respectively. Above 85 kg of BW, Pdmax was no longer constant for either sex.

Heart failure: strategies to enhance patient self-management.

Successful management of heart failure requires an active partnership between the patient and health care providers. This can be facilitated through a focused patient education plan that begins in acute care and has continuity into the community. Elements of the education plan involve both teaching content areas and self-management behaviors. Clinical pathways for heart failure incorporate teaching and educational strategies to guide the work of the multidisciplinary team, and the advanced practice nurse has tremendous potential in facilitating improved patient outcomes.

Management of elderly patients with primary breast cancer.

From 1974 through 1983, three hundred forty-three patients aged 70 years or older at diagnosis received comprehensive post-operative radiation therapy for localized (Stage I-III) breast cancer following surgical procedures ranging from incisional biopsies to classical radical mastectomy. The 5- and 10-year overall survival rates for this series of elderly patients are 67% and 33%. The respective disease-free survival rates are 67% and 42%. Over one-half of these women were treated by less than total mastectomy. No differences were seen in survival, disease-free survival, or local regional control rates comparing similarly staged patients treated by radical mastectomy, modified radical mastectomy, or tylectomy. Complications were few and seen primarily in those patients subjected to axillary dissection prior to irradiation. Long term survival appears to be achievable in the majority of elderly patients with regionally confined disease at presentation and aggressive treatment with curative intent is warranted. These elderly patients are often poor candidates for radical surgery. In this patient population, conservative surgery with post-operative radiation therapy is well tolerated and provides equivalent results to more radical surgical procedures.

Locally advanced breast carcinoma: results with combined regional therapy.

To define optimal regional treatment as initial management of locally advanced (Stage III & IV) breast cancer, 509 patients treated from 1966-1982 were reviewed. All patients received comprehensive postoperative irradiation of the peripheral lymphatics and chest wall, following surgical procedures varying from incisional biopsy to classical radical mastectomy. Patients were followed from 1 to over 16 years. The survival rate at 5 and 10 years for the entire series is 41% and 26%. Fifty-eight patients having radical surgery for T3 tumors and subsequently found to have negative axillary lymph nodes showed the highest rates of survival, 72% at 5 years and 57% at 10 years. This was significantly better (p less than .01) than patients with T3N+ disease, (5 year survival 44%; 10 year, 29%) and T4N+ disease (44%, 39%). Four hundred seventy patients with non-inflammatory carcinoma and no supraclavicular metastases were considered technically resectable. Three hundred eighty-one of these patients underwent a definitive surgical procedure removing all gross cancer prior to irradiation and, as expected, showed higher rates of local disease control than patients having lesser surgery (79% versus 45%, p less than .01). These patients also showed markedly better rates of survival and relapse-free survival with 50% alive and 38% disease free, versus 14 and 8%, at 5 years (p less than .01). There were no 10 year survivors among the 89 technically resectable patients having less than total gross resection. Long term relapse-free survival of locally advanced breast cancer can be achieved with aggressive combined local-regional therapy. Total resection of all gross cancer prior to irradiation is recommended. Modifications of postoperative radiation therapy techniques are suggested to further improve local control rates for these advanced tumors. This large series provides a baseline for evaluation of current programs adding adjuvant systemic therapy to regional treatment.

Myometrial penetration of endometrial carcinoma as a prognostic factor for patients receiving pre- or postoperative radiation therapy.

From 1966-1980, 227 patients with Stage I endometrial carcinoma were treated by total abdominal hysterectomy, bilateral salpingo-oophorectomy, and either pre- or postoperative external beam pelvic irradiation. All therapy was delivered with megavoltage equipment. There was at least a 4-week interval between irradiation and surgery for 164 patients treated preoperatively. No significant differences were found in subsequent survival or local control at 5 years for those patients left with no residual tumor (81% survival/97% local control), disease confined to the mucosa (83% survival/93% local control), or invasion of the inner half of the myometrium (81% survival/93% local control). However, patients left with deeper myometrial penetration showed a significantly poorer survival rate of 57% (p = 0.02) and a local control rate of only 65% (p = 0.006). For 63 patients treated postoperatively, there was no significant difference in 5-year survival or local control for those patients with disease limited to the inner 1/2 of the myometrium (80% survival/93% local control) compared with more extensive myometrial invasion (75% survival/86% local control). As patients with deep myometrial penetration irradiated postoperatively showed survival rates comparable to patients with lesser extent of invasion, the adverse prognostic effect of deep penetration appears to have been attenuated by subsequent pelvic irradiation. By contrast, residual deep myometrial invasion remained a significant adverse prognostic indicator for patients treated preoperatively. For this group, further treatment seems necessary and postoperative vaginal brachytherapy and/or adjuvant chemotherapy should be considered.

The significance of local recurrence of carcinoma of the breast.

One hundred twenty-one patients with local or regional recurrence of carcinoma of the breast without evidence of distant metastases were treated with megavoltage radiation therapy. All patients had radical or modified radical mastectomy as their initial treatment. The 10 year survival probability of this group of patients is 26%, with a local control probability of 46%. Within this group of patients with recurrent disease, factors found to be associated with a poorer prognosis include peripheral nodal recurrence, advanced initial disease stage and short disease free interval. Contrary to expectation, patients with recurrence within the mastectomy scar (as opposed to chest wall recurrence wide of the scar) or a history of previous radiotherapy had poorer local control rates (although not statistically significant), without effect upon overall survival. Comprehensive radiation therapy (peripheral lymphatic plus chest wall) enhanced the local control rate for the entire group and the survival probability for patients with isolated chest wall recurrence compared with limited radiation therapy fields. (Five year survival probability: chest wall irradiation only = 27%; chest wall and peripheral lymphatic = 54%). Patients given systemic therapy at the time of local recurrence showed no survival benefit. Aggressive, comprehensive radiation therapy is indicated for locally recurrent breast cancer. More effective systemic therapy is needed, especially for higher risk patients.