Deficits in hippocampal‐dependent transfer generalization learning accompany synaptic dysfunction in a mouse model of amyloidosis

Elevated β‐amyloid and impaired synaptic function in hippocampus are among the earliest manifestations of Alzheimer's disease (AD). Most cognitive assessments employed in both humans and animal models, however, are insensitive to this early disease pathology. One critical aspect of hippocampal function is its role in episodic memory, which involves the binding of temporally coincident sensory information (e.g., sights, smells, and sounds) to create a representation of a specific learning epoch. Flexible associations can be formed among these distinct sensory stimuli that enable the “transfer” of new learning across a wide variety of contexts. The current studies employed a mouse analog of an associative “transfer learning” task that has previously been used to identify risk for prodromal AD in humans. The rodent version of the task assesses the transfer of learning about stimulus features relevant to a food reward across a series of compound discrimination problems. The relevant feature that predicts the food reward is unchanged across problems, but an irrelevant feature (i.e., the context) is altered. Experiment 1 demonstrated that C57BL6/J mice with bilateral ibotenic acid lesions of hippocampus were able to discriminate between two stimuli on par with control mice; however, lesioned mice were unable to transfer or apply this learning to new problem configurations. Experiment 2 used the APP_swePS1 mouse model of amyloidosis to show that robust impairments in transfer learning are evident in mice with subtle β‐amyloid‐induced synaptic deficits in the hippocampus. Finally, Experiment 3 confirmed that the same transfer learning impairments observed in APPswePS1 mice were also evident in the Tg‐SwDI mouse, a second model of amyloidosis. Together, these data show that the ability to generalize learned associations to new contexts is disrupted even in the presence of subtle hippocampal dysfunction and suggest that, across species, this aspect of hippocampal‐dependent learning may be useful for early identification of AD‐like pathology. © 2015 Wiley Periodicals, Inc.     

Early Intervention for Psychosis in Canada: What Is the State of Affairs?

Objective:

Early intervention services (EIS) for psychosis have been developed in several countries, including Canada. There is some agreement about the program elements considered essential for improving the long-term outcomes for patients in the early phase of psychotic disorders. In the absence of national standards, the current state of EIS for psychosis in Canada needs to be examined in relation to expert recommendations currently available.

Method:

A detailed online benchmark survey was developed and administered to 11 Canadian academic EIS programs covering administrative, clinical, education, and research domains. In addition, an electronic database and Internet search was conducted to find existing guidelines for EIS. Survey results were then compared with the existing expert recommendations.

Results:

Most of the surveyed programs offer similar services, in line with published expert recommendations (i.e., easy and rapid access, intensive follow-up through case management with emphasis on patient engagement and continuity of care, and a range of integrated evidence-based psychosocial interventions). However, differences are observed among programs in admission and discharge criteria, services for patients at ultra high risk (UHR) for psychosis, patient to clinician ratios, accessibility of services, and existence of specific inpatient units. These seem to diverge from expert recommendations.

Conclusions:

Although Canadian programs are following most expert recommendations on clinical components of care, some programs lack administrative and organizational elements considered essential. Continued mentoring and networking of clinicians through organizations such as the Canadian Consortium for Early Intervention in Psychosis (CCEIP), as well as the development of a fidelity scale through further research, could possibly help programs attain and maintain the best standards of early intervention. However, simply making clinical guidelines available to care providers is not sufficient for changing practices; this will need to be accompanied by adequate funding and support from organizations and policy makers.     

Evaluation of autologous bone marrow in wound healing in animal model: a possible application of autologous stem cells

A study was conducted to evaluate the potential of autologous bone marrow-derived cells in comparison with buffy coat of autologous blood for rapid cutaneous wound healing in rabbit model. Three square full-thickness skin excisional wounds were created in 15 selected experimental animals (rabbit) divided randomly into three groups. The wound was treated with autologous bone marrow cells in plasma (group 1), buffy coat of blood in plasma (group 2) and autologous plasma as control (group 3). Wounds were observed for 30 days for granulation tissue formation, biochemical, histomorphological and histochemical evaluation. In this study, granulation tissue appeared significantly lesser in wounds of group 3 animals followed by group 2 and 1 animals. Neovascularisation, granulation tissue formation, denser, thicker and better arranged collagen fibres, reticulin fibres and elastin fibres formation was more in group 1 as compared with other groups. It was concluded that the application of bone marrow-derived nucleated cells into the wound margins resulted in early and significantly faster rate of complete healing as compared with buffy coat of autologous blood and autologous plasma (control). This approach may be beneficial in various surface wounds that heal at a slower rate and recommended for healing of various complicated wound in future.     

Calcified atherosclerotic plaque - where exactly is the calcium and what does it contain?

Objective  

To understand the morphology and mineral content in calcified atherosclerotic plaques.     

Efficacy and safety of everolimus in elderly patients with metastatic renal cell carcinoma: an exploratory analysis of the outcomes of elderly patients in the RECORD-1 Trial

Background

Elderly patients with metastatic renal cell carcinoma (mRCC) may require special treatment considerations, particularly when comorbidities are present. An understanding of the efficacy and safety of targeted agents in elderly patients with mRCC is essential to provide individualized therapy.

Objective

To evaluate the efficacy and safety of everolimus in elderly patients (those ≥65 and ≥70 yr of age) enrolled in RECORD-1.

Design, setting, and participants

The multicenter randomized RECORD-1 phase 3 trial (Clinicaltrials.gov identifier, NCT00410124; http://www.clinicaltrials.gov) enrolled patients with mRCC who progressed during or within 6 mo of stopping sunitinib and/or sorafenib treatment (n = 416).

Intervention

Everolimus 10 mg once daily (n = 277) or placebo (n = 139) plus best supportive care. Treatment was continued until disease progression or unacceptable toxicity.

Measurements

Median progression-free survival (PFS), median overall survival (OS), and time to deterioration in Karnofsky performance status (TTD-KPS) were assessed using the Kaplan-Meier method; the log-rank test was used to compare treatment arms. Other outcomes evaluated included reduction in tumor burden, overall response rate (ORR), and safety.

Results and limitations

In RECORD-1, 36.8% of patients were ≥65 yr and 17.5% were ≥70 yr of age. PFS, OS, TTD-KPS, reduction in tumor burden, and ORR were similar in the elderly and the overall RECORD-1 population. Everolimus was generally well tolerated in elderly patients, and most adverse events were grade 1 or 2 in severity. The toxicity profile of everolimus was generally similar in older patients and the overall population; however, peripheral edema, cough, rash, and diarrhea were reported more frequently in the elderly regardless of treatment. The retrospective nature of the analyses was the major limitation.

Conclusions

Everolimus is effective and tolerable in elderly patients with mRCC. When selecting targeted therapies in these patients, the specific toxicity profile of each agent and any patient comorbidities should be considered.     

Selective neck dissection in node-positive squamous cell carcinoma of the head and neck

Objective The optimal type of neck dissection in head and neck squamous cell carcinoma (SCC) with clinical cervical metastases has not been determined. The following study was performed to determine the rate of regional control with selective neck dissection (SND) in these patients. Study Design Case series with planned data collection. Settings Single institution, cancer center. Methods and Subjects Patients with cervical lymph node metastases from mucosal cancers of the head and neck who were treated with SND from 2000 to 2010 were selected. Demographics, tumor characteristics, extent of neck dissection, adjuvant treatments, locoregional control, and survival were recorded. Recurrence in the neck and disease-specific survival (DSS) were primary and secondary end points. Results One hundred eight patients underwent SND. Sixty-nine (64%) were male. Median age was 62 (20-89) years. The most common primary site was the oral cavity (71.3%). Ninety-five (88%) received adjuvant treatment. Median follow-up was 21 months. Six patients (5.5%) had isolated recurrence in the dissected neck. Patients with N2C disease had poorer neck recurrence-free survival. At the end of study, 64 (59.3%) patients had no evidence of disease, and 23 (21.3%) had died of disease. Two-year DSS was 76.9%. Number of positive nodes (P = .026) and positive surgical margins (P = .001), among others, were predictors of poorer DSS. Conclusion In a highly selected group of patients with cervical lymph node metastases from head and neck SCC, selective neck dissection is effective in controlling the disease in the neck when performed in the setting of a multimodality treatment, including adjuvant radiotherapy or radiochemotherapy.     

Temporary dermal scatter reduction: quantitative assessment and implications for improved laser tattoo removal

BACKGROUND AND OBJECTIVES: Temporary dermal clearing, i.e., reduction in the attenuation coefficient of the dermis and epidermis, may lead to improved laser tattoo removal by providing increased efficiency of laser delivery to embedded ink particles and enabling the use of shorter wavelength visible lasers more effective on certain inks. STUDY DESIGNS/MATERIALS AND METHODS: In a hairless guinea pig model of human tattoo, we tested both intradermal and transdermal application of glycerol, using visual inspection, spectral analysis, and optical coherence tomography techniques to assess effectiveness. In controlled experiments, we compared the outcomes of single laser treatment sessions for both cleared and uncleared tattoo sites using Q-switched 755 and 532 nm lasers on three different inks. RESULTS: Intradermal injection of clearing agents induced dermal clearing but resulted in necrosis and scar. Transdermal application of clearing agents resulted in moderate reversible clearing, which was localized to the superficial layers of the skin and did not result in complications. Statistically significant differences in laser treatment outcome were observed relative to a number of treatment parameters including the treatment of certain tattoos by short wavelength lasers. CONCLUSIONS: Temporary clearing of superficial skin layers may be performed in an apparently safe and reliable manner. Clearing should lead to increased penetration of laser light to tattoos and should, therefore, increase treatment efficiency. Further study is needed to determine the degree to which this change is of clinical value.     

Tobacco use following liver transplantation for alcoholic liver disease: an underestimated problem.

Alcohol and tobacco use commonly co-occur, with at least 90% of those with an alcohol problem also using tobacco. Thus, 3 years ago when we discovered higher rate of late deaths due to lung and oropharyngeal cancer in patients who had received a transplant for alcoholic liver disease (ALD), we hypothesized that these patients were continuing to expose themselves to tobacco after liver transplantation (post-LTX) and that this behavior was increasing their risk for cancer. We subsequently began a prospective investigation of post-LTX tobacco use in patients having undergone LTX for ALD (n = 172). For 33 recipients we had data starting from our first assessment at 3 months post-LTX and for this subgroup we report on the details of the timing of tobacco use resumption and the redevelopment of nicotine addiction. We found that on average more than 40% are smoking across all time periods. ALD recipients resume smoking early post-LTX, increase their consumption over time, and quickly become tobacco dependent. These data highlight an underrecognized serious health risk for these patients and demonstrate our need for more stringent clinical monitoring and intervention for tobacco use in the pre- and post-LTX periods.     

Comparative Analysis of Outcomes in Living and Deceased Donor Liver Transplants for Primary Sclerosing Cholangitis

Introduction  Primary sclerosing cholangitits (PSC) is a progressive fibrosing cholangiopathy eventually leading to end-stage liver disease (ESLD). While literature for deceased donor liver transplantation (DDLT) for PSC abounds, only a few reports describe live donor liver transplant (LDLT) in the setting of PSC. We present a single-center experience on survival outcomes and disease recurrence for LDLT and DDLT for ESLD secondary to PSC. Aim  The aim of this study was to analyze survival outcomes and disease recurrence for LDLT and DDLT for ESLD secondary to PSC. Patients and Methods  A retrospective review of 58 primary liver transplants for PSC-associated ESLD, performed between May 1995 and January 2007, was done. Patients were divided into two groups based on donor status. Group 1 (n = 14) patients received grafts from living donors, while group 2 (n = 44) patients received grafts from deceased donors. An analysis of survival outcomes and disease recurrence was performed. Recurrence was confirmed based on radiological and histological criteria. Results  Recurrence of PSC was observed in four patients in LDLT group and seven in DDLT group. Retransplantation was required in one patient in LDLT group and nine patients in DDLT group. One patient (7%) among LDLT and six patients (14%) among DDLT died. The difference in patient and graft survival was not statistically significant between the two groups (patient survival, p = 0.60; graft survival, p = 0.24). Conclusion  This study demonstrates equivalent survival outcomes between LDLT and DDLT for PSC; however, the rate of recurrence may be higher in patients undergoing LDLT.     

A prospective comparison of laparoscopic and robotic radical nephrectomy for T1-2N0M0 renal cell carcinoma

Objectives  We prospectively evaluated the safety, feasibility, and efficiency of robotic radical nephrectomy (RRN) for localized renal tumors (T1-2N0M0) and compared this with laparoscopic radical nephrectomy (LRN). Materials and methods  Between October 2006 to August 2007, a prospective data analysis of 15 cases of renal cell carcinoma (RCC) stage T1-2N0M0, undergoing RRN was done. These patients were compared with a contemporary cohort of 15 patients of RCC with clinical stage T1-2N0M0, undergoing LRN. To keep comparison robust, all cases were performed by a single surgeon. Demographic, intra-operative, post-operative outcomes, pathological characteristics and follow-up data of the two groups were recorded and analyzed statistically. Results  Patients in group A (RRN) experienced significantly (P = 0.001) long operating time than group B (LRN). However, mean estimated blood loss, intra-operative and post-operative complications, blood transfusion rate, analgesic requirement, hospital stay and convalescence were comparable in two groups (P < 0.05). There was one conversion to open surgery in group A, and none in group B. The mean follow-up was comparable in two groups (8.3 and 9.1 months, respectively, in group A and B, P = 0.09). There were no local, port-site or distal recurrences in either group. Conclusions  Robotic radical nephrectomy is a safe, feasible and effective for performing radical nephrectomy for localized RCC. Both groups (RRN and LRN) had comparable intra-operative, peri-operative, post-operative and oncological outcomes except for longer operating time with increased cost for RRN. In this comparative study, there were no outstanding benefits of RRN observed over LRN for localized RCC.