AD brain pathology: vascular origins? Results from the HAAS autopsy study

An increasing number of studies suggest a vascular contribution to Alzheimer's disease (AD). One major question these findings raise is whether vascular disease enhances the formation of AD-like lesions, or whether vascular disease just adds to clinical severity. We examined this question in a fully characterized autopsy sample based on the Honolulu Asia Aging Study. We found that AD markers of neurodegeneration (amyloid plaques, cerebral amyloid angiopathy and neurofibrillary tangles) were no more prevalent in those with neuropathologically defined vascular lesions compared to those without lesions. Our study suggests the burden of vascular and AD type lesions are independent of each other, and are consistent with an additive effect of the two types of lesions on cognitive impairment.     

Evaluation of Common Anesthetic and Analgesic Techniques for Tail Biopsy in Mice

Tail biopsy in mice is a common procedure in genetically modified mouse colonies. We evaluated the anesthetic and analgesic effects of various agents commonly used to mitigate pain after tail biopsy. We used a hot-water immersion assay to evaluate the analgesic effects of isoflurane, ice-cold ethanol, ethyl chloride, buprenorphine, and 2-point local nerve blocks before studying their effects on mice receiving tail biopsies. Mice treated with ethyl chloride spray, isoflurane and buprenorphine, and 2-point local nerve blocks demonstrated increased tail-flick latency compared with that of untreated mice. When we evaluated the behavior of adult and preweanling mice after tail biopsy, untreated mice demonstrated behavioral changes immediately after tail biopsy that lasted 30 to 60 min before returning to normal. The use of isoflurane, isoflurane and buprenorphine, buprenorphine, 2-point nerve block, or ethyl chloride spray in adult mice did not significantly improve their behavioral response to tail biopsy. Similarly, the use of buprenorphine and ethyl chloride spray in preweanling mice did not improve their behavioral response to tail biopsy compared with that of the untreated group. However, immersion in bupivacaine for 30 s after tail biopsy decreased tail grooming behavior during the first 30 min after tail biopsy. The anesthetic and analgesic regimens tested provide little benefit in adult and preweanling mice. Given that tail biopsy results in pain that lasts 30 to 60 min, investigators should carefully consider the appropriate anesthetic or analgesic regimen to incorporate into tail-biopsy procedures for mice.Abbreviation: HWI, Hot water immersionGenetically modified mice continue to advance the study of human disease. To obtain DNA for verification of genotype, mice may undergo tissues sample collection from multiple sites, including blood, saliva, hair, and stool. However, tail biopsy of the distal 5 mm continues to be the preferred location of obtaining sufficient DNA for genotyping.^14,19 Tail biopsy involves transecting multiple tissue types, including skin, nervous tissue, muscle, tendons, vasculature, cartilage, and bone,¹⁴ and this technique has the potential to cause short-term pain and distress. Several studies have demonstrated that tail biopsy without anesthesia causes short-term pain or distress that is greatest within the first 1 to 2 h but that may last as long as 5 h.^1,4,20,26 Similar physiologic changes associated with pain and distress were apparent and prolonged in anesthetized control mice.¹Analgesic protocols at the time of biopsy vary among institutions. IACUC policies from several institutions^{3,10,18,28,29} recommend but do not require anesthesia or analgesia for tail biopsy of mice 10 to 21 d old but do require anesthesia or analgesia for older mice. The anesthetic regimens to mitigate the temporary pain associated with tail biopsy at these institutions include immersion in ice-cold ethanol, topical ethyl chloride spray, and isoflurane inhalant anesthesia. Because of their short duration of action, we hypothesized that these agents provide poor management of the postprocedural pain associated with tail biopsy, and we decided to explore other practical options. The use of traditional drugs such as lidocaine, bupivacaine, or buprenorphine may provide more appropriate analgesia for tail biopsy. Here we examined the anesthetic and analgesic effects on mouse behavior after tail biopsy in adult and preweanling outbred NSA mice that had been treated with various analgesics and anesthetics.     

Citalopram for agitation in Alzheimer's disease: design and methods

BackgroundAgitation is one of the most common neuropsychiatric symptoms of Alzheimer’s disease (AD), and is associated with serious adverse consequences for patients and caregivers. Evidence-supported treatment options for agitation are limited. The citalopram for agitation in Alzheimer’s disease (CitAD) study was designed to evaluate the potential of citalopram to ameliorate these symptoms.MethodsCitAD is a randomized, double-masked, placebo-controlled multicenter clinical trial, with two parallel treatment groups assigned in a 1:1 ratio and randomization stratified by clinical center. The study included eight recruiting clinical centers, a chair’s office, and a coordinating center located in university settings in the United States and Canada. A total of 200 individuals having probable AD with clinically significant agitation and without major depression were recruited for this study. Patients were randomized to receive citalopram (target dose of 30 mg/d) or matching placebo. Caregivers of patients in both treatment groups received a structured psychosocial therapy. Agitation was compared between treatment groups using the NeuroBehavioral Rating Scale and the AD Cooperative Study- Clinical Global Impression of Change, which are the primary outcomes. Functional performance, cognition, caregiver distress, and rates of adverse and serious adverse events were also measured.ConclusionThe authors believe the design elements in CitAD are important features to be included in trials assessing the safety and efficacy of psychotropic medications for clinically significant agitation in AD.     

Four-year follow-up of the community intervention '10,000 steps Ghent'

The purpose of this study was to examine the 4-year follow-up effects of the '10,000 steps Ghent' project, which had shown increases in pedometer steps after the first year of implementation (2005-06). All adults who had participated in 2005-06 (n = 866) were recontacted in 2009 and invited to complete the International Physical Activity Questionnaire and a 7-day pedometer log. Long-term effects were analysed using repeated measures analysis of variance tests (time × community, n = 420). In subgroup analyses, age, gender, educational level, employment status, health and risk profile were also included. Results showed that daily step counts increased slightly from 2005 to 2009 in the intervention community (Ghent) and decreased in the comparison community (Aalst) (time × community: P = 0.008). Subgroup analyses showed a positive interaction effect for higher educated (P = 0.026) and healthy (P = 0.005) participants and a negative interaction for those with a poor to moderate health (P = 0.026). For self-reported physical activity, a positive interaction effect was found in those who had already reached 10,000 steps in 2005 (P = 0.037). To conclude, the positive effects seen after 1 year were not maintained after 4 years. However, a decrease from baseline to follow-up, which was seen in the comparison community, was prevented in all Ghent participants, except those with a poor to moderate health.     

Relationships between neighborhood walkability and adults' physical activity: How important is residential self-selection?

The study's aims were to examine whether residential self-selection differed according to socio-demographic characteristics and objectively assessed neighborhood walkability; and, whether objectively assessed walkability was a significant correlate of physical activity (PA) beyond residential self-selection. In total, 412 adults (aged 20-65 years) completed a socio-demographic questionnaire, the long IPAQ, a neighborhood selection questionnaire and wore an accelerometer for seven days. Walkability characteristics were an important reason for selecting the current neighborhood and were more important for women, older and less-educated adults, but not for high-walkable neighborhood residents. Both in the total sample and in participants with high residential self-selection scores, walkability was positively related to active transportation and objectively measured moderate-to-vigorous PA. Designing walkable neighborhoods may help to increase adults' PA, even in those for whom walkability is an important criterion when choosing their neighborhood. However, findings from studies with longitudinal and controlled designs are required to provide more strongly causal evidence.     

Ramucirumab as Second-Line Therapy in Metastatic Gastric Cancer: Real-World Data from the RAMoss Study

Background

Ramucirumab—alone or combined with paclitaxel—represents one of the main options for patients failing first-line treatment for advanced gastric cancer.

Objective

The RAMoss study aimed to evaluate the safety and efficacy profile of ramucirumab in the “real-life setting”.

Patients and Methods

Patients from 25 Italian hospitals started therapy consisting of ramucirumab 8 mg/kg i.v. d1,15q28 with or without paclitaxel 80 mg/m² i.v. d1,8,15q28. The primary endpoint was safety, and secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).

Results

One hundred sixty-seven patients with disease progression on first-line therapy received ramucirumab as monotherapy (10%) or combined with paclitaxel (90%). Median treatment duration was 4 months (1–17 months). Global incidence of grade (G) 3–4 toxicity was 9.6%, and for neutropenia 5.4%; treatment was discontinued due to toxicity in 3% of patients. The most frequent adverse events (AE) were G1–2 fatigue (27.5%), G1–2 neuropathy (26.3%), and G1–2 neutropenia (14.9%). ORR was 20.2%. Stable disease was observed in 39.2% of patients, with a disease control rate of 59.4%. With a median follow-up of 11 months, median PFS was 4.3 months (95% confidence interval [CI] 4.1–4.7), whereas median OS was 8.0 months (95% CI: 7.09–8.9). In a multivariate analysis, ECOG performance status <1 or ≥1 (HR 1.13, 95% CI 1.0–1.27, p?=?0.04) and the presence versus absence of peritoneal metastases (HR 1.57, 95% CI 1.63–2.39, p?=?0.03) were independent poor prognostic factors.

Conclusions

These “real-life” efficacy data on ramucirumab treatment are in line with previous randomized trials. Ramucirumab is well tolerated in daily clinical practice.

     

Familial aggregation of endometriosis in a large pedigree of rhesus macaques

BACKGROUND: Endometriosis occurs in several non-human primate species that have menstrual cycles. This study investigated the prevalence and familial aggregation of endometriosis in one of those species, the rhesus macaque. METHODS: Between 1978 and 2001, 142 animals with endometriosis were identified from necropsy and surgical records and through the use of magnetic resonance imaging (MRI) at the Wisconsin National Primate Research Center, Madison, USA. All cases were used to build one large multigenerational pedigree and nine nuclear families comprising 1602 females in total. By 2002, the pedigrees contained 124 cases diagnosed at necropsy; 17 at surgery and three at MRI. Female animals that had died aged > or = 10 years without endometriosis, had both ovaries until at least 1 year prior to death, and had a full necropsy, were considered unaffected. RESULTS: The prevalence of endometriosis among necropsied animals aged > or = 10 years in the colony was 31.4% [95% confidence interval (CI) 26.9-35.9%]; prevalence increased with rising age and calendar age at death. Familial aggregation of endometriosis was strongly suggested by a significantly higher average kinship coefficient among affecteds compared with unaffecteds (P < 0.001) and a higher recurrence risk for full sibs (0.75; 95% CI 0.45-1.0) compared with maternal half sibs (0.26; 95% CI 0.10-0.41) and paternal half sibs (0.18; 95% CI 0.02-0.34). The segregation ratio among affected mothers (44.2%) was not significantly higher compared with unaffected mothers (36.6%). CONCLUSIONS: The results support familial aggregation of endometriosis in the rhesus macaque, and indicate that this is a promising animal model for the investigation of mode of inheritance, the location of potential genetic susceptibility loci and the influence of environmental factors.     

French multicenter experience with the GORE TIGRIS Vascular Stent in superficial femoral and popliteal arteries

Background

Preliminary results in small single-center studies after stenting with the GORE TIGRIS Vascular Stent (W. L. Gore & Associates, Flagstaff, Ariz) show promising short-term primary patency rates, but larger, multicenter studies are needed. This study therefore investigated the performance of the GORE TIGRIS Vascular Stent at three different centers in France in patients with symptomatic peripheral artery disease.