Structured cognition and neural systems: from rats to language

Much of animal and human cognition is compositional in nature: higher order, complex representations are formed by (rule-governed) combination of more primitive representations. We review here some of the evidence for compositionality in perception and memory, motivating an approach that takes ideas and techniques from computational linguistics to model aspects of structural representation in cognition. We summarize some recent developments in our work that, on the one hand, use algorithms from computational linguistics to model memory consolidation and the formation of semantic memory, and on the other hand use insights from the neurobiology of memory to develop a neurally inspired model of syntactic parsing that improves over existing (not cognitively motivated) models in computational linguistics. These two theoretical studies highlight interesting analogies between language acquisition, semantic memory and memory consolidation, and suggest possible neural mechanisms, implemented in computational algorithms that may underlie memory consolidation.     

Trends in admissions to internal medicine wards in a community hospital in Israel

BACKGROUND: Epidemiological studies are useful both for investigating possible etiologic factors and for determining the extent of health provisions required. In an attempt to improve the quality of care, we have analyzed the trends of admissions to the four internal medicine wards in a community hospital in Israel. METHODS: Data was collected on admission to all of the internal medicine wards of Hasharon Hospital, Rabin Medical Center, Petach-Tikva, Israel, from 1999 to 2004, including discharge diagnosis, duration of stay, and mortality. The data source was the "Bina" data warehouse system of Clalit Health Services. RESULTS: The yearly admission rate was 10,482+/-386. Ninety-six percent of the admissions were of Jews and 3% were of Arabs. Most of the patients were older than 75 years (43.1%); 23.6% were between 65 and 74 years of age. The readmission rate was 7.4% within 1 week and 16.3% within 1 month. The three most common discharge diagnoses, not including pre-existing illnesses, were: coronary artery disease-related (21.9%), heart failure (5.4%), and pneumonia (5.6%). The average duration of stay was 4.6+/-0.1 days. Patients admitted for newly diagnosed malignancy, pneumonia, or CVA had a longer duration of stay (7.1, 6.8, and 6.5 days, respectively). There was a steady decline in mortality from 4.5% in 1999 to 4.2% in 2004. CONCLUSION: In the 5-year period studied, there was a changing trend in mortality rate, hospital duration rate, and patient age.     

Development of a screening tool for identifying elderly people at risk of abuse by their caregivers

OBJECTIVE: This study developed and assessed an instrument to identify older people at high risk of abuse based on Reis and Nahmiash's Indicators of Abuse (IOA) screen. METHOD: A total of 108 people 65 and older, hospitalized in internal medicine departments at two major hospitals in Israel, were screened together with their principal caregivers. The interview was based on the expanded IOA (E-IOA) and a list of evident signs of abuse. RESULTS: Reliability and validity of the E-IOA were tested and confirmed. Indicators proved to be a significant predictor of evident signs of abuse. The E-IOA correctly discerned 92.7% of those at high risk for abuse and 97.9% of those who did not suffer abuse. The main indicators for risk were behavioral problems, emotional problems, and family problems of the caregiver and the elderly person. Fourteen (13%) experienced abuse. DISCUSSION: The proposed assessment tool can be an instrumental guide to identify elderly people who suffer abuse (unidentified) or who are at high risk.     

Gracilis Muscle Transposition for Fistulas Between the Rectum and Urethra or Vagina

Purpose This study was designed to assess the efficacy of gracilis muscle transposition in repairing rectovaginal and rectourethral fistulas. Methods Data were retrieved from a retrospective chart review of patients who underwent gracilis muscle transposition for fistulas between the rectum and urethra/vagina. All patients had fecal diversion as a preliminary or concurrent step to fistula repair. Follow-up data were gathered from outpatient clinic visits. Success was defined as a healed fistula after stoma closure. Results Six females and three males, aged 30 to 64 years, underwent gracilis muscle transpositions from 1999 to 2005. One pouch-vaginal, three rectourethral, and five rectovaginal fistulas were repaired. The etiologies were Crohn's disease (n = 2), iatrogenic injury to the rectum during radical prostatectomy (n = 2), previous pelvic irradiation for rectal cancer (n = 2) or for cervical cancer (n = 1), recurrent perianal abscesses with fistulas (n = 1), and obstetric tear (n = 1). Seven patients underwent previous medical and surgical repair attempts. There were no intraoperative complications. Postoperative complications included perineal wound infection (n = 1) and at the colostomy closure (n = 2). There were no long-term sequelae. At a median follow-up period of 14 (range, 1–66) months since stoma closure, the fistula healed in seven patients. One patient refused ileostomy closure. One patient with severe Crohn's proctitis has a persistent rectovaginal fistula. Conclusions Gracilis muscle transposition is a viable option for repairing fistulas between the urethra, vagina, and the rectum, especially after failed perineal or transanal repairs. It is associated with low morbidity and a good success rate. Underlying Crohn's disease and previous radiation are associated with poor prognosis. Presented at The Joint Meeting of the Israel Society of Colon and Rectal Surgery and the Israeli Society of Endoscopic Surgery, Eilat, Israel, December 16 to 18, 2004. Reprints are not available.     

Intima media thickness in childhood obesity: relations to inflammatory marker, glucose metabolism, and blood pressure

Obesity in childhood is discussed to be associated with hypertension, dyslipidemia, impaired glucose metabolism, and chronic inflammation. It has not yet been studied in obese children which of these cardiovascular risk factors are related to intima media thickness (IMT), a noninvasive marker for early atherosclerotic changes. We collected the clinical data (age, sex, pubertal stage, percentage of body fat, SD score of body mass index [SDS-BMI]) and measured systolic blood pressure [SBP] and diastolic blood pressure [DBP], triglycerides [TGs], high- and low-density lipoprotein cholesterol, glucose, insulin, and high-sensitivity C-reactive protein [hsCRP]) in 96 obese children (median age, 11 years). The control group was composed of 25 nonobese children of the same age, sex, and pubertal stage. We determined the carotid IMT of all the patients by B-mode ultrasound with a 14-MHz linear transducer. Obese children demonstrated a significantly (P < .001) thicker intima media (median, 0.6 mm) as compared with the control group (median IMT, 0.4 mm). IMT was significantly correlated to the SDS-BMI (r = 0.38, P < .001), percentage of body fat (r = 0.39, P < .001), SBP (r = 0.39, P < .001) and DBP (r = 0.29, P = .002), glucose (r = 0.30, P = .001), and hsCRP levels (r = 0.29, P = .002). In stepwise backward multiple linear regression analysis, IMT correlated significantly to BMI (r2 = 0.05, P = .044), SBP (r2 = 0.15, P = .013), glucose (r2 = 0.05, P = .028), and hsCRP (r2 = 0.07, P = .005). Because IMT is increased in obese children, vascular changes in obesity seem to occur already in childhood. These changes are related to the cardiovascular risk factors of obesity, especially hypertension, chronic inflammation, and impaired glucose metabolism.     

Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer

The protein kinase BRAF is a key component of the RAS-RAF signaling pathway which plays an important role in regulating cell proliferation, differentiation, and survival. Mutations in BRAF at codon 600 promote catalytic activity and are associated with 8% of all human (solid) tumors, including 8% to 10% of colorectal cancers (CRC). Here, we report the preclinical characterization of vemurafenib (RG7204; PLX4032; RO5185426), a first-in-class, specific small molecule inhibitor of BRAF(V600E) in BRAF-mutated CRC cell lines and tumor xenograft models. As a single agent, vemurafenib shows dose-dependent inhibition of ERK and MEK phosphorylation, thereby arresting cell proliferation in BRAF(V600)-expressing cell lines and inhibiting tumor growth in BRAF(V600E) bearing xenograft models. Because vemurafenib has shown limited single-agent clinical activity in BRAF(V600E)-mutant metastatic CRC, we therefore explored a range of combination therapies, with both standard agents and targeted inhibitors in preclinical xenograft models. In a BRAF-mutant CRC xenograft model with de novo resistance to vemurafenib (RKO), tumor growth inhibition by vemurafenib was enhanced by combining with an AKT inhibitor (MK-2206). The addition of vemurafenib to capecitabine and/or bevacizumab, cetuximab and/or irinotecan, or erlotinib resulted in increased antitumor activity and improved survival in xenograft models. Together, our findings suggest that the administration of vemurafenib in combination with standard-of-care or novel targeted therapies may lead to enhanced and sustained clinical antitumor efficacy in CRCs harboring the BRAF(V600E) mutation.