The hippocampus uses information just encountered to guide efficient ongoing behavior

Adaptive ongoing behavior requires using immediate sensory input to guide upcoming actions. Using a novel paradigm with volitional exploration of visuo‐spatial scenes, we revealed novel deficits among hippocampal amnesic patients in effective spatial exploration of scenes, indicated by less‐systematic exploration patterns than those of healthy comparison subjects. The disorganized exploration by amnesic patients occurred despite successful retention of individual object locations across the entire exploration period, indicating that exploration impairments were not secondary to rapid decay of scene information. These exploration deficits suggest that amnesic patients are impaired in integrating memory for recent actions, which may include information such as locations just visited and scene content, to plan immediately forthcoming actions. Using a novel task that measured the on‐line links between sensory input and behavior, we observed the critical role of the hippocampus in modulating ongoing behavior. © 2013 Wiley Periodicals, Inc.     

Interleukin–1 receptor antagonist gene polymorphism as a disease severity factor in systemic lupus erythematosus

Objective. We have previously described associations between an allele of the interleukin–1 receptor antagonist gene (IL1RN) and several inflammatory diseases. In this study we tested the IL1RN gene as a possible marker in patients with systemic lupus erythematosus (SLE). Methods. Eighty–one SLE patients and 261 ethnically matched control subjects were genotyped by polymerase chain reaction. Results. We found an increase in both frequency and carriage rate of IL1RN*2 in the SLE group. This association strengthened with extensive disease and particularly with the presence of photosensitivity and discoid skin lesions. Conclusion. We describe a novel association between IL1RN*2 and SLE. Carriage of the allele seems to influence severity rather than susceptibility to SLE. We postulate that the association of this polymorphism with disease severity is a widespread feature of common inflammatory and autoimmune diseases.     

Lymphatic vessel density, microvessel density and lymphangiogenic growth factor expression in colorectal cancer

OBJECTIVE: Microvessel density (MVD) has been studied as a prognostic marker in human cancers. Quantification of lymphatic vessel density (LVD) is now possible by using new antibodies. Expression of the lymphangiogenic growth factors, VEGF-C and VEGF-D, is associated with poorer clinicopathological outcomes in various tumours. The aim of this study was to quantify LVD and MVD in colorectal cancer, determine the relationship between LVD, MVD and clinicopathological variables and examine the relationship between LVD and tumour expression of VEGF-C and VEGF-D. METHOD: Thirty primary colorectal cancers were immunostained for CD34, lymph vessel endothelial hyaluronan receptor-1 (LYVE-1), VEGF-A and VEGF-D using standard techniques. LVD and MVD were determined by Chalkley grid counting. Tumours were assessed for the presence or absence of LYVE-1 positive lymphatics at different areas within the tumour and the tumour was scored for VEGF-C and VEGF-D immunostaining intensity at the invading tumour edge. Non-parametric tests were used for statistical analysis and a P-value of <0.05 was taken as significant. RESULTS: Lymph vessel endothelial hyaluronan receptor-1 was an excellent lymphatic vessel marker. Within normal bowel wall, lymphatic vessels were found rarely in the superficial colonic mucosa, but were numerous in the submucosa and muscularis propria. In the majority of tumours, lymphatic vessels were located in the peri-tumoural area, intra-tumoural vessels were sparse and tended to be narrow with closed lumina. At the invading tumour edge, VEGF-C expression was higher (P = 0.028) and VEGF-D expression lower (P = 0.011), in tumours in which lymphatic vessels were present. No significant differences between LVD and any clinicopathological variable or route of metastasis were identified. CONCLUSION: Lymphatic vessel density and MVD can be quantified in colorectal carcinoma using immunohistochemical techniques. The balance between expression of VEGF-C and VEGF-D at the invading tumour edge may enhance lymphatic metastasis, by promoting tumour lymphangiogenesis or by activation of pre-existing lymphatic vessels. No relationship was identified between LVD and clinicopathological variables.     

Evidence for peripheral clearance of cerebral Abeta protein following chronic,active Abeta immunization in PSAPP mice

Immunization with amyloid-beta (Abeta) peptide in mouse models of Alzheimer's disease has been reported to decrease cerebral Abeta levels and improve behavioral deficits. Several mechanisms have been proposed, including antibody-induced phagocytosis of Abeta by cerebral microglia and increased efflux of Abeta from the brain to the periphery. The latter mechanism was suggested in mice undergoing acute, passive transfer of an Abeta monoclonal antibody. Here, PSAPP transgenic mice were actively immunized by a single intraperitoneal injection of synthetic Abeta followed by chronic intranasal administration of Abeta with the mucosal adjuvant, Escherichia coli heat-labile enterotoxin, LT, twice weekly for 8 weeks. Serum from Abeta-immunized mice had an average of 240 microg/ml of anti-Abeta-specific antibodies; these antibodies had epitope(s) within Abeta1-15 and were of immunoglobulin (Ig) isotypes IgG2b, IgG2a, and IgG1. Immunization led to a 75% decrease in plaque number (P < 0.0001) and a 58% decrease in Abetax-42 levels (P < 0.026) in brain, and gliosis and neuritic dystrophy were diminished. No pathological effects of the immunization were observed in kidney, spleen, or snout. Serum Abeta levels increased 28-fold in immunized mice (53.06 ng/ml) compared to controls (1.87 ng/ml). Most of the Abeta in the serum of the immunized mice was bound to antibodies. We conclude that following active immunization, anti-Abeta antibodies sequester serum Abeta and may increase central nervous system to serum Abeta clearance.     

Antiarrhythmic efficacy of propranolol: comparison of low and high serum concentrations

Propranolol has been effective in suppressing ventricular arrhythmias in up to 70% of patients in some series; however, a wide range of concentrations was required to produce this degree of efficacy. In one series, 40% of responders required high serum concentrations (greater than 500 ng/ml) in excess of those required for physiologic beta-receptor blockade (25 to 150 ng/ml). To assess the relative contribution of high concentration electrophysiologic effects to antiarrhythmic efficacy the results of programmed electrical stimulation were compared at high and low (beta-blocking) concentrations in 28 patients with inducible sustained ventricular tachycardia. Propranolol was given as a series of loading and maintenance infusions producing first a mean concentration of 130 +/- 72 ng/ml (beta-blocking) and then a mean concentration of 743 +/- 523 ng/ml (high). Beta-blockade was assessed by the percent reduction in exercise-induced tachycardia. Near maximal beta-blockade was achieved by a concentration of 150 ng/ml. At a low concentration, 6 of 28 patients had a response to propranolol (complete in 5 and partial in 1). At a high concentration, one additional patient had a complete response while three had a partial antiarrhythmic response. At high concentrations of propranolol there was a significant shortening of the QTc interval relative to that seen during the low dose infusion. No other significant electrophysiologic changes occurred at high versus low concentration. In summary, an antiarrhythmic response to propranolol occurs most frequently at a beta-blocking concentration. High concentration electrophysiologic effects occur and these appear to contribute to antiarrhythmic efficacy in some patients.     

Influence of Genetics on Disease Susceptibility and Progression

For many chronic diseases, the influence of genetics is complex and phenotypes do not conform to simple Mendelian patterns of inheritance. Discussed here are two types of genetic influences on healthy aging. The first involves variation in the gene sequence itself and how this may influence disease susceptibility, progression, and severity, interacting with other recognized risk factors. The second involves epigenetic regulatory mechanisms that may potentially provide insight into how environmental influences affect the expressed genome, thus improving our understanding of the genetic mechanisms underlying multifactorial diseases. The interleukin-1 family of cytokines can be used to illustrate how genetic sequence variation may affect such diseases. This cytokine family plays a key role in mediating inflammation, which is now understood to be a central component of a growing number of chronic diseases. Recent work has revealed many sequence variations in the regulatory DNA of genes encoding important members of the interleukin-1 family, and these variations are associated with differential effects on the inflammatory response. The interactions of environmental factors with both DNA sequence variations and epigenetic modifications are likely to determine the phenotypes of multifactorial diseases of aging as well as the phenotype of healthy aging.