Citations

The biological changes that occur in the brains of Alzheimer's disease (AD) patients are thought to begin long before the onset of clinical symptoms. Although current therapeutic agents have been approved only for patients with mild to moderate AD, Alzheimer‐type pathology in patients with mild to moderate AD is already quite advanced. One impetus for the development of the concept of mild cognitive impairment (MCI) was the attempt to recognize AD early in its clinical expression and to determine whether it is possible through therapeutic interventions to improve the memory impairment at this stage or delay further progression to dementia. To this end, several clinical trials have been conducted in patients with MCI. On September 8 and 9, 2004 a meeting of the Alzheimer's Association Research Roundtable was held at which experts in the field of MCI convened to review the collective experience from these trials and to consider potential approaches that might improve MCI clinical trials in the future. This article summarizes the presentations and discussions of that meeting.

Abstract Non-alcoholic fatty liver disease (NAFLD) is common and may progress to cirrhosis and its complications. The pathogenesis of steatosis and cellular injury is thought to be related mostly to insulin resistance and oxidative stress. Therefore, management entails identification and treatment of metabolic risk factors, improving insulin sensitivity, and increasing antioxidant defences in the liver. Weight loss and exercise improve insulin sensitivity. Bariatric surgery may improve liver histology in patients with morbid obesity. Insulin sensitising drugs showed promise in pilot trials as have a number of hepatoprotective agents. Further randomised, well controlled trials are required to determine the efficacy of these drugs.

Abstract Background: Aging, body composition, and sex steroids jointly determine GH production. However, the actions of any given factor are confounded by the effects of the other two. Hypothesis: Age and abdominal visceral fat (AVF) mass govern GH secretion via individually distinctive mechanisms, which can be unmasked by short-term sex steroid deprivation. Design/Subjects: In a university setting, healthy pre- and postmenopausal volunteers underwent GnRH agonist-induced down-regulation for 6 wk to deplete ovarian sex steroids. GH secretion was evaluated by frequent blood sampling, saline vs. dual secretagogue infusions, an irregularity statistic, variable waveform deconvolution analysis, and a simplified feedback model. Computerized tomography was used to estimate AVF mass. Outcomes/Measures: In the sex steroid-deficient milieu, postmenopausal compared with premenopausal women exhibited 1) lower concentrations of IGF-I (P = 0.028) and GH (P < 0.05); 2) reduced pulsatile, but elevated basal, GH secretion (P < 0.05); 3) more irregular GH patterns (P = 0.027); 4) an attenuated GH response to simultaneous GHRH/GH-releasing peptide-2 stimulation (P < 0.01); and 5) more rapid onset of GH release within secretory bursts (P < 0.01). In contrast, AVF negatively forecast GH responses to l-arginine/GH-releasing peptide-2 (r2 = 0.45; P < 0.001) and l-arginine/GHRH (r2 = 0.57; P = 0.007). From these marked contrasts, model-based analyses predicted distinguishable mechanisms by which aging and AVF alter pulsatile GH production. Conclusion: Under limited confounding by sex steroids, age and body composition modulate GH secretion via highly selective peptidyl pathways in healthy women.

Abstract With the increasing life expectancy in developed countries, the incidence of Alzheimer's disease (AD) and thus its socioeconomic impact are growing. Increasing knowledge over the last years about the pathomechanisms involved in AD allow for the development of specific treatment strategies aimed at slowing down or even preventing neuronal death in AD. However, this requires also that (1) AD can be diagnosed with high accuracy, because non‐AD dementias would not benefit from an AD‐specific treatment; (2) AD can be diagnosed in very early stages when any intervention would be most effective; and (3) treatment efficacy can be reliably and meaningfully monitored. Although there currently is no ideal biomarker that would fulfill all these requirements, there is increasing evidence that a combination of currently existing neuroimaging and cerebrospinal fluid (CSF) and blood biomarkers can provide important complementary information and thus contribute to a more accurate and earlier diagnosis of AD. The Alzheimer's Disease Neuroimaging Initiative (ADNI) is exploring which combinations of these biomarkers are the most powerful for diagnosis of AD and monitoring of treatment effects.

Abstract The present study examines the thesis that pulsatile GH secretion is controlled simultaneously by three principal signals; viz., GHRH, GH-releasing peptide (GHRP, ghrelin), and somatostatin (SS). According to this ensemble notion, no single regulatory peptide acts alone or can be interpreted in isolation. Therefore, to investigate gender-specific control of pulsatile GH secretion, we designed dual-effector stimulation paradigms in eight young men and six women as follows: 1) l-arginine/GHRH (to clamp low SS and high GHRH input); 2) l-arginine/GHRP-2 (to clamp low SS and high GHRP drive); 3) GHRH/GHRP-2 (to clamp high GHRH and high GHRP feedforward); vs. 4) saline (unclamped). Statistical comparisons revealed that: 1) fasting pulsatile GH secretion was 7.6-fold higher in women than men (P < 0.001); 2) l-arginine/GHRH and l-arginine/GHRP-2 evoked, respectively, 4.6- and 2.2-fold greater burst-like GH release in women than men (P < 0.001 and P = 0.015); and 3) GHRH/GHRP-2 elicited comparable GH secretion by gender. In the combined cohorts, estradiol concentrations positively predicted responses to l-arginine/GHRP-2 (r2 = 0.49, P = 0.005), whereas testosterone negatively predicted those to l-arginine/GHRH (r2 = 0.56, P = 0.002). Based upon a simplified biomathematical model of three-peptide control, the current outcomes suggest that women maintain greater GHRH potency, GHRP efficacy, and opposing SS outflow than men. This inference upholds recent clinical precedence and yields valid predictions of sex differences in self-renewable GH pulsatility.

Purpose To describe the demographic and tumor related characteristics and outcomes for patients with primary T-cell CNS lymphoma (TPCNSL). Patients and Methods A retrospective series of patients with TPCNSL was compiled from twelve cancer centers in seven countries. Results We identified 45 patients with a median age of 60 years (range, 3 to 84 years). Twenty (44%) had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Twenty-six (58%) had involvement of a cerebral hemisphere and sixteen (36%) had lesions of deeper sites in the brain. Serum lactate dehydrogenase was elevated in 7 (32%) of 22 patients, and CSF protein was elevated in 19 of 24 patients (79%) with available data. The median disease-specific survival (DSS) was 25 months (95% CI, 11 to 38 months). The 2- and 5-year DSS were 51% (95% CI, 35% to 66%) and 17% (95% CI, 6% to 34%), respectively. Univariate and multivariate analyses were conducted for age (≤ 60 v > 60 years), PS (0 or 1 v 2, 3, or 4), involvement of deep structures of the CNS (no v yes), and methotrexate (MTX) use in the primary treatment (yes v no). Only PS and MTX use were significantly associated with better outcome with hazard ratios of 0.2 (95% CI, 0.1 to 0.4) and 0.4 (95% CI, 0.2 to 0.8), respectively. Conclusion This is the largest series ever assembled of TPCNSL. The presentation and outcome appear similar to that of B cell PCNSL. PS 0 or 1 and administration of MTX are associated with better survival.