Impaired ILK Function Is Associated with Deficits in Hippocampal Based Memory and Synaptic Plasticity in a FASD Rat Model.

Fetal Alcohol Spectrum Disorder (FASD) is an umbrella term that encompasses a wide range of anatomical and behavioral problems in children who are exposed to alcohol during the prenatal period. There is no effective treatment for FASD, because of lack of complete characterization of the cellular and molecular mechanisms underlying this condition. Alcohol has been previously characterized to affect integrins and growth factor signaling receptors. Integrin Linked Kinase (ILK) is an effector of integrin and growth-factor signaling which regulates various signaling processes. In FASD, a downstream effector of ILK, Glycogen Synthase Kinase 3ß (GSK3ß) remains highly active (reduced Ser9 phosphorylation). GSK3ß has been known to modulate glutamate receptor trafficking and channel properties. Therefore, we hypothesize that the cognitive deficits accompanying FASD are associated with impairments in the ILK signaling pathway. Pregnant Sprague Dawley rats consumed a "moderate" amount of alcohol throughout gestation, or a calorie-equivalent sucrose solution. Contextual fear conditioning was used to evaluate memory performance in 32-33-day-old pups. Synaptic plasticity was assessed in the Schaffer Collateral pathway, and hippocampal protein lysates were used to evaluate ILK signaling. Alcohol exposed pups showed impaired contextual fear conditioning, as compared to control pups. This reduced memory performance was consistent with decrease in LTP as compared to controls. Hippocampal ILK activity and GSK3ß Ser21/9 phosphorylation were significantly lower in alcohol-exposed pups than controls. Increased synaptic expression of GluR2 AMPA receptors was observed with immunoprecipitation of post-synaptic density protein 95 (PSD95). Furthermore, immunoprecipitation of ILK revealed a decreased interaction with GluR2. The ILK pathway appears to play a significant role in memory and synaptic plasticity impairments in FASD rats. These impairments appear to be mediated by reduced GSK3ß regulation and increased synaptic stabilization of the calcium-impermeable GluR2 AMPA receptors.

Screening for hepatocellular carcinoma in Alaska natives infected with chronic hepatitis B: a 16-year population-based study.

The benefits of screening hepatitis B surface antigen (HBsAg)-positive carriers for hepatocellular carcinoma (HCC) in terms of long-term survival have not been established. We conducted a prospective 16-year, population-based cohort study to determine the impact of screening for HCC in 1,487 HBsAg-positive Alaska native carriers with alpha-fetoprotein (AFP) determinations every 6 months. Men and nonpregnant women with an elevated AFP level were evaluated for the presence of HCC by ultrasound (US) examination. The long-term survival rate for patients whose HCC was detected by the screening program was compared with a historical control group of Alaska native patients with HCC from the same population who were clinically diagnosed with HCC between 1969 and October 1982, through a National Cancer Institute-sponsored Cancer Registry. Between October 1982 and December 1998, 26,752 AFP determinations in HBsAg carriers were performed. One or more AFP elevations were found in 61 men and 39 nonpregnant women. HCC was diagnosed in 32 patients (24 men and 8 women). HCC tumors less than 6 cm were found in 23 patients; 22 patients had resections, and 1 patient refused a resection. Compared with 12 patients with hepatitis B virus (HBV)-related HCC diagnosed from 1969 to October 1982, before this program, the 5- and 10-year survival rate for the 32 patients with HCC were 42% (P =.008) and 30% (P =.07), respectively. Five- and 10-year tumor-free survival rates for carriers who had a normal AFP level on initial screening and subsequently developed HCC were 29% (P =.004) and 24% (P =.024), respectively. Screening of HBsAg carriers with semiannual AFP was effective in detecting most HCC tumors at a resectable stage and significantly prolonged survival rates when compared with historical controls in this population.