A distinctive interaction between memory and chronic daytime somnolence in asymptomatic APOE e4 homozygotes

STUDY OBJECTIVES: To correlate memory measures with a trait measure of chronic daytime somnolence in cognitively normal individuals with different gene doses of the apolipoprotein E (APOE) e4 allele, a common Alzheimer's disease susceptibility gene. DESIGN: Cross-sectional, exploratory study of cognitive abilities in APOE e4 homozygotes (HMZ) (n=42), heterozygotes (HTZ), (n=42) and noncarriers (NC) (n=42) who are matched for age, gender, educational level, and family history of dementia. SETTING: Tertiary care academic medical center. PARTICIPANTS: Cognitively normal residents of Maricopa County, Arizona who are 30-70 years of age, genotyped for APOE, and have no history of a sleep disorder INTERVENTIONS: N/A. MEASUREMENTS: Epworth Sleepiness Scale (ESS) and a battery of neuropsychological tests RESULTS: Age, education, gender, and insomnia complaints did not significantly differ among groups. Despite normal baseline memory scores, memory declined with increasing ESS on all eight memory measures in the HMZ, two of eight in the HTZ, and one of eight in the NC. Differences between HMZ and NC on the slope of memory decline with increasing ESS reached statistical significance on two verbal memory measures, AVLT Long-Term Memory (p=0.048) and Percent Delayed Recall (p=0.035). CONCLUSIONS: Chronic daytime somnolence is associated with a distinctive decline in verbal memory in cognitively normal APOE e4 HMZ, a group at particularly high risk of Alzheimer's disease. Additional studies are needed to confirm these exploratory findings and to determine the effects of acute somnolence on cognition in these genetic subgroups.     

Dissociation of hepatitis A virus antigen-anti-HAV antibody complexes by 2-mercaptoethanol and dithiothreitol

Intravenous inoculation of two marmosets and one chimpanzee with hepatitis A virus (HAV) resulted in the replication of virus in liver, excretion of HAV particles in stool, and the appearance of circulating antibodies specific for hepatitis A. The development of an early antibody response in the chimpanzee and in one of the two infected marmosets was shown to interfere with the serologic detection of HAV antigen (HAV Ag) in homogenates of acute phase liver tissue obtained from these animals. Treatment of HAV Ag-positive and IgM anti-HAV-positive liver homogenates with thiol reducing compounds was shown to release HAV Ag from in vitro formed immune complexes. The increased RIA response for HAV Ag in homogenates treated with 2-mercaptoethanol (2-ME) or dithiothreitol (DTT) was further shown not to be due to activation of HAV Ag itself or to a nonspecific effect on the RIA coating antibody, radiolabeled probe, or homogenized liver tissue. IgG and IgM double-antibody sandwich RIAs for HAV Ag were also compared for their ability to detect HAV Ag under reducing and nonreducing conditions. Application of the 2-ME or DTT treatment procedure to the serologic detection of other viral antigens or viruses whose presence in blood, stool, tissue macerate, or other milieu may be masked by specific antibody appears to be feasible.     

The use of computer-assisted video image analysis in the enumeration of immuno-stained cells in tissue sections.

A novel method of computer-assisted video image analysis (VIA) was used to determine the number of immunostained cells in tissue sections. This method permitted an accurate and objective quantification of cells of a particular phenotype. This enumeration was achieved by measuring the area stained by a test monoclonal antibody (such as the T cell marker, CD3) and comparing it with the area stained by a leukocyte common (LCA) monoclonal antibody (CD45). The proportion of T cells within the total leukocyte population in a particular tissue was then calculated. The differentiation of positive (stained) and negative (unstained) cells was uniformly maintained by setting the computer to detect a threshold for staining intensity. This enabled consistency to be maintained within a tissue section as well as between sections stained with the same antibody. In the present study, we determined the phenotype of leukocytes in colonic carcinomas by VIA and compared this with results obtained by normal visual analysis. The VIA method showed distinct advantages over normal visual analysis especially in sections which contained moderate numbers of stained cells.     

Decorin inhibition of PDGF-stimulated vascular smooth muscle cell function: potential mechanism for inhibition of intimal hyperplasia after balloon angioplasty

Decorin is a small proteoglycan that binds to transforming growth factor-beta (TGF-beta) and inhibits its activity. However, its interaction with platelet-derived growth factor (PDGF), involved in arterial repair after injury, is not well characterized. The objectives of this study were to assess decorin-PDGF and decorin-PDGF receptor (PDGFR) interactions, the in vitro effects of decorin on PDGF-stimulated smooth muscle cell (SMC) functions and the in vivo effects of decorin overexpression on arterial repair in a rabbit carotid balloon-injury model. Decorin binding to PDGF was demonstrated by solid-phase binding and affinity cross-linking assays. Decorin potently inhibited PDGF-stimulated PDGFR phosphorylation. Pretreatment of rabbit aortic SMC with decorin significantly inhibited PDGF-stimulated cell migration, proliferation, and collagen synthesis. Decorin overexpression by adenoviral-mediated gene transfection in balloon-injured carotid arteries significantly decreased intimal cross-sectional area and collagen content by approximately 50% at 10 weeks compared to beta-galactosidase-transfected or balloon-injured, non-transfected controls. This study shows that decorin binds to PDGF and inhibits its stimulatory activity on SMCs by preventing PDGFR phosphorylation. Decorin overexpression reduces intimal hyperplasia and collagen content after arterial injury. Decorin may be an effective therapy for the prevention of intimal hyperplasia after balloon angioplasty.     

Coeliac disease, adenocarcinoma of jejunum and in situ squamous carcinoma of oesophagus

The development of both adenocarcinoma of the jejunum and in situ squamous carcinoma of the oesophagus in an adult coeliac patient is described. Good evidence that adenocarcinoma of jejunum occurs more frequently in patients with coeliac disease has recently become available though this association has been suggested for some time. While oesophageal carcinoma has long been associated with coeliac disease, in situ carcinoma of oesophagus has not been previously described in these circumstances. We feel that the risk of this complication, as calculated from published series, warrants a screening programme for oesophageal malignancy in adult coeliacs.     

Alcohol and the Psychophysiological Detection of Deception

Psychophysiological detection of deception examinations were conducted on 40 subjects. Of these, 32 were “guilty” of a mock crime and 8 were innocent. Sixteen guilty subjects committed the crime while intoxicated and the remaining 16 committed the crime sober. These two groups of guilty subjects were subdivided such that half of each group was examined with the polygraph while intoxicated and the other half was examined while sober. Two questioning techniques were used in the examination, a Control Question Test and the Guilty Knowledge Test. Measures of skin resistance, heart rate and respiration were recorded. The principal findings were that alcohol intoxication during the crime reduced detectability with detection scores derived from the measurement of skin resistance responses on the Control Question Test and on the Guilty Knowledge Test. The analyses of guilt/innocent classifications, based on the detection scores, showed these classifications to be affected by alcohol intoxication.     

Quantitation of the reconstruction quality of a four-dimensional computed tomography process for lung cancer patients

We have developed a four-dimensional computed tomography (4D CT) technique for mapping breathing motion in radiotherapy treatment planning. A multislice CT scanner (1.5 mm slices) operated in ciné mode was used to acquire 12 contiguous slices in each couch position for 15 consecutive scans (0.5 s rotation, 0.25 s between scans) while the patient underwent simultaneous quantitative spirometry measurements to provide a sorting metric. The spirometry-sorted scans were used to reconstruct a 4D data set. A critical factor for 4D CT is quantifying the reconstructed data set quality which we measure by correlating the metric used relative to internal-object motion. For this study, the internal air content within the lung was used as a surrogate for internal motion measurements. Thresholding and image morphological operations were applied to delineate the air-containing tissues (lungs, trachea) from each CT slice. The Hounsfield values were converted to the internal air content (V). The relationship between the air content and spirometer-measured tidal volume (v) was found to be quite linear throughout the lungs and was used to estimate the overall accuracy and precision of tidal volume-sorted 4D CT. Inspection of the CT-scan air content as a function of tidal volume showed excellent correlations (typically r>0.99) throughout the lung volume. Because of the discovered linear relationship, the ratio of internal air content to tidal volume was indicative of the fraction of air change in each couch position. Theoretically, due to air density differences within the lung and in room, the sum of these ratios would equal 1.11. For 12 patients, the mean value was 1.08 +/- 0.06, indicating the high quality of spirometry-based image sorting. The residual of a first-order fit between v and V was used to estimate the process precision. For all patients, the precision was better than 8%, with a mean value of 5.1% +/- 1.9%. This quantitative analysis highlights the value of using spirometry as the metric in sorting CT scans. The 4D reconstruction provides the CT data required to measure the three-dimensional trajectory of tumor and lung tissue during free breathing.     

Simple spike firing in the posterior lateral cerebellar cortex of Macaque Mulatta was correlated with success–failure during a visually guided reaching task

Evidence has been accumulating which supports a role for the cerebellum in motor learning. Motor learning is though to be mediated by complex spikes acting as an error signal, which when firing in conjunction with simple spike activity modify synapses between parallel fibers and Purkinje cells. We studied the activity of neurons in the posterior lateral cerebellar cortex of macaques that were performing reaches to visual targets. We found that simple spike firing in many of these neurons was modulated by whether the monkey successfully hit the target or not. The success–failure modulation was present for reaches using either arm and could persist for several hundred milliseconds into a period when the monkey was constrained from moving its arms. This temporally extended success–failure activity could interact with complex spike firing in order to enhance learning, particularly when the motor command is temporally separated from sensory feedback.     

Enterotoxigenic Escherichia coli in developing countries: epidemiology, microbiology, clinical features, treatment, and prevention

ETEC is an underrecognized but extremely important cause of diarrhea in the developing world where there is inadequate clean water and poor sanitation. It is the most frequent bacterial cause of diarrhea in children and adults living in these areas and also the most common cause of traveler's diarrhea. ETEC diarrhea is most frequently seen in children, suggesting that a protective immune response occurs with age. The pathogenesis of ETEC-induced diarrhea is similar to that of cholera and includes the production of enterotoxins and colonization factors. The clinical symptoms of ETEC infection can range from mild diarrhea to a severe cholera-like syndrome. The effective treatment of ETEC diarrhea by rehydration is similar to treatment for cholera, but antibiotics are not used routinely for treatment except in traveler's diarrhea. The frequency and characterization of ETEC on a worldwide scale are inadequate because of the difficulty in recognizing the organisms; no simple diagnostic tests are presently available. Protection strategies, as for other enteric infections, include improvements in hygiene and development of effective vaccines. Increases in antimicrobial resistance will dictate the drugs used for the treatment of traveler's diarrhea. Efforts need to be made to improve our understanding of the worldwide importance of ETEC.