Scarring trachoma is associated with polymorphism in the tumor necrosis factor alpha (TNF-alpha) gene promoter and with elevated TNF-alpha levels in tear fluid

Tumor necrosis factor alpha (TNF-alpha) may play a central role in the disease pathogenesis which occurs as a consequence of chlamydial infection. To investigate the importance of TNF-alpha gene promoter polymorphisms and TNF-alpha levels in tear fluid in scarring trachoma, a large matched-pair case-control study was performed in The Gambia. The -308A allele was present in a higher proportion of patients (28.4%) than controls (18.4%), with an increasing association for homozygotes (chi2 for trend, P = 0.032; allele frequency, 0.163 in patients and 0.099 in controls; chi2, P = 0.025). For the -238A allele, the association was similar but not significant. The disease association was highly significant when the number of either -308A or -238A sites in an individual was considered (P = 0.003). TNF-alpha promoter alleles are tightly linked to some HLA class I and II alleles, but multivariate analysis confirmed that the disease associations were independent of HLA, although a class I allele, A*6802, is also associated with disease. TNF-alpha was more frequently detected in tear samples from patients (27.6%) than from controls (15.9%), increasingly so for higher levels of detectable TNF-alpha (P = 0.015). Among patients, detectable TNF-alpha in tears was highly associated with the presence of ocular chlamydial infection (P < 0.001). The results indicate that TNF-alpha plays a major role in the tissue damage and scarring which occurs as a consequence of Chlamydia trachomatis infection.     

Effect of postnatal exposure to a PCB mixture in monkeys on multiple fixed interval-fixed ratio performance

Behavioral impairment as a consequence of PCB exposure beginning in utero has been reported in both humans and animals. The present study assessed the behavioral consequences of postnatal exposure to PCBs. Male monkeys (Macaca fascicularis) were dosed from birth to 20 weeks of age with 7.5 microgram(s)/kg/day of a PCB mixture representative of the PCBs typically found in human breast milk (eight monkeys) or vehicle (four monkeys). At 4 years of age, performance under a multiple fixed interval (FI)-fixed ratio (FR) schedule of reinforcement was assessed. The FI component was more sensitive to disruption as a result of PCB exposure than was the FR component. PCB-exposed monkeys displayed shorter mean interresponse times (IRTs) than controls, particularly during the earlier sessions of the experiment. Similarly, the increase in pause time characteristic of the acquisition of typical FI performance emerged more slowly across sessions in the PCB-treated group. However, the number of short IRTs (less than 5 s) remained greater in the treated group compared to controls over the 48-session duration of the experiment. On the FR component, control monkeys decreases the mean pause time across sessions whereas the PCB-treated group did not; there were no differences between groups for absolute value of average IRT or pause time. The results of this study extend previous research in this cohort of monkeys, and provide further evidence that PCB exposure limited to the early postnatal period and resulting in environmentally relevant body burdens produces long-term behavioral effects.     

Molecular dissection of effector cell protease receptor-1 recognition of factor Xa. Assignment of critical residues involved in antibody reactivity and ligand binding

Receptor-mediated assembly of blood proteases on vascular cells maintains the hemostatic balance and initiates intracellular signal transduction. Effector cell protease receptor-1 (EPR-1) is an approximately 62-kDa vascular cell membrane receptor for the clotting protease factor Xa, participating in thrombin formation and lymphocyte activation. Here, recombinant EPR-1 fragments were engineered in the frame of intercellular adhesion molecule-1, transfected in mammalian cells, and analyzed for antibody recognition and ligand binding. Chimeric transfectants containing the EPR-1 sequence Met1-Arg60 bound the immunosuppressive anti-EPR-1 monoclonal antibody (mAb) 2E1. In contrast, transfected cells expressing the EPR-1 sequence Pro120-Ala154 were recognized by the functionally inhibitory anti-EPR-1 mAbs 9D4 and B6, bound 125I-factor Xa in a reaction quantitatively indistinguishable from that of wild-type EPR-1 transfectants, and promoted factor Xa concentration-dependent prothrombin activation in the absence of exogenous factor V/Va. Chimeric transfectants expressing the COOH terminus end of the EPR-1 extracellular domain (Ala157-Glu221) did not bind anti-EPR-1 mAbs and did not associate with factor Xa. Mutagenesis of Asn131 or Lys133 in the EPR-1 ligand recognition domain abolished factor Xa binding by 80 +/- 5.5 and 96 +/- 4%, respectively, while mutation of Lys126, Gly128, Asn129, and Asn134 was without effect. A synthetic peptide duplicating the EPR-1 sequence S123PGKPGNQNSKNEPP137 dose dependently inhibited factor V/Va-independent thrombin generation of resting endothelium (IC50 approximately 1 microM), while the adjacent EPR-1 sequence P136PKK-RERERSSHCYP150 was ineffective. These findings demonstrate that EPR-1 contains two spatially distinct functional domains implicated in lymphocyte activation (Met1-Arg60) or factor Xa binding and prothrombin activation (Pro120-Ala154). These interacting sequences may provide a novel potential target for inhibition of factor Xa-dependent vascular cell responses.     

Effects of fatty acid oxidation on glucose utilization by isolated hepatocytes

We have studied the inhibitory action of long- and short-chain fatty acids on hepatic glucose utilization in hepatocytes isolated from fasted rats. The rates of hepatic glucose phosphorylation and glycolysis were determined from the tritiated products of [2-3H] and [6-3H]glucose metabolism, respectively. The difference between these was taken as an estimate of the 'cycling' between glucose and glucose-6-phosphate. In the presence of 40 mM glucose this cycling was estimated at 0.68 mumol/min/g wet wt. Glucose phosphorylation was unaffected during palmitate and hexanoate oxidation to ketone bodies but glycolysis was inhibited. The rate of glucose cycling was increased during this phase to 1.25 mumol/min/g. Following the complete metabolism of the fatty acids, glycolysis was reinstated and cycling rates returned to control levels. Hepatic glucose cycling appears to be an important component of the glucose/fatty acid cycle.     

The effect of verbal elaborations on memory in young and older adults

The Stein paradigm was used to examine the circumstances under which verbal elaborations enhance memory in young and older adults. Subjects studied target adjectives that were embedded in one of three sentence contexts that varied in elaboration of the subject-adjective relationship: (1) nonelaborated base sentences; (2) base sentences with semantically consistent, but arbitrary verbal, elaborations; and (3) base sentences with explanatory verbal elaborations that clarified the significance of the subject-adjective relationship. The presence of the elaborations was varied at encoding and retrieval, and cued recall of the target adjectives was tested with incidental and intentional learning procedures. In Experiments 1A and 1B, explanatory elaborations at encoding and retrieval yielded the largest memorial facilitation for both young and older adults, and the benefit was comparable for the incidental and intentional learning measures. In Experiment 2, age-related differences in recall were minimal with explanatory elaborations at encoding and retrieval, but larger age differences occurred in the nonelaborated comparison conditions. In Experiment 3, explanatory elaborations present at encoding but not at retrieval enhanced recall when the original Stein stimuli were used, but not with the present stimuli. The implications of these results with regard to the mnemonic efficacy of verbal elaborations for young and older adults are discussed.     

Microsatellite loci for stringless bees

What ethical concerns regarding the application of new antidementia compounds are pertinent to the best interests of patients with Alzheimer's disease and their caregivers? Based on collected preliminary anecdotal accounts, these concerns are important and should be considered carefully by clinicians, researchers, and families.     

Flow reversal in the descending aorta: a guide to intraoperative assessment of aortic regurgitation with transesophageal echocardiography

This study assessed the value of biplane transesophageal echocardiographic assessment of diastolic flow reversal in the descending aorta as an alternative to Doppler color flow imaging in determining severity of aortic regurgitation. In 45 patients undergoing cardiac operations, the severity of aortic regurgitation was assessed by semiquantitative grading of the width of the Doppler color flow regurgitant jet relative to the left ventricular outflow tract, and the presence of diastolic flow reversal was assessed with pulsed-wave Doppler measurements at three sites in the descending aorta. In four patients, the diastolic flow reversal method was the only available form of assessment because of inadequate visualization of the left ventricular outflow tract beneath a mitral valve prosthesis. Diastolic flow reversal in the descending aorta was not observed in patients without aortic regurgitation and was always present in patients with severe aortic regurgitation. Aortic valve replacement successfully eliminated descending aortic flow reversal in all 19 patients in whom it was present before valve replacement. Identification of diastolic flow reversal at multiple sites in the descending aorta with biplane transesophageal echocardiography helps to confirm the presence of severe aortic regurgitation and can serve as an alternative method of assessment when visualization of the left ventricular outflow tract is impaired.