CD28-independent, TRAF2-dependent costimulation of resting T cells by 4-1BB ligand

4-1BB ligand (4-1BBL) is a member of the tumor necrosis factor (TNF) family expressed on activated antigen-presenting cells. Its receptor, 4-1BB, is a member of the TNF receptor family expressed on activated CD4 and CD8 T cells. We have produced a soluble form of 4-1BBL using the baculovirus expression system. When coimmobilized on plastic with anti-CD3, soluble 4-1BBL induces interleukin (IL)-2 production by resting CD28+ or CD28- T cells, indicating that 4-1BBL can function independently of other cell surface molecules, including CD28, in costimulation of resting T cell activation. At low concentrations of anti-CD3, 4-1BBL is inferior to anti-CD28 in T cell activation. However, when 4-1BB ligand is provided together with strong TCR signals, then 4-1BBL and anti-CD28 are equally potent in stimulation of IL-2 production by resting T cells. We find that TNF receptor-associated factor (TRAF)1 or TRAF2 associate with a glutathione S-transferase-4-1BB cytoplasmic domain fusion protein in vitro. In T cells, we find that association of TRAF1 and TRAF2 with 4-1BB requires 4-1BB cross-linking. In support of a functional role for TRAF2 in 4-1BB signaling, we find that resting T cells isolated from TRAF2-deficient mice or from mice expressing a dominant negative form of TRAF2 fail to augment IL-2 production in response to soluble 4-1BBL. Thus 4-1BB, via the TRAF2 molecule, can provide CD28-independent costimulatory signals to resting T cells.     

Management of bronchobiliary fistula as a late complication of hepatic resection

Bronchobiliary fistula is an uncommon but remarkable complication after hepatic resection. The case reported illustrates the clinical presentation and preferred initial management of these fistulae. A 61-year-old white male underwent two wedge resections for colorectal metastases to the liver with removal of a portion of the right diaphragm. Four years later, he developed obstructive jaundice secondary to tumor recurrence in the porta hepatis, which required endoscopic stent placement, radiation, and chemotherapy. Almost 2 years later, he developed frank biliptysis. Percutaneous transhepatic cholangiography (PTC) revealed occlusion of the common hepatic duct stent and a bronchobiliary fistula. With adequate reestablishment of common duct drainage, the patient rapidly improved and was discharged free of symptoms. Bronchobiliary fistulae are rare complications of hepatic resection that can present from days to years after operation. Endoscopic retrograde cholangiopancreatography and PTC are the diagnostic studies of choice and offer the possibility of therapeutic intervention. Although large series in the literature emphasize the surgical management of bronchobiliary fistulae, the reoperative procedures tend to be complicated, with a significant morbidity and mortality. Nonsurgical interventions via endoscopic retrograde cholangiopancreatography or PTC are more recently notably successful when resolution of a distal biliary obstruction is accomplished. Only after aggressive attempts at nonoperative, interventional techniques have failed should operative approaches be entertained.     

Comparative studies on mammalian Hoxc8 early enhancer sequence reveal a baleen whale-specific deletion of a cis-acting element

Variations in regulatory regions of developmental control genes have been implicated in the divergence of axial morphologies. To find potentially significant changes in cis-regulatory regions, we compared nucleotide sequences and activities of mammalian Hoxc8 early enhancers. The nucleotide sequence of the early enhancer region is extremely conserved among mammalian clades, with five previously described cis-acting elements, A-E, being invariant. However, a 4-bp deletion within element C of the Hoxc8 early enhancer sequence is observed in baleen whales. When assayed in transgenic mouse embryos, a baleen whale enhancer (unlike other mammalian enhancers) directs expression of the reporter gene to more posterior regions of the neural tube but fails to direct expression to posterior mesoderm. We suggest that regulation of Hoxc8 in baleen whales differs from other mammalian species and may be associated with variation in axial morphology.     

The perinatal mortality rate as an indicator of quality of care in international comparisons

Priming and recollection are expressions of human memory mediated by different brain events. These brain events were monitored while people discriminated words from nonwords. Mean response latencies were shorter for words that appeared in an earlier study phase than for new words. This priming effect was reduced when the letters of words in study-phase presentations were presented individually in succession as opposed to together as complete words. Based on this outcome, visual word-form priming was linked to a brain potential recorded from the scalp over the occipital lobe about 450 ms after word onset. This potential differed from another potential previously associated with recollection, suggesting that distinct operations associated with these two types of memory can be monitored at the precise time that they occur in the human brain.     

Potentially avoidable hospitalizations: inequalities in rates between US socioeconomic groups

OBJECTIVES: The National Hospital Discharge Survey (NHDS) was used to evaluate potentially avoidable hospital conditions as an indicator of equity and efficiency in the US health care system. METHODS: With the use of 1990 data from the NHDS, the National Health Interview Survey, and the census, national rates of hospitalization were calculated for avoidable conditions by age, race, median income of zip code, and insurance status. RESULTS: An estimated 3.1 million hospitalizations were for potentially avoidable conditions. This was 12% of all hospitalizations in 1990 (excluding psychiatric admissions, women with deliveries, and newborns). Rates of potentially avoidable hospitalizations were higher for persons living in middle- and low-income areas than for persons living in high-income areas, and were higher among Blacks than among Whites. These class and racial differences were also found among the privately insured. Differences among income and racial groups for persons aged 65 and over were not significant. CONCLUSIONS: Inequalities in potentially avoidable hospitalizations suggest inequity and inefficiency in the health care delivery system. Avoidable hospital conditions are a useful national indicator to monitor access to care.     

Effects of LY215490, a competitive alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist, on the micturition reflex in the rat

The effects of glutamate receptor antagonists on urinary bladder and external urethral sphincter- (EUS) electromyogram (EMG) activity were evaluated in unanesthetized decerebrate rats. In normal rats, LY215490, an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist, in small i.v. doses (1-3 mg/kg) decreased bladder contraction amplitude (BC-Amp) by 29% and EUS-EMG by 41%; whereas a large dose (10 mg/kg) completely abolished bladder and EUS-EMG activity. LY215490 injected intrathecally in small doses (0.01-0.1 microg) decreased BC-Amp by 20% and EUS-EMG by 62%; whereas large doses (1-10 microg) completely abolished bladder and EUS-EMG activity. LY215490 (0.1 microg i.t.) increased bladder capacity by 28% and decreased voiding efficiency by 44%. Combined i.t. administration of small doses of LY215490 (0.1 microg) and MK-801 (1 microg), an N-methyl-D-aspartate (NMDA) receptor antagonist, which individually had little effect on BC-Amp, markedly suppressed bladder activity. In chronic spinal rats, LY215490 (10 mg/kg i.v.) abolished EUS-EMG activity and decreased BC-Amp by 41%. Intrathecal injections of LY215490 were also less effective in chronic spinal rats; a 10-microg dose producing only a partial block (53%) of BC-Amp, but complete block of EUS-EMG. In chronic spinal rats, MK-801 (1 mg/kg i.v.) abolished EUS-EMG activity and decreased BC-Amp by 36%. Pretreatment with MK-801 (1 mg/kg i.v.) did not enhance the effect of LY215490 on bladder activity in chronic spinal rats. These data suggest that AMPA glutamate receptors have a major role in the excitatory pathways controlling bladder and EUS activity in spinal cord intact rats. However, in chronic spinal rats, AMPA and NMDA receptors are essential for EUS reflexes, but are responsible for only a part of reflex bladder activity.     

Effect of relative humidity on the store stability of spray-dried beta-carotene nanoemulsions

In order to overcome the limitations of liquid-base emulsion system, beta-carotene nanoemulsions stabilized by modified starch were spray-dried to powders after the emulsification process. The powders showed a good dissolution in water and the reconstituted emulsions had similar particle sizes with the fresh nanoemulsions. A 30 days storage test was carried out to investigate the effect of relative humility (RH) on the storage stability of beta-carotene powders at 25.0 °C. The beta-carotene degradation profiles over time were found to fit well with a Weibull model and also closely related to the film property of the matrix, moisture sorption property and glass transition temperature of the powder. The results showed that modified starches with lower film oxygen permeability had a higher retention of beta-carotene during storage. The glass transition temperature of powder in different RH also affected the rate of beta-carotene degradation. Overall these results provide useful information for choosing wall materials and storage conditions to protect nutraceuticals in delivery systems.