Taking the V out of genes V environment

Tumor necrosis factor-alpha (TNF-alpha) is thought to be an important mediator in the pathogenesis of neonatal septicemia. To assess the role of TNF-alpha in neonatal sepsis, serum levels of TNF-alpha were measured in a group of neonates with septicemia and compared with the levels of gestational-postnatal, age-matched healthy controls. The relationships between severity of infection, the nature of causative microorganisms, and TNF-alpha levels were also investigated in this prospective study. A total of 49 infants (25 full-term, 24 preterm) with proven sepsis and 40 healthy infants (20 full-term, 20 preterm) were included. Serum TNF-alpha levels were measured using the TNF-alpha immunoradiometric assay. The median level of TNF-alpha was found to be significantly higher in infants suffering from sepsis (154 pg/mL) particularly in those with septic shock (242.5 pg/mL) as compared to healthy controls (61.5 pg/mL) (p < 0.001). No correlation was found between TNF-alpha and postnatal ages, gestational ages or birth weights of the infants. TNF-alpha levels were not different in surviving and terminal neonates. Although serum, TNF-alpha levels were found to be slightly higher in gram-negative septicemia, the difference was not significant. These findings suggest that TNF-alpha plays an important role in the pathophysiology of neonatal septicemia, but its importance as a prognostic factor is not yet clear.     

The carboxyl terminus of interferon-gamma contains a functional polybasic nuclear localization sequence

Cytokines such as interferon-gamma (IFN-gamma), which utilize the well studied JAK/STAT pathway for nuclear signal transduction, are themselves translocated to the nucleus. The exact mechanism for the nuclear import of IFN-gamma or the functional role of the nuclear translocation of ligand in signal transduction is unknown. We show in this study that nuclear localization of IFN-gamma is driven by a simple polybasic nuclear localization sequence (NLS) in its COOH terminus, as verified by its ability to specify nuclear import of a heterologous protein allophycocyanin (APC) in standard import assays in digitonin-permeabilized cells. Similar to other nuclear import signals, we show that a peptide representing amino acids 95-132 of IFN-gamma (IFN-gamma(95-132)) containing the polybasic sequence 126RKRKRSR132 was capable of specifying nuclear uptake of the autofluorescent protein, APC, in an energy-dependent fashion that required both ATP and GTP. Nuclear import was abolished when the above polybasic sequence was deleted. Moreover, deletions immediately NH2-terminal of this sequence did not affect the nuclear import. Thus, the sequence 126RKRKRSR132 is necessary and sufficient for nuclear localization. Furthermore, nuclear import was strongly blocked by competition with the cognate peptide IFN-gamma(95-132) but not the peptide IFN-gamma(95-125), which is deleted in the polybasic sequence, further confirming that the NLS properties were contained in this sequence. A peptide containing the prototypical polybasic NLS sequence of the SV40 large T-antigen was also able to inhibit the nuclear import mediated by IFN-gamma(95-132). This observation suggests that the NLS in IFN-gamma may function through the components of the Ran/importin pathway utilized by the SV40 T-NLS. Finally, we show that intact IFN-gamma, when coupled to APC, was also able to mediate its nuclear import. Again, nuclear import was blocked by the peptide IFN-gamma(95-132) and the SV40 T-NLS peptide, suggesting that intact IFN-gamma was also transported into the nucleus through the Ran/importin pathway. Previous studies have suggested a direct intracellular role for IFN-gamma in the induction of its biological activities. Based on our data in this study, we suggest that a key intracellular site of interaction of IFN-gamma is the one with the nuclear transport mechanism that occurs via the NLS in the COOH terminus of IFN-gamma.     

Residues Val254, His256, and Phe259 of the angiotensin II AT1 receptor are not involved in ligand binding but participate in signal transduction

The role of the external third of helix VI of the angiotensin II (AII) AT1 receptor for the interaction with its ligand and for the subsequent signal transduction was investigated by individually replacing residues 252-256 by Ala, and residues 259 or 261 by Tyr, and permanently transfecting the resulting mutants to Chinese hamster ovary (CHO) cells. Binding experiments showed no great changes in affinity of any of the mutants for AII, [Sar1]-AII, or [Sar1, Leu8]-AII, but the affinity for the nonpeptide antagonist DuP753 was significantly decreased. The inositol phosphate response to AII was remarkably decreased in mutants V254A, H256A, and F259Y. These results indicate that AT1 residues Val254, His256, and Phe259 are not involved in ligand binding but participate in signal transduction. Based in these results and in others from the literature, it is suggested that, in addition to the His256 imidazole ring, the Phe259 aromatic ring interacts with the AII's Phe8, thus contributing to the signal-triggering mechanism.     

Percutaneous balloon pericardiotomy for patients with recurrent pericardial effusion: using a novel double-balloon technique with one long and one short balloon

Percutaneous balloon pericardiotomy is effective and less invasive for the treatment of recurrent pericardial effusion. This study suggests that the double-balloon method with 1 longer and 1 shorter balloon is the procedure of choice for percutaneous balloon pericardiotomy.     

Comparison of the biodistribution and the efficacy of monoclonal antibody 323/A3 labeled with either 131I or 186Re in human ovarian cancer xenografts

The effects of arginine vasopressin (AVP) and oxytocin (OT) upon thyroid-stimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine (FT3) release were studied in euthyroid rats. Intracerebroventricular (i.c.v.) infusion of AVP in doses of 0.5 ng or 5 ng led to significant increases in plasma levels of TSH as well as FT4 and FT3. The effects of OT injected i.c.v. in similar doses were not consistent (there was no parallel between the changes of respective hormones plasma levels). It may be concluded that vasopressin modulate the pituitary-thyroid system function; AVP is probably a physiological stimulator of TSH and thyroid hormones secretion.     

The Employee Health Care Value Survey: round one

In a groundbreaking arrangement, a consortium of large employers--the Xerox, GTE, and Digital Equipment Corporations--launched the Employee Health Care Value Survey during fall 1993. Completed by 24,306 employees, this survey was used to develop comparable methods for assessing corporate health care benefit strategies. It also enabled fair comparisons of thirty-two health plans across the country on more than sixty criteria. Variation in performance among plans was substantial, with managed care plans--particularly prepaid group practices and individual practice associations (IPAs)--recording the most favorable rankings on disenrollment, overall satisfaction, and other measures of "bottom-line performance." Variation in enrollees' health among plans was more modest, with indemnity enrollees posing a somewhat greater illness burden to their plans than enrollees of other plan types. The employers and evaluated health plans are now using the results for multiple purposes, including quality improvement initiatives, employee-based plan performance reports, employee contribution strategies, and health promotion programs.