TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor

We investigated the potential for 9-cis-retinoic acid in the differentiation therapy of neuroblastoma using an N-type neuroblastoma cell line, SH SY 5Y, as an experimental model. In these cells, 9-cis-retinoic acid is more effective than other isomers at inducing the expression of RAR-beta. An RAR-alpha-specific antagonist inhibited the induction of RAR-beta in response to all-trans-but not to 9-cis-retinoic acid. This indicates that the mechanism of gene induction by 9-cis-retinoic acid differs markedly from all-trans-retinoic acid. 9-cis-retinoic acid is also better than all-trans at producing sustained morphological differentiation and inhibition of proliferation of SH SY 5Y cells. Although N-type neuroblastoma cells are not thought to undergo apoptosis in response to all-trans-retinoic acid, we observed a significant degree of apoptosis in SH SY 5Y cells treated with 9-cis-retinoic acid for 5 days and then cultured in the absence of retinoid, an effect not observed in cells treated with the all-trans isomer. These results suggest that 9-cis- and all-trans-retinoic acid have distinct biological properties and that 9-cis retinoic acid may be clinically effective in neuroblastoma by inducing both differentiation and apoptosis under an appropriate treatment regimen.     

Renal failure associated with hepatitis C virus infection. Improvement in renal function after treatment with interferon-alpha

Hepatitis C virus infection can result in mixed cryoglobulinemia and associated clinical syndromes including membranoproliferative glomerulonephritis. Reports regarding the efficacy of interferon-alpha (IFN-alpha) in the treatment of patients with membranoproliferative glomerulonephritis and chronic hepatitis C infection have been inconclusive regarding improvement of renal function. We describe two patients with chronic hepatitis secondary to hepatitis C virus complicated by mixed cryoglobulinemia and membranoproliferative glomerulonephritis who developed severe renal failure which resolved after treatment with standard doses of IFN-alpha 2b.     

The impact of the neonatal resuscitation program guidelines (NRPG) on the neonatal mortality in a hospital in Zhuhai, China

AIM: The neonatal resuscitation program (NRPG) was first introduced in our hospital to replace the traditional resuscitation (TR) program in 1993. TR has been in existence in China for a long time. The implementation of NRPG was timely in reducing the number of infant mortality and also to disseminate to the many hospitals in China which are still practising TR. METHOD: A perspective study of 4,751 newborns with 366 asphyxiated babies in a period of 2 years was carried out. A previous sample of 1,722 live births under the TR program was compared as a controlled group statistically. RESULTS: From August 1993 to August 1995, when NRPG was exclusively implemented in our hospital, only 16 newborns died within 7 days, out of 4,751 births (3.4%) with 2 deaths in the delivery room. Seventeen newborns died within 7 days out of 1,722 births (9.9+) in the TR group, with 10 deaths in the delivery room. From the data shown, it can be clearly seen that perinatal neonatal mortality rate was reduced almost 3 times after NRPG was implemented (chi(2) = 10.54, p < 0.01). The follow-up results of 21 cases of severe asphyxia at 2 months--1 year of age were normal except for one with cerebral palsy. CONCLUSIONS: Our study showed that NRPG was indeed a very effective and feasible technique during the delivery process in the reduction of neonatal mortality. It is important to disseminate widely the knowledge and technique of NRPG in places where TR is still being widely practiced especially in developing countries.     

Function of protonatable residues in the flagellar motor of Escherichia coli: a critical role for Asp 32 of MotB

Rotation of the bacterial flagellar motor is powered by a transmembrane gradient of protons or, in some species, sodium ions. The molecular mechanism of coupling between ion flow and motor rotation is not understood. The proteins most closely involved in motor rotation are MotA, MotB, and FliG. MotA and MotB are transmembrane proteins that function in transmembrane proton conduction and that are believed to form the stator. FliG is a soluble protein located on the cytoplasmic face of the rotor. Two other proteins, FliM and FliN, are known to bind to FliG and have also been suggested to be involved to some extent in torque generation. Proton (or sodium)-binding sites in the motor are likely to be important to its function and might be formed from the side chains of acidic residues. To investigate the role of acidic residues in the function of the flagellar motor, we mutated each of the conserved acidic residues in the five proteins that have been suggested to be involved in torque generation and measured the effects on motility. None of the conserved acidic residues of MotA, FliG, FliM, or FliN proved essential for torque generation. An acidic residue at position 32 of MotB did prove essential. Of 15 different substitutions studied at this position, only the conservative-replacement D32E mutant retained any function. Previous studies, together with additional data presented here, indicate that the proteins involved in motor rotation do not contain any conserved basic residues that are critical for motor rotation per se. We propose that Asp 32 of MotB functions as a proton-binding site in the bacterial flagellar motor and that no other conserved, protonatable residues function in this capacity.     

Protection from lethal malaria in transgenic mice expressing sickle hemoglobin

Previous studies from our laboratories have shown that transgenic mice expressing high levels of beta S globin are well-protected from Plasmodium chabaudi adami and partially protected against P berghei (Shear et al, Blood 81:222, 1993). We have now infected transgenic mice expressing low (39%), intermediate (57%), and high (75%) levels of beta S with the virulent strain of P yoelii (17XL) that appears to cause cerebral malaria. We find that the level of protection in these three groups of mice correlates positively with the level of beta S chain expression in the mice. Seven of nine mice expressing the high level of beta S recovered from infection, as did 7 of 9 mice expressing the intermediate level of beta S. Control mice and mice expressing the lower level of beta S all succumbed to infection. In mice expressing high and intermediate levels of beta S, parasites were found almost exclusively in reticulocytes during recovery, suggesting that mature red blood cells expressing beta S are more resistant than reticulocytes. These studies confirm epidemiologic data and offer insight into the mechanism of protection of sickle trait individuals against falciparum malaria.     

Oral delivery of group A streptococcal cell walls augments circulating TGF-beta and suppresses streptococcal cell wall arthritis

Oral administration of autoantigens can influence the outcome of experimental autoimmune diseases, yet little is known about nonself Ag-induced tolerance. In this study, we administered group A streptococcal cell wall (SCW) peptidoglycan-polysaccharide complexes orally and monitored the impact on SCW-induced erosive polyarthritis. Oral administration of low dose SCW (3 microg/day), initiated 7 days before an arthritogenic dose of systemic SCW, virtually eliminated the joint swelling and destruction typically observed during both the acute and chronic phases of the arthritis. High (300 microg), but not intermediate (30 microg), dose regimens also profoundly inhibited the disease. Most previous studies have demonstrated that prior feeding is required for efficacy, yet oral feeding of low dose SCW suppressed the evolution of arthritis even when administration was begun 10-15 days after induction of the arthritis. While the synovial inflammatory cell infiltration and expression of proinflammatory cytokines were markedly suppressed, no local enhancement of the regulatory cytokines IL-4, IL-10, and TGF-beta was detected. Oral administration of low dose SCW, however, up-regulated circulating levels of TGF-beta, concomitant with decreased circulating TNF-alpha and suppression of chronic arthritis. Moreover, IL-10 was increased in tolerized spleen lymphocytes, and unexpectedly, this SCW-specific IL-10 production was TGF-beta dependent. These data support a pivotal role for TGF-beta, although not necessarily in the joint, in the regulation of specific immune tolerance responsible for suppressed synovial inflammation and matrix destruction. The distant induction and up-regulation of regulatory cytokines and/or cells may contribute to the inhibition of the immune response through blunted infiltration of inflammatory cells to the joint.