Helicobacter pylori iceA, clinical outcomes, and correlation with cagA: a meta-analysis

Background

Although the iceA (induced by contact with epithelium) allelic types of Helicobacter pylori have been reported to be associated with peptic ulcer, the importance of iceA on clinical outcomes based on subsequent studies is controversial. The aim of this study was to estimate the magnitude of the risk for clinical outcomes associated with iceA.

Methods

A literature search was performed using the PubMed and EMBASE databases for articles published through April 2011. Published case-control studies examining the relationship between iceA and clinical outcomes (gastritis, peptic ulcer, including gastric ulcer and duodenal ulcer, and gastric cancer) were included.

Results

Fifty studies with a total of 5,357 patients were identified in the search. Infection with iceA1-positive H. pylori increased the overall risk for peptic ulcer by 1.26-fold (95% confidence interval [CI], 1.09–1.45). However, the test for heterogeneity was significant among these studies. Sensitivity analysis showed that the presence of iceA1 was significantly associated with peptic ulcer (odds ratio [OR] = 1.25, 95% CI = 1.08–1.44). The presence of iceA2 was inversely associated with peptic ulcer (OR = 0.76, 95% CI = 0.65–0.89). The presence of iceA was not associated with gastric cancer. Most studies examined the cagA status; however, only 15 studies examined the correlation and only 2 showed a positive correlation between the presence of cagA and iceA1.

Conclusion

Our meta-analysis confirmed the importance of the presence of iceA for peptic ulcer, although the significance was marginal.     

Ectopic dermal ridge configurations on the interdigital webbings and postaxial marginal portion of the hindlimb in Hammertoe mutant mice (Hm)

The effects of the hereditary malformation of Hammertoe mutant mice (gene symbol Hm) on the digital pads and dermal ridge configurations on their hindlimbs were examined. In the wild‐type (+/+) mice with normally separated digits, dermal ridges developed only on the pads. Heterozygous (Hm/+) and homozygous (Hm/Hm) mutant mice, however, had a broad big toe, fused interdigital soft tissues, reduced claws, an extra rudimentary postaxial digit and camptodactyly. The dermal ridges appeared not only on the pads, affected in their number and configurations, but also on the ventral surface of the interdigital webbings and postaxial marginal area exhibiting an extra rudimentary digit and webbing. These aberrant configurations may be related to the abnormal occurrence of programmed cell death (PCD) in the interdigital zones and the postaxial marginal portion in Hm/+ and Hm/Hm mice. That is, the diminished cell death may fail to decrease the cell density in the interdigital zones and postaxial marginal portion and result in the webbing and an extra rudimentary digit and webbing, respectively. Simultaneously, it could also interrupt the migration of surviving cells of these areas toward the neighboring digits and the distal area of the sole and produce the ectopic dermal ridges on the way to the as yet unformed (presumptive) digital and plantar volar pads. The present findings suggest that normal interdigital and pre/postaxial PCD contributes not only to the separation of digits, the initial formation of individual digits of different sizes, and the inhibition of the extra digit but also to the development of the presumptive digital and plantar pads, including dermal ridges. J. Morphol., 2008. © 2008 Wiley‐Liss, Inc.     

DNA methylation errors in cloned mice disappear with advancement of aging

Cloned animals have various health problems. Aberrant DNA methylation is a possible cause of the problems. Restriction landmark genomic scanning (RLGS) that enabled us to analyze more than 1,000 CpG islands simultaneously demonstrated that all cloned newborns had aberrant DNA methylation. To study whether this aberration persists throughout the life of cloned individuals, we examined genome-wide DNA methylation status of newborn (19.5 dpc, n=2), adult (8-11 months old, n=3), and aged (23-27 months old, n=4) cloned mice using kidney cells as representatives. In the adult and aged groups, cloning was repeated using cumulus cells of the adult founder clone of each group as nucleus donor. Two newborn clones had three with aberrantly methylated loci, which is consistent with previous reports that all cloned newborns had DNA methylation aberrations. Interestingly, we could detect only one aberrantly methylated locus in two of the three adult clones in mid-age and none of four senescent clones, indicating that errors in DNA methylation disappear with advancement of animals' aging.     

Glucokinase thermolability and hepatic regulatory protein binding are essential factors for predicting the blood glucose phenotype of missense mutations

To better understand how glucokinase (GK) missense mutations associated with human glycemic diseases perturb glucose homeostasis, we generated and characterized mice with either an activating (A456V) or inactivating (K414E) mutation in the gk gene. Animals with these mutations exhibited alterations in their blood glucose concentration that were inversely related to the relative activity index of GK. Moreover, the threshold for glucose-stimulated insulin secretion from islets with either the activating or inactivating mutation were left- or right-shifted, respectively. However, we were surprised to find that mice with the activating mutation had markedly reduced amounts of hepatic GK activity. Further studies of bacterially expressed mutant enzymes revealed that GK(A456V) is as stable as the wild type enzyme, whereas GK(K414E) is thermolabile. However, the ability of GK regulatory protein to inhibit GK(A456V) was found to be less than that of the wild type enzyme, a finding consistent with impaired hepatic nuclear localization. Taken together, this study indicates that it is necessary to have knowledge of both thermolability and the interactions of mutant GK enzymes with GK regulatory protein when attempting to predict in vivo glycemic phenotypes based on the measurement of enzyme kinetics.     

Roles of Tom70 in Import of Presequence-containing Mitochondrial Proteins

Mitochondrial protein traffic requires precise recognition of the mitochondrial targeting signals by the import receptors on the mitochondrial surface including a general import receptor Tom20 and a receptor for presequence-less proteins, Tom70. Here we took a proteome-wide approach of mitochondrial protein import in vitro to find a set of presequence-containing precursor proteins for recognition by Tom70. The presequences of the Tom70-dependent precursor proteins were recognized by Tom20, whereas their mature parts exhibited Tom70-dependent import when attached to the presequence of Tom70-independent precursor proteins. The mature parts of the Tom70-dependent precursor proteins have the propensity to aggregate, and the presence of the receptor domain of Tom70 prevents their aggregate formation. Therefore Tom70 plays the role of a docking site for not only cytosolic chaperones but also aggregate-prone substrates to maintain their solubility for efficient transfer to downstream components of the mitochondrial import machineries.     

Tim23–Tim50 pair coordinates functions of translocators and motor proteins in mitochondrial protein import

Mitochondrial protein traffic requires coordinated operation of protein translocator complexes in the mitochondrial membrane. The TIM23 complex translocates and inserts proteins into the mitochondrial inner membrane. Here we analyze the intermembrane space (IMS) domains of Tim23 and Tim50, which are essential subunits of the TIM23 complex, in these functions. We find that interactions of Tim23 and Tim50 in the IMS facilitate transfer of precursor proteins from the TOM40 complex, a general protein translocator in the outer membrane, to the TIM23 complex. Tim23–Tim50 interactions also facilitate a late step of protein translocation across the inner membrane by promoting motor functions of mitochondrial Hsp70 in the matrix. Therefore, the Tim23–Tim50 pair coordinates the actions of the TOM40 and TIM23 complexes together with motor proteins for mitochondrial protein import.     

Hydrogen peroxide stimulates tetrahydrobiopterin synthesis through the induction of GTP-cyclohydrolase I and increases nitric oxide synthase activity in vascular endothelial cells

Tetrahydrobiopterin (BH4), which is an essential cofactor for nitric oxide synthase (NOS), is generally accepted as an important molecular target for oxidative stress. This study examined whether hydrogen peroxide (H(2)O(2)), one of the reactive oxygen species (ROS), affects the BH4 level in vascular endothelial cells (ECs). Interestingly, the addition of H(2)O(2) to ECs markedly increased the BH4 level, but not its oxidized forms. The H(2)O(2)-induced increase in the BH4 level was blocked by the inhibitor of GTP-cyclohydrolase I (GTPCH), which is the rate-limiting enzyme of BH4 synthesis. Moreover, H(2)O(2) induced the expression of GTPCH mRNA, and the inhibitors of protein synthesis blocked the H(2)O(2)-induced increase in the BH4 level. The expression of the inducible isoform of NOS (iNOS) was slightly induced by the treatment with H(2)O(2). Additionally, the L-citrulline formation from L-arginine, which is the marker for NO synthesis, was stimulated by the treatment with H(2)O(2), and the H(2)O(2)-induced L-citrulline formation was strongly attenuated by NOS or GTPCH inhibitor. These results suggest that H(2)O(2) induces BH4 synthesis via the induction of GTPCH, and the increased BH4 is coupled with NO production by coinduced iNOS. H(2)O(2) appears to be one of the important signaling molecules to regulate the BH4-NOS system.     

Involvement of splenocytes in the control of corpus luteum function in the rat

We previously found that splenectomy caused a 1-day delay in ovulation in cycling rats. In the present study, the role of the spleen or splenocytes in corpus luteum function was investigated by comparing long-term splenectomized (SPX) rats with intact controls. When the rats were cervically stimulated on the day of proestrus, both SPX and control rats showed prolonged diestrus for 16 days associated with an increase in serum progesterone (P). However, in SPX rats, 20 alpha-dihydroprogesterone (20 alpha-OHP) concentrations were double those of controls throughout the period of pseudopregnancy. The concentration of total progestin (P plus 20 alpha-OHP) was also higher in SPX rats. All of these phenomena were normalized by injecting the animals with splenocytes. Taken together with our previous findings, these results indicate that splenocytes are involved in the control of ovarian function.     

Amino acid neurotransmitters and their receptors in the brain synaptosomes of acute hepatic failure rats

Ammonia contents in the brain stem and prosencephalon markedly increased in a rat model of acute hepatic failure induced by partial hepatectomy following CCl4 intoxication. In hepatic failure rats, synaptosomal glutamic acid (excitatory amino acid neurotransmitter) contents decreased significantly in the prosencephalon, and GABA (inhibitory amino acid neurotransmitter) contents decreased significantly in the brain stem. The molar ratio of glutamic acid to glutamine significantly diminished in the brain stem. Glutamic acid decarboxylase activity in the synaptosomes and the binding of [3H]glutamic acid and [3H]GABA to synaptosomal membrane preparations were unchanged in acute hepatic failure rats. These results indicate than an insufficiency of both excitatory and inhibitory neurotransmitter amino acids is induced by high ammonia contents in the synaptosomes of the brain stem during acute hepatic failure.