Radiation-induced-thymic lymphoma occurs in young,but not in old mice

Young mice exposed to fractionated whole-body irradiation develop thymic lymphoma. By using young and old mice, we examined the effect of age on the occurrence of radiation-induced thymic lymphoma in mice. In the first experiment, young and old mice were grafted with newborn thymus under kidney capsule and then treated with fractionated whole-body irradiation (FWI). In the second and third experiments, four combinations of bone marrow chimeras were constructed by transplanting bone marrow cells from young and old mice into young and old mice. Then these chimera mice were grafted with newborn thymus and treated with fractionated whole-body irradiation. The results in the present study indicate that the incidence of thymic lymphoma is influenced by age factors of thymic microenvironment, bone marrow, and host environment. If they are all young, the incidence of thymic lymphoma is high. If one of these is old, the incidence definitely decreases. Thymic lymphoma never occurred in old thymic environment even in the presence of young thymocytes. In conclusion, age advantage is present in the induction of thymic lymphoma after the treatment with FWI and the incidence definitely decreases in the presence of old factors.     

Amyloidosis modifier genes in the less amyloidogenic a/j mouse strain

Apolipoprotein A-II is deposited as an amyloid fibril in aged mice (senile AApoAII amyloidosis). Although mouse strains with the apolipoprotein A-II c allele (Apoa2(c)) generally develop early-onset and severe senile amyloidosis, the A/J strain shows significantly less amyloid deposition. To identify genes that modify spontaneous amyloidosis development in the A/J mouse, we performed a genome-wide screening using hybrid mice derived from A/J and SAMP1 mice, which have Apoa2(c) and age-associated severe amyloid deposition. Our genetic analysis revealed that the lower levels of amyloidosis in the A/J strain were polygenically controlled. We found two chromosome locations associated with amyloidosis. One of these regions was in the chromosome 19 telomeric region, where the A/J alleles modify amyloidosis in an additive manner. The second region was in the chromosome 4 telomeric region, where the A/J alleles modify amyloidosis in a dominant manner. Perlecan and group II secretory phospholipase A2, located on the significantly linked region of chromosome 4, were compared in this study. These findings are for understanding the genetic mechanism of amyloidosis-related diseases and their prevention.     

Congenital middle ear cholesteatoma: experience in 48 cases

We studied 48 patients (48 ears) with congenital cholesteatoma who underwent surgery at our department from 1979 to 2000, and investigated symptoms at initial onset, tympanic membrane findings, cholesteatoma configuration and site, type of surgical procedure, and surgical outcome. Patients were from 2 to 62 years old (mean: 16.7 years), with 60.4% aged 15 years or younger. The symptom at initial onset was hearing loss in most (58.2%). Hearing loss was the main symptom in all with open type cholesteatoma, and most of these patients had normal tympanic membrane findings. The cholesteatoma was located mainly in the superior posterior portion of the tympanic cavity in many patients. The site of involvement was the tympanic cavity in 12 (25.0%), mastoid cavity in 2 (4.2%) and the petrous apex in 1 (2.1%). In many of (31 ears, 64.6%), the cholesteatoma was advanced and extended from the tympanic cavity to the mastoid antrum. For 23 of the 48 ears, treatment was completed in one operation. The remaining 25 ears required staged surgery. Loss of the structure of the upper part of the stapes was seen in 58.3% of patients, so most underwent type IV ossiculoplasty, with types III and I next most common.     

Whole-blood manganese levels and brain manganese accumulation in children receiving long-term home parenteral nutrition

Recent reports attribute neurological and cerebral disorders to the accumulation of manganese (Mn) in the brain in patients receiving home parenteral nutrition (HPN). It is desirable to control the amount of Mn delivered to these patients, but a suitable method for monitoring an individual's Mn status and assessing Mn accumulation remains debatable. The aim of this study was to evaluate whether whole-blood manganese levels (WB-Mn) correlate with the accumulation of Mn in the brains of children who receive long-term HPN, using magnetic resonance imaging (MRI) of the brain. Six patients who had received HPN (duration of HPN, 18-137 months) were included in this study. The daily parenteral doses of Mn were calculated while on HPN. WB-Mn was measured and T1-weighted MRI of the brain was obtained for each patient with a 1.5-T MR imager. Twelve months after the withdrawal of Mn from HPN, measurements of WB-Mn and brain MRI were repeated in all patients except for one who was lost after initial examination. The same examinations were performed on an additional patient who had been successfully weaned off a 179 month course of HPN 20 months prior to the initial examination. The parenteral dose of Mn while receiving HPN ranged from 15.7 to 91.5 micro g/kg/day. Initially, MRI showed hyperintensity in the globus pallidus in all patients and in the anterior pituitary in one patient. WB-Mn was elevated in four patients, but was in the normal range in the remaining three. Following subsequent measurements 12 months later, WB-Mn was normal in all patients and MRI hyperintensity remained in the globus pallidus in one patient. One patient was lost after the initial examinations. WB-Mn does not necessarily correlate with the accumulation of Mn in the brain. Periodic MRI should be performed in patients receiving long-term NPN to monitor for excessive Mn accumulation in the brain.     

CMT4A: identification of a Hispanic GDAP1 founder mutation

Mutations of the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) cause autosomal recessive Charcot-Marie-Tooth disease type 4A. We report four additional families with recessive mutations (487C-->T, Q163X; 359G-->A, R120Q) of GDAP1; Q163X occurred in three unrelated Hispanic families that had the same haplotype suggesting a Spanish founder mutation. Both the Q163X and the R120Q mutation cause demyelination and axonal loss. The patients had symptoms within the first two years of life and involvement of cranial, sensory, and enteric nerves. Neuropathology showed loss of large myelinated fibers, onion bulb formations and focal folding of the outer myelin lamina.     

Structural and functional diversity in the PAR1b/MARK2‐binding region of Helicobacter pylori CagA

Helicobacter pylori (H. pylori) cagA‐positive strains are associated with gastritis, peptic ulcerations, and gastric adenocarcinoma. Upon delivery into gastric epithelial cells, the cagA‐encoded CagA protein specifically binds and aberrantly activates SHP‐2 oncoprotein in a manner that is dependent on CagA tyrosine phosphorylation. CagA‐deregulated SHP‐2 then elicits aberrant Erk activation while causing an elongated cell shape known as the hummingbird phenotype. In polarized epithelial cells, CagA also binds to PAR1b/MARK2 and inhibits the PAR1b kinase activity, thereby disrupting tight junctions and epithelial cell polarity independent of CagA tyrosine phosphorylation. We show here that the CagA‐multimerization (CM) sequence that mediates interaction of CagA with PAR1b is not only essential for the CagA‐triggered junctional defects but also plays an important role in induction of the hummingbird phenotype by potentiating CagA‐SHP‐2 complex formation. We also show that the CM sequence of CagA isolated from East Asian H. pylori (referred to as the E‐CM sequence) binds PAR1b more strongly than that of CagA isolated from Western H. pylori (referred to as the W‐CM sequence). Within Western CagA species, the ability to bind PAR1b is proportional to the number of W‐CM sequences. Furthermore, the level of PAR1b‐binding activity of CagA correlates with the magnitude of junctional defects and the degree of hummingbird phenotype induction. Our findings reveal that structural diversity in the CM sequence is an important determinant for the degree of virulence of CagA, a bacterial oncoprotein that is associated with gastric carcinogenesis. (Cancer Sci 2008; 99: 2004–2011)     

Binding site(s) on P-glycoprotein for a newly synthesized photoaffinity analog of agosterol A

Agosterol A (AG-A) is a novel agent that reverses P-glycoprotein (P-gp) and multidrug resistance protein-1 (MRP1)-meditated multidrug resistance (MDR). We have synthesized [125I]11-azidophenyl agosterol A (azidoAG-A), a photoaffinity analog of AG-A, and characterized its binding to P-gp in membrane vesicles prepared from multidrug-resistant P-gp-overexpressing KB-C2 cells. The photoanalog photolabeled intact P-gp and both the N- and C-terminal fragments of P-gp. [125I]AzidoAG-A is transported by P-gp and the intracellular accumulation of both [125I]azidoAG-A and [3H]AG-A in KB-C2 cells was lower than that in the parental drug-sensitive KB-3-1 cells. [125I]AzidoAG-A bound to the drug binding site(s) on P-gp because photoaffinity labeling of P-gp was inhibited by a variety of known P-gp substrates, including anticancer, reversing, and anti-human immunodeficiency virus (HIV) agents. The binding of [125I]azidoAG-A to P-gp differs from the binding of other photolabeled probes such as iodoaryl-azidoprazosin (IAAP) to P-gp and from the binding of [125I]azidoAG-A to MRP1 based on the differing effects of flupentixol and glutathione (GSH) on their binding. Thus, [125I]azidoAG-A will be a useful tool to elucidate the structure and function of P-gp because it directly binds to the drug binding site(s) on P-gp, is transported by P-gp, and exhibits different P-gp binding characteristics than IAAP.