Huge ameloblastic carcinoma of the mandible with metastases treated in several different ways.

Ameloblastic carcinoma is an extremely rare, aggressive, malignant tumour that is most common in the mandible. Because of its rarity there is no general approach to treatment. We present a rare case of an ameloblastic carcinoma with multiple metastases in a 63-year-old Japanese man that was treated in several different ways, including chemoradiotherapy and immunotherapy.

Contributions of ADP and ATP to the increase in skeletal muscle blood flow after manual acupuncture stimulation in rats.

OBJECTIVE: To investigate the contributions of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) to the increase in skeletal muscle blood flow (MBF) observed following manual acupuncture (MA) stimulation in rats. METHODS: Male Sprague-Dawley rats were used as experimental animals (300-370 g, n=40). MA was applied to the right tibialis anterior muscle (TA) for 1 min using a stainless steel acupuncture needle. In eight rats, high-performance liquid chromatography with the microdialysis technique was used to measure local extracellular concentrations of ATP, ADP, adenosine monophosphate (AMP), and adenosine in the TA. In the remaining 32 rats, fluorescent microspheres (15 µm in diameter) were used to measure MBF in the TA following pre-treatment with either the P2 receptor antagonist suramin (100 mg/kg intra-arterially) or saline (control) (n=16 each). Rats receiving MA (Suramin+MA and Saline+MA groups, n=8 each) were compared with untreated rats (Suramin and Saline groups, n=8). RESULTS: MA significantly increased the local extracellular concentration of ATP, ADP, and adenosine (p<0.05, before MA vs 30 min after MA). In addition, MA significantly increased MBF in rats pre-treated with saline or suramin (p<0.01, Saline vs Saline+MA; p<0.05, Suramin vs Suramin+MA, respectively). However, suramin significantly suppressed this MA-induced increase in MBF (p<0.05, Saline+MA vs Suramin+MA). CONCLUSIONS: These results suggest that both ATP and ADP partially contribute to the MA-induced increase in MBF via P2 receptors. However, further studies are needed to clarify the contributions of other vasodilators.

Effects of HLA-DPB1 genotypes on chronic hepatitis B infection in Japanese individuals.

Significant associations of HLA-DP alleles with chronic hepatitis B (CHB) infection are evident in Asian and Arabian populations, including Japanese, Han Chinese, Korean, and Saudi Arabian populations. Here, significant associations between CHB infection and five DPB1 alleles (two susceptibility alleles, DPB1(*) 05:01 and (*) 09:01, and three protective alleles, DPB1(*) 02:01, (*) 04:01, and (*) 04:02) were confirmed in a population comprising of 2582 Japanese individuals. Furthermore, odds ratios for CHB were higher for those with both DPB1 susceptibility alleles than for those with only one susceptibility allele; therefore, effects of susceptibility alleles were additive for risk of CHB infection. Similarly, protective alleles showed an additive effect on protection from CHB infection. Moreover, heterozygotes of any protective allele showed stronger association with CHB than did homozygotes, suggesting that heterozygotes may bind a greater variety of hepatitis B-derived peptides, and thus present these peptides more efficiently to T-cell receptors than homozygotes. Notably, compound heterozygote of the protective allele (any one of DPB1*02:01, *04:01, and *04:02) and the susceptible allele DPB1*05:01 was significantly associated with protection against CHB infection, which indicates that one protective HLA-DPB1 molecule can provide dominant protection. Identification of the HLA-DPB1 genotypes associated with susceptibility to and protection from CHB infection is essential for future analysis of the mechanisms responsible for immune recognition of hepatitis B virus antigens by HLA-DPB1 molecules.

Mid-flexion laxity is greater after posterior-stabilised total knee replacement than with cruciate-retaining procedures: A computer navigation study.

There are several methods for evaluating stability of the joint during total knee replacement (TKR). Activities of daily living demand mechanical loading to the knee joint, not only in full extension, but also in mid-flexion. The purpose of this study was to compare the varus-valgus stability throughout flexion in knees treated with either cruciate-retaining or posterior-stabilised TKR, using an intra-operative navigation technique. A total of 34 knees underwent TKR with computer navigation, during which the investigator applied a maximum varus-valgus stress to the knee while steadily moving the leg from full extension to flexion both before and after prosthetic implantation. The femorotibial angle was measured simultaneously by the navigation system at every 10° throughout the range of movement. It was found that posterior-stabilised knees had more varus-valgus laxity than cruciate-retaining knees at all angles examined, and the differences were statistically significant at 10° (p = 0.0093), 20° (p = 0.0098) and 30° of flexion (p = 0.0252).

Validating a Markov model of treatment for hepatitis C virus-related hepatocellular carcinoma.

OBJECTIVE: We created and validated a Markov model to simulate the prognosis with treatment for HCV-related hepatocellular carcinoma (HCC) for assessment of cost-effectiveness for alternative treatments of HCC. METHOD: Markov state incorporated into the model consisted of the treatment as a surrogate for HCC stage and underlying liver function. Retrospective data of 793 patients from three university hospitals were used to determine Kaplan-Meier survival curves for each treatment and transition probabilities were derived from them. RESULTS: There was substantial overlap in the 95% CIs of the Markov model predicted and the Kaplan-Meier survival curves for each therapy. The predicted survival curves were also similar with those from the nationwide survey data supporting the external validity of our model. CONCLUSIONS: Our Markov model estimates for prognosis with HCC have both internal and external validity and should be considered applicable for estimating cost-effectiveness related to HCC.

Anomalous bumpy structures in the capture cross sections of antiprotons by helium.

We investigate the state-specified capture process of antiprotons by helium. Freezing one of the two electrons, we reduce this four-body rearrangement problem into a three-body problem. The capture cross sections are calculated by solving the Chew-Goldberger-type integral equation. Differing from the capture of antiprotons by hydrogen atoms, the bumpy structures are revealed in the total angular momentum dependent capture cross sections. Further analysis shows that the bumps arise from the partial channel closing due to the removal of the energy degeneracy in the antiprotonic helium.

Numerical observation of the rescattering wave packet in laser-atom interactions.

We present a full-quantum nonperturbative method to study the electron rescattering process in the intense laser-atom interactions. We separate the ionized wave function from the background by solving the time-integral equation. Imposing the incoming boundary condition on the wave function, we reproduce the motion of the rescattering wave packet predicted by the rescattering theory. Our calculated rescattering energies differ significantly from the semiclassical ones. The difference would be substantial for the evaluation of the rescattering induced dynamics such as the molecular dissociation.

Deficiency of CIZ, a nucleocytoplasmic shuttling protein, prevents unloading-induced bone loss through the enhancement of osteoblastic bone formation in vivo.

Disuse osteoporosis is a major cause to increase the risk of fractures in bed-ridden patients whose numbers are increasing in our modern society. However, the mechanisms underlying the sensing of mechanical stress in bone are largely unknown. CIZ localizes at cell adhesion plaque and transfers into nuclear compartments and activates promoters of the genes encoding enzymes, which degrade matrix proteins to link signals from the cell adhesion site to nuclear events. We examined whether this nucleocytoplasmic shuttling protein would be involved in mediation of mechanical stress signaling. Unloading based on tail suspension reduced bone volume in wild-type mice. In contrast, CIZ-deficient mice revealed suppression in such reduction of bone mass due to unloading. Histomorphometric analysis revealed that unloading suppressed the levels of osteoblastic bone formation parameters, and such suppression of bone formation parameters was blocked by CIZ-deficiency. Osteoclastic bone resorption parameters were similar regardless of CIZ-deficiency after 2-week unloading. Mineralized nodule formation in the cultures of bone marrow cells obtained from the bone of mice subjected to unloading was suppressed in wild-type mice. CIZ deficiency blocked such reduction in nodule formation induced by unloading. These data indicated that nucleocytoplasmic shuttling protein, CIZ, plays a pivotal role in the response of bone mass in unloading condition.

Unloading-induced bone loss was suppressed in gold-thioglucose treated mice.

Loss of mechanical stress causes bone loss. However, the mechanisms underlying the unloading-induced bone loss are largely unknown. Here, we examined the effects of gold-thioglucose (GTG) treatment, which destroys ventromedial hypothalamus (VMH), on unloading-induced bone loss. Unloading reduced bone volume in control (saline-treated) mice. Treatment with GTG-reduced bone mass and in these GTG-treated mice, unloading-induced reduction in bone mass levels was not observed. Unloading reduced the levels of bone formation rate (BFR) and mineral apposition rate (MAR). GTG treatment also reduced these parameters and under this condition, unloading did not further reduce the levels of BFR and MAR. Unloading increased the levels of osteoclast number (Oc.N/BS) and osteoclast surface (Oc.S/BS). GTG treatment did not alter the basal levels of these bone resorption parameters. In contrast to control, GTG treatment suppressed unloading-induced increase in the levels of Oc.N/BS and Oc.S/BS. Unloading reduced the levels of mRNA expression of the genes encoding osteocalcin, type I collagen and Cbfa1 in bone. In contrast, GTG treatment suppressed such unloading-induced reduction of mRNA expression. Unloading also enhanced the levels of fat mass in bone marrow and mRNA expression of the genes encoding PPARgamma2, C/EBPalpha, and C/EBPbeta in bone. In GTG-treated mice, unloading did not increase fat mass and the levels of fat-related mRNA expression. These results indicated that GTG treatment suppressed unloading-induced alteration in bone loss.

State-specified protonium formation in low-energy antiproton-hydrogen-atom collisions.

We calculate state-specified protonium-formation cross sections in low-energy antiproton-hydrogen-atom collisions by solving the Chew-Goldberger-type integral equation directly instead of integrating the traditional differential scattering equation. Separating the incident wave from the total wave function, we calculate only the scattered outgoing wave propagated by the Green function. The scattering boundary condition is hence automatically satisfied without the tedious procedure of adjusting the wave function at the asymptotic region. The formed protonium atoms tend to be distributed in higher angular momentum l and higher principle quantum number n states as the collision energy increases. The present method has the advantage over the traditional ones in the sense that the required memory size and the computational time are much smaller, and accordingly the problem can be solved with higher accuracy.

Type I interferon receptor and response to interferon therapy in chronic hepatitis C patients: a prospective study.

The type I interferon (IFN) receptor consists of at least two subunits, IFNAR1 and IFNAR2. We previously found a correlation between IFNAR1 and IFNAR2 expression in liver, and a correlation in IFNAR2 expression, but not in IFNAR1, between liver and peripheral blood mononuclear cells (PBMCs). The aim of this study was to prospectively assess whether IFNAR2 expression levels in PBMCs as well as in liver act as markers for predicting response to IFN therapy in chronic hepatitis C patients. Fifty-two Japanese patients with chronic hepatitis C, were enrolled. IFNAR2 mRNA was quantified using competitive polymerase chain reaction, in liver and PBMC specimens, and of the 52 patients assigned to receive a 6-month course of interferon-alpha therapy, 36 patients who received more than 300 million units of interferon were analysed. IFNAR2 mRNA expression levels were significantly higher in liver than in PBMCs in all 36 patients (P = 0.016). Seventeen sustained virologic responders showed lower pretreatment hepatitis C virus (HCV)-RNA levels (P = 0.017) in serum and higher pretreatment levels of IFNAR2 mRNA in liver (P = 0.007), but not in PBMCs, compared with nonsustained virologic responders. In multivariate analysis, these factors were independently associated with a sustained virologic response (i.e. HCV-RNA level: odds ratio 0.23, 95% CI 0.038-0.864; and IFNAR2 in liver: odds ratio 1.116, 95% CI 1.015-1.227). Hence, IFNAR2 expression levels in liver, but not in PBMCs, is predictive of response to IFN treatment in chronic hepatitis C patients.

Interferon treatment improves survival in chronic hepatitis C patients showing biochemical as well as virological responses by preventing liver-related death.

Interferon therapy for chronic hepatitis C reduces the risk of hepatocellular carcinoma, especially among virological and biochemical responders. However, little is known about the effect of interferon therapy on mortality. We studied the long-term effect of interferon therapy on mortality in patients with chronic hepatitis C. For this retrospective cohort study, 2954 patients with chronic hepatitis C were recruited, of whom 2698 received interferon therapy and 256 did not. The effect of interferon therapy on survival was assessed by standardized mortality ratio (SMR) based on published mortality data for the general Japanese population and by risk ratio calculated by proportional hazard regression. Over 6.0 +/- 2.2 years follow-up, death from liver-related diseases was observed in 69 (68%) of 101 deaths among interferon-treated patients and in 42 (81%) of 52 deaths among untreated patients. Compared with the general population, overall mortality was high among untreated patients (SMR: 2.7; 95% CI: 2.0-3.6) but not among interferon-treated patients (SMR: 0.9; 95% CI: 0.7-1.1). Liver-related mortality was extremely high among untreated patients (SMR: 22.2; 95% CI: 16.0-30.0) and less among interferon-treated patients (SMR: 5.5; 95% CI: 4.3-6.9). The risk of death from all causes was lower for interferon-treated than untreated patients (risk ratio: 0.47; 95% CI: 0.261-0.836; P = 0.01). The risk of death from liver-related diseases was significantly lower for sustained virological responders (risk ratio: 0.04; 95% CI: 0.005-0.301; P = 0.002) compared with untreated patients, but not for nonsustained virological responders. Sustained biochemical responders (risk ratio: 0.03; 95% CI: 0.004-0.230; P < 0.001) and transient biochemical responders (risk ratio: 0.18; 95% CI: 0.063-0.532; P = 0.002) showed a significantly reduced risk of death from liver-related death, whereas biochemical nonresponders did not. Hence interferon treatment improved survival in chronic hepatitis C patients showing a biochemical as well as a virological response by preventing liver-related deaths.

Endovascular surgery for intracranial aneurysm. Histopathological analysis after embolization using balloon or coil.

SUMMARY: Recently, endovascular surgery became common approach for management of intracranial aneurysms. Though its efficacy, this approach is still new and under development. Here, we report our clinical experience in patients treated with two methods - balloon or Gugliemi detachable coil. In addition, to understand better the mechanisms underlying postoperative complications, we studied them in histopathological specimens of patients and in a model of experimental aneurysm. From our data we conclude that choice of appropriate therapeutic method should respect specific conditions of patients as well as of facility. Careful postoperative studies including examination of intravascular surface by endovascular scope examination would be useful for prediction of possible complications.

Interferon retreatment reduces or delays the incidence of hepatocellular carcinoma in patients with chronic hepatitis C.

Inhibition of hepatocarcinogenesis is a crucial issue in treating chronic hepatitis C patients, especially those who do not respond completely to interferon therapy. Interferon has been reported to reduce the incidence of hepatocellular carcinoma (HCC) not only in sustained virological responders but also in transient biochemical responders. However, the incidence of HCC increases in 5 years or more after interferon therapy in transient biochemical responders. The aim of this study is to assess whether interferon retreatment reduces the incidence of HCC in chronic hepatitis C patients in whom hepatitis C virus was not eradicated during initial interferon therapy. We enrolled 309 patients who were not sustained virological responders after initial interferon treatment consisting of a total dose of more than 250 megaunits of interferon and were followed for more than 2 years after treatment. Ninety-nine patients received interferon retreatment and 210 did not. Two courses of interferon therapy were administered in 84, three courses in 14 and five courses in one. The incidence of HCC was compared between patients with retreatment and those without. In the clinical characteristics, retreated patients were younger and followed up for a longer time period. The cumulative incidence of HCC was significantly lower in retreated patients. In multivariate analysis, patients' age (P=0.018) and the number of courses of interferon therapy (P=0.022) were independently associated with HCC incidence. These results suggest that interferon retreatment reduces or delays the incidence of HCC in chronic hepatitis C patients who did not completely respond to initial therapy.

Single nucleotide polymorphisms of the mannose-binding lectin are associated with susceptibility to primary biliary cirrhosis.

Although the immunopathogenesis of primary biliary cirrhosis (PBC) remains unknown, familial clustering of patients with PBC suggests an important role for genetic factors. In addition, recent data support the thesis that the mucosal immune response against intraluminal pathogens may be involved with the onset of PBC. Mannose-binding lectin (MBL) is a key factor in innate mucosal defenses and has several key single nucleotide polymorphisms (SNPs). To study whether MBL gene SNPs are associated with susceptibility to PBC, we studied 65 patients with PBC and 218 controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequence specific priming-polymerase chain reaction (SSP-PCR) to examine four polymorphic loci: two (H/L and X/Y) within the promoter region and the other two (P/Q and A/B) within exon-1. We also analyzed serum MBL concentrations. Interestingly, the prevalence of haplotype HYPA, leading to hyper-production of MBL, as well as HYPA/HYPA genotype were significantly increased in PBC compared to controls (0.53 vs. 0.44, P=0.031; 33.9%vs. 17.0%, P=0.003, respectively). Furthermore, individuals homozygous for HYPA had a significantly increased risk for PBC (odds ratio (OR)=2.51, 95% confidence interval (CI)=1.34-4.66). Our results demonstrate that the MBL genotype can be significantly associated with increased risk for PBC, and further, that increased production of MBL plays a critical role in immunopathogenesis.

Frequent presence of HBV in the sera of HBsAg-negative, anti-HBc-positive blood donors.

BACKGROUND: Recent studies have revealed that HBV may not be cleared even after the disappearance of serum HBsAg. The purpose of this study was to investigate whether the replication of HBV persists in HBsAg-negative blood donors who lack apparent liver disease. STUDY DESIGN AND METHODS: Serum HBV was examined by using PCR coupled with Southern blotting in 50 blood donors who were identified to be HBsAg negative but anti-HBc positive. RESULTS: HBV DNA was detected in the sera from 19 (38%) of 50 donors. In 11 of the 19, HBV existed exclusively as immune complexes, while HBV presumably did not exist as immune complexes in the remaining eight. The levels of HBV DNA were similar to those in patients who had recovered from acute HBV. Some nucleotide substitutions, which did not confer amino acid changes in the major epitope of HBsAg, were found in the preS-S regions. CONCLUSION: The replication of HBV is ongoing in a substantial proportion of healthy blood donors who have anti-HBc. Blood from such donors may contain very low levels of HBV free of immune complex formation and should be excluded for transfusion. The fact that such blood donors apparently lacked liver disease suggests no pathogenicity of such "occult" HBV.

A possible role of hypervariable region 1 quasispecies in escape of hepatitis C virus particles from neutralization.

We examined serial changes in the hypervariable region 1(HVR1) quasispecies both in immune and nonimmune complexed hepatitis C virus (HCV) particles from 12 patients with chronic hepatitis C to elucidate the mechanism by which genetic diversification of HCV during the course of infection allows escape of virus from the humoural immune response. Immune and nonimmune complexes were separated by differential flotation centrifugation and immunoprecipitation, and their HVR1 quasispecies were determined by subcloning and sequencing. The presence of a specific antibody against a specific viral clone in serum was examined in two patients by Western blotting of the corresponding recombinant HVR1 protein. The distribution of HVR1 quasispecies in both immune and nonimmune complexes conspicuously changed over time in most of the patients studied. In seven patients, various HCV clones serially shifted from nonimmune complexes to immune complexes. In four of them, a group of clones with similar HVR1 sequences to each other remained predominant in nonimmune complexes, whereas minor clones with sequences considerably divergent from the predominant clones shifted from nonimmune complexes to immune complexes. These results suggest a mechanism for persistent infection of HCV, in which major HCV clones escape from neutralization by anti-HVR1 antibodies by generating considerably divergent minor 'decoy' clones which may be preferentially neutralized.

Differentiation of human acute myeloid leukaemia cells in primary culture in response to cotylenin A, a plant growth regulator.

Cotylenin A, which has a diterpenoid tricarbocyclic skeleton, has been isolated as a plant growth regulator, has been shown to affect several physiological processes of higher plants and have differentiation-inducing activity in several myeloid leukaemia cell lines. We examined the effect of cotylenin A on the differentiation of leukaemic cells that were freshly isolated from acute myeloid leukaemia (AML) patients in primary culture. Cotylenin A significantly stimulated both functional and morphological differentiation of leukaemia cells in 9 out of 12 cases. This differentiation-inducing activity was more potent than those of all-trans retinoic acid and 1alpha,25-dihydroxyvitamin D3 (VD3). Treatment with a combination of cotylenin A and VD3 was more effective than cotylenin A or VD3 alone at inducing the monocytic differentiation of AML cells.

Geographic distribution of hepatitis B virus (HBV) genotype in patients with chronic HBV infection in Japan.

The geographic distribution of hepatitis B virus (HBV) genotypes in Japan and its clinical relevance are poorly understood. We studied 731 Japanese patients with chronic HBV infection. HBV genotype was determined by the restriction fragment length polymorphism (RFLP) method after polymerase chain reaction (PCR). Of the 720 patients with positive PCR, 12 (1.7%) were HBV genotype A, 88 (12.2%) were genotype B, 610 (84.7%) were genotype C, 3 (0.4%) were genotype D, and 7 (1.0%) were of mixed genotype. Over 94% of patients on the Japanese mainland had genotype C, while 60% of the patients on Okinawa, the most southern islands, and 22.9% in the Tohoku area, the northern part of the mainland, harbored genotype B. Compared with genotype C patients, genotype B patients were older (53.6 to 42.2 years; P <.01), had a lower rate of positive hepatitis B e antigen (HBeAg) (18.4% to 50.6%; P <.01), and a lower level of serum HBV DNA (5.02 to 5.87 log genome equivalents (LGE)/mL; P <.01). The mean age of the genotype B patients with hepatocellular carcinoma was 70.1 +/- 9.2 years, compared with 55.2 +/- 9.7 of genotype C patients (P <.01). These results indicate that genotypes C and B are predominant in Japan, and there are significant differences in geographic distribution and clinical characteristics among the patients with the different genotypes.

[A possible role of human leukocyte antigen(HLA) typing for predicting response to interferon therapy in chronic hepatitis C].

Hepatitis C viral load, genotype and/or staging of liver fibrosis are known to be factors for predicting response to interferon(IFN) therapy in patients with chronic hepatitis C. The aim of this study is to investigate if human leukocyte antigen(HLA) typing is related to the response to IFN therapy. The seventy six Japanese patients were studied and categorized into two groups: 46 patients with chronic hepatitis C (Group A) and 30 with liver disease unrelated to HCV infection(Group B). In addition, 39 patients who were treated with IFN were classified into complete responders(CR) and non-complete responders (NR). There was not any differences in HLA typing between group A and B, but the frequency of HLA class I B51(5) was higher in CR than in NR patients(p = 0.045). When restricted to those who had low viral load(under 10(55) copies/ml) and genotype 2a or 2b, HLA class I CW1 was found in 7 responders(70%) and in 1 non-responder(14%) (p = 0.023). HLA class II DR9 was not found in responders but in 3 non-responders(p = 0.022). These preliminary results suggest that HLA types may be related response to IFN therapy in patients with chronic hepatitis C.