Specific mitochondrial DNA mutation in mice regulates diabetes and lymphoma development

It has been hypothesized that respiration defects caused by accumulation of pathogenic mitochondrial DNA (mtDNA) mutations and the resultant overproduction of reactive oxygen species (ROS) or lactates are responsible for aging and age-associated disorders, including diabetes and tumor development. However, there is no direct evidence to prove the involvement of mtDNA mutations in these processes, because it is difficult to exclude the possible involvement of nuclear DNA mutations. Our previous studies resolved this issue by using an mtDNA exchange technology and showed that a G13997A mtDNA mutation found in mouse tumor cells induces metastasis via ROS overproduction. Here, using transmitochondrial mice (mito-mice), which we had generated previously by introducing G13997A mtDNA from mouse tumor cells into mouse embryonic stem cells, we provide convincing evidence supporting part of the abovementioned hypothesis by showing that G13997A mtDNA regulates diabetes development, lymphoma formation, and metastasis--but not aging--in this model.     

A Paced Auditory Serial Addition Task evokes stress and differential effects on masseter-muscle activity and haemodynamics

This study aimed to determine autonomic and jaw-muscle activities, and haemodynamic responses, to acute experimental mental stress in humans. Eleven healthy men (25.2 ± 3.0 years of age) and five healthy women (23.0 ± 3.7 years of age) performed a standardized mental stress task, the Paced Auditory Serial Addition Task (PASAT). Autonomic function, such as heart rate variability (HRV), and haemodynamic changes were recorded simultaneously. The success rate of the PASAT decreased with increased pace and duration. Low-frequency (5.8 ± 1.1 ms(2)) and high-frequency (5.3 ± 0.6 ms(2)) components of HRV decreased during the PASAT (to 5.0 ± 0.9 ms(2) and 4.6 ± 1.1 ms(2), respectively) as an indication of acute stress. Oxygenated haemoglobin in the masseter muscle (14.6 ± 2.2 10(4) units mm(-3)) remained at an elevated level during the PASAT (15.5 ± 2.5 10(4) units mm(-3)), whereas deoxygenated haemoglobin (7.8 ± 2.3 10(4) units mm(-3)) showed a consistent decrease (to 6.8 ± 2.1 10(4) units mm(-3)). Total haemoglobin and jaw-muscle electromyographic (EMG) activity did not change during the PASAT. Thus, PASAT-induced mental stress changed the parasympathetic/sympathetic balance of the heart and had an acute influence on jaw-muscle haemodynamics, but not on jaw-muscle EMG activity. This non-invasive experimental set-up can be applied to study the effects of repeated or longer-lasting mental stress in order to further the understanding of pathophysiological mechanisms in craniofacial pain conditions.     

Survey on examinations for diagnosis of bone marrow failure in Japan: a report from the Japanese National Research Group on Idiopathic Bone Marrow Failure Syndromes

Using a registration sheet of a prospective registration system for aplastic anemia (AA)/myelodysplastic syndromes (MDS), by the National Research Group on Idiopathic Bone Marrow Failure Syndromes, Japan, we carried out a survey on examinations for diagnosis of bone marrow failure. Bone marrow trephine biopsy was performed in 66 of 105 cases (63%) [Original diagnosis: AA 51 cases (80%), MDS 12 (32%), undiagnosable 3 (75%)]. Bone marrow aspiration was performed in all cases, and aspiration was performed at least twice in 36 cases (34%). The first-line anatomic site for bone marrow aspiration was the posterior iliac crest (62%). Cytogenetic examination was performed in 93%. The concordance rate between the original and the central review diagnosis was 93% among the studied cases: AA, Idiopathic cytopenia of undetermined significance (ICUS) and MDS in total. Flow cytometry analysis to detect paroxysmal nocturnal hemoglobinuria (PNH)-type blood cells was performed in 32%.     

Effects of tacrolimus on dermatomyositis and polymyositis: a prospective, open, non-randomized study of nine patients and a review of the literature

Dermatomyositis (DM) and polymyositis (PM) are often refractory to conventional therapy with corticosteroids sometimes combined with immune-suppressing agents and can lead to severe disability if these treatments are unsuccessful. In this prospective, open, non-randomized study, we examined the efficacy of tacrolimus (FK506), an immunosuppressant, in nine patients with DM (n?=?5) or PM (n?=?4) who did not respond to previous therapy. Outcomes included compound muscle strength, ambulatory status, and serum creatine kinase activity measured at intervals after starting tacrolimus. At 6?months after the introduction of tacrolimus, all five patients with DM and three patients with PM showed clinical improvements. Patients with a disease duration of <4?years and those with trough level of tacrolimus >5?ng/ml tended to have better outcomes than those with longer disease duration or lower trough levels. There were no side effects other than moderate hypertension and aggravation of diabetes mellitus. Tacrolimus was beneficial in the majority of patients with PM or DM refractory to corticosteroid therapy. It was also effective in four patients who were previously treated with other immunosuppressants or intravenous immunoglobulin combined with corticosteroids. These results warrant further studies as to the efficacy of tacrolimus compared to other immunosuppressing agents.     

Successful treatment of a chronic-phase T-315I-mutated chronic myelogenous leukemia patient with a combination of imatinib and interferon-alfa

The T315I BCR-ABL mutation in chronic myelogenous leukemia (CML) patients is responsible for up to 20% of all clinically observed resistance. This mutation confers resistance not only to imatinib, but also to second-generation BCR-ABL tyrosine kinases, such as nilotinib and dasatinib. A number of strategies have been implemented to overcome this resistance, but allogeneic stem cell transplantation remains the only established therapeutic option for a cure. A 61-year-old male was diagnosed with Philadelphia chromosome-positive chronic-phase CML in 2002. He was initially treated with imatinib and complete cytogenetic response (CCyR) was achieved 12 months later. However, after 18 months, a loss of CCyR was observed and a molecular study at 24 months revealed a T315I mutation of the BCR-ABL gene. At 30 months, imatinib/interferon-alfa (IFNα) combination therapy was initiated in an effort to overcome the resistance. Thirty months later, he re-achieved CCyR, and the T315I BCR-ABL mutation disappeared at 51 months. To our knowledge, this is the first case report showing the effectiveness of imatinib/IFNα combination therapy for CML patients bearing the T315I BCR-ABL mutation.     

High WT1 mRNA expression after induction chemotherapy and FLT3-ITD have prognostic impact in pediatric acute myeloid leukemia: a study of the Japanese Childhood AML Cooperative Study Group

The prognostic value of WT1 mRNA expression in pediatric acute myeloid leukemia (AML) remains controversial. A sample of newly diagnosed (n?=?158) AML patients from the Japanese Childhood AML Cooperative Treatment Protocol, AML 99, were simultaneously analyzed for WT1 expression, cytogenetic abnormalities and gene alterations (FLT3, KIT, MLL, and RAS). WT1 expression (including more than 2,500 copies/??gRNA) was detected in 122 of the 158 (77.8?%) initial diagnostic AML bone marrow samples (median 45,500 copies/??gRNA). Higher WT1 expression was detected in French American British (FAB)-M0, M3, M7 and lower expression in M4 and M5. Higher WT1 expression was detected in AML with inv(16), t(15;17) and Down syndrome and lower in AML with 11q23 abnormalities. Multivariate analyses demonstrated that FLT3-internal tandem duplication (ITD), KIT mutation, MLL-partial tandem duplication were correlated with poor prognosis; however, higher WT1 expression was not. FLT3-ITD was correlated with WT1 expression and prognosis. Furthermore, 74 WT1 expression after induction chemotherapy was analyzed. Higher WT1 expression after induction chemotherapy was significantly correlated with M1 or M2/M3 marrow, FLT3-ITD and poor prognosis. Multivariate analyses in 74 AML patients revealed that FLT3-ITD, MLL-PTD, and KIT mutations were associated with poor prognosis; however, NRAS Mutation, KRAS mutation and high WT1 expression (>10,000 copies/??gRNA) did not show poor prognosis. Our findings suggest that higher WT1 expression at diagnosis does not correlate with poor prognosis, but that WT1 expression after induction chemotherapy is considered to be a useful predictor of clinical outcome in pediatric AML.     

The administration of pitavastatin augments creatinine clearance associated with reduction in oxidative stress parameters: acute and early effects

Background

Chronic kidney disease (CKD) is a serious health problem worldwide. Therapies that can halt the progression of CKD are limited, and the identification of new strategies for CKD treatment is therefore important. Pitavastatin, one of the newest statins introduced to the market, has been shown to exhibit some beneficial effects on renal and endothelial function.

Method

We enrolled 12 healthy volunteers for our study. With or without pitavastatin administration, creatinine clearance (Ccr), urinary albumin excretion, lipid status, and oxidative stress markers were evaluated in acute and early phases after administration of the drug.

Results

A single pitavastatin administration increased Ccr and reduced oxidative stress parameters, such as 8-OHdG levels and isoprostane production, within 6 h, without altering lipid status in healthy participants. A two-week treatment with pitavastatin lowered total and LDL cholesterol and triglycerides but not HDL cholesterol at 7 and 14 days. This change in lipid profile is associated with enhanced Ccr and the suppression of oxidative stress parameters. Urinary albumin excretion was reduced after either acute or chronic administration of pitavastatin, although this effect was not yet significant.

Conclusion

We found that pitavastatin augmented Ccr and reduced oxidative stress parameters in healthy subjects. These data suggest that pitavastatin affects renal outcomes in both lipid status-dependent and -independent manners. These observations suggest that pitavastatin treatment could be beneficial for CKD patients.     

A case of naturally occurring visual field loss in a chimpanzee with an arachnoid cyst

Deficits in the occipital cortex have varying consequences among mammalian species. Such variations are indicative of evolutionary transitions in the striate cortical contribution to visually guided behavior. However, little is known about the role of the striate cortex in visually guided behavior in chimpanzees due to ethical concerns about invasive experiments and methodological limitations such as the inability to monitor gaze movements. We had the opportunity to study the behavioral consequences of a deficit in the occipital cortex in a chimpanzee with a naturally occurring arachnoid cyst in her right occipital lobe. We assessed the chimpanzee's ability to detect a small light probe (0.5 visual degree, Michelson contrast>0.9) presented at several locations in the visual field while monitoring gaze direction using an infra-red remote eye-tracker recently introduced to studies of great apes. The results showed the chimpanzee was unable to detect the probe in the lower left quadrant of the visual field, suggesting severe loss of contrast sensitivity in a part of hemivisual field that is retinotopically corresponded to the hemisphere of the cyst. A chimpanzee with a naturally occurring deficit in the right striate cortex and the availability of remote eye-tracking technology presented a unique opportunity to compare the role of the occipital lobe in visually guided behavior among various primate species.