Pharmacokinetics of anticoagulants apixaban, dabigatran, edoxaban and rivaroxaban in elderly Japanese patients with atrial fibrillation treated in one general hospital.

Steady-state plasma concentrations of anticoagulants and the time since the previous administration in mainly outpatients with atrial fibrillation administered standard or reduced doses were analyzed for 110 elderly Japanese subjects (mean age, 76 years) treated with apixaban (2.5 or 5.0 mg twice daily), dabigatran etexilate (110 or 150 mg twice daily), edoxaban (30 or 60 mg once daily) or rivaroxaban (10 or 15 mg once daily) at one general hospital. The pharmacokinetics in patients treated with standard and reduced doses of the four anticoagulants using liquid chromatography-tandem mass spectrometry was compared with the concentration ranges estimated using physiologically based pharmacokinetic modeling. Reduced doses of anticoagulants resulted in relatively small pharmacokinetic variations compared with the standard dose. Statistical analyses revealed that renal impairment is likely not the sole determinant factor for high plasma concentrations of apixaban, dabigatran, edoxaban and rivaroxaban. Patients with atrial fibrillation should be treated with the correct doses of oral anticoagulants as specified in the package inserts (e.g. reduced doses for elderly patients, patients with low body weights and in combination with P-glycoprotein inhibitor drugs) to avoid excessive or insufficient doses of direct oral anticoagulants.

Vertebral artery-to-vertebral artery bypass with interposed radial artery or occipital artery grafts: surgical technique and report of three cases.

BACKGROUND: The treatment of unclippable vertebral artery (VA) aneurysms incorporating the posterior inferior cerebellar artery with parent artery preservation is among one of the most formidable challenges for cerebrovascular microsurgery and endovascular surgery. We propose that intracranial VA reconstruction using an extracranial VA-to-intracranial VA (VA-VA) bypass with a radial artery graft or an occipital artery graft may be an additional technique in the armamentarium to treat these formidable lesions. The rationale, surgical technique, and complications are discussed. METHODS: Three illustrative cases are described, in which the lesions were a VA dissecting aneurysm with ischemic lesions, bilateral asymptomatic unruptured VA aneurysms, and a VA giant aneurysm with subarachnoid hemorrhage. RESULTS: The partial extreme lateral infrajugular transcondylar approach was used. Computed tomographic angiography was useful for preoperative evaluation of the depth of the distal aneurysmal neck. A VA-VA bypass was performed in two patients. Because there was another ipsilateral aneurysm at the V2 segment in one patient, an external carotid artery-VA bypass was performed. Although two patients were discharged with good clinical results, one patient with subarachnoid hemorrhage died because of brainstem infarction. CONCLUSIONS: The VA-VA bypass using a radial artery graft or an occipital artery graft is an option that can be considered in the strategy for treating VA aneurysms to preserve the normal anatomic vascular configuration in the posterior circulation.

Frequent and variable abnormalities in p14 tumor suppressor gene in glioma cell lines.

Ten glioma cell lines were examined for abnormalities of exon 1beta of the p14 gene and then for abnormalities of the entire p14 gene with the use of previous findings of other exons. Abnormalities of exon 1beta and the entire p14 gene were detected in eight of ten cases: homozygous deletion of the entire gene in six cases, hemizygous deletion of exon 1beta with homozygous deletion of downstream exons in one case, and hemizygous deletion of the entire coding region with a missense mutation (A97V) at the C-terminal nucleolar localization domain in one case. The remaining two cases revealed no such abnormalities. p14 gene expression was observed in the latter two cases and one case with A97V mutation in the hemizygously deleted coding region, but not in the others, including one case with only exon 1beta. In the three cases with p14 gene expression, immunocytochemistry revealed p14 nucleolar staining, suggesting the retention of the functional activity of p14 protein and, in the case with the A97V mutation, an insufficient mutational effect as well. The present findings of the frequent and variable p14 gene abnormalities, including rare-type ones with or without sufficient mutational effect in glioma cell lines, might be of value for better understanding of the p14 gene and its related pathways in glioma carcinogenesis.

Altered chemical metabolites in the amygdala-hippocampus region contribute to autistic symptoms of autism spectrum disorders.

BACKGROUND: Although several previous studies have been conducted, the neural basis of autism spectrum disorder (ASD) is poorly understood. The objective of the present study was to determine whether individuals with ASD have altered brain chemical metabolites and whether such alterations are related to their autistic symptoms. METHODS: N-acetylaspartate (NAA)/creatine (Cr) and choline/Cr ratios in the right medial temporal lobe (MTL), medial prefrontal cortex, and cerebellar vermis were measured in 38 individuals with ASD (mean age = 12.9 years), including 12 with autism, 15 with Asperger's Disorder, and 11 with pervasive developmental disorder not otherwise specified (PDD-NOS), and 16 matched healthy control subjects (mean age = 11.5 years) with proton magnetic resonance spectroscopy. Autistic symptoms were assessed by the Childhood Autistic Rating Scale-Tokyo Version. RESULTS: There was a significant group difference for NAA/Cr ratio in the right MTL between the autism, Asperger's Disorder, PDD-NOS, and control groups (p < .001), and the autism group had a significantly lower NAA/Cr ratio compared with the PDD-NOS (p < .001) and control (p < .001) groups. In the ASD group, there was a significant negative correlation between NAA/Cr ratio in the right MTL and their Childhood Autistic Rating Scale-Tokyo Version total scores (r = -.44, p = .01) and subscales of emotional response (r = -.38, p = .02) and listening response (r = -.54, p = .001). CONCLUSIONS: The results of the present study suggest that subjects with ASD have abnormalities of neural integrity in the amygdala-hippocampus region that are related to their severity and social impairments.

Primary malignant lymphoma of the brain: frequent abnormalities and inactivation of p14 tumor suppressor gene.

Ten primary central nervous system lymphomas (PCNSL, brain lymphomas) were examined for p14 gene exon 1beta deletion, mutation and methylation by Southern blot analysis, nucleotide analysis of polymerase chain reaction clones and Southern blot-based methylation assay. In Southern blot analysis, from the signal densities of the hybridized bands and their similarities to those of exons 2 and 3 in our previous quantitative study, we found that exon 1beta was homozygously deleted in four cases, hemizygously deleted in five cases and not deleted in one case. Thus, the same deletion patterns covered the entire p14 gene for all cases except for one case, which suggested the hemizygous deletion of exons 1beta and 2 and homozygous deletion of exon 3. In addition, although exon 1beta mutation is rare in various tumors, we detected a missense mutation (L50R) in one case with a hemizygous deletion. Methylation of the 5'CpG island of the p14 gene was not suggested for any case without homozygous deletion. Our observation of frequent p14 gene abnormalities (90%) and inactivation (40-60%) was in striking contrast to the same pathological subtype of systemic lymphoma in which p14 gene abnormalities and inactivation were infrequent, suggesting a difference in carcinogenesis between PCNSL and systemic lymphoma.

[Optimal treatment of urolithiasis pain].

Many drugs have been used in the treatment of renal colic, but the safest and most effective drug has not yet been clearly defined. A questionnaire was used to collate the types of treatment for renal colic used by Japanese urologists. The main treatments were nonsteroidal analgesic (suppository) and anticholinergic agent. A new protocol was developed on the basis of this result, and its effect on renal colic was verified. The combination of an injection of a local anesthetic and pointillage was found to be superior to non-steroidal analgesic anti-inflammatory drugs and anticholinergic agent in terms of both duration of action and effectiveness.

Primary malignant lymphoma of the brain: mutation pattern of rearranged immunoglobulin heavy chain gene.

Using reverse transcription-polymerase chain reaction (RT-PCR), six primary brain lymphomas, pathologically diagnosed as diffuse large B-cell lymphoma, were examined for rearranged VH-D-JH sequences of the immunoglobulin heavy chain gene, focusing on somatic mutations and intraclonal heterogeneity. The reliability of the isolated PCR clones was confirmed by in situ hybridization (ISH) with complementarity-determining region (CDR) 3 oligonucleotide probes. Sequence analysis of the PCR clones revealed a high frequency of somatic mutation, ranging from 8.8 to 27.3% (mean 18.2%) in the VH gene segments in all the lymphomas. A significantly lower frequency of replacement (R) mutations than expected was also seen in their frameworks (FRs) in all cases. These findings suggested that the precursor cells were germinal center (GC)-related cells in these lymphomas. However, despite extensive cloning experiments, intraclonal heterogeneity was not detected in any case except for one in which it could not be ruled out. Thus, it seemed likely that all of our brain lymphomas were derived from GC-related cells and that at least most of them were from post-GC cells.