The anterior medullary–anterior pontomesencephalic venous system and its bridging veins communicating to the dural sinuses: normal anatomy and drainage routes from dural arteriovenous fistulas

Introduction  We evaluated the normal venous anatomy of the anterior medullary/anterior pontomesencephalic venous (AMV/APMV) system and bridging veins connected to the dural sinuses using magnetic resonance (MR) imaging and demonstrated cases of dural arteriovenous fistulas (DAVFs) with bridging venous drainage. Materials and methods  MR images obtained using a 3D gradient echo sequence in 70 patients without lesions affecting the deep or posterior venous channels were reviewed to evaluate the normal anatomy of the AMV/APMV system and bridging veins. MR images and digital subtraction angiography in 80 cases with intracranial or craniocervical junction DAVFs were reviewed to evaluate the bridging venous drainage from DAVFs. Results  MR images clearly revealed AMV/APMV in 35 cases. Fifteen cases showed a direct connection between AMV and APMV, while 15 cases showed an indirect communication via the transverse pontine vein or the bridging vein. In the five remaining cases, the AMV and APMV end separately to the bridging vein or the transverse pontine vein. Bridging veins were identified in 34 cases, connecting to the cavernous sinus in 33, to the suboccipital cavernous sinus in 11, and the inferior petrosal sinus in five cases. In 80 DAVF cases, seven of 40 cavernous sinus DAVFs, two craniocervical junction DAVFs, and one inferior petrosal sinus DAVF drained via bridging veins to the brain stem. Conclusion  The AMV/APMV and bridging veins showed various anatomies and frequently showed a connection to the cavernous sinus. Knowledge of the venous anatomy is helpful for the diagnosis and intravascular treatment of DAVFs.     

A requirement for DICER to maintain full promoter CpG island hypermethylation in human cancer cells

Promoter hypermethylation is a prevalent phenomenon, found in virtually all cancer types studied thus far, and accounts for tumor suppressor gene silencing in the absence of genetic mutations. The mechanism behind the establishment and maintenance of such aberrant hypermethylation has been under intense study. Here, we have uncovered a link between aberrant gene silencing associated with promoter CpG island DNA methylation and the siRNA/miRNA processing enzyme, DICER, in human cancer cells. By comparing demethylated HCT116 colon cancer cells with HCT116 cells genetically rendered hypomorphic for DICER, we identified a group of epigenetically silenced genes that became reactivated in the absence of functional DICER. This reactivation is associated with a dramatic loss of localized promoter DNA hypermethylation. Thus, intact DICER is required to maintain full promoter DNA hypermethylation of select epigenetically silenced loci in human cancer cells.     

Previous or Occult Hepatitis B Virus Infection in Hepatitis C Virus-Associated Hepatocellular Carcinoma Without Hepatic Fibrosis

We investigated the role of hepatitis B virus infection in development of hepatocellular carcinoma in hepatitis C virus-infected patients without hepatic fibrosis. Of 253 patients, 8 lacked hepatic fibrosis (group 1); group 2 included the remaining 245 patients. Clinicopathologic findings were compared between the groups. Hepatitis B x gene was sought in cancers and adjoining noncancerous liver. Group 1 showed better liver function parameters and milder active hepatitis than group 2. The proportion of patients with anti-hepatitis B virus antibody tended to be higher in group 1 than in group 2. The proportion of patients with hepatitis B x RNA in cancers was significantly higher in group 1 than in group 2. All group 1 patients had previous or occult hepatitis B virus infection. Previous or occult hepatitis B virus infection may be critical in development of hepatocellular carcinomas in hepatitis C virus-infected patients without hepatic fibrosis.     

Retinal mean transit time in patients with primary open-angle glaucoma and normal-tension glaucoma

PURPOSE: To compare the mean transit time (MTT) of retinal circulation in eyes with primary open-angle glaucoma (POAG) and eyes with normal-tension glaucoma (NTG) and examine the possible relationship between MTT and visual field damage, expressed as mean deviation (MD). METHODS: Video fluorescein angiography was performed in 40 patients with POAG or NTG. Dye curves for fluorescein passing through the retinal arteries and veins were used to calculate MTT in each patient with a computer-assisted technique based on an impulse-response analysis (MTT(IR)). RESULTS: We were able to analyse MTT(IR) in all 40 angiograms. Mean (SD) MTT(IR) was 5.0 (1.5) seconds in eyes with POAG and 4.7 (1.4) seconds in eyes with NTG. The difference was not statistically significant. There was a weak but significant correlation between the MD and MTT(IR) (MTT(IR) = 4.12-0.08*MD; r = -0.49, p = 0.0013). CONCLUSIONS: The results demonstrate that loss of neuronal tissue in glaucoma is combined with an effect on the retinal circulation and that the effect is similar in eyes with NTG and eyes with POAG.     

A new lipophilic pro-vitamin C, tetra-isopalmitoyl ascorbic acid (VC-IP), prevents UV-induced skin pigmentation through its anti-oxidative properties

BACKGROUND: Vitamin C, which is a strong anti-oxidant, plays an important role in maintaining physiological states. In dermatology, Vitamin C is used for treatment of various skin problems such as de-pigmentation of hyperpigmented spots. However, Vitamin C has limited stability and permeability, and development of a Vitamin C derivative with improved properties is needed. OBJECTIVE: We evaluated the effect of a lipophilic Vitamin C derivative, tetra-isopalmitoyl ascorbic acid (VC-IP), on ultraviolet (UV)-induced skin pigmentation, to determine its potential as a more effective form of Vitamin C. METHODS: The release of Vitamin C from VC-IP was examined using a reconstructed skin model following topical application of VC-IP. Anti-oxidative and anti-inflammatory activities of VC-IP were tested in cultured human keratinocytes. Subsequently, clinical test was done to clarify the effect of VC-IP on UVB-induced skin pigmentation. RESULTS: VC-IP released Vitamin C in physiological conditions and worked as pro-Vitamin C. In subsequent experiments, we found that VC-IP suppressed the elevation of intracellular peroxide after UVB irradiation, and enhanced cellular tolerance against UVB and reactive oxygen species such as hydrogen peroxide and tert-butyl hydroperoxide. Furthermore, VC-IP reduced the production of interleukin-1alpha and prostaglandin E2 in UVB-irradiated keratinocytes and suppressed melanocyte proliferation in conditioned culture medium prepared from UVB-irradiated keratinocytes. Finally, in a clinical study, topical application of a 3% VC-IP cream for 3 weeks suppressed pigmentation after UVB irradiation. CONCLUSIONS: These results demonstrate that VC-IP is a precursor of Vitamin C, and effectively suppresses UVB-induced skin pigmentation, possibly through its anti-oxidative activity.     

Combination of early and delayed SPET imaging using technetium-99m ethyl cysteinate dimer immediately after local intra-arterial thrombolysis

The aim of this study was to investigate the prognostic utility of post-treatment technetium-99m ethyl cysteinate dimer (^99mTc-ECD) single-photon emission tomography (SPET) for predicting ischemic tissue outcome in cases involving embolic middle cerebral artery occlusion treated with local intra-arterial thrombolysis. We examined twenty-five patients with a moderately ischemic area determined using pretreatment technetium-99m hexamethylpropylene amine oxime (^99mTc-HMPAO) SPET, and with complete recanalization within 6 h. Post-treatment ^99mTc-ECD SPET studies, consisting of scanning for 0.5-6.5 min (early scan) and 15-21 min (delayed scan) after tracer injection, were performed immediately after thrombolysis. The extent of the affected area outlined on pretreatment ^99mTc-HMPAO SPET was used for the post-treatment early and delayed ^99mTc-ECD SPET images, and the AR/CE ratio (ratio of affected regional activity to cerebellar activity) was calculated. The washout index of ^99mTc-ECD in the affected area was also calculated by dividing the difference between the AR/CE ratio in the early and delayed images by the AR/CE ratio in the early image. Twelve patients without infarction or with small subcortical/basal ganglial infarction, ten with medium or large cortical infarction, and three with hemorrhage were identified by follow-up computed tomography. Although the AR/CE ratio in post-treatment early ^99mTc-ECD SPET images was significantly higher in the hemorrhagic group than in the cortical infarction group, this value did not differentiate the reversible ischemia group from either the cortical infarction or the hemorrhagic group. The AR/CE ratio in post-treatment delayed ^99mTc-ECD SPET images statistically differentiated the reversible ischemia group from both the cortical infarction and the hemorrhagic group. However, the difference between the cortical infarction and hemorrhagic groups was not statistically significant. The washout index of ^99mTc-ECD statistically differentiated all three groups. This study demonstrated that a combination of early and delayed ^99mTc-ECD SPET imaging performed immediately after thrombolysis predicts ischemic tissue outcome.     

Epigenetic inactivation of CHFR in human tumors

Cell-cycle checkpoints controlling the orderly progression through mitosis are frequently disrupted in human cancers. One such checkpoint, entry into metaphase, is regulated by the CHFR gene encoding a protein possessing forkhead-associated and RING finger domains as well as ubiquitin-ligase activity. Although defects in this checkpoint have been described, the molecular basis and prevalence of CHFR inactivation in human tumors are still not fully understood. To address this question, we analyzed the pattern of CHFR expression in a number of human cancer cell lines and primary tumors. We found CpG methylation-dependent silencing of CHFR expression in 45% of cancer cell lines, 40% of primary colorectal cancers, 53% of colorectal adenomas, and 30% of primary head and neck cancers. Expression of CHFR was precisely correlated with both CpG methylation and deacetylation of histones H3 and H4 in the CpG-rich regulatory region. Moreover, CpG methylation and thus silencing of CHFR depended on the activities of two DNA methyltransferases, DNMT1 and DNMT3b, as their genetic inactivation restored CHFR expression. Finally, cells with CHFR methylation had an intrinsically high mitotic index when treated with microtubule inhibitor. This means that cells in which CHFR was epigenetically inactivated constitute loss-of-function alleles for mitotic checkpoint control. Taken together, these findings shed light on a pathway by which mitotic checkpoint is bypassed in cancer cells and suggest that inactivation of checkpoint genes is much more widespread than previously suspected.     

Reduced-intensity stem-cell transplantation for adult acute lymphoblastic leukemia: a retrospective study of 33 patients

Efficacy of reduced-intensity stem-cell transplantation (RIST) for acute lymphoblastic leukemia (ALL) was investigated in 33 patients (median age, 55 years). RIST sources comprised 20 HLA-identical related donors, five HLA-mismatched related, and eight unrelated donors. Six patients had undergone previous transplantation. Disease status at RIST was first remission (n=13), second remission (n=6), and induction failure or relapse (n=14). All patients tolerated preparatory regimens and achieved neutrophil engraftment (median, day 12.5). Acute and chronic graft-versus-host disease (GVHD) developed in 45 and 64%, respectively. Six patients received donor lymphocyte infusion (DLI), for prophylaxis (n=1) or treatment of recurrent ALL (n=5). Nine patients died of transplant-related mortality, with six deaths due to GVHD. The median follow-up of surviving patients was 11.6 months (range, 3.5-37.3 months). The 1-year relapse-free and overall survival rates were 29.8 and 39.6%, respectively. Of the 14 patients transplanted in relapse, five remained relapse free for longer than 6 months. Cumulative rates of progression and progression-free mortality at 3 years were 50.9 and 30.4%, respectively. These findings suggest the presence of a graft-versus-leukemia effect for ALL. RIST for ALL is worth considering for further evaluation.     

Ketone bodies as markers for Type 1 (insulin-dependent) diabetes and their value in the monitoring of diabetic control

Summary Serum levels of acetoacetate, 3-hydroxybutyrate and the 3-hydroxybutyrate/acetoacetate ratio were determined in Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic patients by a new sensitive method. Efforts were made to differentiate Type 1 and Type 2 diabetes by serum levels of ketone bodies and to determine whether their measurement is a useful way of monitoring diabetic control. In Type 2 diabetes, serum levels of total ketone bodies did not exceed 2.0 mmol/l even if the patients were untreated or poorly controlled. In Type 1 diabetic subjects, treated with once or twice daily injections of insulin, morning serum levels of acetoacetate, 3-hydroxybutyrate and total ketone bodies were significantly elevated by four-, ten- and sevenfold, respectively. In Type 2 diabetic subjects treated with diet or sulphonylureas, serum levels of 3-hydroxybutyrate were highest before breakfast, next highest before dinner and decreased after each meal. The changes were roughly inversely proportional to serum insulin levels. In addition, insulin treatment normalized fasting serum levels of ketone bodies better than diet or sulphonylurea treatment. Acetoacetate was also significantly increased in both types of diabetes to a lesser extent, but no apparent diurnal rhythm was observed. Determination of serum levels of ketone bodies is useful for the diagnosis of Type 1 diabetes (those with total ketone bodies > 2 mmol/l) and for detecting insufficient insulin therapy.     

Long-term survival and aldosterone secretion pattern of aldosteronoma in culture

In an attempt to obtain an in vitro experimental model for aldosteronoma, primary culture was initiated with adenomas from 3 patients with primary aldosteronism. The cells grown in culture retained the morphology and functional properties characteristic of aldosteronoma cells well for periods of up to 200 days. The cells formed monolayer cell colonies and showed an epithelioid morphology with small nuclei containing prominent nucleoli. The cells possessed a clear, eosinophilic cytoplasm resembling that of aldosteronoma cells in vivo. The cultured cells continued to secrete large amounts of aldosterone throughout the culture period. The cells responded to angiotensin II and III by increased release of aldosterone into the culture medium. They also responded to Db-cAMP and ACTH by increased secretion of the hormone.