Management and prognosis of cysts developed on long-term follow-up after Gamma Knife radiosurgery for intracranial arteriovenous malformations

BACKGROUND: Delayed cyst formation is a well-recognized complication after radiosurgery for intracranial AVM. The objective of the present study was the evaluation of the different management options for these lesions and the corresponding prognosis of patients. METHODS: Between 2000 and 2005, 12 patients with intracranial AVM initially treated by GKR were reevaluated at Tokyo Women's Medical University because of delayed cyst formation in the vicinity of the target area. There were 7 men and 5 women. The mean age of the patients was 31.8 years at the time of GKR and 41.1 years at the time of complication. The average period between treatment and diagnosis of the complication constituted 6.7 years. All AVMs had lobar location and showed complete angiographic obliteration after GKR. RESULTS: The most common neurological signs and symptoms at the time of cyst presentation were headache (10 cases) and seizures (4 cases). Two patients were asymptomatic. Three patients underwent surgery soon after the diagnosis of the cyst, whereas initial observation was done in another 9. Among the latter, 5 patients had to be treated surgically thereafter because of persistent or aggravated neurological symptoms associated with radiological cyst expansion. Four other patients, including both asymptomatic ones, are in stable condition without surgery. Follow-up after treatment of the cyst varied from 7 to 60 months (average, 34.3 months). All patients are in good condition. CONCLUSIONS: Although delayed formation of cysts after GKR for intracranial AVM should be considered as a complication of the radiosurgical treatment, it has a relatively good prognosis. Observation can be recommended as initial option for compensated and asymptomatic patients.     

Benefits of cyclosporine absorption profiling in nephrotic syndrome: preprandial once-daily administration of cyclosporine microemulsion improves slow absorption and can standardize the absorption profile

AIM: Cyclosporine is known to improve proteinuria in nephrotic syndrome (NS), but is also associated with drug-related renal impairment. In this case series, therapeutic drug monitoring using the absorption profile was applied to adults with NS to investigate the efficacy and safety of once-daily administration of cyclosporine microemulsion (CSAME). METHODS: Twenty patients received CSAME starting at 100-175 mg/day (1.4-3.1 mg/kg per day) once daily after breakfast. The area under the concentration-time curve up to 4 h after administration of cyclosporine (AUC(0-4 h)) was determined in each patient within 1 week after the start of CSAME treatment. Thereafter, the dose of CSAME was adjusted according to the absorption profile. RESULTS: After 6 months, treatment with CSAME improved efficacy test values compared with those prior to treatment, and the severe nephrotic state was eliminated in all patients. No changes in serum creatinine or blood urea nitrogen levels were observed. The dose of CSAME was adjusted so that AUC(0-4 h) and the peak level fell within the range of target values, resulting in a significant decrease in the mean dose of cyclosporine (P = 0.0001). Time of peak level was variable among patients, but when CSAME was administered before breakfast, good absorption was achieved in all patients. CONCLUSION: By monitoring the absorption profile in patients with NS, a once-daily administration of CSAME was used to achieve both efficacy and a reduction in total exposure to the drug. Preprandial administration provided a more stable absorption profile of cyclosporine. The authors hope this method will become standard procedure during cyclosporine treatment in these patients.     

Promoter hypermethylation profile of cell cycle regulator genes in pituitary adenomas

Aberrant hypermethylation of CpG islands in the promoter region plays a causal role in the inactivation of various key genes involved in the cell cycle regulatory cascade, which could result in a loss of cell cycle control. The aim of the present study was to examine in more detail the prevalence and role of the promoter methylation of genes with a proven involvement in the cell cycle regulation of pituitary adenomas, since their tumorigenesis has not yet been clearly defined. We profiled the CpG island methylation status of a series of well-characterized cell cycle regulation genes: the RB1, p14 ^ARF , p15 ^INK4b , p16 ^INK4a , p21 ^Waf1/Cip1 , p27 ^Kip1 , and p73 genes, in 34 pituitary adenomas as determined by a methylation-specific polymerase chain reaction assay. Promoter hypermethylation of the RB1, p14 ^ARF , p15 ^INK4b , p16 ^INK4a , p21 ^Waf1/Cip1 , p27 ^Kip1 , and p73 genes was detected in 12 (35%), 2 (6%), 11 (32%), 20 (59%), 1 (3%), 0 (0%), and 4 (12%) of the adenomas, respectively. In total, 88% (30 of 34) of the adenomas displayed methylation of at least one of such cell cycle regulatory genes, especially methylation of the member genes of the RB1 pathway (29 of 34; 85%). Promoter hypermethylation of p15 ^INK4b coincided with RB1 and/or p16 ^INK4a methylation, whereas RB1 and p16 ^INK4a methylations tended to be mutually exclusive (p = 0.0048). Furthermore, promoter hypermethylations of p14 ^ARF , p21 ^Waf1/Cip1 , and p73 (not belonging to the member genes of the RB1 pathway) were also coincident with RB1 and/or p16 ^INK4a methylation except in one p73 methylated case. In contrast, none of the clinicopathological features, including the cell proliferation index, was significantly correlated with any particular methylation status. Our results suggested that aberrant hypermethylation of the key cell cycle regulatory genes occurs at a relatively high frequency in pituitary adenomas, especially in RB1 pathway genes with promoter hypermethylation of the p16 ^INK4a gene being the most common deregulation. We further obtained evidence to indicate that RB1 and p16 ^INK4a methylations tended to be mutually exclusive, but did occasionally coincide with other cell cycle regulation gene methylations.     

Histidine decarboxylase expression in pancreatic endocrine cells and related tumors

Histidine decarboxylase (HDC) is an enzyme for decarboxylating l-histidine to histamine and is expressed in various types of cells including neuroendocrine tumors. Recent findings have demonstrated a high percentage of HDC immunoreactivity in many neuroendocrine tumors, including carcinoid tumors, small cell carcinomas of the lung, pheochromocytomas, and medullary carcinomas of the thyroid. HDC immunostaining was applied to pancreatic islet cells and related tumors to explore possible expression of HDC as a wide spectrum marker for neuroendocrine differentiation. A total of 24 cases (22 pancreatic endocrine neoplasms, one small cell carcinoma of the pancreas, and one mixed exocrine-endocrine carcinoma) along with normal pancreatic tissue were immunostained with the anti-HDC antibody. In a normal pancreas, a double immunostaining revealed possible colocalization of HDC with glucagon- or insulin-positive cells in the islets. Seventeen of 22 pancreatic endocrine neoplasms (77%) were found to be positive for HDC, and no distinct relation to hormonal activity was observed. One small cell carcinoma was strongly positive to HDC. One non-functional tumor with mixed exocrine and endocrine components showed a diffuse positive immunostaining for HDC, and some neoplastic glucagon- or somatostatin (SRIF)-positive cells coexpressed HDC. In conclusion, we demonstrated that the majority of pancreatic endocrine tumors expressed HDC, and we suggest that HDC is a wider new marker for neuroendocrine differentiation.     

Measurement of placental oxygenation by transabdominal near-infrared spectroscopy

The uteroplacental circulation in the placenta can have a major impact on the fetus. Near infrared spectroscopy (NIRS) is the noninvasive method of measuring changes in blood volumes and oxygen concentrations in living tissue. The purpose of this study is to monitor changes in placental tissue oxygen index (TOI) levels, in patients with intrauterine fetal growth restriction during pregnancy, using NIRS. We measured placental TOI values of 15 normal pregnant woman and 15 patients with intrauterine growth restriction admitted to our hospital. The placenta was assessed by ultrasound examination and NIRS was performed on all patients. The TOI values of the IUGR group when hospitalized was 78.6 +/- 1.6 (SD). This value was significantly higher than that of the controls (78.6 +/- 1.6 [SD] versus 70.2 +/- 0.4 [SD]). And the TOI values of the IUGR group, when measured before delivery, were 77.8 +/- 1.6 (SD). The TOI values of the IUGR group before delivery were significantly higher than those of the control group (77.8 +/- 1.6 [SD] versus 70.3 +/- 0.4 [SD]). We propose that NIRS is a candidate, noninvasive method for assessing placental oxygen dynamics on a real-time basis. In the near future it may contribute to perinatal medical practice.     

Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, reduces delayed neuronal death following transient forebrain ischemia in the adult rat hippocampus

Recent evidence indicates that statins have beneficial effects on the brain in the ischemic condition. However, there is a lack of studies related to the effect of statins on delayed neuronal death. We investigated the effect of prophylactic therapy with pravastatin on delayed neuronal death in the rat hippocampus. The rats were given a daily dose of 20 mg/kg of pravastatin orally for 14 days. Transient forebrain ischemia was induced by the four-vessel occlusion method. Three days after ischemia, surviving neurons of the hippocampal CA1 subfield were counted. Our results demonstrated that prophylactic statin treatment significantly reduced delayed neuronal death after transient forebrain ischemia. Our findings suggest that prophylactic statin treatment may be useful in preventing functional neurological disorders after transient cerebral ischemic insult.     

Lotus japonicus nodulation is photomorphogenetically controlled by sensing the red/far red (R/FR) ratio through jasmonic acid (JA) signaling

Light is critical for supplying carbon to the energetically expensive, nitrogen-fixing symbiosis between legumes and rhizobia. Here, we show that phytochrome B (phyB) is part of the monitoring system to detect suboptimal light conditions, which normally suppress Lotus japonicus nodule development after Mesorhizobium loti inoculation. We found that the number of nodules produced by L. japonicus phyB mutants is significantly reduced compared with the number produced of WT Miyakojima MG20. To explore causes other than photoassimilate production, the possibility that local control by the root genotype occurred was investigated by grafting experiments. The results showed that the shoot and not the root genotype is responsible for root nodule formation. To explore systemic control mechanisms exclusive of photoassimilation, we moved WT MG20 plants from white light to conditions that differed in their ratios of low or high red/far red (R/FR) light. In low R/FR light, the number of MG20 root nodules dramatically decreased compared with plants grown in high R/FR, although photoassimilate content was higher for plants grown under low R/FR. Also, the expression of jasmonic acid (JA) -responsive genes decreased in both low R/FR light-grown WT and white light-grown phyB mutant plants, and it correlated with decreased jasmonoyl-isoleucine content in the phyB mutant. Moreover, both infection thread formation and root nodule formation were positively influenced by JA treatment of WT plants grown in low R/FR light and white light-grown phyB mutants. Together, these results indicate that root nodule formation is photomorphogenetically controlled by sensing the R/FR ratio through JA signaling.     

Disappearance of intima over the stent and ulcer formation after intracoronary radiation for in-stent restenosis.

Little is known about the alterations of the vascular surface after radiation therapy for in-stent restenosis in humans, even though animal experiments suggest that delayed healing of the neointima is a cause of late thrombosis. Coronary angioscopy, together with coronary angiography, was performed at 3 months follow-up of 7 patients with in-stent restenosis who underwent beta-radiation therapy. Minimal lesion diameter (MLD) of the lesion increased from 1.00+/-0.30 mm (immediately before) to 2.44+/-0.39 mm (immediately after) and the MLD was well maintained 3 months later (2.34+/-0.62 mm) without any cases of restenosis. In 5 patients, the intima was so thin that some stent struts could be seen through it on angioscopy and in 2 of those, the intima over the stent had disappeared and 1 patient showed ulceration of the vascular wall beneath the stent. After intracoronary radiation therapy, the intima can become so thin that some stent struts are exposed to the lumen, which may be related to the occurrence of late thrombosis. Accordingly, patients who are treated with intracoronary radiation therapy may need long-term antiplatelet therapy.     

Hepatitis C virus core protein inhibits deoxycholic acid-mediated apoptosis despite generating mitochondrial reactive oxygen species

Background Hepatitis C virus (HCV) core protein is known to cause oxidative stress and alter apoptosis pathways. However, the apoptosis results are inconsistent, and the real significance of oxidative stress is not well known. The aim of this study was twofold. First, we wanted to confirm whether core-induced oxidative stress was really significant enough to cause DNA damage, and whether it induced cellular antioxidant responses. Second, we wanted to evaluate whether this core-induced oxidative stress and the antioxidant response to it was responsible for apoptosis changes. Methods HCV core protein was expressed under control of the Tet-Off promoter in Huh-7 cells and HeLa cells. We chose to use deoxycholic acid (DCA) as a model because it is known to produce both reactive oxygen species (ROS) and apoptosis. Results Core expression uniformly increased ROS and 8-hydroxy-2′-deoxyguanosine (8-OHdG) under basal and DCA-stimulated conditions. Core protein expression also increased manganese superoxide dismutase levels. Core protein inhibited DCA-mediated mitochondrial membrane depolarization and DCA-mediated activation of caspase-9 and caspase-3, despite the increase in ROS by DCA. Core protein inhibited DCA-mediated apoptosis by increasing Bcl-x_L protein and decreasing Bax protein, without affecting the proportion of Bax between mitochondria and cytosol, resulting in suppression of cytochrome c release from mitochondria into cytoplasm. Conclusions HCV core protein induces oxidative DNA damage, whereas it inhibits apoptosis that is accompanied by enhancement of ROS production. Thus, oxidative stress and apoptosis modulation by core protein are independent of each other.