Treating activated CD4+ T cells with either of two distinct DNA methyltransferase inhibitors, 5-azacytidine or procainamide, is sufficient to cause a lupus-like disease in syngeneic mice.

Human antigen-specific CD4+ T cells become autoreactive after treatment with various DNA methylation inhibitors, including 5-azacytidine, procainamide, and hydralazine. This suggests a mechanism that could contribute to the development of some forms of autoimmunity. In this report we have asked whether T cells treated with DNA methylation inhibitors can induce autoimmunity. Murine CD4+ T cells were treated with 5-azacytidine or procainamide and were shown to respond to syngeneic antigen-presenting cells, similar to CD4+ human T cell clones treated with these drugs. Functional characterization demonstrated that cells treated with either drug spontaneously lysed syngeneic macrophages and secreted IL-4, IL-6, and IFN-gamma. Adoptive transfer of 5-azacytidine- or procainamide-treated cells into unirradiated syngeneic recipients induced an immune complex glomerulonephritis and IgG anti-DNA and antihistone antibodies. These experiments demonstrate that T cells treated with either of two distinct DNA methyltransferase inhibitors are sufficient to induce a lupus-like disease. It is possible that the lysis of macrophages, together with the release of cytokines promoting B cell differentiation, contributes to the autoantibody production and immune complex deposition. These results suggest that environmental agents that inhibit DNA methylation could interact with T cells in vivo to produce a lupus-like illness, a mechanism that could have relevance to drug-induced and idiopathic lupus.     

Vimentin and glial fibrillary acidic protein in human brain tumors

Using the peroxidase-antiperoxidase (PAP) technique, we examined 35 primary brain tumors for expression of vimentin and GFAP. Both low-grade and high-grade astrocytomas contained vimentin-positive and GFAP-positive cells. Ependymomas also stained for both markers. In gliosarcomas, the glioblastomatous portions stained like astrocytomas, while only vimentin stain was seen in the fibrosarcomatous portions. Medulloblastomas and oligodendrogliomas were negative for both vimentin and GFAP, while meningiomas contained scattered areas of vimentin-positive cells. These results suggest that the expression of vimentin and GFAP is mostly confined to glial-derived tumors, and that vimentin can potentially be a useful marker for distinguishing undifferentiated GFAP-negative glial tumors and mesenchymal tumors from primitive neuroectodermal tumors.     

Perigastric lymph node metastasis does not affect the survival of squamous cell carcinoma of the oesophagus treated with two‐field oesophagectomy

Aim: There are some discrepancies as to the prognostic value of perigastric lymph node (LN) metastasis in the survival of squamous oesophageal carcinoma. The present study aimed to compare survival following standard oesophagectomy in the treatment of squamous oesophageal carcinoma with or without perigastric abdominal LN metastasis. Methods: From 1998 to 2003, 17 patients with squamous cell carcinoma of the mid or lower oesophagus who had abdominal LN metastasis upon pathological examination underwent Ivor Lewis oesophagectomy. They did not receive further adjuvant therapy. The clinical outcomes of this cohort were compared to a control of 34 patients of similar age, gender and T staging who had no perigastric nodal diseases upon oesophagectomy. Results: There was no significant difference between the two groups in terms of the demographics, tumour size, differentiation of the tumour, duration of operation, volume of blood loss, and the type of oesophagectomy. The cumulative 3‐year survival rate was similar between those with abdominal LN metastasis or those without abdominal LN metastasis (52.9% vs 47.1%; log–rank test P = 0.61).There was also no significant difference in the rates of recurrence between the two groups (58.8% vs 58.8%; P = 0.1). Conclusions: Perigastric LN metastasis over the lesser curvature, left gastric artery and pericardial regions does not affect the survival of patients with squamous cell carcinoma of the oesophagus treated by two‐field oesophagectomy.     

Effects of intrathecal injection of nimodipine, ω-conotoxin GVIA, calmidazolium, and KN-62 on the antinociception induced by cold water swimming stress in the mouse

The present study was designed to determine if spinal calcium channels, calmodulin, and calcium/calmodulin-dependent protein kinase II were involved in the production of antinociception induced by cold water swimming stress (CWSS). The effects of intrathecal (i.t.) injection of nimodipine, ω-conotoxin GVIA, calmidazolium, or (S)-5-isoquinolinesulfonic acid, 4-[2-[(5-isoquinolinyl-sulfonyl)methylamino]-3-oxo-3-(4-phenyl-1-piperazinyl)-propyl]phenyl ester (KN-62) on CWSS-induced antinociception were studied in ICR mice. The antinociception was assessed by the tail-flick test. CWSS produced inhibition of the tail-flick response. Various doses of nimodipine (10–40 ng), ω-conotoxin GVIA (5–40 ng), calmidazolium (10–40 ng), or KN-62 (5–40 ng) injected i.t. alone did not show any antinociceptive effect in the tail-flick test. I.t. pretreatment with ω-conotoxin GVIA, calmidazolium, or KN-62 dose dependently attenuated the CWSS-induced inhibition of the tail-flick response. However, i.t. pretreatment with nimodipine did not affect the inhibition of the tail-flick response induced by CWSS. Our results suggest that spinal N-type calcium channel, calmodulin and calcium/calmodulin-dependent protein kinase II may be involved in the production of antinociception induced by CWSS. On the other hand, CWSS-induced antinociception appears not to be mediated via the spinal L-type calcium channel.     

Effect of vitamin C on plasma total antioxidant status in patients with paraquat intoxication.

This study was conducted to evaluate whether vitamin C (VC) was associated with total antioxidant status (TAS) in human plasma and to determine the usefulness of VC on TAS in the treatment of patients with paraquat poisoning. VC and TAS were measured in 56 healthy subjects. Then, various concentrations (1-100 mg/dl) of VC in pooled plasma from 10 volunteers were constructed in vitro and TAS was measured. The VC and TAS were measured in vivo at 0.5, 1, 2, 3, 5, 7, 9, and 11 h after injection of VC (50 mg/kg) in seven volunteers and pharmacokinetic data were calculated. Finally, various amounts of VC (100, 500, 1000, 3000 mg/day, and 3000 mg/8 h) were given to 10 paraquat-poisoned patients for 5 consecutive days, and blood was taken for TAS 1 h after each injection. The means (SD) of VC and TAS in healthy subjects were 2.22 (0.16) mmol/l and 0.48 (0.10) mg/dl, respectively. Positive correlation between VC and TAS was observed in both in vitro and in healthy volunteers. The pharmacokinetic results in vivo were as follows: means (SD) of distribution volume, area under curve, plasma clearance, half life, C(max), and T(max) were 32.0 (4.4) l, 36.4 (11.3) mg h/dl, 2.13 (1.36) l/h, 10.2 (7.8) h, 17.1 (7.1) mg/dl, and 0.64 (0.24) h, respectively. Estimated loading and maintenance doses of VC were 2278 mg and 146 mg/h, respectively. The means of TAS were increased over 5 consecutive days as 2.26, 2.76, 2.81, 3.18, and 3.58 mmol/l in paraquat patients. All patients were recovered within mean (SD) 21.2 (5.4) admission days. Our data suggested that VC was a significant antioxidant as TAS in human plasma and that increased TAS by high doses of VC could be useful as a free radical scavenger for paraquat poisoned patients.     

Regulation of calcium influx and phospholipase C activity by indoleamines in dinoflagellate Crypthecodiniurn cohnii

Abstract: Exogenous indoleamines such as melatonin and 5-methoxytryptamine have been shown to induce cyst formation (encystment) in many species of dinoflagellate. Induction of inositol phosphates formation by indoleamine has previously been demonstrated in Crypthecodiniurn cohnii . In addition, depletion of extracellular Ca²⁺ blocks the indoleamine-induced encystment. In the present study, 12 indoleamines (including melatonin and related compounds) were examined for their abilities to induce Ca²⁺ influx, inositol phosphates formation, and encystment in C. cohnii . The results showed that melatonin, 5-methoxytryptamine, and the peptide toxin mastoparan stimulated ⁴⁵Ca²⁺ influxes in dose- and time-dependent manners. The EC₅₀ values of 5-methoxytrypramine and mastoparan to stimulate ⁴⁵Ca²⁺ uptake were 2 mM and 35 μM, respectively. The 5-methoxytryptamine- and mastoparan-induced ⁴⁵Ca²⁺ influx were partially attenuated by the calcium channel blockers, verapamil and ruthenium red. A series of indoleamines were examined for their structure-activity relationship on the induction of encystment and formation of inositol phosphates. Melatonin-induced inositol phosphates formation was completely blocked by U73122, indicating the possible involvement of phospholipase C. Taken together, we conclude that indoleamines may induce encystment of the dinoflagellate C. cohnii via parallel activation of phospholipase C and Ca²⁺ influx signaling pathways. However, activation of phospholipase C and Ca²⁺ influx are not always necessary or sufficient for inducing encystment. Also, these data provided the first direct evidence of a Ca²⁺ influx regulating mechanism in dinoflagellate C. cohnii .     

Preventing violence in at-risk African-American youth.

Homicide and nonfatal injuries resulting from interpersonal violence are significant contributors to the excess early mortality and morbidity of African-American youth. Although there is growing recognition of the need for prevention programs specifically directed to these youth, culturally relevant programs to reduce aggression and victimization in high-risk racial and ethnic groups are virtually nonexistent. This article reports preliminary findings of a program to train African-American adolescents in social skills, an approach which shows promise as a means of preventing violence. The pilot study suggests a need for continued research on this and other prevention approaches to reduce the disproportionate--and preventable--risk of injury or death for this vulnerable population.     

Family study of Rh haplotype frequencies in Taiwan

Two hundred and two families (404 parents and 448 children) were typed for Rh antigens. The most common Rh haplotype is R1R1 followed by R1R2 and R1r. R1r', R2r', R0r', R0r and r'r are all very rare. The results of observed and expected haplotype frequencies do not differ significantly except few rare phenotypes. However, there are some major differences between Caucasian and Chinese populations in certain Rh genotypes. Although r is the second common genotype in Rh system among Caucasian but is rather rare in Chinese.     

Improving outcome of CAPD: twenty-five years' experience in a single Korean center.

BACKGROUND: Continuous ambulatory peritoneal dialysis (CAPD) is an established treatment for end-stage renal disease (ESRD). We investigated the outcome of CAPD over a period of 25 years at our institution. METHODS: CAPD has been performed in 2301 patients in 25 years. After excluding patients with less than 3 months of follow-up and missing data, we evaluated 1656 patients who started peritoneal dialysis between November 1981 and December 2005. Data for sex, age, primary disease, comorbidities, follow-up duration, cause of death, and cause of technique failure were collected. We also examined data for urea kinetic modeling (UKM), beginning in 1990, and peritonitis episodes, including causative organisms, starting in 1992. RESULTS: Compared to incident patients from 1981-1992, mean age and incidence of ESRD caused by diabetic nephropathy increased in patients from 1993 to 2005. Technique survival after 5 and 10 years was 71.9% and 48.1% respectively. Technique survival was significantly higher in patients who started CAPD after 1992 than in those who started before 1992. Peritonitis was the main reason for technique failure. Overall peritonitis rate was 0.38 episodes per patient-year, with a significant downward trend to 0.29 per patient-year over 10 years, corresponding to a decrease in gram-positive peritonitis. Patient survival after 5 and 10 years was 69.8% and 51.8% respectively. Patient survival improved significantly during 1992-2005 compared to 1981-1992 after adjustment for age, gender, diabetes, and cardiovascular comorbidities [hazard ratio (HR) 0.68, p < 0.01]. Subgroup analysis based on UKM revealed that dialysis adequacy did not affect patient survival. However, diabetes (HR 2.78, p < 0.001), older age (per 1 year: HR 1.06; p < 0.001), serum albumin level (per 1 g/dL: increase, HR 0.52; p < 0.05), and cardiovascular comorbidities (HR 2.32, p < 0.01) were identified as significant risk factors. CONCLUSION: Technique survival has improved due partly to a decrease in peritonitis, which was attributed to a decrease in gram-positive peritonitis. Patient survival has also improved considering increases in aged patients and ESRD caused by diabetes. The mortality rate of CAPD is still high in older, diabetic, malnourished, and cardiovascular diseased patients. A more careful management of higher risk groups will be needed to improve the outcome of CAPD patients in the future.