Association between mortality risk and the number, location, and sequence of subsequent fractures in the elderly.

The mortality risk showed a positive correlation as the number of subsequent fractures increased. Hip fracture showed the greatest association with mortality risk, followed by vertebral fracture. For the combination of hip and vertebral fracture, a hip fracture after a vertebral fracture showed the highest mortality risk. INTRODUCTION: It is unclear whether subsequent fractures or a certain location and sequence of subsequent fractures are associated with mortality risk in the elderly. We aimed to investigate the relationship between subsequent fractures and mortality risk. METHODS: Using the Korean National Health Insurance Research Database, we analyzed the cohort data of 24,756 patients aged > 60 years who sustained fractures between 2002 and 2013. Cox regression was used to assess the mortality risk associated with the number, locations, and sequences of subsequent fractures. RESULTS: Mortality hazard ratios (HRs) for women and men were shown to be associated with the number of subsequent fractures (one, 1.63 (95% confidence interval [CI], 1.48-1.80) and 1.42 (95% CI, 1.28-1.58); two, 1.75 (95% CI, 1.47-2.08) and 2.03 (95% CI, 1.69-2.43); three or more, 2.46(95% CI, 1.92-3.15) and 1.92 (95% CI, 1.34-2.74), respectively). For women, the mortality risk was high when hip (HR, 2.49; 95% CI, 1.80-3.44) or vertebral (HR, 1.40; 95% CI, 1.03-1.90) fracture occurred as a second fracture. Compared with a single hip fracture, there was a high mortality risk in the group with hip fracture after the first vertebral fracture (HR, 2.90; 95% CI, 1.86-4.54), followed by vertebral fracture after the first hip fracture (HR, 1.90; 95% CI, 1.12-3.22). CONCLUSION: The mortality risk showed a positive correlation as the number of subsequent fractures increased. Hip fracture showed the greatest association with mortality risk, followed by vertebral fracture. For the combination of hip and vertebral fracture, a hip fracture after a vertebral fracture showed the highest mortality risk.

Lack of association between early menopause and non-alcoholic fatty liver disease in postmenopausal women.

Background: The possibility of an association between early menopause and the risk of non-alcoholic fatty liver disease (NAFLD) is as yet unclear.Methods: The subjects consisted of 4354 postmenopausal women who participated in the 2010-2012 Korea National Health and Nutrition Examination Survey. Early, normal, and late menopause were defined as age at menopause <45 years, 45-54 years, and ≥55 years, respectively. NAFLD was defined by a hepatic steatosis index of >36.Results: When compared with normal menopausal women, early or late menopausal women had no significant differences in the odds ratios (ORs) of NAFLD: OR = 1.05, 95% confidence interval (CI), 0.83-1.32 and OR = 1.02, 95% CI, 0.75-1.39, respectively. These results remained similar after adjustment for known risk factors for NAFLD, reproductive factors, and comorbidities. The OR for NAFLD per 1-year increase in age at menopause was 1.01 (95% CI, 0.99-1.03; p = 0.329). The prevalence of advanced fibrosis was 2.1% (95% CI, 0.7-6.4%), 2.2% (95% CI, 1.3-3.8%), and 3.9% (95% CI, 1.2-12.2%) in early, normal, and late menopausal women, respectively.Conclusions: This study provides no evidence for an association of early menopause with NAFLD risk. However, NAFLD-related advanced fibrosis is highly prevalent in postmenopausal women.

Patient compliance with cervical smear surveillance in a shared-care setting.

OBJECTIVE: To examine patient compliance with cervical smear surveillance at a primary care center. METHODS: A retrospective study included data from patients referred from a tertiary center, to a University of Hong Kong primary care center following colposcopy for continuing cervical smear surveillance between January 1, 2005 and December 31, 2006. Patient records were reviewed and details of the initial screening or treatment that led to referral and the three subsequent follow-up screenings were examined. A multivariate analysis was performed to identify factors that were associated with increased odds of patients not attending follow-up screening. RESULTS: In total, records from 833 patients were included. Of these patients, 348 (41.8%) failed to attend at least one screening, with 172 (49.4%) of this group attending after being reminded. The compliance rate prior to patients being reminded of screening follow-up decreased across the three follow-up screenings, with 706 (84.8%) patients attending their first follow-up visit and 561 (67.3%) patients attending the third. In the multivariate analysis, being younger than 50years old, having a history of smoking, and not having undergone medical treatment related to cervical cancer screening previously were associated with increased odds of not attending follow-up screening (all P<0.05). CONCLUSION: Patients at increased risk of non-compliance with screening follow-up should receive particular attention and counselling regarding screening.

Role of leukotrienes in N-(3,5-dichlorophenyl)succinimide (NDPS) and NDPS metabolite nephrotoxicity in male Fischer 344 rats.

The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) can induce marked nephrotoxicity in rats following a single intraperitoneal (ip) administration of 0.4mmol/kg or greater. Although NDPS induces direct renal proximal tubular toxicity, a role for renal vascular effects may also be present. The purpose of this study was to examine the possible role of vasoconstrictor leukotrienes in NDPS and NDPS metabolite nephrotoxicity. Male Fischer 344 rats (4 rats/group) were administered diethylcarbamazine (DEC; 250 or 500mg/kg, ip), an inhibitor of LTA(4) synthesis, 1h before NDPS (0.4mmol/kg, ip), N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS, 0.1, 0.2, or 0.4mmol/kg, ip), or N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA, 0.1mmol/kg, ip) or vehicle. In a separate set of experiments, the LTD(4) receptor antagonist LY171883 (100mg/kg, po) was administered 0.5h before and again 6h after NDHS (0.1mmol/kg, ip) or 2-NDHSA (0.1mmol/kg, ip) or vehicle. Renal function was monitored for 48h post-NDPS or NDPS metabolite. DEC markedly reduced the nephrotoxicity induced by NDPS and its metabolites, while LY171883 treatments provided only partial attenuation of NDHS and 2-NDHSA nephrotoxicity. These results suggest that leukotrienes contribute to the mechanisms of NDPS nephrotoxicity.

Synthetic peptides containing ITIM-like sequences of IREM-1 (CD300F) differentially regulate MyD88 and TRIF-mediated TLR signalling through activation of SHP and/or PI3K.

The immune receptor expressed on myeloid cells 1 (IREM-1/CD300F) has been shown to inhibit various inflammatory processes in myeloid cells, such as macrophages and mast cells. IREM-1 exerts its inhibitory effect through its intracellular immunoreceptor tyrosine-based inhibition motifs (ITIMs). In order to generate immunomodulatory molecules that can regulate the inflammatory activation of macrophages, decapeptides representing each of the five ITIM-like sequences in the cytoplasmic tail of IREM-1 were synthesized in conjugation with human immunodeficiency virus-transactivator of transcription (HIV-TAT(48-57)), which was added to promote internalization of the peptides. Interestingly, all these TAT-ITIM fusion peptides inhibited Toll-like receptor (TLR)-mediated production of proinflammatory molecules, including matrix metalloproteinase (MMP)-9, tumour necrosis factor (TNF)-α, monocyte chemotactic protein-1 (MCP-1) and interleukin (IL)-8. When various TLR ligands were used to stimulate the human macrophage-like cell line human acute monocytic leukaemia cell line (THP)-1, the TAT-ITIM peptides blocked both myeloid differentiation factor 88 (MyD88) and Toll-interleukin 1 receptor (TIR)-domain-containing adapter-inducing interferon-ß (TRIF)-mediated TLR signalling pathways. Utilization of specific inhibitors and detection of the active form of signalling adaptors by Western blot analysis further demonstrated that the inhibitory effects of these TAT-ITIM peptides require activation of Src homology 2 (SH2)-containing tyrosine phosphatase (SHP) and/or phosphoinositide 3-kinase (PI3K). These data indicate that these synthetic peptides may be used to regulate immune responses that involve TLR-mediated inflammatory activation of macrophages.

Randomised clinical trial: the efficacy of a 10-day sequential therapy vs. a 14-day standard proton pump inhibitor-based triple therapy for Helicobacter pylori in Korea.

BACKGROUND: The eradication rates of Helicobacter pylori (H. pylori) using a proton pump inhibitor (PPI)-based triple therapy have declined due to antibiotic resistance worldwide. AIM: To compare the eradication rate of the 10-day sequential therapy for H. pylori infection with that of the 14-day standard PPI-based triple therapy. METHODS: This was a prospective, randomised, controlled study. A total of 409 patients with H. pylori infection were randomly assigned to receive either the 10-day sequential therapy regimen, which consisted of pantoprazole (40 mg) plus amoxicillin (1000 mg) twice a day for 5 days, then pantoprazole (40 mg) with clarithromycin (500 mg) and metronidazole (500 mg) twice a day for another five consecutive days or the 14-day PPI-based triple therapy regimen, which consisted of pantoprazole (40 mg) with amoxicillin (1000 mg) and clarithromycin (500 mg) twice a day for 14 days. The pre- and post-treatment H. pylori status were assessed by rapid urease test, urea breath test, or histology. Successful eradication was confirmed at least 4 weeks after finishing the treatment. RESULTS: In the intention-to-treat analysis, the eradication rates of the 10-day sequential therapy and of the 14-day PPI-based triple therapy were 85.9% (176/205) and 75.0% (153/205), respectively (P = 0.006). In the per-protocol analysis, the eradication rates were 92.6% (175/205) and 85% (153/204), respectively (P = 0.019). There was no statistically significant difference between the two investigated groups regarding the occurrence of adverse event rates (18.9% vs. 13.3%, P = 0.143). CONCLUSION: The 10-day sequential therapy achieved significantly higher eradication rates than the 14-day standard PPI-based triple therapy in Korea.

Dual projections of tuberomammillary neurons to whisker-related, sensory and motor regions of the rat.

The primary goal of this study was to examine in the rat whether neurons in the tuberomammillary nucleus (TMN) provide axon collaterals to whisker-related, sensorimotor regions at cortical and brainstem levels, using two different retrograde tracers. When injections were made at primary sensory (S1) barrel field/primary whisker motor (M1) cortices, dual-projecting TMN neurons were observed mainly in the ventrolateral subdivision; the projection was almost exclusively ipsilateral. On the other hand, following injections of tracers into whisker-related, principal sensory trigeminal (Pr5)/lateral facial motor (Mo7) nuclei, dual-projecting cells were observed mainly in the dorsomedial subdivision; the projection was bilateral with a slight contralateral dominance. Taken together, the present observation demonstrated that each subdivision of the TMN possessed a differential functional organization with respect to its collateral projection to whisker-related sensorimotor targets, suggesting that the histaminergic projection might play a modulatory role in vibrissal sensorimotor integration, which allows the guidance of behavioral action essential for the survival of the animal.

Immune receptor expressed on myeloid cells 1 (IREM-1) inhibits B cell activation factor (BAFF)-mediated inflammatory regulation of THP-1 cells through modulation of the activities of extracellular regulated kinase (ERK).

The immune receptor expressed on myeloid cells 1 (IREM-1) has been known to regulate the activities of myeloid cells through its immunoreceptor tyrosine-based inhibition motifs (ITIMs) in its intracellular region. In order to investigate its effect on macrophage activation, a human macrophage cell line (THP-1) was tested after stimulation of its membrane-bound form of B cell activation factor (BAFF), which has been shown to modulate inflammatory activities through induction of proinflammatory mediator expression and suppression of phagocytosis. IREM-1-specific monoclonal antibodies detected the expression of high levels of IREM-1 in THP-1 cells. Cross-linking of IREM-1 with these antibodies resulted in the blockage of the BAFF-mediated expression of interleukin (IL)-8 and matrix metalloproteinase (MMP)-9 through inhibition of the activation of extracellular regulated kinase (ERK) and phosphorylation/degradation of IκB. Furthermore, cross-linking of IREM-1 also reversed the BAFF-mediated inhibition of phagocytosis. In order to demonstrate the role of ITIM in the IREM-1-mediated suppression of BAFF signalling, a decapeptide containing YADL (an ITIM in IREM-1) was fused with HIV-TAT(48-57) which was required for the internalization of the synthetic polypeptide (TAT-YADL). TAT-YADL, but not control peptides, recapitulated the effect of the anti-IREM-1 monoclonal antibody. These observations indicate that IREM-1 exerted its inhibitory effect on BAFF-medicated signalling through ITIM-mediated regulation of ERK activities in THP-1 cells.

Genetic fuzzy classifier for sleep stage identification.

Soft-computing techniques are commonly used to detect medical phenomena and help with clinical diagnoses and treatment. In this work, we propose a design for a computerized sleep scoring method, which is based on a fuzzy classifier and a genetic algorithm (GA). We design the fuzzy classifier based on the GA using a single electroencephalogram (EEG) signal that detects differences in spectral features. Polysomnography was performed on four healthy young adults (males with a mean age of 27.5 years). The sleep classifier was designed using a sleep record and tested on the sleep records of the subjects. Our results show that the genetic fuzzy classifier (GFC) agreed with visual sleep staging approximately 84.6% of the time in detection of wakefulness (WA), shallow sleep (SS), deep sleep (DS), and rapid eye movement (REM) stages.

What factors are related to delayed treatment in individuals at high risk for psychosis?

BACKGROUND: Previous studies have shown that the individuals at high risk for psychosis suffer from depression, anxiety, and deficits in social functioning. The present report describes help-seeking behaviours, baseline psychopathology, and duration of attenuated psychotic symptoms (DUAPS) and their associations with other variables. METHODS: Using the Comprehensive Assessment of At-Risk Mental States (CAARMS), we conducted systematic evaluations of individuals at high risk for psychosis. Help-seeking behaviours, current Axis I diagnoses, DUAPS, and baseline psychopathology were investigated. Demographic and clinical characteristics of short and long DUAPS groups were compared. RESULTS: Thirty-eight subjects were recruited from nine centres. Participants seldom sought psychiatric services at their first help-seeking contact, and the mean DUAPS was 22.00 +/- 28.59 months. Most participants had current Axis I diagnoses, and depressive disorder NOS was the most common of these. Higher levels of depression, anxiety, obsessive-compulsive symptoms, and functional impairment were also identified. We found no significant differences between short and long DUAPS groups in baseline psychopathology. However, we observed significantly lesser distressing intensity of thought contents and significantly greater social impairment in the long-DUAPS group. CONCLUSION: These findings suggest that high-risk subjects frequently received delayed treatment despite symptomatic distress and functional impairment. No direct evidence supporting the delayed effect of the DUAPS on baseline psychopathology was found.

Collateral projection from the forebrain and mesopontine cholinergic neurons to whisker-related, sensory and motor regions of the rat.

The primary goal of this anatomical study was to examine in the rat whether cholinergic neurons provide axon collaterals to whisker-related, sensorimotor regions at cortical, thalamic, and brainstem levels, using a combined method of retrograde tracing and choline acetyltransferase (ChAT) immunostaining. First, when injections were made at primary sensory (S1) barrel field/primary whisker motor (M1) cortices, cholinergic neurons with dual projections were observed in the basal nucleus of Meynert (BM), mainly at middle level; the projection was almost exclusively ipsilateral (99%+/-0.7%, n=6). Second, following unilateral injections of tracers into ventroposteromedial (VPM) barreloids/ventrolateral (VL) thalamic nucleus, dual-projecting cells were observed in the mesopontine tegmental complex including the pedunculopontine tegmental (PTg) and laterodorsal tegmental (LDTg) nuclei, mainly at rostral to middle levels; the projection exhibited ipsilateral dominance, i.e., 67%+/-1.3% (n=6) for the PTg and 64%+/-1.2% (n=6) for the LDTg. Finally, when injections were made at whisker-related, principal sensory trigeminal (Pr5)/facial motor (Mo7) nuclei, a relatively small number of labeled neurons were observed in the PTg and the LDTg at middle to caudal levels; within LDTg, labeled cells occupied the ventral portion of the dorsal LDTg as well as the ventral LDTg (LDTgV). This projection exhibited contralateral preponderance, i.e., 67%+/-2.0% (n=6) for the PTg and 69%+/-3.2% (n=6) for the LDTg. Taken together, the present observations demonstrated that each division of the BM, PTg, and LDTg possessed a differential functional organization with respect to its collateral projection to whisker-related sensorimotor targets, suggesting that the cholinergic projection might play a modulatory role in vibrissal sensorimotor integration, which allows the guidance of behavioral action essential for the survival of the animal.

Collateral projection from the locus coeruleus to whisker-related sensory and motor brain regions of the rat.

The primary goal of this study was to examine whether the locus coeruleus (LC) provides collateral projections to whisker-related, sensorimotor brain regions. After injections of retrograde tracers into the primary sensory (S1) barrel field/primary whisker motor (M1) cortices, ventroposteromedial (VPM)/ventrolateral (VL) thalamic nuclei, or principal sensory trigeminal (Pr5)/facial motor (Mo7) nuclei, the distribution of double-labeled neurons within the LC was examined. Our observations indicated that a large number of individual LC cells provided axon collaterals to S1-M1 or VPM-VL regions, whereas only a few projected to Pr5-Mo7 nuclei. The laterality and the distribution of dual-projecting LC neurons were as follows. 1) The neurons projecting to the S1-M1 cortices were predominantly ipsilateral (96% +/- 0.7%). Labeled neurons were located ventrally at the rostral pole but were evenly distributed along the dorsoventral aspect of the principal LC. 2) The cells projecting to the VPM-VL nuclei were bilateral, with ipsilateral (68% +/- 2.3%) dominance. Neurons were observed at the rostrocaudal extent of the LC, where the labeling was most pronounced at the ventral, principal LC. 3) The neurons projecting to the Pr5-Mo7 regions exhibited slightly contralateral (56% +/- 2.9%) dominance, where labeled cells were confined within the ventral margin of the principal subdivision. Taken together, the present observations demonstrate that each subdivision of the LC possesses a differential functional organization with respect to its collateral projection to whisker-related sensorimotor targets, suggesting that the nucleus might play a modulatory role in vibrissal sensorimotor integration that allows the guidance of behavioral action essential for the survival of the animal.

Glucocorticoid-induced tumour necrosis factor receptor-related protein-mediated macrophage stimulation may induce cellular adhesion and cytokine expression in rheumatoid arthritis.

Glucocorticoid-induced tumour necrosis factor receptor (TNFR)-related protein (GITR) is one of the T cell co-stimulatory molecules and is associated with the pathogenesis of a number of autoimmune diseases. We investigated the expression patterns of GITR in human arthritic synovium and the role of GITR in the pathogenesis of rheumatoid arthritis (RA). Immunohistochemical analyses revealed the expression of GITR and its cognate ligand, GITRL, in macrophages in RA, but not in osteoarthritis (OA), synovium. To investigate the role of GITR in macrophage functions, primary macrophages from RA patients and a human macrophage cell line, THP-1, were analysed. Stimulation of the macrophages with anti-GITR monoclonal antibody induced up-regulation of intercellular adhesion molecule (ICAM)-1 and subsequent aggregation/adhesion, which was enhanced by the presence of extracellular matrix proteins and blocked by anti-ICAM-1 monoclonal antibody. The validity of these in vitro observations was confirmed by immunohistochemical analyses of RA synovium, which showed strong expression of ICAM-1 in GITR-positive macrophages. Additionally, GITR stimulation induced expression of proinflammatory cytokines/chemokines and matrix metalloproteinase-9 in synovial macrophages. These data indicate that GITR, expressed on macrophages in human RA synovium, may enhance inflammatory activation of macrophages by promoting cytokine gene expression and adhesion between cells and to extracellular matrix in RA synovium.

Prevertebral soft tissue swelling after anterior cervical discectomy and fusion with plate fixation.

Airway complications after anterior cervical surgery are rare but potentially lethal. The purpose of this study was to identify the natural course of prevertebral soft tissue swelling after one- or two-level anterior cervical discectomy and fusion (ACDF) in order to prevent lethal airway obstruction after ACDF. Eighty-seven patients scheduled for one- or two-level ACDF were studied prospectively. Lateral radiographs of the cervical spine were taken preoperatively, postoperatively on the day of surgery and on the first, second, third, fourth, and fifth days after operation. Prevertebral soft tissue was measured from C2 to C6 on cervical spine lateral radiographs. The anteroposterior (AP) thickness of the prevertebral soft tissue was measured at each cervical level from C2 to C6. Prevertebral soft tissue swelling occurred postoperatively and increased markedly on the second day after operation. The maximum swelling was found on the second and third days. In fusions above C5 swelling was most prominent at C2, 3. Gradual decrease in swelling was observed after the fourth postoperative day. Prominent swelling was noted at the second, third, and fourth cervical levels. There was no significant difference in swelling when comparing one-level and two-level ACDF. Only one patient required reintubation (1.1%). In conclusion, in this prospective study of 87 patients fused at one or two levels in the cervical spine peak prevertebral soft tissue swelling was observed on the second and third days after the surgery.

Bacterial diversity in selenium reduction of agricultural drainage water amended with rice straw.

Bacterial reduction of the Se oxyanions selenate [Se(VI)] and selenite [Se(IV)] to elemental selenium [Se0] is an important biological process in removing Se from drainage water. This study was conducted to characterize the molecular diversity of bacterial populations involved in Se reduction of drainage water amended with rice (Oryza sativa L.) straw and also to monitor the bacterial community shifts during the course of the study. Selenate was removed in the drainage water by the bacteria 5 to 6 d after addition of rice straw. Six Se(VI)- and 32 Se(IV)-reducing bacteria were isolated from rice straw containing sterilized drainage water. Three Se(VI)- and two Se(IV)-reducing bacteria were also isolated from the drainage water. Identification of Se(VI)- and Se(IV)-reducing bacteria by 16S rDNA sequence analysis showed a broad phylogenetic diversity in Se-reducing assemblages. Three major phyla (Proteobacteria, Actinobacteria, and Firmicutes) of bacterial domain with numerous classes, orders, and families constituted the Se-reducing bacterial community. We documented changes in the composition of bacterial assemblages in the drainage water amended with rice straw using polymerase chain reaction (PCR)-denaturing gradient gel electrophoresis (DGGE) of 16S rDNA. The Shannon-Weaver index (H') revealed higher bacterial diversity at Day 6 in the sterilized and Day 4 in the non-sterilized drainage water amended with rice straw. The results of this study suggest that rice straw, a good source of carbon and energy, harbors a wide range of bacteria useful in Se reduction and may be used in removing Se from drainage water.

Delayed vertebral collapse with neurological deficits secondary to osteoporosis.

Delayed vertebral collapse after osteoporotic spinal fractures may cause progressive kyphosis, neurological deficits, and chronic back pain. We treated 14 consecutive patients with posterolateral decompression and posterior reconstruction and followed them over a period ranging from 24 to 54 months. The mean age was 67 (range: 62-72) years and the fracture level was T12 and L1. Seven patients were graded as Frankel stage C and seven as stage D. The mean segmental kyphotic angle was 22.6 degrees (7-29 degrees ) preoperatively, 4.4 degrees (1-6 degrees ) postoperatively, and 6.8 degrees (2-15 degrees ) at the final follow-up. The pain score on a visual analogue scale improved from 9.5 preoperatively to 2.7 postoperatively, and the neurological status improved in all patients. Bone fusion was present 9 months after operation. Of four surgical complications, two were dural tears, one a superficial infection, and there was one death due to an acute adrenal insufficiency. Posterolateral decompression with posterior reconstruction is a useful treatment for patients with delayed osteoporotic vertebral collapse.

Effect of three n-acetylamino acids on N-(3,5-dichlorophenyl)succinimide (NDPS) and ndps metabolite nephrotoxicity in Fischer 344 rats.

The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) induces nephrotoxicity in mammals characterized as polyuric renal failure and proximal tubular necrosis. Recent studies have suggested that NDPS-induced nephrotoxicity may be mediated by metabolites arising from the nephrotoxic NDPS metabolites N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and/or N-(3,5-dichlorophenyl)-2-succinamic acid (2-NDHSA). The purpose of this study was to examine the effects of N-acetylcysteine (NAC), a nucleophilic agent, and two nonnucleophilic N-acetylamino acids, N-acetylserine (NAS) and N-acetylalanine (NAA), on NDPS and NDPS metabolite-induced nephrotoxicity. Male Fischer 344 rats (4-8/group) were administered intraperitoneally (ip) an N-acetylamino acid (1 mmol/kg) 2 h before an ip injection of NDPS (0.4 mmol/kg), NDHS (0.1 mmol/kg), 2-NDHSA (0.1 mmol/kg), or vehicle. Renal function was then monitored at 24 and 48 h. NAC pretreatment markedly attenuated NDPS-, NDHS-, and 2-NDHSA-mediated nephrotoxicity. The nonnucleophilic N-acetylamino acids (NAS, NAA) only partly reduced NDPS and NDHS nephrotoxicity, and they had little effect on 2-NDHSA nephrotoxicity. These results suggest that reactive NDPS metabolites may be formed from NDHS and 2-NDHSA and that nucleophilic substrates (e.g., NAC) may offer protection from NDPS-induced nephrotoxicity. However, mechanisms other than chemical neutralization of reactive NDPS metabolites may also be contributing to the attenuation of NDPS nephrotoxicity, since nonnucleophilic N-acetylamino acids (e.g., NAA) also provided some protection against NDPS and NDHS nephrotoxicity.

In vitro nephrotoxicity induced by chloronitrobenzenes in renal cortical slices from Fischer 344 rats.

Chloronitrobenzenes are important chemical intermediates in the manufacture of industrial, agricultural and pharmaceutical agents. Toxicity induced by the various chloronitrobenzene isomers in vivo includes hematotoxicity, immunotoxicity, hepatotoxicity and nephrotoxicity. The purpose of the study was to determine the direct nephrotoxic effects of nitrobenzene and ten chlorinated nitrobenzene derivatives using renal cortical slices as the in vitro model. Renal cortical slices were prepared from kidneys of untreated, male Fischer 344 rats and incubated with nitrobenzene (1.0-5.0 mM), a chloronitrobenzene (0.5-5.0 mM) or vehicle for 2 h. At the end of the 2 h incubation, tissue gluconeogenesis capacity (pyruvate-stimulated gluconeogenesis) and lactate dehydrogenase (LDH) release were determined as measures of cellular function and cytotoxicity. Based on decreased pyruvate-stimulated gluconeogenesis and increased LDH release, the order of decreasing nephrotoxic potential was trichloronitrobenzenes>dichloronitrobenzenes>monochloronitrobenzenes>nitrobenzene. Among the mono- and dichloronitrobenzenes, 1-chloro-3-nitrobenzene and 3,4-dichloronitrobenzene were the most potent nephrotoxicants, while the two trichloronitrobenzenes tested exhibited similar nephrotoxic potentials. These results demonstrate that chloronitrobenzenes are directly nephrotoxic in vitro and that increasing the number of chloro groups increases the nephrotoxic potential of the resulting chloronitrobenzene derivative.

Induction of caspase-11 by inflammatory stimuli in rat astrocytes: lipopolysaccharide induction through p38 mitogen-activated protein kinase pathway.

Caspase-11 plays a crucial role in both inflammation and apoptosis. Caspase-11 not only activates caspase-1, that is required for the maturation of proinflammatory cytokines such as interleukin (IL)-1 and IL-18, but also activates caspase-3, leading to cellular apoptosis under pathological conditions. Here, we cloned the rat homolog of caspase-11, and investigated its inducibility by inflammatory stimuli and signal transduction pathways involved. Deduced amino acid sequence of rat caspase-11 showed 88.7% similarity to mouse caspase-11, and in vitro translation of rat caspase-11 cDNA yielded approximately a 43 kDa polypeptide, which was in agreement with predicted protein size generated from full-length rat caspase-11 cDNA. The expression of caspase-11 was strongly induced at both mRNA and protein levels by inflammatory stimuli such as lipopolysaccharide (LPS), interferon-gamma, and tumor necrosis factor-alpha in C6 rat glial cells as well as primary astrocytes. LPS induced activation of both p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) in C6 cells. However, SB203580 (specific inhibitor of p38 kinase), but not PD98059 (specific inhibitor of ERK kinase), inhibited LPS induction of caspase-11, indicating that induction of caspase-11 by LPS in astrocytes was mediated through the p38 MAPK pathway. Inflammatory induction of caspase-11 in astrocytes may play an important role in both inflammatory responses involving these cells and auto-regulatory apoptosis of activated astrocytes in inflammatory sites.

Cytoprotective effect of Scutellaria baicalensis in CA1 hippocampal neurons of rats after global cerebral ischemia.

Based on the use of Scutellaria baicalensis for the treatment of stroke in traditional Oriental medicine, the current study was carried out to evaluate neuroprotective effects of S. baicalensis after transient global ischemia using rat 4-vessel occlusion model. Methanol extracts from the dried roots of S. baicalensis (0.1-10 mg/kg) administered intra-peritoneally significantly protected CA1 neurons against 10 min transient forebrain ischemia as demonstrated by measuring the density of neuronal cells stained with Cresyl violet. Methanol extract of S. baicalensis inhibited microglial tumor necrosis factor-alpha (TNF-alpha) and nitric oxide production, and protected PC12 cells from hydrogen peroxide-induced toxicity in vitro.