Subclinical deterioration of left ventricular function in patients with juvenile-onset systemic lupus erythematosus.

OBJECTIVES: Patients with systemic lupus erythematosus (SLE) have a higher risk of myocardial involvement, which can result in ventricular dysfunction. Little is known about the chronic influence of SLE on heart function in children and adolescents. This is the first study to demonstrate long-term changes in left ventricular function in patients with juvenile-onset SLE. METHODS: This was a longitudinal study of 92 patients with juvenile-onset SLE. Two-dimensional echocardiography was performed by a single pediatric cardiologist at baseline, with follow-up at six-month intervals. Clinical and laboratory parameters, disease activity, treatment, nailfold capillaroscopy, and the traditional risk factors for atherosclerosis were evaluated. The baseline comparison of ventricular function was performed against 50 age-matched controls, and the follow-up results were analyzed using generalized estimating equations. RESULTS: The patients' mean age at baseline was 15.9 ± 4.3 years, the mean disease duration was 3.6 ± 3.2 years, and the mean follow-up duration was 4.5 ± 1.6 years. At baseline, the mean left ventricular ejection fraction (LVEF) was 74.7 ± 5.6% and the mean E/A ratio of left ventricular diastolic filling was 1.7 ± 0.3 (E: the peak velocity at rapid left ventricular filling; A: the peak velocity during left atrial contraction). The LVEF of the SLE patients was similar to the healthy controls and it did not change during the follow-up period. In contrast, the E/A ratio was lower in the SLE patients than in the healthy controls (1.7 ± 0.3 versus 1.88 ± 0.37; p = 0.002), and it decreased significantly with time (B ± SE, -0.013 ± 0.006, p = 0.023). In multiple analyses, abnormal microvasculature in nailfold capillaroscopy had a negative effect on LVEF progression (p = 0.039). Disease duration of SLE and proteinuria were risk factors associated with the descent of E/A ratio (p = 0.014 and p = 0.015, respectively). CONCLUSION: In patients with juvenile-onset SLE who were free of cardiac symptoms, there was evidence of declining ventricular diastolic function with time. Abnormal nailfold microvasculature, proteinuria and longer disease duration were the main risk factors for worsening of ventricular function.

Clinical Decision Making Ability of Nursing Students in a Tertiary Hospital

Decision making in nursing is one of the most important skills nurses must apply and utilize in their nursing practice. The aim of this study was to determine the perception of clinical decision making ability among nursing students. A descriptive crosssectional study was conducted in a tertiary hospital. A total of 54 nursing students were recruited using a modified version of Clinical Decision Making in Nursing Scale (CDMNS) adapted from Jenkins (1985). The findings showed good CDMNS score with mean and standard deviation of (124.24±12.713). The four sub-scales of CDMNS were: searching for alternative (33.24±4.821), canvassing (28.74±3.514), evaluation and re-evaluation (31.43±3.922), searching for information(30.83±4.765). Nineteen (35%) of the participants chose nursing as their first choice, whereas 35 participants (65%) did not. Thirthy seven (69%) participants were satisfied with their nursing competency, 17 (31%) were unsatisfied. There were significant differences between searching for alternatives, evaluation and re-evaluation, and nursing as their first choice (p=<0.05). There were also significant differences between searching for alternatives and satisfaction with nursing competency (p=<0.05). There was significant difference between education level and searching for alternatives and information (p=<0.05). The nursing students possessed adequate clinical decision making ability. Although most of the nursing students did not choose nursing as their first choice, they sought for alternatives and evaluated-reevaluated during their decision making process. Nursing students’ satisfaction also contributed to appropriate clinical decision making in the critical care setting.

Quality of life after radiosurgery for cerebral arteriovenous malformation patients who present with seizure.

BACKGROUND AND PURPOSE: This study assessed the quality of life (QOL) and employment status after radiosurgery for arteriovenous malformation (AVM) patients who presented with seizure. METHODS: Between 1997 and 2006, 78 AVM patients who presented with seizure and received radiosurgery were assessed using serial imaging tests, clinical evaluations that included employment status, and a QOL survey. The QOL questionnaire was developed as a retrospective screening tool to estimate the present QOL and the patient's self-rated relative changes (trend values) in QOL after radiosurgery. These results were correlated to one another using the Engel seizure frequency scoring system. RESULTS: The follow-up periods ranged from 48.0 to 151.0 months (mean, 92.5). The mean trend values and mean QOL scores in patients with seizure freedom or AVM obliteration were significantly greater than in patients without these outcomes (all P values < 0.05). Good radiosurgical outcomes were associated with attaining employment (all P values < 0.05). However, differences in employment status were not significant (P = 0.186) despite a higher proportion of patients who described their workplace activity as improved compared with their pre-radiosurgical activity at the last follow-up evaluation. CONCLUSIONS: Radiosurgery may improve QOL and employment status in AVM patients, especially patients who experience seizure freedom or AVM obliteration.

Unrelated cord blood transplantation for thalassaemia: a single-institution experience of 35 patients.

Our study was designed to prospectively determine whether or not unrelated cord blood transplantation (CBT) can produce outcomes comparable to related donor transplantation for children with ß-thalassaemia. In 35 patients, 40 transplants were performed between October 2003 and September 2009. HLA matching at enrolment was 6/6 (n=8), 5/6 (n=16), 4/6 (n=27), or 3/6 (n=1) by low-resolution HLA-A, -B, and high-resolution DRB1. These patients received non-manipulated grafts without ex vivo expansion or T-cell depletion. The median number of nucleated and CD34+ cells infused was 7.8 × 10(7)/kg (range, 2.8-14.7 × 10(7)/kg) and 4.0 × 10(5)/kg (range, 1.7-19.9 × 10(5)/kg), respectively. The 5-year OS and thalassaemia-free survival after the first transplant were 88.3 and 73.9%, respectively. The cumulative incidence of TRM at 2 years was 11.7%. Fourteen patients developed chronic skin GVHD. Thirty patients were alive and transfusion-independent with a Lansky performance score ≥80% achieved between 6 and 76 months post transplant (median, 36 months). These data compare acceptably with the survival rates of related-donor BMT for thalassaemia and suggest that patients without an available HLA-compatible sibling but who have well-matched unrelated donors should also be considered for CBT.

Heme oxygenase-1 mediates nicotine- and lipopolysaccharide-induced expression of cyclooxygenase-2 and inducible nitric oxide synthase in human periodontal ligament cells.

BACKGROUND AND OBJECTIVE: Although heme oxygenase-1 (HO-1) plays a key role in inflammation, its anti-inflammatory effects and mechanism of action in periodontitis are still unknown. This study aimed to identify the effects of HO-1 on the proinflammatory mediators activated by nicotine and lipopolysaccharide (LPS) stimulation in human periodontal ligament (PDL) cells. MATERIAL AND METHODS: The production of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) was evaluated using Griess reagent and an enzyme immunoassay, respectively. The expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and HO-1 proteins was evaluated by Western blot analysis. RESULTS: Lipopolysaccharide and nicotine synergistically induced the production of NO and PGE(2) and increased the protein expression of iNOS, COX-2 and HO-1. Treatment with an HO-1 inhibitor and HO-1 small interfering RNAs blocked the LPS- and nicotine-stimulated NO and PGE(2) release as well as the expression of iNOS and COX-2. CONCLUSION: Our data suggest that the nicotine- and LPS-induced inflammatory effects on PDL cells may act through a novel mechanism involving the action of HO-1. Thus, HO-1 may provide a potential therapeutic target for the treatment of periodontal disease associated with smoking and dental plaque.

IAN5 polymorphisms are associated with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a representative autoimmune disease, which is frequently associated with lymphopenia. Biobreeding (BB) rat is a typical animal model which develops autoimmune diseases with lymphopenia which results from a frame-shift mutation in the immune-associated nucleotide (IAN) 5 gene. IAN5 is involved in the regulation of T-cell activation and survival. To examine the association of IAN5 gene with SLE, we scrutinised the single nucleotide polymorphisms (SNPs) in the IAN5 gene. We conducted a case-control study where 132 SLE patients, 505 rheumatoid arthritis (RA) patients, and 546 controls were genotyped for four SNPs in the IAN5 gene. Two SNPs (+2071C > T and +2677G > A) were associated with susceptibility to SLE (P = 0.040 and 0.045, respectively), and -4432G > A SNP was associated with the development of leukopenia (P = 0.028) and the requirement of steroid pulse therapy (P = 0.040) in SLE patients. Haplotype analyses showed that Ht1(CTCG) was associated with susceptibility to SLE (P = 0.036), and Ht4(ACCG), Ht5(ACTA) and Ht6(GCCG) were associated with the development of nephritis (P = 0.017, 0.019, 0.022, respectively). In conclusion, the IAN5 polymorphisms were associated with susceptibility to SLE and the development of clinical disease manifestations in a strictly Korean population.

Evaluation of tumour response after gamma knife radiosurgery for residual vestibular schwannomas based on MRI morphological features.

OBJECTIVE: To evaluate tumour response after gamma knife (GK) radiosurgery for residual vestibular schwannoma (VS) based on MRI morphological features. METHODS: Sixty-one patients with histopathologically confirmed VS underwent GK radiosurgery with marginal tumour doses of 9.0-14.0 Gy (mean, 12.5). Mean tumour volume at GK radiosurgery was 3.65 ml (range, 0.52-15.50). GK radiosurgery was performed 0.3-95.7 months (median, 5.8) after microsurgery. Tumour volumes and half-reduction time were calculated using serial MRI. The morphological features of VS were documented by pre-microsurgical MRI. Histopathological investigation included Antoni-type dominance, the proliferation marker Ki-67 and tumour vascularity. RESULTS: Median duration of radiological follow-up was 53.7 months (range, 24.1-102.2) and the 8-year actuarial tumour control rate was 93.5%. No factor was associated with tumour control, although a cystic VS had borderline significance (p = 0.089). Mean tumour half-reduction time was 8.70 years (range, 0.57-79.89) and tumour half-reduction time in cystic VS proved to be significantly shorter than those in solid VS (p = 0.006). Thrombotic vessels (p = 0.015) and abnormal vessel proliferation (p = 0.003) were significantly more prominent in cystic VS than those in solid VS. CONCLUSIONS: GK radiosurgery appeared to be an effective treatment modality for residual tumour control after microsurgery. Owing to having relatively abundant tumour vascularity, residual solid portions of cystic VS resulted in efficient shrinkage after GK radiosurgery. Therefore, GK radiosurgery was found to be a rewarding therapeutic approach to the residual solid portions of cystic VS.

Costunolide inhibits production of tumor necrosis factor-alpha and interleukin-6 by inducing heme oxygenase-1 in RAW264.7 macrophages.

OBJECTIVES: Heme oxygenase (HO)-1 expression via nuclear factor-erythroid 2-related factor 2 (Nrf2) activation has an ability to inhibit tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 production. Costunolide has been reported to inhibit IL-1 production, but whether other cytokines could be inhibited remains to be confirmed. We investigated the effects of costunolide and its components (alpha-methylene-gamma-butyrolactone; CH2-BL, alpha-methyl-gamma-butyrolactone; CH3-BL, and gamma-butyrolactone; BL) on HO-1 expression as well as TNF-alpha and IL-6 production in RAW264.7 macrophages. METHODS: HO-1 expression and Nrf2 nuclear accumulation were analyzed by Western blot analysis. The production of TNF-alpha and IL-6 in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS) was assayed by ELISA. RESULTS: Costunolide and CH2-BL induced HO-1 expression and Nrf2 nuclear accumulation, whereas CH3-BL and BL did not. Pre-incubation with costunolide inhibited LPS-induced production of TNF-alpha and IL-6. The inhibitory effects of costunolide on TNF-alpha and IL-6 production were abrogated by tin protoporphyrin, an HO inhibitor. CONCLUSIONS: Costunolide is an effective HO-1 inducer capable of inhibiting macrophage-derived pro-inflammatory cytokines. CH2-BL moiety of costunolide is essential for Nrf2 activation leading to HO-1 expression.

Mechanism of cyclosporine-induced overgrowth in gingiva.

UNLABELLED: Cyclosporine A (CsA) is a widely used immunosuppressant but with significant side-effects, such as gingival overgrowth. This study investigates how CsA induces gingival proliferation and shows the effects of the CsA-associated signaling messengers, IL-6 and TGF-beta1, on gingival proliferation. CsA increased both IL-6 and TGF-beta1 levels. In addition to CsA, an IL-6 or TGF-beta1 treatment also induced gingival fibroblast proliferation. Inhibiting the cytokine resulted in the suppression of CsA-induced proliferation. MAPKs and PI3K are known to be involved in cell proliferation. Therefore, the effect of CsA on the kinase activities was examined. The results showed that both p38 MAPK and PI3K are essential for gingival fibroblast proliferation. TGF-beta1 and IL-6 and their associated signaling transduction may be novel bona fide molecular targets for the prevention of gingival overgrowth in CsA-treated patients. ( ABBREVIATIONS: MAPK, mitogen-activated protein kinase; P13K, phosphatidylinositol 3-kinase.)

Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin.

We investigated the cytoprotective mechanisms of flunarizine in cisplatin-induced death of auditory cells. Concomitant with an increase in viability, treatment with flunarizine resulted in a marked dissociation of Nrf2/Keap1 and subsequent intranuclear translocation of Nrf2, which was mediated by PI3K-Akt signaling. Overexpression of Nrf2 protected cells from cisplatin along with transcriptional activation of ARE to generate heme oxygenase-1 (HO-1). Pretreatment with flunarizine predominantly increased the transcriptional activity of HO-1 among Nrf2-driven transcripts, including HO-1, NQO1, GCLC, GCLM, GST micro-1, and GSTA4. Furthermore, both pharmacological inhibition and siRNA transfection of HO-1 completely abolished the flunarizine-mediated protection of HEI-OC1 cells and the primary rat (P2) organ of Corti explants from cisplatin. These results suggest that Nrf2-driven transcriptional activation of ARE through PI3K-Akt signaling augments the generation of HO-1, which may be a critically important determinant in cellular response toward cisplatin and the cytoprotective effect of flunarizine against cisplatin.

Dexamethasone protects primary cultured hepatocytes from death receptor-mediated apoptosis by upregulation of cFLIP.

Dexamethasone (DEX) pretreatment protected hepatocytes from TNF-alpha plus actinomycin D (ActD)-induced apoptosis by suppressing caspase-8 activation and the mitochondria-dependent apoptosis pathway. DEX treatment upregulated cellular FLICE inhibitory protein (cFLIP) expression, but did not alter the protein levels of Bcl-2, Bcl-xL, Mcl-1, and cIAP as well as Akt activation. The increased cFLIP mRNA level by DEX was inhibited by ActD, indicating that DEX upregulates cFLIP expression at the transcriptional step. DEX also inhibited Jo2-mediated hepatocyte apoptosis by blocking the formation of the death-inducing signaling complex and caspase-8 activation. Specific downregulation of cFLIP expression using siRNA reversed the antiapoptotic effect of DEX by increasing caspase-8 activation. Moreover, DEX administration into mice increased cFLIP expression in the liver and prevented Jo2-induced hepatic injury by inhibiting caspase-8 and -3 activities. Our results indicate that DEX exerts a protective role in death receptor-induced in vitro and in vivo hepatocyte apoptosis by upregulating cFLIP expression.

Delayed bleeding after gamma knife surgery for meningioma.

We report the occurrence of haemorrhage in a meningioma after gamma knife surgery.A 52-year-old woman had undergone gamma knife radiosurgery for a growing meningioma in the left tentorial hiatus three years earlier (A radiation dose of 15 Gy was administered to the margin, with a maximum dose of 30 Gy, Fig. 1a). The size of the mass decreased steadily, and central lucency was seen in the follow-up magnetic resonance images, a usual finding seen after gamma knife surgery (MRI, Fig. 1b). However, a MRI taken at the 30-month follow-up showed the tumour to be swollen, and peritumoural oedema had increased (Fig. 1c). Three years later, apoplectic symptoms occurred, and computed tomography revealed a peritumoural haemorrhage, with oedema (Fig. 1d). An emergency craniotomy was carried out, and the biopsy showed a transitional type of meningioma, with vasculopathy and necrosis. After operation she had a right hemiparesis and a visual defect.

MCP-1 gene regulatory region polymorphism in Chinese children with mild, moderate and near-fatal asthma.

BACKGROUND: A polymorphism in the monocyte chemoattractant protein 1 (MCP-1) gene regulatory region has been associated with asthma in Caucasians. This polymorphism is possibly endemic to the Asian region, but its impact on Asian populations is unclear. In addition, the relationship of this marker with life-threatening asthma has not been clarified. The aim of this study was to test the genetic association between the MCP-1 -2518A/G polymorphism and asthma/atopy in a cohort of Chinese children, with particular emphasis on those patients who had experienced life-threatening asthma attacks. METHODS: Forty-eight children with near-fatal asthma, 134 mild-to-moderate asthmatics, 69 allergic-disorder cases without asthma, and 107 nonasthmatic, nonatopic control children were genotyped by a polymerase chain reaction-based assay. RESULTS: Comparison of the four groups of children (n = 358) revealed no detectable differences in genotype or allele frequencies of the MCP-1 -2518A/G polymorphism. There was no evidence of association between the polymorphism and any of the outcomes of interest including clinical severity, blood eosinophil count, atopy, total serum IgE levels, and degree of bronchial hyper-responsiveness. CONCLUSION: These results suggest that the MCP-1 -2518A/G polymorphism is not a risk factor for near-fatal asthma. Furthermore, this polymorphism seems to play no role in the development of asthma or atopy in Chinese subjects, possibly as a result of the genetic heterogeneity between Asian and Caucasian populations with respect to regulation of MCP-1 expression. Our results underscore the necessity of accounting for ethnic background in the investigation of asthma-predisposition genes.