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.

Brachytherapy for high grade prostate cancer induces distinct changes in circulating CD4 and CD8 T cells - Implications for systemic control.

This exploratory study is a follow up to our previous investigation of immune response in the circulation of high-grade Gleason 9 prostate cancer patients treated with EBRT + BT compared to EBRT alone. Notably, EBRT + BT demonstrates the potential to elicit an effect on CD4/CD8 ratio which may have attributed to improved clinical response to therapy. Our findings show promise for leveraging circulating immune cells as predictive biomarkers for radiotherapy response.

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.

Coronary artery dilation among patients with paediatric-onset systemic lupus erythematosus.

OBJECTIVES: This study aimed to evaluate increased coronary artery dimensions in patients with paediatric-onset systemic lupus erythematosus (SLE) in comparison with healthy controls, and to identify risk factors associated with increased coronary artery dimensions in the SLE patients. METHODS: As part of a longitudinal cohort study of coronary artery disease (CAD) in paediatric-onset SLE, 83 children with SLE and 36 healthy controls were enrolled for a cross-sectional analysis. Their coronary artery diameters were measured by echocardiography while their body mass index (BMI), blood pressure, and other cardiovascular factors were recorded. The age at diagnosis, serum uric acid (UA) and creatinine levels, and other lupus-related factors were further evaluated in SLE patients. Data were analysed using linear regression. RESULTS: Mean body surface area (BSA)-adjusted dimensions of the left coronary artery (LCA) and right coronary artery (RCA) were significantly larger in SLE patients than in controls (both p < 0.001). The age at diagnosis, BMI, and serum UA and creatinine levels were associated with LCA and RCA diameters. There were no correlations between the coronary artery diameters and blood pressure, SLE duration, SLE Disease Activity Index (SLEDAI), C-reactive protein (CRP), C3, C4, anti-double-stranded-DNA (anti-dsDNA), or lipid profile. In multivariate analysis, serum UA level, age at diagnosis, and BMI were consistently associated with coronary artery dimensions (p < 0.001, p = 0.008, and p = 0.006 for LCA; p = 0.020, 0.013, and 0.008 for RCA). CONCLUSIONS: Increased coronary artery diameters were found in children with SLE and were associated with higher serum UA levels. The pathogenic mechanisms warrant further investigation.

Response After Repeated Ketamine Injections in a Rat Model of Neuropathic Pain.

Ketamine, an N-methyl-D-aspartate antagonist, reduces pain by decreasing central sensitization and pain windup. However, chronic ketamine use can cause tolerance, dependency, impaired consciousness, urinary symptoms, and abdominal pain. This study aimed to investigate the effects of repeated ketamine injections and ketamine readministration after discontinuation in a rat model of neuropathic pain. To induce neuropathic pain, partial sciatic nerve ligation (PSNL) was performed in 15 male Wistar rats, and these animals were divided into three groups: PSNL (control), PSNL + ketamine 5 mg/kg (K5), and PSNL + ketamine 10 mg/kg (K10; n=5 each). Ketamine was injected intraperitoneally daily for 4 weeks, discontinued for 2 weeks, and then readministered for 1 week. Following PSNL, the mechanical withdrawal threshold was determined weekly using the Von Frey. The K10 group showed a significant increase in the mechanical withdrawal threshold, presented here as the target force (in g), at 21 and 28 days compared to the time point before ketamine injection (mean±SE, 276.0±24.0 vs. 21.6±2.7 and 300.0±0.0 vs. 21.6±2.7, respectively; P<0.01) and at 14, 21, and 28 days compared to the control group (108.2±51.2 vs. 2.7±1.3, 276.0±24.0 vs. 2.5±1.5, and 300.0±0.0 vs. 4.0±0.0, respectively; P<0.05). However, in the K10 group, the ketamine effects decreased significantly at 7 days after readministration compared to those after 28 days of repeated injections (P<0.05). In the K10 group, repeated ketamine injections showed a significant increase in antinociceptive effect for >2 weeks, but this ketamine effect decreased after drug readministration.

Curcumin protects against ovariectomy-induced bone loss and decreases osteoclastogenesis.

Curcumin has anti-oxidative activity. In view of the increasing evidence for a biochemical link between increased oxidative stress and reduced bone density we hypothesized that curcumin might increase bone density by elevating antioxidant activity in some target cell type. We measured bone density by Micro-CT, enzyme expression levels by quantitative PCR or enzyme activity, and osteoclast (OC) formation by tartrate-resistant acid phosphatase staining. The bone mineral density of the femurs of curcumin-administered mice was significantly higher than that of vehicle-treated mice after ovariectomy (OVX) and this was accompanied by reduced amounts of serum collagen-type I fragments, which are markers of bone resorption. Curcumin suppressed OC formation by increasing receptor activator of nuclear factor-κB ligand (RANKL)-induced glutathione peroxidase-1, and reversed the stimulatory effect of homocysteine, a known H(2) O(2) generator, on OC formation by restoring Gpx activity. Curcumin generated an aberrant RANKL signal characterized by reduced expression of nuclear factor of activated T cells 2 (NFAT2) and attenuated activation of mitogen-activated protein kinases (ERK, JNK, and p38). Curcumin thus inhibited OVX-induced bone loss, at least in part by reducing osteoclastogenesis as a result of increased antioxidant activity and impaired RANKL signaling. These findings suggest that bone loss associated with estrogen deficiency could be attenuated by curcumin administration.

Immune cell profiling in Gleason 9 prostate cancer patients treated with brachytherapy versus external beam radiotherapy: An exploratory study.

This exploratory study evaluates immunological changes in high-risk Gleason 9 prostate cancer patients treated with EBRT+BT compared to EBRT alone. Notably, BT demonstrates the potential to elicit a T cell response which may support further investigation using circulating immune cells as predictive and prognostic biomarkers for radiotherapy response.

Pediatric lupus in Asia.

Of all patients with systemic lupus erythematosus (SLE), 15-20% are diagnosed during childhood, with disease onset prior to the age of 16 years. Because disease expression in SLE is influenced by environment factors and differs between racial and ethnic groups. The aims of this review were to describe prevalence, clinical manifestations, common infectious complications, and outcome of pediatric-onset SLE in Asia. The prevalence of pediatric-onset SLE was 6.3-19.3 per 100,000 in Asia. The ratio of female to male was 4.7-6.2. The mean age at diagnosis of pediatric-onset SLE was 8.6-13.5 years. The most common clinical features of pediatric-onset SLE in Asia were cutaneous rashes, arthritis, hematological involvement and nephritis. The occurrence of nephritis varies from 29% to 81%. The most common histopathology of lupus nephritis was diffuse proliferative glomerulonephritis (WHO Class-IV) which occurred in 39.4-54% of case of lupus nephritis. Pediatric-onset SLE patients with infections have poor outcomes than uninfected patients. Gram-negative bacilli are the most common microorganisms responsible for bacteremia in Asian patients with SLE. Recurrent major infections predict poorer disease outcome and associated organ damage in pediatric-onset SLE. Improving the survival of SLE patients was reported in Asia in recent decades. The survival was 92% at the age of 5 years, 86% at 10 years and 79% at 15 years in children with SLE in Taiwan in 2008.

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.

Results of 15 Gy HDR-BT boost plus EBRT in intermediate-risk prostate cancer: Analysis of over 500 patients.

PURPOSE/OBJECTIVE: To report biochemical control associated with single fraction 15 Gy high-dose-rate brachytherapy (HDR-BT) boost followed by external beam radiation (EBRT) in patients with intermediate-risk prostate cancer. MATERIALS AND METHODS: A retrospective chart review of all patients with intermediate-risk disease treated with a real-time ultrasound-based 15 Gy HDR-BT boost followed by EBRT between 2009 and 2016 at a single quaternary cancer center was performed. Freedom from biochemical failure (FFBF), cumulative incidence of androgen deprivation therapy use for biochemical or clinical failure post-treatment (CI of ADT) and metastasis-free survival (MFS) outcomes were measured. RESULTS: 518 patients met the inclusion criteria for this study. Median age at HDR-BT was 67 years (IQR 61-72). 506 (98%) had complete pathologic information available. Of these, 146 (28%) had favorable (FIR) and 360 (69%) had unfavorable (UIR) intermediate-risk disease. 83 (16%) received short course hormones with EBRT + HDR. Median overall follow-up was 5.2 years. FFBF was 91 (88-94)% at 5 years. Five-year FFBF was 94 (89-99)% and 89 (85-94)% in FIR and UIR patients, respectively (p = 0.045). CI of ADT was 4 (2-6)% at 5 years. Five-year CI of ADT was 1 (0-3)% and 5 (2-8)% in FIR and UIR patients, respectively (p = 0.085). MFS was 97 (95-98)% at 5 years. Five-year MFS was 100 (N/A-100)% and 95 (92-98)% in FIR and UIR patients, respectively (p = 0.020). CONCLUSION: In this large cohort of intermediate-risk prostate cancer patients, 15 Gy HDR-BT boost plus EBRT results in durable biochemical control and low rates of ADT use for biochemical failure.

Prostate-specific Antigen Bounce After Stereotactic Body Radiotherapy for Prostate Cancer: A Pooled Analysis of Four Prospective Trials.

AIMS: We conducted a pooled analysis of four prospective stereotactic body radiotherapy (SBRT) trials of low- and intermediate-risk prostate cancer to evaluate the incidence of prostate-specific antigen (PSA) bounce and its correlation with the time-dose-fraction schedule. The correlation between bounce with PSA response at 4 years (nadir PSA < 0.4 ng/ml) and biochemical failure-free survival (BFFS) was also explored. MATERIALS AND METHODS: The study included four treatment groups: 35 Gy/five fractions once per week (QW) (TG-1; n = 84); 40 Gy/five fractions QW (TG-2; n = 100); 40 Gy/five fractions every other day (TG-3; n = 73); and 26 Gy/two fractions QW (TG-4; n = 30). PSA bounce was defined as a rise in PSA by 0.2 ng/ml (nadir + 0.2) or 2 ng/ml (nadir + 2.0) above nadir followed by a decrease back to nadir. Patients with fewer than three follow-up PSA tests were excluded from the pooled analysis. RESULTS: In total, 287 patients were included, with a median follow-up of 5.0 years. The pooled 5-year cumulative incidence of bounce by nadir + 2.0 was 8%. The 2-year cumulative incidences of PSA bounce by nadir + 0.2 were 28.9, 21, 19.6 and 16.7% (P = 0.12) and by nadir + 2.0 were 7.2, 8, 2.7 and 6.7% (P = 0.32) for TG-1 to TG-4, respectively. Multivariable analysis revealed that for nadir + 2.0, pre-treatment PSA (odds ratio 0.49; 95% confidence interval 0.26-0.97) correlated with PSA bounce. Although PSA bounce by nadir + 0.2 (odds ratio 0.10; 95% confidence interval 0.04-0.24) and nadir + 2.0 (odds ratio 0.29; 95% confidence interval 0.09-0.93) was associated with a lower probability of PSA response at 4 years, there was no association between bounce by nadir + 0.2 (hazard ratio 0.36; 95% confidence interval 0.08-1.74) or nadir + 2 (hazard ratio 1.77; 95% confidence interval 0.28-11.07) with BFFS. CONCLUSION: The incidence of PSA bounce was independent of time-dose-fraction schedule for prostate SBRT. One in 13 patients experienced a bounce high enough to be misinterpreted as biochemical failure, and clinicians should avoid early salvage interventions in these patients. There was no association between PSA bounce and BFFS.

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.

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.

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.

Long-term Toxicity and Health-related Quality of Life after Single-fraction High Dose Rate Brachytherapy Boost and Hypofractionated External Beam Radiotherapy for Intermediate-risk Prostate Cancer.

AIMS: To report health-related quality of life (HRQOL) and toxicity in prostate cancer patients treated with single-fraction high dose rate (HDR) brachytherapy boost and external beam radiotherapy (EBRT). MATERIALS AND METHODS: Patients with intermediate-risk prostate cancer were accrued to a phase II clinical trial of 15 Gy HDR boost and EBRT to a dose of 37.5 Gy in 15 fractions. HRQOL (Expanded Prostate Cancer Index Composite [EPIC]), urinary symptoms (International Prostate Symptom Score [IPSS]), erectile function (International Index of Erectile Function [IIEF]) and toxicity (Common Terminology Criteria for Adverse Events [CTCAE], version 3.0) were monitored prospectively. Univariate and multivariate logistic regression analysis was used to investigate associations between HRQOL/toxicity and baseline covariates. RESULTS: The median follow-up time was 5.2 years. The change in the median EPIC scores from baseline to year 5 in the urinary domain was from 91 to 85 (P = 0.0028), in the bowel domain was from 98 to 96 (P = 0.03), in the sexual domain was from 63 to 35 (P < 0.0001) and the hormonal domain remained unchanged at 95 (P = 0.93). Fifty-nine per cent and 46% of the patients with normal erectile function at baseline remained potent at year 1 and year 5, respectively. Late genitourinary toxicity grade 1, 2 and ≥3 occurred in 29, 59 and 4% of patients, respectively. The rates of late gastrointestinal toxicity grade 1, 2 and ≥3 were documented as 45, 19 and 0%, respectively. On multivariate logistic regression analysis, patients with larger prostates were more likely to develop a urinary late toxicity grade ≥2 (P = 0.01). The dose to 10% of the urethra was the only factor associated with a decline in the EPIC urinary domain score (P = 0.012). Prostate volume >43 ml was associated with higher late genitourinary toxicity grade ≥2. CONCLUSIONS: Single 15 Gy HDR brachytherapy with EBRT has a low rate of late genitourinary and gastrointestinal toxicities. Late urinary morbidity may be minimised by limiting the dose to the urethra, particularly for patients with larger prostates.

Stereotactic Body Radiotherapy versus Low Dose Rate Brachytherapy for Localised Prostate Cancer: a Cost-Utility Analysis.

AIMS: To conduct a cost-utility analysis comparing stereotactic body radiotherapy (SBRT) with low dose rate brachytherapy (LDR-BT) for localised prostate cancer (PCa). MATERIALS AND METHODS: A decision-analytic Markov model was developed from the healthcare payer perspective to simulate the history of a 66-year-old man with low-risk PCa. The model followed patients yearly over their remaining lifetimes. Health states included 'recurrence-free', 'biochemical recurrence' (BR), 'metastatic' and 'death'. Transition probabilities were based on a retrospective cohort analysis undertaken at our institution. Utilities were derived from the literature. Costs were assigned in 2015 Canadian dollars ($) and reflected Ontario's health system and departmental costs. Outcomes included quality-adjusted life years (QALYs), costs and incremental cost-effectiveness ratios. A willingness-to-pay threshold of $50 000/QALY was used. RESULTS: SBRT was the dominant strategy with 0.008LYs and 0.029QALYs gained and a reduction in cost of $2615. Under base case conditions, our results were sensitive to the BR probability associated with both strategies. LDR-BT becomes the preferred strategy if the BR with SBRT is 1.3*[baseline BR_SBRT] or if the BR with LDR-BT is 0.76*[baseline BR_LDR-BT]. When assuming the same BR for both strategies, LDR-BT becomes marginally more effective with 0.009QALYs gained at a cost of $272 848/QALY. CONCLUSIONS: SBRT represents an economically attractive radiation strategy. Further research should be carried out to provide longer-term follow-up and high-quality evidence.

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.)

Carbon monoxide and nitric oxide protect against tumor necrosis factor-alpha-induced apoptosis in osteoblasts: HO-1 is necessary to mediate the protection.

BACKGROUND: Carbon monoxide (CO) and nitric oxide (NO) each have unique roles for various inflammatory states, including inflammatory bone resorption. Although it is known that NO can induce the expression of the cytoprotective enzyme HO-1, there is no information as to whether the protective effect of CO requires NO production or whether CO must induce the expression of HO-1 to exert its functional effects. METHODS: Murine osteoblast cells, MC3T3E1 osteoblasts, were cultured for CO and NO-associated HO-1 experiments and were transfected with pcDNA 3, pcDNA 3-HO-1, control siRNA or HO-1 siRNA using Nucleofector. For cell death measurement, MTT and annexin V assays were used. We performed Western blotting to check the expressions of HO-1 and iNOs and measured the HO-1 enzyme activity. We also measured the amounts of nitrite and nitrate using Griess reagents. RESULTS: The increased expression of HO-1 is required for the protective effect of NO and a single treatment of CO can increase the expression of HO-1, and this is also important for the protective effect of CO in MC3T3E1 osteoblasts. CO as well as NO attenuates the TNF-alpha-induced apoptosis in osteoblasts. The anti-apoptotic effect of CO or NO is not mediated by cGMP, and CO has no effect on the release of NO. The inhibition of HO-1 with using the HO-1 inhibitor ZnPP or HO-1 siRNA resulted in a striking increase of apoptosis in the CO/TNF-alpha-treated cells. Furthermore, HO-1 overexpression showed resistance against the TNF-alpha-induced cytotoxicity in the MC3T3E1 osteoblasts. CONCLUSIONS: There is a need for HO-1 expression to mediate the protection provided by exogenous CO or NO in osteoblasts.

Nitric oxide protects PC12 cells from serum deprivation-induced apoptosis by cGMP-dependent inhibition of caspase signaling.

Although nitric oxide (NO) induces neuronal cell death under some conditions, it also can prevent apoptosis resulting from growth factor withdrawal. We investigated the molecular mechanism by which NO protects undifferentiated and differentiated PC12 cells from trophic factor deprivation-induced apoptosis. PC12 cells underwent apoptotic death in association with increased caspase-3-like activity, DNA fragmentation, poly(ADP-ribose) polymerase (PARP) cleavage, and cytochrome c release after 24 hr of serum withdrawal. The apoptosis of PC12 cells was inhibited by the addition of NO-generating donor S-nitroso-N-acetylpenicillamine (SNAP) (5-100 microM) and the specific caspase-3-like protease inhibitor Ac-Asp-Glu-Val-Asp-aldehyde (Ac-DEVD-cho) but not the YVADase (or caspase-1-like protease) inhibitor N-acetyl-Tyr-Val-Ala-Asp-aldehyde (Ac-YVAD-cho). SNAP and Ac-DEVD-cho prevented the increase in DEVDase (caspase-3-like protease) activity. The SNAP-mediated suppression of DEVDase activity was only minimally reversed by the incubation of cell lysate with dithiothreitol, indicating that NO did not S-nitrosylate caspase-3-like proteases in PC12 cells. Western blot analysis showed that NO inhibited the proteolytic activation of caspase-3. The cGMP analog 8-bromo-cGMP (8-Br-cGMP) blocked apoptotic cell death, caspase-3 activity and activation, and cytochrome c release. The soluble guanylyl cyclase inhibitor 1-H-oxodiazol-[1,2,4]-[4,3-a] quinoxaline-1-one (CODQ) significantly attenuated NO-mediated, but not 8-Br-cGMP-dependent, inhibition of apoptotic cell death, PARP cleavage, cytochrome c release, and DEVDase activity. Furthermore, the protein kinase G inhibitor KT5823 reversed both SNAP- and 8-Br-cGMP-mediated anti-apoptotic events. All these apoptotic phenomena were also suppressed by NO production through neuronal NO synthase gene transfer into PC12 cells. Furthermore, similar findings were observed in differentiated PC12 cells stimulated to undergo apoptosis by NO donors and NGF deprivation. These findings indicate that NO protects against PC12 cell death by inhibiting the activation of caspase proteases through cGMP production and activation of protein kinase G.