Denosumab-induced hypocalcemia in a patient with hyperthyroidism: a case report.

Denosumab is a humanized monoclonal antibody targeting the receptor activator of nuclear factor kappa-B ligand (RANKL). Denosumab is an effective treatment for osteoporosis but can cause hypocalcemia. We present a case of denosumab-induced hypocalcemia in a patient with hyperthyroidism with a high bone turnover state. A 48-year-old postmenopausal woman was diagnosed with hyperthyroidism and osteoporosis and received antithyroid drugs (propylthiouracil 200 mg/day) and denosumab. After 2 months of taking medication, the patient complained of numbness and tingling in the hands and feet and was diagnosed with hypocalcemia (calcium, 5.8 mg/dL; ionized calcium, 0.83 mmol/L). Alfacalcidol (0.5 µg/day) and calcium carbonate (3000 mg/day) were prescribed. Subsequently, the patient's symptoms improved, and her serum calcium level normalized. The risk of denosumab-induced hypocalcemia may be increased in patients with diseases related to high bone turnover, such as hyperthyroidism; therefore, caution is needed.

Incidence of subsequent osteoporotic fractures after distal radius fractures and mortality of the subsequent distal radius fractures: a retrospective analysis of claims data of the Korea National Health Insurance Service.

A better understanding of the features of subsequent fractures after distal radius fracture (DRF) is important for the prevention of further osteoporotic fractures. This study found that the cumulative incidence of subsequent osteoporotic fractures in South Korea increased over time and that the mortality rates of subsequent DRFs were lower than those of first-time DRFs. INTRODUCTION: We examined the incidence of osteoporotic fractures following distal radius fractures (DRFs) and the mortality rate after subsequent DRFs using claims data from the Korea National Health Insurance (KNHI) Service. METHODS: We identified records for 41,417 patients with first-time DRFs in 2012. The occurrence of osteoporotic fractures of the spine, hip, wrist, and humerus at least 6 months after the index DRF was tracked through 2016. All fractures were identified by specific diagnosis and procedure codes. One-year mortality rates and standardized mortality ratios (SMRs) for initial and subsequent DRFs were calculated for all patients. RESULTS: The 4-year cumulative incidence of all subsequent osteoporotic fractures was 14.74% (6105/41,417; 9.47% in men, 15.9% in women). The number of associated subsequent fractures was 2850 for the spine (46.68%), 2271 for the wrist (37.2%), 708 for the hip (11.6%), and 276 for the humerus (4.52%). The cumulative mortality rate 1 year after the first-time and subsequent DRF was 1.47% and 0.71%, respectively, and the overall SMR was 1.48 (95% CI: 1.37-1.61) and 0.71 (95% CI: 0.42-1.21), respectively. CONCLUSION: The cumulative incidence of osteoporotic fractures following DRFs increased over the study period and was higher among women. The cumulative mortality rates and SMRs of subsequent DRFs were lower than those of first-time DRFs at the 1-year follow-up. Given the increasing incidence rate of DRFs, the incidence of subsequent osteoporotic fractures may also increase.

Factors affecting willingness to get assessed and treated for osteoporosis.

Individuals with poor knowledge of osteoporosis and lower socioeconomic status, including being single and having a lower level of annual income, are less likely to be assessed or treated for osteoporosis. Individuals with particular osteoporosis risk factors such as smokers and heavy drinkers are overlooked for diagnosis. Further study is needed to identify and address the existing barriers and to promote osteoporosis management for women with these risk factors. INTRODUCTION: Despite the negative health consequences of osteoporosis and the availability of effective treatment, a pervasive and persistent prevention care gap for osteoporosis remains present throughout the world. We attempted to identify the factors affecting the willingness of patients to either undergo or avoid assessment and treatment for osteoporosis. METHODS: A nationwide online survey was conducted in 926 Korean women over age 50. The survey included questions addressing three domains: (1) clinical and socio-demographic characteristics, (2) questions concerning the reasons for undergoing or avoiding osteoporosis assessment or treatment, and (3) knowledge of osteoporosis as measured using the modified Korean version of Facts on Osteoporosis Quiz. The assessed and non-assessed participants were compared in terms of their clinical and socioeconomic statuses, reasons for undergoing or avoiding osteoporosis management, and levels of knowledge of osteoporosis. RESULTS: The highest-ranked reason for undergoing osteoporosis assessment was fear of osteoporotic fracture, while the highest-ranked reason for avoiding osteoporosis assessment was not feeling a need to get tested for osteoporosis. Participants who sought assessment for osteoporosis were older and more likely to be married, and had greater knowledge of osteoporosis than those who did not seek assessment. The two groups were found to be similar in terms of tobacco use and daily alcohol use. Patients who had been diagnosed with osteoporosis but either did not initiate or discontinued osteoporosis treatment within 1 year were younger and had lower levels of annual income than those who began and continued treatment. CONCLUSION: Individuals with poor knowledge of osteoporosis and those of lower socioeconomic status, including those who were single and had a lower level of annual income, were less likely to be assessed and treated for osteoporosis. Individuals with particular osteoporosis risk factors such as smokers and heavy drinkers are overlooked for diagnosis. Further study is needed to identify and address the existing barriers and to promote osteoporosis management for women with these risk factors.

An experimental approach for real time mass spectrometric CVD gas phase investigations.

This is a report on the first setup of a recently developed, extremely sensitive and very fast 3D quadrupole ion trap mass spectrometer inline in a metalorganic vapour phase epitaxy (MOVPE) system. This setup was developed ultimately for the decomposition- and the interaction analysis of various established as well as novel metalorganic sources for MOVPE deposition of III/V semiconductors. To make in-situ gas phase and growth interaction analysis on a new level of sensitivity possible without disturbing the MOVPE growth process itself, an optimized experimental connection of the mass spectrometer to the MOVPE system is required. This work reports on the realization of such an experimental setup and provides first proof of concept for decomposition analysis. In addition, a comparison to previous studies and gas-phase analysis at MOVPE systems will be given in this work.

Prognostic value of tumor-infiltrating lymphocytes in Epstein-Barr virus-associated gastric cancer.

BACKGROUND: This study explored the prognostic impact of tumor-infiltrating lymphocytes (TILs) and investigated whether three histologic subtypes (lymphoepithelioma-like carcinoma, carcinoma with Crohn's disease-like lymphoid reaction, and conventional-type adenocarcinoma) could stratify a prognostic subset for patients with Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC). MATERIALS AND METHODS: After reviewing 1318 consecutive cases of surgically resected or endoscopic submucosal dissected gastric cancers, 120 patients were identified as EBV-positive using EBV-encoded RNA in situ hybridization. The evaluation of the percentage of intratumoral (iTu-) and stromal (str-) TILs was carried out, and the cases were also subclassified into three histologic subtypes as noted above. RESULTS: Among the 120 patients, 73 patients (60.8%) and 60 patients (50.0%) were determined as str-TIL-positive and iTu-TIL-positive, respectively. In a univariate analysis, str-TIL-positivity was significantly associated with longer recurrence-free survival (RFS; P = 0.002) and disease-free survival (DFS; P = 0.008), yet not overall survival (OS; P = 0.145). While iTu-TIL-positivity has a tendency of favorable outcome indicator for DFS and OS, but statistically significant differences were not shown, respectively (RFS, P = 0.058; DFS, P = 0.151; OS, P = 0.191). In a multivariate analysis using a Cox proportional hazard model adjusted for age, pTNM stage, lymphatic invasion, perineural invasion, and venous invasion; histologic subtype, WHO classification, and str-TIL-positivity were independently or tentatively associated with favorable RFS (hazard ratio [HR] = 12.193, 95% confidence interval [95% CI] 1.039-143.055, P = 0.047) or DFS (HR = 4.836, 95% CI 0.917-25.525, P = 0.063). CONCLUSION: The histologic subclassification and TILs can be used to predict RFS and DFS for patients with EBVaGC.

Anticancer effects of suberoylanilide hydroxamic acid in esophageal squamous cancer cells in vitro and in vivo.

The effects of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, have not been studied in esophageal squamous cell cancer (ESCC). Cell viability assay; flow cytometry for cell cycle and annexin V apoptosis assays; assays for cell migration, invasion, and adhesion to extracellular matrix (ECM); and immunoblotting and immunofluorescence staining were performed in three ESCC cell lines. Tumor xenograft with semiquantitative immunohistochemistry was used to study the effects of SAHA in vivo. SAHA effectively inhibited growth of ESCC cells with half-inhibitory concentrations (IC50 ) ranging from 2.6 to 6.5 µmol/L. SAHA restored acetylation of histone 3 lysine 9 (H3K9Ac) and histone 4 lysine 12 (H4K12Ac) with an induction of G1 or G2 cell cycle arrest and apoptosis. Expression of cell cycle checkpoint regulatory proteins including cyclin-dependent kinases (CDKs) and cyclins was decreased, whereas expression of cell cycle suppressors, p21, p27, and Rb was increased in ESCC cells after SAHA treatment. SAHA inhibited migration, invasion, and ECM adhesion in ESCC cells with an induction of E-cadherin expression. SAHA significantly inhibited growth of ESCC tumors with increased expression of p21, p27, Rb, and E-cadherin while decreasing expression of CDK4 and cyclin D1 within the murine tumors. In conclusion, SAHA had antigrowth activity against ESCC cells in vitro and in vivo while inhibiting cell migration, cell invasion, and ECM adhesion, suggesting its potential as an epigenetic therapeutic agent for ESCC.

The effect of montelukast and antiadhesion barrier solution on the capsule formation after insertion of silicone implants in a white rat model.

BACKGROUND AND PURPOSES: Capsular contracture is one of the most severe complications that can occur in breast surgery following silicone implant insertion. The purpose of this study was to investigate the effect of montelukast and antiadhesion barrier solution (AABS) on reducing capsular formation and their possible synergism. MATERIALS AND METHODS: This study was approved by the Animal Ethics Committee (Reference No. KNU 2012-33) and was conducted in accordance with the Kyungpook National University - Institutional Animal Care and Use Committee, Animal Ethics Committee. The experiments in this study were conducted in vivo in 4 groups of 24 rats. Following silicone implant insertion, the pocket was injected with different agents. Group I (control group) was given normal saline injections into the pocket and fed with pure water. Group II was given injections of AABS and fed with pure water. Group III was given injections of normal saline and the medication montelukast during the experimental period. Group IV was given injections of AABS and montelukast as postoperative medication. Peri-implant capsules were excised after 8 weeks and were evaluated for transparency, inflammatory cell content, capsule thickness, collagen pattern and TGF-ß expression. RESULTS: The capsules in the experimental groups (i.e., groups II-IV) were significantly more transparent than those in group I (controls; p < 0.05, Student's t test). The mean capsule thickness of the experimental groups II (296 ± 14.76 µm), III (280 ± 14.77 µm) and IV (276 ± 39.28 µm) was smaller than that of the control group I (361 ± 35.43 µm). Compared to the control group, the histologic findings in the experimental groups suggested a decreased inflammatory response occurring in the peri-implant capsules as they exhibited minor vascularization and a reduced number of mast cells and macrophages. The collagen patterns in the experimental groups were of a lower density than in the control group with the former showing a loose, tidy collagen pattern. The amounts of TGF-ß and collagen I were higher in the control group than in the experimental groups. Group IV (the synergic effect group) had a more pronounced effect on all the parameters examined than that in groups II and III with separate drug administration. CONCLUSIONS: Montelukast and AABS reduced the thickness, the inflammatory cell infiltrate and the myofibroblast content of the peri-implant capsules around silicone implants in this white rat model. They lowered the expression of the fibrotic mediator, TGF-ß, and inhibited the peri-implant capsular fibrosis. Therefore, montelukast and AABS are effective in the reduction of silicone-induced peri-implant capsular formation.

Dietary exposure of Hong Kong adults to fatty acid esters of 3-monochloropropane-1,2-diol.

A total of 290 individual food samples were collected in Hong Kong, China, for 3-monochloropropane-1,2-diol (3-MCPD) fatty acid esters analysis. Most samples were processed food and in ready-to-eat form. The results show that the levels of 3-MCPD fatty acid esters were high in biscuits, fats and oils, snacks and Chinese pastry with mean bound 3-MCPD levels of 440, 390, 270 and 270 µg kg⁻¹, respectively. The dietary exposures to bound 3-MCPD of average and high adult consumers were estimated to be 0.20 and 0.53 µg kg bw⁻¹ day⁻¹, respectively. The primary toxicological concern of 3-MCPD fatty acid esters is its potential to release 3-MCPD in vivo during digestion in the gastrointestinal tract. 3-MCPD would affect the kidney, the central nervous system and the male reproductive system of rats. Assuming that 100% of the 3-MCPD was released from 3-MCPD fatty acid esters by hydrolysis in the digestive system, the dietary exposures to 3-MCPD for average and high adult consumers were only 10% and 26% of the provisional maximum tolerable daily intake (PMTDI) of 3-MCPD established by the Joint Food and Agriculture Organization/World Health Organization Expert Committee on Food Additives (JECFA) (2 µg kg bw⁻¹ day⁻¹), respectively. The results suggest that both average and high adult consumers are unlikely to experience major toxicological effects of 3-MCPD.

Vitamin D and diabetes in Koreans: analyses based on the Fourth Korea National Health and Nutrition Examination Survey (KNHANES), 2008-2009.

AIMS: A causal relationship between vitamin D deficiency and the incidence of diabetes mellitus has been suggested, but little research has been conducted on the Korean population. METHODS: We analysed the glucose tolerance status and serum 25-hydroxyvitamin D concentrations in 12263 subjects >19 years old who were registered for the Korea National Health and Nutrition Examination Survey, 2008-2009. RESULTS: Various demographic variables such as gender, age, season, resident area, physical activity, smoking, alcohol, marital status, education and occupation were associated with serum 25-hydroxyvitamin D concentrations. After adjusting for these variables as confounders, 25-hydroxyvitamin D concentrations in subjects with diabetes were significantly lower than those in subjects with normal glucose tolerance and those with impaired fasting glucose (P=0.005). Compared with the ≥ 75 nmol/l subgroup of serum 25-hydroxyvitamin D concentration, the odds ratios and 95% confidence intervals for diabetes mellitus were 1.206 (95%CI 0.948-1.534) in the 50- to 74-nmol/l subgroup, 1.339 (1.051-1.707) in the 25-to 49-nmol/l subgroup and 1.759 (1.267-2.443) in the <25-nmol/l subgroup. Compared with the serum ≥ 75-nmol/l 25-hydroxyvitamin D subgroup, serum insulin and homeostasis model assessment 2%B, a marker of insulin secretory capacity, were significantly higher, and homeostasis model assessment 2%S, a marker of insulin sensitivity, was significantly lower in the <25- and 25- to 49-nmol/l serum 25-hydroxyvitamin D subgroups than those in the other subgroups (P<0.001). CONCLUSIONS: The findings suggest that vitamin D deficiency, possibly involving altered insulin sensitivity, is associated with an increased risk for diabetes mellitus in the Korean population.

Integration of CNS survival and differentiation by HIF2α.

Hypoxia-inducible factor (HIF) 1α and HIF2α and the inhibitor of apoptosis survivin represent prominent markers of many human cancers. They are also widely expressed in various embryonic tissues, including the central nervous system; however, little is known about their functions in embryos. Here, we show that zebrafish HIF2α protects neural progenitor cells and neural differentiation processes by upregulating the survivin orthologues birc5a and birc5b during embryogenesis. Morpholino-mediated knockdown of hif2α reduced the transcription of birc5a and birc5b, induced p53-independent apoptosis and abrogated neural cell differentiation. Depletion of birc5a and birc5b recaptured the neural development defects that were observed in the hif2α morphants. The phenotypes induced by HIF2α depletion were largely rescued by ectopic birc5a and birc5b mRNAs, indicating that Birc5a and Birc5b act downstream of HIF2α. Chromatin immunoprecipitation assay revealed that HIF2α binds to birc5a and birc5b promoters directly to modulate their transcriptions. Knockdown of hif2α, birc5a or birc5b reduced the expression of the cdk inhibitors p27/cdkn1b and p57/cdkn1c and increased ccnd1/cyclin D1 transcription in the surviving neural progenitor cells. The reduction in elavl3/HuC expression and enhanced pcna, nestin, ascl1b and sox3 expression indicate that the surviving neural progenitor cells in hif2α morphants maintain a high proliferation rate without terminally differentiating. We propose that a subset of developmental defects attributed to HIF2α depletion is due in part to the loss of survivin activity.

Management of choledochal cyst: 30 years of experience and results in a single center.

BACKGROUND: Choledochal cyst is usually diagnosed in childhood. Early treatment can prevent further complication. We report on our series of patients over the past 30 years. METHODS: A retrospective study was performed on all pediatric patients who presented with choledochal cyst from January 1978 to December 2008. The main outcome measures recorded were the clinical presentation, management, and long-term outcome of the patients. RESULTS: Eighty-three patients presented to us during the caption period with a mean age at diagnosis of 45 months (0 month to 16 years). Diagnoses were made antenatally in 15 patients. The most common symptoms were abdominal pain (n = 39) and jaundice (n = 35). Seventy-five patients had surgery, in which 72 patients had resection of the cyst and Roux-en-Y hepaticojejunostomy. Ten were performed by laparoscopic means. We categorized the cysts based on the Todani classification. There was no mortality. No malignant change was documented. For those 4 who had Caroli disease, 2 underwent liver transplantation and 2 had hepatectomy. Overall early complication rate was 5.3% (4/75). CONCLUSIONS: Complete excision of cyst with Roux-en-Y hepaticojejunostomy is the treatment of choice, and the late result is good. Laparoscopic surgery is feasible. Long-term follow-up is necessary. There is no evidence to suggest that some type IV cysts are the result of disease progression from type I cysts.

Periodontal regeneration using ex vivo autologous stem cells engineered to express the BMP-2 gene: an alternative to alveolaplasty.

The regeneration of the periodontal attachment apparatus remains clinically challenging because of the involvement of three tissue types and the complexity of their relationship. Human recombinant bone morphogenic protein-2 (rhBMP-2) can accelerate the regeneration of bone and cementum and the insertion of periodontal ligament fibers but may lead to a deranged periodontal relationship, ankylosis and root resorption.This study evaluated a novel approach to regeneration of the periodontal attachment apparatus using a combination of ex vivo autologous bone marrow mesenchymal stem cells (MSCs) engineered by replication-defective adenovirus to express the BMP-2 gene and Pluronic F127 (PF127). Twenty-four periodontal defects were surgically created in 12 New Zealand white rabbits and randomly assigned to three experimental groups with MSCs: the advBMP-2 group; the advbetagal group; the MSC group and one control group: PF127 only. The regenerated periodontal attachment apparatus was assessed histologically and the total regenerated bone volume was calculated from three-dimensional computed tomography analysis.This approach regenerated not only cementum with Sharpey's fiber insertion, but also statistically significant quantities of bone, re-establishing a more normal relationship among the components of the regenerated periodontal attachment apparatus, which is beneficial for the maintenance of periodontal health.Ex vivo gene transfer using stem cells as vectors may provide an advantage of slower BMP-2 release, increasing cementogenesis. There is regeneration of the periodontal attachment apparatus, whereas direct usage of the protein (rhBMP-2) yields unhinged periodontal relationship. Thus, this approach may represent an alternative means for periodontal alveolar bone graft in clinical settings.

Factors related to lymph node metastasis and the feasibility of endoscopic mucosal resection for treating poorly differentiated adenocarcinoma of the stomach.

BACKGROUND AND AIM: Endoscopic mucosal resection (EMR) is currently not accepted as an alternative treatment to surgery in early gastric cancer (EGC) of the undifferentiated histologic type. The present retrospective analysis examined the correlation of various histologic factors with the presence of lymph node metastasis (LNM). PATIENTS AND METHODS: A retrospective analysis on 234 patients with poorly differentiated EGC who underwent radical gastrectomy with D2 lymph node dissection was undertaken. Several clinicopathologic factors were investigated to identify predictive factors for LNM: age, sex, type of operation, tumor location, tumor size, gross type, ulceration, lymphatic invasion, and depth of invasion. RESULTS: Of the 234 lesions with poorly differentiated EGC, half (n = 116) already showed submucosal invasion in the resection specimen; 25.9 % of those (30/116) were limited to the upper third (SM1). Of the lesions confined to the mucosa, LNM was found in 3.4 % (4/118). With minor submucosal infiltration (SM1), the LNM rate was lower (0/30) in our patient population. Only with SM2/3 infiltration did the LNM rate sharply rise to around 30 %. The cut-off for submucosal infiltration depth was 500 microm (0/32 LNM), above which LNM rates were substantial (31.2 %; 24/77). There was limited correlation between the SM1-3 classification and actual measurement of submucosal infiltration depth. In a multivariate analysis, tumor size ( P = 0.033), depth of invasion ( P = 0.004), and lymphatic invasion ( P < 0.001) were associated with LNM. CONCLUSION: Poorly differentiated EGC confined to the mucosa or with minimal submucosal infiltration (

Multicenter phase II study of docetaxel plus oxaliplatin combination chemotherapy in patients with advanced gastric cancer: Daegu Gyeongbuk Oncology Group.

The present study was conducted to evaluate the efficacy and safety of a combination regimen of docetaxel plus oxaliplatin in patients with advanced gastric cancer. Patients with previously untreated metastatic or recurrent, measurable gastric cancer received intravenous docetaxel 65 mg m(-2) plus oxaliplatin 120 mg m(-2) on day 1 based on a 3-week cycle. Forty-two patients were enrolled in the current study, among whom 39 were assessable for efficacy and all assessable for toxicity. One complete response and 18 partial responses were confirmed, giving an overall response rate of 45.2% (95% confidence interval (CI); 31.7-59.7%). At a median follow-up of 7.7 months, the median time to progression and median overall survival was 5.7 (95% CI; 4.3-7.2) months and 9.9 (95% CI; 7.8-12.0) months, respectively. Grade 3/4 neutropenia occurred in 11 patients (26.1%) and febrile neutropenia was observed in four patients (9.5%). The common non-haematologic toxicity was fatigue (grade 1/2, 61.9%) and nausea (grade 1/2, 47.7%). The combination of docetaxel and oxaliplatin was found to be well tolerated and effective in patients with advanced gastric cancer.

Carcinoid tumour of the kidney in a Chinese woman presenting with loin pain.

Renal carcinoid tumours are uncommon. The aetiology is not yet fully understood and there is still no useful diagnostic tool for detecting them. We report our experience managing a Chinese woman with a primary renal carcinoid tumour.

Vascular endothelial growth factor gene polymorphisms associated with prognosis for patients with gastric cancer.

BACKGROUND: The present study analyzed vascular endothelial growth factor (VEGF) gene polymorphisms and their impact on the prognosis for patients with gastric cancer. PATIENTS AND METHODS: Five hundred and three consecutive patients with surgically resected gastric adenocarcinoma were enrolled in the present study. The genomic DNA was extracted from paraffin-embedded tissue and four VEGF (-460T > C, -116G > A, +405G > C, and +936C > T) gene polymorphisms were determined using a polymerase chain reaction-restriction fragment length polymorphism assay. RESULTS: The survival analysis showed no association of three VEGF gene polymorphisms with the prognosis. For the +936C > T polymorphism, the T/T genotype, however, had a worse overall survival (OS) compared with the C/C genotype (P = 0.037). The -460 T/C or C/C genotype was a poor prognostic factor in patients with stage 0 or I gastric cancer (OS: hazard ratio (HR) = 3.96, disease-free survival (DFS): HR = 4.87). In the haplotype analysis, the CACC haplotype was associated with a significantly worse survival when compared with the TGGC haplotype (OS: HR = 1.72, DFS: HR = 1.73). CONCLUSIONS: VEGF gene polymorphisms were found to be an independent prognostic marker for patients with gastric cancer. Consequently, the analysis of VEGF gene polymorphisms can help identify patient subgroups at high risk of a poor disease outcome.

Randomized clinical trial of splenectomy versus splenic preservation in patients with proximal gastric cancer.

BACKGROUND: Preservation or removal of the spleen during total gastrectomy for proximal gastric cancer is a matter of debate. METHODS: A randomized clinical trial included patients with gastric adenocarcinoma who underwent total gastrectomy either with (104 patients) or without (103) splenectomy. Postoperative outcome in the two groups was compared, including morbidity, mortality and survival. RESULTS: Gastrectomy combined with splenectomy tended to be associated with slightly higher morbidity and mortality rates, a slightly greater incidence of lymph node metastasis at the splenic hilum and along the splenic artery, and marginally better survival, but there were no statistically significant differences between the groups. Splenectomy had no impact on survival in patients with metastatic lymph nodes at the hilum of the spleen or in those with metastatic lymph nodes along the splenic artery. CONCLUSION: These results do not support the use of prophylactic splenectomy to remove macroscopically negative lymph nodes near the spleen in patients undergoing total gastrectomy for proximal gastric cancer.

Induction of endothelial iNOS by 4-hydroxyhexenal through NF-kappaB activation.

Lipid peroxidation and its end-product, 4-hydroxyhexenal (HHE), are known to affect redox balance during aging, which causes various degenerative processes including vascular alterations from endothelial cell deterioration. To better understand the molecular action of HHE in the development of vascular abnormalities during the aging process, we investigated whether the upregulation of inducible endothelial nitric oxide synthase (iNOS) by HHE is mediated through nuclear factor kappaB (NF-kappaB) activation. Results indicate that HHE stimulates iNOS by the transcriptional regulation of NF-kappaB activation through cytosolic kappaB degradation inhibitors (IkappaB). Pretreatment with NF-kappaB inhibitors Bay 11-7082 and N-acetyl cysteine (NAC) suppressed the upregulation of iNOS by blunting IkappaB degradation and NF-kappaB binding activity. Because inflammatory stimuli induce iNOS to generate large amounts of nitric oxide (NO), intracellular NO levels in the presence of Bay 11-7082, NAC, and caffeic acid methyl ester were estimated. These inhibitors significantly suppressed the HHE-induced NO levels to a basal level. These findings strongly suggest that in endothelial cells, HHE induces iNOS gene expression through NF-kappaB activation, which can lead to vascular dysfunction by the activation of various proinflammatory genes.

Ex vivo gene therapy in autologous bone marrow stromal stem cells for tissue-engineered maxillofacial bone regeneration.

This study examines the clinical relevance of tissue engineering integrating gene therapy and polymer science to bone regeneration. Bilateral maxillary defects (3 x 1.2 cm(2)) in 20 miniature swine were bridged with a bioresorbable internal splint. Constructs were created using ex vivo adenovirus bone morphogenetic protein (BMP)-2-mediated gene transfer to the expanded bone marrow mesenchymal stem cells (MSCs) 7 days before implantation. Controls were performed using adenovirus beta-galactosidase. The BMP-2 cell/construct displayed white solid bone formation after 3 months. Meanwhile, the hematoxylin and eosin and Von Kossa stains demonstrated exhibited mature woven bone with good mineralization. Additionally, three-dimensional computer tomography imaging revealed a nearly complete infraorbital rim repair. Quantitative analysis demonstrated a significant difference (P<0.001) in bone formation. Finally, biomechanical testing revealed no statistically significant difference in the maximal compressive strength of new bone formed by BMP-2 cell constructs and the normal maxilla. The data evidenced de novo bone formation capable of sustaining axial compressive loads. The measurement results showed that ex vivo replication defective adenovirus-mediated human BMP-2 gene transfer to MSCs enhances autologous bone formation in the repair of maxillary defects.