Plasma neutrophil gelatinase-associated lipocalin levels are positively associated with diabetic retinopathy in patients with Type 2 diabetes.

AIM: To assess the relationship between plasma neutrophil gelatinase-associated lipocalin (NGAL) levels and diabetic retinopathy in patients with Type 2 diabetes. METHODS: In total, 204 patients with Type 2 diabetes were investigated in this cross-sectional study. They were classified as having no diabetic retinopathy, non-proliferative diabetic retinopathy (NPDR) or proliferative retinopathy (PDR), according to the degree of diabetic retinopathy. Thus, diabetic retinopathy in the patients in this study was either NPDR or PDR. RESULTS: Plasma NGAL concentrations were significantly higher in patients with diabetic retinopathy than in those without. The mean plasma NGAL levels differed significantly according to the severity of diabetic retinopathy (no diabetic retinopathy, 120.8 ng/ml; NPDR, 217.8 ng/ml; PDR, 372.4 ng/ml; P for trend = 0.002) after adjustment for other covariates. In multivariable analysis, plasma NGAL levels were significantly associated with diabetic retinopathy (odds ratio for each standard deviation increase in the logarithmic value, 7.75; 95% confidence interval, 2.04-29.41, P = 0.003). CONCLUSION: Plasma NGAL levels were positively associated with diabetic retinopathy in patients with Type 2 diabetes.

Physiological serum bilirubin concentrations are inversely associated with the prevalence of cardiovascular autonomic neuropathy in patients with Type 2 diabetes.

AIMS: Although severe hyperbilirubinaemia causes kernicterus in neonates, normal to modestly elevated bilirubin concentrations have been reported to be neuroprotective. However, the relationship between serum bilirubin concentrations and cardiovascular autonomic neuropathy in patients with Type 2 diabetes is currently unknown. This study assessed the relationships between physiological serum total bilirubin concentrations and cardiovascular autonomic neuropathy in patients with Type 2 diabetes. METHODS: A total of 2991 patients with Type 2 diabetes were investigated in this cross-sectional study. Cardiovascular autonomic neuropathy was diagnosed by a cardiovascular reflex test. According to the American Diabetes Association criteria, the degree of cardiovascular autonomic dysfunction was graded into normal, early, definite and severe. Cardiovascular autonomic neuropathy was either definite or severe in the present study. An analysis of covariance after adjustment for other covariates was performed. A logistic regression model was used to assess an association of cardiovascular autonomic neuropathy with serum total bilirubin tertiles. RESULTS: Serum total bilirubin concentrations were significantly lower in subjects with cardiovascular autonomic neuropathy. The mean total bilirubin values differed significantly according to the severity of cardiovascular autonomic dysfunction (normal 13.0 µmol/l; early 12.3 µmol/l; definite 11.8 µmol/l; severe 10.1 µmol/l; P for trend < 0.001) after adjustment for other covariates. In multivariate analysis, serum total bilirubin levels were significantly associated with cardiovascular autonomic neuropathy (odds ratio 0.36; 95% CI 0.21-0.63 for the highest vs. the lowest bilirubin tertile, P < 0.001). CONCLUSIONS: Serum total bilirubin concentrations within the physiologic range are inversely associated with the prevalence of cardiovascular autonomic neuropathy in patients with Type 2 diabetes.

Serum bilirubin concentrations are positively associated with serum C-peptide levels in patients with Type 2 diabetes.

AIMS: To investigate the relationship between physiological serum total bilirubin concentrations and serum C-peptide levels in Korean patients with Type 2 diabetes. METHODS: A total of 588 patients with Type 2 diabetes were investigated in this cross-sectional study. Fasting C-peptide level, 2-h postprandial C-peptide level and ΔC-peptide (postprandial C-peptide minus fasting C-peptide) level were measured in all patients. RESULTS: Fasting C-peptide level, postprandial C-peptide level and ΔC-peptide level tended to be higher in patients with higher bilirubin concentrations. Partial correlation analysis showed that serum bilirubin levels were significantly correlated with fasting C-peptide level (r = 0.159, P < 0.001), postprandial C-peptide level (r = 0.209, P < 0.001) and ΔC-peptide level (r = 0.186, P < 0.001) after adjustment for other covariates. In the multivariate model, the association between serum bilirubin concentrations and serum C-peptide levels remained significant after adjustment for confounding factors including age, gender, familial diabetes, hypertension, hyperlipidaemia, BMI, HbA1c , duration of diabetes and associated liver function tests (fasting C-peptide level: ß = 0.083, P = 0.041; postprandial C-peptide level: ß = 0.106, P = 0.005; ΔC-peptide level: ß = 0.096, P = 0.015, respectively). CONCLUSIONS: Serum bilirubin concentrations within the physiological range were positively associated with serum C-peptide levels in patients with Type 2 diabetes.

Efficacy and safety of glimepiride/metformin sustained release once daily vs. glimepiride/metformin twice daily in patients with type 2 diabetes.

AIMS: The study investigated the clinical equivalence in reducing haemoglobin A1c (A1C) between glimepiride/metformin sustained release (GM-SR) 2/500 mg, a fixed-dose combination, once daily and glimepiride/metformin (GM) 1/250 mg, a fixed-dose combination, twice daily in patients with type 2 diabetes (T2D). METHODS: A multicentre, randomised, double-blind, double-dummy study was conducted in 14 hospitals in Korea. Inclusion criteria were age 30-75 years, T2D diagnosis no longer than 10 years previously, A1C between 7% and 10%, and body mass index <40 kg/m(2) . A total of 207 subjects were randomised into the GM-SR group (n=101) or the GM group (n=106). Participants were assessed at baseline, 8 weeks and 16 weeks after treatment. RESULTS: After 16 weeks treatment, no difference in baseline-adjusted changes of A1C (primary efficacy variable) was observed between the two groups (-0.59% for GM-SR group vs. -0.61% for GM group, 95% CI: -0.17 to 0.21; p=0.84). In addition, there were no significant differences in secondary efficacy parameters between the two groups, including changes in A1C up to week 8, changes in fasting plasma glucose (FPG) and 2-h-postprandial plasma glucose up to week 8 and week 16, response rate, drug compliance and hypoglycaemic events. However, there was a difference in baseline-adjusted changes of FPG between the two groups (-1.01 mmol/l for GM-SR group vs. -1.52 mmol/l for GM group, p=0.01 in the intention to treat set). CONCLUSIONS: GM-SR 2/500 mg once daily was as effective as GM 1/250 mg twice daily in lowering A1C. In addition, no difference was noted in hypoglycaemic events between the two groups.

Risk factors for pelvic organ prolapse.

OBJECTIVES: To evaluate the risk factors for pelvic organ prolapse (POP) and to determine the relationship between these risk factors and stage or other components of POP. METHODS: 244 patients with primary POP and 314 women without POP were included. Age, parity, smoking, body mass index (BMI), menopause, and hormone replacement therapy (HRT) were investigated. RESULT: Independent risk factors for POP included age over 70, parity higher than 3, and menopause. Age, parity, menopause, and HRT were significantly associated with stage of POP. Genital hiatus (GH) and perineal body (PB) showed a significant positive and negative correlation with age and parity, respectively. Menopause and HRT were also associated with them. CONCLUSION: Age, parity and menopause are possible risk factors of POP and associated with the lengths of GH and PB in POP women. Further, these risk factors and HRT are significantly correlated with the severity of the disease.

Surgical repair of anterior wall vaginal defects.

OBJECTIVE: To compare the clinical efficacy of 3 surgical procedures for central types of anterior vaginal wall defect. METHODS: A total of 138 patients diagnosed with central types of anterior vaginal wall defect who underwent classic transvaginal repair (n=72), transvaginal repair with polypropylene mesh (n=28), and internal repair (n=38) were followed up for at least 1 year. RESULTS: There were no differences in development of fever, vaginal erosion, detrusor overactivity, and voiding difficulty among the 3 groups, but the incidence of postoperative urinary tract infections was significantly higher in the polypropylene mesh repair group. The difference in preoperative and postoperative hemoglobin levels and wound infection incidence were significantly higher in the internal repair group. Moreover, the recurrence rate of the anterior vaginal wall defect was significantly higher at 1 year in the internal repair group. CONCLUSION: Transvaginal surgical repair seems to be more efficacious than internal surgical repair for central types of anterior vaginal wall defects.

Upfront plerixafor plus G-CSF versus cyclophosphamide plus G-CSF for stem cell mobilization in multiple myeloma: efficacy and cost analysis study.

Cyclophosphamide plus G-CSF (C+G-CSF) is one of the most widely used stem cell (SC) mobilization regimens for patients with multiple myeloma (MM). Plerixafor plus G-CSF (P+G-CSF) has demonstrated superior SC mobilization efficacy when compared with G-CSF alone and has been shown to rescue patients who fail mobilization with G-CSF or C+G-CSF. Despite the proven efficacy of P+G-CSF in upfront SC mobilization, its use has been limited, mostly due to concerns of high price of the drug. However, a comprehensive comparison of the efficacy and cost effectiveness of SC mobilization using C+G-CSF versus P+G-CSF is not available. In this study, we compared 111 patients receiving C+G-CSF to 112 patients receiving P+G-CSF. The use of P+G-CSF was associated with a higher success rate of SC collection defined as ⩾5 × 10(6) CD34+ cells/kg (94 versus 83%, P=0.013) and less toxicities. Thirteen patients in the C+G-CSF arm were hospitalized owing to complications while none in the P+G-CSF group. C+G-CSF was associated with higher financial burden as assessed using institutional-specific costs and charges (P<0.001) as well as using Medicare reimbursement rates (P=0.27). Higher rate of hospitalization, increased need for salvage mobilization, and increased G-CSF use account for these differences.

Comparison of the efficacy of Burch colposuspension, pubovaginal sling, and tension-free vaginal tape for stress urinary incontinence.

OBJECTIVE: To compare the cure rate and confirm the clinical efficacy of the 3 most frequently performed surgical procedures for stress urinary incontinence (SUI). METHODS: Between January 2001 and May 2003, 92 women with SUI were randomly assigned to undergo the Burch colposuspension (n=33), pubovaginal sling (n=28), or tension-free vaginal tape (n=31) at the Department of Obstetrics and Gynecology, Yonsei Medical Center, Seoul, Korea. Patient characteristics, urodynamic study results, cure rates at 3, 6, and 12 months, and complication rates were compared using the chi2 test. RESULTS: There were no statistically significant differences in the cure rates initially, but after 12 months the cure rate of the pubovaginal sling procedure was found to be significantly higher than those of the tension-free vaginal tape or Burch colposuspension procedures. CONCLUSION: The cure rate of the pubovaginal sling procedure was significantly higher after 1 year, but no difference in efficacy was observed between the 2 other procedures. A randomized prospective study of a larger population should be conducted.

Serum Cystatin C Levels are Positively Associated with Cardiovascular Autonomic Neuropathy in Patients with Type 2 Diabetes.

AIMS: Previous studies have reported that cystatin C is associated with degenerative disorder in the nervous system. However, the relationship between serum cystatin C concentrations and cardiovascular autonomic neuropathy (CAN) in patients with type 2 diabetes is currently unknown. The aim of this study was to assess the relationships between serum cystatin C levels and CAN in patients with type 2 diabetes. METHODS: A total of 357 patients with type 2 diabetes were studied in this cross-sectional study. CAN was diagnosed by a cardiovascular autonomic reflex test. According to the American Diabetes Association criteria, the degree of cardiovascular autonomic dysfunction was graded as normal, early, definite, or severe. CAN was either definite or severe in the subjects of the present study. RESULTS: Serum cystatin C concentrations were significantly higher in patients with CAN than in those without CAN. The mean cystatin C levels differed significantly according to the degree of cardiovascular autonomic dysfunction (normal, 0.78 mg/l; early, 0.79 mg/l; definite, 0.87 mg/l; severe, 0.90 mg/l; P for trend=0.021) after adjustment for other covariates. In multivariate analysis, serum cystatin C levels were significantly associated with CAN (odds ratio [OR] of each standard deviation increase in the logarithmic value, 5.25; 95% confidence interval [CI], 1.17-23.70, P=0.025). CONCLUSIONS: Serum cystatin C levels are positively associated with CAN in patients with type 2 diabetes.

Effect of petroleum ether extract of Panax ginseng roots on proliferation and cell cycle progression of human renal cell carcinoma cells.

Panax ginseng roots have long been used as a medicinal herb in oriental countries. We have investigated anti-proliferative effects of lipid soluble Panax ginseng components on human renal cancer cell lines. Petroleum ether extract of Panax ginseng roots (GX-PE) or its partially purified preparation (7:3 GX) was added to cultures of three human renal cell carcinoma (RCC) cell lines, A498, Caki-1, and CURC II. Proliferation of RCC cells was estimated by a [3H]thymidine incorporation assay and cell cycle distribution was analyzed by flow cytometry. GX-PE, 7:3 GX, panaxydol and panaxynol inhibited proliferation of all three RCC cell lines in a dose dependent manner in vitro with an order of potency, 7:3 GX > panaxydol > panaxynol = GX-PE. Additive effect of interleukin 4 was also demonstrated, most prominently in Caki-1 which responded poorly to GX-PE alone. Analysis of cell cycle in CURC II and Caki-1 treated with GX-PE demonstrated increase in G1 phase population and corresponding decrease in S phase population. The present study demonstrated that proliferation of human RCC cell lines were inhibited by lipid soluble components of Panax ginseng roots by blocking cell cycle progression at G1 to S phase transition.

Increased vascular endothelin-1 gene expression with unaltered nitric oxide synthase levels in fructose-induced hypertensive rats.

The present study aimed to investigate whether altered expression levels of endothelin-1 (ET-1) and nitric oxide synthase (NOS) are related to the development of insulin-resistant hypertension. Male Sprague-Dawley rats were fed a fructose-rich diet for 5 weeks. Systolic blood pressure significantly increased in fructose-fed rats. While serum free fatty acid (FFA) and plasma nitrite/nitrate (NOx) levels did not significantly differ between the fructose-fed and control groups, plasma insulin and serum triglyceride (TG) concentrations significantly increased in the former. ET-1 mRNA expression in the aorta increased to 195% in fructose-fed rats. Neither the protein expression of constitutive NOS (cNOS) nor that of inducible NOS (iNOS) were significantly affected by fructose feeding. However, NOx levels in the aorta were significantly increased. These results indicate that an increased expression of vascular ET-1 may be causally related to the development of hypertension in fructose-fed rats. However, an altered role of the vascular nitric oxide (NO) pathway may not be primarily involved in the development of fructose-induced hypertension.

Tuberculous aneurysm of the abdominal aorta: endovascular repair using stent grafts in two cases.

Tuberculous aneurysm of the aorta is exceedingly rare. To date, the standard therapy for mycotic aneurysm of the abdominal aorta has been surgery involving in-situ graft placement or extra-anatomic bypass surgery followed by effective anti-tuberculous medication. Only recently has the use of a stent graft in the treatment of tuberculous aortic aneurysm been described in the literature. We report two cases in which a tuberculous aneurysm of the abdominal aorta was successfully repaired using endovascular stent grafts. One case involved is a 42-year-old woman with a large suprarenal abdominal aortic aneurysm and a right psoas abscess, and the other, a 41-year-old man in whom an abdominal aortic aneurysm ruptured during surgical drainage of a psoas abscess.

Microfabricated surface designs for cell culture and diagnosis.

Grooved and holed surfaces with a well fabricated design may serve as microsubstrates for cell culture and microreactors for diagnosis. In this study, the authors prepared chemically treated, micrometer scale grooved and holed glass surfaces by combined surface modification and ultraviolet (UV) excimer laser ablation techniques, as follows. 1) Microcell-culture substrate: Amino group attached glass surfaces, prepared by the treatment with an aminopropylsilane, were condensed with a carboxylated radical initiator. Subsequently, polyacrylamide was grafted by surface initiated radical polymerization to create a very hydrophilic surface layer. Ultraviolet excimer laser beams (KrF: 248 nm) were irradiated through a microscope onto surfaces to create grooves or holes that were 10 and 50 microns in width or diameter, respectively. The depth, depending on the irradiation light strength, ranged from a few to several tenths of a micrometer. On endothelial cell (EC) seeding, ECs adhered and grew on the bottoms of the grooved or holed surface where glass was exposed on ablation. Little cell adhesion was observed on non ablated, grafted surfaces. Endothelial cells aligned along the groove, resulting in very narrow tube like tissue formation, whereas ECs tended to form a multilayered spherical aggregate in a hole. A single cell resided in a 10 microns square hole. 2) Microreactor for diagnosis: The glass surface, treated with a fluorinated silane, was ablated to create round holes. On addition of a few microliters of water, water could be quantitatively transferred into a hole because of the water repellent characteristics of non ablated, fluorinated glass. As a model of a microreactor, enzyme reactions to affect different levels of glucose were carried out in tiny holed surfaces.

Oral hygiene training programmes in long-stay hospitals.

It is gratifying that as a direct long term result of a survey conducted by the author in a geriatric hospital in Liverpool, a dental health programme for such patients is currently being implemented by members of the Community Dental Service staff. The results of the survey indicated that the treatment need for the elderly is mainly a restorative one, largely concerned with complete dentures. The survey also demonstrated, however, that half of all long-stay patients are incapable of maintaining a reasonable level of oral hygiene for themselves and were unaware of their own dental needs. It is important that there should be supervision of these patients to maintain oral hygiene standards and ensure early identification of oral pathology. It is these problems that the programmes which are now being implemented attempt to address. This is an account of the author's involvement in their development.

Effect of hypoxia on generation of neurospheres from adipose tissue-derived canine mesenchymal stromal cells.

Adipose tissue-derived mesenchymal stromal cells (AT-MSCs) are good candidates for cell therapy due to the accessibility of fat tissue and the abundance of AT-MSCs therein. Neurospheres are free-floating spherical condensations of cells with neural stem/progenitor cell (NSPC) characteristics that can be derived from AT-MSCs. The aims of this study were to examine the influence of oxygen (O2) tension on generation of neurospheres from canine AT-MSCs (AT-cMSCs) and to develop a hypoxic cell culture system to enhance the survival and therapeutic benefit of generated neurospheres. AT-cMSCs were cultured under varying oxygen tensions (1%, 5% and 21%) in a neurosphere culture system. Neurosphere number and area were evaluated and NSPC markers were quantified using real-time quantitative PCR (qPCR). Effects of oxygen on neurosphere expression of hypoxia inducible factor 1, α subunit (HIF1A) and its target genes, erythropoietin receptor (EPOR), chemokine (C-X-C motif) receptor 4 (CXCR4) and vascular endothelial growth factor (VEGF), were quantified by qPCR. Neural differentiation potential was evaluated in 21% O2 by cell morphology and qPCR. Neurospheres were successfully generated from AT-cMSCs at all O2 tensions. Expression of nestin mRNA (NES) was significantly increased after neurosphere culture and was significantly higher in 1% O2 compared to 5% and 21% O2. Neurospheres cultured in 1% O2 had significantly increased levels of VEGF and EPOR. There was a significant increase in CXCR4 expression in neurospheres generated at all O2 tensions. Neurosphere culture under hypoxia had no negative effect on subsequent neural differentiation. This study suggests that generation of neurospheres under hypoxia could be beneficial when considering these cells for neurological cell therapies.

A laminin-2-derived peptide promotes early-stage peripheral nerve regeneration in a dual-component artificial nerve graft.

The DLTIDDSYWYRI motif (Ln2-P3) of human laminin-2 has been reported to promote PC12 cell attachment through syndecan-1; however, the in vivo effects of Ln2-P3 have not been studied. In Schwann cells differentiated from skin-derived precursors, the peptide was effective in promoting cell attachment and spreading in vitro. To examine the effects of Ln2-P3 in peripheral nerve regeneration in vivo, we developed a dual-component poly(p-dioxanone) (PPD)/poly(lactic-co-glycolic acid) (PLGA) artificial nerve graft. The novel graft was coated with scrambled peptide or Ln2-P3 and used to bridge a 10 mm defect in rat sciatic nerves. The dual-component nerve grafts provided tensile strength comparable to that of a real rat nerve trunk. The Ln2-P3-treated grafts promoted early-stage peripheral nerve regeneration by enhancing the nerve regeneration rate and significantly increased the myelinated fibre density compared with scrambled peptide-treated controls. These findings indicate that Ln2-P3, combined with tissue-engineering scaffolds, has potential biomedical applications in peripheral nerve injury repair.

Factors impacting stem cell mobilization failure rate and efficiency in multiple myeloma in the era of novel therapies: experience at Memorial Sloan Kettering Cancer Center.

Thalidomide, lenalidomide and bortezomib have increasingly been incorporated in first-line induction therapies for multiple myeloma. Concerns regarding the impact of these agents, especially lenalidomide, on stem cell mobilization prompted us to re-evaluate the risk factors that impact mobilization, including exposure to novel induction regimens. Among 317 patients who proceeded to stem cell collection after induction therapy between 2000 and 2009, the rate of mobilization failure, defined as the inability to collect 5 × 10(6) CD34+ cells/kg following the first collection attempt, was 13%. By multivariate analysis, independent risk factors associated with mobilization failure included older age (P=0.04), lower platelet count (P=0.002) and use of single-agent G-CSF for mobilization (P<0.0001). When considering for outcome measurement stem cell collection efficiency measured by the number of CD34+ cells yielded per pheresis performed during first collection attempt, lower platelet count, use of single-agent G-CSF and older age were also associated with lower efficiency. In this population mobilized mostly with cyclophosphamide and G-CSF, the use of lenalidomide during induction was not associated with a lower stem cell collection efficiency by multivariate analysis. The data support the current International Multiple Myeloma Working Group guidelines recommending the use of cyclophosphamide and G-CSF based mobilization for patients previously exposed to lenalidomide.

Therapeutic effect of high-intensity focused ultrasound combined with transarterial chemoembolisation for hepatocellular carcinoma <5 cm: comparison with transarterial chemoembolisation monotherapy--preliminary observations.

OBJECTIVE: To retrospectively compare the therapeutic effects of combined high-intensity focused ultrasound (HIFU) and transarterial chemoembolisation (TACE) with TACE alone for the treatment of non-advanced hepatocellular carcinomas (HCCs) <5 cm. METHODS: We retrospectively reviewed the tumour responses of 32 HCCs of 25 patients who underwent combined HIFU and TACE, and 46 HCCs of 32 patients who underwent TACE only. The mean follow-up observation of the TACE+HIFU group was on average 31 months and that of the TACE group was 33 months. Those patients who had undergone any other treatment modality (including systemic chemotherapy) during the follow-up observation period were excluded. The therapeutic effects were classified according to the modified Response Evaluation Criteria In Solid Tumors (mRECIST): complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Additionally, we defined CR', PR', SD' and PD' as the therapeutic effects "per tumour". RESULTS: The disease control rate calculated using the RECIST criteria (CR+PR+SD/All) was 48% in the HIFU+TACE group and 47% in the TACE group (p=0.78, Fisher's exact test). The disease control rate "per tumour" (CR'+PR'+SD'/All) was 78% in the HIFU+TACE group and 54% in the TACE group (p=0.035, Fisher's exact test). In the HIFU+TACE group, no HIFU-related complications requiring treatment were observed. The median survival time was 57 months in TACE+HIFU group and 36 months in the TACE group (p=0.048). CONCLUSION: This preliminary study shows that the combination therapy of HIFU and TACE is more effective than TACE monotherapy for treating HCCs <5 cm.

Metastatic acinar cell carcinoma of the liver from a benign-appearing pancreatic lesion: a mimic of hepatocellular carcinoma.

Acinar cell carcinoma (ACC) is a rare pancreatic tumour with a favourable prognosis compared with the more common ductal adenocarcinoma. The radiological findings of this tumour have been described in the literature; however, only limited data are available regarding the metastatic features of ACC of the liver, the most common metastatic site. We report a case of ACC of the pancreas with a hepatic metastasis from a benign-appearing malignant pancreatic lesion.