Developing a predictive model for distinguishing invasive nail unit melanoma from nail unit melanoma in situ.

BACKGROUND: Clinical information that distinguishes invasive nail unit melanoma from nail unit melanoma in situ before surgery would aid physicians in the decision-making process and estimating prognosis. However, limited information is available on the detailed demographic and dermoscopic features of invasive nail unit melanoma and nail unit melanoma in situ for differential diagnosis. OBJECTIVE: This study aimed to investigate the demographic data and dermoscopic features of invasive nail unit melanoma and nail unit melanoma in situ and establish a predictive model for differentiating these two forms of nail unit melanoma. METHODS: A retrospective observational study of ninety-seven patients diagnosed with nail unit melanoma (59 in situ and 38 invasive cases) in four healthcare centres in South Korea (three tertiary referral hospitals and one second referral hospital) from March 2014 to December 2019. RESULTS: A multivariable analysis revealed that ulcer (odds ratio = 21.6, confidence interval = 2.1-219.8, P = 0.009), total melanonychia (odds ratio = 17.6, confidence interval = 3.0-104.0, P = 0.002), nail plate destruction (odds ratio = 10.9, confidence interval = 2.0-59.4, P = 0.006) and polychromia (odds ratio = 5.3, confidence interval = 1.36-20.57, P = 0.016) were distinctive dermoscopic features of invasive nail unit melanoma. A predictive model with scores ranging from 0 to 6 points demonstrated a reliable diagnostic value (C-statistic = 0.902) in differentiating invasive nail unit melanoma from nail unit melanoma in situ. CONCLUSIONS: Invasive nail unit melanoma and nail unit melanoma in situ have different dermoscopic features. A predictive model based on morphologic dermoscopic features could aid in differentiating invasive nail unit melanoma from nail unit melanoma in situ.

Early complications after percutaneous radiofrequency ablation for hepatocellular carcinoma: an analysis of 1,843 ablations in 1,211 patients in a single centre: experience over 10 years.

AIM: To evaluate the incidence of adverse events and associated factors after radiofrequency ablation (RFA) in patients with hepatocellular carcinoma within 30 days. MATERIALS AND METHODS: The early complications that occurred within 30 days after RFA at a single institution from January 2000 to July 2010 were reviewed in order to evaluate the morbidity, mortality, and risk factors associated with the complications. In total, 1,211 patients (845 men, 70.5%) with a mean age of 68 years (range, 27-88 years) underwent 1,843 RFA procedures. RESULTS: The overall incidence rate of complications was 6.8% (125 cases). Major complications (n=36, 2%) included liver abscess (n=15, 0.8%), intraperitoneal bleeding (n=8, 0.4%), liver failure (n=5, 0.3%), variceal bleeding (n=3, 0.2%), haemothorax (n=2, 0.1%), cholecystitis (n=2, 0.1%), and bowel perforation (n=1, 0.1%). Among the minor complications (n=89, 4.8%), the most common was the post RFA syndrome accompanied by pain and fever (n=75, 4.1%). Other minor complications included significant pleural effusion (n=7, 0.4%), skin wound infection (n=4, 0.2%), and thermal injuries to the skin (n=3, 0.2%). Procedural infections significantly increased with tumour size (OR=1.379; 95% confidence interval [CI], 1.191-1.579; p<0.001), and multiple overlapping ablations (OR=1.118; 95% CI, 1.019-1.227, p=0.018). Thrombocytopenia (<50,000/µl), prothrombin time, and serum albumin level were significantly associated with post-RFA bleeding episodes (p=0.041, p=0.021, and p=0.003, respectively). The overall mortality rate was 0.3% (three cases of hepatic failure, two case of sepsis, and one case of renal failure). CONCLUSIONS: RFA is a safe and effective local treatment for hepatocellular carcinoma. Careful selection of patients and appropriate RFA planning could decrease procedural mortality and morbidity.

Serum 25-hydroxyvitamin D cutoffs for functional bone measures in postmenopausal osteoporosis.

This study sought to determine the minimal serum 25-hydroxyvitamin D [25(OH)D] concentration required to maintain bone health in postmenopausal women with low bone mass. A serum 25(OH)D concentration of 20 ng/mL rather than 30 ng/mL was appropriate for bone health. INTRODUCTION: There is no consensus on the minimal serum 25-hydroxyvitamin D [25(OH)D] concentration required to maintain bone health. The aim of this study was to investigate the relationship between 25(OH)D measured via liquid chromatography-mass spectrometry (LC-MS/MS), which is the current gold standard, and biochemical markers of bone turnover, PTH, and bone mineral densitometry (BMD). METHODS: The medical records of 750 postmenopausal women newly diagnosed with osteoporosis or osteopenia at Samsung Medical Center from 2009 to 2014 were investigated. Subjects were divided into four groups according to serum 25(OH)D concentration: <10, 10-20, 20-30, and ≥30 ng/mL. Serum concentrations of bone-specific alkaline phosphatase (BS-ALP), carboxy-terminal cross-linking telopeptide of type 1 collagen (CTx), intact PTH (iPTH), and BMD were compared among the four groups using analysis of covariance. Thresholds of 25(OH)D were then assessed using spline plots and locally weighted regression smoothing (LOESS) plots. RESULTS: 25(OH)D was negatively correlated with serum BS-ALP, CTx, and iPTH. Only femur neck and total femur BMD had significant positive relationships with 25(OH)D. Cutoff values of 11.9 and 9.7 ng/mL were estimated from the spline plots of femur neck and total femur BMD, respectively. For iPTH, the LOESS plot showed a steep decrease to a serum 25(OH)D concentration of about 20 ng/mL, followed by a plateau. CONCLUSIONS: According to this study, a serum 25(OH)D concentration of 20 ng/mL, rather than 30 ng/mL, was appropriate for bone health.

Effect of high dietary sodium on bone turnover markers and urinary calcium excretion in Korean postmenopausal women with low bone mass.

BACKGROUND/OBJECTIVES: High salt intake is a well-recognized risk factor of osteoporosis for its modulating effect on calcium metabolism. To understand the effect of dietary sodium on bone turnover, we evaluated the association between urinary sodium excretion and bone turnover markers in Korean postmenopausal women with low bone mass. SUBJECTS/METHODS: A retrospective review of medical records at a single institution identified 537 postmenopausal women who were first diagnosed with osteopenia or osteoporosis between 2008 and 2013. Subjects were stratified by low (<2 g/day, n=77), moderate (2-4.4 g/day, n=354) and high (⩾4.4 g/day, n=106) sodium excretion. A 24-h urine was collected to estimate sodium, calcium and creatinine. Bone turnover markers and calciotropic hormones were measured in serum. Bone mineral density (BMD) was assessed using dual-energy X-ray absorptiometry. RESULTS: Sodium intake was positively associated with urinary sodium excretion (P=0.006, r=0.29). Bone turnover markers were significantly higher in the moderate-to-high urinary sodium excretion group (⩾2 g/day) than in the low urinary sodium excretion group (<2 g/day); CTX-I (C-telopeptides of type I collagen) was 21.3% higher (P=0.001) and osteocalcin (OC) was 15.7% higher (P=0.004). Calciotropic hormones and BMD were not significantly different across the sodium excretion groups. CONCLUSIONS: High urinary sodium excretion (⩾2 g/day) increased bone turnover markers in Korean postmenopausal women, suggesting that excessive sodium intake might accelerate bone turnover.

Association between the extent of urinary albumin excretion and glycaemic variability indices measured by continuous glucose monitoring.

AIMS: The contribution of glycaemic variability to the microvascular complication of diabetes has not been established. We examined whether there is an independent association between indices of glycaemic variability in continuous glucose monitoring and extent of albuminuria. METHODS: A total of 173 patients with Type 2 diabetes (without insulin therapy, n = 96; with insulin therapy, n = 77) who had unexplained large fluctuations in blood glucose values underwent three-day continuous glucose monitoring. We used a multinomial logistic regression model to determine whether the indices of glycaemic variability independently affected the odds of having a spot urine albumin/creatinine ratio of 30-299 mg/g and ≥ 300 mg/g. RESULTS: Higher standard deviation (P = 0.002), mean of daily differences (P = 0.023) and mean amplitude of glycaemic excursion (P = 0.043) significantly increased the odds of having a urine albumin/creatinine ratio of ≥ 300 mg/g. In multivariable analysis, only higher standard deviation, but not mean amplitude of glycaemic excursion and mean of daily differences, independently increased the odds of having a urine albumin/creatinine ratio of ≥ 300 mg/g (P = 0.025). Coefficient of variation (sd/mean) was not associated with the odds of having a urine albumin/creatinine ratio of 30-299 or ≥ 300 mg/g. CONCLUSIONS: The independent association between standard deviation and the extent of albuminuria was lost when the measures were normalized by mean glucose level. At least in terms of relative measures of glycaemic variability, we failed to demonstrate an independent association between glycaemic variability and albuminuria extent in patients with inadequately controlled Type 2 diabetes.

Gastric bypass in Type 2 diabetes with BMI < 30: weight and weight loss have a major influence on outcomes.

AIM: To assess factors influencing glycaemic control following gastric bypass surgery in patients with Type 2 diabetes and BMI< 30 kg/m(2) . METHODS: Prospective longitudinal study of 103 patients with inadequate glycaemic control who underwent gastric bypass surgery at Soonchunhyang University, Seoul, Korea (n = 66) and Min-Sheng General Hospital, Taipei, Taiwan (n = 37). Procedures were performed August 2009 to January 2011. Key outcome measures were excellent glycaemic control of Type 2 diabetes defined as HbA1c < 42 mmol/mol (≤6%); inadequate response defined as HbA1c > 53 mmol/mol (> 7%). Analysis was conducted using binary logistic regression, and cut-points obtained from receiver operator characteristics. RESULTS: Excellent glycaemic control was achieved in 31 (30%) at 1 year. Diabetes duration of < 7 years and BMI > 27 kg/m(2) provided independent predictors and useful cut-points. Likelihood of excellent glycaemic control for an individual could be estimated using loge (Odds) = -6.7 + (0.26 × BMI) + (-1.2 × diabetes duration). Baseline BMI of < 27 kg/m(2) and baseline C-peptide of < 2.0ng/ml, best predicted a poor glycaemic response. In those with favourable baseline characteristics percentage weight loss (%WL) had a dominant influence on glycaemic outcomes. Baseline C-peptide (> 2.4 ng/ml) and subsequent percentage weight loss (> 16%) were associated with excellent glycaemic control. Higher BMI was associated with greater percentage weight loss. CONCLUSION: In patients with Type 2 diabetes and BMI < 30 kg/m(2) , glycaemic response to gastric bypass is predicted by higher baseline BMI, shorter disease duration and higher fasting C-peptide. Post-surgery weight loss has a dominant effect. Baseline BMI and weight loss have a major influence on outcomes.

Autophagy deficiency in beta cells leads to compromised unfolded protein response and progression from obesity to diabetes in mice.

AIMS/HYPOTHESIS: The unfolded protein response (UPR) in endoplasmic reticulum (ER) and autophagy are known to be related. We investigated the role of autophagy in UPR of pancreatic beta cells and the susceptibility of autophagy-deficient beta cells to the ER stress that is implicated in the development of diabetes. METHODS: Rat insulin promoter (RIP)-Cre(+);autophagy-related 7 (Atg7)(F/W) mice were bred with ob/w mice to derive RIP-Cre(+);Atg7(F/F)-ob/ob mice and to induce ER stress in vivo. GFP-LC3(+)-ob/ob mice were generated to examine in vivo autophagic activity. Real-time RT-PCR was performed to study the expression of the genes of the UPR machinery. Proteolysis was assessed by determining release of incorporated radioactive leucine. RESULTS: Production of UPR machinery was reduced in autophagy-deficient beta cells, which was associated with diminished production of p85α and p85ß regulatory subunits of phosphoinositide 3-kinase. Because of compromised UPR machinery, autophagy-deficient beta cells were susceptible to ER stressors in vitro. When mice with beta cell-specific autophagy deficiency, which have mild hyperglycaemia, were bred with ob/ob mice to induce ER stress in vivo, severe diabetes developed, which was accompanied by an increase in beta cell death and accumulation of reactive oxygen species. The increased demand for UPR present in obesity was unmet in autophagy-deficient beta cells. Autophagy level and autophagic activity were enhanced by lipid, while proteolysis was reduced. CONCLUSIONS/INTERPRETATION: These results suggest that autophagy is important for intact UPR machinery and appropriate UPR in response to lipid injury that increases demand for UPR. Autophagy deficiency in pancreatic beta cells may contribute to the progression from obesity to diabetes.

Use of the hilar plate looping technique for bile duct dissection in living donor liver transplantation significantly reduces recipient biliary complications.

Biliary complications remain a major cause of morbidity after liver transplantation, especially in living donor liver transplantation (LDLT). Maintaining adequate blood supply to the bile duct is important for the prevention of biliary complications. The objective of this study was to analyze the effects of different techniques for bile duct anastomosis on posttransplantation biliary complications. From August 2005 to August 2008, 121 liver transplantations were performed at our center. Among the total 121 liver transplant recipients, 68 patients underwent a LDLT using a right lobe graft and were enrolled in this study. We used classic dissection for the first 38 recipients and the hilar plate looping technique for the next 30 patients. The hilar plate looping technique involves the looping of the complete hilar plate and Glissonian sheath around the hepatic duct after full dissection of the right hepatic artery and portal vein. Biliary complications were defined as bilomas or strictures that developed within 6 months after transplantation and required surgical or radiological intervention. There were no significant demographic differences between the 2 groups. The incidence of complications was 15 (39.5%) for classic dissection and 3 (18.8%) for hilar plate looping. Furthermore, there were no biliary strictures in the hilar plate looping group, and there was a significant difference in the complication rate between the 2 groups (P = .011). In conclusion, the hilar plate looping technique during LDLT significantly reduces recipient biliary complications.

Impact of graft type on remnant liver regeneration: right hepatectomy versus extended right hepatectomy.

Right hepatectomy with the middle hepatic vein (MHV) affects venous return and function of the remaining liver. We compared the remnant liver volume in the donors of resection with or without the MHV on the remnant liver volume regeneration. Living donors who had undergone right hepatectomy without MHV (RH group; n = 36) and those with MHV (ERH group; n = 19) were reviewed. Volume regeneration of segments I-III, segment IV, and total remnant liver volume was assessed at postoperative day (POD) 7 and 30 using a computed tomography-based volumetry program. According to the measured volume data, we calculated the liver remnant volume and the rate of liver remnant volume increase. The regeneration rate of segment IV was significantly low in the ERH group compared with that in the RH group at POD 7 and POD 30 (160% vs 141%; P = .018 and 189% vs 154%; P = .007). In contrast, the regeneration rate of the total remnant liver volume was not significantly different between the 2 groups (173% vs 175%; P = .758 and 199% vs 198%; P = .880). In conclusion, extended right hepatectomy can be safely performed with careful preoperative evaluation without significant impairment of remnant liver regeneration.

Role of autophagy in ß-cell function and mass.

Type 2 diabetes (T2D) is characterized by decreased insulin secretion and action. Decreased insulin secretion results from a reduction in pancreatic ß-cell mass and/or function. Apoptosis, oxidative stress, mitochondrial dysfunction and endoplasmic reticulum (ER) stress responses including JNK activation have been suggested as mechanisms for the changes of pancreatic ß-cells in T2D; however, the underlying causes were not clearly elucidated. Autophagy is an intracellular process that plays crucial roles in cellular homeostasis through degradation and recycling of organelles. We have reported increased apoptosis and decreased proliferation of ß-cells with resultant reduction in the ß-cell mass in ß-cell-specific autophagy-deficient mice. Morphological analysis of ß-cells revealed accumulation of ubiquitinated proteins, swollen mitochondria and distended ER. Insulin secretory function ex vivo was also impaired. As a result, ß-cell-specific autophagy-deficient mice showed hypoinsulinaemia and hyperglycaemia. These results suggested that autophagy is necessary to maintain the structure, mass and function of pancreatic ß-cells. In addition, as autophagy may play a protective role against ER stress and rejuvenates organelle function, impaired autophagy may lead to mitochondrial dysfunction and ER stress, which have been implicated as potential causes of insulin resistance. Therefore, in addition to ß-cell homeostasis, dysregulated autophagy may possibly be involved in diverse aspects of the pathogenesis of diabetes.

Classification and valuation of postoperative complications in a randomized trial of open versus laparoscopic ventral herniorrhaphy.

PURPOSE: Generic instruments used for the valuation of health states (e.g., EuroQol) often lack sensitivity to notable differences that are relevant to particular diseases or interventions. We developed a valuation methodology specifically for complications following ventral incisional herniorrhaphy (VIH). METHODS: Between 2004 and 2006, 146 patients were prospectively randomized to undergo laparoscopic (n = 73) or open (n = 73) VIH. The primary outcome of the trial was complications at 8 weeks. A three-step methodology was used to assign severity weights to complications. First, each complication was graded using the Clavien classification. Second, five reviewers were asked to independently and directly rate their perception of the severity of each class using a non-categorized visual analog scale. Zero represented an uncomplicated postoperative course, while 100 represented postoperative death. Third, the median, lowest, and highest values assigned to each class of complications were used to derive weighted complication scores for open and laparoscopic VIH. RESULTS: Open VIH had more complications than laparoscopic VIH (47.9 vs. 31.5%, respectively; P = 0.026). However, complications of laparoscopic VIH were more severe than those of open VIH. Non-parametric analysis revealed a statistically higher weighted complication score for open VIH (interquartile range: 0-20 for open vs. 0-10 for laparoscopic; P = 0.049). In the sensitivity analysis, similar results were obtained using the median, highest, and lowest weights. CONCLUSION: We describe a new methodology for the valuation of complications following VIH that allows a direct outcome comparison of procedures with different complication profiles. Further testing of the validity, reliability, and generalizability of this method is warranted.

Up-regulated macrophage migration inhibitory factor protects apoptosis of dermal fibroblasts in patients with systemic sclerosis.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that has been demonstrated to regulate the apoptosis of several cell types. Dysregulated apoptosis of fibroblasts has been implicated in a variety of fibrotic diseases, including systemic sclerosis (SSc). In this study, we investigated the role of MIF in the apoptosis of dermal fibroblasts. The concentrations of MIF were measured in sera and in culture supernatants of peripheral blood mononuclear cells (PBMCs) and dermal fibroblasts by enzyme-linked immunosorbent assay. The degree of apoptosis was determined by colorimetric assay, and signalling pathways were examined by Western blot. The results showed that serum levels of MIF were significantly higher in patients with SSc (n = 47) than in healthy controls (n = 56). Stimulation of PBMCs by anti-CD3 and anti-CD28 increased the production of MIF by fourfold over the constitutive levels. SSc dermal fibroblasts produced higher amounts of MIF than normal dermal fibroblasts. When treated with sodium nitroprusside (SNP), SSc dermal fibroblasts showed a lower degree of apoptosis compared with normal dermal fibroblasts. Exogenous MIF (1-100 ng/ml) inhibited SNP-induced apoptosis of dermal fibroblasts dose-dependently. Both extracellular regulated kinase (ERK) inhibitor (PD98059) and protein kinase B (Akt) inhibitor (LY294002) almost completely blocked the inhibitory effect of MIF on apoptosis. Furthermore, MIF increased the expression of Bcl-2, phospho-ERK and phospho-Akt activity in dermal fibroblasts. Taken together, our data suggest that MIF released by activated T cells and dermal fibroblasts decreases the apoptosis of dermal fibroblasts through activation of ERK, Akt and Bcl-2 signalling pathways, which might be associated with excessive fibrosis in SSc.

Effects of fermi liquid interactions on the shot noise of an SU(N) Kondo quantum dot.

We study shot noise in the current of quantum dots whose low-energy behavior corresponds to an SU(N) Kondo model, focusing on the case N=4 relevant to carbon nanotube dots. For general N, two-particle Fermi-liquid interactions have two distinct effects: they can enhance the noise via backscattering processes with an N-dependent effective charge, and can also modify the coherent partition noise already present without interactions. For N=4, in contrast with the SU(2) case, interactions enhance shot noise solely through an enhancement of partition noise. This leads to a nontrivial prediction for experiment.

Intracellular K(+) inhibits apoptosis by suppressing the Apaf-1 apoptosome formation and subsequent downstream pathways but not cytochrome c release.

Cellular ionic homeostasis, fundamentally K(+) homeostasis, has been implicated as a critical regulator of apoptosis. The intracellular K(+) efflux on apoptotic insult and suppression of apoptosis by high concentration of extracellular K(+) or after inhibition of this efflux by K(+) channel blockers have established the crucial role of K(+) in turning on the apoptotic machinery. Several contrasting observations have reported the antiapoptotic effect of intracellular K(+) concentration to be the result of inhibition of cytochrome c release from mitochondria, but the exact inhibitory mechanism remains obscure. However, here we show the blockage of K(+) efflux during apoptosis did not affect cytochrome c release from the mitochondria, still completely inhibited the formation of the apoptosome comprising Apaf-1, cytochrome c, caspase-9 and other accessories. As a consequence of this event, procaspase-9, -3, -8 and other death-related proteins were not processed. Furthermore, physiological concentrations of K(+) also inhibited the processing of procaspase-3 by purified caspase-8 or -9, the nucleosomal DNA fragmentation by purified DFF40/CAD and the nuclear fragmentation to varying extents. Altogether, these findings suggest that the efflux of K(+) is prerequisite not only for the formation of the apoptosome but also for the downstream apoptotic signal-transduction pathways.

Prognostic significance of the expression of Smad4 and Smad7 in human gastric carcinomas.

BACKGROUND: Transforming growth factor-beta (TGF-beta) modulates the growth and function of many cells, including those with malignant transformation. Smad proteins have been identified as major components in the intracellular signaling of TGF-beta family members. PATIENTS AND METHODS: To clarify the correlations between clinicopathologic profiles and the patient's survival, the expression of common mediator Smad (Smad4) and inhibitory Smad (Smad7) were evaluated immunohistochemically in 304 consecutive gastric carcinomas using the tissue array method. RESULTS: Positive Smad4 expression was observed in 266 (87.5%) tumors and positive Smad7 expression in 98 (32.2%) tumors. The prognosis of patients with a Smad4-positive tumor was significantly better than that of the patients with a negative tumor. The survival rate was significantly higher in patients with negative Smad7 expression than those with positive Smad7 expression. In subgroup analysis according to TNM (tumour-node-metastasis) stage, both Smad4 and Smad7 showed most significant prognostic differences in stage I gastric cancer patients. Multivariate analysis indicated that tumor size, depth of invasion, lymph node metastasis and Smad7 expression were independent prognostic factors. CONCLUSION: Enhanced expression of the TGF-beta signaling inhibitor Smad7 may present one of the novel mechanisms of TGF-beta resistance in human gastric carcinomas.

Validating risk-adjusted surgical outcomes: chart review of process of care.

OBJECTIVE: The primary purpose of this study was to validate risk-adjusted surgical outcomes as indicators of the quality of surgical care at US Department of Veterans Affairs (VA) hospitals. The secondary purpose was to validate the risk-adjustment models for screening cases for quality review. DESIGN: We compared quality of care, determined by structured implicit chart review, for patients from hospitals with higher and lower than expected operative mortality and morbidity (hospital-level tests) and between patients with high and low predicted risk of mortality and morbidity who died or developed complications (patient-level tests). SUBJECTS: 739 general, peripheral vascular and orthopedic surgery cases sampled from the 44 VA hospitals participating in the National VA Surgical Risk Study. MAIN OUTCOME MEASURES: A global rating of quality of care based on chart review. RESULTS: Ratings of overall quality of care did not differ significantly between patients from hospitals with higher and lower than expected mortality and morbidity. On some of the secondary measures, patient care was rated higher for hospitals with lower than expected operative mortality. At the patient level of analysis, those who died or developed complications and had a high predicted risk of mortality or morbidity were rated higher on quality of care than those with a low predicted risk of adverse outcome. CONCLUSIONS: The absence of a relationship between most of our measures of process of care and risk-adjusted outcomes may be due to an insensitivity of chart reviews to hospital-level differences in quality of care. Site visits to National VA Surgical Risk Study hospitals with high and low risk-adjusted mortality and morbidity have detected differences on a number of dimensions of quality. The patient-level findings suggest that the risk-adjustment models are useful for screening adverse outcome cases for quality of care review.