Person:

Zheng, Hui

Objective: The A1C-Derived Average Glucose (ADAG) study demonstrated a linear relationship between (HbA_{1c}) and mean plasma glucose (MPG). As glucose variability (GV) may contribute to glycation, we examined the association of several glucose variability indices and the MPG-(HbA_{1c}) relationship. Research Design and Methods: Analyses included 268 patients with type 1 diabetes and 159 with type 2 diabetes. MPG during 3 months was calculated from 7-point self-monitored plasma glucose and continuous glucose monitoring. We calculated three different measures of GV and used a multiple-step regression model to determine the contribution of the respective GV measures to the MPG-(HbA_{1c}) relationship. Results: GV, as reflected by SD and continuous overlapping net glycemic action, had a significant effect on the MPG-(HbA_{1c}) relationship in type 1 diabetic patients so that high GV led to a higher (HbA_{1c}) level for the same MPG. In type 1 diabetes, the impact of confounding and effect modification of a low versus high SD at an MPG level of 160 mg/dL on the (HbA_{1c}) level is 7.02 vs. 7.43 and 6.96 vs. 7.41. All GV measures showed the same tendency. Conclusions: In only type 1 diabetic patients, GV shows a significant interaction with MPG in the association with (HbA_{1c}). This effect is more pronounced at higher (HbA_{1c}) levels. However, the impact of GV on the (HbA_{1c}) level in type 1 diabetes is modest, particularly when (HbA_{1c}) is close to the treatment target of 7%.

Background: Lymph node metastases are prognostically significant in pancreatic ductal adenocarcinoma. Little is known about the significance of direct lymph node invasion. Aim: The aim of this study is to find out whether direct lymph node invasion has the same prognostic significance as regional nodal metastases. Methods: Retrospective review of patients resected between 1/1/1993 and 7/31/2008. “Direct” was defined as tumor extension into adjacent nodes, and “regional” was defined as metastases to peripancreatic nodes. Results: Overall, 517 patients underwent pancreatic resection for adenocarcinoma, of whom 89 had one positive node (direct 26, regional 63), and 79 had two positive nodes (direct 6, regional 68, both 5). Overall, survival of node-negative patients was improved compared to patients with positive nodes (N0 30.8 months vs. N1 16.4 months; p < 0.001). There was no survival difference for patients with direct vs. regional lymph node invasion (p = 0.67). Patients with one positive node had a better overall survival compared to patients with ≥2 positive nodes (22.3 and 15 months, respectively; p < 0.001). The lymph node ratio (+LN/total LN) was prognostically significant after Cox regression (p < 0.001). Conclusions: Isolated direct invasion occurs in 20% of patients with one to two positive nodes. Node involvement by metastasis or by direct invasion are equally significant predictors of reduced survival. Both the number of positive nodes and the lymph node ratio are significant prognostic factors.

In animal models and human cross-sectional studies, vitamin D deficiency has been associated with liver disease progression. Vitamin D supplementation has been suggested as a treatment to prevent disease progression. We sought to evaluate the role of vitamin D levels in predicting chronic liver disease development. We conducted a nested case-control study of vitamin D levels in subjects with (cases) and without (controls) liver histologic progression or clinical decompensation over the course of the HALT-C Trial. Vitamin D levels were measured at 4 points over 45 months. 129 cases and 129 aged-matched controls were included. No difference in baseline vitamin D levels were found between cases and controls. (44.8 ng/mL vs. 44.0 ng/mL, P = 0.74). Vitamin D levels declined in cases and controls over time (P = 0.0005), however, there was no difference in the level of decline (P = 0.37). Among study subjects with diabetes mellitius, baseline vitamin D levels were higher in cases, 49.9 ng/mL, than controls, 36.3 ng/mL. (P = 0.03) In addition, baseline vitamin D levels were higher in black case subjects, 32.7 ng/mL, than in black control subjects, 25.2 ng/mL (P = 0.08) No difference in vitamin D levels was found between patients with and without progression of hepatitis C-associated liver disease over 4 years. Our data do not suggest any role for vitamin D supplementation in patients with advanced chronic hepatitis C and raise the possibility that higher vitamin D levels may be associated with disease progression.

Background: No targeted immunotherapies reverse type 1 diabetes in humans. However, in a rodent model of type 1 diabetes, Bacillus Calmette-Guerin (BCG) reverses disease by restoring insulin secretion. Specifically, it stimulates innate immunity by inducing the host to produce tumor necrosis factor (TNF), which, in turn, kills disease-causing autoimmune cells and restores pancreatic beta-cell function through regeneration. Methodology/Principal Findings Translating these findings to humans, we administered BCG, a generic vaccine, in a proof-of-principle, double-blind, placebo-controlled trial of adults with long-term type 1 diabetes (mean: 15.3 years) at one clinical center in North America. Six subjects were randomly assigned to BCG or placebo and compared to self, healthy paired controls (n = 6) or reference subjects with (n = 57) or without (n = 16) type 1 diabetes, depending upon the outcome measure. We monitored weekly blood samples for 20 weeks for insulin-autoreactive T cells, regulatory T cells (Tregs), glutamic acid decarboxylase (GAD) and other autoantibodies, and C-peptide, a marker of insulin secretion. BCG-treated patients and one placebo-treated patient who, after enrollment, unexpectedly developed acute Epstein-Barr virus infection, a known TNF inducer, exclusively showed increases in dead insulin-autoreactive T cells and induction of Tregs. C-peptide levels (pmol/L) significantly rose transiently in two BCG-treated subjects (means: 3.49 pmol/L [95% CI 2.95–3.8], 2.57 [95% CI 1.65–3.49]) and the EBV-infected subject (3.16 [95% CI 2.54–3.69]) vs.1.65 [95% CI 1.55–3.2] in reference diabetic subjects. BCG-treated subjects each had more than 50% of their C-peptide values above the 95th percentile of the reference subjects. The EBV-infected subject had 18% of C-peptide values above this level. Conclusions/Significance: We conclude that BCG treatment or EBV infection transiently modified the autoimmunity that underlies type 1 diabetes by stimulating the host innate immune response. This suggests that BCG or other stimulators of host innate immunity may have value in the treatment of long-term diabetes. Trial Registration ClinicalTrials.gov NCT00607230

Postoperative delirium is associated with increased morbidity, mortality and cost. However, its neuropathogenesis remains largely unknown, partially owing to lack of animal model(s). We therefore set out to employ a battery of behavior tests, including natural and learned behavior, in mice to determine the effects of laparotomy under isoflurane anesthesia (Anesthesia/Surgery) on these behaviors. The mice were tested at 24 hours before and at 6, 9 and 24 hours after the Anesthesia/Surgery. Composite Z scores were calculated. Cyclosporine A, an inhibitor of mitochondria permeability transient pore, was used to determine potential mitochondria-associated mechanisms of these behavioral changes. Anesthesia/Surgery selectively impaired behaviors, including latency to eat food in buried food test, freezing time and time spent in the center in open field test, and entries and duration in the novel arm of Y maze test, with acute onset and various timecourse. The composite Z scores quantitatively demonstrated the Anesthesia/Surgery-induced behavior impairment in mice. Cyclosporine A selectively ameliorated the Anesthesia/Surgery-induced reduction in ATP levels, the increases in latency to eat food, and the decreases in entries in the novel arm. These findings suggest that we could use a battery of behavior tests to establish a mouse model to study postoperative delirium.

Objectives: To determine the prevalence of incidentally found cases of gallbladder cancer, the incidence of residual disease at reexploration, and the changes in the mode of presentation, treatment, and survival of patients with gallbladder cancer during a period of more than 4 decades. Design: Retrospective case series. Setting: University-affiliated tertiary care center. Patients: Between January 1, 1962, and March 1, 2008, 402 patients with gallbladder cancer were identified and their clinicopathologic data were analyzed. Interventions: Surgical treatment, radiotherapy, and chemotherapy. Main Outcome Measures: Incidentally discovered gallbladder cancer, incidence of residual disease, and differences in presentation, treatment, and survival. Results: Surgical exploration was performed in 260 patients (64.7%), of whom 151 (58.1%) underwent resection. The median age of the patients was 72 years, and 72.3% were female. Between January 1, 1994, and March 1, 2008, 6881 laparoscopic cholecystectomies were performed, and there were 17 incidentally discovered cases of gallbladder cancer (0.25%). Residual disease on reexploration was identified in 0 of 2 patients with T1 tumor, 3 of 13 patients with T2 tumor, and 8 of 10 patients with T3 tumor (P = .01). Patients with stage IV disease (34 [13.1%] diagnosed from 1962-1979; 34 [13.1%] diagnosed from 1980-1997; and 22 [8.5%] diagnosed from 1998-2008) had a median survival of 4 months (range, 0-37 months). Concomitant liver resections increased in the third study period (11.1%, 10.1%, and 54.3%; P < .001), with an increase in negative margins (33.3%, 42.0%, and 63.0%; P = .01). Cox regression analysis identified T stage and surgical margin status as significant prognostic factors. Conclusions: Gallbladder cancer is incidentally found during 0.25% of laparoscopic cholecystectomies. As T stage increases, the likelihood of residual disease on reexploration increases. Although many patients with gallbladder cancer present with incurable disease and have very poor survival, the overall prognosis is improving, likely because of more extensive operations.

Background: Possible mass lesions identified on ultrasound (US) of the gallbladder may prompt an aggressive surgical intervention due to the possibility of a malignant neoplasm. Aim: This study aims to utilize a large modern series of patients with gallbladder lesions identified on US to evaluate imaging characteristics consistent with malignancy. Methods: A retrospective review was conducted of gallbladder ultrasound reports and clinicopathologic data of patients with a mass identified on US. Results: Approximately 59,271 abdominal ultrasounds and 9,117 cholecystectomies were performed between February 2000 and February 2010. We identified 213 patients with a questionable gallbladder neoplasm on ultrasonography who underwent surgical exploration. Median age was 52 years (range = 11–87 years) and 147 (69%) were females. Final pathology demonstrated no neoplasm in 130 patients (61%), while 32 patients (15%) had a wall adenomyoma, 36 (17%) had a polyp (five of which were malignant), 14 (7%) had an adenocarcinoma not arising from a polyp, and one patient had a cystic papillary neoplasm. The smaller the lesion, the more likely it was to be a pseudo-mass. For lesions measuring <5 mm on US, 83% had no lesion found on final pathology. Significant predictors of malignancy were age >52 years (p < 0.001), presence of gallstones on US (p = 0.004), size >9 mm (p < 0.001), evidence of invasion at the liver interface (p < 0.001), and wall thickening >5 mm (p < 0.001). Shape (sessile or penduculated), echogenicity (echogenic or isoechoic), or presence of flow on Doppler were not predictors of malignancy. An US size of ≤9 mm had a negative predictive value of 100% for malignancy. Conclusions: Despite improvements in imaging, most apparent lesions measuring <5 mm on US are not identified in the surgical specimen. US size >9 mm, age >52 years, US suggestion of invasion at the liver interface, and wall thickening >5 mm, especially in the presence of gallstones, should raise the suspicion of malignancy.

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide and its progressive form, steatohepatitis, will be the leading indication for liver transplant by 2020. While risk factors for steatohepatitis have been identified, little work has been performed to identify factors protective against NAFLD development. Aim This study sought to identify factors predictive of normal liver histology in a bariatric cohort. Methods: Patients undergoing weight loss surgery with liver biopsies at the time of surgery were included. Patients with other causes of chronic liver disease were excluded. Results: One hundred fifty-nine patients were included. Forty-nine patients had normal liver histology and 110 patients had NAFLD. Several previously identified factors associated with normal liver histology were found. Black race was the strongest predictor of the absence of NAFLD with an odds ratio (OR) of 6.8, 95% confidence interval (CI) 2.4–18.9. Low HOMA-IR was also associated with normal histology (OR 1.4, 95% CI 1.03–1.9). In contrast, low HDL was associated with a decreased chance of normal histology (OR 0.38, 95% CI 0.05–0.83). Interestingly, a novel protective factor, the absence of obstructive sleep apnea (OSA) was strongly associated with normal histology (OR 5.6, 95% CI 2.0–16.1). In multivariate regression controlling for BMI, black race, absence of OSA, low HOMA-IR and low ALT independently predicted normal liver histology with an area under the ROC curve of 0.85. Conclusions: Our study confirmed several factors associated with normal liver histology, including black race and identified a novel factor, absence of OSA. Further evaluation of these factors will allow for improved understanding of the pathogenesis of NAFLD.

Background: Pancreatic ductal adenocarcinoma represents 90% of pancreatic cancers and is an important cause of cancer death in the United States. Operative resection remains as the only treatment providing prolonged survival, but even after a curative resection, 5-year survival rates are low. Our aim was to identify the prognostic factors for long-term survival after resection of pancreatic ductal adenocarcinoma related to patients, treatments, and tumor biology. Methods: Retrospective review identified 959 patients who underwent resection of their pancreatic adenocarcinoma between February 1985 and December 2010, of whom 499 were resected before November 2006 and represent the cohort we describe in this study. Patient, tumor, and treatment-related variables were assessed for their associations with 5- and 10-year overall survival. Results: Of the 499 patients, 49% were female and median age was 65 years. The majority of patients had stage IIb disease (60%). Actual 5-year survival after resection of pancreatic adenocarcinoma was 19% (95/499), and actual 10-year survival was 10% (33/329). Significant clinicopathologic factors predicting 5- and 10-year survival were negative margins and negative nodal status. Interestingly, 41% (39/95) of long-term survivors had positive nodes and 24% (23/95) had positive margins. Conclusion: Pancreatic ductal adenocarcinoma demonstrates a very heterogeneous biology, but patients with negative resection margins and node negative cancers are more likely to survive 5 years after resection. However, our series demonstrates that the biology of the cancer rather than simple pathologic factors determine a patient's prognosis.

OBJECTIVE To compare three continuous glucose monitoring (CGM) devices in subjects with type 1 diabetes under closed-loop blood glucose (BG) control. RESEARCH DESIGN AND METHODS Six subjects with type 1 diabetes (age 52 ± 14 years, diabetes duration 32 ± 14 years) each participated in two 51-h closed-loop BG control experiments in the hospital. Venous plasma glucose (PG) measurements (GlucoScout, International Biomedical) obtained every 15 min (2,360 values) were paired in time with corresponding CGM glucose (CGMG) measurements obtained from three CGM devices, the Navigator (Abbott Diabetes Care), the Seven Plus (DexCom), and the Guardian (Medtronic), worn simultaneously by each subject. Errors in paired PG–CGMG measurements and data reporting percentages were obtained for each CGM device. RESULTS The Navigator had the best overall accuracy, with an aggregate mean absolute relative difference (MARD) of all paired points of 11.8 ± 11.1% and an average MARD across all 12 experiments of 11.8 ± 3.8%. The Seven Plus and Guardian produced aggregate MARDs of all paired points of 16.5 ± 17.8% and 20.3 ± 18.0%, respectively, and average MARDs across all 12 experiments of 16.5 ± 6.7% and 20.2 ± 6.8%, respectively. Data reporting percentages, a measure of reliability, were 76% for the Seven Plus and nearly 100% for the Navigator and Guardian. CONCLUSIONS A comprehensive head-to-head-to-head comparison of three CGM devices for BG values from 36 to 563 mg/dL revealed marked differences in performance characteristics that include accuracy, precision, and reliability. The Navigator outperformed the other two in these areas.