Serum Dipeptidyl Peptidase-4 Activity in Insulin Resistant Patients with Non-Alcoholic Fatty Liver Disease: A Novel Liver Disease Biomarker

Background

In a cross-sectional study we studied the fasting serum DPP-4 enzymatic activity (sDPP-4) and the insulin resistance index (HOMA2-IR) in gliptin naïve patients with type 2 diabetes and in non-alcoholic fatty liver disease (NAFLD) and in healthy controls (CNTRL).

Methods and Findings

sDPP-4 was measured by kinetic assay in 39 NAFLD (F/M:19/20, mean age: 47.42 yrs) and 82 type 2 diabetes (F/M:48/34, 62.8 yrs) patients and 26 (F/M:14/12, 35.3 yrs) controls. Definition of T2D group as patients with type 2 diabetes but without clinically obvious liver disease created non-overlapping study groups. Diagnosis of NAFLD was based on ultrasonography and the exclusion of other etiololgy. Patients in T2D and NAFLD groups were similarly obese. 75 g CH OGTT in 39 NAFLD patients: 24-NGT, 4-IGT or IFG (“prediabetes”), 11-type 2 diabetes. HOMA2-IR: CNTRL: 1.44; T2D-group: 2.62 (p = 0.046 vs CNTRL, parametric tests); NAFLD(NGTonly): 3.23 (p = 0.0013 vs CNTRL); NAFLD(IFG/IGT/type 2 diabetes): 3.82 (p<0.001 vs CNTRL, p = 0.049 vs 2TD group). sDPP-4 activity was higher in NAFLD both with NGT (mean:33.08U/L) and abnormal glucose metabolism (30.38U/L) than in CNTRL (25.89U/L, p<0.001 and p = 0.013) or in T2D groups (23.97U/L, p<0.001 and p = 0.004). Correlations in NAFLD among sDPP-4 and ALT: r = 0.4637,p = 0.0038 and γGT: r = 0.4991,p = 0.0017 and HOMA2-IR: r = 0.5295,p = 0.0026 and among HOMA2-IR and ALT: r = 0.4340,p = 0.0147 and γGT: r = 0.4128,p = 0.0210.

Conclusions

The fasting serum DPP-4 activity was not increased in T2D provided that patients with liver disease were intentionally excluded. The high serum DPP-4 activities in NAFLD were correlated with liver tests but not with the fasting plasma glucose or HbA1C supporting that the excess is of hepatic origin and it might contribute to the speedup of metabolic deterioration. The correlation among γGT, ALT and serum DPP-4 activity and also between serum DPP-4 activity and HOMA2-IR in NAFLD strongly suggests that serum DPP-4 activity should be considered as a novel liver disease biomarker.     

Effect of Meal Ingestion on Liver Stiffness in Patients with Cirrhosis and Portal Hypertension

Background and Aims

Liver stiffness is increasingly used in the non-invasive evaluation of chronic liver diseases. Liver stiffness correlates with hepatic venous pressure gradient (HVPG) in patients with cirrhosis and holds prognostic value in this population. Hence, accuracy in its measurement is needed. Several factors independent of fibrosis influence liver stiffness, but there is insufficient information on whether meal ingestion modifies liver stiffness in cirrhosis. We investigated the changes in liver stiffness occurring after the ingestion of a liquid standard test meal in this population.

Methods

In 19 patients with cirrhosis and esophageal varices (9 alcoholic, 9 HCV-related, 1 NASH; Child score 6.9±1.8), liver stiffness (transient elastography), portal blood flow (PBF) and hepatic artery blood flow (HABF) (Doppler-Ultrasound) were measured before and 30 minutes after receiving a standard mixed liquid meal. In 10 the HVPG changes were also measured.

Results

Post-prandial hyperemia was accompanied by a marked increase in liver stiffness (+27±33%; p<0.0001). Changes in liver stiffness did not correlate with PBF changes, but directly correlated with HABF changes (r = 0.658; p = 0.002). After the meal, those patients showing a decrease in HABF (n = 13) had a less marked increase of liver stiffness as compared to patients in whom HABF increased (n = 6; +12±21% vs. +62±29%,p<0.0001). As expected, post-prandial hyperemia was associated with an increase in HVPG (n = 10; +26±13%, p = 0.003), but changes in liver stiffness did not correlate with HVPG changes.

Conclusions

Liver stiffness increases markedly after a liquid test meal in patients with cirrhosis, suggesting that its measurement should be performed in standardized fasting conditions. The hepatic artery buffer response appears an important factor modulating postprandial changes of liver stiffness. The post-prandial increase in HVPG cannot be predicted by changes in liver stiffness.     

The Relationship of Omental and Subcutaneous Adipocyte Size to Metabolic Disease in Severe Obesity

Objective

Several studies have reported the existence of a subgroup of obese individuals with normal metabolic profiles. It remains unclear what factors are responsible for this phenomenon. We proposed that adipocyte size might be a key factor in the protection of metabolically healthy obese (MHO) individuals from the adverse effects of obesity.

Subjects

Thirty-five patients undergoing bariatric surgery were classified as MHO (n = 15) or metabolically unhealthy obese (MUO, n = 20) according to cut-off points adapted from the International Diabetes Federation definition of the metabolic syndrome. Median body mass index (BMI) was 48 (range 40–71).

Results

There was a moderate correlation between omental adipocyte size and subcutaneous adipocyte size (r = 0.59, p<0.05). The MHO group had significantly lower mean omental adipocyte size (80.9±10.9 µm) when compared with metabolically unhealthy patients (100.0±7.6 µm, p<0.0001). Mean subcutaneous adipocyte size was similar between the two groups (104.1±8.5 µm versus 107.9±7.1 µm). Omental, but not subcutaneous adipocyte size, correlated with the degree of insulin resistance as measured by HOMA-IR (r = 0.73, p<0.0005), as well as other metabolic parameters including triglyceride/HDL-cholesterol ratio and HbA1c. Twenty-eight patients consented to liver biopsy. Of these, 46% had steatohepatitis and fibrosis. Fifty percent (including all the MHO patients) had steatosis only. Both omental and subcutaneous adipocyte size were significantly associated with the degree of steatosis (r = 0.66, p<0.0001 and r = 0.63, p<0.005 respectively). However, only omental adipocyte size was an independent predictor of the presence or absence of fibrosis.

Conclusion

Metabolically healthy individuals are a distinct subgroup of the severely obese. Both subcutaneous and omental adipocyte size correlated positively with the degree of fatty liver, but only omental adipocyte size was related to metabolic health, and possibly progression from hepatic steatosis to fibrosis.     

Intraoperative Hyperglycemia during Liver Resection: Predictors and Association with the Extent of Hepatocytes Injury

Background

Patients undergoing liver resection are at risk for intraoperative hyperglycemia and acute hyperglycemia is known to induce hepatocytes injury. Thus, we aimed to evaluate whether intraoperative hyperglycemia during liver resection is associated with the extent of hepatic injury.

Methods

This 1 year retrospective observation consecutively enrolled 85 patients undergoing liver resection for hepatocellular carcinoma. Blood glucose concentrations were measured at predetermined time points including every start/end of intermittent hepatic inflow occlusion (IHIO) via arterial blood analysis. Postoperative transaminase concentrations were used as surrogate parameters indicating the extent of surgery-related acute hepatocytes injury.

Results

Thirty (35.5%) patients developed hyperglycemia (blood glucose > 180 mg/dl) during surgery. Prolonged (≥ 3 rounds) IHIO (odds ratio [OR] 7.34, P = 0.004) was determined as a risk factors for hyperglycemia as well as cirrhosis (OR 4.07, P = 0.022), lower prothrombin time (OR 0.01, P = 0.025), and greater total cholesterol level (OR 1.04, P = 0.003). Hyperglycemia was independently associated with perioperative increase in transaminase concentrations (aspartate transaminase, β 105.1, standard error 41.7, P = 0.014; alanine transaminase, β 81.6, standard error 38.1, P = 0.035). Of note, blood glucose > 160 or 140 mg/dl was not associated with postoperative transaminase concentrations.

Conclusions

Hyperglycemia during liver resection might be associated with the extent of hepatocytes injury. It would be rational to maintain blood glucose concentration < 180 mg/dl throughout the surgery in consideration of parenchymal disease, coagulation status, lipid profile, and the cumulative hepatic ischemia in patients undergoing liver resection for hepatocellular carcinoma.     

Platelet Turnover in Stable Coronary Artery Disease – Influence of Thrombopoietin and Low-Grade Inflammation

Background

Newly formed platelets are associated with increased aggregation and adverse outcomes in patients with coronary artery disease (CAD). The mechanisms involved in the regulation of platelet turnover in patients with CAD are largely unknown.

Aim

To investigate associations between platelet turnover parameters, thrombopoietin and markers of low-grade inflammation in patients with stable CAD. Furthermore, to explore the relationship between platelet turnover parameters and type 2 diabetes, prior myocardial infarction, smoking, age, gender and renal insufficiency.

Methods

We studied 581 stable CAD patients. Platelet turnover parameters (immature platelet fraction, immature platelet count, mean platelet volume, platelet distribution width and platelet large cell-ratio) were determined using automated flow cytometry (Sysmex XE-2100). Furthermore, we measured thrombopoietin and evaluated low-grade inflammation by measurement of high-sensitive CRP and interleukin-6.

Results

We found strong associations between the immature platelet fraction, immature platelet count, mean platelet volume, platelet distribution width and platelet large cell ratio (r = 0.61–0.99, p<0.0001). Thrombopoietin levels were inversely related to all of the platelet turnover parameters (r = −0.17–−0.25, p<0.0001). Moreover, thrombopoietin levels were significantly increased in patients with diabetes (p = 0.03) and in smokers (p = 0.003). Low-grade inflammation evaluated by high-sensitive CRP correlated significantly, yet weakly, with immature platelet count (r = 0.10, p = 0.03) and thrombopoietin (r = 0.16, p<0.001). Also interleukin-6 correlated with thrombopoietin (r = 0.10, p = 0.02).

Conclusion

In stable CAD patients, thrombopoietin was inversely associated with platelet turnover parameters. Furthermore, thrombopoietin levels were increased in patients with diabetes and in smokers. However, low-grade inflammation did not seem to have a substantial impact on platelet turnover parameters.     

A Pilot Study on Factors Involved with Work Participation in the Early Stages of Multiple Sclerosis

Background

Up to 30% of recently diagnosed MS patients lose their jobs in the first four years after diagnosis. Taking into account the personal and socio-economic importance of sustaining employment, it is of the utmost importance to examine factors involved with work participation.

Objective

To investigate differences in self-reported functioning in recently diagnosed MS patients with and without a paid job.

Methods

Self-reports of physical and cognitive functioning, depression, anxiety and fatigue were gathered from 44 relapsing-remitting MS patients diagnosed within 3 years.

Results

Patients with a paid job (57%) reported better physical functioning (p<0.001), better memory functioning (p = 0.01) and a lower physical impact of fatigue (p = 0.018) than patients without a paid job. Physical functioning was the main predictor of employment status in a logistic regression model. In those with a paid job better memory functioning (r = 0.54, p = 0.005) and a lower social impact of fatigue (r = −0.46, p = 0.029) correlated with an increased number of working hours.

Conclusion

Better physical functioning is the primary factor involved with increased work participation in early MS. Better self-reported memory functioning and less social fatigue were associated with increased working hours. These findings highlight the importance of battling these symptoms in the early stages of MS.     

Risk of Obstructive Sleep Apnea with Daytime Sleepiness Is Associated with Liver Damage in Non-Morbidly Obese Patients with Nonalcoholic Fatty Liver Disease

Background

A high prevalence of obstructive sleep apnea syndrome (OSAS) has been reported in severely obese patients with nonalcoholic fatty liver disease (NAFLD), but few studies have evaluated OSAS in non-morbidly obese NAFLD patients.

Aims

To determine the prevalence of risk for OSAS with or without daytime sleepiness in non-morbidly obese patients with NAFLD and evaluate the association with the severity of liver damage.

Methods

We considered 159 consecutive patients with histological NAFLD and body mass index (BMI) <35 Kg/m², and 80 controls without ultrasonographic steatosis matched for age, sex, and BMI. OSAS risk was determined by positivity for Berlin questionnaire (BQ), and daytime sleepiness by the Sleepness Epworth Scale (ESS). Liver damage was evaluated according to the NAFLD activity score.

Results

In NAFLD patients, BQ alone was positive in 39 (25%), ESS in 8 (5%), and both in 13 (8%, OSAS with sleepines); p = ns vs. controls without steatosis. In NAFLD patients at risk for OSAS with (but not in those without) sleepiness, we observed a higher prevalence of nonalcoholic steatohepatitis (NASH; 11/13, 85% vs. 72/146, 49%; p = 0.018), and of clinically significant fibrosis (stage>1; 9/13, 69% vs. 39/146, 27%; p = 0.003). At multivariate logistic regression analysis, OSAS with sleepiness was strongly associated with NASH and fibrosis>1 independently of known clinical risk factors such as age, gender, BMI, diabetes, and ALT levels (OR 7.1, 95% c.i. 1.7–51, p = 0.005 and OR 14.0, 95% c.i. 3.5–70, p = 0.0002, respectively).

Conclusions

A proportion of NAFLD patients without severe obesity is at risk for OSAS with daytime sleepiness, which is associated with the severity of liver damage independently of body mass and other cofactors.     

Effects of Nucleoside Analogue on Patients with Chronic Hepatitis B-Associated Liver Failure: Meta-Analysis

Purpose

The effectiveness of nucleoside analogue on patients with chronic hepatitis B-associated liver failure is still controversial. To address this issue, we did a review of the literatures and analyzed the data with emphasis on the survival and reduction in serum HBV DNA level.

Methods

We searched 11 randomized controlled trials that included 654 patients with chronic hepatitis B-associated liver failure. 340 patients adopted nucleoside analogue, such as lamivudine (LAM), entecavir (ETV), telbivudine (LdT), or tenofovir disoproxil fumarate (TDF), and the remaining 314 patients adopted no nucleoside analogue or placebo. A meta-analysis was carried out to examine the survival, HBV e antigen serologic conversion, and reduction in serum HBV DNA level. The pooled odds ratio (OR) was used to reflect the treatment effects.

Results

The overall analysis revealed nucleoside analogue significantly improved 1-month(OR = 2.10; 95% CI, [1.29, 3.41]; p = 0.003), 3-month (OR = 2.15; 95% CI, [1.26, 3.65]; p = 0.005), 12-month survival (OR = 4.62; 95% CI, [1.96, 10.89]; p = 0.0005). Comparison of 3-month HBV DNA showed significant reduction for adoptive nucleoside analogue patients (OR = 54.47; 95% CI, [16.37, 201.74]; p<0.00001). Comparison of 3-month HBV e antigen serologic conversion showed a highly significant improvement of HBV e antigen lost for patients received adoptive antiviral therapy (OR = 6.57; 95% CI, [1.64, 26.31]; p = 0.008).

Conclusions

The benefits of nucleoside analogue on patients with chronic hepatitis B-associated liver failure is significant for improving patient survival, HBV e antigen serologic conversion, and rapid reduction of HBV DNA levels.     

Imported Amoebic Liver Abscess in France

Background

Worldwide, amoebic liver abscess (ALA) can be found in individuals in non-endemic areas, especially in foreign-born travelers.

Methods

We performed a retrospective analysis of ALA in patients admitted to French hospitals between 2002 and 2006. We compared imported ALA cases in European and foreign-born patients and assessed the factors associated with abscess size using a logistic regression model.

Results

We investigated 90 ALA cases. Patient median age was 41. The male:female ratio was 3.5∶1. We were able to determine the origin for 75 patients: 38 were European-born and 37 foreign-born. With respect to clinical characteristics, no significant difference was observed between European and foreign-born patients except a longer lag time between the return to France after traveling abroad and the onset of symptoms for foreign-born. Factors associated with an abscess size of more than 69 mm were being male (OR = 11.25, p<0.01), aged more than 41 years old (OR = 3.63, p = 0.02) and being an immigrant (OR = 11.56, p = 0.03). Percutaneous aspiration was not based on initial abscess size but was carried out significantly more often on patients who were admitted to surgical units (OR = 10, p<0.01). The median time to abscess disappearance for 24 ALA was 7.5 months.

Conclusions/Significance

In this study on imported ALA was one of the largest worldwide in terms of the number of cases included males, older patients and foreign-born patients presented with larger abscesses, suggesting that hormonal and immunological factors may be involved in ALA physiopathology. The long lag time before developing ALA after returning to a non-endemic area must be highlighted to clinicians so that they will consider Entamoeba histolytica as a possible pathogen of liver abscesses more often.     

Gene Expression Profiles Accurately Predict Outcome Following Liver Resection in Patients with Metastatic Colorectal Cancer

Purpose

The aim of this study was to build a molecular prognostic model based on gene signatures for patients with completely resected hepatic metastases from colorectal cancer (MCRC).

Methods

Using the Illumina HumanHT-12 gene chip, RNA samples from the liver metastases of 96 patients who underwent R0 liver resection were analyzed. Patients were randomly assigned to a training (n = 60) and test (n = 36) set. The genes associated with disease-specific survival (DSS) and liver-recurrence-free survival (LRFS) were identified by Cox-regression and selected to construct a molecular risk score (MRS) using the supervised principle component method on the training set. The MRS was then evaluated in the independent test set.

Results

Nineteen and 115 genes were selected to construct the MRS for DSS and LRFS, respectively. Each MRS was validated in the test set; 3-year DSS/LRFS rates were 42/32% and 79/80% for patients with high and low MRS, respectively (p = 0.007 for DSS and p = 0.046 for LRFS). In a multivariate model controlling for a previously validated clinical risk score (CRS), the MRS remained a significant predictor of DSS (p = 0.001) and LRFS (p = 0.03). When CRS and MRS were combined, the patients were discriminated better with 3-year DSS/LRFS rates of 90/89% in the low risk group (both risk scores low) vs 42/26% in the high risk group (both risk scores high), respectively (p = 0.002/0.004 for DSS/LRFS).

Conclusion

MRS based on gene expression profiling has high prognostic value and is independent of CRS. This finding provides a potential strategy for better risk-stratification of patients with liver MCRC.     

Viscoelastic Parameters for Quantifying Liver Fibrosis: Three-Dimensional Multifrequency MR Elastography Study on Thin Liver Rat Slices

Objective

To assess in a high-resolution model of thin liver rat slices which viscoelastic parameter at three-dimensional multifrequency MR elastography has the best diagnostic performance for quantifying liver fibrosis.

Materials and Methods

The study was approved by the ethics committee for animal care of our institution. Eight normal rats and 42 rats with carbon tetrachloride induced liver fibrosis were used in the study. The rats were sacrificed, their livers were resected and three-dimensional MR elastography of 5±2 mm liver slices was performed at 7T with mechanical frequencies of 500, 600 and 700 Hz. The complex shear, storage and loss moduli, and the coefficient of the frequency power law were calculated. At histopathology, fibrosis and inflammation were assessed with METAVIR score, fibrosis was further quantified with morphometry. The diagnostic value of the viscoelastic parameters for assessing fibrosis severity was evaluated with simple and multiple linear regressions, receiver operating characteristic analysis and Obuchowski measures.

Results

At simple regression, the shear, storage and loss moduli were associated with the severity of fibrosis. At multiple regression, the storage modulus at 600 Hz was the only parameter associated with fibrosis severity (r = 0.86, p<0.0001). This parameter had an Obuchowski measure of 0.89+/−0.03. This measure was significantly larger than that of the loss modulus (0.78+/−0.04, p = 0.028), but not than that of the complex shear modulus (0.88+/−0.03, p = 0.84).

Conclusion

Our high resolution, three-dimensional multifrequency MR elastography study of thin liver slices shows that the storage modulus is the viscoelastic parameter that has the best association with the severity of liver fibrosis. However, its diagnostic performance does not differ significantly from that of the complex shear modulus.     

Bioimpedance Identifies Body Fluid Loss after Exercise in the Heat: A Pilot Study with Body Cooling

Purpose

Assessment of post-exercise changes in hydration with bioimpedance (BI) is complicated by physiological adaptations that affect resistance (R) and reactance (Xc) values. This study investigated exercise-induced changes in R and Xc, independently and in bioelectrical impedance vector analysis, when factors such as increased skin temperature and blood flow and surface electrolyte accumulation are eliminated with a cold shower.

Methods

Healthy males (n = 14, 24.1±1.7 yr; height (H): 182.4±5.6 cm, body mass: 72.3±6.3 kg) exercised for 1 hr at a self-rated intensity (15 BORG) in an environmental chamber (33°C and 50% relative humidity), then had a cold shower (15 min). Before the run BI, body mass, hematocrit and Posm were measured. After the shower body mass was measured; BI measurements were performed continuously every 20 minutes until R reached a stable level, then hematocrit and Posm were measured again.

Results

Compared to pre-trial measurements body mass decreased after the run and Posm, Hct, R/H and Xc/H increased (p<0.05) with a corresponding lengthening of the impedance vector along the major axis of the tolerance ellipse (p<0.001). Changes in Posm were negatively related to changes in body mass (r = −0.564, p = 0.036) and changes in Xc/H (r = −0.577, p = 0.041).

Conclusions

Present findings showed that after a bout of exercise-induced dehydration followed by cold shower the impedance vector lengthened that indicates fluid loss. Additionally, BI values might be useful to evaluate fluid shifts between compartments as lower intracellular fluid loss (changed Xc/R) indicated greater Posm increase.     

Association of Eosinophilic Inflammation with FKBP51 Expression in Sputum Cells in Asthma

Background

Airway eosinophilia is a predictor of steroid responsiveness in steroid-naïve asthma. However, the relationship between airway eosinophilia and the expression of FK506-binding protein 51 (FKBP51), a glucocorticoid receptor co-chaperone that plays a role in steroid insensitivity in asthma, remains unknown.

Objective

To evaluate the relationship between eosinophilic inflammation and FKBP51 expression in sputum cells in asthma.

Methods

The FKBP51 mRNA levels in sputum cells from steroid-naïve patients with asthma (n = 31) and stable asthmatic patients on inhaled corticosteroid (ICS) (n = 28) were cross-sectionally examined using real-time PCR. Associations between FKBP51 levels and clinical indices were analyzed.

Results

In steroid-naïve patients, the FKBP51 levels were negatively correlated with eosinophil proportions in blood (r = −0.52) and sputum (r = −0.57), and exhaled nitric oxide levels (r = −0.42) (all p<0.05). No such associations were observed in patients on ICS. In steroid-naïve patients, improvement in forced expiratory volume in one second after ICS initiation was correlated with baseline eosinophil proportions in blood (r = 0.74) and sputum (r = 0.76) and negatively correlated with FKBP51 levels (r = −0.73) (all p<0.0001) (n = 20). Lastly, the FKBP51 levels were the lowest in steroid-naïve asthmatic patients, followed by mild to moderate persistent asthmatic patients on ICS, and the highest in severe persistent asthmatic patients on ICS (p<0.0001).

Conclusions

Lower FKBP51 expression in sputum cells may reflect eosinophilic inflammation and glucocorticoid responsiveness in steroid-naïve asthmatic patients.     

Unhealthy Alcohol Use,HIV Infection and Risk of Liver Fibrosis in Drug Users with Hepatitis C

Aim

To analyze alcohol use, clinical data and laboratory parameters that may affect FIB-4, an index for measuring liver fibrosis, in HCV-monoinfected and HCV/HIV-coinfected drug users.

Patients and Methods

Patients admitted for substance abuse treatment between 1994 and 2006 were studied. Socio-demographic data, alcohol and drug use characteristics and clinical variables were obtained through hospital records. Blood samples for biochemistry, liver function tests, CD4 cell count, and serology of HIV and HCV infection were collected at admission. Multivariate linear regression was used to analyze the predictors of FIB-4 increase.

Results

A total of 472 (83% M, 17% F) patients were eligible. The median age at admission was 31 years (Interquartile range (IQR) 27–35 years), and the median duration of drug use was 10 years (IQR 5.5–15 years). Unhealthy drinking (>50 grams/day) was reported in 32% of the patients. The FIB-4 scores were significantly greater in the HCV/HIV-coinfected patients (1.14, IQR 0.76–1.87) than in the HCV-monoinfected patients (0.75, IQR 0.56–1.11) (p<0.001). In the multivariate analysis, unhealthy drinking (p = 0.034), lower total cholesterol (p = 0.042), serum albumin (p<0.001), higher GGT (p<0.001) and a longer duration of addiction (p = 0.005) were independently associated with higher FIB-4 scores in the HCV-monoinfected drug users. The effect of unhealthy drinking on FIB-4 scores disappeared in the HCV/HIV-coinfected patients, whereas lower serum albumin (p<0.001), a lower CD4 cell count (p = 0.006), higher total bilirubin (p<0.001) and a longer drug addiction duration (p<0.001) were significantly associated with higher FIB-4 values.

Conclusions

Unhealthy alcohol use in the HCV-monoinfected patients and HIV-related immunodeficiency in the HCV/HIV-coinfected patients are important risk factors associated with liver fibrosis in the respective populations     

Plasma Levels of Soluble Urokinase-Type Plasminogen Activator Receptor Associate with the Clinical Severity of Acute Puumala Hantavirus Infection

Objectives

Urokinase-type plasminogen activator receptor is a multifunctional glycoprotein, the expression of which is increased during inflammation. It is known to bind to β₃-integrins, which are elementary for the cellular entry of hantaviruses. Plasma soluble form of the receptor (suPAR) levels were evaluated as a predictor of severe Puumala hantavirus (PUUV) infection and as a possible factor involved in the pathogenesis of the disease.

Design

A single-centre prospective cohort study.

Subjects and Methods

Plasma suPAR levels were measured twice during the acute phase and once during the convalescence in 97 patients with serologically confirmed acute PUUV infection using a commercial enzyme-linked immunosorbent assay (ELISA).

Results

The plasma suPAR levels were significantly higher during the acute phase compared to the control values after the hospitalization (median 8.7 ng/ml, range 4.0–18.2 ng/ml vs. median 4.7 ng/ml, range 2.4–12.2 ng/ml, P<0.001). The maximum suPAR levels correlated with several variables reflecting the severity of the disease. There was a positive correlation with maximum leukocyte count (r = 0.475, p<0.001), maximum plasma creatinine concentration (r = 0.378, p<0.001), change in weight during the hospitalization (r = 0.406, p<0.001) and the length of hospitalization (r = 0.325, p = 0.001), and an inverse correlation with minimum platelet count (r = −0.325, p = 0.001) and minimum hematocrit (r = −0.369, p<0.001).

Conclusion

Plasma suPAR values are markedly increased during acute PUUV infection and associate with the severity of the disease. The overexpression of suPAR possibly activates β₃-integrin in PUUV infection, and thus might be involved in the pathogenesis of the disease.     

Relationship between Optical Coherence Tomography and Electrophysiology of the Visual Pathway in Non-Optic Neuritis Eyes of Multiple Sclerosis Patients

Purpose

Loss of retinal ganglion cells in in non-optic neuritis eyes of Multiple Sclerosis patients (MS-NON) has recently been demonstrated. However, the pathological basis of this loss at present is not clear. Therefore, the aim of the current study was to investigate associations of clinical (high and low contrast visual acuity) and electrophysiological (electroretinogram and multifocal Visual Evoked Potentials) measures of the visual pathway with neuronal and axonal loss of RGC in order to better understand the nature of this loss.

Methods

Sixty-two patients with relapsing remitting multiple sclerosis with no previous history of optic neuritis in at least one eye were enrolled. All patients underwent a detailed ophthalmological examination in addition to low contrast visual acuity, Optical Coherence Tomography, full field electroretinogram (ERG) and multifocal visual evoked potentials (mfVEP).

Results

There was significant reduction of ganglion cell layer thickness, and total and temporal retinal nerve fibre layer (RNFL) thickness (p<0.0001, 0.002 and 0.0002 respectively). Multifocal VEP also demonstrated significant amplitude reduction and latency delay (p<0.0001 for both). Ganglion cell layer thickness, total and temporal RNFL thickness inversely correlated with mfVEP latency (r = −0.48, p<0.0001 respectively; r = −0.53, p<0.0001 and r = −0.59, p<0.0001 respectively). Ganglion cell layer thickness, total and temporal RNFL thickness also inversely correlated with the photopic b-wave latency (r = −0.35, p = 0.01; r = −0.33, p = 0.025; r = −0.36, p = 0.008 respectively). Multivariate linear regression model demonstrated that while both factors were significantly associated with RGC axonal and neuronal loss, the estimated predictive power of the posterior visual pathway damage was considerably larger compare to retinal dysfunction.

Conclusion

The results of our study demonstrated significant association of RGC axonal and neuronal loss in NON-eyes of MS patients with both retinal dysfunction and post-chiasmal damage of the visual pathway.     

Predictive Factors for Reintubation following Noninvasive Ventilation in Patients with Respiratory Complications after Living Donor Liver Transplantation

Background

Postoperative respiratory complications are a major cause of mortality following liver transplantation (LT). Noninvasive ventilation (NIV) appears to be effective for respiratory complications in patients undergoing solid organ transplantation; however, mortality has been high in patients who experienced reintubation in spite of NIV therapy. The predictors of reintubation following NIV therapy after LT are not exactly known.

Methods

Of 511 adult patients who received living-donor LT, data on the 179 who were treated by NIV were retrospectively examined.

Results

Forty-three (24%) of the 179 patients who received NIV treatment required reintubation. Independent factors associated with reintubation by multivariate logistic regression analysis were controlled preoperative infections (odds ratio [OR] 8.88; 95% confidence interval (CI) 1.64 to 48.11; p = 0.01), ABO-incompatibility (OR 4.49; 95% CI, 1.50 to 13.38; p = 0.007), and presence of postoperative pneumonia at the time of starting NIV (OR 3.28; 95% CI, 1.02 to 11.01; p = 0.04). The reintubated patients had a significant higher rate of postoperative infectious complications and a significantly longer intensive care unit stay than those in whom NIV was successful (p<0.0001). Of the 43 reintubated patients, 22 (51.2%) died during hospitalization following LT vs. 8 (5.9%) of the 136 patients in whom NIV was successful (p<0.0001).

Conclusions

Because controlled preoperative infection, ABO-incompatibility or pneumonia prior to the start of NIV were independent risk factors for reintubation following NIV, caution should be used in applying NIV in patients with these conditions considering the high rate of mortality in patients requiring reintubation following NIV.     

Insulin-Like Growth Factor 1 Receptor (IGF1R) Expression and Survival in Operable Squamous-Cell Laryngeal Cancer

Introduction

Prognosis of patients with operable laryngeal cancer is highly variable and therefore potent prognostic biomarkers are warranted. The insulin-like growth factor receptor (IGFR) signaling pathway plays a critical role in laryngeal carcinogenesis and progression.

Patients and Methods

We identified all patients with localized TNM stage I–III laryngeal cancer managed with potentially curative surgery between 1985 and 2008. Immunohistochemical (IHC) expression of IGF1R-alpha, IGF1R-beta and IGF2R was evaluated using the immunoreactive score (IRS) and mRNA levels of important effectors of the IGFR pathway were assessed, including IGF1R, IGF-binding protein 3 (IGFBP3), suppressor of cytokine signaling 2 (SOCS2) and members of the MAP-kinase (MAP2K1, MAPK9) and phosphatidyl-inositol-3 kinase (PIK3CA, PIK3R1) families. Cox-regression models were applied to assess the predictive value of biomarkers on disease-free survival (DFS) and overall survival (OS).

Results

Among 289 eligible patients, 95.2% were current or ex smokers, 75.4% were alcohol abusers, 15.6% had node-positive disease and 32.2% had received post-operative irradiation. After a median follow-up of 74.5 months, median DFS was 94.5 months and median OS was 106.3 months. Using the median IRS as the pre-defined cut-off, patients whose tumors had increased IGF1R-alpha cytoplasm or membrane expression experienced marginally shorter DFS and significantly shorter OS compared to those whose tumors had low IGF1R-alpha expression (91.1 vs 106.2 months, p = 0.0538 and 100.3 vs 118.6 months, p = 0.0157, respectively). Increased mRNA levels of MAPK9 were associated with prolonged DFS (p = 0.0655) and OS (p = 0.0344). In multivariate analysis, IGF1R-alpha overexpression was associated with a 46.6% increase in the probability for relapse (p = 0.0374). Independent predictors for poor OS included node-positive disease (HR = 2.569, p<0.0001), subglottic/transglottic localization (HR = 1.756, p = 0.0438) and IGF1R-alpha protein overexpression (HR = 1.475, p = 0.0504).

Conclusion

IGF1R-alpha protein overexpression may serve as an independent predictor of relapse and survival in operable laryngeal cancer. Prospective evaluation of the IGF1R-alpha prognostic utility is warranted.     

Laparoscopic versus Open Hepatectomy with or without Synchronous Colectomy for Colorectal Liver Metastasis: A Meta-Analysis

Background

To compare short-term and long-term results of colorectal patients undergoing laparoscopic and open hepatectomy. Moreover, outcomes of laparoscopic versus open procedures for simultaneous primary colorectal tumor and liver metastasis resection were compared.

Methods

A systematic search was conducted in the PubMed and EmBase databases (until Oct. 22. 2013) with no limits. Bibliographic citation management software (EndNote X6) was used for extracted literature management. Quality assessment was performed according to a modification of the Newcastle-Ottawa Scale. The data were analyzed using Review Manager (Version 5.1), and sensitivity analysis was performed by sequentially omitting each study.

Results

Finally, 14 studies, including a total of 975 CLM (colorectal liver metastasis) patients, compared laparoscopic with open hepatectomy. 3 studies of them, including a total of 107 CLM patients, compared laparoscopic with open procedures for synchronous hepatectomy and colectomy. Laparoscopic hepatectomy was associated with a significantly less blood loss, shorter hospitalization time, and less operative transfusion rate. In addition, lower hospital morbidity rate (OR = 0.57, 95%CI:0.42–0.78, P = 0.0005) and better R0 resection (OR = 2.44, 95%CI:1.21–4.94, P = 0.01) were observed in laparoscopic hepatectomy. For long-term outcomes, there were no significant differences between two surgical procedures on recurrence and overall survival. In comparison of synchronous hepatectomy and colectomy, laparoscopic procedure displayed shorter hospitalization (MD = −3.40, 95%CI:−4.37–2.44, P<0.00001) than open procedure. Other outcomes, including surgical time, estimated blood loss, hospital morbidity, and overall survival did not differ significantly in the comparison.

Conclusions

Laparoscopic hepatectomy with or without synchronous colectomy are acceptable for selective CLM patients. We suggest standard inclusion criteria of CLM patients be formulated.     

Management of Deep Brain Stimulator Battery Failure: Battery Estimators,Charge Density,and Importance of Clinical Symptoms

Objective

We aimed in this investigation to study deep brain stimulation (DBS) battery drain with special attention directed toward patient symptoms prior to and following battery replacement.

Background

Previously our group developed web-based calculators and smart phone applications to estimate DBS battery life (http://mdc.mbi.ufl.edu/surgery/dbs-battery-estimator).

Methods

A cohort of 320 patients undergoing DBS battery replacement from 2002–2012 were included in an IRB approved study. Statistical analysis was performed using SPSS 20.0 (IBM, Armonk, NY).

Results

The mean charge density for treatment of Parkinson’s disease was 7.2 µC/cm²/phase (SD = 3.82), for dystonia was 17.5 µC/cm²/phase (SD = 8.53), for essential tremor was 8.3 µC/cm²/phase (SD = 4.85), and for OCD was 18.0 µC/cm²/phase (SD = 4.35). There was a significant relationship between charge density and battery life (r = −.59, p<.001), as well as total power and battery life (r = −.64, p<.001). The UF estimator (r = .67, p<.001) and the Medtronic helpline (r = .74, p<.001) predictions of battery life were significantly positively associated with actual battery life. Battery status indicators on Soletra and Kinetra were poor predictors of battery life. In 38 cases, the symptoms improved following a battery change, suggesting that the neurostimulator was likely responsible for symptom worsening. For these cases, both the UF estimator and the Medtronic helpline were significantly correlated with battery life (r = .65 and r = .70, respectively, both p<.001).

Conclusions

Battery estimations, charge density, total power and clinical symptoms were important factors. The observation of clinical worsening that was rescued following neurostimulator replacement reinforces the notion that changes in clinical symptoms can be associated with battery drain.