Anthropometric and Clinical Factors Associated with Mortality in Subjects with Nonalcoholic Fatty Liver Disease

Aim

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and may be associated with increased mortality. Our aim was to determine whether anthropometric measures are independently associated with mortality in NAFLD.

Methods

The third National Health and Nutrition Examination Surveys (1988–1994) data was used. Extensive radiologic, serologic and clinical data were available. NAFLD was defined as moderate-to-severe hepatic steatosis on the hepatic ultrasound in the absence of any cause of chronic liver disease (e.g. hepatitis C virus RNA negative, hepatitis B-surface antigen negative, normal transferrin saturation and alcohol consumption <20 gram/day). Anthropometric measures [body mass index (kg/m²), waist, hip, arm, and thigh circumferences (cm), waist-to-hip ratio, percentage of body fat, and sum of skinfolds (mm)], laboratory measures and clinico-demographic data were analyzed. Statistical analyses were conducted with SUDAAN 10.0.

Results

A total of 10,565 adult participants were included [2,510 (weighted 21 %) with NAFLD and 8,055 non-NAFLD controls]. In multivariate analysis, NAFLD was independently associated with being Mexican-American (including Hispanic or other ethnicity), larger waist circumference (cm), type-2 diabetes, insulin resistance and hypertension. After about 14 years (median) of follow up, liver-specific mortality was independently associated with NAFLD and being White.

Conclusions

Components of metabolic syndrome, and Mexican-American ethnicity are independently associated with NAFLD. Furthermore, NAFLD is an independent predictors of liver-specific mortality in men and Whites.     

On translation of antibody drug conjugates efficacy from mouse experimental tumors to the clinic: a PK/PD approach

Objectives of the present investigation were: (1) to compare three literature reported tumor growth inhibition (TGI) pharmacodynamic (PD) models and propose an optimal new model that best describes the xenograft TGI data for antibody drug conjugates (ADC), (2) to translate efficacy of the ADC Trastuzumab-emtansine (T-DM1) from mice to patients using the optimized PD model, and (3) to apply the translational strategy to predict clinically efficacious concentrations of a novel in-house anti-5T4 ADC, A1mcMMAF. First, the performance of all four of the PD models (i.e. 3 literature reported + 1 proposed) was evaluated using TGI data of T-DM1 obtained from four different xenografts. Based on the estimates of the pharmacodynamic/pharmacokinetic (PK/PD) modeling, a secondary parameter representing the efficacy index of the drug was calculated, which is termed as the tumor static concentration (TSC). TSC values derived from all four of the models were compared with each other, and with literature reported values, to assess the performance of these models. Subsequently, using the optimized PK/PD model, PD parameters obtained from different cell lines, human PK, and the proposed translational strategy, clinically efficacious doses of T-DM1 were projected. The accuracy of projected efficacious dose range for T-DM1 was verified by comparison with the clinical doses. Aforementioned strategy was then applied to A1mcMMAF for projecting its efficacious concentrations in clinic. TSC values for A1mcMMAF, obtained by fitting TGI data from 4 different xenografts with the proposed PK/PD model, were estimated to range from 0.6 to 11.5 μg mL^?1. Accordingly, the clinically efficacious doses for A1mcMMAF were projected retrospectively. All in all, the improved PD model and proposed translational strategy presented here suggest that appropriate correction for the clinical exposure and employing the TSC criterion can help translate mouse TGI data to predict first in human doses of ADCs.     

Non-purulent low-grade infection as cause of pain following shoulder surgery: preliminary results

Low-grade infection was systematically searched for in all revision shoulder surgeries by harvesting tissue samples. Ten consecutive patients were identified with a non-purulent low-grade infection of the shoulder. All of these patients suffered from pain and eight were stiff. Preoperative aspiration in eight patients yielded bacterial growth in only one case. Serum C-reactive protein levels were normal in seven out of 10 cases. Propionibacterium acnes was identified in seven, coagulase-negative Staphylococcus in two and Staphylococcus saccharolyticus in one case. The delay between harvesting the tissue samples and detection of bacterial growth averaged eight days (range, 2–17). After debridement and antibiotic treatment for a mean of 4.5 months, tissue samples were repeatedly harvested in nine patients due to persistent pain. The infection was microbiologically eradicated in six out of nine cases that had a repeated biopsy. However, nine out of 10 patients continued to suffer from moderate to severe pain. Low-grade infection of the shoulder can be a cause of persistent pain and stiffness. The results of antibiotic treatment are disappointing. Further studies are necessary to analyse this difficult pathology.     

Tumor immune escape by the loss of homeostatic chemokine expression

The novel keratinocyte-specific chemokine CCL27 plays a critical role in the organization of skin-associated immune responses by regulating T cell homing under homeostatic and inflammatory conditions. Here we demonstrate that human keratinocyte-derived skin tumors may evade T cell-mediated antitumor immune responses by down-regulating the expression of CCL27 through the activation of epidermal growth factor receptor (EGFR)-Ras-MAPK-signaling pathways. Compared with healthy skin, CCL27 mRNA and protein expression was progressively lost in transformed keratinocytes of actinic keratoses and basal and squamous cell carcinomas. In vivo, precancerous skin lesions as well as cutaneous carcinomas showed significantly elevated levels of phosphorylated ERK compared with normal skin, suggesting the activation of EGFR-Ras signaling pathways in keratinocyte-derived malignancies. In vitro, exogenous stimulation of the EGFR-Ras signaling pathway through EGF or transfection of the dominant-active form of the Ras oncogene (H-RasV12) suppressed whereas an EGFR tyrosine kinase inhibitor increased CCL27 mRNA and protein production in keratinocytes. In mice, neutralization of CCL27 led to decreased leukocyte recruitment to cutaneous tumor sites and significantly enhanced primary tumor growth. Collectively, our data identify a mechanism of skin tumors to evade host antitumor immune responses.     

Tracheoscopy assisted repair of tracheo-esophageal fistula (TARTEF): a 10-year experience

BACKGROUND: Fiberoptic tracheoscopy assisted repair of tracheoesophageal fistula (TARTEF) has been reported to be useful for the surgeon with regards to identification of the fistula and proper fistula ligation. The aim of this article is to report our 10-year experience using TARTEF with intermittent positive pressure ventilation (IPPV) during tracheoesophageal fistula (TEF) repair in newborns. METHODS: With ethical committee approval, we included all patients undergoing TARTEF from 1995-2005. Variables of interest were (1) respiratory deterioration caused by gastric inflation because of IPPV during surgery and endoscopy; (2) detection of additional airway anomalies; (3) success of intubation of the fistula; (4) other side effects or adverse events. Data are given in median and range. RESULTS: Forty-seven neonates with TARTEF were included. Mean gestational age was 37 weeks (31-42) and mean weight was 2.5 kg (1.1-3.8). The patients were intubated with tracheal tubes size 2.5-3.5 mm ID. Appropriately sized fiberoptic bronchoscopes with an outer diameter of 2.0, 2.4 and 2.8 mm were used; passed through the lumen of the tracheal tube (TT) thereby requiring the use of IPPV to ensure adequate ventilation. No respiratory deterioration was noted as a consequence of intraoperative fiberoptic manipulation within the trachea or because of gastric hyperinflation with IPPV. In all patients, the TEF was successfully penetrated with the fiberscope and this clearly helped the surgeon to rapidly identify and dissect the fistula. In two patients a tracheal bronchus was identified. In two patients accidental extubation occurred during endoscopic confirmation of successful fistula repair. CONCLUSIONS: While fiberoptic TARTEF through the tracheal tube with IPPV did expedite and facilitate surgery, it did not cause clinically relevant impairment of ventilation. Careful manipulation during fiberoptic assessment is required to avoid tube displacement.     

Case report: radiofrequency ablation-induced renal-pelvic obstruction resulting in nephrectomy

Radiofrequency ablation (RFA) has emerged as a minimally invasive nephron-sparing treatment for small (<4-cm) renal tumors. Post-RFA complications have been reported. We describe a patient who developed complete renal-pelvic obstruction after RFA. To our knowledge, this is the first such case to be reported and the second reported renal-unit loss as the result of collecting-system obstruction after RFA.