Regulated expression of the IL-31 receptor in bronchial and alveolar epithelial cells, pulmonary fibroblasts, and pulmonary macrophages.

Interleukin-31 (IL-31), an IL-6 cytokine family member, is proposed to play a role in animal models of airway hyperreactivity. It is produced by activated T cells and signals via a heterodimeric receptor complex composed of IL-31Ralpha and OSMRbeta. Only low levels of IL-31Ralpha expression have been demonstrated in pulmonary epithelial cell lines, however, and little is known about the ability to regulate its expression and signaling. Therefore, primary cultures of human bronchial and alveolar epithelial cells, pulmonary fibroblasts, pulmonary macrophages, and established lines of immortalized bronchial epithelial cells (HBE) and alveolar carcinoma cells (A549) were analyzed by RT-PCR, immunoblotting, and thymidine incorporation. Distinct, cell type-specific regulation of IL-31Ralpha expression was detected. Transforming growth factor-beta (TGF-beta) enhanced IL-31Ralpha mRNA expression in primary cultures and established lines of epithelial cells, but not in macrophages. In contrast, interferon-gamma (IFN-gamma) induced IL-31Ralpha mRNA expression in macrophages. IL-31Ralpha protein expression was below detection threshold in primary epithelial cell cultures but was detectable in A549 cells and increased with TGF-beta treatment. In HBE and A549 cells, TGF-beta pretreatment increased IL-31-mediated Stat3 and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. In A549 cells, TGF-beta magnified IL-31-dependent suppression of proliferation. The data suggest that increased IL-31Ralpha expression correlates with an enhanced response to IL-31.     

A prospective study of serum pseudocholinesterase levels in patients with chronic spinal pain: a preliminary study

STUDY DESIGN: One-dimensional polyacrylamide gel electrophoresis was used to study serum esterase enzymatic activity in three groups of patients and one group of normal volunteers. OBJECTIVES: To determine whether there is a statistically significant correlation between variations of serum pseudocholinesterase and the perception of pain in patients with chronic spinal pain. SUMMARY OF BACKGROUND DATA: Changes in levels of cholinesterase in the extracellular space of the brain and in the cerebral spinal fluid have been found to be associated in animal pain experimentation. METHODS: Ninety-three surgical patients with chronic spinal pain, six surgical control subjects operated for conditions not associated with pain, 21 normal control volunteers, and nine disabled patients receiving monetary benefits were studied. The patients were analyzed for a period of time by rating the perception of their pain with a visual assessment score at the time venous blood was drawn. Serum samples were prepared, serum pseudocholinesterase was monitored, separated, and quantified according to Allen et al.5 Paired sample t tests were used to statistically evaluate the data. RESULTS: A trend of correlation was noted between preoperative serum pseudocholinesterase levels and visual assessment score: serum pseudocholinesterase levels increased as visual assessment score increased. The mean preoperative serum pseudocholinesterase level of chronic spinal pain patients (1313; SE = 26), which was significantly higher than the mean levels of the normal control volunteers (941; SE = 24; P<0.001) and that of surgical control subjects (1018; SE = 63; P <0.01), decreased significantly with anesthesia (P<0.005). The mean preoperative serum pseudocholinesterase level of the surgical controls, however, remained unchanged with anesthesia. A correlation demonstrated between visual assessment score and serum pseudocholinesterase in chronic spinal pain patients was not observed in six of nine patients receiving disability payments for more than a year. CONCLUSIONS: Measurements of quantitative alterations of serum pseudocholinesterase levels may be useful in the treatment of patients with chronic spinal pain.     

Advances in pharmacotherapy for primary biliary cirrhosis

Introduction: Primary biliary cirrhosis (PBC) is a chronic autoimmune liver disease mostly seen in middle-aged women characterized by progressive nonsuppurative destruction of small bile ducts resulting in intrahepatic cholestasis, parenchymal injury and ultimately end-stage liver disease. Despite major breakthroughs in our understanding of PBC, there remains only one FDA-approved agent for treatment: ursodeoxycholic acid (UDCA) to which one-third of patients are unresponsive.

Areas covered: Biochemical response to treatment with UDCA is associated with excellent survival rates in PBC patients. However, there is a need for alternative treatments for nonresponders. Results from human epidemiological and genetic studies as well as preclinical studies in PBC animal models have provided a strong impetus for the development of new therapeutic agents. In this review, we discuss the recent advances in translational research in PBC focusing on promising therapeutic approaches, namely immune-based targeted therapies and agents targeting the synthesis and circulation of bile acids.

Expert opinion: We are in a new era for the development of novel therapies for PBC. Data on fibrates, budesonide and obeticholic acid offer encouragement for nonresponders to UDCA.     

Effect of constant light on rhythmic gastric functions in fasting rats

The effects of four weeks of continuous illumination (LL), a subacute stress, on gastric mucosal endogenous aggressive and defensive factors were studied. Young male Sprague-Dawley rats were used with two different illumination regimens: LL and 12 hr light/12 hr dark (LD). At the end of three to four weeks of either regimen of illumination, gastric acid secretion, pepsin secretion, mucus secretion, and potential difference (PD) were studied. All gastric parameters, except mucus secretion, were significantly reduced by LL. The reduction in acid secretion (13.3%) was not significant after Bonferroni correction for the fourt tests Pepsin secretion and PD were 27.9% and 24.6% less, respectively. These differences were significant after Bonferroni correction. The LD rats showed significant circadian rhythms for acid, mucus, and pepsin secretion. The LL rats showed significant rhythmicity for these same parameters with period lengths different from 24 hr. Gross inspection of the gastric mucosa indicated that 69.8% of the LL rats had lesion scores of 1.0 or higher, while none of the LD rats had scores above 0.5.The authors acknowledge the Salt Lake Veterans Administration Medical Center, Department of Research, for support of this study.     

Effect of chelation therapy on endothelial function in patients with coronary artery disease: PATCH substudy

OBJECTIVES: The purpose of this study was to evaluate the effect of chelation therapy with ethylenediamine tetraacetic acid (EDTA) on endothelium-dependent vasomotor responses in patients with documented coronary artery disease (CAD). BACKGROUND: Oxidative stress plays an important role in the dysfunction of endothelium and development of atherosclerosis. Modification of cardiac risk factors and employment of antioxidants have been shown to improve endothelial function. Ethylenediamine tetraacetic acid chelation therapy is considered to be a complementary therapy for patients with CAD and is proposed to have antioxidant properties. METHODS: A total of 47 patients enrolled in the Program to Assess Alternative Treatment Strategies to Achieve Cardiac Health (PATCH) participated in this substudy and had complete data. High-resolution ultrasound was used to assess endothelium-dependent brachial artery flow-mediated vasodilation (FMD) in patients with CAD in a randomized, double-blind, and placebo-controlled fashion. Patients were randomized to chelation therapy or placebo. The primary end point was the absolute difference in FMD after the first and 33rd treatments (6 months) of study groups compared with their baselines. RESULTS: At the baseline, the study population had mild impairment of FMD (7.2 +/- 3.4%). The first chelation treatment did not change FMD as compared with placebo (chelation 6.5 +/- 3.5% vs. placebo 7.4 +/- 2.9%; p value = 0.371). The brachial artery studies at six months did not demonstrate significant differences in FMD between study groups (placebo 7.3 +/- 3.4% vs. chelation 7.3 +/- 3.2%; p value = 0.961). CONCLUSIONS: Our results suggest that EDTA chelation therapy in combination with vitamins and minerals does not provide additional benefits on abnormal vasomotor responses in patients with CAD optimally treated with proven therapies for atherosclerotic risk factors.     

Grandmothers raising grandchildren: family structure and well-being in culturally diverse families

PURPOSE: This study addressed well-being of grandmothers raising grandchildren in coparenting and custodial households in a sample of African American, Latino, and White grandmothers. DESIGN AND METHODS: A sample of 1,058 grandmothers was recruited through the schools and media. Grandmothers raising or helping to raise school-aged grandchildren in Los Angeles were interviewed, and analyses were conducted within ethnic groups. RESULTS: African American grandmothers experienced equal well-being in coparenting and custodial families; however, if the stresses related to the parents' problems were removed by statistical control, they favored the custodial arrangement. Latino grandmothers had greater well-being in coparenting families, reflecting a tradition of intergenerational living. White custodial grandmothers experienced somewhat higher levels of affect (positive and negative) but showed no difference in other types of well-being. IMPLICATIONS: The cultural lens through which grandparenthood is viewed has a marked impact on the adaptation to custodial or coparenting family structures.     

Perioperative Outcomes Following Surgical Resection of Renal Cell Carcinoma with Inferior Vena Cava Thrombus Extending Above the Hepatic Veins: A Contemporary Multicenter Experience

Background

Surgery for renal cell carcinoma (RCC) patients with inferior vena cava (IVC) thrombus above the hepatic veins is technically complex and associated with an increased risk of perioperative morbidity and mortality. However, minimal data exist that describe contemporary perioperative outcomes at major referral centers or the prognostic factors associated with poor outcomes.

Objective

To determine the preoperative predictors of major complications and 90-d mortality after surgery in RCC patients who have IVC thrombus above the hepatic veins.

Design, setting, and participants

We reviewed medical records of all RCC patients who had IVC tumor thrombus above hepatic veins and had had surgery between January 2000 and December 2012 at the Mayo Clinic, M.D. Anderson Cancer Center, University of Texas Southwestern Medical Center, and the University of Wisconsin Hospital.

Outcome measurement and statistical analysis

Major complications recorded were defined as ≥3A according to the Clavien-Dindo system within 90 d of surgery. Univariate and multivariate analyses were used to evaluate associations of preoperative variables with risk of major complications or 90-d mortality.

Results and limitations

A total of 162 patients were identified for study (level 3, 4 in 69, 93 patients, respectively, according to the Neves classification). Cardiopulmonary bypass was used in 60 of 162 patients (37.5%), and 40 patients (24.7%) had preoperative angioembolization. Major complications were reported in 55 patients (34.0%), with the most common being respiratory, cardiac, and hematologic issues. After multivariate analysis, preoperative systemic symptoms and level 4 thrombus were independently associated with increased risk of major complications. Mortality was reported in 17 patients (10.5%) within 90 d after surgery. After multivariate analysis, Eastern Cooperative Oncology Group (ECOG) performance status (PS) and low serum albumin were preoperative factors independently associated with increased risk of 90-d mortality.

Conclusions

Contemporary perioperative mortality and major complication rates for RCC patients who have upper-level thrombus are 10% and 34%, respectively. Patients who have ECOG PS >1 or low serum albumin have increased risk for perioperative mortality.     

Identification of insulin-like growth factor binding protein-3 as a farnesyl transferase inhibitor SCH66336-induced negative regulator of angiogenesis in head and neck squamous cell carcinoma.

The farnesyl transferase inhibitor (FTI) SCH66336 has been shown to have antitumor activities in head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo. However, its mechanism of action has not been well defined. Here, we report that the insulin-like growth factor (IGF) binding protein (IGFBP)-3 mediates antitumor activities of SCH66336 in HNSCC by inhibiting angiogenesis. SCH66336 significantly suppressed HNSCC tumor growth and angiogenesis via mechanisms that are independent of H-Ras and RhoB. By inducing IGFBP-3 secretion from HNSCC cells, this compound suppresses angiogenic activities of endothelial cells, including vessel formation in chorioallantoic membranes of chick, endothelial cell sprouting from chick aorta, and capillary tube formation of human umbilical vascular endothelial cells (HUVEC). Knockdown of IGFBP-3 expression in HNSCC cells by RNA interference or depletion of IGFBP-3 in HUVECs by neutralizing antibody effectively blocked the effects of IGFBP-3 secreted from SCH66336-treated HNSCC cells on HUVECs. These findings suggest that IGFBP-3 could be a primary target for antitumor activities of FTIs and that IGFBP-3 is an effective therapeutic approach against angiogenesis in HNSCC.