Cholesterol ester and triglyceride metabolism in intact fibroblasts from patients with Wolman's disease and cholesterol ester storage disease

Cholesterol ester and triglyceride metabolism was examined in intact fibroblast monolayers from normal individuals and patients with Wolman's disease and cholesterol ester storage disease. Cholesterol esters were introduced into cells by incubation in medium containing [3H]cholesteryl linoleate (CL) bound to human low density lipoprotein. Triglycerides were introduced by incubation with glycerol tri[1-14C]oleate (triolein) bound to human very low-density lipoprotein. Both types of mutant cell lines accumulated the unhydrolyzed substrates to a greater extent than did normal cells with the greatest accumulation observed in Wolman's disease cells. Wolman's disease cells hydrolyzed CL at 10-22% and triolein at 11-19% the rate of normal cells; cholesterol ester storage disease cells hydrolyzed these substrates at 28-49 and 30-47% the normal rate, respectively. In contrast, assays of acid lipase activity in cell lysates revealed less than 1% of control activity in both disorders. The data suggest that the mutant acid lipase present in Wolman's disease and cholesterol ester storage disease is more active in the intact cell than assays of cell lysates would indicate. In addition, the differences observed between the two disorders provide a biochemical explanation for the different phenotypes associated with the two disorders.     

Acute Appendicitis During Pregnancy: Different from the Nonpregnant State?

Background

Acute appendicitis is the most common nonobstetric indication for surgical intervention during pregnancy. However, the current literature is scarce and composed of relatively small case series. We aimed to compare the presentation, management, and surgical outcomes of presumed acute appendicitis between a contemporary cohort of pregnant women and nonpregnant women of reproductive age.

Methods

The study group included 92 pregnant patients who underwent appendectomy for presumed acute appendicitis at a single tertiary medical center in 2000–2014. Preoperative, operative, and postoperative clinical data were derived from medical records and compared to data for 494 nonpregnant patients of reproductive age who underwent appendectomy in 2004–2007 at the same institution.

Results

Median age was 28 years (range 25–33) in the study group and 26 years (range 20–34) in the control group (P = 0.1). There were no between-group differences in mean white blood cell count, patient interval, hospital interval, or operative time. Preoperative abdominal ultrasound was used in a significantly higher proportion of patients in the pregnant group than in the nonpregnant group (73 and 27 %, respectively, P < 0.001) and computed tomography, in a significantly lower proportion of patients (1 vs. 16 %, respectively, P < 0.001) . The two groups had similar rates of negative appendectomy (23 and 22 %, P = 0.9), complicated appendicitis (12 and 11 %, P = 0.9), and overall postoperative complications (15 and 12 %, P = 0.3).

Conclusions

The clinical presentation and outcome of presumed acute appendicitis are similar in pregnant women and nonpregnant women of reproductive age. Therefore, similar perioperative management algorithms may be applied in both patient populations.

     

Prognostic relevance of immunohistochemical subclassification of diffuse large B-cell lymphoma in two prospective phase III clinical trials

Purpose:Until now molecular biologic techniques have not been easily used in daily clinical practice to stratify patients for therapeutic purposes. Therefore, we have investigated the prognostic relevance of the immunohistochemical (IHC) germinal center B-cell (GCB) versus non-GCB diffuse large B-cell lymphoma (DLBCL) subtypes.Patients and Methods:We have analyzed tumor samples from patients treated in 2 prospective multicenter phase III trials, ie HOVON 25 (patients ≥ 65 years, n = 153) and HOVON 26 (patients < 65 years, n = 144) using whole sections (WS) or tissue microarray (TMA). CD10, BCL6, and MUM1 were applied in a specific IHC algorithm. The effect on clinical outcome using WS or TMA and variations in cut-off levels of these markers was also investigated.Results:The GCB subtype was not associated with a better OS in either trial. Small differences were observed in the HOVON 25 trial between techniques, with TMA showing a better outcome for GCB than did WS. Variation of cut-off levels in the specific algorithm did not improve the prediction of clinical outcome.Conclusion:We did not observe a consistent predictive power of the GCB and non-GCB classification by IHC in this large series of DLBCL patients treated with CHOP. This underscores the need to determine the biologic variation and the standardization of the protein expression levels and to further study the relevance of prognostic IHC classifications, preferably in phase III clinical trials.     

Aircraft disinsection

Aircraft disinsection has been an international practice since the 1920s, the purpose of which is to protect public health, the environment, agriculture, and livestock by the eradication of disease vectors. Although most nations of the world have discontinued this practice, about 20 continue with this requirement. Aircraft disinsection is sanctioned by international law with the World Health Organization (WHO) publishing general procedural guidelines in the International Health Regulations (IHR). There are currently four acceptable procedures: blocks away, top of descent, on arrival, and residual. A 2% pyrethrum solution, a naturally occurring substance found in the chrysanthemum flower, or several synthetic pyrethroids, are the recommended agents because they are extremely effective insecticides which pose minimal health risks. Although the use of insecticides for aircraft disinsection is controversial, national policies compelling this requirement must be respected. This paper will explore the background of aircraft disinsection, the procedures, the types of agents, and the toxicity. If aircraft disinsection is regulatory policy, it should be done in accordance with WHO procedures. Residual application is probably the most efficacious method. The use of air curtains or plastic strips should be explored as an alternative to the use of chemicals.     

Combination of sunitinib with anti‐tumor vaccination inhibits T cell priming and requires careful scheduling to achieve productive immunotherapy

Sunitinib, a protein tyrosine kinase inhibitor is the frontline therapy for renal and gastrointestinal cancers. We hypothesized that by virtue of its well documented tumor apoptosis and immune adjuvant properties, combination of Sunitinib with anti‐tumor immunotherapeutics will provide synergistic inhibition of tumor growth. Our study was designed to evaluate the impact of Sunitinib on immunotherapy mediated anti‐tumor immune responses and evaluate its efficacy as a combinatorial therapy with tumor targeted immunotherapeutic vaccination. Mice immunized with recombinant α‐lactalbumin, a lactation protein expressed on majority of breast tumors were treated with 1 mg of Sunitinib for seven consecutive days beginning (1) concurrently, on the day of α‐lactalbumin immunization or (2) sequentially, on day 9 after immunization. Ten‐day lymph nodes or 21 day spleens were tested by ELISPOT assays and flow cytometry to evaluate responsiveness to α‐lactalbumin immunization in presence of Sunitinib and distribution of cells involved in T cell antigen priming and proliferation in different lymphoid compartments. In addition, therapeutic efficacy of the α‐lactalbumin/ Sunitinib combination was evaluated by monitoring tumor growth in the 4T1 transplanted tumor model. Our studies reveal that concurrent administration of Sunitinib with active vaccination against a targeted tumor antigen inhibits priming to the immunogen due to a drastic decrease in CD11b+CD11c+ antigen presenting cells, leading to failure of vaccination. However, sequential delivery of Sunitinib timed to avoid the priming phase of vaccination results in the desired vaccination mediated boost in immune responses.