Clinical Outcomes in Critically Ill Patients Associated With the Use of Complex vs Weight‐Only Predictive Energy Equations

Background: The energy intake goal is important to achieving energy intake in critically ill patients, yet clinical outcomes associated with energy goals have not been reported. Methods: This secondary analysis used the Improving Nutrition Practices in the Critically III International Nutrition Surveys database from 2007–2009 to evaluate whether mortality or time to discharge alive is related to use of complex energy prediction equations vs weight only. The sample size was 5672 patients in the intensive care unit (ICU) ≥4 days and a subset of 3356 in the ICU ≥12 days. Mortality and time to discharge alive were compared between groups by regression, controlling for age, sex, admission type, Acute Physiology and Chronic Health Evaluation II score, ICU geographic region, actual energy intake, and obesity. Results: There was no difference in mortality between the use of complex and weight‐only equations (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.86–1.15), but obesity (OR, 0.83; 95% CI, 0.71–0.96) and higher energy intake (OR, 0.65; 95% CI, 0.56–0.76) had lower odds of mortality. Time to discharge alive was shorter in patients fed using weight‐only equations (hazard ratio [HR], 1.11; 95% CI, 1.01–1.23) in patients staying ≥4 days and with greater energy intake (HR, 1.19; 95% CI, 1.06–1.34) in patients in the ICU ≥12 days. Conclusion: These data suggest that higher energy intake is important to survival and time to discharge alive. However, the analysis was limited by actual energy intake <70% of goal. Delivery of full goal intake will be needed to determine the relationship between the method of determining energy goal and clinical outcomes.     

Feasibility of Accessing Data in Hospitalized Patients to Support Diagnosis of Malnutrition by the Academy‐A.S.P.E.N. Malnutrition Consensus Recommended Clinical Characteristics

Background: The feasibility of accessing data in hospitalized patients to support a malnutrition diagnosis using the new Academy of Nutrition and Dietetics–American Society for Parenteral and Enteral Nutrition (AND‐A.S.P.E.N.) consensus recommended clinical characteristics of malnutrition is largely unknown. We sought to characterize baseline practice to guide the development of appropriate interventions for implementation of the recommended approach. Materials and Methods: A cross‐sectional survey was conducted of 262 consecutive adults who were referred for dietitian or nutrition support team assessments at 2 tertiary teaching hospitals in Pennsylvania. The availability of data to support the proposed AND‐A.S.P.E.N. approach and the resulting malnutrition diagnoses were examined. Results: Mean ± SD age was 58.2 ± 17.1 years, and half were female. Food intake history was available for 76%, weight history for 67%, and physical examination for loss of fat and muscle mass for 94% and for edema for 84%. Hand‐grip strength was not available. The prevalence of malnutrition among the patients referred for nutrition assessment was 6.7% moderate, 7.6% severe with acute illness; 12.2% moderate, 11% severe with chronic illness; and 0.8% moderate, 0.4% severe with social circumstances. Decline in typical food intake and weight loss were the most commonly used clinical characteristics. Conclusion: Data could generally be accessed to support the AND‐A.S.P.E.N. consensus clinical characteristics for malnutrition diagnosis, but further testing in multiple care settings is needed before these observations may be generalized. Training in assessment methods and dissemination of the necessary tools will be necessary for full implementation.     

Preclinical Evaluation and Dosimetry of [111In]CHX-DTPA-scFv78-Fc Targeting Endosialin/Tumor Endothelial Marker 1 (TEM1)

Purpose

Endosialin/tumor endothelial marker-1 (TEM1) is an attractive theranostic target expressed by the microenvironment of a wide range of tumors, as well as by sarcoma and neuroblastoma cells. We report on the radiolabeling and preclinical evaluation of the scFv78-Fc, a fully human TEM1-targeting antibody fragment cross-reactive with mouse TEM1.

Procedures

The scFv78-Fc was conjugated with the chelator p-SCN-Bn-CHX-A”-DTPA, followed by labeling with indium-111. The number of chelators per molecule was estimated by mass spectrometry. A conventional saturation assay, extrapolated to infinite antigen concentration, was used to determine the immunoreactive fraction of the radioimmunoconjugate. The radiopharmaceutical biodistribution was assessed in immunodeficient mice grafted with Ewing’s sarcoma RD-ES and neuroblastoma SK-N-AS human TEM1-positive tumors. The full biodistribution studies were preceded by a dose-escalation experiment based on the simultaneous administration of the radiopharmaceutical with increasing amounts of unlabeled scFv78-Fc. Radiation dosimetry extrapolations to human adults were obtained from mouse biodistribution data according to established methodologies and additional assumptions concerning the impact of the tumor antigenic sink in the cross-species translation.

Results

[¹¹¹In]CHX-DTPA-scFv78-Fc was obtained with a radiochemical purity >?98 % after 1 h incubation at 42 °C and ultrafiltration. It showed good stability in human serum and >?70 % immunoreactive fraction. Biodistribution data acquired in tumor-bearing mice confirmed fast blood clearance and specific tumor targeting in both xenograft models. The radiopharmaceutical off-target uptake was predominantly abdominal. After a theoretical injection of [¹¹¹In]CHX-DTPA-scFv78-Fc to the reference person, the organs receiving the highest absorbed dose would be the spleen (0.876 mGy/MBq), the liver (0.570 mGy/MBq) and the kidneys (0.298 mGy/MBq). The total body dose and the effective dose would be 0.058 mGy/MBq and 0.116 mSv/MBq, respectively.

Conclusions

[¹¹¹In]CHX-DTPA-scFv78-Fc binds specifically to endosialin/TEM1 in vitro and in vivo. Dosimetry estimates are in the range of other monoclonal antibodies radiolabeled with indium-111. [¹¹¹In]CHX-DTPA-scFv78-Fc could be potentially translated into clinic.

     

Juvenile elastoma without germline mutations in LEMD3 gene: A case of Buschke‐Ollendorff syndrome?

We report the case of a 6‐year‐old Caucasian girl with clinical and histopathologic features of Buschke‐Ollendorff syndrome. Histologic examination of skin lesions showed thick, curly, elastic fibers in the derma. Bone lesions compatible with Buschke‐Ollendorff syndrome were found in the girl's mother. Mutations in LEMD3 are pathogenic for Buschke‐Ollendorff syndrome. Analysis of all exons and exon‐intron junctions of LEMD3 did not reveal any germline mutations.     

Histopathology of the pulp of primary molars with active and arrested dentinal caries

The purpose of this study was to compare the histological appearance of the pulp of human primary molars with active and arrested lesions. The sample consisted of 36 primary molars (18 with active lesions and 18 with arrested lesions) extracted from 35 children between 5 to 9 years of age. The histological diagnosis was classified in normal pulp, transitional stage, partial pulpitis, total pulpitis and total necrosis, and then subdivided in three subgroups: treatable, untreatable and questionable. Results showed that normal pulp or transitional stage (treatable category) was diagnosed in 50% of teeth with arrested lesions, compared to 11.1% of teeth with active lesions. Partial pulpitis (questionable category) was present in 38.8% with arrested lesions compared to 22.2% with active lesions. Total pulpitis and total necrosis (untreatable category) was diagnosed in 11.2% with arrested lesions compared to 66.7% with active lesions. The observed frequencies of histological categories between both groups were statistically significant (P < 0.05). Histologically, pulp reaction under active and arrested lesions in primary molars revealed the formation of a basophilic calcio-traumatic line at the junction of the primary and reparative dentin, formation of reparative dentin and a regular odontoblastic layer in 60% of the cases. Results indicated that the type of lesion (active or arrested) is a good indicator of the histological status of the pulp.     

Docosahexaenoic acid induces apoptosis in the human PaCa-44 pancreatic cancer cell line by active reduced glutathione extrusion and lipid peroxidation

We investigated the ability of fatty acids to induce growth inhibition and apoptosis in the human PaCa-44 pancreatic cancer cell line and the mechanism(s) underlying apoptosis. Butyric acid, alpha-linoleic acid, and docosahexaenoic acid (DHA) were supplemented at 200 microM concentration in the medium of cell cultures. Our results showed that all fatty acids inhibited cell growth, whereas only DHA induced cell apoptosis. An oxidative process was implicated in apoptosis induced by DHA because butylated hydroxytoluene and vitamin E prevented lipid peroxidation and reversed apoptosis. Intracellular and extracellular glutathione [reduced glutathione (GSH) and oxidized glutathione (GSSG)] concentrations were measured following DHA treatment in the presence or in the absence of GSH extrusion inhibitors such as cystathionine or methionine. DHA induced intracellular GSH depletion without affecting intracellular GSSG concentration and increased extracellular GSH and GSSG levels. Intracellular GSH depletion and extracellular GSH increase were both reversed by cystathionine. Inhibition of active GSH extrusion from the cell by cystathionine or methionine completely reversed lipid peroxidation and apoptosis. These data document the antiproliferative and apoptotic activities of DHA. The date provide evidence that intracellular GSH depletion represents an active extrusion process rather than a consequence of an oxidative stress, suggesting a causative role of GSH depletion in DHA-induced apoptosis.