Lorenzo Anez-Bustillos

Finite element analysis and CT-based structural rigidity analysis to assess failure load in bones with simulated lytic defects

There is an urgent need to improve the prediction of fracture risk for cancer patients with bone metastases. Pathological fractures that result from these tumors frequently occur in the femur. It is extremely difficult to determine the fracture risk even for experienced physicians. Although evolving, fracture risk assessment is still based on inaccurate predictors estimated from previous retrospective studies. As a result, many patients are surgically over-treated, whereas other patients may fracture their bones against expectations. We mechanically tested ten pairs of human cadaveric femurs to failure, where one of each pair had an artificial defect simulating typical metastatic lesions. Prior to testing, finite element (FE) models were generated and computed tomography rigidity analysis (CTRA) was performed to obtain axial and bending rigidity measurements. We compared the two techniques on their capacity to assess femoral failure load by using linear regression techniques, Students t-tests, the Bland-Altman methodology and Kendall rank correlation coefficients. The simulated FE failure loads and CTRA predictions showed good correlation with values obtained from the experimental mechanical testing. Kendall rank correlation coefficients between the FE rankings and the CTRA rankings showed moderate to good correlations. No significant differences in prediction accuracy were found between the two methods. Non-invasive fracture risk assessment techniques currently developed both correlated well with actual failure loads in mechanical testing suggesting that both methods could be further developed into a tool that can be used in clinical practice. The results in this study showed slight differences between the methods, yet validation in prospective patient studies should confirm these preliminary findings.

Intravenous Fat Emulsion Formulations for the Adult and Pediatric Patient Understanding the Differences

Intravenous fat emulsions (IVFEs) provide essential fatty acids (EFAs) and are a dense source of energy in parenteral nutrition (PN). Parenterally administered lipid was introduced in the 17th century but plagued with side effects. The formulation of IVFEs later on made it a relatively safe component for administration to patients. Many ingredients are common to all IVFEs, yet the oil source(s) and its (their) percentage(s) makes them different from each other. The oil used dictates how IVFEs are metabolized and cleared from the body. The fatty acids (FAs) present in each type of oil provide unique beneficial and detrimental properties. This review provides an overview of IVFEs and discusses factors that would help clinicians choose the optimal product for their patients.

A Hybrid Approach in the Treatment of Post-Myocardial Infarction Ventricular Septal Defect

Development of ventricular septal defect (VSD) is a rare but serious complication of transmural myocardial infarction (MI). The incidence of post-MI VSDs is reduced significantly with thrombolytic therapy, yet mortality remains high. Surgical repair is difficult and can be complicated by a recurrent VSD in some cases. Percutaneous catheter-based closure techniques can be used to treat these patients. This case report demonstrates the successful application of a hybrid approach utilizing initial surgical and subsequent percutaneous techniques for the recurrence in the treatment of a post-MI VSD.

Redefining essential fatty acids in the era of novel intravenous lipid emulsions

The essentiality of fatty acids was determined by the Burrs in the 1920s. It is commonly accepted that provision of linoleic (LA) and alpha-linolenic acids (ALA) prevents and reverses essential fatty acid deficiency (EFAD). Development of alternative injectable lipid emulsions (ILE) low in LA and ALA has raised concern about their ability to prevent EFAD. This review provides biochemical evidence coupled with observations from animal and human studies that aim to characterize which fatty acids are truly essential to prevent EFAD. Retroconversion pathways and mobilization from body stores suggest that arachidonic and docosahexaenoic acids (ARA and DHA - the main derivatives of LA and ALA, respectively) also prevent EFAD. Our group first proposed the essentiality of ARA and DHA by feeding mice exclusively these fatty acids and proving that they prevent EFAD. Survival for 5 generations on this diet provides additional evidence that growth and reproductive capabilities are maintained. Moreover, the use of fish oil-based ILE, with minimal LA and ALA and abundant DHA and ARA, for treatment of intestinal failure-associated liver disease, does not result in EFAD. These findings challenge the essentiality of LA and ALA in the presence of ARA and DHA. Evidence discussed in this review supports the idea that ARA and DHA can independently fulfill dietary essential fatty acid requirements. The imminent introduction of new ILE rich in ARA and DHA in the United States highlights the importance of understanding their essentiality, especially when provision of ALA and LA is below the established daily minimum requirement.

Predictors of failure of fish-oil therapy for intestinal failure–associated liver disease in children

BACKGROUND Parenteral fish-oil (FO) therapy is a safe and effective treatment for intestinal failure-associated liver disease (IFALD). Patients whose cholestasis does not resolve with FO may progress to end-stage liver disease. OBJECTIVE We sought to identify factors associated with the failure of FO therapy in treating IFALD to guide prognostication and referral guidelines. DESIGN Prospectively collected data for patients treated with FO at Boston Childrens Hospital from 2004 to 2014 were retrospectively reviewed. Resolution of cholestasis was defined as sustained direct bilirubin (DB) <2 mg/dL, and treatment failure as liver transplantation or death while DB was >2 mg/dL as of July 2015. Demographics, laboratory values, and medical history at FO therapy initiation were compared between patients who achieved resolution of cholestasis and those who failed therapy. RESULTS Among 182 patients treated with FO, 86% achieved resolution of cholestasis and 14% failed therapy. Patients who failed therapy had median (IQR) lower birth weight [1020 g (737, 1776 g) compared with 1608 g (815, 2438 g); P = 0.03] and were older at FO initiation [20.4 wk (9.9, 38.6 wk) compared with 11.7 wk (7.3, 21.4 wk); P = 0.02] than patients whose cholestasis resolved. Patients who failed therapy had more advanced liver disease at therapy initiation than patients whose cholestasis resolved, as evidenced by lower median (IQR) γ-glutamyltransferase [54 U/L (41, 103 U/L) compared with 112 U/L (76, 168 U/L); P < 0.001], higher DB [10.4 mg/dL (7.5, 14.1 mg/dL) compared with 4.4 mg/dL (3.1, 6.6 mg/dL); P < 0.001], and a higher pediatric end-stage liver disease (PELD) score [22 (14, 25) compared with 12 (7, 15); P < 0.001]. A PELD score of ≥15, history of gastrointestinal bleeding, age at FO initiation ≥16 wk, presence of nongastrointestinal comorbidities, and mechanical ventilation at FO initiation were independent predictors of treatment failure. CONCLUSIONS Most infants with IFALD responded to FO therapy with resolution of cholestasis, and liver transplantation was rarely required. Early FO initiation once biochemical cholestasis is detected in parenteral nutrition-dependent patients is recommended. This trial was registered at clinicaltrials.gov as NCT00910104.

A Comparison of Fish Oil Sources for Parenteral Lipid Emulsions in a Murine Model

Background: Fat emulsions are important components of parenteral nutrition (PN). Fish oil (FO) emulsions reverse cholestasis in PN-associated liver disease. There are 2 FO monographs. One is “FO; rich in omega-3 fatty acids” (NFO). The other, “omega-3 acids,” (PFO), is enriched in omega-3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The purpose of this study is to compare the effects of 20% NFO and PFO emulsions produced in the laboratory in a murine model. Methods: Emulsions were compounded containing different oils: soybean oil (SO), NFO, and two PFOs differing in percentage of fatty acids as triglycerides (PFO66 and PFO90). Chow-fed mice received saline, one of the above emulsions, or a commercial FO (OM) intravenously (2.4 g/kg/day) for 19 days. On day 19, animals were euthanized. Livers, spleens, and lungs were procured for histologic analysis. Results: OM, SO, NFO, and PFO90 were well-tolerated clinically. PFO66 resulted in tachypnea and lethargy for ~1 minute following injections. At euthanasia, PFO66 and PFO90 groups had organomegaly. Histologically, these groups had splenic and hepatic fat-laden macrophages, and lungs had scattered fat deposits. Other groups had normal organs. Conclusions: PFO emulsions present an attractive possibility for improving inflammation in PN-dependent patients by concentrating anti-inflammatory EPA and DHA. However, 20% PFO emulsions were poorly tolerated and precipitated adverse end organ sequelae, suggesting that they may not be safe. Development of novel manufacturing methods may achieve safe 20% PFO parenteral emulsions, but by established formulation methods, these emulsions were clinically suboptimal despite meeting pharmacopeial standards.

Microstructural, Densitometric and Metabolic Variations in Bones from Rats with Normal or Altered Skeletal States

Background High resolution μCT, and combined μPET/CT have emerged as non-invasive techniques to enhance or even replace dual energy X-ray absorptiometry (DXA) as the current preferred approach for fragility fracture risk assessment. The aim of this study was to assess the ability of µPET/CT imaging to differentiate changes in rat bone tissue density and microstructure induced by metabolic bone diseases more accurately than current available methods. Methods Thirty three rats were divided into three groups of control, ovariectomy and vitamin-D deficiency. At the conclusion of the study, animals were subjected to glucose (18FDG) and sodium fluoride (Na18F) PET/CT scanning. Then, specimens were subjected to µCT imaging and tensile mechanical testing. Results Compared to control, those allocated to ovariectomy and vitamin D deficiency groups showed 4% and 22% (significant) increase in 18FDG uptake values, respectively. DXA-based bone mineral density was higher in the vitamin D deficiency group when compared to the other groups (cortical bone), yet μCT-based apparent and mineral density results were not different between groups. DXA-based bone mineral density was lower in the ovariectomy group when compared to the other groups (cancellous bone); yet μCT-based mineral density results were not different between groups, and the μCT-based apparent density results were lower in the ovariectomy group compared to the other groups. Conclusion PET and micro-CT provide an accurate three-dimensional measurement of the changes in bone tissue mineral density, as well as microstructure for cortical and cancellous bone and metabolic activity. As osteomalacia is characterized by impaired bone mineralization, the use of densitometric analyses may lead to misinterpretation of the condition as osteoporosis. In contrast, µCT alone and in combination with the PET component certainly provides an accurate three-dimensional measurement of the changes in both bone tissue mineral density, as well as microstructure for cortical and cancellous bone and metabolic activity.

Assessment of Micronutrient Status in Critically Ill Children: Challenges and Opportunities

Micronutrients refer to a group of organic vitamins and inorganic trace elements that serve many functions in metabolism. Assessment of micronutrient status in critically ill children is challenging due to many complicating factors, such as evolving metabolic demands, immature organ function, and varying methods of feeding that affect nutritional dietary intake. Determination of micronutrient status, especially in children, usually relies on a combination of biomarkers, with only a few having been established as a gold standard. Almost all micronutrients display a decrease in their serum levels in critically ill children, resulting in an increased risk of deficiency in this setting. While vitamin D deficiency is a well-known phenomenon in critical illness and can predict a higher need for intensive care, serum concentrations of many trace elements such as iron, zinc, and selenium decrease as a result of tissue redistribution in response to systemic inflammation. Despite a decrease in their levels, supplementation of micronutrients during times of severe illness has not demonstrated clear benefits in either survival advantage or reduction of adverse outcomes. For many micronutrients, the lack of large and randomized studies remains a major hindrance to critically evaluating their status and clinical significance.

Intranasal delivery of VEGF enhances compensatory lung growth in mice

Vascular endothelial growth factor (VEGF) has previously been demonstrated to accelerate compensatory lung growth (CLG) in mice and may be a useful therapy for pulmonary hypoplasia. Systemic administration of VEGF can result in side effects such as hypotension and edema. The aim of this study was to explore nasal delivery as a route for intrapulmonary VEGF administration. Eight-week-old C57BL/6 male mice underwent left pneumonectomy, followed by daily nasal instillation of VEGF at 0.5 mg/kg or isovolumetric saline. Lung volume measurement, morphometric analysis, and protein expression studies were performed on lung tissues harvested on postoperative day (POD) 4. To understand the mechanism by which VEGF accelerates lung growth, proliferation of human bronchial epithelial cells (HBEC) was assessed in a co-culture model with lung microvascular endothelial cells (HMVEC-L) treated with and without VEGF (10 ng/mL). The assay was then repeated with a heparin-binding EGF-like growth factor (HB-EGF) neutralizing antibody ranging from 0.5–50 μg/mL. Compared to control mice, the VEGF-treated group displayed significantly higher lung volume (P = 0.001) and alveolar count (P = 0.005) on POD 4. VEGF treatment resulted in increased pulmonary expression of HB-EGF (P = 0.02). VEGF-treated HMVEC-L increased HBEC proliferation (P = 0.002) while the addition of an HB-EGF neutralizing antibody at 5 and 50 μg/mL abolished this effect (P = 0.01 and 0.002, respectively). These findings demonstrate that nasal delivery of VEGF enhanced CLG. These effects could be mediated by a paracrine mechanism through upregulation of HB-EGF, an epithelial cell mitogen.

Assessment of axial bone rigidity in rats with metabolic diseases using CT-based structural rigidity analysis

Methods A total of 30 rats were divided equally into normal, ovariectomized, and partially nephrectomized groups. Cortical and trabecular bone segments from each animal underwent micro-CT to assess their average and minimum axial rigidities using structural rigidity analysis. Following imaging, all specimens were subjected to uniaxial compression and assessment of mechanically-derived axial rigidity. Results The average structural rigidity-based axial rigidity was well correlated with the average mechanically-derived axial rigidity results (R 2 = 0.74). This correlation improved significantly (p < 0.0001) when the CT-based Structural Rigidity Analysis (CTRA) minimum axial rigidity was correlated to the mechanically-derived minimum axial rigidity results (R 2 = 0.84). Tests of slopes in the mixed model regression analysis indicated a significantly steeper slope for the average axial rigidity compared with the minimum axial rigidity (p = 0.028) and a significant difference in the intercepts (p = 0.022). The CTRA average and minimum axial rigidities were correlated with the mechanically-derived average and minimum axial rigidities using paired t-test analysis (p = 0.37 and p = 0.18, respectively). Conclusions In summary, the results of this study suggest that structural rigidity analysis of micro-CT data can be used to accurately and quantitatively measure the axial rigidity of bones with metabolic pathologies in an experimental rat model. It appears that minimum axial rigidity is a better model for measuring bone rigidity than average axial rigidity.