Multicompartmental Trauma Induces Persistent Inflammation and Organ Injury.

INTRODUCTION: Previous preclinical models of multicompartmental injury have investigated its effects for durations of less than 72 h and the long-term effects have not been defined. We hypothesized that a model of multicompartmental injury would result in systemic inflammation and multiorgan dysfunction that persists at 1 wk. METHODS: Male and proestrus female Sprague-Dawley rats (n = 16/group) underwent polytrauma (PT) (unilateral right lung contusion, hemorrhagic shock, cecectomy, bifemoral pseudofractures) and were compared to naive controls. Weight, hemoglobin, plasma neutrophil gelatinase-associated lipocalin, and plasma toll-like receptor 4 were evaluated on days two and seven. Bilateral lungs were sectioned, stained and assessed for injury at day seven. Comparisons were performed in Graphpad with significance defined as ∗P <0.05. RESULTS: Rats who underwent PT had significant weight loss and anemia at day 2 (P = 0.001) compared to naïve rats which persisted at day 7 (P = 0.001). PT rats had elevated plasma neutrophil gelatinase-associated lipocalin at day 2 compared to naïve (P <0.0001) which remained elevated at day 7 (P <0.0001). Plasma toll-like receptor 4 was elevated in PT compared to naïve at day 2 (P = 0.03) and day 7 (P = 0.01). Bilateral lungs showed significant injury in PT cohorts at day 7 compared to naïve (P <0.0004). PT males had worse renal function at day seven compared to females (P = 0.02). CONCLUSIONS: Multicompartmental trauma induces systemic inflammation and multiorgan dysfunction without recovery by day seven. However, females demonstrate improved renal recovery compared to males. Long-term assessment of preclinical PT models are crucial to better understand and evaluate future therapeutic immunomodulatory and anti-inflammatory treatments.

Effect of bead size and doxorubicin loading on tumor cellular injury after transarterial embolization and chemoembolization in a rat model of hepatocellular carcinoma.

Embolic agents used in transarterial embolization for intermediate stage hepatocellular carcinoma reduce blood flow into tumors and can deliver anticancer drugs. Tumor blood supply can be interrupted using doxorubicin-eluting beads (DEB-TACE) or non-loaded beads (TAE) of different calibers. In this preclinical study, we characterized the extent of remaining stressed tumor cells after treatment, hypoxia within the surviving tumor regions, and inflammatory immune cell infiltrates after embolization with 40-60 or 70-150 µm with non-loaded or doxorubicin-loaded beads at 3 and 7 days after treatment. TAE-treated tumors had more stressed and surviving tumor cells after 3 days, irrespective of bead size, compared with DEB-TACE-treated tumors. Hypoxic stress of residual cells increased after treatment with 70-150 µm beads without or with doxorubicin. Treatment with DEB-TACE of 70-150 µm resulted in increased inflammation and proliferation in the adjacent parenchyma. Inflammatory cell infiltrates were reduced at the periphery of tumors treated with 40-60 µm DEB-TACE.

Application of Trifluoroacetic Acid as a Theranostic Agent for Chemical Ablation of Solid Tissue.

PURPOSE: To evaluate trifluoroacetic acid (TFA) as a theranostic chemical ablation agent and determine the efficacy of TFA for both noninvasive imaging and tissue destruction. MATERIALS AND METHODS: Fluorine-19 magnetic resonance imaging (19F-MRI) was optimized at 7 T using a custom-built volume coil. Fluorine images were acquired with both rapid acquisition with relaxation enhancement and balanced steady-state free precession (bSSFP) sequences with varying parameters to determine the optimal sequence for TFA. The theranostic efficacy of chemical ablation was examined by injecting TFA (100 µL; 0.25, 0.5, 1.0, and 2.0M) into ex vivo porcine liver. 19F and proton MRI were acquired and superimposed to visualize distribution of TFA in tissue and quantify sensitivity. Tissue damage was evaluated with gross examination, histology, and fluorescence microscopy. RESULTS: The optimal 19F-MRI sequence was found to be bSSFP with a repetition time of 2.5 ms and flip angle of 70°. The minimum imageable TFA concentration was determined to be 6.7 ± 0.5 mM per minute of scan time (0.63×0.63×5.00 mm voxel), and real-time imaging (temporal resolution of at least 1 s-1) was achieved with 2M TFA both in vitro and in ex vivo tissue. TFA successfully coagulated tissue, and damage was locally confined. In addition to hepatic cord disruption, cytoskeletal collapse and chromatin clumping were observed in severely damaged areas in tissues treated with 0.5M or higher TFA concentrations. CONCLUSIONS: TFA was determined to be a theranostic agent for chemical ablation of solid tissue. Ablation was both efficacious and imageable in ex vivo healthy tissue, even at low concentrations or with high temporal resolution.

Broad spectrum proteomics analysis of the inferior colliculus following acute hydrogen sulfide exposure.

Acute exposure to high concentrations of H2S causes severe brain injury and long-term neurological disorders, but the mechanisms involved are not known. To better understand the cellular and molecular mechanisms involved in acute H2S-induced neurodegeneration we used a broad-spectrum proteomic analysis approach to identify key molecules and molecular pathways involved in the pathogenesis of acute H2S-induced neurotoxicity and neurodegeneration. Mice were subjected to acute inhalation exposure of up to750 ppm of H2S. H2S induced behavioral deficits and severe lesions including hemorrhage in the inferior colliculus (IC). The IC was microdissected for proteomic analysis. Tandem mass tags (TMT) liquid chromatography mass spectrometry (LC-MS/MS)-based quantitative proteomics was applied for protein identification and quantitation. LC-MS/MS identified 598, 562, and 546 altered proteomic changes at 2 h, and on days 2 and 4 post-H2S exposure, respectively. Of these, 77 proteomic changes were statistically significant at any of the 3 time points. Mass spectrometry data were subjected to Perseus 1.5.5.3 statistical analysis, and gene ontology heat map clustering. Expressions of several key molecules were verified to confirm H2S-dependent proteomics changes. Webgestalt pathway overrepresentation enrichment analysis with Panther engine revealed H2S exposure disrupted several biological processes including metabotropic glutamate receptor group 1 and inflammation mediated by chemokine and cytokine signaling pathways among others. Further analysis showed that energy metabolism, integrity of blood-brain barrier, hypoxic, and oxidative stress signaling pathways were also implicated. Collectively, this broad-spectrum proteomics data has provided important clues to follow up in future studies to further elucidate mechanisms of H2S-induced neurotoxicity.

Relation of comorbidities and patient navigation with the time to diagnostic resolution after abnormal cancer screening.

BACKGROUND: Whether patient navigation improves outcomes for patients with comorbidities is unknown. The aims of this study were to determine the effect of comorbidities on the time to diagnostic resolution after an abnormal cancer screening test and to examine whether patient navigation improves the timeliness and likelihood of diagnostic resolution for patients with comorbidities in comparison with no navigation. METHODS: A secondary analysis of comorbidity data collected by Patient Navigation Research Program sites using the Charlson Comorbidity Index (CCI) was conducted. The participants were 6,349 patients with abnormal breast, cervical, colon, or prostate cancer screening tests between 2007 and 2011. The intervention was patient navigation or usual care. The CCI data were highly skewed across projects and cancer sites, and the CCI scores were categorized as 0 (CCI score of 0 or no comorbidities identified; 76% of cases); 1 (CCI score of 1; 16% of cases), or 2 (CCI score ≥ 2; 8% of cases). Separate adjusted hazard ratios for each site and cancer type were obtained, and then they were pooled with a meta-analysis random effects methodology. RESULTS: Patients with a CCI score ≥ 2 had delayed diagnostic resolution after an abnormal cancer screening test in comparison with those with no comorbidities. Patient navigation reduced delays in diagnostic resolution, with the greatest benefits seen for those with a CCI score ≥ 2. CONCLUSIONS: Persons with a CCI score ≥ 2 experienced significant delays in timely diagnostic care in comparison with patients without comorbidities. Patient navigation was effective in reducing delays in diagnostic resolution among those with CCI scores > 1. Cancer 2017;123:312-318. © 2016 American Cancer Society.

Effects of Dietary Resistant Starch on the Wnt Signaling Pathway and Preneoplastic Cells in the Colons of Azoxymethane-Treated Rats.

Dietary resistant starch (RS) has been suggested to reduce colonic neoplasia. To determine the effects of digestion-resistant cornstarch on colonic carcinogenesis and Wnt signaling in azoxymethane (AOM)-treated F344 rats, diets containing naturally occurring RS from corn lines derived partially from Guat209 (GUAT), AR16035 (AR), or a hybrid (ARxGUAT), containing 34.5 ± 2.0, 0.2 ± 0.1, and 1.9 ± 0.1% RS, respectively, were fed at 55% of the diet. GUAT-fed rats had increased cecal content and tissue weight and decreased cecal pH compared with AR- or ARxGUAT-fed rats. Numbers of aberrant crypt foci (ACF) were not different among diet groups. Increased numbers of crypts/focus were observed in AOM-injected rats fed GUAT compared with rats fed other diets. ß-catenin mRNA expression of the crypts was significantly increased in GUAT-fed rats injected with AOM relative to those injected with saline. These findings suggest that selected dietary RSs may at some level further enhance colonocyte proliferation and differentiation in an AOM-treated colon.

Effects of trauma, hemorrhagic shock, and chronic stress on lung vascular endothelial growth factor.

BACKGROUND: Vascular endothelial growth factor (VEGF) and its receptors (VEGFR-1 and VEGFR-2) regulate vascular permeability and endothelial cell survival. We hypothesized that hemorrhagic shock (HS) and chronic stress (CS) would increase expression of lung VEGF and its receptors, potentiating pulmonary edema in lung tissue. MATERIALS AND METHODS: Male Sprague-Dawley rats aged 8-9 wk were randomized: naïve control, lung contusion (LC), LC followed by HS (LCHS), and LCHS with CS in a restraint cylinder for 2 h/d (LCHS/CS). Animals were sacrificed on days 1 and 7. Expressions of lung VEGF, VEGFR-1, and VEGFR-2 were determined by polymerase chain reaction. Lung Injury Score (LIS) was graded on light microscopy by inflammatory cell counts, interstitial edema, pulmonary edema, and alveolar integrity (range: 0 = normal; 8 = severe injury). RESULTS: Seven days after LC, lung VEGF and VEGFR-1 were increased, and lung tissue healed (LIS: 0.8 ± 0.8). However, 7 d after LCHS and LCHS/CS, lung VEGF and VEGFR-1 expressions were decreased. VEGFR-2 was also decreased after LCHS/CS. LIS was elevated 7 d after LCHS and LCHS/CS (6.5 ± 1.0 and 8.2 ± 0.8). Increased LIS after LCHS and LCHS/CS was because of higher inflammatory cell counts, increased interstitial edema, and loss of alveolar integrity, whereas pulmonary edema was unchanged. CONCLUSIONS: Elevation of lung VEGF and VEGFR-1 expressions after LC alone was associated with healing of injured lung tissue. Expressions of VEGF, VEGFR-1, and VEGFR-2 were reduced after LCHS and LCHS/CS, and injured lung tissue did not heal. Persistent lung injury after severe trauma was because of inflammation rather than pulmonary edema.

Effect of topical ophthalmic latanoprost 0.005% solution alone and in combination with diclofenac 0.1% solution in healthy horses: a pilot study.

OBJECTIVE: To evaluate the effect of topical ophthalmic 0.005% latanoprost alone and in combination with 0.1% diclofenac on healthy horses. ANIMALS STUDIED: Twelve healthy adult horses. PROCEDURES: A randomized, masked crossover design was used with horses divided into three groups for once daily treatment in one randomly selected eye. For arm 1 of the study, Group D (n = 3) received 0.1% diclofenac, Group L (n = 3) received 0.005% latanoprost, and Group DL (n = 6) received 0.005% latanoprost and 0.2 ml of 0.1% diclofenac. For arm 2 of the study, horses from Group D and L were placed into Group DL and horses from Group DL were placed into either Group D or L. Evaluations of intraocular pressure (IOP), vertical pupil diameter, aqueous flare, conjunctival hyperemia, epiphora, blepharospasm, and blepharoedema were performed 4 times daily on days 1 and 2 (baseline), days 3 to 7 (arm 1 treatment), days 8 to 11 (washout), days 12 to 16 (arm 2 treatment), and days 17 and 18 (return to baseline). RESULTS: During the treatment period, significant reduction in IOP and vertical pupil diameter occurred in treated eyes of Groups L and DL, but not Group D. These variables did not differ significantly between Groups L and DL. Blepharospasm, blepharoedema, epiphora, and conjunctival hyperemia scores were significantly higher in Group L than in Groups D and DL. CONCLUSIONS: Latanoprost reduced IOP in healthy horses and signs of drug-induced discomfort were mitigated by concurrent use of diclofenac.

The impact of patient navigation on the delivery of diagnostic breast cancer care in the National Patient Navigation Research Program: a prospective meta-analysis.

Patient navigation is emerging as a standard in breast cancer care delivery, yet multi-site data on the impact of navigation at reducing delays along the continuum of care are lacking. The purpose of this study was to determine the effect of navigation on reaching diagnostic resolution at specific time points after an abnormal breast cancer screening test among a national sample. A prospective meta-analysis estimated the adjusted odds of achieving timely diagnostic resolution at 60, 180, and 365 days. Exploratory analyses were conducted on the pooled sample to identify which groups had the most benefit from navigation. Clinics from six medical centers serving vulnerable populations participated in the Patient Navigation Research Program. Women with an abnormal breast cancer screening test between 2007 and 2009 were included and received the patient navigation intervention or usual care. Patient navigators worked with patients and their care providers to address patient-specific barriers to care to prevent delays in diagnosis. A total of 4675 participants included predominantly racial/ethnic minorities (74 %) with public insurance (40 %) or no insurance (31 %). At 60 days and 180 days, there was no statistically significant effect of navigation on achieving timely diagnostic care, but a benefit of navigation was seen at 365 days (aOR 2.12, CI 1.36-3.29). We found an equal benefit of navigation across all groups, regardless of race/ethnicity, language, insurance status, and type of screening abnormality. Patient navigation resulted in more timely diagnostic resolution at 365 days among a diverse group of minority, low-income women with breast cancer screening abnormalities. Trial registrations clinicaltrials.gov Identifiers: NCT00613275, NCT00496678, NCT00375024, NCT01569672.

Activation of autophagy and nucleotide-binding domain leucine-rich repeat-containing-like receptor family, pyrin domain-containing 3 inflammasome during Leishmania infantum-associated glomerulonephritis.

Chronic kidney disease is a major contributor to human and companion animal morbidity and mortality. Renal complications are sequelae of canine and human visceral leishmaniasis (VL). Despite the high incidence of infection-mediated glomerulonephritis, little is known about pathogenesis of VL-associated renal disease. Leishmania infantum-infected dogs are a naturally occurring model of VL-associated glomerulonephritis. Membranoproliferative glomerulonephritis type I [24 of 25 (96%)], with interstitial lymphoplasmacytic nephritis [23 of 25 (92%)], and glomerular and interstitial fibrosis [12 of 25 (48%)] were predominant lesions. An ultrastructural evaluation of glomeruli from animals with VL identified mesangial cell proliferation and interposition. Immunohistochemistry demonstrated significant Leishmania antigen, IgG, and C3b deposition in VL dog glomeruli. Asymptomatic and symptomatic dogs had increased glomerular nucleotide-binding domain leucine-rich repeat-containing-like receptor family, pyrin domain containing 3 and autophagosome-associated microtubule-associated protein 1 light chain 3 associated with glomerular lesion severity. Transcriptional analyses from symptomatic dogs confirmed induction of autophagy and inflammasome genes within glomeruli and tubules. On the basis of temporal VL staging, glomerulonephritis was initiated by IgG and complement deposition. This deposition preceded presence of nucleotide-binding domain leucine-rich repeat-containing-like receptor family, pyrin domain containing 3-associated inflammasomes and increased light chain 3 puncta indicative of autophagosomes in glomeruli from dogs with clinical VL and renal failure. These findings indicate potential roles for inflammasome complexes in glomerular damage during VL and autophagy in ensuing cellular responses.

Effect of Dietary-Resistant Starch on Inhibition of Colonic Preneoplasia and Wnt Signaling in Azoxymethane-Induced Rodent Models.

Dietary fiber has been reported to prevent preneoplastic colon lesions. The aim of this study was to determine the effect of resistant starches, novel dietary fibers, on the development of colonic preneoplasia and Wnt signaling in azoxymethane (AOM)-treated rats and mice fed resistant starches at 55% of the diet after AOM treatment. Another objective was to determine the effect of resistant starches on the development of preneoplasia in rats treated with antibiotics (Ab), administered between AOM treatment and resistant starch feeding. Diets containing resistant starches, high-amylose (HA7), high-amylose-octenyl succinic anhydride (OS-HA7), or high-amylose-stearic acid (SA-HA7) were compared with control cornstarch (CS). The resistant starch content of the diets did not alter the yield of colonic lesions but animals treated with AOM and fed the diet with the highest resistant starch content, SA-HA7 developed the highest average aberrant crypt foci (ACF) per animal. Mice fed the OS-HA7 diet had decreased expression of some upstream Wnt genes in the colonic crypts. This study suggests that further research is needed to determine if resistant starch impacts colon carcinogenesis in rodents.

The Public Health Framework of Legalized Marijuana in Colorado.

On January 1, 2014, Colorado became the first state in the nation to sell legal recreational marijuana for adult use. As a result, Colorado has had to carefully examine potential population health and safety impacts as well as the role of public health in response to legalization. We have discussed an emerging public health framework for legalized recreational marijuana. We have outlined this framework according to the core public health functions of assessment, policy development, and assurance. In addition, we have discussed challenges to implementing this framework that other states considering legalization may face.

Impact of patient navigation in eliminating economic disparities in cancer care.

BACKGROUND: Patient navigation may reduce cancer disparities associated with socioeconomic status (SES) and household factors. This study examined whether these factors were associated with delays in diagnostic resolution among patients with cancer screening abnormalities and whether patient navigation ameliorated these delays. METHODS: This study analyzed data from 5 of 10 centers of the National Cancer Institute's Patient Navigation Research Program, which collected SES and household data on employment, income, education, housing, marital status, and household composition. The primary outcome was the time to diagnostic resolution after a cancer screening abnormality. Separate adjusted Cox proportional hazard models were fit for each SES and household factor, and an interaction between that factor and the intervention status was included. RESULTS: Among the 3777 participants (1968 in the control arm and 1809 in the navigation intervention arm), 91% were women, and the mean age was 44 years; 43% were Hispanic, 28% were white, and 27% were African American. Within the control arm, the unemployed experienced a longer time to resolution than those employed full-time (hazard ratio [HR], 0.85; P = .02). Renters (HR, 0.81; P = .02) and those with other (ie, unstable) housing (HR, 0.60; P < .001) had delays in comparison with homeowners. Never married (HR, 0.70; P < .001) and previously married participants (HR, 0.85; P = .03) had a longer time to care than married participants. There were no differences in the time to diagnostic resolution with any of these variables within the navigation intervention arm. CONCLUSIONS: Delays in diagnostic resolution exist by employment, housing type, and marital status. Patient navigation eliminated these disparities in the study sample. These findings demonstrate the value of providing patient navigation to patients at high risk for delays in cancer care.

A patient navigation intervention for drug-involved former prison inmates.

BACKGROUND: Former prison inmates experience high rates of hospitalizations and death during the transition from prison to the community, particularly from drug-related causes and early after release. The authors designed a randomized controlled trial (RCT) of patient navigation to reduce barriers to health care and hospitalizations for former prison inmates. METHODS: Forty former prison inmates with a history of drug involvement were recruited and randomized within 15 days after prison release. Participants were randomized to receive 3 months of patient navigation (PN) with facilitated enrollment into an indigent care discount program (intervention) or facilitated enrollment into an indigent care discount program alone (control). Structured interviews were conducted at baseline, 3 months, and 6 months. Outcomes were measured as a change in self-reported barriers to care and as the rate of health service use per 100 person-days. RESULTS: The mean number of reported barriers to care was reduced at 3 and 6 months in both groups. At 6 months, the rate of emergency department/urgent care visits per 100 person-days since baseline was 1.1 among intervention participants and 0.5 among control participants (P = .04), whereas the rate of hospitalizations per 100 person-days was 0.2 in intervention participants and 0.6 in control participants (P = .04). CONCLUSIONS: Recruitment of former inmates into an RCT of patient navigation was highly feasible, but follow-up was limited by rearrests. Results suggest a significantly lower rate of hospitalizations among navigation participants, although the rate of emergency department/urgent care visits was not improved. Patient navigation is a promising, pragmatic intervention that may be effective at reducing high-cost health care utilization in former prison inmates.

A pulse-dose topical 1% 5-fluorouracil treatment regimen in a young dog with corneal squamous cell carcinoma.

PURPOSE: To describe the use of a pulse-dose topical 5-fluorouracil (5-FU) treatment regimen in a Pug dog with corneal squamous cell carcinoma (SCC). METHODS: A 1-year-old, spayed female Pug was evaluated for a corneal perforation of the right eye, which was surgically stabilized with a conjunctival pedicle graft. At the time of medial canthoplasty 7 weeks later, two areas of gray-white discoloration had developed medial and lateral to the graft. Biopsy samples were obtained via superficial keratectomy while under general anesthesia. RESULTS: Definitive diagnosis of corneal SCC was made through histopathological examination of the surgical biopsies. Thoracic radiography and submandibular lymph node cytology revealed no evidence of metastatic neoplasia. Following healing of the corneal biopsy sites, topical 1% 5-FU ointment was applied four times daily for four consecutive days once a month, for six treatment cycles. Twenty-three months after diagnosis, the patient remains visual and comfortable with no evidence of SCC recurrence. Long-term therapy with once daily topical 1% cyclosporine solution was used to manage corneal pigmentation bilaterally. CONCLUSIONS: The pulse-therapy 1% 5-FU protocol was a successful, convenient, and cost-effective adjunctive treatment with few adverse effects.

Schirmer tear test I and rebound tonometry findings in healthy calves.

OBJECTIVE: To describe Schirmer tear test I and rebound tonometry findings in healthy bovine calves. ANIMALS STUDIED: Thirty-three clinically normal dairy breed calves of mean (SD) 11 (1.1) weeks (range, 9.3-13.3 weeks) of age were evaluated. PROCEDURES: A Schirmer tear test I was performed on each eye followed by tonometry, using a TonoVet(®) without topical anesthesia. We report means (SD) and statistical analysis of data for each assay. RESULTS: For both Schirmer tear test (STT) I and tonometry, significant differences were not found between fellow eyes (P = 0.1536 and P = 0.83, respectively). The mean (SD) STT I value of all eyes was 20.4 (5.0) mm/min (range, 9-34 mm/min) while the mean (SD) intraocular pressure (IOP) value of all eyes was 15.2 (5.2) mmHg (range, 7-25 mmHg). CONCLUSIONS: This study reports normal data for the STT I and rebound tonometry in calves. This data may be useful in complete ophthalmic examinations of cattle, guiding diagnosis of glaucoma, uveitis, and keratoconjunctivitis sicca. However, results of these diagnostic modalities must be interpreted in light of clinical signs, given the wide range of normal values obtained in this study.

Effect of topical ophthalmic dorzolamide(2%)-timolol(0.5%) solution and ointment on intraocular pressure in normal horses.

OBJECTIVE: To compare the effect of commercially available solution and compounded ointment formulations of dorzolamide(2%)-timolol(0.5%) on intraocular pressure (IOP) of normal horses. ANIMALS: Eighteen clinically normal horses. PROCEDURES: A randomized, masked prospective design was used with horses divided into two equal groups. One eye of each horse was selected for topical ophthalmic treatment with either 0.2 mL of dorzolamide(2%)-timolol(0.5%) solution or 0.2 g of dorzolamide(2%)-timolol(0.5%) ointment every 12 h for 5 days. The contralateral eye of horses in both groups was untreated. Rebound tonometry was performed every 6 h starting 2 days prior to and ending 2 days after the treatment period. RESULTS: The mean IOP reduction in eyes treated with the solution or ointment formulations was 13%. Untreated eyes in both groups experienced a lesser but still statistically significant reduction in IOP. The IOP values did not return to baseline within 48 h of the last treatment. CONCLUSIONS AND CLINICAL RELEVANCE: The commercially available solution and compounded ointment formulations of ophthalmic dorzolamide(2%)-timolol(0.5%) had similar effects on IOP in normal horses. Persistent IOP reduction following cessation of treatment may indicate prolonged drug effect or acclimation of horses to tonometry.

Hypothalamic-pituitary-adrenal axis in lethal canine Staphylococcus aureus pneumonia.

The clinical significance and even existence of critical illness-related corticosteroid insufficiency is controversial. Here, hypothalamic-pituitary-adrenal (HPA) function was characterized in severe canine Staphylococcus aureus pneumonia. Animals received antibiotics and titrated life-supportive measures. Treatment with dexamethasone, a glucocorticoid, but not desoxycorticosterone, a mineralocorticoid, improves outcome in this model. Total and free cortisol, adrenocorticotropic hormone (ACTH). and aldosterone levels, as well as responses to exogenous ACTH were measured serially. At 10 h after the onset of infection, the acute HPA axis stress response, as measured by cortisol levels, exceeded that seen with high-dose ACTH stimulation but was not predictive of outcome. In contrast to cortisol, aldosterone was largely autonomous from HPA axis control, elevated longer, and more closely associated with survival in early septic shock. Importantly, dexamethasone suppressed cortisol and ACTH levels and restored ACTH responsiveness in survivors. Differing strikingly, nonsurvivors, sepsis-induced hypercortisolemia, and high ACTH levels as well as ACTH hyporesponsiveness were not influenced by dexamethasone. During septic shock, only serial measurements and provocative testing over a well-defined timeline were able to demonstrate a strong relationship between HPA axis function and prognosis. HPA axis unresponsiveness and high aldosterone levels identify a septic shock subpopulation with poor outcomes that may have the greatest potential to benefit from new therapies.

Costs and outcomes evaluation of patient navigation after abnormal cancer screening: evidence from the Patient Navigation Research Program.

BACKGROUND: Navigators can facilitate timely access to cancer services, but to the authors' knowledge there are little data available regarding their economic impact. METHODS: The authors conducted a cost-consequence analysis of navigation versus usual care among 10,521 individuals with abnormal breast, cervical, colorectal, or prostate cancer screening results who enrolled in the Patient Navigation Research Program study from January 1, 2006 to March 31, 2010. Navigation costs included diagnostic evaluation, patient and staff time, materials, and overhead. Consequences or outcomes were time to diagnostic resolution and probability of resolution. Differences in costs and outcomes were evaluated using multilevel, mixed-effects regression modeling adjusting for age, race/ethnicity, language, marital status, insurance status, cancer, and site clustering. RESULTS: The majority of individuals were members of a minority (70.7%) and uninsured or publically insured (72.7%). Diagnostic resolution was higher for navigation versus usual care at 180 days (56.2% vs 53.8%; P = .008) and 270 days (70.0% vs 68.2%; P < .001). Although there were no differences in the average number of days to resolution between the 2 groups (110 days vs 109 days; P = .63), the probability of ever having diagnostic resolution was higher for the navigation group versus the usual-care group (84.5% vs 79.6%; P < .001). The added cost of navigation versus usual care was $275 per patient (95% confidence interval, $260-$290; P < .001). There was no significant difference in stage distribution among the 12.4% of patients in the navigation group vs 11% of the usual-care patients diagnosed with cancer. CONCLUSIONS: Navigation adds costs and modestly increases the probability of diagnostic resolution among patients with abnormal screening test results. Navigation is only likely to be cost-effective if improved resolution translates into an earlier cancer stage at the time of diagnosis.

Dietary resistant starch prevents urinary excretion of vitamin D metabolites and maintains circulating 25-hydroxycholecalciferol concentrations in Zucker diabetic fatty rats.

BACKGROUND: Type 2 diabetes (T2D) is the leading cause of nephropathy in the United States. Renal complications of T2D include proteinuria and suboptimal serum 25-hydroxycholecalciferol (25D) concentrations. 25D is the major circulating form of vitamin D and renal reabsorption of the 25D-vitamin D-binding protein (DBP) complex via megalin-mediated endocytosis is believed to determine whether 25D can be activated to 1,25-dihydroxycholecalciferol (1,25D) or returned to circulation. We previously demonstrated that excessive urinary excretion of 25D-DBP and albuminuria occurred in rats with type 1 diabetes (T1D) and T2D. Moreover, feeding rats with T1D high-amylose maize partially resistant to digestion [resistant starch (RS)] prevented excretion of 25D-DBP without significantly affecting hyperglycemia. OBJECTIVE: We used Zucker diabetic fatty (ZDF) rats, a model of obesity-related T2D, to determine whether feeding RS could similarly prevent loss of vitamin D and maintain serum 25D concentrations. METHODS: Lean control Zucker rats (n = 8) were fed a standard semi-purified diet (AIN-93G) and ZDF rats were fed either the AIN-93G diet (n = 8) or the AIN-93G diet in which cornstarch was replaced with RS (550 g/kg diet; 35% resistant to digestion) (n = 8) for 6 wk. RESULTS: RS attenuated hyperglycemia by 41% (P < 0.01) and prevented urinary DBP excretion and albuminuria, which were elevated 3.0- (P < 0.01) and 3.6-fold (P < 0.01), respectively, in control diet-fed ZDF rats. Additionally, urinary excretion of 25D (P = 0.01) and 1,25D (P = 0.03) was higher (89% and 97%, respectively), whereas serum 25D concentrations were 31% lower (P < 0.001) in ZDF rats fed the control diet compared with RS-fed ZDF rats. Histopathologic scoring of the kidney revealed that RS attenuated diabetes-mediated damage by 21% (P = 0.12) despite an ∼50% decrease in megalin protein abundance. CONCLUSIONS: Taken together, these data provide evidence that suggests vitamin D balance can be maintained by dietary RS through nephroprotective actions in T2D, which are independent of vitamin D supplementation and renal expression of megalin.