Evaluating the performance of Bayesian geostatistical prediction with physical barriers in the Chesapeake Bay.

The Chesapeake Bay is one of the most widely studied bodies of water in the United States and around the world. Routine monitoring of water quality indicators (e.g., salinity) relies on fixed sampling stations throughout the Bay. Utilizing this rich monitoring data, various methods produce surface predictions of water quality indicators to further characterize the health of the Bay as well as to support wildlife and human health research studies. Bayesian approaches for geostatistical modelling are becoming increasingly popular and can be preferred over frequentist approaches because full and exact inference can be computed, along with more accurate characterization of uncertainty. Traditional geostatistical prediction methods assume a Euclidean distance between two points when characterizing spatial dependence as a function of distance. However, Euclidean approaches may not be appropriate in estuarine environments when water-land boundaries are crossed during the modelling process. In this study, we compare stationary and barrier INLA geostatistical models with a classic kriging geostatistical model to predict salinity in the Chesapeake Bay during 4 months in 2019. Cross-validation is conducted for each approach to evaluate model performance based on prediction accuracy and precision. The results provide evidence that the two Bayesian-based models outperformed ordinary kriging, especially when examining prediction accuracy (most notably in the tributaries). We also suggest that the non-Euclidean model accounts for the appropriate water-based distances between sampling locations and is likely better at characterizing the uncertainty. However, more complex bodies of water may better showcase the capabilities and efficacy of the physical barrier INLA model.

Quantification of Blood Velocity with 4D Digital Subtraction Angiography Using the Shifted Least-Squares Method.

BACKGROUND AND PURPOSE: 4D-DSA provides time-resolved 3D-DSA volumes with high temporal and spatial resolutions. The purpose of this study is to investigate a shifted least squares method to estimate the blood velocity from the 4D DSA images. Quantitative validation was performed using a flow phantom with an ultrasonic flow probe as ground truth. Quantification of blood velocity in human internal carotid arteries was compared with measurements generated from 3D phase-contrast MR imaging. MATERIALS AND METHODS: The centerlines of selected vascular segments and the time concentration curves of each voxel along the centerlines were determined from the 4D-DSA dataset. The temporal shift required to achieve a minimum difference between any point and other points along the centerline of a segment was calculated. The temporal shift as a function of centerline point position was fit to a straight line to generate the velocity. The proposed shifted least-squares method was first validated using a flow phantom study. Blood velocities were also estimated in the 14 ICAs of human subjects who had both 4D-DSA and phase-contrast MR imaging studies. Linear regression and correlation analysis were performed on both the phantom study and clinical study, respectively. RESULTS: Mean velocities of the flow phantom calculated from 4D-DSA matched very well with ultrasonic flow probe measurements with 11% relative root mean square error. Mean blood velocities of ICAs calculated from 4D-DSA correlated well with phase-contrast MR imaging measurements with Pearson correlation coefficient r = 0.835. CONCLUSIONS: The availability of 4D-DSA provides the opportunity to use the shifted least-squares method to estimate velocity in vessels within a 3D volume.

Stranded seed displacement, migration, and loss after permanent prostate brachytherapy as estimated by Day 0 fluoroscopy and 4-month postimplant pelvic x-ray.

PURPOSE: The aim of the study was to determine the incidence of local displacement, distant seed migration to the chest, and seed loss after permanent prostate brachytherapy (PPB) with stranded seeds (SSs) using sequential two-dimensional fluoroscopic pelvic and chest x-rays. METHODS AND MATERIALS: Between October 2010 and April 2014, a total of 137 patients underwent PPB and 4-month followup pelvic and chest x-ray imaging. All patients had exclusively SSs placed and an immediate postimplant fluoroscopic image of the seed cluster. Followup x-ray images were evaluated for the number, location, and displacement of seeds in comparison to Day 0 fluoroscopic images. Significant seed displacement was defined as seed displacement >1 cm from the seed cluster. Followup chest x-rays were evaluated for seed migration to the chest. RESULTS: Seed migration to the chest occurred in 3 of the 137 patients (2%). Seed loss occurred in 38 of the 137 patients (28%), with median loss of one seed (range, 1-16), and total seeds loss of 104 of 10,088 (1.0%) implanted. Local seed displacement was seen in 12 of the 137 patients (8.8%), and total seeds displaced were 0.15% (15/10,088). CONCLUSIONS: SS placement in PPB is associated with low rates of substantial seed loss, local displacement, or migration to the chest. Comparing immediate postimplant fluoroscopic images to followup plain x-ray images is a straightforward method to supplement quality assurance in PPB and was found to be useful in identifying cases where seed loss was potentially of clinical significance.

Functional and radioligand binding characterization of the α1L-adrenoceptor subtype of the human vas deferens.

Alpha1 -adrenoceptor antagonists can cause ejaculatory dysfunction as an adverse effect. Contractions of the human vas deferens are mediated via α1A -adrenoceptors, and this study investigated whether the low affinity state of this receptor (α1L -adrenoceptor) is involved in mediating contractions of this tissue. The potency of agonists and the affinity of receptor subtype selective antagonists were determined in functional experiments and in [(3) H]tamsulosin binding experiments to identify the α1 -adrenoceptor subtype population present in the human vas deferens. The α1A -adrenoceptor selective agonist A61603 was a full agonist and was 250-fold more potent than noradrenaline. Prazosin antagonized contractile responses to phenylephrine with a low affinity (pKd = 8.6). Only high concentrations of RS17053 antagonized responses to phenylephrine and yielded a relatively low affinity estimate of 7.0. BMY7378 (α1D -adrenoceptor selective) gave a low affinity estimate (pKd = 6.7), whilst tamsulosin (α1A - and α1D -adrenoceptor selective) had a high affinity (pKd = 9.9). [(3) H]Tamsulosin bound to human vas deferens membranes with a high affinity (pKd = 10.0). Prazosin, RS17053 and BMY7378 competed with [(3) H]tamsulosin with low affinities for a single population of binding sites (pKd values of 8.5, 7.2 and 6.3, respectively). These functional and radioligand binding data indicate that the human vas deferens possesses a homogeneous population of α1 -adrenoceptors which have the pharmacological properties of the putative α1L -adrenoceptor, the same functional receptor previously identified in the human prostate.

Risk for transmission of Naegleria fowleri from solid organ transplantation.

Primary amebic meningoencephalitis (PAM) caused by the free-living ameba (FLA) Naegleria fowleri is a rare but rapidly fatal disease of the central nervous system (CNS) affecting predominantly young, previously healthy persons. No effective chemotherapeutic prophylaxis or treatment has been identified. Recently, three transplant-associated clusters of encephalitis caused by another FLA, Balamuthia mandrillaris, have occurred, prompting questions regarding the suitability of extra-CNS solid organ transplantation from donors with PAM. During 1995-2012, 21 transplant recipients of solid organs donated by five patients with fatal cases of PAM were reported in the United States. None of the recipients developed PAM, and several recipients tested negative for N. fowleri by serology. However, historical PAM case reports and animal experiments with N. fowleri, combined with new postmortem findings from four patients with PAM, suggest that extra-CNS dissemination of N. fowleri can occur and might pose a risk for disease transmission via transplantation. The risks of transplantation with an organ possibly harboring N. fowleri should be carefully weighed for each individual recipient against the potentially greater risk of delaying transplantation while waiting for another suitable organ. In this article, we present a case series and review existing data to inform such risk assessments.

Acute gastric necrosis after routine oesophagogastroduodenoscopy with therapeutic argon plasma coagulation.

A 56-year-old woman presented to the accident and emergency department with peritonitis 2 days after a routine oesophagogastroduodenoscopy. She was taken to theatre with the finding of gastric necrosis. Blood and peritoneal cultures grew group A haemolytic Streptococcus. Histology revealed normal vasculature, no volvulus but marked neutrophilia in the submucosa with an intact mucosa. The stomach was resected and the patient recovered in the intensive care unit but overwhelming acidosis progressed to multiorgan failure and treatment was eventually withdrawn. Acute phlegmonous gastritis has been well described in the literature but mainly before the advent of antibiotics. The most common organism is group A haemolytic Streptococcus (commonly found in throat infections) and predisposing factors include instrumentation. Should antibiotics be given at the start of an oesophagogastroduodenoscopy and should routine procedures be delayed if active upper respiratory tract infections are present?

Range extension of the vulnerable dwarf marmoset, Callibella humilis (Roosmalen et al. 1998), and first analysis of its long call structure.

We present two new records for the vulnerable dwarf marmoset, Callibella humilis. The first record, based on observed and photographed individuals, is from a campinarana area on the left (west) bank of the Rio Madeirinha, a left (west)-bank tributary of the Rio Roosevelt in the state of Amazonas, municipality of Novo Aripuanã and extends the distribution of the species ~270 km southwards, to the left (west) bank of the rio Roosevelt. The second record is based on an individual collected from the mouth of the Rio Roosevelt, at less than 10 km from the type locality of Mico marcai. This indicates that the species occurs sympatrically with M. marcai and probably Mico melanurus. We also present the first sonogram analysis of its long call structure, which shows some similarities, in the note duration and frequency, with Cebuella pygmaea and Mico argentatus.

Glucocorticoids and histone deacetylase inhibitors cooperate to block the invasiveness of basal-like breast cancer cells through novel mechanisms.

Aggressive cancers often express E-cadherin in cytoplasmic vesicles rather than on the plasma membrane and this may contribute to the invasive phenotype of these tumors. Therapeutic strategies are not currently available that restore the anti-invasive function of E-cadherin in cancers. MDA-MB-231 cells are a frequently used model of invasive triple-negative breast cancer, and these cells express low levels of E-cadherin that is mislocalized to cytoplasmic vesicles. MDA-MB-231 cell lines stably expressing wild-type E-cadherin or E-cadherin fused to glutathione S-transferase or green fluorescent protein were used as experimental systems to probe the mechanisms responsible for cytoplasmic E-cadherin localization in invasive cancers. Although E-cadherin expression partly reduced cell invasion in vitro, E-cadherin was largely localized to the cytoplasm and did not block the invasiveness of the corresponding orthotopic xenograft tumors. Further studies indicated that the glucocorticoid dexamethasone and the highly potent class I histone deacetylase (HDAC) inhibitor largazole cooperated to induce E-cadherin localization to the plasma membrane in triple-negative breast cancers, and to suppress cellular invasion in vitro. Dexamethasone blocked the production of the cleaved form of the CDCP1 (that is, CUB domain-containing protein 1) protein (cCDCP1) previously implicated in the pro-invasive activities of CDCP1 by upregulating the serine protease inhibitor plasminogen activator inhibitor-1. E-cadherin preferentially associated with cCDCP1 compared with the full-length form. In contrast, largazole did not influence CDCP1 cleavage, but increased the association of E-cadherin with γ-catenin. This effect on E-cadherin/γ-catenin complexes was shared with the nonisoform selective HDAC inhibitors trichostatin A (TSA) and vorinostat (suberoylanilide hydroxamic acid, SAHA), although largazole upregulated endogenous E-cadherin levels more strongly than TSA. These results demonstrate that glucocorticoids and HDAC inhibitors, both of which are currently in clinical use, cooperate to suppress the invasiveness of breast cancer cells through novel, complementary mechanisms that converge on E-cadherin.

Vibro-acoustography imaging of permanent prostate brachytherapy seeds in an excised human prostate--preliminary results and technical feasibility.

OBJECTIVE: The objective in this work is to investigate the feasibility of using a new imaging tool called vibro-acoustography (VA) as a means of permanent prostate brachytherapy (PPB) seed localization to facilitate post-implant dosimetry (PID). METHODS AND MATERIALS: Twelve OncoSeed (standard) and eleven EchoSeed (echogenic) dummy seeds were implanted in a human cadaver prostate. Seventeen seeds remained after radical retropubic prostatectomy. VA imaging was conducted on the prostate that was cast in a gel phantom and placed in a tank of degassed water. 2-D magnitude and phase VA image slices were obtained at different depths within the prostate showing location and orientation of the seeds. RESULTS: VA demonstrates that twelve of seventeen (71%) seeds implanted were visible in the VA image, and the remainder were obscured by intra-prostatic calcifications. Moreover, it is shown here that VA is capable of imaging and locating PPB seeds within the prostate independent of seed orientation, and the resulting images are speckle free. CONCLUSION: The results presented in this research show that VA allows seed detection within a human prostate regardless of their orientation, as well as imaging intra-prostatic calcifications.

In vitro comparative study of vibro-acoustography versus pulse-echo ultrasound in imaging permanent prostate brachytherapy seeds.

BACKGROUND: Permanent prostate brachytherapy (PPB) is a common treatment for early stage prostate cancer. While the modern approach using trans-rectal ultrasound guidance has demonstrated excellent outcome, the efficacy of PPB depends on achieving complete radiation dose coverage of the prostate by obtaining a proper radiation source (seed) distribution. Currently, brachytherapy seed placement is guided by trans-rectal ultrasound imaging and fluoroscopy. A significant percentage of seeds are not detected by trans-rectal ultrasound because certain seed orientations are invisible making accurate intra-operative feedback of radiation dosimetry very difficult, if not impossible. Therefore, intra-operative correction of suboptimal seed distributions cannot easily be done with current methods. Vibro-acoustography (VA) is an imaging modality that is capable of imaging solids at any orientation, and the resulting images are speckle free. OBJECTIVE AND METHODS: The purpose of this study is to compare the capabilities of VA and pulse-echo ultrasound in imaging PPB seeds at various angles and show the sensitivity of detection to seed orientation. In the VA experiment, two intersecting ultrasound beams driven at f(1)=3.00 MHz and f(2)=3.020 MHz respectively were focused on the seeds attached to a latex membrane while the amplitude of the acoustic emission produced at the difference frequency 20 kHz was detected by a low frequency hydrophone. RESULTS: Finite element simulations and results of experiments conducted under well-controlled conditions in a water tank on a series of seeds indicate that the seeds can be detected at any orientation with VA, whereas pulse-echo ultrasound is very sensitive to the seed orientation. CONCLUSION: It is concluded that vibro-acoustography is superior to pulse-echo ultrasound for detection of PPB seeds.

Identification of uterine leiomyoma genes developmentally reprogrammed by neonatal exposure to diethylstilbestrol.

Environmental exposures during development can alter susceptibility later in life to adult diseases including uterine leiomyoma, a phenomenon termed developmental reprogramming. The goal of this study was to identify genes developmentally reprogrammed by diethylstilbestrol (DES) and aberrantly expressed in leiomyomas. Transcriptional profiling identified 171 genes differentially expressed in leiomyomas relative to normal myometrium, of which 6/18 genes with putative estrogen responsive elements and confirmed to be estrogen-responsive in neonatal uteri were reprogrammed by neonatal DES exposure. Calbindin D9k and Dio2, normally induced by estrogen, exhibited elevated expression in DES-exposed animals during both phases of the estrus cycle. Gdf10, Car8, Gria2, and Mmp3, genes normally repressed by estrogen, exhibited elevated expression in DES-exposed animals during the proliferative phase, when estrogen is highest. These data demonstrate that neonatal DES exposure causes reprogramming of estrogen-responsive genes expressed in uterine leiomyomas, leading to over-expression of these genes in the myometrium of exposed animals prior to the onset of tumorigenesis.

Differential regulation of mast cell cytokines by both dexamethasone and the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580.

Activated mast cells generate multiple cytokines but it is not known if these can be differentially regulated by pharmacological agents. We report here that the glucocorticoid dexamethasone (DEX) preferentially inhibited Ag-induced expression of IL-4 and IL-6 mRNA relative to TNF-alpha mRNA in RBL-2H3 cells. Likewise, the drug more readily inhibited release of IL-4 than TNF-alpha protein. SB203580, an inhibitor of p38 mitogen-activated protein kinase (MAPK), enhanced Ag-induced TNF-alpha mRNA expression without affecting IL-4 or IL-6 mRNA. At the protein level, SB203580 exerted little effect on TNF-alpha release but inhibited IL-4 release; notably, the ratio of TNF-alpha : IL-4 increased markedly with the concentration of SB203580, confirming the differential regulation of these cytokines. PD98059, an inhibitor of MAPK kinase (MEK), a component of the p44/42 MAPK pathway, partially inhibited Ag-induced expression of mRNA for all three cytokines while cyclosporin A inhibited Ag-induced IL-4 and IL-6 mRNA more readily than TNF-alpha mRNA. Ag activation of the cells led to phosphorylation of p38 and p44/42 MAPK but this was not influenced by DEX. In conclusion, mast cell cytokines can be differentially regulated pre- and post-translationally by DEX and SB203580 but there does not appear to be a direct mechanistic link between the actions of these two drugs.

Reliability of radiographs in defining union of internally fixed fractures.

We assessed whether radiographs can predict union of internally fixed fractures, and therefore be used as end-points in studies of fracture healing. Forty-seven radiographic series of forearm, femoral and tibial fractures treated by internal fixation over a 3-year period were reviewed. All forearm fractures were treated with dynamic compression plates (DCP), and all tibial and femoral fractures with intra-medullary nails. Callus formation and fracture line filling with time were measured on each radiograph. The ability of five orthopaedic surgeons to chronologically rank the blinded radiographs and to agree on the point of union was assessed. Correlation between callus formation, fracture line filling and union was noted. The ability of surgeons to correctly rank the radiographs and to agree on the point of union was in the order of 70%. Callus formation and union progression was significant in femoral fractures (P<0.05). Fracture line filling and union progression showed significance in the forearm (P<0.01) and femoral groups (P<0.05). Taking serial radiographs to assess healing would have led to only one early intervention. Radiographs do not define union in internally fixed fractures with sufficient accuracy to enable their use as end-points of fracture healing. Studies quoting radiographic end-points should be interpreted with care.

Superior renoprotective effects of combination therapy with ACE and AGE inhibition in the diabetic spontaneously hypertensive rat.

AIMS/HYPOTHESIS: Diabetic renal disease has been postulated to progress as a result of an interaction between metabolic and haemodynamic pathways. Our aim was to assess the functional, structural, molecular and cellular aspects of renal disease in an experimental model of diabetes with associated hypertension. METHOD: Streptozotocin-induced diabetic spontaneously hypertensive rats were randomised to no treatment, the ACE inhibitor, perindopril (2 mg/l), the AGE formation inhibitor, aminoguanidine (1 g/l) and a combination of both agents and were followed for 32 weeks. RESULTS: Diabetes was associated with a considerable increase in albumin excretion rate. Both aminoguanidine and perindopril retarded the increase in albuminuria, which was completely abrogated by combination therapy. Glomerulosclerosis and tubulointerstitial damage was reduced by both monotherapies with further renoprotection afforded by combination therapy in both cases. Combination therapy was also associated with a superior restoration in diabetes-induced nephrin protein depletion compared to either monotherapy. TGFbeta1 expression as assessed by in situ hybridisation was increased in the diabetic rats and reduced by perindopril and aminoguanidine. CONCLUSION/INTERPRETATION: These findings indicate that in the context of diabetes-related renal injury, blocking both the renin-angiotensin and advanced glycation pathways offers superior renoprotection and could be considered as a therapeutic strategy in the prevention and retardation of progressive-diabetic renal injury.

Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy.

AIMS: Although ACE inhibitors slow progression of diabetic renal disease, the mortality and morbidity is still high. As other hormonal factors are involved, inhibition of vasopeptidases could further reduce progression. We studied dual inhibition of angiotensin converting enzyme and neutral endopeptidase in a model of progressive diabetic renal injury. The major endpoints were reductions in systemic blood pressure, albuminuria and renal structural injury. METHODS: Diabetic spontaneously hypertensive rats were treated with the ACE inhibitor perindopril (mg.kg(-1).day(-1)) or the vasopeptidase inhibitor omapatrilat at doses of 10 (oma10) and 40 (oma40) mg.kg(-1).day(-1) for 32 weeks. In vivo ACE and NEP inhibition was quantitated by in vitro autoradiography. Renal structural injury was assessed by measurement of the glomerulosclerotic (GS) index and tubulointerstitial area (TI). The expression of transforming growth factor beta, beta-inducible gene-h3 and nephrin were also quantitated. RESULTS: Despite a similar reduction in blood pressure by perindopril and oma10, greater attenuation of albuminuria was afforded by oma10, with a complete amelioration observed with oma40. Oma40 lead to a 33% reduction in renal NEP binding and this was associated with less albuminuria and prevention of GS, TI area and overexpression of TGFbeta and betaig-h3. Diabetes-associated reduction in nephrin expression was restored by both drugs. CONCLUSION/INTERPRETATION: These findings suggest that other vasoactive mechanisms in addition to angiotensin II are important in the prevention of diabetic nephropathy, and that vasopeptidase inhibition might confer an advantage over blockade of the RAS alone in the treatment of diabetic renal disease.

Human herpesvirus 8 genome is not found in whole bone marrow core biopsy specimens of patients with plasma cell dyscrasias.

Recently, molecular evidence of the gamma herpesvirus, human herpesvirus 8 (HHV-8), was found in the nonmalignant bone marrow stromal cells of patients with multiple myeloma using a polymerase chain reaction (PCR)-based assay. Other investigators have been unable to confirm either the presence of HHV-8 using molecular techniques or serologic evidence of prior infection with HHV-8. In order to maximize the likelihood of detection of small quantities of the virus and minimize the risk of potential nucleic acid contamination, we used entire bone marrow biopsy core specimens for DNA extraction and amplification. These specimens included both malignant plasma cells and bone marrow stromal cells and were subjected to minimal manipulation prior to DNA extraction and PCR. We tested eight patients with various plasma cell dyscrasias and compared them to negative controls with non-Hodgkin's lymphoma using standard PCR assays utilizing the KS330(233)primers and probe for HHV-8. This assay is reproducibly positive in Kaposi's sarcoma tissue. We found no evidence of HHV-8 DNA in either the lymphoma controls or the samples from patients with the plasma cell dyscrasias using these methods. We conclude that HHV-8 is unlikely to play a major role in the pathogenesis of the plasma cell dyscrasias in the majority of patients with these diseases. This report adds to the body of evidence that HHV-8 is not associated with plasma cell dyscrasias like multiple myeloma.

Systolic and diastolic cardiac dysfunction early after the initiation of doxorubicin therapy: significance of gender and concurrent mediastinal radiation.

Diastolic and systolic left ventricular (LV) function may be affected early after the initiation of doxorubicin therapy. However, the role of mediastinal radiation and other cytotoxic agents in the production of these early cardiac effects is unclear. In this study LV diastolic and systolic function were assessed before and after doxorubicin (223+/-122 mg.m-2; range, 40-618) in 33 patients. After doxorubicin, LV ejection fraction declined (0.61+/-0.08 to 0.56+/-0.08, P=0.0008), peak filling rate decreased (3.38+/-1.10 to 2.82+/-0.62 end diastolic volumes/s, P=0.006), and time to peak filling rate increased (162+/-39 to 182+/-45 ms, P=0.04). The changes in LV systolic and diastolic function were not related to doxorubicin dose and the use of other cytotoxic agents; the decrease in LV ejection fraction with doxorubicin was more notable in men and in patients who received mediastinal irradiation concurrently with doxorubicin. It is concluded that the use of doxorubicin was associated with the simultaneous early development of LV systolic and diastolic dysfunction. Male gender and concurrent mediastinal irradiation were independent influences, but doxorubicin dose and the use of other cytotoxic agents were not associated with worse cardiac dysfunction.