Fast diffusion kurtosis imaging of fibrotic mouse kidneys.

Diffusion kurtosis imaging (DKI) is sensitive to tissue microstructure and may therefore be useful in the diagnosis and monitoring of disease in brain and body organs. Generally, diffusion magnetic resonance imaging (dMRI) in the body is challenging because of the heterogeneous body composition, which can cause image artefacts as a result of chemical shifts and susceptibility differences. In addition, the abdomen possesses physiological factors (e.g. breathing, heartbeat, blood flow) which may severely reduce image quality, especially when echo planar imaging is employed, as is typical in dMRI. Collectively, these challenging measurement conditions impede the use and exploration of DKI in the body. This impediment is further exacerbated by the traditionally large amount of data required for DKI and the low signal-to-noise ratio at the b-values needed to effectively probe the kurtosis regime. Recently introduced fast DKI techniques reduce the challenge of DKI in the body by decreasing the data requirement substantially, so that, for example, triggering and breath-hold techniques may be applied for the entire DKI acquisition without causing unfeasible scan times. One common pathological condition for which body DKI may be of immediate clinical value is kidney fibrosis, which causes progressive changes in organ microstructure. With its sensitivity to microstructure, DKI is an obvious candidate for a non-invasive evaluation method. We present preclinical evidence indicating that the rapidly obtainable tensor-derived mean kurtosis ( W̅) distinguishes moderately fibrotic kidneys from healthy controls. The presence and degree of fibrosis are confirmed by histology, which also indicates fibrosis as the main driver behind the DKI differences observed between groups. We therefore conclude that fast kurtosis is a likely candidate for an MRI-based method for the detection and monitoring of renal fibrosis. We provide protocol recommendations for fast renal DKI in humans based on a b-value optimisation performed using data acquired at 3 T in normal human kidney.

Skeletal phenotypes in adult patients with osteogenesis imperfecta-correlations with COL1A1/COL1A2 genotype and collagen structure.

Osteogenesis imperfecta (OI) is characterized by a high fracture rate and great heterogeneity. This cross-sectional study presents skeletal investigations and protein analyses in 85 adult OI patients. We find significant differences in bone mass, architecture, and fracture rate that correlate well with the underlying biochemical and molecular abnormalities. INTRODUCTION: OI is a hereditary disease characterized by compromised connective tissue predominantly caused by mutations in collagen type 1 (COL-1) encoding genes. Widespread symptoms reflect the ubiquity of COL-1 throughout the body. The purpose of this study was to improve our understanding of clinical manifestations by investigating anthropometry and skeletal phenotypes (DXA, HRpQCT) in an adult OI population and compare the findings to underlying COL-1 genotype and structure. METHODS: The study comprised 85 OI patients aged 45 (19-78) years, Sillence type I (n = 58), III (n = 12), and IV (n = 15). All patients underwent DXA, HRpQCT, spine X-ray, biochemical testing, and anthropometry. COL1A1 and COL1A2 were sequenced and 68 OI causing mutations identified (46 in COL1A1, 22 in COL1A2). Analysis of COL-1 structure (quantitative/qualitative defect) by SDS-PAGE was performed in a subset (n = 67). RESULTS: A qualitative collagen defect predisposed to a more severe phenotype with reduced aBMD, more fractures, and affected anthropometry compared to patients with a quantitative COL-1 defect (p < 0.05). HRpQCT revealed significant differences between patients with OI type I and IV. Patients with type I had lower vBMD (p < 0.005), thinner cortexes (p < 0.001), and reduced trabecular number (p < 0.005) compared to patients with type IV indicating that HRpQCT may distinguish type I from type IV better than DXA. CONCLUSION: The defective collagen in patients with OI has pronounced effects on the skeleton. The classical OI types based on the clinical classification show profound differences in bone mass and architecture and the differences correlate well with the underlying biochemical and molecular collagen abnormalities.

Epiphytic bacterial communities of the alga Fucus vesiculosus in oil-contaminated water areas of the Barents Sea.

Taxonomic compositions of epiphytic bacterial communities in water areas differing in levels of oil pollution were revealed. In total, 82 bacterial genera belonging to 16 classes and 11 phyla were detected. All detected representatives of epiphytic bacterial communities belonged to the phyla Actinobacteria, Bacteroidetes, Planctomycetes, Proteobacteria, Verrucomicrobia, Acidobacteria, Cyanobacteria, Firmicutes, and Fusobacteria and candidate division TM7. The ratio of the phyla in the communities varied depending on the levels of oil pollution. New data on taxonomic composition of uncultivated epiphytic bacterial communities of Fucus vesiculosus were obtained.

Next-generation sequencing identifies germline MRE11A variants as markers of radiotherapy outcomes in muscle-invasive bladder cancer.

BACKGROUND: Muscle-invasive bladder cancer (MIBC) can be cured by radical radiotherapy (RT). We previously found tumour MRE11 expression to be predictive of survival following RT in MIBC, and this was independently validated in a separate institute. Here, we investigated germline MRE11A variants as possible predictors of RT outcomes in MIBC, using next-generation sequencing (NGS). PATIENTS AND METHODS: The MRE11A gene was amplified in germline DNA from 186 prospectively recruited MIBC patients treated with RT and sequenced using bar-coded multiplexed NGS. Germline variants were analysed for associations with cancer-specific survival (CSS). For validation as a prognostic or predictive marker, rs1805363 was then genotyped in a cystectomy-treated MIBC cohort of 256 individuals. MRE11A mRNA isoform expression was measured in bladder cancer cell lines and primary tumour samples. RESULTS: Carriage of at least one of six (five novel) rare variants was associated with the worse RT outcome (hazard ratio [HR] 4.04, 95% confidence interval [95% CI] 1.42-11.51, P = 0.009). The single-nucleotide polymorphism (SNP), rs1805363 (minor allele frequency 11%), was also associated with worse CSS (per-allele HR 2.10, 95% CI 1.34-3.28, Ptrend = 0.001) following RT in MIBC, with a gene-dosage effect observed, but no effect seen on CSS in the cystectomy cohort (Ptrend = 0.89). Furthermore, rs1805363 influenced relative MRE11A isoform expression, with increased isoform 2 expression with carriage of the rs1805363 minor A allele. CONCLUSIONS: Germline MRE11A SNP rs1805363 was predictive of RT, but not of cystectomy outcome in MIBC. If successfully validated in an independent RT-treated cohort, this SNP could be a useful clinical tool for selecting patients for bladder-conserving treatment.

Human malaria parasites in continuous culture.

Plasmodium falciparum can now be maintained in continuous culture in human erythrocytes incubated at 38 degrees C in RPMI 1640 medium with human serum under an atmosphere with 7 percent carbon dioxide and low oxygen (1 or 5 percent). The original parasite material, derived from an infected Aotus trivirgatus monkey, was diluted more than 100 million times by the addition of human erythrocytes at 3- or 4-day intervals. The parasites continued to reproduce in their normal asexual cycle of approximately 48 hours but were no longer highly synchronous. The have remained infective to Aotus.

Induction of crisis forms in cultured Plasmodium falciparum with human immune serum from Sudan.

Serums from 90 individuals from three areas in Sudan were tested for inhibitory activity against cultures of Plasmodium falciparum. In addition to inhibitory activity against merozoite invasion, all of the serums demonstrated, in varying degrees, the ability to retard intraerythrocyte development, leading to crisis forms and parasite deterioration. These retardation factors could be removed by absorption of immune serum with parasite-infected erythrocytes and were demonstrable in purified immunoglobulin fractions. Serum from donors in hypoendemic Khartoum did not retard parasite development.

Making the most of Papua New Guinea's biodiversity: Establishment of an integrated set of programs that link botanical survey with pharmacological assessment in "The Land of the Unexpected"

An integrated and coordinated set of programs has been established to meet ICBG goals in Papua New Guinea (PNG). Here we give an overview of the PNG ICBG and focus on the key elements and major steps taken to establish a program necessary for the pharmacological assessment of botanicals and traditional medicines in PNG and, by extrapolation, in other developing countries.

Probabilistic modelling of combined sewer overflow using the First Order Reliability Method.

This paper presents a new and alternative method (in the context of urban drainage) for probabilistic hydrodynamical analysis of drainage systems in general and especially prediction of combined sewer overflow. Using a probabilistic shell it is possible to implement both input and parameter uncertainties on an application of the commercial urban drainage model MOUSE combined with the probabilistic First Order Reliability Method (FORM). Applying statistical characteristics on several years of rainfall, it is possible to derive a parameterization of the rainfall input and the failure probability and return period of combined sewer overflow to receiving waters can be found.

Unmet informational and supportive care needs of patients with muscle invasive bladder cancer: A systematic review of the evidence.

BACKGROUND: Little is known about the unmet supportive care needs of patients affected by muscle invasive bladder cancer (MIBC). We set out to determine the different domains of unmet supportive care needs for patients affected by MIBC. LITERATURE SEARCH: A systematic review was conducted according to the PRISMA Statement Guidelines. A sensitive search was performed in electronic databases (DARE, Cochrane, MEDLINE, BNI, PsychINFO, EMBASE and CIHAHL) from the earliest date available to January 2017. DATA EVALUATION: 1405 references were retrieved, 8 articles met the eligibility criteria and were appraised and ranked by strength using the levels of evidence. SYNTHESIS: Individual unmet needs were classified into the following domains: patient-clinician communication, daily living needs, health system/information needs, practical needs, family-related needs, social needs, psychological needs, physical needs and intimacy needs. Patients reported high unmet needs at diagnosis and into survivorship. CONCLUSIONS: This review contributes to a greater understanding of the unmet supportive care needs of patients affected by MIBC. Findings reflect a paucity of research, but existing studies indicated needs commonly related to intimacy, informational, physical and psychological needs. Despite the emerging evidence-base, the current within study limitations precludes our understanding about how the needs of patients evolve over time.

Genetic Polymorphisms in Organic Cation Transporter 1 Attenuates Hepatic Metformin Exposure in Humans.

Metformin has been used successfully to treat type 2 diabetes for decades. However, the efficacy of the drug varies considerably from patient to patient and this may in part be due to its pharmacokinetic properties. The aim of this study was to examine if common polymorphisms in SLC22A1, encoding the transporter protein OCT1, affect the hepatic distribution of metformin in humans. We performed noninvasive 11 C-metformin positron emission tomography (PET)/computed tomography (CT) to determine hepatic exposure in 12 subjects genotyped for variants in SLC22A1. Hepatic distribution of metformin was significantly reduced after oral intake in carriers of M420del and R61C variants in SLC22A1 without being associated with changes in circulating levels of metformin. Our data show that genetic polymorphisms in transporter proteins cause variation in hepatic exposure to metformin, and it demonstrates the application of novel imaging techniques to investigate pharmacogenetic properties in humans.

The Convective Transport of Active Species in the Tropics (CONTRAST) Experiment.

The Convective Transport of Active Species in the Tropics (CONTRAST) experiment was conducted from Guam (13.5° N, 144.8° E) during January-February 2014. Using the NSF/NCAR Gulfstream V research aircraft, the experiment investigated the photochemical environment over the tropical western Pacific (TWP) warm pool, a region of massive deep convection and the major pathway for air to enter the stratosphere during Northern Hemisphere (NH) winter. The new observations provide a wealth of information for quantifying the influence of convection on the vertical distributions of active species. The airborne in situ measurements up to 15 km altitude fill a significant gap by characterizing the abundance and altitude variation of a wide suite of trace gases. These measurements, together with observations of dynamical and microphysical parameters, provide significant new data for constraining and evaluating global chemistry climate models. Measurements include precursor and product gas species of reactive halogen compounds that impact ozone in the upper troposphere/lower stratosphere. High accuracy, in-situ measurements of ozone obtained during CONTRAST quantify ozone concentration profiles in the UT, where previous observations from balloon-borne ozonesondes were often near or below the limit of detection. CONTRAST was one of the three coordinated experiments to observe the TWP during January-February 2014. Together, CONTRAST, ATTREX and CAST, using complementary capabilities of the three aircraft platforms as well as ground-based instrumentation, provide a comprehensive quantification of the regional distribution and vertical structure of natural and pollutant trace gases in the TWP during NH winter, from the oceanic boundary to the lower stratosphere.

Epirubicin cardiotoxicity: a study of 135 patients with advanced breast cancer.

The cardiotoxicity of epirubicin (EPI) was evaluated clinically, radiologically, with ECG, and with multiple ECG-gated radionuclide determination of the left ventricular ejection fraction (LVEF) during rest in 135 patients with advanced breast cancer. The EPI doses were 60 mg/m2 on days 1 and 8 every 4 weeks or 45 mg/m2 plus vindesine 3 mg/m2 on the same schedule. The median cumulative dose of EPI was 500 mg/m2 (range, 47 to 1,563). Eight of the 135 patients developed congestive heart failure (CHF). Of 67 patients treated with EPI less than 500 mg/m2, none developed CHF. Among 48 patients treated with doses between 500 and 1,000 mg/m2, one had CHF (2%; 95% confidence limits, 0.1 to 11.1). Among 20 patients who received EPI from 1,000 to 1,563 mg/m2, seven developed CHF (35%; 95% confidence limits, 15.4 to 59.2). Four patients died due to cardiotoxicity. The risk of EPI cardiotoxicity at the present schedule is considerable at doses above 1,000 mg/m2. At doses between 500 and 1,000 mg/m2 the risk of CHF decreases, and at doses below 500 mg/m2, it is negligible. For all patients, the prevalence of CHF was 6% and the sensitivity of LVEF high (95%), mainly due to the low incidence of CHF. Among the 20 patients who received EPI at more than 1,000 mg/m2, the prevalence of CHF was 35% and the sensitivity only 64%. The specificity was maximally 62%. Our results suggest that LVEF is of no value as a predictor for CHF.

Evaluating sexual function in women after radical cystectomy as treatment for bladder cancer.

OBJECTIVE: Sexual function remains a relatively unexplored field within urology, especially for female patients who have undergone radical cystectomy (RC). The aim of this study was to shed light on this area. MATERIALS AND METHODS: The Female Sexual Function Index (FSFI) questionnaire and other selective questions regarding sexual function were sent to 71 women who had undergone RC and were alive 1 year postsurgery. Forty-one completed questionnaires were returned and analysed using simple descriptive statistical analysis, owing to the small sample size. RESULTS: The median age of the patients was 67 years (range 39-91 years). Seventy-eight per cent reported being sexually active before surgery and 37% post-surgery. The median FSFI score postsurgery was 4.8 (range 1.2-32). The highest FSFI score was seen in the category of satisfaction, which consists of questions regarding closeness with partner, sexual relationship and overall sex life. Lowest FSFI scores were seen for lubrication, orgasm and pain. Twenty-seven per cent of patients wanted more information on the impact RC would have on their sex lives and many asked for information for their partners. CONCLUSION: Despite being based on a limited number of patients, this study indicates a need for improvement within this field. Most patients scored below 26 on the FSFI questionnaire, the cut-off for sexual dysfunction. However, many reported being satisfied overall. Thus, the physician's main goal is to identify patients in need of more information and guidance before and after surgery.

A mathematical model approach quantifying patients' response to changes in mechanical ventilation: evaluation in volume support.

This paper presents a mathematical model-approach to describe and quantify patient-response to changes in ventilator support. The approach accounts for changes in metabolism (V̇O2, V̇CO2) and serial dead space (VD), and integrates six physiological models of: pulmonary gas-exchange; acid-base chemistry of blood, and cerebrospinal fluid; chemoreflex respiratory-drive; ventilation; and degree of patients' respiratory muscle-response. The approach was evaluated with data from 12 patients on volume support ventilation mode. The models were tuned to baseline measurements of respiratory gases, ventilation, arterial acid-base status, and metabolism. Clinical measurements and model simulated values were compared at five ventilator support levels. The models were shown to adequately describe data in all patients (χ(2), p > 0.2) accounting for changes in V̇CO2, VD and inadequate respiratory muscle-response. F-ratio tests showed that this approach provides a significantly better (p < 0.001) description of measured data than: (a) a similar model omitting the degree of respiratory muscle-response; and (b) a model of constant alveolar ventilation. The approach may help predict patients' response to changes in ventilator support at the bedside.

A mathematical model approach quantifying patients' response to changes in mechanical ventilation: Evaluation in pressure support.

PURPOSE: This article evaluates how mathematical models of gas exchange, blood acid-base status, chemical respiratory drive, and muscle function can describe the respiratory response of spontaneously breathing patients to different levels of pressure support. METHODS: The models were evaluated with data from 12 patients ventilated in pressure support ventilation. Models were tuned with clinical data (arterial blood gas measurement, ventilation, and respiratory gas fractions of O2 and CO2) to describe each patient at the clinical level of pressure support. Patients were ventilated up to 5 different pressure support levels, for 15 minutes at each level to achieve steady-state conditions. Model-simulated values of respiratory frequency (fR), arterial pH (pHa), and end-tidal CO2 (FeCO2) were compared to measured values at each pressure support level. RESULTS: Model simulations compared well to measured data with Bland-Altman bias and limits of agreement of fR of 0.7 ± 2.2 per minute, pHa of -0.0007 ± 0.019, and FeCO2 of -0.001 ± 0.003. CONCLUSION: The models describe patients' fR, pHa, and FeCO2 response to changes in pressure support with low bias and narrow limits of agreement.

Inhibition of the growth of Plasmodium falciparum in vitro by covalent modification of hemoglobin.

Antimalarial effects might be expected from compounds that modify hemoglobin. Dibromoaspirin and bis(dibromosalicyl) diesters decrease gelation of hemoglobin by specific covalent modification (acetylation and crosslinking) of this protein but do not interfere with oxygen transport. These compounds were toxic to malaria parasites when continuously present in culture, as were drugs with similar pharmacological effects such as indomethacin, ibuprofen, and phenylbutazone. Aspirin and acetaminophen were much less effective. When erythrocytes were pretreated with these compounds prior to parasite exposure, only dibromoaspirin and dibromosalicyl diesters prevented parasite development. The modified hemoglobin was highly resistant to digestion by cathepsin D and parasite proteases, suggesting that covalent modifications of hemoglobin that do not disrupt normal hemoglobin function have antimalarial effects.

Neuroendocrine aspects of attention deficit hyperactivity disorder.

This article summarizes the existing neuroendocrine literature and reports the growth hormone response to stimulation with L-dopa and clonidine in male children and adolescents with attention deficit hyperactivity disorder. Because growth hormone secretion is regulated by monoamine neurotransmitters, hyposecretion of growth hormone may reflect generalized changes in the neurochemical substrate of this disorder. With refinement, these neuroendocrine challenge tests may become unique biologic markers in identifying attention deficit hyperactivity disorder in children and adolescents.

Increased plasma levels of soluble ICAM-1 and ELAM-1 (E-selectin) during acute Plasmodium falciparum malaria.

Acute P. falciparum malaria is associated with a loss of antigen-responsiveness of peripheral T cells, depletion of T cells characterized by high surface expression of the adhesion molecule LFA-1, and increased plasma levels of the T-cell activation marker soluble IL-2 receptor (sIL-2R). In the present study we show that clinical episodes of P. falciparum malaria produced an increase in plasma levels of soluble ICAM-1 (sICAM-1) and ELAM-1 (sELAM-1). The increase was transient and subsided slowly (sICAM-1) or rapidly (sELAM-1) following drug cure. The increases in plasma sICAM-1 and sELAM-1 were significantly correlated, and were furthermore associated with a concomitant increase in plasma levels of sIL-2R. Finally, plasma levels of sICAM-1, but not sELAM-1, were inversely correlated to the fraction of peripheral T cells having high surface expression of LFA-1, the receptor for T-cell adhesion to ICAM-1. Taken together, these observations suggest that acute P. falciparum malaria is characterized by a state of endothelial inflammation associated with the adherence of activated T cells.

Human T-cell recognition of synthetic peptides representing conserved and variant sequences from the merozoite surface protein 2 of Plasmodium falciparum.

Merozoite surface protein 2 (MSP2) is a malaria vaccine candidate currently undergoing clinical trials. We analyzed the peripheral blood mononuclear cell (PBMC) response to synthetic peptides corresponding to conserved and variant regions of the FCQ-27 allelic form of MSP2 in Ghanaian individuals from an area of hyperendemic malaria transmission and in Danes without exposure to malaria. PBMC from 20-39% of Ghanaians responded to each of the peptides by proliferation and 29-36% had PBMC which produced interferon-gamma (IFN-gamma) in response to peptide stimulation. In Danes, there was no proliferation to two of the peptides and only PBMC from 5% of the individuals proliferated to the other three peptides. IFN-gamma production was not detected to any peptide. In both Danes and Ghanaians in only a few instances was IL-4 detected in the PBMC cultures. Overall PBMC from 79% of the Ghanaians responded by proliferation and/or cytokine secretion to at least one of three peptides tested, whereas responses were only observed in 14% of Danes (P = 0.002). These data suggest that the Ghanaians had expanded peripheral blood T-cell populations recognizing the peptides as a result of natural infection. The findings are encouraging for the development of a vaccine based on these T-epitope containing regions of MSP2, as the peptides were broadly recognized suggesting that they can bind to diverse HLA alleles and also because they include conserved MSP2 sequences. Immunisation with a vaccine construct incorporating the sequences present in these peptides could thus be expected to be immunogenic in a high percentage of individuals and lead to the establishment of memory T-cells, which can be boosted through natural infection.

Differential T-cell expression of LFA-1 in residents from Africa and Denmark. Description of the phenomenon and its possible basis.

All circulating T cells constitutively express the adhesion molecule leukocyte function-associated antigen 1 (LFA-1; CD11a/CD18) at either low or high surface density. In the present paper we have compared the expression of the LFA-1 alpha-chain CD11a on peripheral T cells obtained from indigenous Africans with permanent residence in Africa to T cells from indigenous Danes with permanent residence in Denmark. The Africans had a higher percentage of T cells with high CD11a expression than did Danish donors. The difference was evident in both the CD3-, CD4+, and CD8+ subsets. The difference did not appear to reflect a higher degree of peripheral T-cell activation in the African donors, as T-cell expression of the activation marker IL-2 receptor (CD25) was similar in the two groups. Furthermore, we observed no apparent correlation between CD3+ CD11a(hi) and CD3+ CD25+ values in individual donors. LFA-1 expression on T cells obtained from expatriate Africans with long-term residence in Denmark resembled that of Danish permanent residents more than that of Africans with permanent residence in Africa. In addition, T cells obtained from two expatriate Danes with long-term residence in rural Africa were phenotypically similar to those from African permanent residents. The data suggest that the observed difference is environmental rather than ethnic and may reflect the degree of exposure to infectious agents.