A 3D image-based modelling approach for understanding spatiotemporal processes in phosphorus fertiliser dissolution, soil buffering and uptake by plant roots.

Phosphorus (P) is a key yield-limiting nutrient for crops, but the main source of P fertiliser is finite. Therefore, efficient fertilisation is crucial. Optimal P application requires understanding of the dynamic processes affecting P availability to plants, including fertiliser dissolution rate and soil buffer power. However, standard soil testing methods sample at fixed time points, preventing a mechanistic understanding of P uptake variability. We used image-based modelling to investigate the effects of fertiliser dissolution rate and soil buffer power on P uptake by wheat roots imaged using X-ray CT. We modelled uptake based on 1-day, 1-week, and 14-week dissolution of a fixed quantity of total P for two common soil buffer powers. We found rapid fertiliser dissolution increased short-term root uptake, but total uptake from 1-week matched 1-day dissolution. We quantified the large effects root system architecture had on P uptake, finding that there were trade-offs between total P uptake and uptake per unit root length, representing a carbon investment/phosphorus uptake balance. These results provide a starting point for predictive modelling of uptake from different P fertilisers in different soils. With the addition of further X-ray CT image datasets and a wider range of conditions, our simulation approach could be developed further for rapid trialling of fertiliser-soil combinations to inform field-scale trials or management.

Understanding and breaking the intergenerational cycle of abuse in families enrolled in routine mental health services: study protocol for a randomized controlled trial and two non-interventional trials investigating mechanisms of change within the UBICA II consortium.

BACKGROUND: Parents' mental illness (MI) and parental history of early life maltreatment (ELM) are known to be significant risk factors for poor parenting while poor parenting is a crucial mediator of the intergenerational continuity of child maltreatment. Hence, maltreatment prevention programs for families with an MI parent, which pay particular attention to experiences of ELM in the parent, are urgently needed. Parental mentalizing was previously found to mediate successful parenting. Interventions aimed at improving the parental mentalizing capacity reduced maltreatment risk in parents. The aim of the present study is to investigate the effectiveness of a mentalization-based parenting-counseling in acutely mentally ill parents currently treated at a psychiatric hospital. METHODS: Mentalization-based parenting-counseling (MB-PC) vs. enhanced standard clinical care (SCC+) will be administered in a cluster-randomized-controlled trial (RCT). Patients treated at psychiatric hospitals with children between 1.5 and 15 years will be included in the trial. MB-PC will be administered as a 12-h combined individual and group program enriched by social counseling (over a course of 5 weeks) as add-on to standard clinical care, while the control condition will be standard clinical care plus a 90-min psychoeducation workshop on positive parenting. Primary efficacy endpoint is self-reported parenting practices at follow-up. Embedded within the RCT will be two sub-studies investigating social cognition and dyadic synchrony as biobehavioral mechanisms of change. DISCUSSION: The main goal of the present study is to investigate ways to break the intergenerational continuity of maltreatment by assessing the benefits of a prevention program which aims at improving parenting in vulnerable mothers and fathers. MB-PC is a short, low-cost intervention which can be delivered by nurses and social workers and is applicable to MI patients with children with a broad range of diagnoses. If it is shown to be effective, it can be directly implemented into standard psychiatric hospital care thereby providing help to prevent child maltreatment. TRIAL REGISTRATION: German Clinical Trials Register DRKS00017398 . Registered on 5 July 2019.

Effects of dietary menhaden oil on growth and reproduction in gilts farrowed by sows that consumed diets containing menhaden oil during gestation and lactation.

In sows, n-3 fatty acids increase litter sizes, however, effects on gilt reproductive development have not been adequately studied. Moreover, not determined are effects of feeding n-3 fatty acids to sows on reproduction in offspring. The objective here was to determine effects of 4% dietary menhaden oil on growth and puberty in gilts farrowed by sows fed menhaden oil. Sows (n = 44) were assigned to: (1) control gestation and lactation diets, or (2) diets including menhaden oil. For primiparous sows only, total litter size and born alive were greater (P < 0.05) in females fed menhaden oil. Conversely, pigs from primiparous controls were heavier (P < 0.05) than pigs from primiparous sows fed menhaden oil (parity by diet interactions, P < 0.01). Diet did not affect (P > 0.20) other sow and litter characteristics. At weaning, 84 gilts from control- or menhaden oil sows were placed three gilts per pen and provided control diets or diets containing menhaden oil. Nursery and grow-finish feed intake and feed efficiency were similar (P > 0.21) for gilts from the different sows and weight gain was similar (P > 0.24) for gilts fed control or menhaden diets. Gilts fed menhaden oil tended to eat less in the nursery (1.18±0.08 kg v. 0.98±0.08 kg; P = 0.09) and overall (1.83±0.04 kg v. 1.72±0.04 kg; P = 0.06). Thus, overall feed to gain was greater (2.52±0.03 v. 2.33±0.03; P < 0.01) and nursery (2.12±0.04 v. 1.80±0.04; P = 0.10) and grow-finish (3.07±0.19 v. 2.58±0.19; P = 0.08) feed to gain tended to be greater, for control gilts. Age at puberty was greater (P = 0.02) for gilts from menhaden oil-fed sows (205.1±3.2 days) compared to gilts from controls (193.9±3.2 days) and tended to be greater (P = 0.09), for controls (203.5±3.2 days) compared to gilts fed menhaden oil (195.5±3.2 days). A tendency existed (P = 0.09) for greater follicular fluid in gilts fed menhaden oil, however, ovulation rate and ovarian, luteal and uterine weights were not affected by sow diet, gilt diet or the interaction (P > 0.23). Feeding gilts menhaden oil enhanced feed efficiency and hastened puberty onset. Gilts from sows consuming menhaden oil exhibited delayed puberty and retaining females from sows fed this feedstuff may be ill advised.

Non-Invasive Management of Peripheral Arterial Disease.

BACKGROUND: Peripheral arterial disease (PAD) is common and symptoms can be debilitating and lethal. Risk management, exercise, radiological and surgical intervention are all valuable therapies, but morbidity and mortality rates from this disease are increasing. Circulatory enhancement can be achieved using simple medical electronic devices, with claims of minimal adverse side effects. The evidence for these is variable, prompting a review of the available literature. METHODS: Embase and Medline were interrogated for full text articles in humans and written in English. Any external medical devices used in the management of peripheral arterial disease were included if they had objective outcome data. RESULTS: Thirty-one papers met inclusion criteria, but protocols were heterogenous. The medical devices reported were intermittent pneumatic compression (IPC), electronic nerve (NMES) or muscle stimulators (EMS), and galvanic electrical dressings. In patients with intermittent claudication, IPC devices increase popliteal artery velocity (49-70 %) and flow (49-84 %). Gastrocnemius EMS increased superficial femoral artery flow by 140 %. Over 4.5-6 months IPC increased intermittent claudication distance (ICD) (97-150 %) and absolute walking distance (AWD) (84-112 %), with an associated increase in quality of life. NMES of the calf increased ICD and AWD by 82 % and 61-150 % at 4 weeks, and 26 % and 34 % at 8 weeks. In patients with critical limb ischaemia IPC reduced rest pain in 40-100 % and was associated with ulcer healing rates of 26 %. IPC had an early limb salvage rate of 58-83 % at 1-3 months, and 58-94 % at 1.5-3.5 years. No studies have reported the use of EMS or NMES in the management of CLI. CONCLUSION: There is evidence to support the use of IPC in the management of claudication and CLI. There is a building body of literature to support the use of electrical stimulators in PAD, but this is low level to date. Devices may be of special benefit to those with limited exercise capacity, and in non-reconstructable critical limb ischaemia. Galvanic stimulation is not recommended.

Effect of Cranberry Extract on the Frequency of Bacteriuria in Dogs with Acute Thoracolumbar Disk Herniation: A Randomized Controlled Clinical Trial.

BACKGROUND: Dogs with spinal cord injury are at increased risk of developing bacteriuria due to increased residual urine volume. Cranberry extract inhibits binding of E. coli to uroepithelial cells, potentially reducing risk of bacteriuria. HYPOTHESIS: Cranberry extract reduces risk of bacteriuria in dogs after acute TL-IVDH. ANIMALS: Client-owned dogs with acute onset TL-IVDH causing nonambulatory status. METHODS: Randomized, placebo-controlled, blinded, prospective clinical trial. Dogs with acute TL-IVDH were recruited 48 hours postoperatively and randomized to receive cranberry extract or placebo in a masked fashion. Urine cultures and neurological examinations were performed 2, 4, and 6 weeks postoperatively. The number of dogs with bacteriuria (all bacterial species) and bacteriuria (E. coli) were primary and secondary outcome measures and were evaluated using chi-squared test. Urine antiadhesion activity (AAA) was measured in a subset (N = 47) and examined in a secondary analysis evaluating additional risk factors for bacteriuria. RESULTS: Bacteriuria was detected 17 times in 94 dogs (6 placebo, 11 cranberry, P = .12). There were 7 E. coli. positive cultures (1 placebo, 6 cranberry, P = .09). Dogs in both groups had positive urine AAA (14/21: placebo, 16/26: cranberry), and dogs with urine AAA had significantly fewer E. coli positive cultures (n = 1) than dogs without it (n = 4) (P = .047). CONCLUSIONS AND CLINICAL IMPORTANCE: This clinical trial did not show a benefit of oral cranberry extract but had low power. Cranberry extract supplementation did not impact urine AAA, but a possible association between urine AAA and lower risk of E. coli bacteriuria was identified. Other doses could be investigated.

Randomised Controlled Trial: Potential Benefit of a Footplate Neuromuscular Electrical Stimulation Device in Patients with Chronic Venous Disease.

OBJECTIVES: Chronic venous disease (CVD) is common, affecting a quarter of the population. Current conservative methods of treatment aim to prevent progression of disease by reducing ambulatory venous pressure. Neuromuscular electrical stimulation (NMES) refers to the use of electrical impulses to elicit muscle contraction. This pilot randomised controlled trial investigates the effect of a footplate NMES device (REVITIVE) on venous flow parameters, limb oedema, and quality of life outcome measures in patients with CVD. METHODS: Twenty-two patients with Clinical Etiological Anatomical and Pathophysiological (CEAP) clinical class C2-C4 venous disease were randomised to receive a sham or test device. The recommended duration of use was for 30 minutes daily for 6 weeks. Venous flow parameters (duplex ultrasound), limb volume (optoelectric volumeter), and quality of life outcome measures were measured at baseline and after 6 weeks. RESULTS: The mean age of participants was 62 years, body mass index 28.6, with a 15:7 female preponderance. There was a significant difference in the percentage change in femoral vein flow parameters (from baseline) between the test and sham group while using the device (Week 0 time-averaged mean velocity 102.4% vs. -9.1%, p < .0001; volume flow 107.9% vs. -3.7%, p < .0001; peak velocity 377.7% vs. -6.7%, p < .0001). Limb volume was observed to increase significantly in the sham group (2.0% at Week 0 and 1.2% at Week 6; p < .01). This was prevented in the test group (+0.8% at Week 0 and 1.0% at Week 6; p = .06). There was a significant difference in the Aberdeen Varicose Vein Questionnaire between the two groups over the 6 weeks. CONCLUSIONS: This trial demonstrated a significant difference in venous flow parameters and prevention of orthostatic limb oedema with NMES. There was a positive effect on quality of life. Larger studies are required to determine the clinical significance of this in patients with venous disease.

"What about diet?" A qualitative study of cancer survivors' views on diet and cancer and their sources of information.

Given the abundance of misreporting about diet and cancer in the media and online, cancer survivors are at risk of misinformation. The aim of this study was to explore cancer survivors' beliefs about diet quality and cancer, the impact on their behaviour and sources of information. Semi-structured interviews were conducted with adult cancer survivors in the United Kingdom who had been diagnosed with any cancer in adulthood and were not currently receiving treatment (n = 19). Interviews were analysed using Thematic Analysis. Emergent themes highlighted that participants were aware of diet affecting risk for the development of cancer, but were less clear about its role in recurrence. Nonetheless, their cancer diagnosis appeared to be a prompt for dietary change; predominantly to promote general health. Changes were generally consistent with healthy eating recommendations, although dietary supplements and other non-evidence-based actions were mentioned. Participants reported that they had not generally received professional advice about diet and were keen to know more, but were often unsure about information from other sources. The views of our participants suggest cancer survivors would welcome guidance from health professionals. Advice that provides clear recommendations, and which emphasises the benefits of healthy eating for overall well-being, may be particularly well-received.

Conservative management for female urinary incontinence and pelvic organ prolapse review 2013: Summary of the 5th International Consultation on Incontinence.

AIMS: The objective of the 5th International Consultation on Incontinence (ICI) chapter on Adult Conservative Management was to review and summarize the new evidence on conservative management of urinary incontinence (UI) and pelvic organ prolapse (POP) in order to compile a current reference source for clinicians, health researchers, and service planners. In this paper, we present the review highlights and new evidence on female conservative management. METHODS: Revision and updates of the 4th ICI Report using systematic review covering years 2008-2012. RESULTS: Each section begins with a brief definition and description of the intervention followed by a summary, where possible, of both the state and level of evidence for prevention and treatment, and ends with a "grade of recommendation." The paper concludes with areas identified as requiring further research. CONCLUSIONS: For UI, there are no prevention trials on lifestyle interventions. There are, however, few new intervention trials of lifestyle interventions involving weight loss and fluid intake with improved levels of evidence and grade of recommendation. Outside of pre- and post-natal pelvic floor muscle training (PFMT) trials for the prevention of female UI, there is a dearth of PFMT prevention trials for women with UI. PFMT remains the first-line treatment for female UI with high levels of evidence and grades of recommendation. Bladder training levels of evidence and grades of recommendation are maintained. For POP, new evidence supports the effectiveness of physiotherapy in the treatment of POP and there are now improved levels of evidence and grades of recommendation. Neurourol. Urodynam. 35:15-20, 2016. © 2014 Wiley Periodicals, Inc.

Improving paediatric outreach services for urban Aboriginal children through partnerships: views of community-based service providers.

BACKGROUND: In Australia, Aboriginal children experience significantly poorer health outcomes compared with non-Aboriginal children. Health policies aimed at improving Aboriginal health outcomes include interventions in the early childhood period. There is a need for government health services to work in partnership with Aboriginal people and other services to achieve the highest level of health possible for Aboriginal children, who often require a range of services to meet complex needs. AIM: This paper describes the views of service providers on how paediatric outreach services work in partnership with other services, Aboriginal families and the community and how those partnerships could be improved to maximize health outcomes for children. METHODS: In-depth, semi-structured interviews and focus groups were conducted with managers and service providers over a 6-week period in 2010. The views and suggestions of participants were documented and a thematic analysis was undertaken. RESULTS AND DISCUSSION: Analysis of two focus groups with seven service providers and five individual interviews with service managers resulted in the identification of four themes: (i) using informal and formal ways of working; (ii) cultivating effective relationships; (iii) demonstrating cultural sensitivity; and (iv) forging strong leadership. Use of formal and informal approaches facilitated effective relationships between service providers and Aboriginal families and communities. Partnerships with the community were founded on a culturally appropriate model of care that recognized a holistic approach to health and wellness. Leadership emerged as an essential component of effective partnerships, cultivating the ethos of the workplace and creating an environment where collaboration is supported. CONCLUSION: Culturally appropriate child health services, which utilize effective relationships and employ a range of informal and formal collaboration with other services and community members, are well positioned to implement health policy and improve access to services for Aboriginal children with better health outcomes as a result.

Influence of Carbon and Microbial Community Priming on the Attenuation of Uranium in a Contaminated Floodplain Aquifer.

The capacity for subsurface sediments to sequester radionuclide contaminants, such as uranium (U), and retain them after bioremediation efforts are completed is critical to the long-term stewardship of re-mediated sites. In U bioremediation strategies, carbon amendment stimulates bioreduction of U(VI) to U(IV), immobilizing it within the sediments. Sediments enriched in natural organic matter are naturally capable of sequestering significant U, but may serve as sources to the aquifer, contributing to plume persistence. Two types of organic-rich sediments were compared to better understand U release mechanisms. Sediments that were artificially primed for U removal were retrieved from an area previously biostimulated while detrital-rich sediments were collected from a location never subject to amendment. Batch incubations demonstrated that primed sediments rapidly removed uranium from the groundwater, whereas naturally reduced sediments released a sizeable portion of U before U(VI)-reduction commenced. Column experiments confirmed that U release persisted for 65 pore volumes in naturally reduced sediments, demonstrating their sink-source behavior. Acetate addition to primed sediments shifted the microbial community from sulfate-reducing bacteria within Desulfobacteraceae to the iron-reducing Geobacteraceae and Firmicutes, associated with efficient U(VI) removal and retention, respectively. In contrast, Geobacteraceae communities in naturally reduced sediments were replaced by sequences with similarity to Pseudomonas spp. during U release, while U(VI) removal only occurred with enrichment of Firmicutes. These investigations stress the importance of characterizing zones with heterogeneous carbon pools at U-contaminated sites prior to the determination of a remedial strategy to identify areas, which may contribute to long-term sourcing of the contaminants.

Haemodynamic changes with the use of neuromuscular electrical stimulation compared to intermittent pneumatic compression.

INTRODUCTION: Enhancement of peripheral circulation has been shown to be of benefit in many vascular disorders, and the clinical effectiveness of intermittent pneumatic compression is well established in peripheral vascular disease. This study compares the haemodynamic efficacy of a novel neuromuscular electrical stimulation device with intermittent pneumatic compression in healthy subjects. METHODS: Ten healthy volunteers (mean age 27.1 ± 3.8 years, body mass index 24.8 ± 3.6 kg/m(2)) were randomised into two groups, in an interventional crossover trial. Devices used were the SCD Express™ Compression System, (Covidien, Ireland) and the geko™, (Firstkind Ltd, UK). Devices were applied bilaterally, and haemodynamic measurements taken from the left leg. Changes to haemodynamic parameters (superficial femory artery and femoral vein) and laser Doppler measurements from the hand and foot were compared. RESULTS: Intermittent pneumatic compression caused 51% (p = 0.002), 5% (ns) and 3% (ns) median increases in venous peak velocity, time-averaged maximum velocity and volume flow, respectively; neuromuscular electrical stimulator stimulation caused a 103%, 101% and 101% median increases in the same parameters (all p = 0.002). The benefit was lost upon deactivation. Intermittent pneumatic compression did not improve arterial haemodynamics. Neuromuscular electrical stimulator caused 11%, 84% and 75% increase in arterial parameters (p < 0.01). Laser Doppler readings taken from the leg were increased by neuromuscular electrical stimulator (p < 0.001), dropping after deactivation. For intermittent pneumatic compression, the readings decreased during use but increased after cessation. Hand flux signal dropped during activation of both devices, rising after cessation. DISCUSSION: The neuromuscular electrical stimulator device used in this study enhances venous flow and peak velocity in the legs of healthy subjects and is equal or superior to intermittent pneumatic compression. This warrants further clinical and economic evaluation for deep venous thrombosis prophylaxis and exploration of the haemodynamic effect in venous pathology. It also enhances arterial time-averaged maximum velocity and flow rate, which may prove to be of clinical use in the management of peripheral arterial disease. The effect on the microcirculation as evidenced by laser Doppler fluximetry may reflect a clinically beneficial target in microvascular disease, such as in the diabetic foot.

Unplanned alcohol withdrawal: a survey of consecutive admissions to an acute medical unit in 2010 and 2011.

BACKGROUND: Alcohol-related presentations to hospital have been increasing in the UK in recent years, including the occurrence of acute withdrawal. This study sought to better characterize the clinical features, patterns of treatment and outcomes in this patient group. METHODS: Patients admitted to the Acute Medical Unit of York Hospital due to acute alcohol withdrawal are normally treated according to a protocol that involves both fixed-dose and symptom-triggered drug administration. Admissions between 2010 and 2011 inclusive were studied. RESULTS: There were 211 admission episodes solely due to acute alcohol withdrawal, involving 127 patients (97 men, 76.4%) with median age of 45 years (interquartile range: 39-52 years). There was a high prevalence of depression (34%), alcoholic liver disease (22%) and drug misuse (12%). Total dose of chlordiazepoxide varied between 0 and 610 mg and tapered rapidly after the first day of admission. Vitamin supplements were administered to >90% of patients, including parenteral and oral in 74%, parenteral alone in 9% and oral alone in 9%. A specialist alcohol nurse reviewed patients while in hospital in 40% of cases. Approximately one-third of patients had multiple admissions for alcohol withdrawal during the study period. CONCLUSION: A high prevalence of physical and mental health disorders was observed. The local policy permitted high initial chlordiazepoxide doses and prompt downward titration, with a broad range of doses between individuals. Approximately 10% required no specific therapy, and there may be opportunities for developing alternative pathways for delivery of care in an ambulatory setting for these patients.

Detection of anthrax toxin genetic sequences by the solid phase oligo-probes.

PURPOSE: There is an urgent need to detect a rapid field-based test to detect anthrax. We have developed a rapid, highly sensitive DNA-based method to detect the anthrax toxin lethal factor gene located in pXO1, which is necessary for the pathogenicity of Bacillus anthracis. MATERIALS AND METHODS: We have adopted the enzyme-linked immunosorbent assay (ELISA) so that instead of capturing antibodies we capture the DNA of the target sequence by a rapid oligo-based hybridization and then detect the captured DNA with another oligoprobe that binds to a different motif of the captured DNA sequences at a dissimilar location. We chose anthrax lethal factor endopeptidase sequences located in pXO1 and used complementary oligoprobe, conjugated with biotin, to detect the captured anthrax specific sequence by the streptavidin-peroxidase-based colorimetric assay. RESULT: Our system can detect picomoles (pMoles) of anthrax (approximately 33 spores of anthrax) and is >1000 times more sensitive than the current ELISA, which has a detection range of 0.1 to 1.0 ng/mL. False positive results can be minimized when various parameters and the colour development steps are optimized. CONCLUSION: Our results suggest that this assay can be adapted for the rapid detection of minuscule amounts of the anthrax spores that are aerosolized in the case of a bioterrorism attack. This detection system does not require polymerase chain reaction (PCR) step and can be more specific than the antibody method. This method can also detect genetically engineered anthrax. Since, the antibody method is so specific to the protein epitope that bioengineered versions of anthrax may not be detected.

Novel methodology to evaluate the effect of residual moisture on epoxy resin sealer/dentine interface: a pilot study.

AIM: To evaluate the sealer/dentine interface associated with an epoxy resin sealer using the combination of Goldner's trichrome stain (GTS) and scanning electron microscopy (SEM) to verify the use of the experimental methodology. METHODOLOGY: Extracted human maxillary incisors (6) were subjected to root canal treatment. Subsequent to pulp removal, canal instrumentation and smear layer removal using EDTA and NaOCl, teeth were randomly and equally assigned to a 'wet' or 'dry' group. The 'dry' group was desiccated (95% ethanol/suction/paper points/air-drying), whilst the 'wet' group was treated with a saline rinse/suction/single paper point. Canals were then filled with an epoxy-based resin sealer and warm vertical gutta-percha compaction. After 7-day storage at 37°C, roots from each group were sectioned into apical, middle and coronal horizontal subsections that were cut and split into paired halves and evaluated with GTS or SEM. With GTS sections, hybrid layer and sealer tubular penetration were measured (n=15 measurements/intracanal location/condition) and evaluated using a two-factor repeated measures analysis of variance. The SEM qualitative analysis of paired sections was included as a complementary confirmation of GTS analyses. RESULTS: In dry and wet groups, there was no conspicuous sealer/dentine interface hybrid layer, irrespective of canal location. However, dry specimens exhibited more uniform sealer distribution with deeper tubular penetration in the coronal and middle third (P<0.05). In contrast, there was decreased sealer distribution and tubule penetration in the apical third, regardless of moisture condition (P<0.05). CONCLUSIONS: The experimental methodology (combination of GTS and SEM) can be used to evaluate the intracanal resin sealer/dentine interface. The pilot data indicated that thorough drying of the root canal system may result in improved epoxy resin sealer distribution and deeper resin sealer tubular penetration, especially in the coronal and middle thirds of root canals.

The hypoxia-selective cytotoxin NLCQ-1 (NSC 709257) controls metastatic disease when used as an adjuvant to radiotherapy.

BACKGROUND: Metastases cause most cancer-related deaths. We investigated the use of hypoxia-selective cytotoxins as adjuvants to radiotherapy in the control of metastatic tumour growth. METHODS: The NLCQ-1, RB6145 and tirapazamine were assessed against the spontaneously metastasising KHT model. Subcutaneous KHT tumours (250 mm(3)) were irradiated with 25 Gy (single fraction) to control primary growth. Equitoxic drug treatments (NLCQ-1 (10 mg kg(-1)) once daily; RB6145 (75 mg kg(-1)) and tirapazamine (13 mg kg(-1)) twice daily) were administered 3-6 days post-radiotherapy when hypoxic cells were evident in lung micrometastases. Mice were culled when 50% of controls exhibited detrimental signs of lung metastases. RESULTS: In total, 95% of control mice presented with lung disease. This was significantly reduced by NLCQ-1 (33%; P=0.0002) and RB6145 (60%; P=0.02). Semi-quantitative grading of lung disease revealed a significant improvement with all treatments, with NLCQ-1 proving most efficacious (median grades: control, 4; NLCQ, 0 (P<0.0001); RB6145, 1 (P<0.001), tirapazamine, 3 (P=0.007)). Positron emission tomography (PET) was evaluated as a non-invasive means of assessing metastatic development. Primary and metastatic KHT tumours showed robust uptake of [(18)F]fluorodeoxyglucose ([(18)F]FDG). Metastatic burden discernable by [(18)F]FDG PET correlated well with macroscopic and histological lung analysis. CONCLUSION: The hypoxia-selective cytotoxin NLCQ-1 controls metastatic disease and may be a successful adjuvant to radiotherapy in the clinical setting.

Changes in MRS neuronal markers and T cell phenotypes observed during early HIV infection.

OBJECTIVE: To determine if changes in brain metabolites are observed during early HIV infection and correlate these changes with immunologic alterations. METHODS: Eight subjects with early HIV infection, 9 HIV-seronegative controls, and 10 chronically HIV-infected subjects without neurologic impairment underwent 1H magnetic resonance spectroscopy. Subjects with early stage infection were identified near the time of HIV seroconversion and imaged within 60 days of an evolving Western blot, while still having detectable plasma virus. Subjects had blood drawn for viral RNA and T cell quantification. RESULTS: Both N-acetylaspartate (NAA) and Glx (glutamate + glutamine) were decreased in the frontal cortical gray matter of seropositive subjects. NAA levels were found to be decreased in the centrum semiovale white matter of chronically HIV-infected subjects, but not in those with early infection. Both HIV-infected cohorts demonstrated a lower number of CD4+ T lymphocytes and a higher number of CD8+ T lymphocytes in their blood. Lower NAA levels in the frontal cortex of subjects with early infection were associated with an expansion of CD8+ T cells, especially effector CD8+ T cells. CONCLUSIONS: These results verify metabolism changes occurring in the brain early during HIV infection. Lower NAA and Glx levels in the cortical gray matter suggests that HIV causes neuronal dysfunction soon after infection, which correlates to the expansion of CD8+ T cells, specifically to an activated phenotype. Utilizing magnetic resonance spectroscopy to track NAA levels may provide important information on brain metabolic health while allowing better understanding of the virus-host interactions involved in CNS functional deficits.

Identification of the potent phytoestrogen glycinol in elicited soybean (Glycine max).

The primary induced isoflavones in soybean, the glyceollins, have been shown to be potent estrogen antagonists in vitro and in vivo. The discovery of the glyceollins' ability to inhibit cancer cell proliferation has led to the analysis of estrogenic activities of other induced isoflavones. In this study, we investigated a novel isoflavone, glycinol, a precursor to glyceollin that is produced in elicited soy. Sensitive and specific in vitro bioassays were used to determine that glycinol exhibits potent estrogenic activity. Estrogen-based reporter assays were performed, and glycinol displayed a marked estrogenic effect on estrogen receptor (ER) signaling between 1 and 10 microM, which correlated with comparable colony formation of MCF-7 cells at 10 microM. Glycinol also induced the expression of estrogen-responsive genes (progesterone receptor and stromal-cell-derived factor-1). Competitive binding assays revealed a high affinity of glycinol for both ER alpha (IC(50) = 13.8 nM) and ER beta (IC(50) = 9.1 nM). In addition, ligand receptor modeling (docking) studies were performed and glycinol was shown to bind similarly to both ER alpha and ER beta. Taken together, these results suggest for the first time that glycinol is estrogenic and may represent an important component of the health effects of soy-based foods.

Promising antituberculosis activity of the oxazolidinone PNU-100480 relative to that of linezolid in a murine model.

Oxazolidinone antibiotics have activity against Mycobacterium tuberculosis. Linezolid, the only marketed oxazolidinone, has been used off-label in combination regimens to treat multidrug-resistant tuberculosis, but its precise contribution to the efficacy of such combinations is unclear. Another oxazolidinone, PNU-100480, has been demonstrated to have more potent activity in vitro and in a murine model of tuberculosis. In this study, we compared the pharmacokinetics and the antituberculosis activities of these two oxazolidinones over a range of doses and found that linezolid has limited activity at clinically relevant doses in the murine model compared to that of PNU-100480, which has potent bactericidal activity, even at lower drug exposures. These findings were unexpected, given the similar in vitro activities of PNU-100480, its major metabolites, and linezolid. Moreover, the incorporation of PNU-100480 dramatically improved the bactericidal activities of regimens containing current first-line antituberculosis drugs and moxifloxacin. For example, the addition of PNU-100480 (100 mg/kg of body weight/day) to the standard daily regimen of rifampin (rifampicin), isoniazid, and pyrazinamide resulted in an additional 2.0-log(10)-unit reduction in lung CFU counts during the first 2 months of treatment. The combination of PNU-100480, moxifloxacin, and pyrazinamide, which does not contain either rifampin or isoniazid, was also more active than rifampin, isoniazid, and pyrazinamide. These results suggest that PNU-100480 may have the potential to significantly shorten the duration of therapy for drug-susceptible as well as multidrug-resistant tuberculosis.

The effects of moxifloxacin ophthalmic solution 0.5% or gatifloxacin ophthalmic solution 0.3% treatment on corneal wound healing in pigmented rabbits following anterior keratectomy.

PURPOSE: These studies examined corneal healing rates, Type-IV collagen and zonula occludens membrane-associated protein (ZO-1) expression, as well as aqueous PGE(2) and IL-1 beta concentrations in pigmented rabbits treated with either moxifloxacin 0.5%, gatifloxacin 0.3% or BSS following anterior keratectomy. METHODS: Anterior keratectomy surgery was followed by topical administration with commercial ophthalmic formulations of either moxifloxacin or gatifloxacin or BSS (TID for 96 h). Images of the fluorescein-stained healing corneas were analyzed for wound area. At 48 or 96 h following surgery, aqueous humor samples were collected and analyzed for the inflammatory mediators PGE(2) and IL-1 beta using an ELISA. The corneas were subsequently evaluated using both scanning and transmission electron microscopy. In a second parallel study, corneas were evaluated at both 48 and 96 h for Type-IV collagen and ZO-1 expression using immunohistochemistry. RESULTS: Fluorescein-stained corneal images at 96 h postsurgery demonstrated that 90% +/- 8% re-epithelialization for moxifloxacin, 81% +/- 14% for gatifloxacin, and 88 +/- 6% for BSS((R)) (P > 0.05). PGE(2 )levels in the aqueous humor of fluoroquinolone treated eyes were reduced at 48 h compared to BSS treated eyes. IL-1 beta was undetectable in all samples. No differences in Type-IV collagen or ZO-1 expression were observed between any treatment groups. There were no differences between groups in histological appearance or in ultrastructural healing processes. CONCLUSIONS: These studies demonstrated that the commercial ophthalmic formulations of moxifloxacin and gatifloxacin were similar to each other in their effects on the levels of aqueous humor PGE(2) and rates of corneal wound re-epithelialization.

Pharmacodynamic interaction of warfarin with cranberry but not with garlic in healthy subjects.

BACKGROUND AND PURPOSE: Patients commonly take complementary medicines in conjunction with warfarin yet evidence supporting the safety or the risk of a herb-drug interaction is lacking. The aim of this study was to investigate the possible impact of two commonly used herbal medicines, garlic and cranberry, on the pharmacokinetics and pharmacodynamics of warfarin in healthy male subjects. EXPERIMENTAL APPROACH: An open-label, three-treatment, randomized crossover clinical trial was undertaken and involved 12 healthy male subjects of known CYP2C9 and VKORC1 genotype. A single dose of 25 mg warfarin was administered alone or after 2 weeks of pretreatment with either garlic or cranberry. Warfarin enantiomer concentrations, INR, platelet aggregation and clotting factor activity were measured to assess pharmacokinetic and pharmacodynamic interactions between warfarin and herbal medicines. KEY RESULTS: Cranberry significantly increased the area under the INR-time curve by 30% when administered with warfarin compared with treatment with warfarin alone. Cranberry did not alter S- or R-warfarin pharmacokinetics or plasma protein binding. Co-administration of garlic did not significantly alter warfarin pharmacokinetics or pharmacodynamics. Both herbal medicines showed some evidence of VKORC1 (not CYP2C9) genotype-dependent interactions with warfarin, which is worthy of further investigation. CONCLUSIONS AND IMPLICATIONS: Cranberry alters the pharmacodynamics of warfarin with the potential to increase its effects significantly. Co-administration of warfarin and cranberry requires careful monitoring.