Characterising 18F-fluciclovine uptake in breast cancer through the use of dynamic PET/CT imaging.

BACKGROUND: 18F-fluciclovine is a synthetic amino acid positron emission tomography (PET) radiotracer that is approved for use in prostate cancer. In this clinical study, we characterised the kinetic model best describing the uptake of 18F-fluciclovine in breast cancer and assessed differences in tracer kinetics and static parameters for different breast cancer receptor subtypes and tumour grades. METHODS: Thirty-nine patients with pathologically proven breast cancer underwent 20-min dynamic PET/computed tomography imaging following the administration of 18F-fluciclovine. Uptake into primary breast tumours was evaluated using one- and two-tissue reversible compartmental kinetic models and static parameters. RESULTS: A reversible one-tissue compartment model was shown to best describe tracer uptake in breast cancer. No significant differences were seen in kinetic or static parameters for different tumour receptor subtypes or grades. Kinetic and static parameters showed a good correlation. CONCLUSIONS: 18F-fluciclovine has potential in the imaging of primary breast cancer, but kinetic analysis may not have additional value over static measures of tracer uptake. CLINICAL TRIAL REGISTRATION: NCT03036943.

Microbiomics of Namib Desert habitats.

The Namib Desert is one of the world's only truly coastal desert ecosystem. Until the end of the 1st decade of the twenty-first century, very little was known of the microbiology of this southwestern African desert, with the few reported studies being based solely on culture-dependent approaches. However, from 2010, an intense research program was undertaken by researchers from the University of the Western Cape Institute for Microbial Biotechnology and Metagenomics, and subsequently the University of Pretoria Centre for Microbial Ecology and Genomics, and their collaborators, led to a more detailed understanding of the ecology of the indigenous microbial communities in many Namib Desert biotopes. Namib Desert soils and the associated specialized niche communities are inhabited by a wide array of prokaryotic, lower eukaryotic and virus/phage taxa. These communities are highly heterogeneous on both small and large spatial scales, with community composition impacted by a range of macro- and micro-environmental factors, from water regime to soil particle size. Community functionality is also surprisingly non-homogeneous, with some taxa retaining functionality even under hyper-arid soil conditions, and with subtle changes in gene expression and phylotype abundances even on diel timescales. Despite the growing understanding of the structure and function of Namib Desert microbiomes, there remain enormous gaps in our knowledge. We have yet to quantify many of the processes in these soil communities, from regional nutrient cycling to community growth rates. Despite the progress that has been made, we still have little knowledge of either the role of phages in microbial community dynamics or inter-species interactions. Furthermore, the intense research efforts of the past decade have highlighted the immense scope for future microbiological research in this dynamic, enigmatic and charismatic region of Africa.

Sustained virological response following chronic hepatitis C treatment is associated with improvement in insulin resistance.

BACKGROUND: Insulin resistance (IR) is a key factor in the development of hepatic steatosis and fibrosis in chronic hepatitis C virus infection. Little is known about the impact of viral clearance on IR. AIM: The aim of this study was to determine the impact of viral clearance on IR. METHODS: Eighty-six patients treated according to standard clinical practice at an Australian teaching hospital between 2003 and 2007 were prospectively studied. Demographic, biochemical and histological data were collected. RESULTS: The mean pretreatment homeostatic model assessment-IR (HOMA-IR) was similar in the sustained virological response (SVR) and non-SVR groups (2.7 ± 0.5 and 2.8 ± 0.4, respectively), and both values were consistent with significant IR. There was a significant improvement in HOMA-IR (from 3.0 ± 1.0 to 2.2 ± 0.5, P = 0.04) at the end of treatment in the SVR group only. This trended towards significance at 6 months post-treatment. Multiple regression analysis found improvement in both gamma-glutamyl transpeptidase and alanine aminotransferase predicted improvement in HOMA-IR when controlled for other potential factors (P = 0.01). CONCLUSIONS: Hepatitis C virus clearance is associated with improvement in IR. Although baseline hepatic fibrosis is a predictor of IR, changes in IR appear to be independent of changes in liver fibrosis. Treatment-related improvement in gamma-glutamyl transpeptidase and alanine aminotransferase seen with improved IR may be a possible marker of reduction of hepatic oxidative stress.

Addition of an organic amendment and/or residue mud to bauxite residue sand in order to improve its properties as a growth medium.

The effects of addition of carbonated residue mud (RMC) or seawater neutralized residue mud (RMS), at two rates, in the presence or absence of added green waste compost, on the chemical, physical and microbial properties of gypsum-treated bauxite residue sand were studied in a laboratory incubation study. The growth of two species commonly used in revegetation of residue sand (Lolium rigidum and Acacia saligna) in the treatments was then studied in a 18-week greenhouse study. Addition of green waste-based compost increased ammonium acetate-extractable (exchangeable) Mg, K and Na. Addition of residue mud at 5 and 10% w/w reduced exchangeable Ca but increased that of Mg and Na (and K for RMS). Concentrations of K, Na, Mg and level of EC in saturation paste extracts were increased by residue mud additions. Concentrations of cations in water extracts were considerably higher than those in saturation paste extracts but trends with treatment were broadly similar. Addition of both compost and residue mud caused a significant decrease in macroporosity with a concomitant increase in mesoporosity and microporosity, available water holding capacity and the quantity of water held at field capacity. Increasing rates of added residue mud reduced the percentage of sample present as discrete sand particles and increased that in aggregated form (particularly in the 1-2 and >10mm diameter ranges). Organic C content, C/N ratio, soluble organic C, microbial biomass C and basal respiration were increased by compost additions. Where compost was added, residue mud additions caused a substantial increase in microbial biomass and basal respiration. L. rigidum grew satisfactorily in all treatments although yields tended to be reduced by additions of mud (especially RMC) particularly in the absence of added compost. Growth of A. saligna was poor in sand alone and mud-amended sand and was greatly promoted by additions of compost. However, in the presence of compost, addition of carbonated mud had a marked depressive effect on both top and root growth. The significant positive effect of compost was attributed to substantial inputs of K and marked reductions in the Na/K ratio in soil solution while the depressive effect of RMC was attributed to its greater alkalinity and consequently higher concentrations of HCO(3)(-) in solution.

Effect of amendment of bauxite processing sand with organic materials on its chemical, physical and microbial properties.

The effects of addition of a range of organic amendments (biosolids, spent mushroom compost, green waste compost and green waste-derived biochar), at two rates, on some key chemical, physical and microbial properties of bauxite-processing residue sand were studied in a laboratory incubation study. Levels of exchangeable cations were not greatly affected by additions of amendments but extractable P was increased significantly by mushroom and green waste composts and massively (i.e. from 11.8 to 966 mg P kg(-1)) by biosolids applications. Levels of extractable NO(3)(-)-N were also greatly elevated by biosolids additions and there was a concomitant decrease in pH. Addition of all amendments decreased bulk density and increased mesoporosity, available water holding capacity and water retention at field capacity (-10 kPa), with the higher rate having a greater effect. Addition of biosolids, mushroom compost and green waste compost all increased soluble organic C, microbial biomass C, basal respiration and the activities of beta-glucosidase, L-asparaginase and alkali phosphatase enzymes. The germination index of watercress grown in the materials was greatly reduced by biosolids application and this was attributed to the combined effects of a high EC and high concentrations of extractable P and NO(3)(-). It was concluded that the increases in water storage and retention and microbial activity induced by additions of the composts is likely to improve the properties of bauxite-processing residue sand as a growth medium but that allowing time for soluble salts, originating from the organic amendments, to leach out may be an important consideration before sowing seeds.

High-performance photorefractive polymers.

Photorefractive materials can form "instant" holograms without time-consuming development steps. Their potential applications include image processing, optical data storage, and correction of image distortion, but the cost of crystal growth and preparation has been a primary impediment to commercial application. Polymers, on the other hand, are low in cost and readily fabricated in a variety of forms. Photorefractive polymers were constructed with performance that matched or exceeded the performance of available photorefractive crystals. The largest observed two-beam energy coupling gain coefficient for the polymers was 56 per centimeter.

A fatal case of phlegmonous colitis in chronic hepatitis C receiving combination interferon and ribavirin therapy.

Phlegmonous colitis is an acute suppurative infection of the large bowel that is rarely described, rapidly fatal and often escapes clinical attention. Patients with chronic hepatic diseases appear to be predisposed to this condition. We report a novel case of fatal phlegmonous colitis in a cirrhotic patient receiving combination pegylated interferon and ribavirin for chronic hepatitis C, highlighting the importance of early recognition of this aggressive infectious entity.

A comparison of the puncturing properties of gelatin and hypromellose capsules for use in dry powder inhalers.

This study investigates capsule puncture in dry powder inhalers. Gelatin and hydroxypropylmethyl cellulose (HPMC) capsules (stored at 11 and 33% relative humidities) were punctured using a pin from a Foradil inhaler, with insertion force measurement via an Instron tester. In HPMC capsules, the force after capsule puncture reduced by half and then increased to a second maximum as the pin shaft entered the hole. In gelatin capsules, the postpuncture force reduced to zero, indicating shell flaps losing contact with the pin. At lower moisture contents, both capsules were less flexible. This provides a tool to measure the shell properties of inhalation capsules.

Development and Validation of a Natural Language Processing Tool to Identify Patients Treated for Pneumonia across VA Emergency Departments.

BACKGROUND: Identifying pneumonia using diagnosis codes alone may be insufficient for research on clinical decision making. Natural language processing (NLP) may enable the inclusion of cases missed by diagnosis codes. OBJECTIVES: This article (1) develops a NLP tool that identifies the clinical assertion of pneumonia from physician emergency department (ED) notes, and (2) compares classification methods using diagnosis codes versus NLP against a gold standard of manual chart review to identify patients initially treated for pneumonia. METHODS: Among a national population of ED visits occurring between 2006 and 2012 across the Veterans Affairs health system, we extracted 811 physician documents containing search terms for pneumonia for training, and 100 random documents for validation. Two reviewers annotated span- and document-level classifications of the clinical assertion of pneumonia. An NLP tool using a support vector machine was trained on the enriched documents. We extracted diagnosis codes assigned in the ED and upon hospital discharge and calculated performance characteristics for diagnosis codes, NLP, and NLP plus diagnosis codes against manual review in training and validation sets. RESULTS: Among the training documents, 51% contained clinical assertions of pneumonia; in the validation set, 9% were classified with pneumonia, of which 100% contained pneumonia search terms. After enriching with search terms, the NLP system alone demonstrated a recall/sensitivity of 0.72 (training) and 0.55 (validation), and a precision/positive predictive value (PPV) of 0.89 (training) and 0.71 (validation). ED-assigned diagnostic codes demonstrated lower recall/sensitivity (0.48 and 0.44) but higher precision/PPV (0.95 in training, 1.0 in validation); the NLP system identified more "possible-treated" cases than diagnostic coding. An approach combining NLP and ED-assigned diagnostic coding classification achieved the best performance (sensitivity 0.89 and PPV 0.80). CONCLUSION: System-wide application of NLP to clinical text can increase capture of initial diagnostic hypotheses, an important inclusion when studying diagnosis and clinical decision-making under uncertainty.

Multicenter study of QuantiFERON®-TB Gold Plus in patients with active tuberculosis.

SETTING: QuantiFERON®-TB Gold Plus (QFT-Plus), recently approved for use in the United States, is a new-generation QuantiFERON assay that differs from its predecessors in that it uses an additional antigen tube containing peptides to elicit both CD8+ and CD4+ T-lymphocyte responses. OBJECTIVE: To assess the sensitivity of QFT-Plus compared with QuantiFERON®-TB Gold In-Tube (QFT-GIT) in participants with active TB. DESIGN: Adult patients with active TB at three US and two Japanese sites were eligible for this study if they had culture-confirmed TB and were either untreated or had received 14 days of anti-tuberculosis treatment. RESULTS: We enrolled 164 participants, nine of whom had indeterminate results. Excluding indeterminate values, there were 150 QFT-GIT-positive results among 159 tests and 146 QFT-Plus-positive results among 157 tests, with sensitivities of respectively 94.3% (95%CI 89.5-97.4) and 93.02% (95%CI 87.8-96.5%). The estimated sensitivities for the two tests were not significantly different (P = 0.16). Overall test agreement was 98.7%, with a κ statistic of 0.89 (95%CI 0.75-1.00). CONCLUSION: In this multisite study, we found that QFT-Plus had similar sensitivity to QFT-GIT in adult patients with active TB.

T cell cytokine responses in persons with tuberculosis and human immunodeficiency virus infection.

Tuberculosis causes more extensive and life-threatening disease in patients with HIV infection than in immunocompetent persons. To investigate the hypothesis that these severe manifestations of tuberculosis may be due to alterations in cytokine production, we evaluated cytokine patterns in HIV-infected tuberculosis patients. Upon stimulation with Mycobacterium tuberculosis in vitro, PBMC from HIV-infected tuberculosis patients had reduced proliferative and type 1 responses, compared with HIV-seronegative tuberculosis patients. The reduction in proliferative responses was independent of the CD4 cell count, but the reduced type 1 response was a direct result of CD4 cell depletion. There was no enhancement of type 2 cytokine production in HIV-infected patients, although production of IL-10 was prominent in all tuberculosis patients. In HIV-infected tuberculosis patients, M. tuberculosis-induced proliferative responses were significantly enhanced by neutralizing antibodies to IL-10 but not by antibodies to IL-4 or by recombinant IL-12. The M. tuberculosis-induced type 1 response was augmented both by antibodies to IL-10 and by recombinant IL-12. Tuberculosis in the context of HIV infection is characterized by diminished type 1 responses, probably induced by immunosuppressive cytokines produced by macrophages/monocytes, rather than by type 2 cells.

Isolation of mycobacterium-reactive CD1-restricted T cells from patients with human immunodeficiency virus infection.

Because CD1-restricted T cells lack CD4 but produce IFN-gamma in response to nonpeptide mycobacterial antigens, they could play a unique role in immunity to tuberculosis. We studied CD1-restricted T cells in the context of HIV infection by expanding CD4(-) T cell lines from 10 HIV-infected patients. Upon stimulation with Mycobacterium tuberculosis antigen or upon exposure to macrophages infected with M. tuberculosis, these T cell lines proliferated, produced IFN-gamma, and showed cytolytic T cell (CTL) activity against macrophages pulsed with mycobacterial antigen, findings consistent with a protective role against M. tuberculosis. Anti-CD1b antibodies abrogated T cell proliferation, IFN-gamma production, and CTL activity, demonstrating that these T cells are CD1 restricted. IFN-gamma production in response to M. tuberculosis was enhanced by antitransforming growth factor-beta in 8/10 lines, and by IL-15 in 2/10 lines. IFN-gamma production was augmented in a nonantigen-specific manner by IL-12 in 4/8 lines. When live HIV was cocultured with CD1-restricted T cell lines, p24 antigen and proviral DNA were not detected, indicating that the T cells were not infectable with HIV. Vaccination strategies aimed at activation and expansion of M. tuberculosis-reactive CD1-restricted T cells in HIV-infected patients may constitute a novel means to provide protection against tuberculosis, while minimizing the risk of enhancing HIV replication through stimulation of CD4(+) cells.

Structure determination and analysis of a bacterial chymotrypsin from Cellulomonas bogoriensis.

The crystal structure of a secreted chymotrypsin from the alkaliphile Cellulomonas bogoriensis has been determined using data to 1.78 A resolution and refined to a crystallographic R factor of 0.167. The crystal structure reveals a large P1 substrate-specificity pocket, as expected for chymotrypsins. The structure is compared with close structural homologues. This comparison does not reveal clear reasons for the alkali tolerance of the enzyme, but the greater compactness of the structure and lowered hydrogen bonding may play a role.

A scintigraphic investigation of the disintegration behaviour of capsules in fasting subjects: a comparison of hypromellose capsules containing carrageenan as a gelling agent and standard gelatin capsules.

Two-piece hard shell capsules made from hypromellose (or hydroxypropyl methylcellulose, HPMC) have been proposed as an alternative to conventional gelatin capsules for oral drug delivery; however, little is known about their in vivo behaviour. The aim of this study was to compare the disintegration of HPMC and gelatin capsules in fasted human subjects using the technique of gamma scintigraphy. HPMC capsules containing carrageenan as a gelling agent (QUALI-V(R), Qualicaps) and gelatin capsules (Qualicaps) of size 0 were filled with a lactose-based mixture. The capsules were separately radiolabelled with indium-111 and technetium-99m. Both capsules were administered simultaneously with 180ml water to eight healthy male subjects following an overnight fast. Each volunteer was positioned in front of the gamma camera and sequential 60s images were acquired in a continuous manner for 30min. No differences in the oesophageal transit of the two types of capsules were noted, with the capsules arriving in the stomach in a matter of seconds. All the capsules disintegrated in the stomach. The mean (+/-S.D.) disintegration time for the HPMC capsules was 9+/-2min (range 6-11min). The corresponding mean time for the gelatin capsules was 7+/-4min (range 3-13min). These disintegration times were not significantly different (P=0.108, paired t-test). In conclusion, HPMC and gelatin capsules show rapid and comparable in vivo disintegration times in the fasted state. HPMC capsules containing carrageenan as a gelling agent therefore offer a practical alternative to gelatin capsules as an oral drug delivery carrier.

Stereological estimates of the basal forebrain cell population in the rat, including neurons containing choline acetyltransferase, glutamic acid decarboxylase or phosphate-activated glutaminase and colocalizing vesicular glutamate transporters.

The basal forebrain (BF) plays an important role in modulating cortical activity and influencing attention, learning and memory. These activities are fulfilled importantly yet not entirely by cholinergic neurons. Noncholinergic neurons also contribute and comprise GABAergic neurons and other possibly glutamatergic neurons. The aim of the present study was to estimate the total number of cells in the BF of the rat and the proportions of that total represented by cholinergic, GABAergic and glutamatergic neurons. For this purpose, cells were counted using unbiased stereological methods within the medial septum, diagonal band, magnocellular preoptic nucleus, substantia innominata and globus pallidus in sections stained for Nissl substance and/or the neurotransmitter enzymes, choline acetyltransferase (ChAT), glutamic acid decarboxylase (GAD) or phosphate-activated glutaminase (PAG). In Nissl-stained sections, the total number of neurons in the BF was estimated as approximately 355,000 and the numbers of ChAT-immuno-positive (+) as approximately 22,000, GAD+ approximately 119,000 and PAG+ approximately 316,000, corresponding to approximately 5%, approximately 35% and approximately 90% of the total. Thus, of the large population of BF neurons, only a small proportion has the capacity to synthesize acetylcholine (ACh), one third to synthesize GABA and the vast majority to synthesize glutamate (Glu). Moreover, through the presence of PAG, a proportion of ACh- and GABA-synthesizing neurons also has the capacity to synthesize Glu. In sections dual fluorescent immunostained for vesicular transporters, vesicular glutamate transporter (VGluT) 3 and not VGluT2 was present in the cell bodies of most PAG+ and ChAT+ and half the GAD+ cells. Given previous results showing that VGluT2 and not VGluT3 was present in BF axon terminals and not colocalized with VAChT or VGAT, we conclude that the BF cell population influences cortical and subcortical regions through neurons which release ACh, GABA or Glu from their terminals but which in part can also synthesize and release Glu from their soma or dendrites.

Excitatory action of hypocretin/orexin on neurons of the central medial amygdala.

The neurons of the lateral hypothalamus that contain hypocretin/orexin (hcrt/orx) are thought to promote arousal through the excitatory action they exert on the multiple areas to which they project within the CNS. We show here that the hcrt/orx peptides can also exert a strong action on the amygdala, a structure known for its implication in emotional aspects of behavior. Indeed, the hcrt/orx peptides, applied in acute rat brain slices, excite a specific class of "low threshold burst" neurons in the central medial (CeM) nucleus which is considered as a major output of the amygdala. These excitatory effects are postsynaptic, mediated by Hcrt2/OX2 receptors and result from the closure of a potassium conductance. They occur on a class of neurons that are also excited by vasopressin acting through V1a receptors. These results suggest that the hcrt/orx system can act through the amygdala to augment arousal and evoke the autonomic and behavioral responses associated with fear, stress or emotion.

Survey of animal shelter managers regarding shelter veterinary medical services.

Veterinary services are increasingly used in animal shelters, and shelter medicine is an emerging veterinary specialty. However, little is known about working relationships between animal shelters and veterinarians. The aims of this survey were to characterize working relationships that shelter personnel have and want with veterinarians, identify opinions that shelter managers have regarding the veterinarians they work with, and determine areas for relationship growth between veterinarians and shelter managers. An electronic survey was distributed to 1373 managers of North American animal shelters; 536 (39.0%) responded. Almost all shelters had some veterinary relationship, and most had regular relationships with veterinarians. The proportion of shelters that used local clinics (73.9%) was significantly higher than the proportion that retained on-site paid veterinarians (48.5%). The proportion of respondents who did not have but wanted a paid on-site veterinarian (42%) was significantly higher than the proportion of respondents who did not use local clinics but wanted to (7.9%). These data suggest shelter managers valued veterinary relationships, and wished to expand on-site veterinary services. Almost all shelters in this study provided some veterinary care, and all respondents identified at least one common infectious disease, which, for most, had a substantial negative impact on shelter successes. Respondents indicated that the most important roles and greatest expertise of veterinarians were related to surgery, diagnosis and treatment of individual animals. Education of both veterinarians and shelter managers may help ensure that shelters benefit from the full range of services veterinarians can provide, including expertise in disease prevention and animal behavior.

Discharge profiles of juxtacellularly labeled and immunohistochemically identified GABAergic basal forebrain neurons recorded in association with the electroencephalogram in anesthetized rats.

The basal forebrain ostensibly plays a dual role in the modulation of cortical activation and behavioral state. It is essential for stimulating cortical activation in association with waking (and paradoxical sleep), yet also important for attenuating cortical activation and promoting slow wave sleep. Using juxtacellular recording and labeling of neurons with Neurobiotin followed by immunohistochemical staining for glutamic acid decarboxylase (GAD), we studied the discharge properties of identified GABAergic basal forebrain neurons in relation to electroencephalographic (EEG) activity in urethane-anesthetized rats to determine the part or parts that they may play in this dual role. The GABAergic neurons displayed distinct discharge profiles in relation to somatosensory stimulation-evoked cortical activation. Whereas a significant minority increased its average discharge rate, the majority decreased its average discharge rate in association with cortical activation. Moreover, subgroups displayed distinct discharge patterns related to different cortical activities, including very regular high-frequency tonic spiking within a gamma EEG frequency range and rhythmic cluster spiking within a theta-like frequency range during cortical activation. During irregular slow EEG activity in absence of stimulation, one subgroup displayed spike bursts correlated with cortical slow oscillations. As relatively large in size and also antidromically activated from the cortex, many GABAergic neurons recorded were considered to be cortically projecting and thus capable of directly modulating cortical activity. Subgroups of GABAergic basal forebrain neurons would thus have the capacity to promote cortical activation by modulating gamma or theta activity and others to attenuate cortical activation by modulating irregular slow oscillations that normally occur during slow wave sleep.