A multi-centre retrospective study of Nocardia speciation and antimicrobial susceptibility in Queensland, Australia.

The study aims to characterise the species identification and antimicrobial susceptibility testing (AST) results of Nocardial isolates from adult patients across major public hospitals in Queensland, Australia, over a 15-year period. A multi-centre retrospective observational study of Nocardia sp. isolates was conducted from 7 major public hospitals in Queensland, Australia, over a 15-year period. Clinical samples from patients aged ≥ 18 years that isolated Nocardia sp. were included. Demographic and clinical data were collected, along with species identification and AST results. Overall, 484 Nocardia sp. were isolated. Most patients were male (297, 61%) with a mean (IQR) age of 60 (51-75) and a median (IQR) Charlson Comorbidity Index of 4 (2-6). Of these, 239 (49%) patients were immunosuppressed. Organisms were most frequently isolated from sputum (174, 36%), and superficial swabs (102, 21%). Patients presented with pulmonary infections (165, 35%) and superficial skin and soft tissue infections (87, 18%) most commonly. One hundred (21%) isolates were deemed pulmonary colonisation and were not treated. Of the speciated organisms, N. nova complex was the most common (93, 19%), followed by N. farcinica complex (79, 16%). Organisms were reliably susceptible to linezolid (240/245, 98%), amikacin (455/470, 97%), and trimethoprim/sulfamethoxazole (459/476, 96%), but less so to imipenem (243/472, 51%) and ceftriaxone (261/448, 58%). This is the largest Australian description of Nocardia sp. to date. Given antimicrobials are often commenced prior to AST results and sometimes even speciation, characterisation of local species and antibiogram data is important to guide empiric choices and local guidelines.

Defining resistance and tolerance traits in Covid-19: towards a stratified medicine approach.

Successful host defence against infectious disease involves resistance (reduce pathogen load) and tolerance (reduce tissue damage associated with pathogen presence). Integration of clinical, immunologic, genetic and therapeutic discoveries has identified defects in both of these responses in the progression from SARS-CoV-2 infection to life-threatening coronavirus disease 2019 (Covid-19) lung injury. Early after infection with SARS-CoV-2, resistance can be compromised by a failed type 1 interferon (IFN-I) response, due to direct viral antagonism of induction and signalling, deleterious host genetic variants (IFNAR2, IFNA10, TYK2 and PLSCR1), and neutralizing auto-antibodies directed against IFN-I (predominantly IFN-α). Later in the disease, after pathogen sensing has activated a pro-inflammatory response, a failure to appropriately regulate this response compromises tolerance resulting in virus-independent immunopathology involving the lung and reticuloendothelial system. Monocytes are activated in the periphery (involving M-CSF, GM-CSF, IL-6, NLRP1 inflammasomes, TYK2 and afucosylated anti-spike IgG) then recruited to the lung (involving CCR2::MCP-3/MCP-1 and C5a::C5aR1 axes) as pro-inflammatory monocyte-derived macrophages, resulting in inflammatory lung injury. Phenotypic and genotypic heterogeneity is apparent in all these responses, identifying 'treatable traits' (therapeutically relevant components of inter-individual variation) which could be exploited to achieve a stratified medicine approach to Covid-19. Overall, Covid-19 pathogenesis re-affirms the importance of resistance in surviving an infectious disease and highlights that tolerance is also a central pillar of host defence in humans and can be beneficially modified using host-directed therapies.

Rhinology Future Debates, an EUFOREA Report.

The first Rhinology Future Debates was held in Brussels in December 2016, organized by EUFOREA (European Forum for Research and Education in Allergy and Airways diseases). The purpose of these debates is to bring novel developments in the field of Rhinology to the attention of the medical, paramedical and patient community, in a highly credible and balanced context. For the first time in Rhinology, a peer to peer scientific exchange with key experts in the field of rhinology and key medical colleagues from leading industries let to a brainstorming and discussion event on a number of hot issues in Rhinology. Novel developments are presented by key experts from industry and/or key thought leaders in Rhinology, and then followed by a lively debate on the potential positioning of new developments in care pathways, the strengths and weaknesses of the novel development(s), and comparisons with existing and/or competing products, devices, and/or molecules. As all debates are recorded and distributed on-line with limited editing (www.rhinology-future.com), EUFOREA aims at maximizing the education of the target groups on novel developments, allowing a critical appraisal of the future and a more rapid implementation of promising novel tools, techniques and/or molecules in clinical practise in Europe. The next Rhinology Future debate will be held in Brussels in December 2017.

Framework selection can influence pharmacokinetics of a humanized therapeutic antibody through differences in molecule charge.

Pharmacokinetic (PK) testing of a humanized (κI, VH3 framework) and affinity matured anti-hepatitis C virus E2-glycoprotein (HCV-E2) antibody (hu5B3.κ1VH3.v3) in rats revealed unexpected fast clearance (34.9 mL/day/kg). This antibody binds to the rat recycling receptor FcRn as expected for a human IgG1 antibody and does not display non-specific binding to baculovirus particles in an assay that is correlated with fast clearance in cynomolgus monkey. The antigen is not expressed in rat so target-dependent clearance does not contribute to PK. Removal of the affinity maturation changes (hu5B3.κ1VH3.v1) did not restore normal clearance. The antibody was re-humanized on a κ4, VH1 framework and the non-affinity matured version (hu5B3.κ4VH1.v1) was shown to have normal clearance (8.5 mL/day/kg). Since the change in framework results in a lower pI, primarily due to more negative charge on the κ4 template, the effect of additional charge variation on antibody PK was tested by incorporating substitutions obtained through phage display affinity maturation of hu5B3.κ1VH3.v1. A variant having a pI of 8.61 gave very fast clearance (140 mL/day/kg) whereas a molecule with pI of 6.10 gave slow clearance (5.8 mL/kg/day). Both antibodies exhibited comparable binding to rat FcRn, but biodistribution experiments showed that the high pI variant was catabolized in liver and spleen. These results suggest antibody charge can have an effect on PK through alterations in antibody catabolism independent of FcRn-mediated recycling. Furthermore, introduction of affinity maturation changes into the lower pI framework yielded a candidate with PK and virus neutralization properties suitable for clinical development.

Comparative physiology of mice and rats: radiometric measurement of vascular parameters in rodent tissues.

A solid understanding of physiology is beneficial in optimizing drug delivery and in the development of clinically predictive models of drug disposition kinetics. Although an abundance of data exists in the literature, it is often confounded by the use of various experimental methods and a lack of consensus in values from different sources. To help address this deficiency, we sought to directly compare three important vascular parameters at the tissue level using the same experimental approach in both mice and rats. Interstitial volume, vascular volume, and blood flow were radiometrically measured in selected harvested tissues of both species by extracellular marker infusion, red blood cell labeling, and rubidium chloride bolus distribution, respectively. The latter two parameters were further compared by whole-body autoradiographic imaging. An overall good interspecies agreement was observed for interstitial volume and blood flow on a weight-normalized basis in most tissues. In contrast, the measured vascular volumes of most rat tissues were higher than for mouse. Mice and rats, the two most commonly utilized rodent species in translational drug development, should not be considered as interchangeable in terms of vascular volume per gram of tissue. This will be particularly critical in biodistribution studies of drugs, as the amount of drug in the residual blood of tissues is often not negligible, especially for biologic drugs (e.g., antibodies) having long circulation half-lives. Physiologically based models of drug pharmacokinetics and/or pharmacodynamics also rely on accurate knowledge of biological parameters in tissues. For tissue parameters with poor interspecies agreement, the significance and possible drivers are discussed.

Morphological measurements and ITS sequences show that the new alder rust in Europe is conspecific with Melampsoridium hiratsukanum in eastern Asia.

Three species of Melampsoridium have been reported to infect hosts in genus Alnus. An epidemic of foliar rust affecting A. glutinosa and A. incana began in Europe in the mid-1990s, and the associated pathogen was identified as Melampsoridium hiratsukanum based on morphology. In this investigation we analyzed the morphology and genetic variation of alder rusts from Europe and Japan and the host specificity of the European epidemic rust. Our results showed that two rusts occur on the leaves of alders native to northern Europe; in Scotland an endemic rust indistinguishable from M. betulinum occurs, whereas alders in areas of Europe affected by the current epidemic were infected by M. hiratsukanum. M. hiratsukanum from naturally infected alder in Finland produced aecia on all Larix species tested but did not infect Betula leaves.

Minor illness and injury: factors influencing attendance at a paediatric accident and emergency department.

AIMS: To gather information on children with minor illness or injury presenting to a paediatric accident and emergency (A&E) department and the decision making process leading to their attendance. METHODS: Prospective questionnaire based survey of 465 children selected by systematic sampling from A&E attenders allocated to the lowest triage category. RESULTS: The study population was statistically representative of the total population of A&E attenders. The lower deprivation categories were over represented. Educational attainment, childcare experience, and parental coping skills were important in relation to A&E attendance. More children attended with injury as opposed to illness. There were no significant demographic differences between those children who presented directly to A&E and those who made prior contact with a GP. Just under half the study population had made contact with a general practitioner (GP) before attending A&E. The majority of those children were directly referred to A&E at that point. GPs referred equivalent numbers of children with illness and injury. CONCLUSIONS: Parents and GPs view paediatric A&E departments as an appropriate place to seek treatment for children with minor illness or injury.

Iron accumulation during cellular senescence.

Iron accumulates as a function of age and is associated with the pathology of numerous age-related diseases. These changes may be caused by altered iron homeostasis at the cellular level, yet this is poorly understood. Therefore, changes in iron content in primary human fibroblasts were studied in culture models of cellular senescence. Total iron content increased exponentially during cellular senescence, reaching approximately 10-fold higher levels than young cells. Increasing intracellular iron levels through iron-citrate supplementation or decreasing intracellular iron levels using iron-selective chelators had little effect on cellular life span and markers of cellular senescence when used at subtoxic doses. However, accelerating cellular senescence with low-dose H(2)O(2) also accelerated senescence-associated iron accumulation. Delaying cellular senescence with N-tert-butyl-hydroxylamine (NtBHA) attenuated senescence-associated iron accumulation. Furthermore, H(2)O(2) or NtBHA had no effect on iron intracellular levels in immortalized fibroblasts. Thus, iron accumulation is not a cause, but a consequence of normal cellular senescence in vitro. Senescence-associated iron accumulation may contribute to the increased oxidative stress and cellular dysfunction seen in senescent cells.

The koniocellular pathway in primate vision.

A neurochemically distinct population of koniocellular (K) neurons makes up a third functional channel in primate lateral geniculate nucleus. As part of a general pattern, K neurons form robust layers through the full representation of the visual hemifield. Similar in physiology and connectivity to W cells in cat lateral geniculate nucleus, K cells form three pairs of layers in macaques. The middle pair relays input from short-wavelength cones to the cytochrome-oxidase blobs of primay visual cortex (V1), the dorsal-most pair relays low-acuity visual information to layer I of V1, and the ventral-most pair appears closely tied to the function of the superior colliculus. Throughout each K layer are neurons that innervate extrastriate cortex and that are likely to sustain some visual behaviors in the absence of V1. These data show that several pathways exist from retina to V1 that are likely to process different aspects of the visual scene along lines that may remain parallel well into V1.

Does beta(3)-adrenoreceptor blockade attenuate acute exercise-induced reductions in leptin mRNA?

We investigated the effect of a single bout of exercise on leptin mRNA levels in rat white adipose tissue. Male Sprague-Dawley rats were randomly assigned to an exercise or control group. Acute exercise was performed on a rodent treadmill and was carried out to exhaustion, lasting an average of 85.5 +/- 1.5 min. At the end of exercise, soleus muscle and liver glycogen were reduced by 88% (P < 0.001). Acutely exercised animals had lower (P < 0.05) leptin mRNA levels in retroperitoneal but not epididymal fat, and this was independent of fat pad weight. To test the hypothesis that beta(3)-adrenergic-receptor stimulation was involved in the downregulation of leptin mRNA in retroperitoneal fat, a second experiment was performed in which rats were randomized into one of four groups: control, control + beta(3)-antagonist, exercise, and exercise + beta(3)-antagonist. A highly selective beta(3)-antagonist (SR-59230A) or vehicle was given by gavage 30 min before exercise or control experiment. Exercise consisted of 55 min of treadmill running, sufficient to reduce liver and muscle glycogen by 70 and 80%, respectively (both P < 0.0001). Again, acute exercise reduced leptin mRNA in retroperitoneal fat (exercise vs. control; P < 0.05), but beta(3)-antagonism blocked this effect (exercise + beta(3)-antagonist vs. control + beta(3)-antagonist; P = 0.42). Unexpectedly, exercise increased serum leptin. This would be consistent with the idea that there are releasable, preformed pools of leptin within adipocytes. We conclude that beta(3)-receptor stimulation is a mechanism by which acute exercise downregulates retroperitoneal adipose tissue leptin mRNA in vivo.

Neuronal chemistry and functional organization in the primate visual system.

Beginning with the first step of visual processing and proceeding outward from that point, the neurons involved in different aspects of vision are distinct. Stated simply, neurons doing different things look different. They often display distinct morphological features and they usually express different molecules. In addition, neurons that perform a common function usually aggregate together to form recognizable layers or compartments that can be studied in isolation because they are neurochemically distinct. Here is found, then, a junction of two major domains in neuroscience research, as discovery of molecular diversity among neurons is exploited to study organization and function of the primate visual system.

Strip-cankering of beech (Fagus sylvatica): Pathology and distribution of symptomatic trees.

The pathology and distribution of European beech trees bearing elongated bark lesions (strip-cankers) were investigated. Two types of canker were recognized: those on small trees (<40 cm diameter at breast height (dbh): 1·4 m above ground level) which bore fruit bodies of the xylariaceous ascomycete Biscogniauxia nummularia (Bull.) O. Kuntze, and those on larger specimens (>40 cm dbh) which were consistently associated with the diatrypaceous ascomycete Eutypa spinosa (Pers.) Tul. & C. Tul. All cankers were strictly annual, having formed during single growing seasons following periods of low water availability. The regional and local distribution of trees bearing lesions also appeared to be correlated with environmental conditions, being most severe where low rainfall or high temperatures had occurred. Population studies of the associated fungi, generally considered as saprotrophs, indicated the presence of unique genotypes within individual cankered trees and provided no evidence for the existence of pathotypes within either species. Within the decay columns which underlay canker surfaces, both B. nummularia and E. spinosa formed longitudinally extensive genets, implying non-mycelial spread in colonization. Suppression of both inter- and intraspecific incompatibility between fungi occurred in regions of canker decay columns with elevated water contents. The possible significance of coexistence between the ascomycetes B. nummularia and 'Hypoxylon purpureum' (sensu Sharland & Rayner, 1989b) and of the formation of heterokaryons by E. spinosa is discussed.

Voluntary wheel running decreases adipose tissue mass and expression of leptin mRNA in Osborne-Mendel rats.

The purpose of this study was to assess the effects of voluntary wheel running on the expression of leptin mRNA in rats that are either sensitive (OM) or resistant (S5B/Pl) to diet-induced obesity. Male OM and S5B/Pl rats had ad libitum access to standard rodent diet and water. At 3-5 weeks of age, animals of both strains were randomly assigned to either an exercise or sedentary control group. The exercise groups had 24-h access to a running wheel, and they trained for 7 weeks. During weeks 1-4, animals in both OM and S5B/Pl exercise groups progressively increased their running. During weeks 5-7, S5B/Pl exercisers tended to run more than did OM (approximately 60 vs. 45 km/week), but by the end of the study both groups had an equally greater heart weight (mg/g body weight) and planteris citrate synthase activity than their sedentary controls. Oral glucose tolerance tests performed during the last week of training revealed that compared with their appropriate controls, insulin sensitivity was enhanced (P < 0.05) in OM but not in the S5B/Pl wheel-running groups. Inguinal, epididymal, and retroperitoneal fat pads weighed less in the running than in the nonrunning groups of both strains (P < 0.01). Additionally, exercised animals had an increased percentage of smaller cells (40-60 microm; P < 0.05) and a decreased percentage of larger cells (120-160 microm; P < 0.05) in the epididymal fat depot. Epididymal leptin mRNA measured by Northern blot analysis was reduced in the exercise-trained rats of both strains (P < 0.05). Furthermore, serum leptin was reduced in exercise-trained compared with the control animals of both strains. In comparison to S5B/Pl, control OM animals exhibited both a higher expression and higher circulating levels of leptin (P < 0.05). While serum leptin levels were decreased and food intake was increased in the exercise-trained animals of both strains (P < 0.05), the exact relationship between exercise, leptin, and food intake in this rat model of dietary obesity remains to be determined. Nonetheless, these results suggest that the expression and secretion of leptin can be influenced by exercise training and that these changes (i.e., reduced expression and secretion of protein) can occur independently of changes in whole-body insulin sensitivity and susceptibility to diet-induced obesity.

Nursing care of the Paratrend 7 sensor.

The Paratrend 7 sensor is a continuous intravascular blood gas sensor that consists of a miniaturized Clark-type PO2 electrode, fibreoptic pH and PCO2 optodes and a thermocouple, the monitor continuously displays the measured pH, PaO2 PaCO2 and temperature of the blood, and the calculated oxygen saturation, BE and SBC. After 7 years of caring for over 200 patients following insertion of the sensor, we describe our nursing experience with particular emphasis on the adequate fixation of the cannula, sensor system and connectors. The maintenance of the sensor through adequate flushing of the arterial line and care of the insertion site is described. Also outlined are the potential advantages to nursing practice of this new monitoring system, with particular reference to early warning of deterioration in respiratory function, closer control of mechanical ventilation and reduction in blood gas sampling and the errors inherent therein.

Fibroblast growth factor (FGF) homologous factors: new members of the FGF family implicated in nervous system development.

Four new members of the fibroblast growth factor (FGF) family, referred to as fibroblast growth factor homologous factors (FHFs), have been identified by a combination of random cDNA sequencing, data base searches, and degenerate PCR. Pairwise comparisons between the four FHFs show between 58% and 71% amino acid sequence identity, but each FHF shows less than 30% identity when compared with other FGFs. Like FGF-1 (acidic FGF) and FGF-2 (basic FGF), the FHFs lack a classical signal sequence and contain clusters of basic residues that can act as nuclear localization signals. In transiently transfected 293 cells FHF-1 accumulates in the nucleus and is not secreted. Each FHF is expressed in the developing and adult nervous systems, suggesting a role for this branch of the FGF family in nervous system development and function.

Continuous intra-arterial blood gas monitoring.

OBJECTIVE: To review the technology, clinical trials and current status of continuous blood gas monitoring in intensive care. DESIGN: The review describes the history, technology, various clinical trials on continuous blood gas monitoring and discusses the various factors which might affect their performance characteristics and outlines their potential role in intensive care and during anaesthesia. CONCLUSIONS: Over the past 10 years a number of continuous intra-arterial blood gas monitoring systems have been developed. The performance characteristics of these systems are comparable. Their levels of accuracy as measured in bench tonometry are not consistently achieved in clinical trials. The potential usefulness of these monitors in various clinical situations has been described in case studies. Controlled studies demonstrating an improvement in outcome with the use of these monitors have not been published.

Continuous measurement of arterial blood gas status during total hip replacement: a prospective study.

The arterial blood gas chemistry was measured continuously in ten patients during primary cemented total hip replacement in order to define more precisely the patterns of changes in blood gases during various stages of the operation. All ten patients demonstrated significant drops in PaO2 after femoral cement implantation and nine of the ten after acetabular cement implantation. The mean drop in PaO2 following acetabular cement expressed as mean +/- SD was 18 +/- 8 mmHg (16 +/- 6%) (P < 0.05) and femoral cement application was 25 +/- 11 mmHg (23 +/- 9%) (P < 0.05). For changes in PaO2 there were corresponding drops in SpO2 in all patients with the femoral cement and in eight patients with the acetabular cement. The mean drop in SpO2 following the application of acetabular and femoral cements respectively were 1.7 +/- 1.5% and 3 +/- 2.45%. No changes in blood PaO2 were observed during dislocation of the hip joint or reaming of acetabulum and femur. In vitro studies revealed no effect of the liquid monomer or the cured cement on the performance of the Clark electrode of the sensor. We suggest that significant drops in PaO2 occur with both acetabular and femoral cement implantation and that the derangements in blood PaO2 last longer than detected by pulse oximetry following cement implantation.

Regulation of calcium-binding protein immunoreactivity in GABA neurons of macaque primary visual cortex.

Monocular deprivation produces an imbalance in visual drive from the two eyes, which in adult macaque V1 leads to marked changes in the neurochemistry of GABA interneurons. Such changes were further examined by studying immunoreactivity for calbindin, calretinin, and parvalbumin, three calcium-binding proteins that mark distinct subpopulations of GABA neurons, in macaques that had been monocularly deprived by intravitreal injection of tetrodotoxin. Deprivation for 5 d or longer produced a reversal in the normal pattern of calbindin immunostaining in layer III, from one in which intense neuronal immunostaining surrounded the cytochrome oxidase-rich puffs to one in which it occupied the puffs. Over the same period, calbindin immunostaining in other layers was reduced across the entire width of deprived-eye columns or extended into flanking regions of normal-eye columns. In contrast, reduction in parvalbumin immunostaining occurred only in deprived-eye columns and included only terminals with short periods of deprivation (up to 17 d) but both terminals and somata with longer periods. No change in calretinin immunoreactivity was observed. These findings demonstrate that GABA neurons of macaque V1 vary in their response to monocular deprivation according to their neurochemistry and position, suggesting that the weight of inputs from the two eyes and the intrinsic characteristics of each GABA population determine how a neuron responds to a change in visual input.

Selective expression and rapid regulation of GABAA receptor subunits in geniculocortical neurons of macaque dorsal lateral geniculate nucleus.

Monocular deprivation in adult macaques produces a rapid down-regulation in GABA and GABAA receptor subunit immunoreactivity in deprived-eye columns of primary visual cortex (VI) but a significantly delayed GABA reduction in deprived layers of the dorsal lateral geniculate nucleus (LGN). These findings, suggesting that normal inhibitory neurotransmission persists in LGN at a time when VI inhibitory mechanisms are greatly altered, are consistent with physiological studies that have demonstrated a greater degree of functional plasticity in VI than in LGN. Nonetheless, functional adaptation to partial loss of visual input has been detected in the LGN, indicating that synaptic plasticity takes place in this nucleus. In the present study, evidence for early changes in inhibitory neurotransmission were examined with immunocytochemical methods to determine if, in the absence of early GABA regulation, GABAA receptor subunits in macaque LGN are affected by adult deprivation. Immunoreactivity for alpha 1 and beta 2/3 subunits of the GABAA receptor was intense within the magnocellular layers and more modest in the parvocellular layers and intercalated layers. In all layers, immunoreactivity was present in the cytoplasm and along the surfaces of relatively large somata and in dense tangles of processes in the neuropil. Double-labeling experiments demonstrated that somata and processes immunoreactive for alpha 1 and beta 2/3 were surrounded by GABA terminals but no cell intensely immunoreactive for either subunit expressed immunoreactivity for GABA, itself. Following periods of monocular deprivation by tetrodotoxin (TTX) injection for 4 days or longer, layers deprived of visual activity displayed levels of alpha 1 and beta 2/3 immunoreactivity markedly lower than those displayed by the adjacent, normally active layers. Such changes were greater as the period of deprivation increased. The changes included a loss of immunostaining in and around somata and in many neuropil elements of deprived layers. These data indicate that GABA and GABAA receptor subunits alpha 1 and beta 2/3 are expressed by separate populations of neurons in macaque LGN that are differentially regulated by visual activity. The findings suggest that rapid, activity-dependent regulation of postsynaptic receptors represents one mechanism for altering synaptic strength in the adult macaque visual system.