Evolving practice: X-linked agammaglobulinemia and lung transplantation.

X-linked agammaglobulinemia (XLA) is a rare primary humoral immunodeficiency syndrome characterized by agammaglobulinemia, recurrent infections and bronchiectasis. Despite the association with end-stage bronchiectasis, the literature on XLA and lung transplantation is extremely limited. We report a series of 6 XLA patients with bronchiectasis who underwent lung transplantation. Short-term outcomes were excellent however long-term outcomes were disappointing with a high incidence of pulmonary sepsis and chronic lung allograft dysfunction (CLAD).

Pharmacokinetics and safety of Intragam 10 NF, the next generation 10% liquid intravenous immunoglobulin, in patients with primary antibody deficiencies.

BACKGROUND AND AIMS: Intragam® 10 NF is the next generation 10% intravenous immunoglobulin with three pathogen reduction steps and a noncarbohydrate stabiliser. This open label, cross-over study in patients with primary immunodeficiency was designed to evaluate whether Intragam 10 NF differed in its pharmacokinetics (PK) compared with Intragam P and to assess Intragam 10 NF safety and tolerability. METHODS: Nineteen primary immunodeficiency patients were administered one cycle of their existing Intragam P dose (0.2-0.8 g/kg 3-4 weekly), followed by seven cycles of Intragam 10 NF administered at the same dosing schedule as Intragam P. The primary objective was to compare serum immunoglobulin G (IgG) trough levels. Secondary endpoints were PK variables, safety and tolerability. RESULTS: There was no significant within-patient difference in the average trough immunoglobulin G concentration between Intragam P and Intragam 10 NF (8.76 g/L, 8.55 g/L respectively) (geometrical mean ratio 1.034; 95% confidence interval 0.996-1.073; P = 0.079). Mean PK parameters for both products were similar, with all 95% confidence interval encompassing 1.0 except for time to maximum concentration. Time to maximum concentration occurred earlier with Intragam 10 NF compared with Intragam P, with a shorter infusion time (mean 1.75 h vs 2.52 h respectively; P < 0.05). Headache was the most frequent treatment-related event following both products. There were no study withdrawals, deaths, or notable changes in laboratory values or vital signs. CONCLUSION: Intragam 10 NF was well tolerated and exhibited similar PK to Intragam P, with the advantage of a 45 min shorter infusion time.

Campylobacteriosis outbreak associated with ingestion of mud during a mountain bike race.

One of the largest reported campylobacteriosis outbreaks in Canada occurred in June 2007 in British Columbia, associated with a mountain bike race that took place in muddy conditions. A retrospective cohort study was conducted and environmental samples were collected and tested. There were 537 racers included in the study and 225 racers (42%) reported diarrhoeal illness after the race. C. jejuni clinical isolates (n=14) were found to be identical by multi-locus sequence typing. Although univariate analysis suggested water consumption and mud exposure as significant risk factors, multivariate analysis revealed that on direct ingestion mud was significantly associated with illness (OR 4·08, 95% CI 2·03-8·21). Contaminated mud was thus the most likely source of Campylobacter infection. We identified other unpublished reports of outbreaks associated with bike races in rainy or muddy conditions; these underscore the importance of educating racers and raising public awareness of the risks of mud ingestion.

Should individuals use influenza vaccine effectiveness studies to inform their decision to get vaccinated?

Studies on the effectiveness of seasonal influenza vaccine can affect an individual's perception of the ability of this vaccine to protect against influenza. However, vaccine effectiveness studies are designed to inform public health decisions rather than for individual decision-making. This overview explains what vaccine effectiveness means and why vaccine effectiveness estimates can vary. Individual variation in the response to seasonal influenza vaccine is based upon risk factors such as age, underlying health conditions, immune status and risk of infection and complications. Therefore, an individual's decision to get vaccinated should be primarily informed by their risk of influenza illness and their risk of transmitting influenza to vulnerable people.

Effectiveness of hand hygiene practices in preventing influenza virus infection in the community setting: A systematic review.

BACKGROUND: Hand hygiene is known to be an effective infection prevention and control measure in health care settings. However, the effectiveness of hand hygiene practices in preventing influenza infection and transmission in the community setting is not clear. OBJECTIVE: To identify, review and synthesize available evidence on the effectiveness of hand hygiene in preventing laboratory-confirmed or possible influenza infection and transmission in the community setting. METHODS: A systematic review protocol was established prior to conducting the review. Three electronic databases (MEDLINE, Embase and the Cochrane Library) were searched to identify relevant studies. Two reviewers independently screened the titles, abstracts and full-texts of studies retrieved from the database searches for potential eligibility. Data extraction and quality assessment of included studies were performed by a single reviewer and validated by a second reviewer. Included studies were synthesized and analyzed narratively. RESULTS: A total of 16 studies were included for review. Studies were of low methodological quality and there was high variability in study design, setting, context and outcome measures. Nine studies evaluated the effectiveness of hand hygiene interventions or practices in preventing laboratory-confirmed or possible influenza infection in the community setting; six studies showed a significant difference, three studies did not. Seven studies assessed the effectiveness of hand hygiene practices in preventing laboratory-confirmed or possible influenza transmission in the community setting; two studies found a significant difference and five studies did not. CONCLUSION: The effectiveness of hand hygiene against influenza virus infection and transmission in the community setting is difficult to determine based on the available evidence. In light of its proven effectiveness in other settings, there is no compelling evidence to stop using good hand hygiene practice to reduce the risk of influenza infection and transmission in the community setting.

Summary of the NACI Seasonal Influenza Vaccine Statement for 2018-2019.

BACKGROUND: There are many different influenza vaccines authorized for use in Canada and new evidence on influenza and vaccines is emerging all the time. The National Advisory Committee on Immunization (NACI) provides recommendations annually regarding seasonal influenza vaccines to the Public Health Agency of Canada (PHAC). OBJECTIVE: To summarize the NACI recommendations regarding the use of seasonal influenza vaccines for the 2018-2019 influenza season in light of two NACI reviews conducted on 1) the risk of serious influenza-related complications in children and adults with neurologic and neurodevelopment conditions and 2) the efficacy/effectiveness of high-dose and adjuvanted inactivated influenza vaccines in persons 65 years of age and older. METHODS: For both topics, NACI's Influenza Working Group developed a predefined search strategy to identify all eligible studies, assessed their quality, summarized and analyzed the findings, proposed recommendations and identified the Grade of evidence that supported them. In light of the evidence, the recommendations were then considered and approved by NACI. RESULTS: NACI concludes there is fair evidence to recommend that children and adults with neurologic and neurodevelopment conditions are groups for whom influenza immunization is particularly recommended (Evidence Grade B recommendation). On choosing influenza vaccines for persons 65 years of age and older, at a programmatic level, NACI recommends that any of the four influenza vaccines available for use should be used. There is insufficient evidence to make a comparative recommendation on the use of these vaccines at a programmatic level (Grade I). At an individual level, NACI recommends that high-dose trivalent inactivated influenza vaccine (TIV) should be offered over standard-dose TIV to persons 65 years of age and older (Grade A). There is insufficient evidence to make comparative recommendations on the use of MF59-adjuvanted TIV and quadrivalent inactivated influenza vaccine over standard-dose TIV (Grade I). CONCLUSION: NACI continues to recommend annual influenza vaccination for all individuals aged six months and older, with particular focus on people at high risk of influenza-related complications or hospitalization, people capable of transmitting influenza to those at high risk, people who provide essential community services and people in direct contact during culling operations with poultry infected with avian influenza.

Regenerating optic axons restore topography after incomplete optic nerve injury.

Following complete optic nerve injury in a lizard, Ctenophorus ornatus, retinal ganglion cell (RGC) axons regenerate but fail to restore retinotectal topography unless animals are trained on a visual task (Beazley et al. [ 1997] J Comp Neurol 370:105-120, [2003] J Neurotrauma 20:1263-1270). Here we show that incomplete injury, which leaves some RGC axons intact, restores normal topography. Strict RGC axon topography allowed us to preserve RGC axons on one side of the nerve (projecting to medial tectum) while lesioning those on the other side (projecting to lateral tectum). Topography and response properties for both RGC axon populations were assessed electrophysiologically. The majority of intact RGC axons retained appropriate topography in medial tectum and had normal, consistently brisk, reliable responses. Regenerate RGC axons fell into two classes: those that projected topographically to lateral tectum with responses that tended to habituate and those that lacked topography, responded weakly, and habituated rapidly. Axon tracing by localized retinal application of carbocyanine dyes supported the electrophysiological data. RGC soma counts were normal in both intact and axotomized RGC populations, contrasting with the 30% RGC loss after complete injury. Unlike incomplete optic nerve injury in mammals, where RGC axon regeneration fails and secondary cell death removes many intact RGC somata, lizards experience a "win-win" situation: intact RGC axons favorably influence the functional outcome for regenerating ones and RGCs do not succumb to either primary or secondary cell death.

Summary of the NACI Statement on Seasonal Influenza Vaccine for 2017-2018.

BACKGROUND: Influenza is a respiratory infection caused primarily by influenza A and B viruses. Vaccination is the most effective way to prevent influenza and its complications. The National Advisory Committee on Immunization (NACI) provides recommendations regarding seasonal influenza vaccines annually to the Public Health Agency of Canada (PHAC). OBJECTIVE: To summarize the NACI recommendations regarding the use of seasonal influenza vaccines for the 2017-2018 influenza season. METHODS: Annual influenza vaccine recommendations are developed by NACI's Influenza Working Group for consideration and approval by NACI, based on NACI's evidence-based process for developing recommendations. The recommendations include a consideration of the burden of influenza illness and the target populations for vaccination; efficacy and effectiveness, immunogenicity and safety of influenza vaccines; vaccine schedules; and other aspects of influenza immunization. These recommendations are published annually on the Agency's website in the NACI Advisory Committee Statement: Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine (the Statement). RESULTS: The annual statement has been updated for the 2017-2018 influenza season to incorporate recommendations for the use of live attenuated influenza vaccine (LAIV) that were contained in two addenda published after the 2016-2017 statement. These recommendations were 1) that egg-allergic individuals may be vaccinated against influenza using the low ovalbumin-containing LAIV licensed for use in Canada and 2) to continue to recommend the use of LAIV in children and adolescents 2-17 years of age, but to remove the preferential recommendation for its use. CONCLUSION: NACI continues to recommend annual influenza vaccination for all individuals aged six months and older, with particular focus on people at high risk of influenza-related complications or hospitalization, people capable of transmitting influenza to those at high risk, and others as indicated.

The dance of the growth cones--where to next?

Axon guidance in the developing nervous system is accomplished by a remarkable structure, the axon growth cone. This structure navigates, often over long distances, to find and synapse with target cells. Transformation of the growth cone to a terminal arbor establishes functional circuitry. The navigational properties of growth cones, and their interactions with target tissue, have been studied widely by examining individual cells in vitro, and have also been inferred from histological sections. Recent advances in labelling techniques and imaging of living cells have enabled direct observation of the growing axon tip in intact embryos as well as in slice preparations. To understand how pathways and terminal arbors are formed, the challenge now is to relate the dynamic morphology and behaviour of living growth cones to surrounding cues in the complex environment of the developing embryo.

Immunization guidance products: Different levels of detail for different uses.

The National Advisory Committee on Immunization (NACI) provides expert and evidence-based advice to the Public Health Agency of Canada (PHAC) on the use of human vaccines in Canada. This advice is presented in a variety of publications for different uses. A recent survey identified some confusion regarding the various NACI publication products. The objective of this article is to identify the level of detail and appropriate uses of the different NACI products. NACI statements provide a synthesis of current evidence and expert opinion on new vaccines or new indications for vaccines to inform immunization practices, policies and programs. NACI literature reviews inform new NACI statements and are published after the statement to inform readers about current literature on a specific immunization topic. The Canadian Immunization Guide (CIG) is a practice-oriented guide that synthesizes all the NACI statements and is updated regularly. NACI statement summaries are published in the Canada Communicable Disease Report (CCDR) and provide a high level overview of these statements shortly after they are published. These products provide a variety of options for users to choose how in-depth they wish to explore the evidence base and process for producing recommendations for immunization in Canada.

Functional morphology of frog retinal ganglion cells and their central projections: the dimming detectors.

Intracellular recordings were made from frog retinal ganglion cell axons in the optic nerve. Following electrophysiological characterisation of receptive field properties, HRP was injected into the axon, and the brain and retina were subsequently stained. The morphologies of retinal ganglion cells, their dendritic domains, and their central projections were determined with light microscopy, and the optic nerve portion of the ganglion cell axon was examined with electron microscopy. This paper describes the structural and functional features of one ganglion cell class, the off units (class IV or dimming detectors) whose characteristic response is a preferential sensitivity to decreasing light intensity within the receptive field. Typical receptive field diameter of these units was about 16 degrees with a range of 3 degrees to more than 30 degrees. Examination of the spatial characteristics of their receptive field centers and surrounds showed that the class IV cells could be divided into two broad categories. Linear class IV cells did not respond to phase-reversal of a fine grating pattern. These linear cells also tended to have clear surround suppression: illumination of the surround diminished their response to light off at the center. The second group responded briskly to each reversal of the fine grating pattern, whatever its position within the receptor field center. These nonlinear class IV cells did not show surround suppression, but rather they had surround antagonism and they responded to light on in the surround. Nonlinear units were much more frequently recorded in frogs maintained in summer conditions (12-hour days, constant 20 degrees C temperature). In spite of this functional heterogeneity, all cells had similar morphology consisting of a large ganglion cell with a large dendritic arbor (400-1,000 microns) confined to a single stratum in the outer third of the inner plexiform layer, a medium-sized axon (2.4-microns diameter), a smallish pretectal arbor, and a large tectal arbor (300-700 microns) at layer 8.

Failure to restore vision after optic nerve regeneration in reptiles: interspecies variation in response to axotomy.

Optic nerve regeneration within the reptiles is variable. In a snake, Viper aspis, and the lizard Gallotia galloti, regeneration is slow, although some retinal ganglion cell (RGC) axons eventually reach the visual centers (Rio et al. [1989] Brain Res 479:151-156; Lang et al. [1998] Glia 23:61-74). By contrast, in a lizard, Ctenophorus ornatus, numerous RGC axons regenerate rapidly to the visual centers, but unless animals are stimulated visually, the regenerated projection lacks topography and animals remain blind via the experimental eye (Beazley et al. [2003] J. Neurotrauma 20:1263-1269). V. aspis, G. galloti, and C. ornatus belong respectively to the Serpentes, Lacertidae, and Agamidae within the Eureptilia, the major modern group of living reptiles comprising the Squamata (snakes, lizards, and geckos) and the Crocodyllia. Here we have extended the findings on Eureptilia to include two geckos (Gekkonidae), Cehyra variegata and Nephrurus stellatus. We also examined a turtle, Chelodina oblonga, the Testudines being the sole surviving representatives of the Parareptilia, the more ancient reptilian group. In all three species, visually elicited behavioral responses were absent throughout regeneration, a result supported electrophysiologically; axonal tracing revealed that only a small proportion of RGC axons crossed the lesion and none entered the contralateral optic tract. RGC axons failed to reach the chiasm in C. oblonga, and in G. variegata, and N. stellatus RGC axons entered the opposite optic nerve; a limited ipsilateral projection was seen in G. variegata. Our results support a heterogeneous response to axotomy within the reptiles, each of which is nevertheless dysfunctional.

Patients with ocular hypertension have abnormal point scotopic thresholds in the superior hemifield.

PURPOSE: To compare light- and fully dark-adapted thresholds at loci within the central visual field in patients with ocular hypertension and glaucoma. METHODS: Eighteen patients with chronic open angle glaucoma, 13 patients with ocular hypertension, and 24 age-matched normals were studied. The Humphrey automated perimeter with the standard background illumination of 31.5 apostilbs was used to determine photopic thresholds at 18 loci within 20 degrees of fixation. Fully dark-adapted thresholds were measured at the same loci after 30 minutes of dark adaptation by automatic, static campimetry. RESULTS: The glaucoma group showed elevated scotopic thresholds. Scotopic defects also were found in a significantly higher proportion of patients with ocular hypertension than in normals. These scotopic defects were predominantly in the superior hemifield. CONCLUSIONS: Scotopic threshold campimetry may identify the subgroup of patients with ocular hypertension who progress to develop glaucomatous field loss identifiable by standard photopic and mesopic perimetry.

Ascorbic acid potentiates the inhibitory effect of dopamine on prolactin release in primary cultured rat pituitary cells.

The chemical structure of dopamine includes an ortho-catechol group which is labile to oxidizing agents. Ascorbic acid, a reducing agent, has in the past been added to the incubation medium in order to protect dopamine against oxidation. However, there has been no thorough examination of the biological effect of ascorbic acid on prolactin release. In this present study we have shown that ascorbic acid has neither a stimulatory nor an inhibitory effect on prolactin release but reduces by approximately two orders of magnitude the concentration of dopamine necessary to inhibit prolactin release from cultured anterior pituitary cells. The strong potentiation effect of ascorbic acid was reproduced using apomorphine. We compared the effect of ascorbic acid and isoascorbic acid on dopamine inhibition of prolactin release. Isoascorbic acid is an epimer of ascorbic acid, having the same reduction-oxidation potential as ascorbic acid, but is less biologically active. Isoascorbic acid was less effective in potentiating the dopaminergic effect than was ascorbic acid, which supports the notion that potentiation by ascorbic acid is not entirely due to its reducing property. In order to dissociate further the chemical protection of dopamine from the biological potentiation, the inhibitory effects of freshly made and 3-h-old dopamine solutions were compared. Neither one of the two solutions contained any ascorbic acid, yet the two solutions did not show any difference in their ability to inhibit prolactin release during the 3-h incubation period, indicating that no significant amount of dopamine was oxidized.(ABSTRACT TRUNCATED AT 250 WORDS)

A high concentration of dopamine preferentially permitted release of newly synthesized prolactin.

We used continuous labelling ([3H]leucine) of cultured adenohypophysial cells to investigate the relationship between the storage and release of newly synthesized and stored prolactin in response to dopamine (1 mumol/l) and thyrotropin-releasing hormone (TRH) (0.1 mumol/l) challenge. Newly synthesized prolactin was identified by the tritium radiation activity incorporated in prolactin. A maximal dose of dopamine (1 mumol/l) could not completely block prolactin release from a primary culture of lactotrophs. During 3 h of continuous labelling under maximal dopaminergic inhibition, newly synthesized prolactin was released which was of a significantly higher specific activity than control groups. In contrast, TRH stimulation produced results consistent with previous observations of the release of predominantly old, stored hormone. However, the absolute amount of the newly synthesized prolactin was increased by the TRH administration, and the increased release of the newly synthesized prolactin could be accounted for by increased levels of synthesis. Our results are consistent with the concept of the existence of a regulated route and a dopamine-insensitive constitutive route of prolactin release which predominantly encompasses newly synthesized hormone. However, the possibility that cellular heterogeneity or that non-dopaminergic prolactin-release inhibiting factor(s) (PIF) is responsible for this observed release cannot be ruled out.

Exercise-related potassium and free fatty acid level changes in coronary artery disease. Responses after moderate intensity training.

Exercise produces changes in circulating levels of potassium and free fatty acids which may provoke arrhythmias in patients with coronary artery disease. Twenty patients participating in 6 weeks of training were studied; 9 of these patients took part in 4 more weeks of training and a third exercise test. After 6 weeks, potassium levels were higher at submaximal levels of exercise, free fatty acid levels were reduced at rest, and at 5, 15, and at 30 min post-exercise. Norepinephrine levels were reduced at submaximal work loads after 6 weeks and increased at maximal work loads. The extra 4 weeks had no additive effect on these metabolic changes. Participation by coronary artery disease patients in a short-term, moderate intensity, exercise training program increases potassium levels at submaximal work loads and reduces levels of free fatty acids at rest and after exercise. The arrhythmogenic relevance of these findings deserves further consideration.

Training on a visual task improves the outcome of optic nerve regeneration.

Optic nerve regeneration in a lizard, Ctenophorus ornatus, is dysfunctional despite survival of most retinal ganglion cells and axon regeneration to the optic tectum. The regenerated retino-tectal projection at 6 months has crude topography but by 1 year is disordered; visually-elicited behavior is absent via the experimental eye. Here, we assess the influence of training on the outcome of optic nerve regeneration. Lizards were trained to catch prey presented within the monocular field of either eye. One optic nerve was then severed and visual stimulation resumed throughout regeneration. In the trained group, presentation was restricted to the eye undergoing optic nerve regeneration; for the untrained group, the unoperated eye was stimulated. Pupil responses returned in trained but not in untrained animals. At 1 year, trained animals oriented to and captured prey; untrained animals demonstrated minimal orienting and failed to capture prey. Regenerated retino-tectal projections were topographic in the trained but not in the untrained group as assessed by in vitro electrophysiological recording and by carbocyanine dye tracing. In vitro electrophysiological recording during application of neurotransmitter antagonists to the tectum revealed that the level of GABAergic inhibition was modest in trained animals but elevated in the untrained group; responses were mainly AMPA-mediated in both groups. We conclude that training improves the behavioral outcome of regeneration, presumably by stabilizing and refining the transient retino-tectal map and preventing a build-up of tectal inhibition. The results suggest that for successful central nerve regeneration to occur in mammals, it may be necessary to introduce training to complement procedures stimulating axon regeneration.

An in vitro technique for electrophysiological mapping of reptilian retinotectal projections.

An in vitro procedure is described for electrophysiological mapping of the retinotectal projections using an eye-cup and brain stem preparation which remains viable for up to 30 h. The technique has been found to be successful in turtles and lizards and may be useful for other species in which metabolism is greatly depressed by low temperatures. There are several advantages over in vivo recording, including the longevity and stability of the preparation, an absence of confounding anaesthetic effects and the ability to record from the retina as well as from the brain. The technique offers opportunities to introduce pharmacological agents via the perfusate or to conduct anatomical tracing studies coincident with electrophysiological recording.

Observations on the commissural projection to the dentate gyrus in the Reeler mutant mouse.

The commissural projection to the displaced granule cells of the dentate gyrus in Reeler mutant mice has been examined with autoradiography, and light and electron microscopy. Commissural terminals in Reeler are confined to the hilar region, in contrast to normal littermates in which this projection is restricted to the inner part of the molecular layer. Granule cell somata in Reeler, but only exceptionally in normal littermates, are invested with spines, which have postsynaptic specializations, but no spine apparatus, and are contacted by presynaptic terminals. Between 20 and 30 h after destruction of the commissural fibres in Reeler, degenerating terminals can be found contacting both somatic and dendritic spines in the hilus; 30 h after decommissuration the number and length of spines on the somata and proximal dendrites of Golgi impregnated cells is greatly reduced, while spines on the distal parts of the dendritic tree are unaffected. A similar pattern of degeneration after decomissuration is found in the inner molecular layer of normal littermates. These results are discussed in terms of factors controlling the normal development of afferent projections. The paper concludes with an analysis of a potential methodological hazard. A change in mean spine length will of itself result in a change in the number of visible spines in golgi material. A quantitative assessment of the relation between spine length and the number of visible spines is developed for spherical cell bodies and cylindrical dendrites.