Polyomavirus-associated Prostatitis in Wistar Han Rats Following Immunosuppression in a Chronic Toxicity Study.

Chronic prostatitis characterized on light microscopic examination by moderate, multifocal, predominantly lymphocytic inflammation associated with epithelial atypia and intranuclear and cytoplasmic inclusion-like material was identified in the prostate gland of 2 Wistar Han rats administered an immunomodulatory test article in a 6-month chronic toxicity study. Transmission electron microscopy of the prostate glands identified 45-nm, nonenveloped, icosahedral virions arranged in paracrystalline array within the cell nuclei in 1 of the 2 rats. The size, shape, location, and array pattern were most consistent with a polyomavirus. The light and electron microscopic findings after immunosuppression in our case have a resemblance to a polyomavirus recently reported to affect prostate gland epithelium in a colony of immunocompromised X-linked severe combined immune deficiency rats. To the best of our knowledge, this is the first report of light and electronic microscopic lesions in the reproductive tract associated with polyomavirus following chronic immunosuppression in a widely used, wild-type Wistar Han rat.

Evaluation of miR-216a and miR-217 as Potential Biomarkers of Acute Exocrine Pancreatic Toxicity in Rats.

Detecting and monitoring exocrine pancreatic damage during nonclinical and clinical testing is challenging because classical biomarkers amylase and lipase have limited sensitivity and specificity. Novel biomarkers for drug-induced pancreatic injury are needed to improve safety assessment and reduce late-stage attrition rates. In a series of studies, miR-216a and miR-217 were evaluated as potential biomarkers of acute exocrine pancreatic toxicity in rats. Our results revealed that miR-216a and miR-217 were almost exclusively expressed in rat pancreas and that circulating miR-216a and miR-217 were significantly increased in rats following administration of established exocrine pancreatic toxicants caerulein (CL) and 1-cyano-2-hydroxy-3-butene (CHB) as well as in rats administered a proprietary molecule known to primarily affect the exocrine pancreas. Conversely, neither microRNA was increased in rats administered a proprietary molecule known to cause a lesion at the pancreatic endocrine-exocrine interface (EEI) or in rats administered an established renal toxicant. Compared with amylase and lipase, increases in miR-216a and miR-217 were of greater magnitude, persisted longer, and/or correlated better with microscopic findings within the exocrine pancreas. Our findings demonstrate that in rats, miR-216a and miR-217 are sensitive and specific biomarkers of acute exocrine pancreatic toxicity that may add value to the measurement of classical pancreatic biomarkers.

Pure autonomic failure.

Pure autonomic failure is a degenerative disorder of the peripheral autonomic nervous system. Patients experience symptomatic hypotension that requires them to sit, squat or lie down to prevent syncope. It is associated with characteristic histopathological findings, resulting in neuronal cytoplasmic inclusions in the peripheral autonomic nerves. These lesions are responsible for defects in the synthesis and release of norepinephrine from sympathetic nerve terminals, resulting in significant hypotension. Patients with autonomic failure also have exaggerated blood pressure responses to common stimuli such as food or fluid intake, heat, exercise and medications. Tilt table (head-up) testing is probably the test most commonly used to establish the diagnosis. However, simple office testing is also useful, such as having the patient stand after lying supine with blood pressure monitoring. Treatment options range from simply increasing fluid and salt intake, and using compressive garments, to medications administered orally, subcutaneously or intravenously in more severe cases.

A systematic review of methods of scoring inhaler technique.

Many inhaler devices are currently used in clinical practice to deliver medication, with each inhaler device offering different benefits to overcome technique issues. Inhaler technique remains poor, contributing to reduced airway drug deposition and consequently poor disease control. Scoring inhaler technique has been used within research as an outcome measure of inhaler technique assessment, and this systematic review collates and evaluates these scoring methods. The review protocol was prospectively registered in PROSPERO (CRD42020218869). A total of 172 articles were screened with 77 included, and the results presented using narrative synthesis due to the heterogeneity of the study design and data. The most frequently used scoring method awarded one point per step in the inhaler technique checklist and was included in 59/77 (77%) of articles; however limited and varied guidance was provided for score interpretation. Other inhaler technique scoring methods included grading the final inhaler technique score, expressing the total score as a percentage/ratio, deducting points from the final score when errors were made, and weighting steps within the checklist depending on how crucial the step was. Vast heterogeneity in the number of steps and content in the inhaler technique checklists was observed across all device types (range 5-19 steps). Only 4/77 (5%) of the inhaler technique measures had undertaken fundamental steps required in the scale development process for use in real world practice. This review demonstrates the demand for a tool that measures inhaler technique and highlights the current unmet need for one that has undergone validation.

Evaluation of telehealth support in an integrated respiratory clinic.

Supporting self-management is key in improving disease control, with technology increasingly utilised. We hypothesised the addition of telehealth support following assessment in an integrated respiratory clinic could reduce unscheduled healthcare visits in patients with asthma and COPD. Following treatment optimisation, exacerbation-prone participants or those with difficulty in self-management were offered telehealth support. This comprised automated twice-weekly telephone calls, with a specialist nurse triaging alerts. We performed a matched cohort study assessing additional benefits of the telehealth service, matching by: confirmed diagnosis, age, sex, FEV1 percent predicted, smoking status and ≥1 exacerbation in the last year. Thirty-four telehealth participants were matched to twenty-nine control participants. The telehealth cohort generated 165 alerts, with 29 participants raising at least one alert; 88 (53.5%) alerts received a call discussing self-management, of which 35 (21%) received definitive advice that may otherwise have required an unscheduled healthcare visit. There was a greater reduction in median exacerbation rate across both telehealth groups at 6 months post-intervention (1 to 0, p < 0.001) but not in control groups (0.5 to 0.0, p = 0.121). Similarly, there was a significant reduction in unscheduled GP visits across the telehealth groups (1.5 to 0.0, p < 0.001), but not the control groups (0.5 to 0.0, p = 0.115). These reductions led to cost-savings across all groups, but greater in the telehealth cohorts. The addition of telehealth support to exacerbation-prone patients with asthma or COPD, following comprehensive assessment and treatment optimisation, proved beneficial in reducing exacerbation frequency and unscheduled healthcare visits and thus leads to significant cost-savings for the NHS.Clinical Trial Registration: ClinicalTrials.gov: NCT03096509.

Toxicopathology of the developing immune system: investigative and development strategies.

Developmental immunotoxicity (DIT) has gained attention with the recognition that environmental chemicals can potentially affect the developing immune system and the incidence of childhood allergic diseases. Preclinical safety assessment of pharmaceuticals for men and women of childbearing potential as well as for pediatric and juvenile indications may require DIT assessments. Draft documents from environmental and chemical regulatory agencies propose strategies that use the rat as a test species and incorporate histopathology and functional testing as endpoints. While there are no guidelines for DIT assessment of pharmaceuticals, current discussions suggest that combining immunotoxicity and developmental and reproductive toxicology studies may serve this purpose. Knowledge of the principles and applications of DIT will facilitate participation in strategy development and effective conduct of relevant studies.

COVID-19: A collision of complement, coagulation and inflammatory pathways.

COVID-19 is frequently accompanied by a hypercoagulable inflammatory state with microangiopathic pulmonary changes that can precede the diffuse alveolar damage characteristic of typical acute respiratory distress syndrome (ARDS) seen in other severe pathogenic infections. Parallels with systemic inflammatory disorders such as atypical hemolytic uremic syndrome (aHUS) have implicated the complement pathway in the pathogenesis of COVID-19, and particularly the anaphylatoxins C3a and C5a released from cleavage of C3 and C5, respectively. C5a is a potent cell signalling protein that activates a cytokine storm-a hyper-inflammatory phenomenon-within hours of infection and the innate immune response. However, excess C5a can result in a pro-inflammatory environment orchestrated through a plethora of mechanisms that propagate lung injury, lymphocyte exhaustion, and an immune paresis. Furthermore, disruption of the homeostatic interactions between complement and extrinsic and intrinsic coagulation pathways contributes to a net pro-coagulant state in the microvasculature of critical organs. Fatal COVID-19 has been associated with a systemic inflammatory response accompanied by a pro-coagulant state and organ damage, particularly microvascular thrombi in the lungs and kidneys. Pathologic studies report strong evidence of complement activation. C5 blockade reduces inflammatory cytokines and their manifestations in animal studies, and has shown benefits in patients with aHUS, prompting investigation of this approach in the treatment of COVID-19. This review describes the role of the complement pathway and particularly C5a and its aberrations in highly pathogenic virus infections, and therefore its potential as a therapeutic target in COVID-19.

Nocturnal temperature-controlled laminar airflow device for adults with severe allergic asthma: the LASER RCT.

BACKGROUND: Severe asthma exacerbations are costly to patients and the NHS, and occur frequently in severely allergic patients. OBJECTIVE: To ascertain whether or not nocturnal temperature-controlled laminar airflow (TLA) device usage over 12 months can reduce severe exacerbations and improve asthma control and quality of life compared with a placebo device, while being cost-effective and acceptable to adults with severe allergic asthma. DESIGN: A pragmatic, multicentre, randomised, double-blind, placebo-controlled, parallel-group, superiority trial with qualitative interviews. The trial included an internal pilot with qualitative focus groups. SETTING: Fourteen hospitals in the UK that manage patients with severe asthma. PARTICIPANTS: Adults (16-75 years) with severe, poorly controlled, exacerbation-prone asthma despite high-intensity treatment, and who are sensitised to a perennial indoor aeroallergen. INTERVENTION: Nocturnal, home-based TLA treatment using an Airsonett® (Airsonett AB, Ängelholm, Sweden) device. The comparator was a placebo device that was identical to the active device except that it did not deliver the laminar airflow. Participants were allocated 1 : 1 to TLA therapy or placebo, minimised by site, origin of case, baseline severe exacerbation frequency, maintenance oral corticosteroid use and pre-bronchodilator forced expiratory volume in 1 second. MAIN OUTCOME MEASURES: Primary outcome - frequency of severe asthma exacerbations occurring within the 12-month follow-up period, defined as worsening of asthma requiring systemic corticosteroids [≥ 30 mg of prednisolone or equivalent daily (or ≥ 50% increase in dose if on maintenance dose of ≥ 30 mg of prednisolone)] for ≥ 3 days. Secondary outcomes - changes in asthma control, lung function, asthma-specific and global quality of life for participants, adherence to the intervention, device acceptability, health-care resource use and cost-effectiveness. RESULTS: Between May 2014 and January 2016, 489 patients consented to participate in the trial, of whom 249 failed screening and 240 were randomised (n = 119 in the treatment group and n = 121 in the placebo group); all were analysed. In total, 202 participants (84%) reported use of the device for 9-12 months. Qualitative analyses showed high levels of acceptability. The mean [standard deviation (SD)] rate of severe exacerbations did not differ between groups [active 1.39 (1.57), placebo 1.48 (2.03); risk ratio 0.92, 95% CI 0.66 to 1.27; p = 0.616]. There were no significant differences in secondary outcomes for lung function, except for a reduction in mean daily peak expiratory flow [mean (SD) difference 14.7 l/minute (7.35 l/minute), 95% CI 0.32 to 29.1 l/minute; p = 0.045) for those in the active device group. There were no differences in asthma control or airway inflammation and no serious harms related to the device. No significant difference between the groups in quality-adjusted life-years gained over 1 year was observed. In addition, there was no difference in generic or disease-specific health-related quality of life overall, although statistically significant higher quality of life at month 6 was observed. Increases in quality of life were not sufficient to offset the annual costs associated with use of the TLA device. LIMITATIONS: Missing outcome data could have resulted in an underestimation of exacerbations and rendered the study inconclusive. CONCLUSIONS: Within the limits of the data, no consistent benefits of the active device were demonstrated, and the differences observed were not sufficient to make the device cost-effective. The types of patients who may benefit from the TLA device, and the reasons for large reductions in exacerbation frequency in severe asthma trials, which also incorporate other methods of recording exacerbations, need to be explored. TRIAL REGISTRATION: Current Controlled Trials ISRCTN46346208. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 29. See the NIHR Journals Library website for further project information.

Allergies (along with viruses) are common triggers of asthma exacerbations or 'attacks', which can cause suffering and frequent visits to the general practitioner or hospital. A new machine known as a temperature-controlled laminar airflow device, which remains at the bedside and is switched on every night, filters out allergy particles in the air of a patient's breathing zone, allowing their lungs to rest in clean air overnight. We tested whether or not this machine could improve the lives of those with severe allergic asthma. We recruited 240 people across 14 centres that treat severe asthma across the UK; approximately half received the active device and the other half received a machine that looked exactly the same but did not remove the allergens (a 'placebo' machine). One in five participants was recruited using newer methods of social media such as Facebook (Facebook, Inc., Menlo Park, CA, USA) and Twitter (Twitter, Inc., San Francisco, CA, USA). Participants found the machine easy to use and to live with and there were no significant side effects. The number of attacks reduced a lot in both participants using the active device and those who used the placebo device ­ two participants in five did not suffer any attacks during the trial. However, there was no difference in the number of attacks between the two groups. This might have been because participants did not record everything that happened to them. There was no difference in measurements showing how well the lungs were working, nor in participants' quality of life after 1 year of participating in the trial. Those who were interviewed told us that the study visits and questionnaires could be burdensome, although it was helpful to think more about their asthma. An improvement was seen in one aspect of participants' breathing as well as in their quality of life after 6 months of using the machine, but these potential health benefits could not outweigh the cost of the machine.

Using the Inflammacheck Device to Measure the Level of Exhaled Breath Condensate Hydrogen Peroxide in Patients With Asthma and Chronic Obstructive Pulmonary Disease (The EXHALE Pilot Study): Protocol for a Cross-Sectional Feasibility Study.

BACKGROUND: Asthma and Chronic Obstructive Pulmonary Disease (COPD) are common conditions that affect over 5 million people in the United Kingdom. These groups of patients suffer significantly from breathlessness and recurrent exacerbations that can be difficult to diagnose and go untreated. A common feature of COPD and asthma is airway inflammation that increases before and during exacerbations. Current methods of assessing airway inflammation can be invasive, difficult to perform, and are often inaccurate. In contrast, measurement of exhaled breath condensate (EBC) hydrogen peroxide (H2O2) is performed during normal tidal breathing and is known to reflect the level of global inflammation in the airways. There is a need for novel tools to diagnose asthma and COPD earlier and to detect increased airway inflammation that precedes an exacerbation. OBJECTIVE: The aim of this study was to explore the use of a new handheld device (called Inflammacheck) in measuring H2O2 levels in EBC. We will study whether it can measure EBC H2O2 levels consistently and whether it can be used to differentiate asthma and COPD from healthy controls. METHODS: We will perform a cross-sectional, feasibility, pilot study of EBC H2O2 levels, as measured by Inflammacheck, and other markers of disease severity and symptom control in patients with asthma and COPD and volunteers with no history of lung disease. Participants will be asked to provide an exhaled breath sample for measurement of their EBC H2O2 using Inflammacheck. The result will be correlated with disease stage, spirometry, fractional exhaled nitric oxide (FeNO), and symptom control scores. RESULTS: This study's recruitment is ongoing; it is anticipated that the results will be available in 2018. CONCLUSIONS: The EXhaled Hydrogen peroxide As a marker of Lung diseasE (EXHALE) pilot study will provide an evaluation of a new method of measuring EBC H2O2. It will assess the device's consistency and ability to distinguish airway inflammation in asthma and COPD compared with healthy controls.

Therapeutic Effects of FGF23 c-tail Fc in a Murine Preclinical Model of X-Linked Hypophosphatemia Via the Selective Modulation of Phosphate Reabsorption.

Fibroblast growth factor 23 (FGF23) is the causative factor of X-linked hypophosphatemia (XLH), a genetic disorder effecting 1:20,000 that is characterized by excessive phosphate excretion, elevated FGF23 levels and a rickets/osteomalacia phenotype. FGF23 inhibits phosphate reabsorption and suppresses 1α,25-dihydroxyvitamin D (1,25D) biosynthesis, analytes that differentially contribute to bone integrity and deleterious soft-tissue mineralization. As inhibition of ligand broadly modulates downstream targets, balancing efficacy and unwanted toxicity is difficult when targeting the FGF23 pathway. We demonstrate that a FGF23 c-tail-Fc fusion molecule selectively modulates the phosphate pathway in vivo by competitive antagonism of FGF23 binding to the FGFR/α klotho receptor complex. Repeated injection of FGF23 c-tail Fc in Hyp mice, a preclinical model of XLH, increases cell surface abundance of kidney NaPi transporters, normalizes phosphate excretion, and significantly improves bone architecture in the absence of soft-tissue mineralization. Repeated injection does not modulate either 1,25D or calcium in a physiologically relevant manner in either a wild-type or disease setting. These data suggest that bone integrity can be improved in models of XLH via the exclusive modulation of phosphate. We posit that the selective modulation of the phosphate pathway will increase the window between efficacy and safety risks, allowing increased efficacy to be achieved in the treatment of this chronic disease. © 2017 American Society for Bone and Mineral Research.

High resolution molecular and histological analysis of renal disease progression in ZSF1 fa/faCP rats, a model of type 2 diabetic nephropathy.

ZSF1 rats exhibit spontaneous nephropathy secondary to obesity, hypertension, and diabetes, and have gained interest as a model system with potentially high translational value to progressive human disease. To thoroughly characterize this model, and to better understand how closely it recapitulates human disease, we performed a high resolution longitudinal analysis of renal disease progression in ZSF1 rats spanning from early disease to end stage renal disease. Analyses included metabolic endpoints, renal histology and ultrastructure, evaluation of a urinary biomarker of fibrosis, and transcriptome analysis of glomerular-enriched tissue over the course of disease. Our findings support the translational value of the ZSF1 rat model, and are provided here to assist researchers in the determination of the model's suitability for testing a particular mechanism of interest, the design of therapeutic intervention studies, and the identification of new targets and biomarkers for type 2 diabetic nephropathy.

Diagnosis and management of injuries from dangerous marine life.

Injuries from marine life encompass a wide spectrum, from mild stings to severe bites. Fortunately most of the injuries are mild, although some may be significant, resulting in death. Most of these injuries can be treated by family physicians with a knowledge of the cause of the pathology. Over the years, there have been many treatment options. Some have actually caused an increase in severity. An important rule in treating these injuries is to inactivate the venom, treat the local reaction or injury, and treat the systemic sequelae. Jellyfish stings are the most common type of marine injury. The tentacles possess nematocysts, which are stinging units that are inactivated by the application of vinegar. Sea urchin and stingray injuries require the removal of the imbedded spines after the wound is soaked in hot water. Coral, sea bathers eruption, and swimmer's itch require thorough scrubbing and irrigation. Sea snakes, cone shells, and venomous fish possess a neurotoxin that requires close monitoring in the event of cardiopulmonary collapse. All of these injuries require tetanus status monitoring and consideration of coverage for infectious sequelae.

Infectious bursal disease virus and proventriculitis in broiler chickens.

Acute necrotic proventriculitis is a naturally occurring disease of broiler chickens that causes proventricular rupture during routine evisceration. Although infectious bursal disease virus (IBDV) has been implicated, it has not been proven to be a direct cause of this disease. To further study the role of IBDV in proventriculitis, proventriculi and bursas were collected during both acute and chronic phases of naturally occurring proventriculitis and from chickens experimentally infected with seven different [BDV strains. All tissues were examined for IBDV by light microscopy, immunohistochemistry (IHC), and real time reverse transcriptase(RT)-polymerase chain reaction (PCR) and for apoptosis by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling method (TUNEL). Tissues from naturally occurring proventriculitis had bursal and proventricular lesions. Two out of four bursas had no IHC-stainable IBDV antigen or RT-PCR detectable IBDV sequences. No proventriculus had IBDV detectable by any of these methods. Bursas from chickens experimentally infected with IBDV had microscopically evident lesions, IBDV was detectable by IHC and RT-PCR, and strong IHC staining for apoptosis was present. Proventriculi from these experimentally exposed chickens had no lesions, low levels of IBDV detectable by IHC or RT-PCR, and very little IHC-stainable apoptosis. We conclude that naturally occurring proventriculitis can occur in the absence of IBDV and that the IBDV strains tested do not directly produce proventriculitis or induce increased proventricular apoptosis.

Attenuation, safety, and efficacy of an infectious bronchitis virus GA98 serotype vaccine.

In 1998, novel strains of infectious bronchitis virus (IBV) were identified in chickens from the southeastern United States and classified as a new serotype designated Georgia 98 (GA98). Because of the widespread nature of the GA98 virus in the southeastern United States and the lack of adequate protection with the DE072 vaccine, we developed a specific vaccine for the GA98 serotype. The GA98/0470/98 isolate of IBV was passaged in embryonating chicken eggs 70 times, and attenuation of the virus was determined in specific-pathogen-free chicks. Pass 70 of the GA98/0470/98 strain of IBV when given at 1 day of age by coarse spray and at 14 days of age in the drinking water at 1 x 10(4.5) 50% embryo infectious dose/bird protected against the homologous GA98 challenge as well as provided good protection against the DE072-type virus. In addition, the vaccine was shown to be adequately attenuated and safe at a 10x dosage.

Mild infectious laryngotracheitis in broilers in the southeast.

During 2001, a mild infectious laryngotracheitis virus (ILTV) infection occurred in broiler flocks in the southeastern United States. Clinical signs included mild tracheitis, swollen sinuses, and conjunctivitis, with no increased mortality and minimal serologic response. Infrequent intranuclear inclusion bodies with or without syncytial cell formation were observed in eyelid, trachea, and larynx and in the chorioallantoic membrane of infected embryos. Immunohistochemistry and a nested infectious laryngotracheitis polymerase chain reaction (ILT PCR) were utilized to confirm the presence of ILTV nucleic acid in fixed tissues. In addition, 2-wk-old specific-pathogen-free (SPF) birds inoculated with field material exhibited the mild signs observed in broilers in the field. Tracheal swabs and tissues taken from these SPF birds were also positive by nested ILT PCR. Restriction fragment length polymorphism analysis of ILT PCR products indicated that ILT virus associated with mild respiratory disease in the southeast is related to the chicken embryo origin vaccine type strains.

Effects of cyclosporin A treatment on the pathogenesis of avian leukosis virus subgroup J infection in broiler chickens with Marek's disease virus exposure.

In this study, we investigated the effects of T-cell suppression on the pathogenesis of subgroup J avian leukosis virus (ALV-J). Chickens were treated with cyclosporin A (CSP) 50 mg/Kg body weight or a corresponding volume of olive oil per every three days after hatching until the end of experiment. Some of the chickens from each treatment group were infected with an isolate of ALV-J, ADOL-7501, at 2 weeks of age. The effects of viral infection were compared to uninfected birds in same treatment group. Intramuscular injection of CSP induced significant T-cell specific immunosuppression determined by decreased cutaneous basophilic hypersensitivity response and decreased lymphocyte mitogenic activity using concanavalin A. Most of the chickens examined had Marek's disease virus infection prior to 3 weeks of age. The percentage of antibody-positive birds and antibody titers were similar in infected chickens between both treatment groups. The ratio of viremic chickens was significantly higher in CSP treated group than that of the Oil treated group. Microscopically, one CSP treated chicken had a nephroblastoma at 10 weeks post infection. At 7 and 10 weeks post-infection, more chickens had myeloid cell infiltrations in multiple organs including heart, liver and occasionally lung. Expression of ALV-J viral antigen determined by immunohistochemical staining was significantly higher in CSP treated chickens than Oil treated chickens at 10 weeks post-infection. This study indicated that chemically-induced T-cell suppression may enhance pathogenicity of the AVL-J virus in broilers.

The effects of cyclophosphamide treatment on the pathogenesis of subgroup J avian leukosis virus (ALV-J) infection in broiler chickens with Marek's disease virus exposure.

Studies were performed to determine the effects of Bcell suppression on the pathogenesis of Subgroup J avian leukosis virus (ALV-J) in broiler chickens. Neonatal chickens were treated with cyclophosphamide (CY) or PBS, and then infected with ALV-J (ADOL-7501) at 2 weeks of age. CY treatment induced B cell specific immunosuppression throughout the experiment confirmed by decreased bursal weight, intact lymphocyte mitogenetic activity stimulated by Con A and increased relative subpopulation of CD3-positive cells as measured by flow cytometry. Chickens in this experiment had Mareks disease virus exposure prior to three weeks of age as determined by the presence of lymphocytic infiltration and antibody. Virus neutralizing antibody against ALV-J was first observed at 6 weeks post-infection in some of the infected chickens in the PBS group. As expected, none of the chickens from the CY group and uninfected chickens developed virus-neutralizing antibody. The viremic status was measured by real time RT-PCR using SYBR green I dye. The percentage of viremic chickens was significantly higher, and more chickens had high titered viremia, in the CY treated group. No neoplastic foci consistent with ALVJ infection were observed in any of the experimental chickens. The frequency and intensity of viral antigen expression determined by immunohistochemistry was significantly higher in tissues from CY treated birds than those of PBS treated chickens at 3 weeks post-infection. This study showed that B cell specific immunosuppression with CY treatment in chickens resulted in increase in viremia and viral antigen load in tissues.

Exertional rhabdomyolysis: early recognition is key.

Exertional rhabdomyolysis is an uncommon diagnosis, but because its complications can be severe, clinicians need a thorough understanding of this syndrome. When skeletal muscle cell membranes are damaged, their intracellular contents enter the bloodstream and can cause potentially serious sequelae, even death. Intense exercise, some viral infections, and certain genetic disorders increase the risk. Serum creatine kinase levels are the diagnostic gold standard. The treatment of rhabdomyolysis consists of early detection, therapy for the underlying cause, measures to prevent renal failure, and correction of metabolic complications.

Chronic administration of an aglycosylated murine antibody of ponezumab does not worsen microhemorrhages in aged Tg2576 mice.

Cerebral vasogenic edema and microhemorrhages are potential safety concerns for compounds intended to treat subjects with Alzheimer's disease (AD) by targeting amyloid ß (Aß). Ponezumab (PF-04360365) is an investigational anti-Aß monoclonal antibody. Two hundred female mice (APP(K670N;M671L); Tg2576) 16-19 months old received an aglycosylated CHO-derived murine surrogate of ponezumab by intraperitoneal administration once weekly for up to 26 weeks at doses of 0, 10, 30, or 100 mg/kg. Drug exposure and plasma Aß levels increased with increasing dose. After 26 weeks, the 100 mg/kg group had significantly greater plasma levels of Aß(1-x) and Aß(x-40) than the vehicle group (p < 0.001). Brain microhemorrhages were identified histologically using hematoxylin and eosin and/or Perls' Prussian blue iron staining. The incidence in the vehicle group was equal to or higher than those of the treated groups. There was no evidence of vasogenic edema. In summary, intraperitoneal administration of a murine surrogate of ponezumab to aged Tg2576 mice for up to 6 months did not produce any compound-related brain microhemorrhage or other pathologies.

IL-21 has a pathogenic role in a lupus-prone mouse model and its blockade with IL-21R.Fc reduces disease progression.

Systemic lupus erythematosus is a complex autoimmune disease characterized by dysregulated interactions between autoreactive T and B lymphocytes and the development of anti-nuclear Abs. The recently described pleiotropic cytokine IL-21 has been shown to regulate B cell differentiation and function. IL-21 is produced by activated T lymphocytes and its interactions with IL-21R are required for isotype switching and differentiation of B cells into Ab-secreting cells. In this report, we studied the impact of blocking IL-21 on disease in the lupus-prone MRL-Fas(lpr) mouse model. Mice treated for 10 wk with IL-21R.Fc fusion protein had reduced proteinuria, fewer IgG glomerular deposits, no glomerular basement membrane thickening, reduced levels of circulating dsDNA autoantibodies and total sera IgG1 and IgG2a, and reduced skin lesions and lymphadenopathy, compared with control mice. Also, treatment with IL-21R.Fc resulted in a reduced number of splenic T lymphocytes and altered splenic B lymphocyte ex vivo function. Our data show for the first time that IL-21 has a pathogenic role in the MRL-Fas(lpr) lupus model by impacting B cell function and regulating the production of pathogenic autoantibodies. From a clinical standpoint, these results suggest that blocking IL-21 in systemic lupus erythematosus patients may represent a promising novel therapeutic approach.