Eosinophil and T Cell Markers Predict Functional Decline in COPD Patients

BACKGROUND. The major marker utilized to monitor COPD patients is forced expiratory volume in one second (FEV1). However, asingle measurement of FEV1 cannot reliably predict subsequent decline. Recent studies indicate that T lymphocytes and eosinophils are important determinants of disease stability in COPD. We therefore measured cytokine levels in the lung lavage fluid and plasma of COPD patients in order to determine if the levels of T cell or eosinophil related cytokines were predictive of the future course of the disease. METHODS. Baseline lung lavage and plasma samples were collected from COPD subjects with moderately severe airway obstruction and emphysematous changes on chest CT. The study participants were former smokers who had not had a disease exacerbation within the past six months or used steroids within the past two months. Those subjects who demonstrated stable disease over the following six months (ΔFEV1 % predicted = 4.7 ± 7.2; N = 34) were retrospectively compared with study participants who experienced a rapid decline in lung function (ΔFEV1 % predicted = -16.0 ± 6.0; N = 16) during the same time period and with normal controls (N = 11). Plasma and lung lavage cytokines were measured from clinical samples using the Luminex multiplex kit which enabled the simultaneous measurement of several T cell and eosinophil related cytokines. RESULTS AND DISCUSSION. Stable COPD participants had significantly higher plasma IL-2 levels compared to participants with rapidly progressive COPD (p = 0.04). In contrast, plasma eotaxin-1 levels were significantly lower in stable COPD subjects compared to normal controls (p < 0.03). In addition, lung lavage eotaxin-1 levels were significantly higher in rapidly progressive COPD participants compared to both normal controls (p < 0.02) and stable COPD participants (p < 0.05). CONCLUSION. These findings indicate that IL-2 and eotaxin-1 levels may be important markers of disease stability in advanced emphysema patients. Prospective studies will need to confirm whether measuring IL-2 or eotaxin-1 can identify patients at risk for rapid disease progression.National Heart, Lung, and Blood Institute (NO1-HR-96140, NO1-HR-96141-001, NO1-HR-96144, NO1-HR-96143; NO1-HR-96145; NO1-HR-96142, R01HL086936-03); The Flight Attendant Medical Research Institute; the Jo-Ann F. LeBuhn Center for Chest Diseas

Borrelia burgdorferi Infection in Biglycan Knockout Mice

Background: Borrelia burgdorferi sensu lato spirochetes (Borrelia) causing Lyme borreliosis are able to disseminate from the initial entry site to distant organs in the host. Outer-surface adhesins are crucial in the bacterial dissemination and adhesion to various tissues. Two well-characterized Borrelia adhesins, decorin-binding proteins A and B, have been shown to bind to 2 host receptors, decorin and biglycan. However, the role of biglycan in Borrelia infection has not been characterized in vivo.Methods: We infected biglycan knockout (KO) and wild-type (WT) C3H mice with strains representing 3 Borrelia genospecies, Borrelia burgdorferi sensu stricto, Borrelia garinii, and Borrelia afzelii. The infection was monitored by measuring joint swelling, Borrelia culture, polymerase chain reaction analysis, and serologic analysis. The host immune responses were analyzed by histological scoring of the inflammation in tissues and by cytokine profiling.Results: B. burgdorferi sensu stricto and B. garinii established long-term infection in mice of both genotypes, while B. afzelii failed to disseminate in KO mice. Further, the B. burgdorferi sensu stricto–infected KO mice had persistent inflammation in the joints.Conclusions: The dissemination and tissue colonization of Borrelia and the inflammatory response of the host differ in a mouse biglycan expression– and Borrelia genospecies–dependent manner.</p

Diamond Blackfan anemia is mediated by hyperactive Nemo-like kinase

Diamond Blackfan Anemia (DBA) is a congenital bone marrow failure syndrome associated with ribosomal gene mutations that lead to ribosomal insufficiency. DBA is characterized by anemia, congenital anomalies, and cancer predisposition. Treatment for DBA is associated with significant morbidity. Here, we report the identification of Nemo-like kinase (NLK) as a potential target for DBA therapy. To identify new DBA targets, we screen for small molecules that increase erythroid expansion in mouse models of DBA. This screen identified a compound that inhibits NLK. Chemical and genetic inhibition of NLK increases erythroid expansion in mouse and human progenitors, including bone marrow cells from DBA patients. In DBA models and patient samples, aberrant NLK activation is initiated at the Megakaryocyte/Erythroid Progenitor (MEP) stage of differentiation and is not observed in non-erythroid hematopoietic lineages or healthy erythroblasts. We propose that NLK mediates aberrant erythropoiesis in DBA and is a potential target for therapy

Perforin, granzyme B, and FasL expression by peripheral blood T lymphocytes in emphysema

<p>Abstract</p> <p>Background</p> <p>It is generally accepted that emphysematous lungs are characterized by an increase in the numbers of neutrophils, macrophages, and CD8⁺T lymphocytes, the lasts having increased cytotoxic activity. Because systemic inflammation is also a component of emphysema, we hypothesize that peripheral CD8⁺T lymphocytes of emphysematous smokers who show evidence of systemic inflammation will have higher expression of cytotoxic molecules.</p> <p>Methods</p> <p>We assessed parameters of systemic inflammation in normal individuals (smokers or non-smokers) and in emphysematous subjects with an active smoking history by measuring serum interleukine-6, C-reactive protein, and tumor necrosis factor. Expression of perforin, granzyme B, and FasL protein by CD8⁺T lymphocytes, CD4⁺T lymphocytes, and natural killer cells were assessed by flow cytometry while perforin, granzyme B, and FasL mRNA expression were measured on purified systemic CD8⁺T lymphocytes by real-time PCR.</p> <p>Results</p> <p>Emphysematous smokers had higher levels of serum interleukine-6 than normal subjects. Even with the presence of systemic inflammation in emphysematous smokers, the percentage of peripheral CD8⁺T lymphocytes, CD4⁺T lymphocytes, and NK cells expressing perforin and granzyme B protein was not different between the three groups.</p> <p>Conclusion</p> <p>Despite evidence of systemic inflammation, peripheral T lymphocytes of emphysematous smokers did not show higher levels of cytotoxic markers, suggesting that increase of activated T lymphocytes in the emphysematous lung may be due to either activation in the lung or specific peripheral recruitment.</p

Study protocol for POSITIF, a randomised multicentre feasibility trial of a brief cognitive-behavioural intervention plus information versus information alone for the treatment of post-stroke fatigue

© 2020 The Author(s). Background: Approximately, half of stroke survivors experience fatigue. Fatigue may persist for many months and interferes with participation in everyday activities and has a negative impact on social and family relationships, return to work, and quality of life. Fatigue is among the top 10 priorities for 'Life after Stroke' research for stroke survivors, carers, and clinicians. We previously developed and tested in a small uncontrolled pilot study a manualised, clinical psychologist-delivered, face-to-face intervention, informed by cognitive behavioural therapy (CBT). We then adapted it for delivery by trained therapists via telephone. We now aim to test the feasibility of this approach in a parallel group, randomised controlled feasibility trial (Post Stroke Intervention Trial In Fatigue, POSITIF). Methods/design: POSITIF aims to recruit 75 stroke survivors between 3 months and 2 years post-stroke who would like treatment for their fatigue. Eligible consenting stroke survivors will be randomised to either a 7-session manualised telephone-delivered intervention based on CBT principles plus information about fatigue, or information only. The aims of the intervention are to (i) provide an explanation for post-stroke fatigue, in particular that it is potentially reversible (an educational approach), (ii) encourage participants to overcome the fear of taking physical activity and challenge negative thinking (a cognitive approach) and (iii) promote a balance between daily activities, rest and sleep and then gradually increase levels of physical activity (a behavioural approach). Fatigue, mood, quality of life, return to work and putative mediators will be assessed at baseline (just before randomisation), at the end of treatment and 6 months after randomisation. POSITIF will determine the feasibility of recruitment, adherence to the intervention and the resources required to deliver the intervention in a larger trial. Discussion: The POSITIF feasibility trial will recruit until 31 January 2020. Data will inform the utility and design of a future adequately powered randomised controlled trial. Trial registration: ClinicalTrials.gov, NCT03551327. Registered on 11 June 2018

Stroke secondary prevention, a non-surgical and non-pharmacological consensus definition : results of a Delphi study

OBJECTIVE: Evidence supporting lifestyle modification in vascular risk reduction is limited, drawn largely from primary prevention studies. To advance the evidence base for non-pharmacological and non-surgical stroke secondary prevention (SSP), empirical research is needed, informed by a consensus-derived definition of SSP. To date, no such definition has been published. We used Delphi methods to generate an evidence-based definition of non-pharmacological and non-surgical SSP. RESULTS: The 16 participants were members of INSsPiRE (International Network of Stroke Secondary Prevention Researchers), a multidisciplinary group of trialists, academics and clinicians. The Elicitation stage identified 49 key elements, grouped into 3 overarching domains: Risk factors, Education, and Theory before being subjected to iterative stages of elicitation, ranking, discussion, and anonymous voting. In the Action stage, following an experience-based engagement with key stakeholders, a consensus-derived definition, complementing current pharmacological and surgical SSP pathways, was finalised: Non-pharmacological and non-surgical stroke secondary prevention supports and improves long-term health and well-being in everyday life and reduces the risk of another stroke, by drawing from a spectrum of theoretically informed interventions and educational strategies. Interventions to self-manage modifiable lifestyle risk factors are contextualized and individualized to the capacities, needs, and personally meaningful priorities of individuals with stroke and their families

Genotype- phenotype correlation and molecular heterogeneity in pyruvate kinase deficiency

Pyruvate kinase (PK) deficiency is a rare recessive congenital hemolytic anemia caused by mutations in the PKLR gene. This study reports the molecular features of 257 patients enrolled in the PKD Natural History Study. Of the 127 different pathogenic variants detected, 84 were missense and 43 non- missense, including 20 stop- gain, 11 affecting splicing, five large deletions, four in- frame indels, and three promoter variants. Within the 177 unrelated patients, 35 were homozygous and 142 compound heterozygous (77 for two missense, 48 for one missense and one non- missense, and 17 for two non- missense variants); the two most frequent mutations were p.R510Q in 23% and p.R486W in 9% of mutated alleles. Fifty- five (21%) patients were found to have at least one previously unreported variant with 45 newly described mutations. Patients with two non- missense mutations had lower hemoglobin levels, higher numbers of lifetime transfusions, and higher rates of complications including iron overload, extramedullary hematopoiesis, and pulmonary hypertension. Rare severe complications, including lower extremity ulcerations and hepatic failure, were seen more frequently in patients with non- missense mutations or with missense mutations characterized by severe protein instability. The PKLR genotype did not correlate with the frequency of complications in utero or in the newborn period. With ICCs ranging from 0.4 to 0.61, about the same degree of clinical similarity exists within siblings as it does between siblings, in terms of hemoglobin, total bilirubin, splenectomy status, and cholecystectomy status. Pregnancy outcomes were similar across genotypes in PK deficient women. This report confirms the wide genetic heterogeneity of PK deficiency.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154955/1/ajh25753.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154955/2/ajh25753_am.pd