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Objectives: Shortness of breath is a common symptom in patients with cancer. However, the mechanisms that underlie this troublesome symptom are poorly understood. Therefore, this study aimed to determine the prevalence of and associated risk factors for shortness of breath in women prior to breast cancer surgery and identify associations between shortness of breath and polymorphisms for potassium channel genes., Methods: Patients were recruited prior to breast cancer surgery and completed a self-report questionnaire on the occurrence of shortness of breath. Genotyping of single nucleotides polymorphism (SNPs) in potassium channel genes was performed using a custom array. Multiple logistic regression analyses were done to identify associations between the occurrence of shortness of breath and SNPs in ten candidate genes., Results: Of the 398 patients, 11.1% reported shortness of breath. These patients had a lower annual household income, a higher comorbidity burden, and a lower functional status. After controlling for functional status, comorbidity burden, genomic estimates of ancestry and self-reported race and ethnicity, the genetic associations that remained significant in the multiple regression analyses were for potassium voltage-gated channel subfamily D ( KCND2) rs12673992, potassium voltage-gated channel modifier subfamily S ( KCNS1) rs4499491, and potassium two pore channel subfamily K ( KCNK2) rs4411107., Conclusions: While these findings warrant replication, they suggest that alterations in potassium channel function may contribute to the occurrence of shortness of breath in women prior to breast cancer surgery., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: As ageing accelerates, frailty increasingly impacts public health. Cough, sputum, wheezing and dyspnea are common respiratory symptoms, and the relationship to frailty is unclear. We aimed to analyze the relationship between respiratory symptoms and frailty., Methods: Cross-sectional and Mendelian randomization (MR) studies were used. Cross-sectional data involved 14,021 participants from the National Health and Nutrition Examination Survey (NHANES). Logistic and linear regression were used to analyze the relationship between respiratory symptoms (cough, sputum, wheezing, dyspnea) and frailty. We adjusted for multiple variables and used propensity score matching (PSM). Mediation analysis was used to explore the role of inflammatory markers and age in the relationship between the two. We analyzed the relationship using a two-sample MR approach with data from genome-wide association studies (GWAS) to enhance causal inference., Results: Observational studies have shown that cough (OR 1.74, 95 CI% 1.44, 2.09), sputum (OR 1.87, 95 CI% 1.57, 2.22), wheezing (OR 2.01, 95 CI% 1.68, 2.40), and dyspnea (OR 2.60, 95 CI% 2.28, 2.97) are associated with an elevated risk of frailty. The PSM results were stable. Mediation analyses indicated that elevated inflammatory markers and advancing age were mediators between respiratory symptoms and frailty. The results of the MR study showed that sputum and wheezing were associated with an elevated frailty index; and in the study of FI on respiratory symptoms, all respiratory symptoms were elevated with elevated FI., Conclusions: Our study identified a potential association between frailty and respiratory symptoms. Inflammation and ageing may be essential factors mediating this association., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Ethics approval: The Ethics Committee of the National Centre for Health Statistics approved the NHANES survey study. All participants signed an informed consent form and data were de-identified, so no additional ethical waivers were required. Consent for publication: Not applicable., (© 2024. The Author(s).)

The COVID-19 pandemic has produced broad clinical manifestations, from asymptomatic infection to hospitalization and death. Despite progress from genomic and clinical epidemiology research, risk factors for developing severe COVID-19 are incompletely understood and identification of modifiable risk factors is desperately needed. We conducted linkage disequilibrium score regression (LDSR) analysis to estimate cross-trait genetic correlation between COVID-19 severity and various polygenic phenotypes. To attenuate the genetic contribution of smoking and BMI, we further conducted sensitivity analyses by pruning genomic regions associated with smoking/BMI and repeating LDSR analyses. We identified robust positive associations between the genetic architecture of severe COVID-19 and both BMI and smoking. We observed strong positive genetic correlation (rg) with diabetes (rg = 0.25) and shortness of breath walking on level ground (rg = 0.28) and novel protective associations with vitamin E (rg = - 0.53), calcium (rg = - 0.33), retinol (rg = - 0.59), Apolipoprotein A (rg = - 0.13), and HDL (rg = - 0.17), but no association with vitamin D (rg = - 0.02). Removing genomic regions associated with smoking and BMI generally attenuated the associations, but the associations with nutrient biomarkers persisted. This study provides a comprehensive assessment of the shared genetic architecture of COVID-19 severity and numerous clinical/physiologic parameters. Associations with blood and plasma-derived traits identified biomarkers for Mendelian randomization studies to explore causality and nominates therapeutic targets for clinical evaluation., (© 2022. The Author(s).)

Most children diagnosed with asthma have respiratory symptoms such as cough, dyspnoea and wheezing, which are also important markers of overall respiratory function. A decade of genome-wide association studies (GWAS) have investigated genetic susceptibility to asthma itself, but few have focused on important respiratory symptoms that characterise childhood asthma.Using whole-genome sequencing (WGS) data for 894 asthmatic trios from a Costa Rican cohort, we performed family-based association tests (FBATs) to assess the association between genetic variants and multiple asthma-relevant respiratory phenotypes: cough, phlegm, wheezing, exertional dyspnoea and exertional chest tightness. We tested whether genome-wide significant associations were replicated in two additional studies: 1) 286 asthmatic trios from the Childhood Asthma Management Program (CAMP), and 2) 2691 African American current or former smokers from the COPDGene study.In the 894 Costa Rican trios, we identified a genome-wide significant association (p=2.16×10 -9 ) between exertional dyspnoea and the single nucleotide polymorphism (SNP) rs10165869, located on chromosome 2q37.3, that was replicated in the CAMP cohort (p=0.023) with the same direction of association (combined p=3.28×10 -10 ). This association was not found in the African American participants from COPDGene. We also found suggestive evidence for an association between SNP rs10165869 and the atypical chemokine receptor 3 ( ACKR3 ).Our finding encourages the secondary association analysis of a wider range of phenotypes that characterise respiratory symptoms in other airway diseases/studies., Competing Interests: Conflict of interest: S. Lee has nothing to disclose. Conflict of interest: J.A. Lasky-Su has nothing to disclose. Conflict of interest: C. Lange has nothing to disclose. Conflict of interest: W. Kim has nothing to disclose. Conflict of interest: P.L. Kumar has nothing to disclose. Conflict of interest: M-L.N. McDonald has nothing to disclose. Conflict of interest: C.A. Vaz Fragoso has nothing to disclose. Conflict of interest: C. Laurie has nothing to disclose. Conflict of interest: B.A. Raby has nothing to disclose. Conflict of interest: J.C. Celedon has received research materials from GSK and Merck (inhaled steroids) and Pharmavite (vitamin D and placebo capsules), in order to provide medications free of cost to participants in NIH-funded studies, unrelated to the current work. Conflict of interest: M.H. Cho has nothing to disclose. Conflict of interest: S. Won has nothing to disclose. Conflict of interest: S.T. Weiss reports that he is an author for UpToDate, PI of several NIH grants and an unpaid advisor to Novartis Pharmaceuticals. Conflict of interest: J. Hecker has nothing to disclose., (Copyright ©ERS 2021.)

HE4 (Human Epididymis Protein 4) encoded by the wfdc2 gene was first identified as a highly expressed factor in human epididymis. HE4 expression levels in malignant lesions are correlated with the clinical manifestations of gynecologic cancers. HE4 serum test has been widely used for the triage of patients suspected of gynecologic cancers, prognosis of cancer patients, and monitoring cancer recurrence. While it is reported that HE4 may actively participate in the regulation of cancer cell proliferation, migration and drug sensitivity, the physiological role(s) of HE4 in embryo development remains unknown. We applied the TALEN-based strategy to generate wfdc2 gene deletion mice for observation of HE4 function in organogenesis. While heterozygous mice were normal in terms of birth weight, reproductivity, and general behaviors, all the neonates with homozygous wfdc2 deletion suffered severe dyspnea and died in 10 h after birth. Biopsy detected pale-colored lungs, and mechanistic studies indicated increased apoptosis in type-I alveolar cells in lung tissues, which caused hypovascular lung tissue, then led to severe dyspnea in wfdc2 -/- neonates. The HE4 knockout mouse has provided an in vivo model for studying the patho-physiological function and relevant molecular pathways of HE4 for the development of respiratory system., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Various phenotypes have been identified for MYH7 gene mutation-related myopathy. Here, we describe a patient with severe muscular weakness and skeletal deformity with de novo heterozygous MYH7 gene mutation., Patient Concerns: A 33-year-old woman presented with early onset of muscular weakness, with delayed motor development during infancy. At age 8 years, she was unable to walk, with signs of skeletal deformity, including the progression of kyphoscoliosis. At age 31 years, she developed dyspnea., Diagnosis: She diagnosed with esophageal hiatal hernia with abdominal CT. In electromyography, short duration, small amplitude motor unit action potential (MUAP), and early recruitment patterns were observed in the involved proximal muscles, suggesting myopathy. Muscle histopathology showed fiber-type disproportion., Interventions: Next-generation sequencing study revealed a heterozygous in-frame deletion variation in the exon 14 of the MYH7 gene (c.1498_1500del/p.Glu500del), which is a novel variation confirmed by conventional Sanger sequencing. Compared with the parental test, this variant was concluded as de novo., Outcomes: She received laparoscopic hiatal hernia repair and Nissen fundoplication for esophageal hiatal hernia. After surgery, her postural dyspnea improved. As there is no fundamental treatment for MYH7-related myopathies, she continued conservative treatment for her symptoms., Conclusion: Here, we presented a rare case of de novo mutation of the myosin head domain in the MYH7 gene. This report broadens both the phenotypic and genotypic spectra of MYH7-related myopathies.

A 58-year-old male patient was admitted at the São Bernardos's Hospital (Setúbal, Portugal) with generalised muscle spasms, dyspnoea, laryngospasm and bronchospasm in the context of severe hypocalcaemia. Despite efforts to correct serum calcium, it remained below average, leading to question the true cause of hypocalcaemia. Low parathyroid hormone and 25-hydroxyvitamin D, along with facial anomalies, palate defect and cognitive impairment with concomitant psychiatric disorder led to a suspicion of a DiGeorge/velocardiofacial/22q11.2 deletion syndrome (DS), which was confirmed through genetic testing. The 22q11.2 DS has a wide phenotypic expression and there are growing reports of diagnosis being made in adulthood. This case report highlights the importance of understanding the cause of refractory hypocalcaemia and alerts medical community to carefully access these patients, for this metabolic disorder may only present in later stages of life., Competing Interests: Competing interests: None delcared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Neurodevelopmental delay accompanied unexplained dyspnea is a highly lethal disease in clinic. This study is to investigate the performance characteristics of trio whole exome sequencing (Trio-WES) in a pediatric setting by presenting our patient cohort and displaying the diagnostic yield. A total of 31 pediatric patients showing neurodevelopmental delay accompanied unexplained dyspnea were admitted to our hospital and referred for molecular genetic testing using Trio-WES. Eight genes namely MMACHC, G6PC, G6PT, ETFDH, OTC, NDUFAF5, SLC22A5, and MAGEL2 were suspected to be responsible for the onset of the clinical symptoms and 6 variants were novel. Standard interpretation according to ACMG guideline showed that the variants were pathogenic. Finally, diagnosis of methylmalonic aciduria and homocystinuria, glycogen storage disease, ornithine transcarbamylase deficiency, glutaric acidemia II, mitochondrial complex 1 deficiency, carnitine deficiency, and Schaaf-Yang syndrome was made in 12 out of the 31 patients. Trio-WES is an effective means for molecular diagnosis of infantile neurodevelopmental delay accompanied unexplained dyspnea. As for molecular etiology identification, when routine potential monogenetic inheritance patterns including de novo, autosomal recessive, autosomal dominant, and X-linked recessive inheritance analysis is negative, physicians should take into account imprinted genes.

Birt-Hogg-Dubé syndrome (BHDS) is a rare hereditary autosomal dominant condition characterised by benign cutaneous lesions, lung cysts, increased risk of spontaneous pneumothorax and renal cancer. It shows great heterogenous presentation within and between affected families. We report a case of a Danish female patient with recurrent pneumothoraces as the first symptom of BHDS. Over the years, she developed skin changes, and a family history of skin changes, pneumothoraces and renal cancer was discovered. BHDS was suspected, a genetic analysis was performed and a pathogenic variation c.1285delC in FLCN gene was detected in the patient. As we stated the diagnosis BHDS, we discovered several undiagnosed family members all of them now entering a lifelong follow-up programme with abdominal imaging because of the increased risk of developing renal cancer. BHDS should be known to oncologists, dermatologists and pulmonologists as the patients most often present to these medical disciplines., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The study investigated the effects of exercise on epigenetic signals and systemic cytokine levels in chronic obstructive pulmonary disease (COPD) individuals. Ten participants of a pulmonary rehabilitation program were submitted to 24 sessions of a supervisioned exercise protocol thrice-weekly (90min/session). Blood samples were collected at baseline, after the 1st session, before and after the 24th session. A DNA hypomethylation status was observed after the 1st session when compared at baseline, while global histone H4 acetylation status was unaltered in any time-points evaluated. No significant changes were observed on cytokine levels after the 1st session. A significant enhancement on interleukin 6 (IL-6) and a decrease on transforming growth factor-beta (TGF-β) levels were found after the 24th session when compared to the pre 24th session. Moreover, 23 sessions of exercise were able to diminish significantly the basal levels of IL-6 and interleukin 8 (IL-8). These data suggest a potential role of epigenetic machinery in mediating the anti-inflammatory effects of exercise in COPD patients., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: Alpha-1 antitrypsin deficiency is a hereditary disease defined at the biological level by a serum alpha-1 antitrypsin level below 11μM/L. The null variants are characterized by undetectable circulating alpha-1 antitrypsin levels. Suspicion of a null variant requires the use of appropriate diagnostic techniques., Case Report: We report the case of a 33-year old patient presenting with dyspnea on exertion, associated with a moderate airflow obstruction, incompletely reversible. His tobacco use was less than 3pack-years. The thoracic CT-scan showed emphysema. The serum alpha-1 antitrypsin level was collapsed. Phenotyping by isoelectrofocusing on agarose gels did not show any band. The study of the SERPINA1 gene, by PCR-sequence of the II, III, IV and V exons and the flanking intronic sequences, allowed identification of the NullQ0ourém allele in homozygous state. This mutation was found in heterozygous state in both parents of the index case and in one of his brothers. The index case showed a rapid aggravation of the airflow obstruction., Conclusion: In the case of a serum alpha-1 antitrypsin deficiency, the analysis of the phenotype of the protein by isoelectrofocusing must be performed as a first-line investigation. The detection of an atypical profile may suggest the presence of deficient alleles other than the PI S and PI Z alleles that can only be characterized by sequencing of the whole SERPINA1 gene. The patients carrying a null mutation have a high risk of severe chronic obstructive pulmonary disease., (Copyright © 2015 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Background: Telomere syndromes have their most common manifestation in idiopathic pulmonary fibrosis and emphysema. The short telomere defect in these patients may manifest systemically as bone marrow failure and liver disease. We sought to understand the causes of dyspnea in telomerase and telomere gene mutation carriers who have no parenchymal lung disease., Methods: Clinical and pathologic data were reviewed as part of a Johns Hopkins-based natural history study of short telomere syndromes including dyskeratosis congenita., Results: Hepatopulmonary syndrome (HPS) was diagnosed in nine of 42 cases (21%). Their age at presentation was significantly younger than that of cases initially presenting with pulmonary fibrosis and emphysema (median, 25 years vs 55 years; P < .001). Cases had evidence of intra- and extrapulmonary arteriovascular malformations that caused shunt physiology. Nodular regenerative hyperplasia was the most frequent histopathologic abnormality, and it was seen in the absence of cirrhosis. Dyspnea and portal hypertension were progressive, and the median time to death or liver transplantation was 6 years (range, 4-10 years; n = 6). In cases that underwent liver transplantation, dyspnea and hypoxia improved, but pulmonary fibrosis subsequently developed., Conclusions: This report identifies HPS as a frequent cause of dyspnea in telomerase and telomere gene mutation carriers. While it usually precedes the development of parenchymal lung disease, HPS may also co-occur with pulmonary fibrosis and emphysema. Recognizing this genetic diagnosis is critical for management, especially in the lung and liver transplantation setting.

Background: Hereditary hemorrhagic telangiectasia (HHT) is a vascular disorder associated with pulmonary AVMs (PAVMs), present in about 30-50% of patients. Dyspnea is frequently reported by about one-half of patients with PAVMs and has been related to the degree of right to left shunting. However, many HHT patients with PAVMs remain asymptomatic and those without PAVMs have been observed to have dyspnea, the cause of which has not been characterized. The study objectives were to determine the prevalence of dyspnea and its etiology in the HHT population., Methods: Retrospective review of over 1000 patients at an HHT Center of Excellence from 1997 to 2010. Patients were categorized as definite HHT if they met ≥3 clinical diagnostic criteria or had a positive genetic diagnosis. Patients were unlikely to have HHT (non-HHT) if they had 1 or fewer diagnostic criteria. Data on dyspnea prevalence (MMRC ≥ 1), PAVMs, underlying cardio-pulmonary disease, symptomatic liver venous malformations, anemia and obesity was reviewed., Results: 506 patients were categorized as having HHT, of which 202 (40%) had confirmed PAVMs. Dyspnea prevalence was 35% (178/506) vs. 18% (50/284, p < 0.0001) in the HHT and non-HHT patients, respectively. With multivariable logistic regression, the odds of dyspnea (MMRC ≥1) was 3.45 (95% CI 2.08-5.71) with the presence of PAVMs in HHT patients. Other independent predictors of dyspnea were older age, underlying cardio-pulmonary disease, anemia, and obesity., Conclusion: Prevalence of dyspnea is significant, evident in about one-third of HHT patients, often associated with PAVMs. It is important to consider other etiologies for dyspnea when assessing patients with HHT., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives: Opioids modulate the perception of breathlessness with a considerable variation in response, with poor correlation between the required opioid dose and symptom severity. The objective of this hypothesis-generating, secondary analysis was to identify candidate single nucleotide polymorphisms (SNP) from those associated with opioid receptors, signalling or pain modulation to identify any related to intensity of breathlessness while on opioids. This can help to inform prospective studies and potentially lead to better tailoring of opioid therapy for refractory breathlessness., Setting: 17 hospice/palliative care services (tertiary services) in 11 European countries., Participants: 2294 people over 18 years of age on regular opioids for pain related to cancer or its treatment., Primary Outcome Measures: The relationship between morphine dose, breathlessness intensity (European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire; EORTCQLQC30 question 8) and 112 candidate SNPs from 25 genes (n=588)., Secondary Outcome Measures: The same measures for people on oxycodone (n=402) or fentanyl (n=429)., Results: SNPs not in Hardy-Weinberg equilibrium or with allele frequencies (<5%) were removed. Univariate associations between each SNP and breathlessness intensity were determined with Benjamini-Hochberg false discovery rate set at 20%. Multivariable ordinal logistic regression, clustering over country and adjusting for available confounders, was conducted with remaining SNPs. For univariate morphine associations, 1 variant on the 5-hydroxytryptamine type 3B (HTR3B) gene, and 4 on the β-2-arrestin gene (ARRB2) were associated with more intense breathlessness. 1 SNP remained significant in the multivariable model: people with rs7103572 SNP (HTR3B gene; present in 8.4% of the population) were three times more likely to have more intense breathlessness (OR 2.86; 95% CIs 1.46 to 5.62; p=0.002). No associations were seen with fentanyl nor with oxycodone., Conclusions: This large, exploratory study identified 1 biologically plausible SNP that warrants further study in the response of breathlessness to morphine therapy., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: We have identified candidate protein and microRNA (miRNA) biomarkers for dyspnea by studying serum, lavage fluid, and urine from military personnel who reported serious respiratory symptoms after they were deployed to Iraq or Afghanistan., Methods: Forty-seven soldiers with the complaint of dyspnea who enrolled in the STudy of Active Duty Military Personnel for Environmental Dust Exposure (STAMPEDE) underwent comprehensive pulmonary evaluations at the San Antonio Military Medical Center. The evaluation included fiber-optic bronchoscopy with bronchoalveolar lavage. The clinical findings from the STAMPEDE subjects pointed to seven general underlying diagnoses or findings including airway hyperreactivity, asthma, low diffusivity of carbon monoxide, and abnormal cell counts. The largest category was undiagnosed. As an exploratory study, not a classification study, we profiled proteins or miRNAs in lavage fluid, serum, or urine in this group to look for any underlying molecular patterns that might lead to biomarkers. Proteins in lavage fluid and urine were identified by accurate mass tag (database-driven) proteomics methods while miRNAs were profiled by a hybridization assay applied to serum, urine, and lavage fluid., Results: Over seventy differentially expressed proteins were reliably identified both from lavage and from urine in forty-eight dyspnea subjects compared to fifteen controls with no known lung disorder. Six of these proteins were detected both in urine and lavage. One group of subjects was distinguished from controls by expressing a characteristic group of proteins. A related group of dyspnea subjects expressed a unique group of miRNAs that included one miRNA that was differentially overexpressed in all three fluids studied. The levels of several miRNAs also showed modest but direct associations with several standard clinical measures of lung health such as forced vital capacity or gas exchange efficiency., Conclusions: Candidate proteins and miRNAs associated with the general diagnosis of dyspnea have been identified in subjects with differing medical diagnoses. Since these markers can be measured in readily obtained clinical samples, further studies are possible that test the value of these findings in more formal classification or case-control studies in much larger cohorts of subjects with specific lung diseases such as asthma, emphysema, or some other well-defined lung disease.

Marfan syndrome (MFS) is an autosomal dominant disorder caused by mutations in the fibrillin 1 gene (FBN1). Neonatal form of MFS is rare and is associated with severe phenotype and a poor prognosis. We report on a newborn girl with neonatal MFS who displayed cyanosis and dyspnea on the first day of life. The main clinical features included mitral and tricuspid valve insufficiency, aortic root dilatation, arachnodactyly, and loose skin. Despite the presence of severe and inoperable heart anomalies, the girl was quite stable on symptomatic treatment and lived up to the 7th month of age when she died due to cardiorespiratory failure. Molecular-genetic studies revealed a novel intronic c.4211-32&#95;-13del mutation in the FBN1 gene. Subsequent in vitro splicing analysis showed this mutation led to exon 35 skipping, presumably resulting in a deletion of 42 amino acids (p.Leu1405&#95;Asp1446del). Interestingly, this mutation is localized outside the region of exons 24-32, whose mutation is responsible for the substantial majority of cases of neonatal MFS. Although the family history of MFS was negative, the subsequent molecular genetic examination documented a mosaicism of the same mutation in the maternal blood cells (10-25% of genomic DNA) and the detailed clinical examination showed unilateral lens ectopy., (© 2014 Wiley Periodicals, Inc.)

Background: Genetic variation in the β-2 adrenergic receptor gene (ADRB2) has been implicated in asthma severity and control with conflicting results. Epigenetic variation in the ADRB2 may play an important role in asthma phenotype., Objective: We aimed to evaluate whether DNA methylation of ADRB2 is associated with asthma phenotypes in inner-city school-aged children., Methods: Multiple CpG sites in the promoter region of ADRB2 gene were analysed in 177 children enrolled in the School Inner-City Asthma Study. Blood- or saliva-derived DNA was measured by bisulphite-polymerase chain reaction pyrosequencing assay. Average percentage DNA methylation across the sites was evaluated for association with asthma severity (report of dyspnoea, night-time symptoms, rescue medication use, and baseline spirometry) and morbidity (school absences and unscheduled healthcare visits). Three clades composed of highly correlated methylation sites within the methylated segment of ADRB2 were further analysed., Results: Methylation of individual sites generally ranged from 0% to 6% with average percentage methylation across sites of 2.4%. Univariate analyses strongly favoured the association of higher percentage methylation with lower asthma severity measured by report of dyspnoea. Furthermore, there was a non-significant trend towards less rescue medication use, night-time symptoms, school absences, activity limitation due to asthma, and improved lung function measurements with increased methylation. Multivariate analysis demonstrated methylation of ADRB2 gene significantly associated with less dyspnoea (odds ratio (OR) 0.2, 95% confidence interval (CI), 0.1-0.6, P = 0.002). Each of the three clades of methylation sites showed a strong, but not statistically significant, effect on decreased dyspnoea., Conclusions and Clinical Relevance: DNA methylation in the ADRB2 gene is associated with decreased asthma symptom severity, suggesting a role for methylation in asthma phenotypes., (© 2013 John Wiley & Sons Ltd.)

Pulmonary alveolar proteinosis (PAP) results from a dysfunction of alveolar macrophages (AMs), chiefly due to disruptions in the signaling of granulocyte macrophage colony-stimulating factor (GM-CSF). We found that mice deficient for the B lymphoid transcription repressor BTB and CNC homology 2 (Bach2) developed PAP-like accumulation of surfactant proteins in the lungs. Bach2 was expressed in AMs, and Bach2-deficient AMs showed alterations in lipid handling in comparison with wild-type (WT) cells. Although Bach2-deficient AMs showed a normal expression of the genes involved in the GM-CSF signaling, they showed an altered expression of the genes involved in chemotaxis, lipid metabolism, and alternative M2 macrophage activation with increased expression of Ym1 and arginase-1, and the M2 regulator Irf4. Peritoneal Bach2-deficient macrophages showed increased Ym1 expression when stimulated with interleukin-4. More eosinophils were present in the lung and peritoneal cavity of Bach2-deficient mice compared with WT mice. The PAP-like lesions in Bach2-deficient mice were relieved by WT bone marrow transplantation even after their development, confirming the hematopoietic origin of the lesions. These results indicate that Bach2 is required for the functional maturation of AMs and pulmonary homeostasis, independently of the GM-CSF signaling.

Introduction: Facioscapulohumeral dystrophy (FSHD) presents classically with facial and shoulder-girdle weakness. We report focal atypical presentations of FSHD. Our aim was to identify focal/unusual phenotypes in genetically confirmed FSHD cases., Methods: We undertook a retrospective review of an academic center database of the period from 1996 to 2011. Of 139 FSHD cases, 7 had atypical genetically confirmed disease. Clinical data were abstracted., Results: Seven cases (4 men) had a mean age of 37 years at onset (range 18-63 years) and mean 43 years at diagnosis (range 20-74 years). Presenting symptoms were monomelic lower limb (n = 3) or upper limb (n = 2) atrophy, or axial weakness (n = 2). Five patients had focal weakness on examination. CK was normal to borderline high. Two patients had a relative with FSHD. Coexistent unusual features included dyspnea (n = 1), S1 radicular pain with calf atrophy (n = 2), and peripheral neuropathy (n = 1). Almost all patients had myopathic EMG changes. DNA analysis showed a D4Z4 EcoRI fragment size ranging from 20 to 37 kilobases., Conclusions: FSHD may present with focal weakness, dyspnea and myopathic EMG changes. These findings should raise the possibility of FSHD., (Copyright © 2012 Wiley Periodicals, Inc.)

Recent studies suggest that in utero exposure of methyl donors influences programming of the fetal immune system in favor of development of allergic disease. The aim of this study was to assess whether the MTHFR C677T polymorphism, folic acid supplementation, and circulating folate and vitamin B-12 concentrations during pregnancy were associated with wheezing, shortness of breath, and atopic dermatitis in offspring. The study was a population-based birth cohort from fetal life until 48 mo (n = 8742). The use of folic acid supplementation during pregnancy was assessed by questionnaire. Plasma folate and serum vitamin B-12 concentrations and the MTHFR C677T polymorphism were available from blood collected in early pregnancy. Atopic dermatitis, wheezing, and shortness of breath in the offspring were assessed by parental-derived questionnaires at 12, 24, 36, and 48 mo. Maternal folate >16.2 nmol/L and vitamin B-12 >178 pmol/L were positively associated with the development of atopic dermatitis [adjusted OR: 1.18 (95% CI: 1.05-1.33) and adjusted OR: 1.30 (95% CI: 1.06-1.60) for the highest quartiles of folate and vitamin B-12 concentrations, respectively] but not with wheezing and shortness of breath. Maternal MTHFR C677T polymorphism and folic acid supplementation were not associated with wheezing, shortness of breath, and atopic dermatitis. No interactions were found by age, family history of atopy, folic acid supplementation, MTHFR C677T polymorphism, or maternal smoking (P-interaction > 0.10). High folate and vitamin B-12 levels during pregnancy are associated with increased prevalence of atopic dermatitis in the offspring. Potential risks of high folate and vitamin B-12 concentrations on allergic outcomes should be evaluated when discussing mandatory fortification programs.

Hereditary inclusion-body myopathy (HIBM) or distal myopathy with rimmed vacuoles (DMRV) is an autosomal recessive disorder characterized by preferential involvement of distal muscles in the lower extremities, especially the anterior compartment of the legs, with relative preservation of the quadriceps.This is referred to as quadriceps-sparing myopathy. Previous reports have revealed exclusive involvement in skeletal muscles. Herein we describe two siblings with typical HIBM/DMRV. The patients developed exertional dyspnea 20-26 years after disease onset. Echocardiogram revealed a cardiomyopathy in both patients. This is the first report of the association between HIBM/DMRV and cardiomyopathy.

We describe the case of an 83-year-old man with a family history of pulmonary hypertension (PH) who presented with severe pulmonary arterial hypertension (PAH) and later tested positive for a novel bone morphogenetic protein receptor 2 (BMPR2) gene mutation. To our knowledge, this may be the oldest reported patient with PAH in whom a BMPR2 mutation was initially identified.

Rationale: Aberrant expression profiles of circulating microRNAs (miRNAs) have been described in various diseases and provide high sensitivity and specificity. We explored circulating miRNAs as potential biomarkers in patients with heart failure (HF)., Objective: The goal of this study was to determine whether miRNAs allow to distinguish clinical HF not only from healthy controls but also from non-HF forms of dyspnea., Methods and Results: A miRNA array was performed on plasma of 12 healthy controls and 12 HF patients. From this array, we selected 16 miRNAs for a second clinical study in 39 healthy controls and in 50 cases with reports of dyspnea, of whom 30 were diagnosed with HF and 20 were diagnosed with dyspnea attributable to non-HF-related causes. This revealed that miR423-5p was specifically enriched in blood of HF cases and receiver-operator-characteristics (ROC) curve analysis showed miR423-5p to be a diagnostic predictor of HF, with an area under the curve of 0.91 (P<0.001). Five other miRNAs were elevated in HF cases but also slightly increased in non-HF dyspnea cases., Conclusion: We identify 6 miRNAs that are elevated in patients with HF, among which miR423-5p is most strongly related to the clinical diagnosis of HF. These 6 circulating miRNAs provide attractive candidates as putative biomarkers for HF.

Familial hypercholesterolemia (FH) is a genetic disease caused by a mutation in low-density lipoprotein (LDL) receptor gene. It causes various presentations including tendon xanthoma and cardiac manifestations. Herein, we present a young patient with homozygous FH (HFH) who presented with dyspnea and chest pain caused by coronary arteries stenosis and treated with coronary artery bypass graft (CABG) surgery at the age of 13 years. To the best of our knowledge, he is one of the youngest patients in the English language literature for whom coronary revascularization has been done in childhood.

Congenital apical left ventricular aneurysm is a rare clinical entity that is different from congenital left ventricular diverticulum. This aneurysm usually occurs as an isolated anomaly. Its clinical presentation varies, and it is usually diagnosed by exclusion. Herein, we report the case of a 54-year-old man who experienced progressively increasing symptoms of congestive cardiac failure. Through the use of contrast echocardiography and angiocardiography, and upon histopathologic examination, he was diagnosed to have a congenital apical left ventricular aneurysm. He was successfully treated by means of left ventricular aneurysmectomy. We discuss the process of diagnosis and surgical correction of the aneurysm, and we briefly review the pertinent medical literature.

We describe a patient with isolated exercise intolerance caused by a new, maternally inherited mutation in mitochondrial DNA. The heteroplasmic T>C transition at position 13271 in MTND5 affects a highly conserved base and segregates with the disease, being present at highest levels in skeletal muscle fibres showing abnormal mitochondrial accumulation. This is the 15th mutation affecting the MTND5 subunit of respiratory chain complex I and confirms this protein as an important site for disease with phenotypes ranging from MELAS and infantile encephalopathies to isolated syndromes affecting a single tissue such as Leber hereditary optic neuropathy and now skeletal muscle.

Although respiration is vital to the survival of all mammals from the moment of birth, little is known about the genetic factors controlling the prenatal maturation of this physiological process. Here we investigated the role of the Phox2a gene that encodes for a homeodomain protein involved in the generation of noradrenergic A6 neurons in the maturation of the respiratory network. First, comparisons of the respiratory activity of fetuses delivered surgically from heterozygous Phox2a pregnant mice on gestational day 18 showed that the mutants had impaired in vivo ventilation, in vitro respiratory-like activity, and in vitro respiratory responses to central hypoxia and noradrenaline. Second, pharmacological studies on wild-type neonates showed that endogenous noradrenaline released from pontine A6 neurons potentiates rhythmic respiratory activity via alpha1 medullary adrenoceptors. Third, transynaptic tracing experiments in which rabies virus was injected into the diaphragm confirmed that A6 neurons were connected to the neonatal respiratory network. Fourth, blocking the alpha1 adrenoceptors in wild-type dams during late gestation with daily injections of the alpha1 adrenoceptor antagonist prazosin induced in vivo and in vitro neonatal respiratory deficits similar to those observed in Phox2a mutants. These results suggest that noradrenaline, A6 neurons, and the Phox2a gene, which is crucial for the generation of A6 neurons, are essential for development of normal respiratory rhythm in neonatal mice. Metabolic noradrenaline disorders occurring during gestation therefore may induce neonatal respiratory deficits, in agreement with the catecholamine anomalies reported in victims of sudden infant death syndrome.

Cardiac abnormalities, cardiomyopathy and skeletal muscle weakness have been described in female carriers of the Xp21 (Duchenne and Becker) muscular dystrophies (J Neurol 1975;209(4):279-285; Br Med J 1969;2:418-420; J AmMed Assoc 1996;275(17):1335-1338; Neurology 1980;30(5):497-501; Neuromusc Disord 1999;9:347-351; Arch Neurol 1989;46:673-675). We have screened volunteers from our Xp21 genetics register and found the prevalence of previously unrecognized, clinically relevant, abnormalities in this group to be less than previously reported. We studied 91 women (56 carriers and 35 controls), aged between 18 and 69 years, from our local population known to the Oxford Regional Genetics Register. Our study included controls, with the investigators being blind to the subject's genetic status. The prevalence of previously unrecognised cardiac abnormalities on echocardiogram and ECG was 18% (10/56). Seven percent (4/56) of carriers had cardiomyopathy, defined by significant LV dilatation and decreased shortening fraction. In most cases, subjects with abnormal cardiac findings were asymptomatic. Echocardiography was more frequently abnormal than electrocardiography, but in many subjects the measurements of left ventricular dimensions were only just outside the normal ranges. The prevalence of skeletal muscle weakness was 12% (7/56). It was usually recognized by the individual, although not previously volunteered, but was mild and did not substantially affect activities of daily living.

OBJECTIVE AND SIGNIFICANCE: To examine functional performance in people with emphysema because of alpha-1 antitrypsin (AAT) deficiency. A severe deficiency of AAT affects 1:3,500 to 1:1,670 Americans who can develop debilitating emphysema in the third to fifth decades of life., Design: Exploratory., Population: People with a severe deficiency of AAT. SAMPLE AND DEMOGRAPHICS: Thirty-three patients (21 men) with a mean age of 47 (SD = 7) years., Years: Data were collected 1993-1996., Methods: Activities patients identified as important on the dyspnea subscale of the Chronic Respiratory Disease Questionnaire were categorized and interpreted within the context of an integrity framework (i.e., effectiveness--or connectedness-related)., Findings: Patients identified over 25 activities. Effectiveness activities, such as bathing, were mentioned most frequently (78%). Connectedness activities, such as playing with children, were mentioned less often (22%) but were ranked more important. Two patients reviewed and supported the content validity of the framework., Conclusions: Results offer insight into the activities patients with genetic emphysema choose to perform and the factors that influence the decision that "the dyspnea is worth it.", Implications: Identifying the activities people with AAT deficiency choose to perform and understanding why these activities are meaningful can guide interventions to help patients maintain a sense of integrity.

To examine possible genetic influence on the sensation of dyspnea and on load compensation, we conducted a twin study using healthy adult pairs (10 monozygotes, MZ, and 9 dizygotes, DZ). The ventilatory response to progressive hypercapnia (HCVR) was examined under three different conditions: hyperoxia (PETO2 > 150 mm Hg), hypoxia (PETO2 maintained at 50 to 55 mm Hg), and hyperoxia with an inspiratory flow-resistive load (17 mm H2O/L/s), with simultaneous assessment of the dyspnea sensation by visual analog scale (VAS). Although the VDZ/VMZ ratio (VMZ and VDZ are within-pair variances in MZ and DZ, respectively) for the slope value of the minute ventilation-PETCO2 regression line was not different from 1 in hyperoxia either with or without an inspiratory load, it was significantly larger than 1 in hypoxia (F = 5.17, p < 0.05), suggesting that a genetic influence on HCVR existed only in the presence of hypoxia. During 3% CO2 inhalation, the VDZ/VMZ ratio for the tidal volume (VT) was larger than 1 in hyperoxic HCVR with loading (F = 7.89, p < 0.01), and that for respiratory frequency (f) was larger than 1 only in hypoxic HCVR (F = 3.59, p < 0.05). At a PETCO2 of 55 mm Hg, the VT ratio was larger than 1 under all conditions (F = 5.91, p < 0.05; F = 6.99, p < 0.05; F = 3.75, p < 0.05; respectively), and the f ratio was significantly larger than 1 again only in hypoxic HCVR (F = 3.48, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

A carrier boar was mated with 6 carrier sows to produce a total of 88 piglets (9 litters), 29.5% of which were 'barkers'. Analysis of these results implicated a recessive gene in the inheritance of the syndrome. Affected piglets were of normal size but developed respiratory distress with hypothermia soon after birth, and several died; survivors were killed within 8 hours of birth. A variety of lesions were seen in the lungs, e.g. immaturity and necrosis of alveolar epithelium, haemorrhages and hyaline membranes. In alveolar wash samples, phospholipids were markedly deficient, and surface tension was invariably higher than in unaffected piglets. All barkers had very small thyroid glands, and many showed signs of congenital hypothyroidism, including hairlessness, retarded ossification and reduced adrenocortical activity. Some of the abnormalities in barker piglets could be attributed to prenatal hypothyroidism, but pathogenesis of the lung abnormalities was less clear since normal maturation of fetal lung seems to depend on adrenocortical rather than thyroid hormones. However, hypothyroidism may have affected lung development indirectly via an effect on adrenal gland function. There are some similarities between this respiratory distress syndrome and parallel conditions in infants and foals.

This report concerns a family in which several members presented an involvement of skeletal and velo-pharyngeal muscles, associated with hypertrophic cardiomyopathy, respiratory disturbances and lens opacities. The mode of transmission is autosomal dominant. The E.M.G. showed neither spontaneous activity nor myotonic discharges. In two patients, the muscle biopsies showed identical changes. By light microscopy it was seen that in numerous type I fibres, the intermyofibrillar network was "rubbed out" and this occurred along with splitting of such fibres. Electron microscopy revealed an intrasarcoplasmic accumulation of an electron-dense granulo-filamentous material: in some areas it formed a mesh of threads around the myofibrils and in others it was disposed regularly in small stacks facing the Z lines. Continuity or structural similarity of this material and the Z lines was not observed; its relationship with the dense strips of leptofibrils is suggested.

The velo-cardio-facial syndrome is one of the most common syndromes of clefting. Previous reports have shown vertical pedigree transmission, but in all cases the gene was maternally transmitted. The genetics of this syndrome had been suspected as autosomal dominant, but X-linked dominant inheritance could not be ruled out. This report describes an instance of male-to-male transmission of the velo-cardio-facial syndrome. In addition, the clinical findings in 60 cases are reported to further delineate the phenotypic spectrum of the syndrome.