Moderation of buprenorphine therapy for cocaine dependence efficacy by variation of the Prodynorphin gene.

PURPOSE: The aim of this secondary analysis was to identify prodynorphin (PDYN) genetic markers moderating the therapeutic response to treatment of cocaine dependence with buprenorphine/naloxone (Suboxone®; BUP). METHODS: Cocaine-dependent participants (N = 302) were randomly assigned to a platform of injectable, extended-release naltrexone (XR-NTX) and one of three daily medication arms: 4 mg BUP (BUP4), 16 mg BUP (BUP16), or placebo (PLB) for 8 weeks (Parent Trial Registration: Protocol ID: NIDA-CTN-0048, Clinical Trials.gov ID: NCT01402492). DNA was obtained from 277 participants. Treatment response was determined from weeks 3 to 7 over each 1-week period by the number of cocaine-positive urines per total possible urines. RESULTS: In the cross-ancestry group, the PLB group had more cocaine-positive urines than the BUP16 group (P = 0.0021). The interactions of genetic variant × treatment were observed in the rs1022563 A-allele carrier group where the BUP16 group (N = 35) had fewer cocaine-positive urines (P = 0.0006) than did the PLB group (N = 26) and in the rs1997794 A-allele carrier group where the BUP16 group (N = 49) had fewer cocaine-positive urines (P = 0.0003) than did the PLB group (N = 58). No difference was observed in the rs1022563 GG or rs1997794 GG genotype groups between the BUP16 and PLB groups. In the African American-ancestry subgroup, only the rs1022563 A-allele carrier group was associated with treatment response. CONCLUSION: These results suggest that PDYN variants may identify patients who are best suited to treatment with XR-NTX plus buprenorphine for cocaine use disorder pharmacotherapy.

Treatment of the Middle Third and Septal Deformity: A Trizonal Approach.

Genetic, developmental, traumatic factors can produce a wide variety of nasal septal deformities in caudal-cephalic/dorsal-maxillary planes alone or in combination. These can be corrected by an endonasal approach through a transfixion incision by resecting, transposing, or utilizing principles of cartilage biomechanics. The authors are proposing a "Rosetta Stone" based on a trizonal analysis of the deviated nose that considers the contribution of each region to the deformity. Clinical assessment of the deviated nose should be segmental as well as global. Surgical correlation of the nasal bones, perpendicular, and quadrilateral plates, lateral cartilages, and turbinates may be necessary to achieve a satisfactory cosmetic and functional results.

Whole genome transcriptome analysis of the stomach resected in human vertical sleeve gastrectomy: cutting more than calories.

Vertical sleeve gastrectomy (VSG) is a surgical weight loss procedure that resects 80% of the stomach, creating a tube linking the esophagus to the duodenum. Because of the efficacy and relative simplicity of VSG, it is preferred in the United States, with VSG currently at >61% of bariatric surgeries performed. Surprisingly, there has never been a complete molecular characterization of the human stomach greater curvature's fundus and corpus. Here we compare and contrast the molecular makeup of these regions. We performed a prospective cohort study to obtain gastric tissue samples from patients undergoing elective VSG. Paired fundus and corpus samples were obtained. Whole genome transcriptome analysis was performed by RNA sequencing (N = 10), with key findings validated by qPCR (N = 24). Participants were primarily female (95.8%) and White (79.15%). Mean body mass index, body weight, and age were 46.1 kg/m2, 121.6 kg, and 43.29 yr, respectively. Overall, 432 gene transcripts were significantly different between the fundus and the corpus (P < 0.05). A significant correlation was found between the RNA sequencing dataset and qPCR validation, demonstrating robust gene expression differences between the fundus and the corpus. Significant genes included progastricsin, acidic chitinase, and gastokine 1 and 2 in both the fundus and the corpus. Of the very highly expressed genes in both regions, 87% were present in both the stomach's fundus and corpus, indicating substantial overlap. Despite significant overlap in the greater curvature gene signature, regional differences exist within the fundus and the corpus. Given that the mechanism of VSG is partly unresolved, the potential that the resected tissue may express genes that influence long-term body weight regulation is unknown and could influence VSG outcomes.

Impact of the COVID-19 pandemic on interventional cardiology fellowship training in the New York metropolitan area: A perspective from the United States epicenter.

BACKGROUND: The healthcare burden posed by the coronavirus disease 2019 (COVID-19) pandemic in the New York Metropolitan area has necessitated the postponement of elective procedures resulting in a marked reduction in cardiac catheterization laboratory (CCL) volumes with a potential to impact interventional cardiology (IC) fellowship training. METHODS: We conducted a web-based survey sent electronically to 21 Accreditation Council for Graduate Medical Education accredited IC fellowship program directors (PDs) and their respective fellows. RESULTS: Fourteen programs (67%) responded to the survey and all acknowledged a significant decrease in CCL procedural volumes. More than half of the PDs reported part of their CCL being converted to inpatient units and IC fellows being redeployed to COVID-19 related duties. More than two-thirds of PDs believed that the COVID-19 pandemic would have a moderate (57%) or severe (14%) adverse impact on IC fellowship training, and 21% of the PDs expected their current fellows' average percutaneous coronary intervention (PCI) volume to be below 250. Of 25 IC fellow respondents, 95% expressed concern that the pandemic would have a moderate (72%) or severe (24%) adverse impact on their fellowship training, and nearly one-fourth of fellows reported performing fewer than 250 PCIs as of March 1st. Finally, roughly one-third of PDs and IC fellows felt that there should be consideration of an extension of fellowship training or a period of early career mentorship after fellowship. CONCLUSIONS: The COVID-19 pandemic has caused a significant reduction in CCL procedural volumes that is impacting IC fellowship training in the NY metropolitan area. These results should inform professional societies and accreditation bodies to offer tailored opportunities for remediation of affected trainees.

Indications and Outcomes of the Osteoplastic Flap Procedure With or Without Obliteration.

OBJECTIVE: To describe the osteoplastic approach and to perform a systematic review of the indications and outcomes of the osteoplastic flap procedure for frontal sinus surgeries with or without obliteration. DATA SOURCES: PubMed, Medline, Google Scholar, and Cochrane databases. REVIEW METHODS: All published studies in the English language on the osteoplastic flap with or without obliteration were identified from 1905 to 2018. All studies with <20 patients were excluded. The number of patients, technique, indications, follow-up period, symptom relief, revision rates, and complications were recorded and analyzed. RESULTS: A systematic review yielded 25 series containing 1374 patients for analysis. Indications for surgery included chronic frontal sinusitis, mucoceles, fractures or traumas, osteomas, neoplasms, and cerebrospinal fluid leak. The mean follow-up period ranged from 12.8 to 144 months. The percentage of patients needing revisions for frontal sinus disease was 6.2%. There was a high rate of symptomatic improvement (85.0%) and a low rate of major complications (0.7%). However, minor complications occurred in 19.4% of patients. CONCLUSION: The osteoplastic flap with or without obliteration has many indications. In an era where endoscopic technique provides excellent access to the frontal sinuses, external approaches remain a useful adjunct, and/or salvage technique. In experienced hands, the osteoplastic flap can yield excellent long-term clinical results, with low rates of complications. Regardless of the surgical approach, long-term follow-up is necessary due to the recurrent nature of frontal sinus disease.

Blinded outcomes and angina assessment of coronary bioresorbable scaffolds: 30-day and 1-year results from the ABSORB IV randomised trial.

BACKGROUND: Previous studies showed more adverse events with coronary bioresorbable vascular scaffolds (BVS) than with metallic drug-eluting stents (DES), although in one randomised trial angina was reduced with BVS. However, these early studies were unmasked, lesions smaller than intended for the scaffold were frequently enrolled, implantation technique was suboptimal, and patients with myocardial infarction, in whom BVS might be well suited, were excluded. METHODS: In the active-controlled, blinded, multicentre, randomised ABSORB IV trial, patients with stable coronary artery disease or acute coronary syndromes aged 18 years or older were recruited from 147 hospitals in five countries (the USA, Germany, Australia, Singapore, and Canada). Enrolled patients were randomly assigned (1:1) to receive polymeric everolimus-eluting BVS (Absorb; Abbott Vascular, Santa Clara, CA, USA) with optimised implantation technique or cobalt-chromium everolimus-eluting stents (EES; Xience; Abbott Vascular, Santa Clara, CA, USA). Randomisation was stratified by diabetic status, whether patients would have been eligible for enrolment in the previous ABSORB III trial, and site. Patients and clinical assessors were masked to randomisation. The primary endpoint was target lesion failure (cardiac death, target vessel myocardial infarction, or ischaemia-driven target lesion revascularisation) at 30 days, tested for non-inferiority with a 2·9% margin for the risk difference. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT02173379, and is closed to accrual. FINDINGS: Between Aug 15, 2014, and March 31, 2017, we screened 18 722 patients for eligibility, 2604 of whom were enrolled. 1296 patients were assigned to BVS, and 1308 patients were assigned to EES. Follow-up data at 30 days and 1 year, respectively, were available for 1288 and 1254 patients with BVS and for 1303 and 1272 patients with EES. Biomarker-positive acute coronary syndromes were present in 622 (24%) of 2602 patients, and, by angiographic core laboratory analysis, 78 (3%) of 2893 of lesions were in very small vessels. Target lesion failure at 30 days occurred in 64 (5·0%) patients assigned to BVS and 48 (3·7%) patients assigned to EES (difference 1·3%, upper 97·5% confidence limit 2·89; one-sided pnon-inferiority=0·0244). Target lesion failure at 1 year occurred in 98 (7·8%) patients assigned to BVS and 82 (6·4%) patients assigned to EES (difference 1·4%, upper 97·5% confidence limit 3·4; one-sided pnon-inferiority=0·0006). Angina, adjudicated by a central events committee at 1 year, occurred in 270 (20·3%) patients assigned to BVS and 274 (20·5%) patients assigned to EES (difference -0·3%, 95% CI -3·4% to 2·9%; one-sided pnon-inferiority=0·0008; two-sided psuperiority=0·8603). Device thrombosis within 1 year occurred in nine (0·7%) patients assigned to BVS and four (0·3%) patients assigned to EES (p=0·1586). INTERPRETATION: Polymeric BVS implanted with optimised technique in an expanded patient population resulted in non-inferior 30-day and 1-year rates of target lesion failure and angina compared with metallic DES. FUNDING: Abbott Vascular.

Anatomical Basis for Lip Reconstruction: The Role of the Modiolus.

OBJECTIVE: The aim of this study was to establish the anatomic basis for functional upper and lower lip reconstruction with locoregional flaps. DESIGN, SETTING, AND PARTICIPANTS: This article is an anatomic fresh cadaver study. RESULTS: For lower lip reconstruction, the modified Bernard-Webster and Karapandzic flaps preserve the modiolus, buccinator, zygomaticus major muscle, and buccal branches of the facial nerve. The Bernard-Webster flap allowed for a larger oral aperture despite a larger defect, but required transection of the lower lip depressors and orbicularis oris. For upper lip reconstruction, the reverse fan flap preserves the modiolus and its muscle attachments. The reverse Karapandzic flap required transection of the lower lip depressors, buccinator, and the zygomaticus major. CONCLUSIONS AND RELEVANCE: Locoregional flaps remain the workhorse for lip reconstruction. This study provides the anatomic basis for the modiolus and its muscular attachments that permit techniques such as the Bernard-Webster flap and the Karapanzic flap to achieve functional lip reconstruction with innervated and denervated tissue.

Rodent vertical sleeve gastrectomy alters maternal immune health and fetoplacental development.

Bariatric surgery is increasingly employed to improve fertility and reduce obesity-related co-morbidities in obese women. Surgical weight loss not only improves the chance of conception but reduces the risk of pregnancy complications including pre-eclampsia, gestational diabetes, and macrosomia. However, bariatric procedures increase the incidence of intrauterine growth restriction (IUGR), fetal demise, thromboembolism, and other gestational disorders. Using our rodent model of vertical sleeve gastrectomy (VSG), we tested the hypothesis that VSG in diet-induced, obese dams would cause immune and placental structural abnormalities that may be responsible for fetal demise during pregnancy. VSG dams studied on gestational day (G) 19 had reduced circulating T-cell (CD3+ and CD8+) populations compared with lean or obese controls. Further, local interleukin (IL) 1ß and IL 1 receptor antagonist (il1rn) cmRNA were increased in placenta of VSG dams. Placental barrier function was also affected, with increased transplacental permeability to small molecules, increased matrix metalloproteinase 9 expression, and increased apoptosis in VSG. Furthermore, we identified increased placental mTOR signaling that may contribute to preserving the body weight of the fetuses during gestation. These changes occurred in the absence of a macronutrient deficit or gestational hypertension in the VSG dams. In summary, previous VSG in dams may contribute to fetal demise by affecting maternal immune system activity and compromise placental integrity.

Endogenous PGI2 signaling through IP inhibits neutrophilic lung inflammation in LPS-induced acute lung injury mice model.

Endogenous prostaglandin I2 (PGI2) has inhibitory effects on immune responses against pathogens or allergens; however, the immunomodulatory activity of endogenous PGI2 signaling in endotoxin-induced inflammation is unknown. To test the hypothesis that endogenous PGI2 down-regulates endotoxin-induced lung inflammation, C57BL/6 wild type (WT) and PGI2 receptor (IP) KO mice were challenged intranasally with LPS. Urine 6-keto-PGF1α, a stable metabolite of PGI2, was significantly increased following the LPS-challenge, suggesting that endogenous PGI2 signaling modulates the host response to LPS-challenge. IPKO mice had a significant increase in neutrophils in the BAL fluid as well as increased proteins of KC, LIX, and TNF-α in lung homogenates compared with WT mice. In contrast, IL-10 was decreased in LPS-challenged IPKO mice compared with WT mice. The PGI2 analog cicaprost significantly decreased LPS-induced KC, and TNF-α, but increased IL-10 and AREG in bone marrow-derived dendritic cells (BMDCs) and bone marrow-derived macrophages (BMMs) compared with vehicle-treatment. These results indicated that endogenous PGI2 signaling attenuated neutrophilic lung inflammation through the reduced inflammatory cytokine and chemokine and enhanced IL-10.

Housing Experiences among Opioid-Dependent, Criminal Justice-Involved Individuals in Washington, D.C.

Residential mobility and type of housing contributes to an individual's likelihood and frequency of drug/alcohol use and committing criminal offenses. Little research has focused simultaneously on the influence of housing status on the use of drugs and criminal behavior. The present study examines how residential mobility (transitions in housing) and recent housing stability (prior 30 days) correlates with self-reported criminal activity and drug/alcohol use among a sample of 504 addicted, treatment-seeking opioid users with a history of criminal justice involvement. Findings suggest that those with a greater number of housing transitions were considerably less likely to self-report criminal activity, and criminal involvement was highest among those who were chronically homeless. Residential mobility was unassociated with days of drug and alcohol use; however, residing in regulated housing (halfway houses and homeless shelters) was associated with a decreased frequency of substance use. The finding that residing at sober-living housing facilities with regulations governing behavior (regulated housing) was associated with a lower likelihood of illicit substance use may suggest that regulated housing settings may influence behavior. Further research in this area should explore how social networks and other related variables moderate the effects of housing type and mobility on crime and substance use.

Secretory IgA Deficiency in Individual Small Airways Is Associated with Persistent Inflammation and Remodeling.

RATIONALE: Maintenance of a surface immune barrier is important for homeostasis in organs with mucosal surfaces that interface with the external environment; however, the role of the mucosal immune system in chronic lung diseases is incompletely understood. OBJECTIVES: We examined the relationship between secretory IgA (SIgA) on the mucosal surface of small airways and parameters of inflammation and airway wall remodeling in chronic obstructive pulmonary disease (COPD). METHODS: We studied 1,104 small airways (<2 mm in diameter) from 50 former smokers with COPD and 39 control subjects. Small airways were identified on serial tissue sections and examined for epithelial morphology, SIgA, bacterial DNA, nuclear factor-κB activation, neutrophil and macrophage infiltration, and airway wall thickness. MEASUREMENTS AND MAIN RESULTS: Morphometric evaluation of small airways revealed increased mean airway wall thickness and inflammatory cell counts in lungs from patients with COPD compared with control subjects, whereas SIgA level on the mucosal surface was decreased. However, when small airways were classified as SIgA intact or SIgA deficient, we found that pathologic changes were localized almost exclusively to SIgA-deficient airways, regardless of study group. SIgA-deficient airways were characterized by (1) abnormal epithelial morphology, (2) invasion of bacteria across the apical epithelial barrier, (3) nuclear factor-κB activation, (4) accumulation of macrophages and neutrophils, and (5) fibrotic remodeling of the airway wall. CONCLUSIONS: Our findings support the concept that localized, acquired SIgA deficiency in individual small airways of patients with COPD allows colonizing bacteria to cross the epithelial barrier and drive persistent inflammation and airway wall remodeling, even after smoking cessation.

Prevalence, Diagnosis, and Treatment Rates of Mood Disorders among Opioid Users under Criminal Justice Supervision.

BACKGROUND: Individuals involved in the criminal justice system have disproportionately high rates of psychiatric disorders when compared to the general U.S. POPULATION: If left untreated, the likelihood of subsequent arrest increases and risk for adverse health consequences is great, particularly among opioid users. OBJECTIVES: To explore the prevalence, characteristics, and treatment of mood disorders among justice involved opioid-dependent populations. METHODS: The current study enrolled 258 treatment-seeking opioid-dependent individuals under community-based criminal justice supervision (e.g., probation, parole) screened from the larger parent study, Project STRIDE, a seek/test/treat randomized control trial (RCT) examining HIV and opioid use treatment. During baseline, individuals were screened for depression using the Patient Health Questionnaire-9 (PHQ-9) and screened for bipolar disorder using the Mood Disorder Questionnaire (MDQ) tool. RESULTS: Overall, 78 (30%) participants screened positive for moderate to severe depression and 54 (21%) screened positive for bipolar disorder. Participants self-reported mood disorders at higher rates than they screened positive for these conditions. Participants screening positive for these conditions experienced significantly greater family, legal, and medical problems on the Addiction Severity Index-Lite (ASI-Lite) than those who did not screen positive. Incidence of a lifetime suicide attempt was found to be associated with a positive screen for both mood disorders. Prescribed psychotropic treatment utilization was similar among those who screened positive for depression or bipolar disorder with approximately 38% reporting taking medication. IMPORTANCE: Findings suggest universal mood disorder screening to improve comprehensive psychiatric care and treatment of opioid-dependent justice-involved individuals.

Chronic spinal cord changes in a high-fat diet-fed male rat model of thoracic spinal contusion.

Individuals that suffer injury to the spinal cord can result in long-term, debilitating sequelae. Spinal cord-injured patients have increased risk for the development of metabolic disease, which can further hinder the effectiveness of treatments to rehabilitate the cord and improve quality of life. In the present study, we sought to understand the impact of high-fat diet (HFD)-induced obesity on spinal cord injury (SCI) by examining transcriptome changes in the area of the injury and rostral and caudal to site of damage 12 wk after injury. Adult, male Long-Evans rats received either thoracic level contusion of the spinal cord or sham laminectomy and then were allowed to recover on normal rat chow for 4 wk and further on HFD for an additional 8 wk. Spinal cord tissues harvested from the rats were processed for Affymetrix microarray and further transcriptomic analysis. Diverse changes in gene expression were identified in the injured cord in genes such as MMP12, APOC4, GPNMB, and IGF1 and 2. The greatest signaling changes occurred in pathways involved in cholesterol biosynthesis and immune cell trafficking. Together, the cord changes in the chronically obese rat following thoracic SCI reveal further potential targets for therapy. These could be further explored as they overlap with genes involved in metabolic disease.

Endothelial HIF signaling regulates pulmonary fibrosis-associated pulmonary hypertension.

Pulmonary hypertension (PH) complicating chronic parenchymal lung disease, such as idiopathic pulmonary fibrosis, results in significant morbidity and mortality. Since the hypoxia-inducible factor (HIF) signaling pathway is important for development of pulmonary hypertension in chronic hypoxia, we investigated whether HIF signaling in vascular endothelium regulates development of PH related to pulmonary fibrosis. We generated a transgenic model in which HIF is deleted within vascular endothelial cells and then exposed these mice to chronic intraperitoneal bleomycin to induce PH associated with lung fibrosis. Although no differences in the degree of fibrotic remodeling were observed, we found that endothelial HIF-deficient mice were protected against development of PH, including right ventricle and pulmonary vessel remodeling. Similarly, endothelial HIF-deficient mice were protected from PH after a 4-wk exposure to normobaric hypoxia. In vitro studies of pulmonary vascular endothelial cells isolated from the HIF-targeted mice and controls revealed that endothelial HIF signaling increases endothelial cell expression of connective tissue growth factor, enhances vascular permeability, and promotes pulmonary artery smooth muscle cell proliferation and wound healing ability, all of which have the potential to impact the development of PH in vivo. Taken together, these studies demonstrate that vascular endothelial cell HIF signaling is necessary for development of hypoxia and pulmonary fibrosis associated PH. As such, HIF and HIF-regulated targets represent a therapeutic target in these conditions.

Factors associated with non-adherence to Buprenorphine-naloxone among opioid dependent African-Americans: A retrospective chart review.

BACKGROUND AND OBJECTIVES: Opioid use disorders are common, chronic relapsing disorders. Buprenorphine (BUP) is an FDA approved medication in the treatment of opioid use disorders, but patient adherence to this medication remains a challenge. To identify risk factors for non-adherence, this chart review study examined the association between DSM-IV Axis I psychiatric disorders, substance use, demographics, and adherence to BUP-naloxone in African-American patients. METHODS: Charts were selected of patients who had ≥5 visits and completed psychometric screens (Patient Health Questionnaire, Mood Disorder Questionnaire, and a posttraumatic stress disorder questionnaire) at the time of the initial visit (N = 50). Urine drug screens (UDS) were also obtained. Treatment adherence was defined as BUP presence in UDS for ≥80% of the visits. RESULTS: A total of 48% of patients were adherent to treatment. Non-adherent patients had higher rates of use for not only opioids, but also cocaine, and alcohol. Cocaine use was associated with BUP-naloxone non-adherence even after controlling for opioid use. Attendance in cognitive behavioral group therapy sessions (CBT) was significantly associated with adherence. Patients endorsing PTSD symptoms showed higher adherence to treatment compared to those who did not endorse these symptoms. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Our results indicate that alcohol and illicit substance use is associated with non-adherence to BUP-naloxone treatment, and suggests that CBT and efforts to promote abstinence from non-opioid substance use may improve adherence among African-Americans. These findings contribute to growing literature on understanding adherence to BUP-naloxone, which is critical to reduce morbidity and mortality.

Extensive phenotyping of individuals at risk for familial interstitial pneumonia reveals clues to the pathogenesis of interstitial lung disease.

RATIONALE: Asymptomatic relatives of patients with familial interstitial pneumonia (FIP), the inherited form of idiopathic interstitial pneumonia, carry increased risk for developing interstitial lung disease. OBJECTIVES: Studying these at-risk individuals provides a unique opportunity to investigate early stages of FIP pathogenesis and develop predictive models of disease onset. METHODS: Seventy-five asymptomatic first-degree relatives of FIP patients (mean age, 50.8 yr) underwent blood sampling and high-resolution chest computed tomography (HRCT) scanning in an ongoing cohort study; 72 consented to bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsies. Twenty-seven healthy individuals were used as control subjects. MEASUREMENTS AND MAIN RESULTS: Eleven of 75 at-risk subjects (14%) had evidence of interstitial changes by HRCT, whereas 35.2% had abnormalities on transbronchial biopsies. No differences were noted in inflammatory cells in BAL between at-risk individuals and control subjects. At-risk subjects had increased herpesvirus DNA in cell-free BAL and evidence of herpesvirus antigen expression in alveolar epithelial cells (AECs), which correlated with expression of endoplasmic reticulum stress markers in AECs. Peripheral blood mononuclear cell and AEC telomere length were shorter in at-risk individuals than healthy control subjects. The minor allele frequency of the Muc5B rs35705950 promoter polymorphism was increased in at-risk subjects. Levels of several plasma biomarkers differed between at-risk subjects and control subjects, and correlated with abnormal HRCT scans. CONCLUSIONS: Evidence of lung parenchymal remodeling and epithelial dysfunction was identified in asymptomatic individuals at risk for FIP. Together, these findings offer new insights into the early pathogenesis of idiopathic interstitial pneumonia and provide an ongoing opportunity to characterize presymptomatic abnormalities that predict progression to clinical disease.

Rare variants in RTEL1 are associated with familial interstitial pneumonia.

RATIONALE: Up to 20% of cases of idiopathic interstitial pneumonia cluster in families, comprising the syndrome of familial interstitial pneumonia (FIP); however, the genetic basis of FIP remains uncertain in most families. OBJECTIVES: To determine if new disease-causing rare genetic variants could be identified using whole-exome sequencing of affected members from FIP families, providing additional insights into disease pathogenesis. METHODS: Affected subjects from 25 kindreds were selected from an ongoing FIP registry for whole-exome sequencing from genomic DNA. Candidate rare variants were confirmed by Sanger sequencing, and cosegregation analysis was performed in families, followed by additional sequencing of affected individuals from another 163 kindreds. MEASUREMENTS AND MAIN RESULTS: We identified a potentially damaging rare variant in the gene encoding for regulator of telomere elongation helicase 1 (RTEL1) that segregated with disease and was associated with very short telomeres in peripheral blood mononuclear cells in 1 of 25 families in our original whole-exome sequencing cohort. Evaluation of affected individuals in 163 additional kindreds revealed another eight families (4.7%) with heterozygous rare variants in RTEL1 that segregated with clinical FIP. Probands and unaffected carriers of these rare variants had short telomeres (<10% for age) in peripheral blood mononuclear cells and increased T-circle formation, suggesting impaired RTEL1 function. CONCLUSIONS: Rare loss-of-function variants in RTEL1 represent a newly defined genetic predisposition for FIP, supporting the importance of telomere-related pathways in pulmonary fibrosis.

Regulation of alveolar procoagulant activity and permeability in direct acute lung injury by lung epithelial tissue factor.

Tissue factor (TF) initiates the extrinsic coagulation cascade in response to tissue injury, leading to local fibrin deposition. Low levels of TF in mice are associated with increased severity of acute lung injury (ALI) after intratracheal LPS administration. However, the cellular sources of the TF required for protection from LPS-induced ALI remain unknown. In the current study, transgenic mice with cell-specific deletions of TF in the lung epithelium or myeloid cells were treated with intratracheal LPS to determine the cellular sources of TF important in direct ALI. Cell-specific deletion of TF in the lung epithelium reduced total lung TF expression to 39% of wild-type (WT) levels at baseline and to 29% of WT levels after intratracheal LPS. In contrast, there was no reduction of TF with myeloid cell TF deletion. Mice lacking myeloid cell TF did not differ from WT mice in coagulation, inflammation, permeability, or hemorrhage. However, mice lacking lung epithelial TF had increased tissue injury, impaired activation of coagulation in the airspace, disrupted alveolar permeability, and increased alveolar hemorrhage after intratracheal LPS. Deletion of epithelial TF did not affect alveolar permeability in an indirect model of ALI caused by systemic LPS infusion. These studies demonstrate that the lung epithelium is the primary source of TF in the lung, contributing 60-70% of total lung TF, and that lung epithelial, but not myeloid, TF may be protective in direct ALI.

Telomerase deficiency delays renal recovery in mice after ischemia-reperfusion injury by impairing autophagy.

The aged population suffers increased morbidity and higher mortality in response to episodes of acute kidney injury (AKI). Aging is associated with telomere shortening, and both telomerase reverse transcriptase (TerT) and RNA (TerC) are essential to maintain telomere length. To define a role of telomerase deficiency in susceptibility to AKI, we used ischemia/reperfusion injury in wild-type mice or mice with either TerC or TerT deletion. Injury induced similar renal impairment at day 1 in each genotype, as assessed by azotemia, proteinuria, acute tubular injury score, and apoptotic tubular epithelial cell index. However, either TerC or TerT knockout significantly delayed recovery compared with wild-type mice. Electron microscopy showed increased autophagosome formation in renal tubular epithelial cells in wild-type mice but a significant delay of their development in TerC and TerT knockout mice. There were also impeded increases in the expression of the autophagosome marker LC3 II, prolonged accumulation of the autophagosome protein P62, an increase of the cell cycle regulator p16, and greater activation of the mammalian target of rapamycin (mTOR) pathway. The mTORC1 inhibitor, rapamycin, partially restored the ischemia/reperfusion-induced autophagy response, without a significant effect on either p16 induction or tubule epithelial cell proliferation. Thus, muting the maintenance of normal telomere length in mice impaired recovery from AKI, owing to an increase in tubule cell senescence and impairment of mTOR-mediated autophagy.