Publications

The intracellular scaffold protein IQGAP1 supports protein complexes in conjunction with numerous binding partners involved in multiple cellular processes. Here, we determined that IQGAP1 modulates airway smooth muscle contractility. Compared with WT controls, at baseline as well as after immune sensitization and challenge, Iqgap1-/- mice had higher airway responsiveness. Tracheal rings from Iqgap1-/- mice generated greater agonist-induced contractile force, even after removal of the epithelium. RhoA, a regulator of airway smooth muscle contractility, was activated in airway smooth muscle lysates from Iqgap1-/- mice. Likewise, knockdown of IQGAP1 in primary human airway smooth muscle cells increased RhoA activity. Immunoprecipitation studies indicated that IQGAP1 binds to both RhoA and p190A-RhoGAP, a GTPase-activating protein that normally inhibits RhoA activation. Proximity ligation assays in primary airway human smooth muscle cells and mouse tracheal sections revealed colocalization of p190A-RhoGAP and RhoA; however, these proteins did not colocalize in IQGAP1 knockdown cells or in Iqgap1-/- trachea. Compared with healthy controls, human subjects with asthma had decreased IQGAP1 expression in airway biopsies. Together, these data demonstrate that IQGAP1 acts as a scaffold that colocalizes p190A-RhoGAP and RhoA, inactivating RhoA and suppressing airway smooth muscle contraction. Furthermore, our results suggest that IQGAP1 has the potential to modulate airway contraction severity in acute asthma.

BACKGROUND

Identifying factors associated with tuberculosis (TB) deaths will inform efforts to prevent deaths.

METHODS

We examined deaths among patients with culture-confirmed TB reported to the California TB Registry during 1994-2008. We calculated the age-adjusted percentage of deaths before and during TB treatment and estimated trends. We constructed multivariable logistic regression models to identify factors associated with death during treatment.

RESULTS

Of 40 125 patients with culture-confirmed TB, 4565 (11%) died: 1146 (25%) died before treatment started, and 3419 (75%) died during treatment. The age-adjusted percentage of patients who died before and during treatment declined from 1994 to 2008 (3.5% to 2%, and 10.4% to 7.2%, respectively, both P < .0001). We identified several risk factors for death that may be addressed with public health efforts: acquired multidrug resistance (adjusted odds ratio [aOR] = 4.67; 95% confidence interval [CI], 2.09-10.45); care in the private sector (aOR = 3.08; 95% CI, 2.75-3.44); and an initial treatment regimen of <3 drugs (aOR = 2.07; 95% CI, 1.63-2.64). We identified other risk factors for death that could be used as markers for intensified diagnostic and treatment processes in hospital: human immunodeficiency virus coinfection; meningeal, peritoneal, and disseminated TB; substance use; and abnormal chest radiograph without cavities.

CONCLUSIONS

In California, 1 in 9 TB patients died with a potentially curable disease. Public health departments might prevent deaths in patients with TB by strengthening partnerships with private providers, intensifying diagnostic and treatment processes for patients at risk of death in hospital, optimizing treatment regimens for patients with comorbidities, and preventing the acquisition of drug resistance.

Claudins are a family of transmembrane proteins that are required for tight junction formation. Claudin (CLDN)-18.1, the only known lung-specific tight junction protein, is the most abundant claudin in alveolar epithelial type (AT) 1 cells, and is regulated by lung maturational agonists and inflammatory mediators. To determine the function of CLDN18 in the alveolar epithelium, CLDN18 knockout (KO) mice were generated and studied by histological, biochemical, and physiological approaches, in addition to whole-genome microarray. Alveolar epithelial barrier function was assessed after knockdown of CLDN18 in isolated lung cells. CLDN18 levels were measured by quantitative PCR in lung samples from fetal and postnatal human infants. We found that CLDN18 deficiency impaired alveolar epithelial barrier function in vivo and in vitro, with evidence of increased paracellular permeability and architectural distortion at AT1-AT1 cell junctions. Although CLDN18 KO mice were born without evidence of a lung abnormality, histological and gene expression analysis at Postnatal Day 3 and Week 4 identified impaired alveolarization. CLDN18 KO mice also had evidence of postnatal lung injury, including acquired AT1 cell damage. Human fetal lungs at 23-24 weeks gestational age, the highest-risk period for developing bronchopulmonary dysplasia, a disease of impaired alveolarization, had significantly lower CLDN18 expression relative to postnatal lungs. Thus, CLDN18 deficiency results in epithelial barrier dysfunction, injury, and impaired alveolarization in mice. Low expression of CLDN18 in human fetal lungs supports further investigation into a role for this tight junction protein in bronchopulmonary dysplasia.

BACKGROUND

Postinfectious glomerulonephritis (PIGN), a form of immune complex GN, is not well-defined in HIV-infected patients. This study characterizes PIGN in this patients' population and determine the impact of histopathological patterns on renal outcome and mortality.

METHODS

HIV-infected patients with PIGN from September 1998 to July 2013 were identified. Archived slides were reviewed by a blinded renal pathologist, classified into acute, persistent and healed PIGN. Groups were compared using Wilcoxon rank-sum and Fisher's exact test. Survival analyses were performed to determine association of histopathological pattern with renal outcome and mortality.

RESULTS

Seventy-two HIV-infected predominantly African American males were identified with PIGN. Median (interquartile range) age and creatinine at the time of renal biopsy was 48 years (41, 53) and 2.5 mg/dl (1.5, 4.9) respectively. Only 2 (3%) had acute PIGN, 42 (58%) had persistent PIGN and 28 (39%) had healed PIGN. Three patients (4%) had IgA-dominant PIGN. Only 46% of the patients had confirmed positive cultures with Staphylococcus the most common infectious agent. During a median follow up of 17 months, the pathological pattern had no impact on renal outcome (P = 0.95). Overall mortality was high occurring in 14 patients (19%); patients with healed PIGN had significantly increased mortality (P = 0.05).

CONCLUSION

In HIV-infected patients, Staphylococcus is the most common cause of PIGN. Renal outcome was not influenced by the histopathological pattern but those with healed PIGN had greater mortality which was potentially due to a confounder not accounted for in the study.

BACKGROUND AND STUDY AIMS

The learning curve for optical diagnosis of colorectal polyps with the narrow-band imaging (NBI) is unknown. To forego histological analysis of diminutive polyps diagnosed optically with high confidence, guidelines recommend ≥ 90 % negative predictive value (NPV) and concordance of ≥ 90 % for surveillance intervals predicted optically and histologically. We aimed to study the learning of optical diagnosis for colorectal polyps.

PATIENTS AND METHODS

We studied five endoscopists as part of a randomized multisite trial comparing near-focus and standard-focus views for optical diagnosis. They trained using a computer-based module, followed by 10 real-time colonoscopies with pathology correlation. Endoscopists then optically diagnosed and resected all the polyps found during 558 consecutive colonoscopies, and diagnoses were compared with pathology. Endoscopists repeated the training module at the study midpoint. NPV and concordance of surveillance intervals for diminutive polyps diagnosed optically with high confidence were measured over time.

RESULTS

Endoscopists showed high diagnostic performance, with a nonsignificant trend toward higher NPV in the second half of the study. For the 445 polyps in the standard-view arm, the NPV was 88.0 % (95 %CI 75.7 % - 95.5 %) in the first half and 95.8 % (88.3 % - 99.1 %) in the second; P = 0.7. Three endoscopists in the first half and four in the second achieved > 90 % NPV. Concordance of surveillance intervals was identical in the first and second halves at 98.1 % (95 %CI 93.3 % - 99.8 %).

CONCLUSIONS

High NPV for the prediction of non-neoplasms with NBI was achieved and maintained in this group of endoscopists who participated in standardized and continued training. Both NPV and surveillance interval agreement indicated high performance in the optical diagnosis of colorectal polyps and exceeded thresholds.