Boaz A. Markewitz

Cytokine-induced expression of a nitric oxide synthase in rat renal tubule cells.

Nitric oxide (NO.) has been implicated in the regulation of renal vascular tone and tubular sodium transport. While the endothelial cell is a well known source of NO(.), recent studies suggest that tubular epithelial cells may constitutively generate NO(.). An inducible isoform of nitric oxide synthase which produces far greater quantities of NO. exists in some cell types. We sought to determine whether kidney epithelial cells exposed to cytokines could express an inducible nitric oxide synthase. Primary cultures of rat proximal tubule and inner medullary collecting duct cells generated NO. on exposure to TNF-alpha and IFN-gamma. NO. production by both cell types was inhibited by NG-monomethyl-L-arginine; this inhibition was partially reversed by the addition of excess L-arginine. Stimulation of kidney epithelial cells with TNF-alpha and IFN-gamma dramatically increased the level of inducible nitric oxide synthase mRNA. In summary, renal proximal tubule and inner medullary collecting duct cells can produce NO. via expression of an inducible isoform of nitric oxide synthase.

Clinical Findings and Demographic Factors Associated With ICU Admission in Utah Due to Novel 2009 Influenza A(H1N1) Infection

BACKGROUND Novel 2009 influenza A(H1N1) infection has significantly affected ICUs. We sought to characterize our regions clinical findings and demographic associations with ICU admission due to novel A(H1N1). METHODS We conducted an observational study from May 19, 2009, to June 30, 2009, of descriptive clinical course, inpatient mortality, financial data, and demographic characteristics of an ICU cohort. A case-control study was used to compare the ICU cohort to Salt Lake County residents. RESULTS The ICU cohort of 47 influenza patients had a median age of 34 years, Acute Physiology and Chronic Health Evaluation II score of 21, and BMI of 35 kg/m2. Mortality was 17% (8/47). All eight deaths occurred among the 64% of patients (n = 30) with ARDS, 26 (87%) of whom also developed multiorgan failure. Compared with the Salt Lake County population, patients with novel A(H1N1) were more likely to be obese (22% vs 74%; P < .001), medically uninsured (14% vs 45%; P < .001), and Hispanic (13% vs 23%; P < .01) or Pacific Islander (1% vs 26%; P < .001). Observed ICU admissions were 15-fold greater than expected for those with BMI > or = 40 kg/m2 (standardized morbidity ratio 15.8, 95% CI, 8.3-23.4) and 1.5-fold greater than expected among those with BMI of 30 to 39 kg/m(2) for age-adjusted and sex-adjusted rates for Salt Lake County. CONCLUSIONS Severe ARDS with multiorgan dysfunction in the absence of bacterial infection was a common clinical presentation. In this cohort, young nonwhites without medical insurance were disproportionately likely to require ICU care. Obese patients were particularly susceptible to critical illness due to novel A(H1N1) infection.

Improving alarm performance in the medical intensive care unit using delays and clinical context.

INTRODUCTION: In an intensive care unit, alarms are used to call attention to a patient, to alert a change in the patients physiology, or to warn of a failure in a medical device; however, up to 94% of the alarms are false. Our purpose in this study was to identify a means of reducing the number of false alarms. METHODS: An observer recorded time-stamped information of alarms and the presence of health care team members in the patient room; each alarm response was classified as effective (action taken within 5 min), ineffective (no response to the alarm), and ignored (alarm consciously ignored or actively silenced). RESULTS: During the 200-h study period, 1271 separate entries by an individual to the room being observed were recorded, 1214 alarms occurred and 2344 tasks were performed. On average, alarms occurred 6.07 times per hour and were active for 3.28 min per hour; 23% were effective, 36% were ineffective, and 41% were ignored. The median alarm duration was 17 s. A 14-s delay before alarm presentation would remove 50% of the ignored and ineffective alarms, and a 19-s delay would remove 67%. Suctioning, washing, repositioning, and oral care caused 152 ignored or ineffective ventilator alarms. DISCUSSION: Introducing a 19-s alarm delay and automatically detecting suctioning, repositioning, oral care, and washing could reduce the number of ineffective and ignored alarms from 934 to 274. More reliable alarms could elicit more timely response, reduce workload, reduce noise pollution, and potentially improve patient safety.

Genotype–phenotype correlation in hereditary hemorrhagic telangiectasia: Mutations and manifestations

Hereditary hemorrhagic telangiectasia (HHT) is a genetically heterogeneous vascular dysplasia with multiple telangiectases and arteriovenous malformations and it is caused by mutations in endoglin gene (ENG) (HHT1) and activin A receptor type II‐like 1 gene (ACVRL1) (HHT2). We evaluated 111 patients with HHT from 34 families by history, examination, screening for vascular malformations, and sequencing of both genes. We found mutations in 26 of the 34 kindreds (76%) analyzed—54% were in ENG and 46% were in ACVRL1. Mutations in ACVRL1 cluster largely in exons 7 and 8, but ENG mutations were widely distributed within that gene. We found that epistaxis had an earlier onset in patients with HHT1 than those with HHT2, but the severity by middle ages was similar. Pulmonary arteriovenous malformations were more frequent and on the average of larger size in HHT1. Hepatic vascular malformations were more common in patients with HHT2. Cerebral arteriovenous malformations were more common in patients with HHT1, but spinal arteriovenous malformations were seen only in patients with HHT2. Truncating mutations in ENG were associated with more affected organs and more severe hemorrhaging than were missense mutations. We conclude that HHT2 has a later onset than HHT1 and the former may disproportionately involve smaller vessels in tissues with more significant vascular remodeling.

Decreased Serum Linezolid Levels in a Critically Ill Patient Receiving Concomitant Linezolid and Rifampin

Serious gram‐positive infections present an increasingly common therapeutic dilemma. Combination antimicrobial regimens (e. g., linezolid with rifampin) aimed at improving bacterial eradication and preventing resistance are often used; however, most data supporting this treatment strategy are not from randomized controlled trials. We describe a patient with disseminated community‐acquired methicillin‐resistant Staphylococcus aureus infection who experienced a possible drug interaction between linezolid and rifampin that resulted in decreased serum linezolid levels. To our knowledge, this is the first published report of a possible drug interaction in a critically ill patient receiving concomitant linezolid and rifampin. Although we hypothesize that the reaction was caused by P‐glycoprotein expression, further study is warranted.

Superoxide released from neutrophils causes a reduction in nitric oxide gas

Exhaled nitric oxide (NO) is increased in some inflammatory airway disorders but not in others such as cystic fibrosis and acute respiratory distress syndrome. NO can combine with superoxide ([Formula: see text]) to form peroxynitrite, which can decompose into nitrate. Activated polymorphonuclear neutrophils (PMNs) releasing[Formula: see text] could account for a reduction in exhaled NO in disorders such as cystic fibrosis. To test this hypothesis in vitro, we stimulated confluent cultures of LA-4 cells, a murine lung epithelial cell line, to produce NO. Subsequently, human PMNs stimulated to produce [Formula: see text] were added to the LA-4 cells. A gradual increase in NO in the headspace above the cultures was observed and was markedly reduced by the addition of PMNs. An increase in nitrate in the culture supernatant fluids was measured, but no increase in nitrite was detected. Superoxide dismutase attenuated the PMN effect, and xanthine/xanthine oxidase reproduced the effect. No changes in epithelial cell inducible NO synthase protein or mRNA were observed. These data demonstrate that [Formula: see text]released from PMNs can decrease NO by conversion to nitrate and suggest a potential mechanism for modulation of NO levels in vivo.

Regulation of endothelin-1 synthesis in human pulmonary arterial smooth muscle cells effects of transforming growth factor-β and hypoxia

OBJECTIVE Endothelin-1 (ET-1) potently regulates pulmonary vascular tone and promotes vascular smooth muscle cell growth. Clinical and animal studies implicate increased ET-1 production in the pathogenesis of primary and secondary pulmonary hypertension. Although pulmonary arterial smooth muscle cells (PASMCs) synthesize ET-1 under basal conditions, it is unknown whether factors that may be important in pulmonary hypertension, such as transforming growth factor-beta (TGF-beta) or hypoxia, augment ET-1 production by these cells. METHODS We determined the effect of TGF-beta and hypoxia on ET-1 release and preproET-1 mRNA from cultured rat and human PASMCs. RESULTS In the basal state, rat and human PASMCs synthesize, on average (mean+/-S.E.M.), 872+/-114 and 563+/-57 pg ET-1/mg cell protein over 24 h, respectively, a level that causes autocrine and paracrine effects in other tissues. TGF-beta significantly increases the expression of preproET-1 mRNA and ET-1 production by both rat and human PASMCs. Hypoxia for 24 h, however, does not affect ET-1 release from rat or human PASMCs. CONCLUSIONS Cultured rat and human PASMCs are a source of ET-1 production. Enhanced ET-1 release from PASMCs may contribute to the pathophysiology of TGF-beta-induced pulmonary hypertension. ET-1 production by PASMCs is unlikely to contribute to the role of ET-1 in hypoxia-induced pulmonary vasoconstriction.

Heritability of vasculopathy, autoimmune disease, and fibrosis in systemic sclerosis: a population-based study.

OBJECTIVE To investigate the familiality of systemic sclerosis (SSc) in relation to Raynauds phenomenon (RP) (a marker of vasculopathy), other autoimmune inflammatory disease, and fibrotic interstitial lung disease (ILD). METHODS A genealogic resource, the Utah Population Database (UPDB), was used to test heritability of RP, other autoimmune disease, and ILD. Diseases were defined by International Classification of Diseases, Ninth Revision codes and identified from statewide discharge data, the University of Utah Health Science Center Enterprise Data Warehouse, and death certificates and were linked to the UPDB for analysis. Familial standardized incidence ratio (FSIR), relative risks (RRs) to first-, second-, third-, and fourth-degree relatives for SSc, RP, other autoimmune disease, and ILD (with 95% confidence intervals [95% CIs]), and population attributable risk (PAR) were calculated. RESULTS A software kinship analysis tool was used to analyze 1,037 unique SSc patients. Fifty SSc families had significant FSIRs, ranging from 2.07 to 17.60. The adjusted PAR was approximately 8%. The RRs were significant for other autoimmune disease in the first-degree relatives (2.49 [95% CI 1.99-3.41], P = 2.42 x 10(-15)) and second-degree relatives (1.48 [95% CI 1.34-2.39], P = 0.002), for RP in first-degree relatives (6.38 [95% CI 3.44-11.83], P = 4.04 x 10(-9)) and second-degree relatives (2.39 [95% CI 1.21-4.74], P = 0.012), and for ILD in first-degree relatives (1.53 [95% CI 1.04-2.26], P = 0.03), third-degree relatives (1.47 [95% CI 1.18-1.82], P = 0.0004), and fourth-degree relatives (1.2 [95% CI 1.06-1.35], P = 0.004). CONCLUSION These data suggest that SSc pedigrees include more RP, autoimmune inflammatory disease, and ILD than would be expected by chance. In SSc pedigrees, genetic predisposition to vasculopathy is the most frequent risk among first-degree relatives.

Comparative Performance of Three Anti-Factor Xa Heparin Assays in Patients in a Medical Intensive Care Unit Receiving Intravenous, Unfractionated Heparin

The availability of automated anti-Xa heparin assays provides the opportunity to manage patient unfractionated heparin levels directly, rather than by the activated partial thromboplastin time. Because critically ill patients can acquire an antithrombin deficiency, we compared the performance of 3 anti-Xa heparin assays, 1 with and 2 without antithrombin supplementation, by analyzing in vitro aliquots of plasma with defined antithrombin levels and specimens from intensive care patients receiving intravenous heparin therapy. Heparin concentration recovery, in vitro, was dependent on the plasma antithrombin concentration for all 3 assays. The antithrombin-supplemented assay demonstrated improved heparin recovery in direct correlation to the heparin concentration in the plasma. The greatest effect of antithrombin supplementation occurred when the antithrombin level dropped below 40%, a level present in only 5% of the patient specimens. Analysis of patient specimens demonstrated significant correlation among the 3 assays. Classification of the clinical adequacy of patient heparin levels showed agreement of 80% or more between the antithrombin-supplemented and nonsupplemented assays. The antithrombin-supplemented assay did not significantly improve clinical usefulness.

Evaluation of a pulmonary graphical display in the medical intensive care unit: an observational study

We developed a pulmonary graphic display that depicts pulmonary physiological variables for intubated, mechanically ventilated patients in a graphical format. The pulmonary graphical display presents multiple respiratory variables and changes are depicted by alterations in shape and color. Learning how this new technology will be integrated and accepted by users is an important step before it is introduced into the clinical arena. This study observed use and acceptance of the pulmonary graphical display by health care providers in an intensive care unit. Investigators noted that physicians, respiratory therapists, and nurses observed the pulmonary graphical display on average six, three, and one times, respectively, per patient room entry. Based on questionnaires, the pulmonary graphical display was perceived as useful, a desirable addition to current ICU monitors, and an accurate representation of respiratory variables.