A Quality Improvement Pilot Project for Noise Reduction in the NICU.

BACKGROUND: Increased noxious noise leads to adverse short-term and long-term effects on the growing neonate. The American Academy of Pediatrics recommends maintaining a noise level of less than 45 decibels (dBA). The average baseline noise level in an open-pod neonatal intensive care unit (NICU) was 62.6 dBA. PURPOSE: The purpose of this pilot project was to reduce the average noise levels by 39% at the end of an 11-week period. METHODS: The location of the project was in a large, high-acuity level IV open-pod layout NICU that consisted of 4 pods, one of which was cardiac-focused. The average baseline noise level in the cardiac pod was 62.6 dBA in a 24-hour period. Noise levels were not monitored before this pilot project. This project was implemented over an 11-week period. Several modes of education were used for parents and staff. Post-education, Quiet Times were implemented at set times twice daily. Noise levels were monitored for 4 weeks during Quiet Times, with weekly noise level updates for staff. General noise levels were collected a final time to evaluate the overall change in the average noise levels. RESULTS: At the end of the project, noise levels decreased from 62.6 dBA to 54 dBA, a 13.7% reduction. IMPLICATIONS FOR PRACTICE AND RESEARCH: At the end of this pilot project it was noted that: Online modules were the best way to educate staff. Parents should be included in the implementation of quality improvement. Healthcare providers need to know and understand that they can make preventative changes to improve the outcomes of the population.

The oDGal Mouse: A Novel, Physiologically Relevant Rodent Model of Sporadic Alzheimer's Disease.

Sporadic Alzheimer's disease (sAD) represents a serious and growing worldwide economic and healthcare burden. Almost 95% of current AD patients are associated with sAD as opposed to patients presenting with well-characterized genetic mutations that lead to AD predisposition, i.e., familial AD (fAD). Presently, the use of transgenic (Tg) animals overexpressing human versions of these causative fAD genes represents the dominant research model for AD therapeutic development. As significant differences in etiology exist between sAD and fAD, it is perhaps more appropriate to develop novel, more sAD-reminiscent experimental models that would expedite the discovery of effective therapies for the majority of AD patients. Here we present the oDGal mouse model, a novel model of sAD that displays a range of AD-like pathologies as well as multiple cognitive deficits reminiscent of AD symptomology. Hippocampal cognitive impairment and pathology were delayed with N-acetyl-cysteine (NaC) treatment, which strongly suggests that reactive oxygen species (ROS) are the drivers of downstream pathologies such as elevated amyloid beta and hyperphosphorylated tau. These features demonstrate a desired pathophenotype that distinguishes our model from current transgenic rodent AD models. A preclinical model that presents a phenotype of non-genetic AD-like pathologies and cognitive deficits would benefit the sAD field, particularly when translating therapeutics from the preclinical to the clinical phase.

Testing of candidate probiotics to prevent dental caries induced by Streptococcus mutans in a mouse model.

AIMS: We evaluated two species of human oral commensal streptococci in protection against dental caries induced by Streptococcus mutans. METHODS AND RESULTS: Candidate probiotics, Streptococcus sp. A12, Streptococcus sanguinis BCC23 and an arginine deiminase mutant of BCC23 (∆arcADS) were tested for their ability to reduce S. mutans-induced caries in an established mouse model. Mice were colonized with a probiotic, challenged with S. mutans, then intermittently reinoculated with a probiotic strain. Oral colonization of each strain and autochthonous bacteria was assessed by quantitative polymerase chain reaction. Both BCC23 strains, but not A12, were associated with markedly reduced sulcal caries, persistently colonized mucosal and dental biofilms, and significantly lowered S. mutans counts. All three strains enhanced mucosal colonization of autochthonous bacteria. In a follow-up experiment, when S. mutans was established first, dental and mucosal colonization of S. mutans was unaltered by a subsequent challenge with either BCC23 strain. Results between BCC23 and BCC23 ∆arcADS were equivalent. CONCLUSIONS: BCC23 is a potential probiotic to treat patients at high caries risk. Its effectiveness is independent of ADS activity, but initial dental cleaning to enhance establishment in dental biofilms may be required. SIGNIFICANCE AND IMPACT OF THE STUDY: In vivo testing of candidate probiotics is highly informative, as effectiveness is not always reflected by genotype or in vitro behaviours.

Nephrophobia: a retrospective study of medical students' attitudes towards nephrology education.

BACKGROUND: Nephrology is a subject which is challenged by a lack of applicants for trainee places. This study addresses the attitudes of medical students towards the subject and explores the causes of this lack of interest amongst potential specialty trainees. METHODS: Students were asked to complete a survey ranking their attitudes towards nephrology and other specialties. This data was collated and analysed to show trends and allow comparison of the attitudes towards each specialty. RESULTS: Students felt that along with geriatrics, their least favourite subject was nephrology. Students felt unconfident in diagnosing, managing and understanding chronic conditions more so than acute conditions. Nephrology was consistently amongst the least popular subject for all areas of diagnosis, management and pathophysiology. Renal anatomy was the only area of nephrology that students felt confident in. The less popular specialties of nephrology and geriatrics had the greatest room for improvement when directly instructed in specialty medical training. CONCLUSIONS: Nephrology remains a problematic and unpopular specialty for medical students, driving their unwillingness to consider it as a future career route. This study identifies areas of misconception amongst medical students toward the specialty and highlights areas for improvement in renal training for students.

In Vivo Colonization with Candidate Oral Probiotics Attenuates Colonization and Virulence of Streptococcus mutans.

A collection of 113 Streptococcus strains from supragingival dental plaque of caries-free individuals were recently tested in vitro for direct antagonism of the dental caries pathogen Streptococcus mutans, and for their capacity for arginine catabolism via the arginine deiminase system (ADS). To advance their evaluation as potential probiotics, twelve strains of commensal oral streptococci with various antagonistic and ADS potentials were assessed in a mouse model for oral (i.e., oral mucosal pellicles and saliva) and dental colonization under four diets (healthy or high-sucrose, with or without prebiotic arginine). Colonization by autochthonous bacteria was also monitored. One strain failed to colonize, whereas oral colonization by the other eleven strains varied by 3 log units. Dental colonization was high for five strains regardless of diet, six strains increased colonization with at least one high-sucrose diet, and added dietary arginine decreased dental colonization of two strains. Streptococcus sp. A12 (high in vitro ADS activity and antagonism) and two engineered mutants lacking the ADS (ΔarcADS) or pyruvate oxidase-mediated H2O2 production (ΔspxB) were tested for competition against S. mutans UA159. A12 wild type and ΔarcADS colonized only transiently, whereas ΔspxB persisted, but without altering oral or dental colonization by S. mutans In testing four additional candidates, S. sanguinis BCC23 markedly attenuated S. mutans' oral and dental colonization, enhanced colonization of autochthonous bacteria, and decreased severity of smooth surface caries under highly cariogenic conditions. Results demonstrate the utility of the mouse model to evaluate potential probiotics, revealing little correlation between in vitro antagonism and competitiveness against S. mutans in vivo IMPORTANCE Our results demonstrate in vivo testing of potential oral probiotics can be accomplished and can yield information to facilitate the ultimate design and optimization of novel anti-caries probiotics. We show human oral commensals associated with dental health are an important source of potential probiotics that may be used to colonize patients under dietary conditions of highly varying cariogenicity. Assessment of competitiveness against dental caries pathogen Streptococcus mutans and impact on caries identified strains or genetic elements for further study. Results also uncovered strains that enhanced oral and dental colonization by autochthonous bacteria when challenged with S. mutans, suggesting cooperative interactions for future elucidation. Distinguishing a rare strain that effectively compete with S. mutans under conditions that promote caries further validates our systematic approach to more critically evaluate probiotics for use in humans.

Is immediate reconstruction of the mandible with nonvascularized bone graft following resection of benign pathology a viable treatment option?

PURPOSE: The purpose of this study was to address the following clinical question: Is immediate reconstruction of the mandible with a nonvascularized bone graft after resection of benign pathology a viable treatment option? Another purpose was to determine whether any variables affect the success of this treatment approach. MATERIALS AND METHODS: The authors implemented a retrospective cohort study from a sample of patients diagnosed with a benign tumor of the mandible who were treated with segmental resection and primary reconstruction with an autogenous nonvascularized bone graft. The predictor variables were age, gender, lesion size, and diagnosis, and the outcome variable was graft success determined by re-establishment of mandibular continuity with sufficient bone for implant placement. The χ(2) test was used for statistical analysis of the categorical data and P values less than .05 were considered statistically significant. RESULTS: Twenty patients with benign mandibular tumors were treated with transoral resection and immediate reconstruction with nonvascularized bone grafts. The mean age was 28.3 years (range, 9 to 63 yr) and 55% (11 of 20) were men. The most common lesion type was ameloblastoma (13 of 20) and all patients underwent reconstruction with autogenous anterior iliac crest bone grafting. Ninety percent of patients (18 of 20) had successful reconstruction. Ten patients underwent successful implant placement and restoration. CONCLUSIONS: Using careful patient selection, treatment of benign pathology with transoral resection and immediate reconstruction with a nonvascularized bone graft from the anterior iliac crest can be successful. In addition, the total treatment time from implant restoration to return to preoperative function is minimized. Therefore, this method of treatment is a viable treatment option and an alternative to delayed reconstruction or reconstruction with vascularized bone flaps.

68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging.

Urea-based inhibitors of the prostate-specific membrane antigen (PSMA) represent low-molecular-weight pepidomimetics showing the ability to image PSMA-expressing prostate tumors. The highly efficient, acyclic Ga(III) chelator N,N'-bis [2-hydroxy-5-(carboxyethyl)benzyl] ethylenediamine-N,N'- diacetic acid (HBED-CC) was introduced as a lipophilic side chain into the hydrophilic pharmacophore Glu-NH-CO-NH-Lys which was found favorable to interact with the PSMA "active binding site". This report describes the syntheses, in vitro binding analyses, and biodistribution data of the radiogallium labeled PSMA inhibitor Glu-NH-CO-NH-Lys(Ahx)-HBED-CC in comparison to the corresponding DOTA conjugate. The binding properties were analyzed using competitive cell binding and enzyme-based assays followed by internalization experiments. Compared to the DOTA-conjugate, the HBED-CC derivative showed reduced unspecific binding and considerable higher specific internalization in LNCaP cells. The (68)Ga complex of the HBED-CC ligand exhibited higher specificity for PSMA expressing tumor cells resulting in improved in vivo properties. (68)Ga labeled Glu-NH-CO-NH-Lys(Ahx)-HBED-CC showed fast blood and organ clearances, low liver accumulation, and high specific uptake in PSMA expressing organs and tumor. It could be demonstrated that the PET-imaging property of a urea-based PSMA inhibitor could significantly be improved with HBED-CC.

Identification of 3,N(4)-etheno-5-methyl-2'-deoxycytidine in human DNA: a new modified nucleoside which may perturb genome methylation.

Methylation of cytidine at dCpdG sequences regulates gene expression and is altered in many chronic inflammatory diseases. Inflammation generates lipid peroxidation (LPO) products which can react with deoxycytidine, deoxyadenosine, and deoxyguanosine in DNA to form pro-mutagenic exocyclic etheno-nucleoside residues. Since 5-methyl-2'-deoxycytidine (5mdC) residues exhibit increased nucleophilicity at N3, they should be even better targets for LPO products. We synthesized and characterized 3,N(4)-etheno-5-methyl-2'-deoxycytidine-3'-phosphate and showed that LPO products can indeed form the corresponding etheno-5mdC (ε5mdC) lesion in DNA in vitro. Our newly developed (32)P-postlabeling method was subsequently used to detect ε5mdC lesions in DNA from human white blood cells, lung, and liver at concentrations 4-10 times higher than that observed for etheno adducts on nonmethylated cytidine. Our new detection method can now be used to explore the hypothesis that this DNA lesion perturbs the DNA methylation status.

EUROCarbDB: An open-access platform for glycoinformatics.

The EUROCarbDB project is a design study for a technical framework, which provides sophisticated, freely accessible, open-source informatics tools and databases to support glycobiology and glycomic research. EUROCarbDB is a relational database containing glycan structures, their biological context and, when available, primary and interpreted analytical data from high-performance liquid chromatography, mass spectrometry and nuclear magnetic resonance experiments. Database content can be accessed via a web-based user interface. The database is complemented by a suite of glycoinformatics tools, specifically designed to assist the elucidation and submission of glycan structure and experimental data when used in conjunction with contemporary carbohydrate research workflows. All software tools and source code are licensed under the terms of the Lesser General Public License, and publicly contributed structures and data are freely accessible. The public test version of the web interface to the EUROCarbDB can be found at http://www.ebi.ac.uk/eurocarb.

Understanding LrgAB Regulation of Streptococcus mutans Metabolism.

Lack of LrgAB renders cariogenic Streptococcus mutans more sensitive to oxidative stress, as well as limits the capacity of this organism to re-uptake pyruvate upon starvation. This study was aimed at investigating the ecological and metabolic contribution of LrgAB to competitive fitness, using S. mutans strains, that either lack or overexpress lrgAB. These experiments revealed that impaired aerobic growth of the ΔlrgAB mutant can be effectively restored by supplementation of pyruvate, and that perturbated expression of lrgAB significantly affects pyruvate flux and the conversion of pyruvate to acetyl-CoA by the Pdh pathway, verifying that LrgAB is closely linked to pyruvate catabolism. In vitro competition assays revealed that LrgAB plays an important role in S. mutans competition with H2O2-producing S. gordonii, an interaction which can also be modulated by external pyruvate. However, no obvious competitive disadvantage was observed against S. gordonii by either the S. mutans lrgAB mutant or lrgAB overexpression strain in vivo using a mouse caries model. Organic acid analysis of mouse dental biofilms revealed that metabolites produced by the host and/or dental plaque microbiota could complement the deficiency of a lrgAB mutant, and favored S. mutans establishment compared to S. gordonii. Collectively, these results reinforce the importance of the oral microbiota and the metabolic environment in the oral cavity battleground, and highlight that pyruvate uptake through LrgAB may be crucial for interspecies competition that drives niche occupancy.

Piloting Me and My Wishes-Videos of Nursing Home Residents' Preferences.

CONTEXT: A key challenge in nursing homes (NHs) is how to attain and clarify resident preferences for care and then communicate these preferences to family members and staff. OBJECTIVES: We evaluated the feasibility and acceptability of Me & My Wishes-person-centered videos of residents discussing their preferences for daily and end-of-life (EOL) care. METHODS: For this descriptive study, Me & My Wishes videos were created with residents in three NHs in the Pacific Northwest. Feasibility was evaluated by tracking resident enrollment, completing and sharing their video, and conducting debriefing interviews to ascertain residents' impressions of the recording process and personalized conversation. After viewing the video, staff and family assessed communication quality via survey-the extent to which they perceived messages from the video (e.g., preferences for EOL) to be timely, accurate, adequate, complete, and credible and items on resident preferences for daily and EOL care. RESULTS: Twenty of 33 residents approached created videos; 18 of these residents shared their videos with family or staff. Residents reported that they liked the opportunity to express their wishes. On a scale of 1-7 (lower is better), mean ratings were 2.0 (family) and 1.3 (staff) for communicating preferences for daily care; 1.9 (family) and 1.2 (staff) for communicating preferences for EOL. Both family and staff reported increased knowledge about resident preferences for daily and EOL care. CONCLUSION: This research supports the feasibility and acceptability of a videotaping approach (Me & My Wishes) for viewing, listening, and discussing residents' preferences for daily and EOL care.

Patient-generated health data and electronic health record integration: a scoping review.

OBJECTIVES: Patient-generated health data (PGHD) are clinically relevant data captured by patients outside of the traditional care setting. Clinical use of PGHD has emerged as an essential issue. This study explored the evidence to determine the extent of and describe the characteristics of PGHD integration into electronic health records (EHRs). METHODS: In August 2019, we conducted a systematic scoping review. We included studies with complete, partial, or in-progress PGHD and EHR integration within a clinical setting. The retrieved articles were screened for eligibility by 2 researchers, and data from eligible articles were abstracted, coded, and analyzed. RESULTS: A total of 19 studies met inclusion criteria after screening 9463 abstracts. Most of the study designs were pilots and all were published between 2013 and 2019. Types of PGHD were biometric and patient activity (57.9%), questionnaires and surveys (36.8%), and health history (5.3%). Diabetes was the most common patient condition (42.1%) for PGHD collection. Active integration (57.9%) was slightly more common than passive integration (31.6%). We categorized emergent themes into the 3 steps of PGHD flow. Themes emerged concerning resource requirements, data delivery to the EHR, and preferences for review. DISCUSSION: PGHD integration into EHRs appears to be at an early stage. PGHD have the potential to close health care gaps and support personalized medicine. Efforts are needed to understand how to optimize PGHD integration into EHRs considering resources, standards for EHR delivery, and clinical workflows.

Baricitinib counteracts metaflammation, thus protecting against diet-induced metabolic abnormalities in mice.

OBJECTIVE: Recent evidence suggests the substantial pathogenic role of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway in the development of low-grade chronic inflammatory response, known as "metaflammation," which contributes to obesity and type 2 diabetes. In this study, we investigated the effects of the JAK1/2 inhibitor baricitinib, recently approved for the treatment of rheumatoid arthritis, in a murine high-fat-high sugar diet model. METHODS: Male C57BL/6 mice were fed with a control normal diet (ND) or a high-fat-high sugar diet (HD) for 22 weeks. A sub-group of HD fed mice was treated with baricitinib (10 mg/kg die, p.o.) for the last 16 weeks (HD + Bar). RESULTS: HD feeding resulted in obesity, insulin-resistance, hypercholesterolemia and alterations in gut microbial composition. The metabolic abnormalities were dramatically reduced by chronic baricitinib administration. Treatment of HD mice with baricitinib did not change the diet-induced alterations in the gut, but restored insulin signaling in the liver and skeletal muscle, resulting in improvements of diet-induced myosteatosis, mesangial expansion and associated proteinuria. The skeletal muscle and renal protection were due to inhibition of the local JAK2-STAT2 pathway by baricitinib. We also demonstrated that restored tissue levels of JAK2-STAT2 activity were associated with a significant reduction in cytokine levels in the blood. CONCLUSIONS: In summary, our data suggest that the JAK2-STAT2 pathway may represent a novel candidate for the treatment of diet-related metabolic derangements, with the potential for EMA- and FDA-approved JAK inhibitors to be repurposed for the treatment of type 2 diabetes and/or its complications.

Patient-generated health data and electronic health record integration: protocol for a scoping review.

INTRODUCTION: The objective of this study is to determine the extent and describe the nature of patient-generated health data (PGHD) integration into electronic health records (EHRs) using systematic scoping methods to review the available literature. PGHD have the potential to enhance decision making by providing the valuable information that may not be ordinarily captured during a routine care visit. These data which are captured from mobile devices, such as smartphones, activity trackers and other sensors, should be integrated into clinical workflows to allow for optimal use by clinicians. METHODS AND ANALYSIS: This study aims to conduct a rigorous scoping review to explore evidence related to the integration of PGHD into EHRs. Using the framework developed by Arksey and O'Malley, we will create a systematic search strategy, chart data from the relevant articles, and use a qualitative, thematic approach to analyse the data. This review will enable the identification of types of integration and describe challenges and barriers to integrating PGHD. ETHICS AND DISSEMINATION: Database searches will be initiated in June 2019. The review is expected to be completed by October 2019. As the content of the full-text articles emerges, the authors will summarise the characteristics related to the integration of PGHD. The findings of this scoping review will identify research gaps and present implications for future research.

Statistical analysis of the Bacterial Carbohydrate Structure Data Base (BCSDB): characteristics and diversity of bacterial carbohydrates in comparison with mammalian glycans.

BACKGROUND: There are considerable differences between bacterial and mammalian glycans. In contrast to most eukaryotic carbohydrates, bacterial glycans are often composed of repeating units with diverse functions ranging from structural reinforcement to adhesion, colonization and camouflage. Since bacterial glycans are typically displayed at the cell surface, they can interact with the environment and, therefore, have significant biomedical importance. RESULTS: The sequence characteristics of glycans (monosaccharide composition, modifications, and linkage patterns) for the higher bacterial taxonomic classes have been examined and compared with the data for mammals, with both similarities and unique features becoming evident. Compared to mammalian glycans, the bacterial glycans deposited in the current databases have a more than ten-fold greater diversity at the monosaccharide level, and the disaccharide pattern space is approximately nine times larger. Specific bacterial subclasses exhibit characteristic glycans which can be distinguished on the basis of distinctive structural features or sequence properties. CONCLUSION: For the first time a systematic database analysis of the bacterial glycome has been performed. This study summarizes the current knowledge of bacterial glycan architecture and diversity and reveals putative targets for the rational design and development of therapeutic intervention strategies by comparing bacterial and mammalian glycans.

Quantitative time- and frequency-domain analysis of the two-pulse COSY revamped by asymmetric Z-gradient echo detection NMR experiment: Theoretical and experimental aspects, time-zero data truncation artifacts, and radiation damping.

The two-pulse COSY revamped by asymmetric Z-gradient echo detection (CRAZED) NMR experiment has the basic form 90 degrees -Gdelta-t(rec)-beta-nGdelta-t(rec)-FID, with a phase-encoding gradient pulse G of length delta applied during the evolution time tau for transverse magnetization, readout pulse beta, rephasing gradient nGdelta, and recovery time t(rec) prior to acquisition of the free-induction decay. Based on the classical treatment of the spatially modulated dipolar demagnetizing field and without invoking intermolecular multiple-quantum coherence, a new formulation of the first-order approximation for the theoretical solution of the nonlinear Bloch equations has been developed. The nth-order CRAZED signal can be expressed as a simple product of a scaling function C(n)(beta,tau) and a signal amplitude function A(n)(t), where the domain t begins immediately after the beta pulse. Using a single-quantum coherence model, a generalized rf phase shift function has also been developed, which explains all known phase behavior, including nth-order echo selection by phase cycling. Details of the derivations are provided in two appendices as supplementary material. For n>1, A(n)(t) increases from zero to a maximum value at t=t(max) before decaying and can be expressed as a series of n exponential decays with antisymmetric binomial coefficients. Fourier transform gives an antisymmetric binomial series of Lorentzians, where the composite lineshape exhibits negative wings, zero integral, and a linewidth that decreases with n. Analytical functions are presented for t(max) and A(n)(t(max)) and for estimating the maximal percent error incurred for A(n)(t(max)) when using the first-order model. The preacquisition delay Delta=delta+t(rec) results in the loss of the data points for t=0 to Delta. Conventional Fourier transformation produces time-zero truncation artifacts (reduced negative wing amplitude, nonzero integral, and reduced effective T(2) ( *)), which can be avoided by time-domain fitting after right shifting the data by Delta. A doped water sample (9.93 mM NiSO(4), 10 mm sample tube) was used to study the behavior of the CRAZED signal for n=1-4 with beta=90 degrees at 7 T (300 MHz (1)H frequency) as a function of Delta, with and without radiation damping. Pulse-acquire experiments were used to determine the relaxation times (T(1)=61.8 ms and T(2) ( *)=29.7 ms), and the radiation damping time constant T(rd)=18.5 ms. When experimental CRAZED data sets were right shifted by Delta, excellent least-squares fits to the first-order model function were obtained for all n using a minimal set of free variables. Without radiation damping the fitted T(2) ( *)values (29.7-30.2 ms) agreed with the reference value. With radiation damping the fitted effective T(2) ( *) values were 16.2 ms for a 90 degrees pulse-acquire experiment and 18.8-20.2 ms for the CRAZED experiment with n=1-4 and signal amplitudes spanning a range of 10(5).

Palliative and End-of-Life Care for Lesbian, Gay, Bisexual, and Transgender (LGBT) Cancer Patients and Their Caregivers.

OBJECTIVE: To identify the unique needs of lesbian, gay, bisexual, and transgender (LGBT) cancer patients and caregivers, and review recommendations supporting more effective and inclusive palliative and end-of-life care. DATA SOURCES: Published research and clinical guidelines. CONCLUSION: Transitions in care raise particular challenges for LGBT patients, including provider communication, perceptions of safety and acceptance, and assessing and respecting patients' definitions of family and spirituality. IMPLICATIONS FOR NURSING PRACTICE: LGBT patients and their caregivers need competent nurses to support them, especially during transitions. Implementing LGBT-inclusive education, training, and practice will improve outcomes for LGBT cancer patients and their caregivers - and potentially all patients.

Stat-3 is required for pulmonary homeostasis during hyperoxia.

Acute lung injury syndromes remain common causes of morbidity and mortality in adults and children. Cellular and physiologic mechanisms maintaining pulmonary homeostasis during lung injury remain poorly understood. In the present study, the Stat-3 gene was selectively deleted in respiratory epithelial cells by conditional expression of Cre-recombinase under control of the surfactant protein C gene promoter. Cell-selective deletion of Stat-3 in respiratory epithelial cells did not alter prenatal lung morphogenesis or postnatal lung function. However, exposure of adult Stat-3-deleted mice to 95% oxygen caused a more rapidly progressive lung injury associated with alveolar capillary leak and acute respiratory distress. Epithelial cell injury and inflammatory responses were increased in the Stat-3-deleted mice. Surfactant proteins and lipids were decreased or absent in alveolar lavage material. Intratracheal treatment with exogenous surfactant protein B improved survival and lung histology in Stat-3-deleted mice during hyperoxia. Expression of Stat-3 in respiratory epithelial cells is not required for lung formation, but plays a critical role in maintenance of surfactant homeostasis and lung function during oxygen injury.

Polyamine-substituted gadolinium chelates: a new class of intracellular contrast agents for magnetic resonance imaging of tumors.

A new class of intracellular contrast agents (CA) for magnetic resonance imaging has been developed, based on Gd(DTPA) with two positively charged amide-linked substituents. Uptake of Gd(DTPA) into cultured tumor cell lines (B16 mouse melanoma, MH3924A Morris hepatoma) was below the detection limit while CA with the melanin-binding pharmacophore 2-(diethylamino)ethylamine reached intracellular concentrations of ca. 0.03 fmol/cell (ca. 20 microM) for melanoma and 0.02 fmol/cell for hepatoma (24 h at 10 microM CA). With the polyamine substituents bis(2-aminoethyl)amine or spermidine, CA uptake increased up to 3-fold for melanoma (0.083 fmol/cell) and 9-fold for hepatoma (0.18 fmol/cell). Uptake of polyamine-substituted CA was reduced by the polyamine transport inhibitor benzyl viologen. Molar relaxivities for three Gd-DTPA-polyamine complexes were in the range 5.6-6.9 for the free complex in solution and 7.7-23.5 s-1 mM-1 for Morris hepatoma cell pellets. T1-weighted magnetic resonance imaging at 2.35 T of rats with MH3924A tumors showed contrast enhancement in tumor at 1 and 24 h postinjection of polyamine-substituted CA.