Lung transcriptional unresponsiveness and loss of early influenza virus control in infected neonates is prevented by intranasal Lactobacillus rhamnosus GG.

Respiratory viral infections contribute substantially to global infant losses and disproportionately affect preterm neonates. Using our previously established neonatal murine model of influenza infection, we demonstrate that three-day old mice are exceptionally sensitive to influenza virus infection and exhibit high mortality and viral load. Intranasal pre- and post-treatment of neonatal mice with Lactobacillus rhamnosus GG (LGG), an immune modulator in respiratory viral infection of adult mice and human preterm neonates, considerably improves neonatal mice survival after influenza virus infection. We determine that both live and heat-killed intranasal LGG are equally efficacious in protection of neonates. Early in influenza infection, neonatal transcriptional responses in the lung are delayed compared to adults. These responses increase by 24 hours post-infection, demonstrating a delay in the kinetics of the neonatal anti-viral response. LGG pretreatment improves immune gene transcriptional responses during early infection and specifically upregulates type I IFN pathways. This is critical for protection, as neonatal mice intranasally pre-treated with IFNß before influenza virus infection are also protected. Using transgenic mice, we demonstrate that the protective effect of LGG is mediated through a MyD88-dependent mechanism, specifically via TLR4. LGG can improve both early control of virus and transcriptional responsiveness and could serve as a simple and safe intervention to protect neonates.

α1,3-Fucosyltransferase-IX, an enzyme of pulmonary endogenous lung stem cell marker SSEA-1, alleviates experimental bronchopulmonary dysplasia.

BACKGROUND: Endogenous pulmonary stem cells (PSCs) play an important role in lung development and repair; however, little is known about their role in bronchopulmonary dysplasia (BPD). We hypothesize that an endogenous PSC marker stage-specific embryonic antigen-1 (SSEA-1) and its enzyme, α1,3-fucosyltransferase IX (FUT9) play an important role in decreasing inflammation and restoring lung structure in experimental BPD. METHODS: We studied the expression of SSEA-1, and its enzyme FUT9, in wild-type (WT) C57BL/6 mice, in room air and hyperoxia. Effects of intraperitoneal administration of recombinant human FUT9 (rhFUT9) on lung airway and parenchymal inflammation, alveolarization, and apoptosis were evaluated. RESULTS: On hyperoxia exposure, SSEA-1 significantly decreased at postnatal day 14 in hyperoxia-exposed BPD mice, accompanied by a decrease in FUT9. BPD and respiratory distress syndrome (RDS) in human lungs showed decreased expression of SSEA-1 as compared to their term controls. Importantly, intraperitoneal administration of FUT9 in the neonatal BPD mouse model resulted in significant decrease in pulmonary airway (but not lung parenchymal) inflammation, alveolar-capillary leakage, alveolar simplification, and cell death in the hyperoxia-exposed BPD mice. CONCLUSIONS: An important role of endogenous PSC marker SSEA-1 and its enzyme FUT9 is demonstrated, indicating early systemic intervention with FUT9 as a potential therapeutic option for BPD. IMPACT: Administration of rhFUT9, an enzyme of endogenous stem cell marker SSEA-1, reduces pulmonary airway (but not lung parenchymal) inflammation, alveolar-capillary leak and cell death in the BPD mouse model. SSEA-1 is reported for the first time in experimental BPD models, and in human RDS and BPD. rhFUT9 treatment ameliorates hyperoxia-induced lung injury in a developmentally appropriate BPD mouse model. Our results have translational potential as a therapeutic modality for BPD in the developing lung.

Chitin-Derived AVR-48 Prevents Experimental Bronchopulmonary Dysplasia (BPD) and BPD-Associated Pulmonary Hypertension in Newborn Mice.

Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity and a key contributor to the large health care burden associated with prematurity, longer hospital stays, higher hospital costs, and frequent re-hospitalizations of affected patients through the first year of life and increased resource utilization throughout childhood. This disease is associated with abnormal pulmonary function that may lead to BPD-associated pulmonary hypertension (PH), a major contributor to neonatal mortality and morbidity. In the absence of any definitive treatment options, this life-threatening disease is associated with high resource utilization during and after neonatal intensive care unit (NICU) stay. The goal of this study was to test the safety and efficacy of a small molecule derivative of chitin, AVR-48, as prophylactic therapy for preventing experimental BPD in a mouse model. Two doses of AVR-48 were delivered either intranasally (0.11 mg/kg), intraperitoneally (10 mg/kg), or intravenously (IV) (10 mg/kg) to newborn mouse pups on postnatal day (P)2 and P4. The outcomes were assessed by measuring total inflammatory cells in the broncho-alveolar lavage fluid (BALF), chord length, septal thickness, and radial alveolar counts of the alveoli, Fulton's Index (for PH), cell proliferation and cell death by immunostaining, and markers of inflammation by Western blotting and ELISA. The bioavailability and safety of the drug were assessed by pharmacokinetic and toxicity studies in both neonatal mice and rat pups (P3-P5). Following AVR-48 treatment, alveolar simplification was improved, as evident from chord length, septal thickness, and radial alveolar counts; total inflammatory cells were decreased in the BALF; Fulton's Index was decreased and lung inflammation and cell death were decreased, while angiogenesis and cell proliferation were increased. AVR-48 was found to be safe and the no-observed-adverse-effect level (NOAEL) in rat pups was determined to be 100 mg/kg when delivered via IV dosing with a 20-fold safety margin. With no reported toxicity and with a shorter half-life, AVR-48 is able to reverse the worsening cardiopulmonary phenotype of experimental BPD and BPD-PH, compared to controls, thus positioning it as a future drug candidate.

Rapid Evolution of the CD8+ TCR Repertoire in Neonatal Mice.

Currently, there is little consensus regarding the most appropriate animal model to study acute infection and the virus-specific CD8(+) T cell (CTL) responses in neonates. TCRß high-throughput sequencing in naive CTL of differently aged neonatal mice was performed, which demonstrated differential Vß family gene usage. Using an acute influenza infection model, we examined the TCR repertoire of the CTL response in neonatal and adult mice infected with influenza type A virus. Three-day-old mice mounted a greatly reduced primary NP(366-374)-specific CTL response when compared with 7-d-old and adult mice, whereas secondary CTL responses were normal. Analysis of NP(366-374)-specific CTL TCR repertoire revealed different Vß gene usage and greatly reduced public clonotypes in 3-d-old neonates. This could underlie the impaired CTL response in these neonates. To directly test this, we examined whether controlling the TCR would restore neonatal CTL responses. We performed adoptive transfers of both nontransgenic and TCR-transgenic OVA(257-264)-specific (OT-I) CD8(+) T cells into influenza-infected hosts, which revealed that naive neonatal and adult OT-I cells expand equally well in neonatal and adult hosts. In contrast, nontransgenic neonatal CD8(+) T cells when transferred into adults failed to expand. We further demonstrate that differences in TCR avidity may contribute to decreased expansion of the endogenous neonatal CTL. These studies highlight the rapid evolution of the neonatal TCR repertoire during the first week of life and show that impaired neonatal CTL immunity results from an immature TCR repertoire, rather than intrinsic signaling defects or a suppressive environment.

Characterization of CD31 expression on murine and human neonatal T lymphocytes during development and activation.

BackgroundCD31, expressed by the majority of the neonatal T-cell pool, is involved in modulation of T-cell receptor signaling by increasing the threshold for T-cell activation. Therefore, CD31 could modulate neonatal tolerance and adaptive immune responses.MethodsLymphocytes were harvested from murine neonates at different ages, human late preterm and term cord blood, and adult peripheral blood. Human samples were activated over a 5-day period to simulate acute inflammation. Mice were infected with influenza; lungs and spleens were harvested at days 6 and 9 post infection and analyzed by flow cytometry.ResultsCD31-expressing neonatal murine CD4+ and CD8a+ T cells increase over the first week of life. Upon in vitro stimulation, human infants' CD4+ and CD8a+ T cells shed CD31 faster in comparison with adults. In the context of acute infection, mice infected at 3 days of age have an increased number of naive and activated CD31+ T lymphocytes at the site of infection at days 6 and 9 post infection, as compared with those infected at 7 days of age; however, the opposite is true in the periphery.ConclusionDifferences in trafficking of CD31+ cytotoxic T lymphocytes (CTLs) during acute influenza infection could modulate tolerance and contribute to a dampened adaptive immune response in neonates.

Characterization of a Novel Regulator of Biofilm Formation in the Pathogen Legionella pneumophila.

Legionella pneumophila is a Gram-negative, facultative intracellular pathogen that causes severe pneumonia known as Legionnaires' disease. The bacterium causes disease when contaminated water is aerosolized and subsequently inhaled by individuals, which allows the bacteria to gain access to the lungs, where they infect alveolar macrophages. L. pneumophila is ubiquitous in the environment, where it survives by growing in biofilms, intracellularly within protozoa, and planktonically. Biofilms are a major concern for public health because they provide a protective niche that allows for the continuous leaching of bacteria into the water supply. In addition, biofilms enhance the survival of the bacteria by increasing resistance to temperature fluctuations and antimicrobial agents. Currently, there is little known about biofilm formation and regulation by L. pneumophila. Here, we present evidence of a specific gene, bffA, which appears to be involved in the regulation of motility, biofilm formation, cellular replication, and virulence of L. pneumophila. A strain lacking bffA has an enhanced biofilm formation phenotype, forming biofilms that are both faster and thicker than wild type. Additionally, the knockout strain has significantly reduced motility, enhanced uptake into amoebae, and altered growth kinetics on solid media. Our data suggest a potential role for bffA in signaling pathways that govern changes in growth rate and motility in response to environmental conditions.

Severity of neonatal influenza infection is driven by type I interferon and oxidative stress.

Neonates exhibit increased susceptibility to respiratory viral infections, attributed to inflammation at the developing pulmonary air-blood interface. IFN I are antiviral cytokines critical to control viral replication, but also promote inflammation. Previously, we established a neonatal murine influenza virus (IV) model, which demonstrates increased mortality. Here, we sought to determine the role of IFN I in this increased mortality. We found that three-day-old IFNAR-deficient mice are highly protected from IV-induced mortality. In addition, exposure to IFNß 24 h post IV infection accelerated death in WT neonatal animals but did not impact adult mortality. In contrast, IFN IIIs are protective to neonatal mice. IFNß induced an oxidative stress imbalance specifically in primary neonatal IV-infected pulmonary type II epithelial cells (TIIEC), not in adult TIIECs. Moreover, neonates did not have an infection-induced increase in antioxidants, including a key antioxidant, superoxide dismutase 3, as compared to adults. Importantly, antioxidant treatment rescued IV-infected neonatal mice, but had no impact on adult morbidity. We propose that IFN I exacerbate an oxidative stress imbalance in the neonate because of IFN I-induced pulmonary TIIEC ROS production coupled with developmentally regulated, defective antioxidant production in response to IV infection. This age-specific imbalance contributes to mortality after respiratory infections in this vulnerable population.

Intratumor C-reactive protein as a biomarker of prognosis in localized renal cell carcinoma.

PURPOSE: Serum C-reactive protein has been shown to have prognostic value in localized and metastatic renal cell carcinoma. However, the prognostic value of intratumor C-reactive protein remains unknown. MATERIALS AND METHODS: A total of 95 patients with resected, clinically localized (T1-T4N0M0) clear cell renal cell carcinoma were followed postoperatively. Intratumor C-reactive protein expression was assessed in surgical specimens using immunohistochemical analysis. Patients were categorized by staining intensity into low risk (staining 0 to 1), intermediate risk (staining 2) and high risk (staining 3) groups. Kaplan-Meier and multivariate Cox regression analyses were used to examine overall survival across patient and disease characteristics. Variables examined in multivariate Cox regression analysis included T stage, Fuhrman nuclear grade, tumor size, preoperative serum C-reactive protein and intratumor C-reactive protein staining. RESULTS: Followup extended up to 46 months with a mean (SD) of 29.8 (11.0) months. Twelve patients (12.6%) died during followup. Of all tumors 49.5%, 25.3% and 25.3% were graded by intratumor C-reactive protein staining as low risk (0 to 1), intermediate risk (2) and high risk (3), respectively. After controlling for variables significant on univariate analysis, patients in the high risk (3) group experienced a 27-fold increased risk of overall mortality compared to those in the low risk (0-1) group (HR 27.767, 95% CI 1.488-518.182). After adjusting for tumor staining, preoperative serum C-reactive protein was not a significant predictor of overall survival (p = 0.741). CONCLUSIONS: Intratumor C-reactive protein may be a robust biomarker of prognosis in patients with localized renal cell carcinoma.

Absolute preoperative C-reactive protein predicts metastasis and mortality in the first year following potentially curative nephrectomy for clear cell renal cell carcinoma.

PURPOSE: C-reactive protein is an inflammatory biomarker associated with tumor burden and metastasis in renal cell carcinoma. Recent studies suggest that preoperative C-reactive protein predicts metastasis and mortality after nephrectomy for localized renal cell carcinoma. However, these studies dichotomized C-reactive protein (typically 10 mg/l or greater vs less than 10 mg/l). Considering the continuous range of C-reactive protein (less than 1 mg/l to greater than 100 mg/l) we assessed the ability of absolute preoperative C-reactive protein to predict metastases and mortality as a continuous variable. MATERIALS AND METHODS: Patients with clinically localized (T1-T3N0M0) clear cell renal cell carcinoma were followed for 1 year postoperatively. Metastases were identified radiologically and mortality was determined by death certificate. Univariate and multivariate binary logistic regression analyses examined 1-year relapse-free survival and overall relative survival across patient and disease characteristics. RESULTS: Of the 130 patients in this study metastases developed in 24.6% and 10.8% of the patients died. Mean (SD) preoperative C-reactive protein for patients in whom metastases did and did not develop was 89.17 (74.17) and 9.16 (30.62) mg/l, respectively. Mean preoperative C-reactive protein for patients who did and did not die was 102.61 (77.32) and 19.52 (46.10) mg/l, respectively. On multivariate analysis SSIGN score (p <0.001) and preoperative C-reactive protein (B 0.027, SE 0.003, p <0.001) were significant predictors of relapse-free survival, and preoperative platelets (p = 0.009) and preoperative C-reactive protein (B 0.011, SE 0.008, p <0.001) were significant predictors of overall relative survival. CONCLUSIONS: Absolute preoperative C-reactive protein is a robust predictor of metastasis and mortality after nephrectomy for localized renal cell carcinoma. Clinicians should consider absolute preoperative C-reactive protein to identify high risk patients for closer surveillance or additional therapy. In addition, predictive algorithms and models of metastasis should consider incorporating C-reactive protein as a continuous variable to maximize predictive ability.

Adenosine deaminase-1 enhances germinal center formation and functional antibody responses to HIV-1 Envelope DNA and protein vaccines.

Adenosine deaminase-1 (ADA-1) plays both enzymatic and non-enzymatic roles in regulating immune cell function. Mutations in the ADA1 gene account for 15% of heritable severe-combined immunodeficiencies. We determined previously that ADA1 expression defines and is instrumental for the germinal center follicular helper T cell (TFH) phenotype using in vitro human assays. Herein, we tested whether ADA-1 can be used as an adjuvant to improve vaccine efficacy in vivo. In vitro, ADA-1 induced myeloid dendritic cell (mDC) maturation as measured by increased frequencies of CD40-, CD83-, CD86-, and HLA-DR-positive mDCs. ADA-1 treatment also promoted the secretion of the TFH-polarizing cytokine IL-6 from mDCs. In the context of an HIV-1 envelope (env) DNA vaccine, co-immunization with plasmid-encoded ADA-1 (pADA) enhanced humoral immunity. Animals co-immunized with env DNA and pADA had significantly increased frequencies of TFH cells in their draining lymph nodes and increased HIV-binding IgG in serum. Next, mice were co-immunized with subtype C env gp160 DNA and pADA along with simultaneous immunization with matched gp140 trimeric protein. Mice that received env gp160 DNA, pADA, and gp140 glycoprotein had significantly more heterologous HIV-specific binding IgG in their serum. Furthermore, only these mice had detectable neutralizing antibody responses. These studies support the use of ADA-1 as a vaccine adjuvant to qualitatively enhance germinal center responses and represent a novel application of an existing therapeutic agent that can be quickly translated for clinical use.

Dissecting the defects in the neonatal CD8+ T-cell response.

The neonatal period presents a complex scenario where the threshold of reactivity toward colonizing microbiota, maternal antigens, autoantigens, and pathogens must be carefully moderated and balanced. CD8+ T cells are critical for the response against intracellular bacteria and viruses, but this immune compartment maintains altered function relative to adult counterparts because of the unique challenges which infants face. Here, we review our current understanding of the factors which may promote the attenuation and altered function of the neonatal CD8+ T-cell response and potential avenues for future study. Specifically, we have focused on the neonatal CD8+ T-cell ontogeny, memory formation, TCR structure and repertoire, TCR inhibitory receptors, and the clinical implications of altered neonatal CD8+ T-cell function. Special emphasis has been placed on examining the response of preterm neonates relative to term neonates and adults.

Neonatal influenza-specific effector CTLs retain elevated CD31 levels at the site of infection and have decreased IFN-γ production.

The underlying mechanisms that regulate neonatal immune suppression are poorly characterized. CD31 (PECAM1) is highly expressed on neonatal lymphocytes and is a known modulator of TCR signaling. To further characterize the role of CD31 in the neonatal CTL response, 3-d and 7-d-old murine neonates were infected with influenza virus and compared to adults. The majority of the pulmonary viral-specific CTLs in the 3-d-old murine neonate retain CD31 expression, whereas adult CTLs have decreased CD31 expression. In addition, CD31+ neonatal viral-specific CTLs demonstrate decreased IFN-γ production, decreased proliferative capacity, and increased likelihood of death. At the peak of infection, sorted neonatal effector CTLs continue to transcribe CD31, indicating a developmental regulation of expression. To explore potential mechanisms for this reduced function, we compared the expression of the transcription factors Eomesodermin (Eomes) and T-bet; there was a significant increase in Eomes paired with a reduction in T-bet in CD31+ neonatal effector CTLs in the lung. Furthermore, in vitro stimulated neonatal CTLs significantly reduce IFN-γ production upon CD31 signaling. Altogether, these data indicate that neonatal CTLs may retain elevated levels of CD31 to maintain peripheral T cell suppression during the bridge to ex utero life.

Public Clonotypes and Convergent Recombination Characterize the Naïve CD8+ T-Cell Receptor Repertoire of Extremely Preterm Neonates.

Respiratory support improvements have aided survival of premature neonates, but infection susceptibility remains a predominant problem. We previously reported that neonatal mice have a rapidly evolving T-cell receptor (TCR) repertoire that impairs CD8+ T cell immunity. To understand the impact of prematurity on the human CD8+ TCR repertoire, we performed next-generation sequencing of the complementarity-determining region 3 (CDR3) from the rearranged TCR variable beta (Vß) in sorted, naïve CD8+ T cells from extremely preterm neonates (23-27 weeks gestation), term neonates (37-41 weeks gestation), children (16-56 months), and adults (25-50 years old). Strikingly, preterm neonates had an increased frequency of public clonotypes shared between unrelated individuals. Public clonotypes identified in preterm infants were encoded by germline gene sequences, and some of these clonotypes persisted into adulthood. The preterm neonatal naïve CD8+ TCR repertoire exhibited convergent recombination, characterized by different nucleotide sequences encoding the same amino acid CDR3 sequence. As determined by Pielou's evenness and iChao1 metrics, extremely preterm neonates have less clonality, and a much lower bound for the number of unique TCR within an individual preterm neonate, which indicates a less rich and diverse repertoire, as compared to term neonates, children, and adults. This suggests that T cell selection in the preterm neonate may be less stringent or different. Our analysis is the first to compare the TCR repertoire of naïve CD8+ T cells between viable preterm neonates and term neonates. We find preterm neonates have a repertoire immaturity which potentially contributes to their increased infection susceptibility. A developmentally regulated, evenly distributed repertoire in preterm neonates may lead to the inclusion of public TCR CDR3ß sequences that overlap between unrelated individuals in the preterm repertoire.

A conserved OmpA-like protein in Legionella pneumophila required for efficient intracellular replication.

The OmpA-like protein domain has been associated with peptidoglycan-binding proteins, and is often found in virulence factors of bacterial pathogens. The intracellular pathogen Legionella pneumophila encodes for six proteins that contain the OmpA-like domain, among them the highly conserved uncharacterized protein we named CmpA. Here we set out to characterize the CmpA protein and determine its contribution to intracellular survival of L. pneumophila Secondary structure analysis suggests that CmpA is an inner membrane protein with a peptidoglycan-binding domain at the C-teminus. A cmpA mutant was able to replicate normally in broth, but failed to compete with an isogenic wild-type strain in an intracellular growth competition assay. The cmpA mutant also displayed significant intracellular growth defects in both the protozoan host Acanthamoeba castellanii and in primary bone marrow-derived macrophages, where uptake into the cells was also impaired. The cmpA phenotypes were completely restored upon expression of CmpA in trans The data presented here establish CmpA as a novel virulence factor of L. pneumophila that is required for efficient intracellular replication in both mammalian and protozoan hosts.

Nonsurgical management of urolithiasis: an overview of expulsive therapy.

Although minimally invasive stone therapies such as shockwave lithotripsy, ureteroscopy, and percutaneous nephrolithotomy are efficacious, these techniques are not free of risks and are relatively expensive. Watchful waiting may be appropriate in patients without infection whose pain can be controlled with oral medication but is associated with pain, uncertainty, potential risks to renal function, and time lost from work. Hydroxyprogesterone, prostaglandin synthetase inhibitors, calcium-channel blockers such as nifedipine, alpha-1 blockers such as tamsulosin, and corticosteroids may have some beneficial effect. Future studies are likely to provide additional data in support of their use.

Renal tumor radiofrequency ablation.

Nephron sparing surgery has become the gold standard for the treatment of small (< 4 cm) renal tumors. More recently, renal tumor ablation, destroying renal tumors with energy based modalities and leaving the tissue in situ, has gained popularity. Radiofrequency ablation (RFA) utilizes heat energy to cause cellular destruction. RFA can be applied laparoscopically, percutaneously, and as an adjunct with partial nephrectomy. A comprehensive MEDLINE search of the English literature from 1990 to present was performed to identify articles on renal RFA. RFA is an effective minimally invasive treatment alternative for small renal masses in patients with significant comorbidities that preclude extirpative surgery. Limited follow up from a number of series demonstrate a success rate of 92%. RFA has proven to be an effective ablative therapy in a number of organ systems. Over the past decade it has been applied to the treatment of small renal tumors. The short-term efficacy and minimum morbidity of RF thermal therapy for renal tumors has been encouraging. RFA provides a versatile tool to add to the urologist's armamentarium in the minimally invasive treatment of renal cancer.

Determination of vinca alkaloids in human plasma by liquid chromatography/atmospheric pressure chemical ionization mass spectrometry.

A sensitive assay was developed for the quantitation of vinblastine, desacetylvinblastine and vincristine using liquid chromatography-atmospheric pressure chemical ionization mass spectrometry (LC-APCI-MS). Analyses were performed on an Ultrasphere C18 microbore column using ammonium acetate as mobile phase. The calibration curves were linear across the range of 0.51-4.00 ng/ml (0.63-4.93 nM) for vinblastine, 0.74-3.93 ng/ml (0.96-5.11 nM) for desacetylvinblastine and 0.30-3.95 ng/ml (0.36-4.79 nM) for vincristine. Vinca alkaloid concentrations were measured with an accuracy and precision within 11%. This assay could be implemented to determine the plasma concentrations for pharmacokinetic studies of vinblastine, desacetylvinblastine and vincristine in conjunction with clinical trials.

The role of spectral selectivity in fluorescence detection for liquid chromatography.

The use of a cut-off filter has been compared with a monochromator for emission energy selection in the fluorescence detector used in the analysis of environmental samples for polycyclic aromatic hydrocarbons by liquid chromatography. The use of a cut-off filter can provide greater sensitivity for compounds that are well separated by the chromatography. However, samples that contain a large number of compounds often result in overlapping peaks, and for such samples, it has been found that the spectral selectivity of monochromatic emission selection reduces the interference due to compounds eluting near the compounds of analytical interest. This spectral selectivity results in greater sensitivity and a smaller quantitation error in the analysis of these complex samples.

Postoperative better than preoperative C-reactive protein at predicting outcome after potentially curative nephrectomy for renal cell carcinoma.

OBJECTIVES: Preoperative C-reactive protein (CRP) predicts metastasis and mortality in localized renal cell carcinoma (RCC). However, the predictive potential of after resection of localized RCC remains unclear. Therefore, we assessed the absolute ability of postoperative CRP to predict metastases and mortality as a continuous variable. METHODS: Patients with clinically localized (T1-T3N0M0) clear-cell RCC were followed for 1 year postoperatively. Metastases were identified radiologically and mortality by death certificate. Univariate and multivariate binary logistic regression analyses examined 1 year relapse-free survival (RFS) and overall survival (OS) across patient and disease characteristics. RESULTS: Of the 110 patients in this study, 16.4% developed metastases and 6.4% died. Mean (SD) postoperative CRP for patients who did and did not develop metastases were 69.06 (73.55) mg/L and 5.27 (7.80), respectively. Mean (SD) postoperative CRP for patients who did and did not die were 89.31 (69.51) mg/L and 10.88 (30.32), respectively. In multivariate analysis, T-stage (OR: 12.452, 95% CI: 2.889-53.660) and postoperative CRP ((B: .080, SE: .025; P < .001) were significant predictors of RFS. T-Stage (OR: 11.715; 95% CI: 1.102-124.519) and postoperative CRP (B: .017; SE: .007; P < .001) were also significant predictors of OS. After adjusting for postoperative CRP, preoperative CRP was not predictive of these outcomes. CONCLUSIONS: Postoperative, not preoperative, CRP is the better predictor of metastasis and mortality following nephrectomy for localized RCC. Clinicians should consider absolute postoperative CRP to identify high-risk patients for closer surveillance or additional therapy. Predictive algorithms should consider incorporating postoperative CRP as a continuous variable to maximize predictive ability.

Antimicrobial mesh versus vaginal wall sling: a comparative outcomes analysis.

PURPOSE: We prospectively compared transvaginal antimicrobial mesh (MycroMesh*) and anterior vaginal wall slings using an outcomes analysis. MATERIALS AND METHODS: Between August 1997 and November 1998 we implanted transvaginal slings in 40 consecutive women randomized to a synthetic mesh (20) or vaginal wall (20) group. All patients had documented stress urinary incontinence on preoperative urodynamics. We prospectively compared postoperative outcomes data obtained from pelvic examinations, cough stress test, cotton swab test and validated patient questionnaires using a visual analog scale. RESULTS: Complete followup was available in all patients. Mean followup was 22 months (range 12 to 27). Stress incontinence was cured in 95% of the mesh and 70% of the vaginal wall group, and pelvic prolapse was cured in 100% and 95%, respectively. Transient de novo urge incontinence was noted in 12.5% of the mesh and 14.3% of the vaginal wall group. Mean postoperative cotton swab angle during Valsalva's maneuver was 20 and 45 degrees for the mesh and vaginal wall groups, respectively. The incidence of urinary retention and tissue erosion was 0% for both groups. The satisfaction rate was 100% and 80% for the mesh and vaginal wall groups, respectively. CONCLUSIONS: The antimicrobial MycroMesh sling was superior to the vaginal wall sling for correction of stress incontinence and pelvic prolapse with comparatively low morbidity.