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Background: Respiratory tract infection is one of the most common reasons for hospitalization among adults, and recent evidence suggests that many of these illnesses are associated with viruses. Although bacterial infection is known to complicate viral infections, the frequency and impact of mixed viral-bacterial infections has not been well studied., Methods: Adults hospitalized with respiratory illness during 3 winters underwent comprehensive viral and bacterial testing. This assessment was augmented by measuring the serum level of procalcitonin (PCT) as a marker of bacterial infection. Mixed viral-bacterial infection was defined as a positive viral test result plus a positive bacterial assay result or a serum PCT level of ≥ 0.25 ng/mL on admission or day 2 of hospitalization., Results: Of 842 hospitalizations (771 patients) evaluated, 348 (41%) had evidence of viral infection. A total of 212 hospitalizations (61%) involved patients with viral infection alone. Of the remaining 136 hospitalizations (39%) involving viral infection, results of bacterial tests were positive in 64 (18%), and PCT analysis identified bacterial infection in an additional 72 (21%). Subjects hospitalized with mixed viral-bacterial infections were older and more commonly received a diagnosis of pneumonia. Over 90% of hospitalizations in both groups involved subjects who received antibiotics. Notably, 4 of 10 deaths among subjects hospitalized with viral infection alone were secondary to complications of Clostridium difficile colitis., Conclusions: Bacterial coinfection is associated with approximately 40% of viral respiratory tract infections requiring hospitalization. Patients with positive results of viral tests should be carefully evaluated for concomitant bacterial infection. Early empirical antibiotic therapy for patients with an unstable condition is appropriate but is not without risk.

CEP-1347 is a potent inhibitor of mixed lineage kinase (MLK), which was investigated for ameliorating HIV-associated neurocognitive disorders. CEP-1347 and atazanavir pharmacokinetics were determined when CEP-1347 50 mg twice daily was administered to HIV-infected patients (n = 20) receiving combination antiretroviral therapy including atazanavir and ritonavir (ATV/RTV, 300/100 mg) once daily continuously. Co-administration of CEP-1347 and ATV/RTV resulted with significant changes in pharmacokinetics of ATV but not RTV. Specifically, an increase in ATV accumulation ratio of 15 % (p = 0.007) and a prolongation of T(½) from 12.7 to 15.9 h (p = 0.002) were observed. The results suggested that co-administration of CEP-1347 with ATV/RTV in HIV-infected patients might result in limited impact on ATV but not on RTV pharmacokinetics.

Background: Comprehensive analyses of host, viral, and immune factors associated with severe respiratory syncytial virus (RSV) infection in adults have not been performed., Methods: Adults with RSV infection identified in both outpatient and inpatient settings were evaluated. Upper and lower respiratory tract virus load, duration of virus shedding, select mucosal chemokine and cytokine levels, humoral and mucosal immunoglobulin responses, and systemic T-cell responses were measured., Results: A total of 111 RSV-infected adults (61 outpatients and 50 hospitalized patients) were evaluated. Hospitalized subjects shed virus in nasal secretions at higher titers and for longer durations than less ill outpatients, had greater mucosal interleukin 6 (IL-6) levels throughout infection, and had higher macrophage inflammatory protein 1α (MIP-1α) levels early in infection. Persons >64 years old and those with more severe disease had a higher frequency of activated T cells in the blood than younger, less ill subjects at infection. Multivariate analysis found that the presence of underlying medical conditions, female sex, increased mucosal IL-6 level, and longer duration of virus shedding were associated with severe disease. Older age and increased nasal MIP-1α levels were of borderline statistical significance., Conclusions: Multiple factors, but not older age, are independently associated with severe RSV infection in adults. The presence of underlying medical conditions had the greatest influence on disease severity.

Background: Clinical diagnosis of pneumonia is difficult and chest radiographs often indeterminate, leading to incorrect diagnoses and antibiotic overuse., Objective: To determine if serum procalcitonin (ProCT) could assist in managing patients with respiratory illness and indeterminate radiographs., Design: Subjects were prospectively enrolled during 2 consecutive winters., Setting: A 520-bed hospital in Rochester, NY., Patients: Five hundred twenty-eight adults admitted with acute respiratory illness were enrolled., Measurements: Serum ProCT, admission diagnoses, and chest radiographic findings were used to derive receiver operating characteristics curves to assess predictive accuracy of ProCT for the presence of infiltrates., Results: Subjects with pneumonia had higher ProCT (median 0.27 ng/ml) than those with exacerbations of chronic obstructive pulmonary disease (0.08 ng/ml), acute bronchitis (0.09 ng/ml), or asthma (0.06 ng/ml). ProCT had moderate accuracy for the presence of infiltrates (area under curve [AUC] 0.72), when indeterminate radiographs were independently classified as infiltrates by a pulmonologist evaluating patients., Conclusions: ProCT may be useful in diagnosing pneumonia when chest radiographs are indeterminate., (Copyright © 2012 Society of Hospital Medicine.)

Modern high-throughput technologies allow us to simultaneously measure the expressions of a huge number of candidate predictors, some of which are likely to be associated with survival. One difficult task is to search among an enormous number of potential predictors and to correctly identify most of the important ones, without mistakenly identifying too many spurious associations. Mere variable selection is insufficient, however, for the information from the multiple predictors must be intelligently combined and calibrated to form the final composite predictor. Many commonly used procedures overfit the training data, miss many important predictors, or both. Although it is impossible to simultaneously adjust for a huge number of predictors in an unconstrained way, we propose a method that offers a middle ground where some partial multivariate adjustments can be made in an adaptive fashion, regardless of the number of candidate predictors. We demonstrate the performance of our proposed procedure in a simulation study within the Cox proportional hazards regression framework, and we apply our new method to a publicly available data set to construct a novel prognostic gene signature for breast cancer survival.

Objective: To understand the relations of mild traumatic brain injury (TBI), blast exposure, and brain white matter structure to severity of posttraumatic stress disorder (PTSD)., Design: Nested cohort study using multivariate analyses., Participants: Fifty-two OEF/OIF veterans who served in combat areas between 2001 and 2008 were studied approximately 4 years after the last tour of duty., Main Measures: PTSD Checklist-Military; Combat Experiences Survey, interview questions concerning blast exposure and TBI symptoms; anatomical magnetic resonance imaging (MRI), and diffusion tensor imaging (DTI) scanning of the brain., Results: PTSD severity was associated with higher 1st percentile values of mean diffusivity on DTI (regression coefficient [r] = 4.2, P = .039), abnormal MRI (r = 13.3, P = .046), and the severity of exposure to combat events (r = 5.4, P = .007). Mild TBI was not significantly associated with PTSD severity. Blast exposure was associated with lower 1st percentile values of fractional anisotropy on DTI (odds ratio [OR] = 0.38 per SD; 95% confidence interval [CI], 0.15-0.92), normal MRI (OR = 0.00, 95% likelihood ratio test CI, 0.00-0.09), and the severity of exposure to traumatic events (OR = 3.64 per SD; 95% CI, 1.40-9.43)., Conclusions: PTSD severity is related to both the severity of combat stress and underlying structural brain changes on MRI and DTI but not to a clinical diagnosis of mild TBI. The observed relation between blast exposure and abnormal DTI suggests that subclinical TBI may play a role in the genesis of PTSD in a combat environment.

Background: Human rhinoviruses (HRV) can be detected by RT-PCR in a large proportion of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) but can also be detected in COPD patients without symptoms., Objectives: The purpose of this study was to compare host, virologic and environmental factors associated with symptomatic and asymptomatic HRV infection., Study Design: One hundred twenty-seven patients with COPD were evaluated every 2 months routinely and for all respiratory illnesses during a one year period. RT-PCR testing for HRV was performed on nasal and sputum samples. Amplification products were sequenced to assign species HRV-A, B or C. Clinical, virologic and environmental factors were compared for those infected with HRV compared to those without HRV infection as well as symptomatic HRV infection and asymptomatic HRV infection., Results: HRVs were detected in 29 participants during 20 illnesses and 11 routine visits. HRV was detected in nasal samples from 15/102 (14.7%) illnesses compared to 2/685 (0.4%) routine visits (p<.0001). Sputum samples were also more frequently positive from illnesses than routine visits [14/72 (19.4%) vs. 16/310 (5.2%) p<.0001]. Contact with school age children was the only factor that was significantly associated with HRV infection and symptomatic HRV illness. Severity of underlying lung disease and virologic factors were not associated with symptomatic illness., Conclusions: Contact with school aged children is a risk factor for both infection and symptomatic HRV illness. Attention to good hand hygiene and avoidance of direct contact with ill children may help patients with COPD avoid HRV related illness., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Purpose: Cisplatin-induced neurotoxicity and ototoxicity (NTX) are important adverse effects after chemotherapy for testicular cancer (TC). Although serum platinum is measurable years after therapy, its impact on NTX has not been evaluated., Patients and Methods: In all, 169 cisplatin-treated survivors of TC provided blood samples at Survey I and reported NTX during Survey I (1998-2002) and Survey II (2007-2008). Serum platinum was quantified by inductively coupled plasma mass spectrometry. Patient-reported outcomes were evaluated with the Scale for Chemotherapy-Induced Neurotoxicity (SCIN), regarding the extent of symptom bother as 0, "not at all"; 1, "a little"; 2, "quite a bit"; or 3, "very much." Summing the six symptom scores yielded a total SCIN score of 0 to 18. Categorizing total SCIN scores into quartiles yielded similar-sized groups with increasing symptoms. Multivariate ordinal logistic regression analyses evaluated associations between NTX and long-term serum platinum levels, adjusting for cisplatin dose, dosing schedule, and age., Results: At Survey I, a significant four- to five-fold association with total SCIN score emerged for the highest serum platinum quartile (odds ratio [OR], 4.69; 95% CI, 1.82 to 12.08). Paresthesias and Raynaud's syndrome (hands and feet) showed significant two- to four-fold increased risks with the highest platinum quartile. At Survey II, total SCIN score remained significantly associated with the highest platinum quartile (OR, 4.28; 95% CI, 1.36 to 13.48). Paresthesias (hands and feet) and tinnitus showed significant three- to four-fold increased risks for the highest platinum quartile. Cumulative cisplatin dose was not associated with total SCIN score or individual SCIN symptoms in multivariate analyses., Conclusion: Here we document a significant relationship between increasing levels of residual serum platinum and NTX severity after adjusting for initial cisplatin dose.

Background: The purpose of this study was to investigate the effect of neoadjuvant chemotherapy with gemcitabine and cisplatin (GC) on pathologic down-staging of patients with locally advanced urothelial cancer (UC) of the bladder., Methods: This was a retrospective cohort study of patients treated with radical cystectomy (RC) for clinical stage cT2-T4, N any, M0 bladder UC at Strong Memorial Hospital from 1999 to 2009. The primary exposure variable was use of neoadjuvant chemotherapy (GC vs none). The primary outcome was stage pT0 at RC. Secondary outcomes included other down-staging end points in the bladder (

Background: A prolonged QT interval corrected for heart rate (QTc) is a major risk factor in patients with long QT syndrome (LQTS). However, heart rate-related risk in this genetic disorder differs among genotypes., Objective: This study hypothesized that risk assessment in LQTS patients should incorporate genotype-specific QT correction for heart rate., Methods: The independent contribution of 4 repolarization measures (the absolute QT interval, and Bazett's, Fridericia's, and Framingham's correction formulas) to the risk of aborted cardiac arrest or sudden cardiac death during adolescence, before and after further adjustment for the RR interval, was assessed in 727 LQTS type 1 and 582 LQTS type 2 patients. Improved QT/RR correction was calculated using a Cox model, dividing the coefficient on log(RR) by that on log(QT)., Results: Multivariate analysis demonstrated that in LQTS type 1 patients 100-ms increments in the absolute QT interval were associated with a 3.3-fold increase in the risk of life-threatening cardiac events (P = .020), and 100-ms decrements in the RR interval were associated with a further 1.9-fold increase in the risk (P = .007), whereas in LQTS type 2 patients, resting heart rate was not a significant risk factor (hazard ratio 1.11; P = .51; P value for heart rate × genotype interaction = .036). Accordingly, analysis of an improved QT correction formula showed that patients with the LQTS type 1 genotype required a greater degree of QT correction for heart rate (improved QTc = QT/RR⁰·⁸) than LQTS type 2 patients (improved QTc = QT/RR⁰·²)., Conclusion: Our findings suggest that risk stratification for life-threatening cardiac events in LQTS patients can be improved by incorporating genotype-specific QT correction for heart rate., (Copyright © 2011 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Pancreatic cancer is known to be associated with VTE, but contemporary rates of incidental and symptomatic VTE events and their association with mortality are incompletely understood. We conducted a retrospective cohort study of consecutive pancreatic adenocarcinoma patients at the University of Rochester from 2006-2009. Data were analysed using a Cox model with time-dependent covariates. A total of 1,151 radiologic exams of 135 patients were included. Forty-seven patients (34.8%) experienced VTE including 12 pulmonary emboli (PE), 28 deep-vein thromboses (DVTs) and 47 visceral vein events. Incidental events comprised 33.3% of PEs, 21.4% of DVTs and 100% of visceral VTE. Median (95% CI) conditional survival beyond three months was 233 (162-322) more days for those without VTE, which was significantly greater than 12 (3-60) days for those with DVT as first event (p<0.0001) and 87 (14-322) days with visceral first events (p=0.022). In multivariate analysis, DVT (HR 25, 95% CI 10-63, p <0.0001), PE (HR 8.9, 95% CI 2.5-31.7, p = 0.007) and incidental visceral events (HR 2.6, 95% CI 1.6-4.2, p =0.0001) were all associated with mortality, though anticoagulants reduced these risks by 70% (26-88%, p = 0.009). In conclusion, VTE occurs in over one-third of contemporary pancreatic cancer patients and, whether symptomatic or incidental, is strongly associated with worsened mortality. The role of anticoagulation in treating incidental or visceral VTE warrants further study.

Objectives: We aimed to identify risk factors for recurrent syncope in children and adolescents with congenital long QT syndrome (LQTS)., Background: Data regarding risk assessment in LQTS after the occurrence of the first syncope episode are limited., Methods: The Prentice-Williams-Peterson conditional gap time model was used to identify risk factors for recurrent syncope from birth through age 20 years among 1,648 patients from the International Long QT Syndrome Registry., Results: Multivariate analysis demonstrated that corrected QT interval (QTc) duration (≥500 ms) was a significant predictor of a first syncope episode (hazard ratio: 2.16), whereas QTc effect was attenuated when the end points of the second, third, and fourth syncope episodes were evaluated (hazard ratios: 1.29, 0.99, 0.90, respectively; p < 0.001 for the null hypothesis that all 4 hazard ratios are identical). A genotype-specific subanalysis showed that during childhood (0 to 12 years), males with LQTS type 1 had the highest rate of a first syncope episode (p = 0.001) but exhibited similar rates of subsequent events as other genotype-sex subsets (p = 0.63). In contrast, in the age range of 13 to 20 years, long QT syndrome type 2 females experienced the highest rate of both first and subsequent syncope events (p < 0.001 and p = 0.01, respectively). Patients who experienced ≥1 episodes of syncope had a 6- to 12-fold (p < 0.001 for all) increase in the risk of subsequent fatal/near-fatal events independently of QTc duration. Beta-blocker therapy was associated with a significant reduction in the risk of recurrent syncope and subsequent fatal/near-fatal events., Conclusions: Children and adolescents who present after an episode of syncope should be considered to be at a high risk of the development of subsequent syncope episodes and fatal/near-fatal events regardless of QTc duration., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Prior work in the CCN field, including our own, suggested to us that there might be co-regulatory activity and function as part of the actions of this family of cysteine rich cytokines. CCN2 is now regarded as a major pro-fibrotic molecule acting both down-stream and independent of TGF-beta1, and appears causal in the disease afflicting multiple organs. Since diabetic renal fibrosis is a common complication of diabetes, and a major cause of end stage renal disease (ESRD), we examined the possibility that CCN3 (NOV), might act as an endogenous negative regulator of CCN2 with the capacity to limit the overproduction of extracellular matrix (ECM), and thus prevent, or ameliorate fibrosis. We demonstrate, using an in vitro model of diabetic renal fibrosis, that both exogenous treatment with CCN3 and transfection with the over-expression of the CCN3 gene in mesangial cells markedly down-regulates CCN2 activity and blocks ECM over-accumulation stimulated by TGF-beta1. Conversely, TGF-beta1 treatment reduces endogenous CCN3 expression and increases CCN2 activity and matrix accumulation, indicating an important, novel yin/yang effect. Using the db/db mouse model of diabetic nephropathy, we confirm the expression of CCN3 in the kidney, with temporal localization that supports these in vitro findings. In summary, the results corroborate our hypothesis that one function of CCN3 is to regulate CCN2 activity and at the concentrations and conditions used down-regulates the effects of TGF-beta1, acting to limit ECM turnover and fibrosis in vivo. The findings suggest opportunities for novel endogenous-based therapy either by the administration, or the upregulation of CCN3.

Risk factors associated with respiratory failure during respiratory syncytial virus (RSV) infection have not been assessed in adults. We identified RSV by quantitative reverse transcription polymerase chain reaction in 58 adults during the 2007-2008 winter. Clinical variables and respiratory secretion viral loads were compared in 26 outpatients and 32 inpatients. Cardiopulmonary diseases were more common among inpatients than outpatients (91% vs 31%, P = .0001), whereas mean RSV load was similar. Nasal viral load was higher in ventilated vs nonventilated hospitalized patients (log(10) 3.7 +/- 1.7 plaque-forming units (PFUs)/mL vs 2.4 +/- 1.1 PFUs/mL, P = .02), and high viral load was independently associated with respiratory failure.

Toll-like receptor-9 (TLR-9) agonists have pleotropic effects on both the innate and adaptive immune systems, including increased antigen expression, enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and T helper cell type 1 shift in the immune response. We combined a TLR-9 agonist (1018 ISS, 0.2 mg/kg sc weekly x 4 beginning day 8) with standard rituximab (375 mg/m(2) weekly x 4) in patients (n = 23) with relapsed/refractory, histologically confirmed follicular lymphoma, and evaluated immunological changes following the combination. Treatment was well-tolerated with no significant adverse events attributable to therapy. Clinical responses were observed in 48% of patients; the overall median progression-free survival was 9 months. Biologically relevant increases in ADCC and circulating CD-3 positive T cells were observed in 35% and 39% of patients, respectively. Forty-five percent of patients had increased T cells and dendritic cells in skin biopsies of 1018 ISS injection sites 24 h post-therapy. Pre- and post-biopsies of tumour tissue demonstrated an infiltration of CD8(+) T cells and macrophages following treatment. This group of patients had favourable clinical outcome despite adverse prognostic factors. This study is the first to histologically confirm perturbation of the local immune microenvironment following systemic biological therapy of follicular lymphoma.

Fibrosis is a major cause of end-stage renal disease, and although initiation factors have been elucidated, uncertainty concerning the downstream pathways has hampered the development of anti-fibrotic therapies. CCN2 (CTGF) functions downstream of transforming growth factor (TGF)-beta, driving increased extracellular matrix (ECM) accumulation and fibrosis. We examined the possibility that CCN3 (NOV), another CCN family member with reported biological activities that differ from CCN2, might act as an endogenous negative regulator of ECM and fibrosis. We show that cultured rat mesangial cells express CCN3 mRNA and protein, and that TGF-beta treatment reduced CCN3 expression levels while increasing CCN2 and collagen type I activities. Conversely, either the addition of CCN3 or CCN3 overexpression produced a marked down-regulation of CCN2 followed by virtual blockade of both collagen type I transcription and its accumulation. This finding occurred in both growth-arrested and CCN3-transfected cells under normal growth conditions after TGF-beta treatment. These effects were not attributable to altered cellular proliferation as determined by cell cycle analysis, nor were they attributable to interference of Smad signaling as shown by analysis of phosphorylated Smad3 levels. In conclusion, both CCN2 and CCN3 appear to act in a yin/yang manner to regulate ECM metabolism. CCN3, acting downstream of TGF-beta to block CCN2 and the up-regulation of ECM, may therefore serve to naturally limit fibrosis in vivo and provide opportunities for novel, endogenous-based therapeutic treatments.

Objective: We sought to determine whether the circumstances preceding an arrhythmic event differed from those preceding a prior control occasion in patients with Long QT Syndrome (LQTS), a well-characterized genetic disorder that puts affected individuals at risk for sudden cardiac death., Methods: Thirty-eight patients (89% female) with LQTS completed a "case-crossover interview" in which each patient served as his/her own control by reporting on circumstances preceding an arrhythmic event (syncope, aborted cardiac arrest, or defibrillator discharge) and preceding a control occasion (the next-to-last birthday). On average the interview was conducted 17 months after the cardiac event and control occasion., Results: During the 24-hour period preceding the cardiac event compared to the day before the control occasion, psychological stress was elevated, peak happiness was reduced, and peak exertion was not significantly different. Rated for the 6-month intervals preceding the event and control occasions, none of these three variables was significantly associated with events., Conclusions: Happiness is associated with a reduction in the 24-hour risk of cardiac events in patients with LQTS, with stress having an opposite effect. To our knowledge, this is the first report indicating that positive emotion may have a protective effect on life-threatening ventricular arrhythmias. This study lends further support to the role of emotions in influencing cardiac events in arrhythmia-prone patients.

The objective of this study was to assess lithium safety and tolerability and to explore its impact on cognition, function, and neuroimaging biomarkers in human immunodeficiency virus (HIV)-infected subjects with cognitive impairment. Fifteen cognitively impaired HIV-infected subjects were enrolled in this 10-week open-label study of lithium 300 mg twice daily. Neuroimaging was performed at baseline and following 10 weeks of treatment and included magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), and functional MRI (fMRI). Thirteen of the 14 subjects (93%) that complied with the study visits were able to complete the study on lithium and 11 out of 13 (79%) completed the study at the originally assigned dose of 300 mg twice daily. There were no significant changes in CD4(+) lymphocyte cell count and plasma HIV RNA. Cognitive performance and depressive mood did not improve significantly after the 10-week lithium treatment; however, neuroimaging revealed a decrease in the glutamate+glutamine (Glx) peak in the frontal gray matter, increased fractional anisotropy, and decreased mean diffusivity in several brain areas, and changes in brain activation patterns, suggestive of improvement. These results suggest that lithium can be used safely in HIV-infected individuals with cognitive impairment. Furthermore, the neuroimaging results suggest that lithium may improve HIV-associated central nervous system (CNS) injury; thus, further investigations of lithium as an adjunctive treatment for HIV-associated cognitive impairment are warranted.

Minocycline and valproic acid are potential adjuvant therapies for the treatment of human immunodeficiency virus (HIV)-associated cognitive impairment. The purpose of this study was to determine whether minocycline alone or in combination with valproic acid affected atazanavir plasma concentrations. Twelve adult HIV-infected subjects whose regimen included atazanavir (300 mg)-ritonavir (100 mg) daily for at least 4 weeks were enrolled. Each subject received atazanavir-ritonavir on day 1, atazanavir-ritonavir plus 100 mg minocycline twice daily on days 2 to 15, and atazanavir-ritonavir plus 100 mg minocycline twice daily and 250 mg valproic acid twice daily on days 16 to 30 with meals. The subjects had 11 plasma samples drawn over a dosing interval on days 1, 15, and 30. The coadministration of minocycline and valproic acid with atazanavir-ritonavir was well tolerated in all 12 subjects (six male; mean [+/- standard deviation] age was 43.1 [8.2] years). The geometric mean ratios (GMRs; 95% confidence interval [CI]) for the atazanavir area under the concentration-time curve from 0 to 24 h at steady state (AUC(0-24)), the plasma concentration 24 h after the dose (C(min)), and the maximum concentration during the dosing interval (C(max)) with and without minocycline were 0.67 (0.50 to 0.90), 0.50 (0.28 to 0.89), and 0.75 (0.58 to 0.95), respectively. Similar decreases in atazanavir exposure were seen after the addition of valproic acid. The GMRs (95% CI) for atazanavir AUC(0-24), C(min), and C(max) with and without minocycline plus valproic acid were 0.68 (0.43 to 1.06), 0.50 (0.24 to 1.06), and 0.66 (0.41 to 1.06), respectively. Coadministration of neither minocycline nor minocycline plus valproic acid appeared to influence the plasma concentrations of ritonavir (P > 0.2). Minocycline coadministration resulted in decreased atazanavir exposure, and there was no evidence that the addition of valproic acid mediated this effect.

Dosing and route of administration of N-acetylcysteine (NAC) for protection against cisplatin (CDDP) nephrotoxicity was investigated in rats. Two models of toxicity were tested: a single high dose of CDDP (10 mg/kg intraperitoneally (IP)), and multiple low dose treatments (1 mg/kg IP twice a day for 4 days, 10 days rest, then repeated). NAC (50-1,200 mg/kg) was given to the rats by IP, oral (PO), intravenous (IV) and intra-arterial (IA) routes. Renal toxicity was determined by blood urea nitrogen (BUN) and creatinine (CR) levels 3 days after treatment. Blood collected 15 min after NAC was analyzed for total NAC. Both models of CDDP administration produced renal toxicity. In the single dose CDDP model, NAC 400 mg/kg given IP and PO produced no renal protection as measured by BUN (131.8 +/- 8.2 and 123.3 +/- 8.2, respectively) or CR (2.3 +/- 0.38 and 1.77 +/- 0.21, respectively). IV NAC reduced nephrotoxicity, (BUN 26.3 +/- 6.8, CR 0.47 +/- 0.15). NAC 50 mg/kg IA gave better protection than IV. In the repeated-dose CDDP model, nephrotoxicity was blocked by 800 mg/kg NAC given IV but not IP. Blood concentrations of total NAC showed a dose response after IV NAC, but high dose NAC (1,200 mg/kg) by the PO route gave very low levels of NAC. Thus the protective properties of NAC are affected by the dose and route of administration.

To date there has been no general consensus regarding the effectiveness of N-acetylcysteine as a protective therapy against contrast medium-induced nephropathy. Several phase III clinical trials have been conducted without a proper understanding of N-acetylcysteine pharmacology, particularly with regard to first-pass hepatic metabolism. A review was conducted of the literature concerning contrast medium-induced nephropathy and new studies of human N-acetylcysteine pharmacology were performed. After an analysis was performed, it was concluded that further phase I and phase II trials are needed. The efficacy of N-acetylcysteine in the prevention of contrast medium-induced nephropathy may be demonstrated with the use of higher doses than used in earlier studies, in combination with parenteral administration.

Sham surgery is used as a control condition in neurosurgical clinical trials in Parkinson's disease (PD) but remains controversial. This study aimed to assess the perspective of patients with PD and the general public on the use of sham surgery controls. We surveyed consecutive patients from a university-based neurology outpatient clinic and a community-based general internal medicine practice. Background information was provided regarding PD and two possible methods of testing the efficacy of a novel gene transfer procedure, followed by questions that addressed participants' opinions related to the willingness to participate and permissibility of blinded and unblinded trial designs. Two hundred eighty-eight (57.6%) patients returned surveys. Patients with PD expressed less willingness to participate in the proposed gene transfer surgery trials. Unblinded studies received greater support, but a majority would still allow the use of sham surgery. Those in favor of sham surgery were more educated and more likely to use societal perspective rationales. Patients with PD are more cautious about surgical research participation than patients with non-PD. Their policy views were similar to others', with a majority supporting the use of sham controls. Future research needs to determine whether eliciting more considered judgments of laypersons would reveal different levels of support for sham surgery., (2007 Movement Disorder Society)

Background: The clinical and radiographic features of respiratory syncytial virus (RSV) infection in elderly hospitalized persons have not been described in detail, to our knowledge, despite its relative frequent occurrence., Methods: Clinical characteristics of 132 RSV infections were compared with 144 influenza A virus infections and with all non-RSV infections in elderly and high-risk persons admitted to the hospital with acute respiratory illness. Radiographic findings were categorized for RSV-infected persons., Results: RSV was more commonly associated with nasal congestion (68% vs. 55%; P=.03), wheezing by history (73% vs. 53%; P=.002) and on examination (82% vs. 68%; P=.02), and lower temperature (P=.004) than influenza A virus. Compared with all non-RSV-infected subjects, nasal congestion (odds ratio [OR], 2.0 [95% confidence interval {CI}, 1.3-2.9]), wheezing on examination (OR, 1.8 [95% CI, 1.2-2.8]), and temperature >37.9 degrees C (OR, 1.6 [95% CI, 1.1-2.4]) were independent predictors of RSV infection, although their sensitivity and specificity were poor. New radiographic infiltrates were seen in approximately half of RSV-infected persons, and pneumonic opacities were typically small and unilateral., Conclusions: Although RSV causes a different clinical syndrome than influenza A virus, it is not readily differentiated on clinical grounds from influenza A nor from all non-RSV illnesses in elderly patients.

Objectives: The aims of this study were: 1) to evaluate risk factors influencing the clinical course of mutation-confirmed adult patients with long QT syndrome (LQTS), 2) to study life-threatening cardiac events as a specific end point in adults, and 3) to examine the protective effect of beta-blocker therapy on cardiac events in adult LQTS patients with known cardiac channel mutations., Background: The clinical course and risk factors for cardiac events in genotype-confirmed adult patients with LQTS have not been previously investigated., Methods: The clinical characteristics of 812 mutation-confirmed LQTS patients age 18 years or older were studied with both univariate and multivariate analyses to determine the genotype-phenotype factors that influence the clinical course of adult patients with this disorder., Results: Female gender, corrected QT (QTc) interval, LQT2 genotype, and frequency of cardiac events before age 18 years were associated with increased risk of having any cardiac events between the ages of 18 and 40 years. Female gender, QTc interval > or =500 ms, and interim syncopal events during follow-up after age 18 years were associated with significantly increased risk of life-threatening cardiac events in adulthood. Beta-blockers provided a 60% reduction in risk of any cardiac event and life-threatening events, with somewhat greater effect in higher-risk subjects., Conclusions: The severity of LQTS in adulthood can be risk stratified with information regarding genotype, gender, QTc duration, and history of cardiac events. Beta-blockers effectively reduce but do not eliminate the risk of both syncopal and life-threatening cardiac events in adult patients with mutation-confirmed LQTS.

Context: Analysis of predictors of cardiac events in hereditary long-QT syndrome (LQTS) has primarily considered syncope as the predominant end point. Risk factors specific for aborted cardiac arrest and sudden cardiac death have not been investigated., Objective: To identify risk factors associated with aborted cardiac arrest and sudden cardiac death during adolescence in patients with clinically suspected LQTS., Design, Setting, and Participants: The study involved 2772 participants from the International Long QT Syndrome Registry who were alive at age 10 years and were followed up during adolescence until age 20 years. The registry enrollment began in 1979 at 5 cardiology centers in the United States and Europe., Main Outcome Measures: Aborted cardiac arrest or LQTS-related sudden cardiac death; follow-up ended on February 15, 2005., Results: There were 81 patients who experienced aborted cardiac arrest and 45 who had sudden cardiac death; 9 of the 81 patients who had an aborted cardiac arrest event experienced subsequent sudden cardiac death. Significant independent predictors of aborted cardiac arrest or sudden cardiac death during adolescence included recent syncope, QTc interval, and sex. Compared with those with no syncopal events in the last 10 years, patients with 1 or 2 or more episodes of syncope 2 to 10 years ago (but none in the last 2 years) had an adjusted hazard ratio (HR) of 2.7; (95% confidence interval [CI], 1.3-5.7; P<.01) and an adjusted HR of 5.8 (95% CI, 3.6-9.4; P<.001), respectively, for life-threatening events; those with 1 syncopal episodes in the last 2 years had an adjusted HR of 11.7 (95% CI, 7.0-19.5; P<.001) and those with 2 or more syncopal episodes in the last 2 years had an adjusted HR of 18.1 (95% CI, 10.4-31.2; P<.001). Irrespective of events occurring more than 2 years ago, QTc of 530 ms or longer was associated with increased risk (adjusted HR, 2.3; 95% CI, 1.6-3.3; P<.001) compared with those having a shorter QTc. Males between the ages of 10 and 12 years had higher risk than females (HR, 4.0; 95% CI, 1.8-9.2; P = .001), but there was no significant risk difference between males and females between the ages of 13 and 20 years. Among individuals with syncope in the past 2 years, beta-blocker therapy was associated with a 64% reduced risk (HR, 0.36; 95% CI, 0.18-0.72; P<.01)., Conclusions: In LQTS, the timing and frequency of syncope, QTc prolongation, and sex were predictive of risk for aborted cardiac arrest and sudden cardiac death during adolescence. Among patients with recent syncope, beta-blocker treatment was associated with reduced risk.

Objectives: We evaluated the incremental prognostic information provided by multiple corrected QT (QTc) measurements on serial electrocardiograms (ECGs) in patients with the inherited long QT syndrome (LQTS)., Background: A baseline QTc of > or =500 ms has been shown to be associated with increased risk of cardiac events among LQTS patients. However, the value of QTc measurements on follow-up ECGs in risk assessment has not been determined., Methods: The risk of a first LQTS-related cardiac event during adolescence was assessed in 375 patients enrolled in the International LQTS Registry for whom serial follow-up ECGs were recorded before age 10., Results: The mean +/- SD difference between the minimum and maximum QTc values on serial ECGs recorded in study patients was 47 +/- 40 ms. The maximum QTc interval recorded before age 10 was the strongest predictor of cardiac events during adolescence (adjusted hazard ratio [HR] = 2.74; p < 0.001). Other follow-up QTc measures, including the baseline, the mean, and the most recent QTc interval recorded before age 10, were less significant risk factors. After adjusting for the maximum QTc value during follow-up, no significant association remained between the baseline QTc value and the risk of subsequent cardiac events (HR = 1.04; p = 0.91)., Conclusions: In LQTS patients, there is a considerable variability in QTc measures in serial follow-up ECGs. The maximum QTc interval provides incremental prognostic information beyond the baseline measurement. We suggest that risk stratification in LQTS patients should include follow-up ECG data.

Background: Previous studies have indicated that, compared with men, women are at increased risk for in-hospital mortality following percutaneous coronary intervention (PCI); however, angioplasty techniques and mortality rates have improved since earlier reports., Hypothesis: We sought to reevaluate and explore further the relationship between gender and angioplasty outcomes in contemporary "real world" practice., Methods: The influence of gender and other covariates on in-hospital mortality and other adverse events among all patients who underwent elective coronary angioplasty in New York State from 1999 to 2001 (n = 106,262) was examined., Results: In-hospital mortality rates for elective angioplasty were low; however, women demonstrated a two-fold mortality excess compared with men (0.6 vs. 0.3%, p < 0.0001). Women were older and more likely than men to demonstrate certain higher-risk features (heart failure, class III-IV angina, renal failure, vascular disease); however, men were more likely to have depressed ejection fraction, prior myocardial infarction, and prior coronary revascularization. Using multivariate analysis adjusting for clinical risk factors, gender remained an independent predictor of in-hospital mortality at all ages. Women were also more likely to experience nonfatal adverse events following PCI, including more frequent need for emergency bypass surgery., Conclusions: Despite improvements in angioplasty outcomes with time, women remain at significantly higher risk of in-hospital death than men after elective PCI. This increased mortality is observed in every age group, even after adjusting for other significant comorbidities.

Many of Meehl's interests converged in his work on personality assessment. In empirical research, development of the K scale of the Minnesota Multiphasic Personality Inventory and various scales of other tests are noteworthy, but his most profound contributions were conceptual and philosophical. Essays on the role of base rates in clinical decision and on construct validity in psychological tests provided vital insights on core issues in assessment. The concept of nomological nets allowed systematic investigation of unobservable theoretical entities, with liberating effects on all natural sciences. An active clinician, Meehl understood deeply the complexities of professional service, but his insistence on empirical validation as the ultimate arbiter of the value of any procedure required all attainable rigor in the scientific foundations of clinical practice.

Recent studies have described malignant stem cells as central to the initiation, growth, and potential relapse of acute and chronic myelogenous leukemia (AML and CML). Because of their important role in pathogenesis, rare and biologically distinct leukemia stem cells (LSCs) represent a critical target for therapeutic intervention. However, to date, very few agents have been shown to directly target the LSC population. The present studies demonstrate that parthenolide (PTL), a naturally occurring small molecule, induces robust apoptosis in primary human AML cells and blast crisis CML (bcCML) cells while sparing normal hematopoietic cells. Furthermore, analysis of progenitor cells using in vitro colony assays, as well as stem cells using the nonobese diabetic/severe combined immunodeficient (NOD/SCID) xenograft model, show that PTL also preferentially targets AML progenitor and stem cell populations. Notably, in comparison to the standard chemotherapy drug cytosine arabinoside (Ara-C), PTL is much more specific to leukemia cells. The molecular mechanism of PTL-mediated apoptosis is strongly associated with inhibition of nuclear factor kappa B (NF-kappaB), proapoptotic activation of p53, and increased reactive oxygen species (ROS). On the basis of these findings, we propose that the activity of PTL triggers LSC-specific apoptosis and as such represents a potentially important new class of drugs for LSC-targeted therapy.

A 12-week pilot project on physical activity was introduced in a day habilitation setting to a group of 12 older adults with intellectual disability and a variety of physical and behavioral conditions. Our purpose was to determine whether (a) this intervention would positively impact physical function in this population, (b) consumers would choose to participate in physical activity sessions, and (c) day habilitation staff could sustain this program beyond the intervention period. Findings indicate that 92% of participants experienced improvement in at least one domain of physical function, physical activity sessions remained a popular activity choice for consumers, and many participants sustained functional gains 1 year after habilitation staff assumed responsibility for sessions.

Objective: To develop and investigate the properties of three performance measures based on risk-adjusted health outcomes for a frail, elderly, community-dwelling population enrolled in a managed, acute, and long-term care program., Design: Retrospective analyses of an administrative dataset containing individual level records with information about socioeconomics, health, functional and cognitive status, diagnoses, and treatments. We estimated risk-adjustment models predicting mortality, decline in functional status, and decline in self-assessed health. Each model includes individual risk factors and indicator variables for the program site in which the individual enrolled. Sites were ranked based on their performance in each risk-adjusted outcome, and the properties of these performance measures were investigated., Setting: Twenty-eight sites of the Program of All-Inclusive Care for the Elderly (PACE) that provide primary, acute, and long-term care services under capitated Medicare and Medicaid payment to a nursing home certifiable, and functionally and cognitively frail community-dwelling elderly population., Study Participants: Three thousand one hundred and thirty-eight individuals who were newly enrolled between 1 January 1998 and 31 December 1999. The average age of these enrollees was 78 years, 27% were male, 50% were diagnosed with dementia, and they had approximately 4 Activities of Daily Living limitations and 7.4 Instrumental Activities of Daily Living limitations., Main Outcome Measures: Risk-adjustment models, performance ranking for each site, and correlations between performance rankings., Results: We present risk-adjustment models for mortality, change in functional status, and self-assessed health status. We found substantial variation across sites in performance, but no correlation between performance with respect to different outcomes., Conclusions: The variations in outcomes suggest that sites can improve their performance by learning from the practices of those with the best outcomes. Further research is required to identify processes of care that lead to best outcomes.

It has been assumed that force enhancement in single fibres of skeletal muscles only occurs on the descending, and not the ascending or plateau region, of the force-length relationship. This assumption has been based, however, on theoretical considerations or isolated experiments, in which neither stretch conditions nor fibre lengths were optimized for force enhancement. Therefore, the purpose of this study was to investigate the residual, steady-state force enhancement following active stretch in single muscle fibres of frog on the ascending limb of the force-length relationship. Twenty-nine stretch experiments on ten single fibres from the lumbrical muscle of the frog Rana pipiens were carried out on the ascending limb of the force-length relationship. Force enhancement was observed in 28 out of the 29 tests. Moreover, the force produced for stretch experiments finishing at optimal fibre length always exceeded the force obtained for an isometric contraction at optimal length. We conclude from these results that steady-state force enhancement occurs systematically on the ascending limb of the force-length relationship, and that the steady-state force in the enhanced state can easily exceed the maximal isometric force of the fibre.

Vanishing white matter disease (VWM) is a progressive cavitating disease of central white matter due to a deficiency of the translation initiation factor eIF2B. Oligodendrocytes appear to be numerically increased in some white matter areas, while decreased in others. We compared oligodendrocytes of cerebral, cerebellar, and pontine white matter from 5 VWM patients with those of age-matched controls by light microscopy and immunohistochemistry using antibodies to activated caspase-3, bak, bax, bcl-2, survivin, and Ki-67, as well as by the TUNEL technique. Oligodendrocytes were identified morphologically and quantified using an ocular grid. We observed statistically significant increases in their densities at all sites; Ki-67-labeled oligodendrocytes were identified in 2 of 5 patients. Apoptotic oligodendrocytes were documented in 3 of 5 patients, while bcl-2 and survivin labeling was observed in 2 of 5 and 2 of 2 patients, respectively. There was a trend toward an increase in apoptotic labeling of oligodendrocytes that was strongest in the cerebrum, the major locus of VWM, in the youngest and most severely affected patients. These data conclusively demonstrate increased oligodendrocytic densities in VWM; the increase is not an artifact of white matter contraction. Our data also document that oligodendrocytes undergo apoptosis, perhaps in conjunction with major neurologic crises, and that a subset of oligodendrocytes are able to persist and proliferate. Conflicting proliferative, cell-death, and survival signals impact the oligodendrocytes of VWM.

Thiol chemoprotective agents can reduce chemotherapy side effects, but clinical use is limited due to concerns of impaired chemotherapeutic efficacy. We evaluated whether an optimized bone marrow chemoprotection regimen impaired the efficacy of enhanced chemotherapy against rat brain tumors. Nude rats with intracerebral human lung carcinoma xenografts were treated with carboplatin, melphalan, and etoposide phosphate delivered intra-arterially with osmotic blood-brain barrier disruption (n = 8/group). Thiol chemoprotection was N-acetyl-L-cysteine (1000 mg/kg) 60 min before chemotherapy and/or sodium thiosulfate (8 g/m(2)) 4 and 8 h after chemotherapy, when the blood-brain barrier is reestablished. Blood counts were obtained before treatment on day 3 and at sacrifice on day 9. N-acetylcysteine serum clearance half-life was 9 to 11 min. Pretreatment with N-acetylcysteine combined with delayed administration of sodium thiosulfate protected against toxicity toward total white cells, granulocytes, and platelets (P = 0.0016). Enhanced chemotherapy reduced intracerebral tumor volume to 4.3 +/- 1.0 mm(3) compared with 29.1 +/- 4.1 mm(3) in untreated animals (P < 0.0001). Tumor volume was 3.7 +/- 0.6 mm(3) in rats that received N-acetylcysteine before and sodium thiosulfate after chemotherapy. The data indicate the efficacy of enhanced chemotherapy for rat brain tumors was not affected by thiol chemoprotection that provided excellent protection for hematological toxicity. Negative interactions of thiols with antitumor efficacy were avoided by temporal and spatial separation of chemoprotectants and chemotherapy.

Risk factors for severe respiratory syncytial virus (RSV) infection were determined in 3 cohorts of adults during 2 consecutive winters (1999-2000 and 2000-2001) in Rochester, New York. Community-dwelling healthy persons > or =65 years old and persons >21 years old who had underlying symptomatic cardiopulmonary conditions were prospectively evaluated for RSV infection. Evidence of infection was also sought in persons who were > or =65 years old or had underlying cardiopulmonary disease and who were hospitalized with acute respiratory symptoms. Sixty-nine RSV infections were identified by culture, reverse-transcription polymerase chain reaction, or serologic testing in the prospective groups, and 61 were identified in the hospitalized group. The presence of underlying chronic pulmonary disease (odds ratio [OR], 3.97), functional disability (OR, 1.67/integer increase in Instruments of Activities of Daily Living score), and low serum neutralizing antibody titer (OR, 5.89) were each independently associated with increased risk of severe disease, defined as "hospitalization with RSV infection." These data suggest that the induction of neutralizing serum antibody with an RSV vaccine may potentially reduce disease severity in adult populations.

We consider the general problem of smoothing correlated data to estimate the nonparametric mean function when a random, but bounded, number of measurements is available for each independent subject. We propose a simple extension to the local polynomial regression smoother that retains the asymptotic properties of the working independence estimator, while typically reducing both the conditional bias and variance for practical sample sizes, as demonstrated by exact calculations for some particular models. We illustrate our method by smoothing longitudinal functional decline data for 100 patients with Huntington's disease. The class of local polynomial kernel-based estimating equations previously considered in the literature is shown to use the global correlation structure in an apparently detrimental way, which explains why some previous attempts to incorporate correlation were found to be asymptotically inferior to the working independence estimator.

Increasing professionalization of psychology, accelerated by expansion of professional schools, has evoked concern among critics, who claim that many practitioners ignore scientific research and engage in practices that are demonstrably useless or harmful. Recent data on admissions to professional schools and performance of professional school graduates show cause for concerns of the critics. If psychology is to maintain its stature as a profession, exclusionary controls as well as hortatory requirements for the practice of psychology and the education of practitioners must be established and enforced. Before more stringent standards can be imposed, convincing means for evaluating competence in professional work and quality in professional education must be developed. Local and institutional actions to advance those aims are proposed.

Objectives: We aimed to determine whether long QT syndrome (LQTS) genotype has a differential effect on clinical course of disease in male and female children and adults after adjustment for QTc duration., Background: Genotype influences clinical course of the LQTS; however, data on the effect of age and gender on this association are limited., Methods: The LQTS genotype, QTc duration, and follow-up were determined in 243 cases of LQTS caused by the KCNQ1 potassium channel gene mutations (LQT1), 209 cases of LQTS caused by the HERG potassium channel gene mutations (LQT2), and 81 cases of LQTS caused by the SCN5A sodium channel gene mutation (LQT3) gene carriers. The probability of cardiac events (syncope, aborted cardiac arrest, or sudden death) was analyzed by genotype, gender, and age (children < or = 15 years and adults 16 to 40 years). In addition, the risk of sudden death and lethality of cardiac events were evaluated in 1,075 LQT1, 976 LQT2, and 324 LQT3 family members from families with known genotype., Results: During childhood, the risk of cardiac events was significantly higher in LQT1 males than in LQT1 females (hazard ratio [HR] = 1.72), whereas there was no significant gender-related difference in the risk of cardiac events among LQT2 and LQT3 carriers. During adulthood, LQT2 females (HR = 3.71) and LQT1 females (HR = 3.35) had a significantly higher risk of cardiac events than respective males. The lethality of cardiac events was highest in LQT3 males and females (19% and 18%), and higher in LQT1 and LQT2 males (5% and 6%) than in LQT1 and LQT2 females (2% for both). CONCLUSIONS; Age and gender have different, genotype-specific modulating effects on the probability of cardiac events and electrocardiographic presentation in LQT1 and LQT2 patients.

Brain capillary endothelial cells form the blood-brain barrier. They are connected by extensive tight junctions, and are polarized into luminal (blood-facing) and abluminal (brain-facing) plasma membrane domains. The polar distribution of transport proteins allows for active regulation of brain extracellular fluid. Experiments on isolated membrane vesicles from capillary endothelial cells of bovine brain demonstrated the polar arrangement of amino acid and glucose transporters, and the utility of such arrangements have been proposed. For instance, passive carriers for glutamine and glutamate have been found only in the luminal membrane of blood-brain barrier cells, while Na-dependent secondary active transporters are at the abluminal membrane. This organization could promote the net removal of nitrogen-rich amino acids from brain, and account for the low level of glutamate penetration into the central nervous system. Furthermore, the presence of a gamma-glutamyl cycle at the luminal membrane and Na-dependent amino acid transporters at the abluminal membrane may serve to modulate movement of amino acids from blood-to-brain. Passive carriers facilitate amino acid transport into brain. However, activation of the gamma-glutamyl cycle by increased plasma amino acids is expected to generate oxoproline within the blood-brain barrier. Oxoproline stimulates secondary active amino acid transporters (Systems A and B(o)+) at the abluminal membrane, thereby reducing net influx of amino acids to brain. Finally, passive glucose transporters are present in both the luminal and abluminal membranes of the blood-brain barrier. Interestingly, a high affinity Na-dependent glucose carrier has been described only in the abluminal membrane. This raises the question whether glucose entry may be regulated to some extent. Immunoblotting studies suggest more than one type of passive glucose transporter exist in the blood-brain barrier, each with an asymmetrical distribution. In conclusion, it is now clear that the blood-brain barrier participates in the active regulation of brain extracellular fluid, and that the diverse functions of each plasma membrane domain contributes to these regulatory functions.

Experimental data are presented for 11 C8-C15 aliphatic alcohols and 12 phthalate and adipate diesters using a slow-stir water solubility test method. The slow stirring method provides more reliable water solubility measurements for these liquid substances than previous studies since the formation of emulsions is avoided. Because the solubility of these chemicals spanned a range of more than six orders of magnitude, several different analytical procedures were employed. The water solubility data reported in this work agree well with other recently reported slow-stir measurements and with structure-property model predictions (SPARC and WSKOWWIN).

The November 2000 NIH report of the Brain Tumor Progress Review Group identified delivering and targeting therapeutic agents as a priority in the treatment of malignant brain tumors. For this reason, the seventh annual Blood-Brain Barrier Disruption Consortium meeting, partially funded by an NIH R13 Grant, focused on recent advances in targeted delivery to the central nervous system, clinical trials for primary and metastatic brain tumors using enhanced chemotherapy delivery, and strategies to lessen the toxicities associated with dose intensive treatments, using thiols.

Background: The hereditary long-QT syndrome is characterized by prolonged ventricular repolarization and a variable clinical course with arrhythmia-related syncope and sudden death. Mutations involving the human ether-a-go-go-related gene (HERG) channel are responsible for the LQT2 form of long-QT syndrome, and in cellular expression studies these mutations are associated with reduction in the rapid component of the delayed rectifier repolarizing current (I(Kr)). We investigated the clinical features and prognostic implications of mutations involving pore and nonpore regions of the HERG channel in the LQT2 form of this disorder., Methods and Results: A total of 44 different HERG mutations were identified in 201 subjects, with 14 mutations located in the pore region (amino acid residues 550 through 650). Thirty-five subjects had mutations in the pore region and 166 in nonpore regions. Follow-up extended through age 40 years. Subjects with pore mutations had more severe clinical manifestations of the genetic disorder and experienced a higher frequency (74% versus 35%; P<0.001) of arrhythmia-related cardiac events occurring at earlier age than did subjects with nonpore mutations. Multivariate Cox proportional hazard regression analysis revealed that pore mutations dominated the risk, with hazard ratios in the range of 11 (P<0.0001) for QTc at 500 ms, with a 16% increase in the pore hazard ratio for each 10-ms increase in QTc., Conclusion: Patients with mutations in the pore region of the HERG gene are at markedly increased risk for arrhythmia-related cardiac events compared with patients with nonpore mutations.

Mechanical loading of bone may be transmitted to osteocytes and osteoblasts via shear stresses at cell surfaces generated by the flow of interstitial fluid. The stimulated production of prostaglandins, which mediates some effects of mechanical loading on bone, is dependent on inducible cyclo-oxygenase 2 (COX-2) in bone cells. We examined the fluid shear stress (FSS) induction of COX-2 gene expression in immortalized MC3T3-E1 osteoblastic cells stably transfected with -371/+70 base pairs (bp) of the COX-2 5'-flanking DNA (Pluc371) and in primary osteoblasts (POBs) from calvaria of mice transgenic for Pluc371. Cells were plated on collagen-coated glass slides and subjected to steady laminar FSS in a parallel plate flow chamber. FSS, from 0.14 to 10 dynes/cm2, induced COX-2 messenger RNA (mRNA) and protein. FSS (10 dynes/cm2) induced COX-2 mRNA within 30 minutes, with peak effects at 4 h in MC3T3-E1 cells and at > or = 8 h in POBs. An inhibitor of new protein synthesis puromycin blocked the peak induction of COX-2 mRNA by FSS. COX-2 promoter activity, measured as luciferase activity, correlated with COX-2 mRNA expression in both MC3T3-E1 and POB cells. FSS induced phosphorylation of extracellular signal-regulated kinase (ERK) in MC3T3-E1 cells, with peak effects at 5 minutes. Inhibiting ERK phosphorylation with the specific inhibitor PD98059 inhibited FSS induction of COX-2 mRNA by 55-70% and FSS stimulation of luciferase activity by > or = 80% in both MC3T3-E1 and POB cells. We conclude that FSS transcriptionally induces COX-2 gene expression in osteoblasts, that the maximum induction requires new protein synthesis, and that induction occurs largely via an ERK signaling pathway.

Monitoring and laboratory data play integral roles alongside fate and exposure models in comprehensive risk assessments. The principle in the European Union Technical Guidance Documents for risk assessment is that measured data may take precedence over model results but only after they are judged to be of adequate reliability and to be representative of the particular environmental compartments to which they are applied. In practice, laboratory and field data are used to provide parameters for the models, while monitoring data are used to validate the models' predictions. Thus, comprehensive risk assessments require the integration of laboratory and monitoring data with the model predictions. However, this interplay is often overlooked. Discrepancies between the results of models and monitoring should be investigated in terms of the representativeness of both. Certainly, in the context of the EU risk assessment of existing chemicals, the specific requirements for monitoring data have not been adequately addressed. The resources required for environmental monitoring, both in terms of manpower and equipment, can be very significant. The design of monitoring programmes to optimise the use of resources and the use of models as a cost-effective alternative are increasing in importance. Generic considerations and criteria for the design of new monitoring programmes to generate representative quality data for the aquatic compartment are outlined and the criteria for the use of existing data are discussed. In particular, there is a need to improve the accessibility to data sets, to standardise the data sets, to promote communication and harmonisation of programmes and to incorporate the flexibility to change monitoring protocols to amend the chemicals under investigation in line with changing needs and priorities.

Objective: To outline from a carer's/family's perspective the ethical concerns raised by research into screening for factors in people at risk of schizophrenia., Method: The need for families and carers of people with schizophrenia to seek a voice in the ethics of research into schizophrenia prevention is described. The possibility that societal myths, literature and language have created sustained ignorance about psychotic illnesses, resulting in fear and/or prejudice, is considered. The impact of these factors greatly exacerbating the burden of schizophrenia for sufferers and their families is discussed., Results: There is evidence that people with schizophrenia share the disadvantages of other disempowered minorities. It is necessary for ethical constraints to be cognisant of this; research should include critically exploring reasons for attempting to eliminate the condition., Conclusions: Development of an ethical framework for prevention research into schizophrenia should include carer/family input. From a carer/family perspective, research into schizophrenia should be directed at ameliorating the effects of the illness by advancing methods of early diagnosis and by finding suitable treatments that do not carry punitive side-effects, thus allowing people with the illness to reach their potential in all aspects of their lives. Therapeutic relief combined with the elimination of social ostracism would greatly benefit people with schizophrenia and their families.