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The usage and disposal of highly abundant single-use and multilayered plastics contribute to significant ecological problems. The thermochemical recovery of these plastics to useful products and chemicals provides opportunity for positive economic and environmental impacts. Most previous research use idealised and unrepresentative feedstocks. To address this, various mixed waste plastics collected from the rejected fraction of a municipal waste recovery facility in Ghana were pyrolyzed at varying temperatures of 450, 500 and 550 °C and their yields compared. The obtained chemical products were analysed using several different techniques. Energy and carbon balances of the processes were produced using the CHNS and energy content of the oil fraction and the compositional results of the pyrolysis gas fraction, the latter of which was measured by Gas Chromatography Thermal Conductivity Detection (GC-TCD). The oils were further assessed via Gas Chromatography Mass Spectrometry (GC-MS) to identify the available valuable compounds. The formed oil contained approximately 40% light hydrocarbons (C6 - C11), 18% middle hydrocarbons (C11 - C16) and 42% heavy hydrocarbon compounds (C16+). The optimal oil yield of 65.9 ± 0.5% and low heating value of 44.7 ± 0.1 MJ/kg for single-use plastics were recorded at highest heating temperatures of 550 and 500 °C, respectively. The findings provide indication that pyrolysis is a fitting solution for energy recovery from waste plastics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Bacteremia refers to the presence of bacteria in the bloodstream, which can lead to a serious and potentially life-threatening condition. In oncology patients, individuals undergoing cancer treatment have a higher risk of developing bacteremia due to a weakened immune system resulting from the disease itself or the treatments they receive. Prompt and accurate detection of bacterial infections and monitoring the effectiveness of antibiotic therapy are essential for enhancing patient outcomes and preventing the development and dissemination of multidrug-resistant bacteria. Traditional methods of infection monitoring, such as blood cultures and clinical observations, are time-consuming, labor-intensive, and often subject to limitations. This manuscript presents an innovative application of infrared spectroscopy of leucocytes of pediatric oncology patients with bacteremia combined with machine learning to diagnose the etiology of infection as bacterial and simultaneously monitor the efficacy of the antibiotic therapy in febrile pediatric oncology patients with bacteremia infections. Through the implementation of effective monitoring, it becomes possible to promptly identify any indications of treatment failure. This, in turn, indirectly serves to limit the progression of antibiotic resistance. The logistic regression (LR) classifier was able to differentiate the samples as bacterial or control within an hour, after receiving the blood samples with a success rate of over 95 %. Additionally, initial findings indicate that employing infrared spectroscopy of white blood cells (WBCs) along with machine learning is viable for monitoring the success of antibiotic therapy. Our follow up results demonstrate an accuracy of 87.5 % in assessing the effectiveness of the antibiotic treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Infantile neuroaxonal dystrophy (INAD) is a rare neurodegenerative disease caused mainly by homozygous or compound heterozygous mutations in the PLA2G6 gene. We generated a human induced pluripotent stem cell (hiPSC) line (ONHi001-A) using fibroblasts derived from a patient with INAD. The patient exhibited c.517C > T (p.Q173X) and c.1634A > G (p.K545R) compound heterozygous mutations in the PLA2G6 gene. This hiPSC line may be useful for studying the pathogenic mechanism underlying INAD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive accumulation of α-synuclein aggregates in form of Lewy bodies. Genome-wide association studies have revealed that human leukocyte antigen (HLA) class II is a PD-associated gene, although the mechanisms linking HLA class II and PD remain elusive. Here, we identified a novel function of HLA class II in the transport of intracellular α-synuclein to the outside of cells. HLA class II molecules and α-synuclein formed complexes and moved to the cell surface at various degrees among HLA-DR alleles. HLA-DR with a DRB5∗01:01 allele, a putative PD-risk allele, substantially translocated normal and conformationally abnormal α-synuclein to the cell surface and extracellular vesicles. α-Synuclein/HLA class II complexes were found in A2058 melanoma cells, which express intrinsic α-synuclein and HLA-DR with DRB5∗01:01. Our findings will expand our knowledge of unconventional HLA class II function from autoimmune diseases to neurodegenerative disorders, shedding light on the association between the GWAS-prioritized PD-risk gene HLA-DR and α-synuclein., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Post-operative pancreatic fistula (POPF) is the most significant cause of morbidity following distal pancreatectomy. Hemopatch™ is a thin, bovine collagen-based hemostatic sealant. We hypothesized that application of Hemopatch™ to the pancreatic stump following distal pancreatectomy would decrease the incidence of clinically-significant POPF., Methods: We conducted a prospective, single-arm, multicentre phase II study of application of Hemopatch™ to the pancreatic stump following distal pancreatectomy. The primary outcome was clinically-significant POPF within 90 days of surgery. A sample size of 52 patients was required to demonstrate a 50% relative reduction in Grade B/C POPF from a baseline incidence of 20%, with a type I error of 0.2 and power of 0.75. Secondary outcomes included incidence of POPF (all grades), 90-day mortality, 90-day morbidity, re-interventions, and length of stay., Results: Adequate fixation Hemopatch™ to the pancreatic stump was successful in all cases. The rate of grade B/C POPF was 25% (95%CI: 14.0-39.0%). There was no significant difference in the incidence of grade B/C POPF compared to the historical baseline (p = 0.46). The 90-day incidence of Clavien-Dindo grade ≥3 complications was 26.9% (95%CI: 15.6-41.0%)., Conclusion: The use of Hemopatch™ was not associated with a decreased incidence of clinically-significant POPF compared to historical rates. (NCT03410914)., (Copyright © 2021 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

KDIGO guidelines recommend dietary phosphate restriction to lower serum phosphate levels in CKD stages 3-5. Recent studies suggest that dietary phosphate intake is only weakly linked to its serum concentration, and the relationship of phosphate intake with adverse outcomes is uncertain. To evaluate this, we used Cox proportional hazards models to assess associations of baseline 24-h urine phosphate excretion with risk of end-stage renal disease (ESRD), all-cause mortality, and mortality subtypes (cardiovascular disease [CVD] and non-CVD) using the Modification of Diet in Renal Disease data. Models were adjusted for demographics, CVD risk factors, iothalamate GFR, and urine protein and nitrogen excretion. Phosphate excretion was modestly inversely correlated with serum phosphate concentrations. There was no association of 24-h urinary phosphate excretion with risk of ESRD, CVD, non-CVD, or all-cause mortality. For comparison, higher serum phosphate concentrations were associated with all-cause mortality (hazard ratio per 0.7 mg/dl higher, 1.15 [95% CI 1.01, 1.30]). Thus, phosphate intake is not tightly linked with serum phosphate concentrations in CKD stages 3-5, and there was no evidence that greater phosphate intake, assessed by 24-h phosphate excretion, is associated with ESRD, CVD, non-CVD, or all-cause mortality in CKD stages 3-5. Hence, factors other than dietary intake may be key determinants of serum phosphate concentrations and require additional investigation., (Copyright © 2015 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Numerous treatments are available that address the core symptoms of posttraumatic stress disorder (PTSD). However, there are a number of related behavioral stress responses that are not assessed with PTSD measures, yet these behavioral stress responses affect quality of life. The goal of the current study was to investigate whether a recently developed measure of behavioral stress response, the Driving Behavior Survey (DBS), was sensitive to change associated with treatment among a group of participants diagnosed with PTSD. The DBS indexes anxious driving behavior, which is frequently observed among individuals with motor vehicle accident-related PTSD. Participants (n = 40) were racially diverse adults (M age = 40.78, 63% women) who met diagnostic criteria for motor vehicle accident-related PTSD. Hierarchical linear modeling analyses indicated that participants who were assigned to a brief, exposure-based intervention displayed significant reductions on the DBS subscales relative to participants assigned to the wait-list control condition (r = .41–.43). Moreover, mediational analyses indicated that the observed reductions on the DBS subscales were not better accounted for by reductions in PTSD. Taken together, these findings suggest that the DBS subscales are sensitive to changes associated with PTSD treatment and can be used to augment outcome assessment in PTSD treatment trials.

The mononuclear phagocyte system comprises cells as diverse as monocytes, macrophages, and dendritic cells (DCs), which collectively play key roles in innate immune responses and the triggering of adaptive immunity. Recent studies have highlighted the role of growth and transcription factors in defining developmental pathways and lineage relations within this cellular compartment. However, contributions of miRNAs to the development of mononuclear phagocytes remain largely unknown. In the present study, we report a comprehensive map of miRNA expression profiles for distinct myeloid populations, including BM-resident progenitors, monocytes, and mature splenic DCs. Each of the analyzed cell populations displayed a distinctive miRNA profile, suggesting a role for miRNAs in defining myeloid cell identities. Focusing on DC development, we found miR-142 to be highly expressed in classic FLT3-L–dependent CD4+ DCs, whereas reduced expression was observed in closely related CD8α+ or CD4- CD8α- DCs. Moreover, mice deficient for miR-142 displayed an impairment of CD4+ DC homeostasis both in vitro and in vivo. Furthermore, loss of miR-142–dependent CD4+ DCs was accompanied by a severe and specific defect in the priming of CD4+ T cells. The results of our study establish a novel role for miRNAs in myeloid cell specification and define miR-142 as a pivotal genetic component in the maintenance of CD4+ DCs.

Prior small studies have shown multiple benefits of frequent nocturnal hemodialysis compared to conventional three times per week treatments. To study this further, we randomized 87 patients to three times per week conventional hemodialysis or to nocturnal hemodialysis six times per week, all with single-use high-flux dialyzers. The 45 patients in the frequent nocturnal arm had a 1.82-fold higher mean weekly stdKt/V(urea), a 1.74-fold higher average number of treatments per week, and a 2.45-fold higher average weekly treatment time than the 42 patients in the conventional arm. We did not find a significant effect of nocturnal hemodialysis for either of the two coprimary outcomes (death or left ventricular mass (measured by MRI) with a hazard ratio of 0.68, or of death or RAND Physical Health Composite with a hazard ratio of 0.91). Possible explanations for the left ventricular mass result include limited sample size and patient characteristics. Secondary outcomes included cognitive performance, self-reported depression, laboratory markers of nutrition, mineral metabolism and anemia, blood pressure and rates of hospitalization, and vascular access interventions. Patients in the nocturnal arm had improved control of hyperphosphatemia and hypertension, but no significant benefit among the other main secondary outcomes. There was a trend for increased vascular access events in the nocturnal arm. Thus, we were unable to demonstrate a definitive benefit of more frequent nocturnal hemodialysis for either coprimary outcome.

We studied here the independent associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality and end-stage renal disease (ESRD) in individuals with chronic kidney disease (CKD). We performed a collaborative meta-analysis of 13 studies totaling 21,688 patients selected for CKD of diverse etiology. After adjustment for potential confounders and albuminuria, we found that a 15 ml/min per 1.73 m² lower eGFR below a threshold of 45 ml/min per 1.73 m² was significantly associated with mortality and ESRD (pooled hazard ratios (HRs) of 1.47 and 6.24, respectively). There was significant heterogeneity between studies for both HR estimates. After adjustment for risk factors and eGFR, an eightfold higher albumin- or protein-to-creatinine ratio was significantly associated with mortality (pooled HR 1.40) without evidence of significant heterogeneity and with ESRD (pooled HR 3.04), with significant heterogeneity between HR estimates. Lower eGFR and more severe albuminuria independently predict mortality and ESRD among individuals selected for CKD, with the associations stronger for ESRD than for mortality. Thus, these relationships are consistent with CKD stage classifications based on eGFR and suggest that albuminuria provides additional prognostic information among individuals with CKD.

Because the vagus nerve is implicated in control of inflammation, we investigated if brain death (BD) causes impairment of the parasympathetic nervous system, thereby contributing to inflammation. BD was induced in rats. Anaesthetised ventilated rats (NBD) served as control. Heart rate variability (HRV) was assessed by ECG. The vagus nerve was electrically stimulated (BD + STIM) during BD. Intestine, kidney, heart and liver were recovered after 6 hours. Affymetrix chip-analysis was performed on intestinal RNA. Quantitative PCR was performed on all organs. Serum was collected to assess TNFalpha concentrations. Renal transplantations were performed to address the influence of vagus nerve stimulation on graft outcome. HRV was significantly lower in BD animals. Vagus nerve stimulation inhibited the increase in serum TNFalpha concentrations and resulted in down-regulation of a multiplicity of pro-inflammatory genes in intestinal tissue. In renal tissue vagal stimulation significantly decreased the expression of E-selectin, IL1beta and ITGA6. Renal function was significantly better in recipients that received a graft from a BD + STIM donor. Our study demonstrates impairment of the parasympathetic nervous system during BD and inhibition of serum TNFalpha through vagal stimulation. Vagus nerve stimulation variably affected gene expression in donor organs and improved renal function in recipients.

We report on a 27-year-old man with Fabry disease who had widespread white-matter lesions (WMLs) despite the absence of renal or cardiac manifestations. Genomic analysis revealed a novel mutation: a GAT deletion at nucleotide position 234-236 in exon 5 of the coding region. After 12 months of enzyme replacement therapy (ERT), most of the WMLs had disappeared. Cell counts and protein levels in the cerebrospinal fluid also decreased. These findings suggest that ERT may play a role in the recovery of WMLs.

Background: Data on the effects of long-term treatment with azithromycin (AZM) on inflammatory markers in cystic fibrosis patients chronically infected with Pseudomonas aeruginosa are scarce. So far there is no pharmacokinetic and clinical data on once-weekly dosage of AZM in CF patients., Methods: In a randomised double-blind, placebo-controlled trial, patients received AZM or placebo 1 per week for 8 weeks (AZM dosage--20-29 kg: 500 mg, 30-39 kg: 750 mg, 40-49 kg: 1000 mg and > or = 50 kg: 1250 mg) after a course of intravenous antipseudomonal antibiotics. Pulmonary function tests, the serum markers LPS-binding protein (LBP), interleukin-8 (IL-8), CRP, P. aeruginosa alginate in sputum samples and quality of life scores were evaluated., Results: Thirty-eight patients (21 AZM/17 placebo) (mean age: 23.7 years; mean FEV(1): 62% of predicted) were recruited. After treatment (mean dose of 21.2 mg/kg body weight once a week) pulmonary function declined in both groups compared to baseline (i.e. after cessation of i.v. antibiotics). The AZM group was significantly better for mean changes in serum CRP (AZM: +0.9 mg/l, placebo: +21.6 mg/l, p=0.019), lipopolysaccharide binding protein in serum, LBP (AZM: +0.9 microg/ml, placebo: +7.0 microg/ml, p=0.015), serum interleukin-8 (AZM: -3.1 pg/ml, placebo: +2.9 pg/ml, p=0.001) and alginate in sputum (AZM: +85 microg/ml, placebo: +353 microg/ml, p=0.048). Quality of life was significantly better after AZM and there was no increase in treatment-related adverse events., Conclusion: Once-weekly azithromycin ameliorated inflammatory reactions and improved quality of life. A decline of pulmonary function after cessation of i.v. antibiotics could not be prevented.

The Modification of Diet in Renal Disease (MDRD) Study examined the effects of strict blood pressure control and dietary protein restriction on the progression of kidney disease. Here, we retrospectively evaluated outcomes of nondiabetic participants with stages 2-4 chronic kidney disease (CKD) from randomized and nonrandomized cohorts of the MDRD Study. Kidney failure and survival status through December of 2000, were obtained from the US Renal Data System and the National Death Index. Event rates were calculated for kidney failure, death, and a composite outcome of death and kidney failure. In the 1666 patients, rates for kidney failure were four times higher than that for death. Kidney failure was a more likely event than death in subgroups based on baseline glomerular filtration rate, proteinuria, kidney disease etiology, gender, and race. It was only among those older than 65 that the rate for death approximated that for kidney failure. In contrast to other populations with CKD, our study of relatively young subjects with nondiabetic disease has found that the majority of the participants advanced to kidney failure with a low competing risk of death. In such patients, the primary emphasis should be on delaying progression of kidney disease.

Background: In 1997, the National Heart, Lung, and Blood Institute of the National Institutes of Health established a Registry to better characterize the demographic, clinical, physiologic and radiographic features of patients with lymphangioleiomyomatosis (LAM). Herein we report data collected at enrollment from patients who had either undergone transplant prior to enrollment, underwent transplant during the 5-year study, or were evaluated/wait-listed for lung transplant during the 5-year study., Methods: The LAM Registry enrolled patients from six clinical centers between August 1998 and October 2001. On entry, patients filled-out questionnaires covering their medical history, symptoms, treatment and quality of life (SF-36 and St. George's Respiratory Questionnaire). Enrollees underwent blood laboratory work and testing for arterial blood gases and pulmonary function. Follow-up was done at 6-month and/or yearly intervals. Diagnoses were confirmed by biopsy or typical clinical presentation plus computerized tomography (CT) findings confirmed by independent expert radiologists. A total of 243 women were enrolled. Of these, 13 (5.3%) had been transplanted at time of entry (Group A), 21 (8.6%) were transplanted during the study (Group B), and 48 (19.8%) were either wait-listed for transplant or underwent evaluation after enrollment during the study period (Group C). The remaining 161 (66.3%) registrants were neither considered for nor listed for transplant during the Registry period (Group D)., Results: One-third of patients in a large sample of LAM patients had either been transplanted or were being considered for transplant. At enrollment, patients who had already been transplanted and those not in need of transplant (Groups A and D) had better pulmonary function and quality-of-life scores compared with patients who subsequently underwent lung transplant during the Registry period (Group B)., Conclusions: In this large Registry of LAM patients, lung transplantation appears to be associated both with significantly improved lung function and quality of life compared with patients with advanced disease.

Fetuin-A is a serum protein that inhibits vascular calcification such that lower levels are associated with a higher prevalence of vascular calcification and mortality risk among end-stage renal disease populations. We analyzed data of 822 persons in the Modification of Diet in Renal Disease study, a randomized, controlled trial of persons with predominantly non-diabetic stage 3-4 chronic kidney disease (CKD). Serum fetuin-A levels were measured in baseline serum. Survival status and cause of death were determined by the National Death Index. Cox proportional hazard models evaluated the association of fetuin-A levels with all-cause and cardiovascular mortality. Glomerular filtration ranged from 13 to 55 ml per min per 1.73 m(2). During a median follow-up of 9.5 years, 25% of persons died from any cause and 12% died from a cardiovascular cause. Compared to the lowest tertile, no association was found between the highest fetuin-A tertile and all-cause or cardiovascular mortality. Similarly, no association was found between fetuin-A as a continuous variable and all-cause or cardiovascular mortality. Our study shows that serum fetuin-A levels are not related to all-cause or cardiovascular mortality among persons with predominantly non-diabetic stage 3 or 4 CKD.

Observational studies suggest improvements with frequent hemodialysis (HD), but its true efficacy and safety remain uncertain. The Frequent Hemodialysis Network Trials Group is conducting two multicenter randomized trials of 250 subjects each, comparing conventional three times weekly HD with (1) in-center daily HD and (2) home nocturnal HD. Daily HD will be delivered for 1.5-2.75 h, 6 days/week, with target eK(t)/V(n) > or = 0.9/session, whereas nocturnal HD will be delivered for > or = 6 h, 6 nights/week, with target stdK(t)/V of > or = 4.0/week. Subjects will be followed for 1 year. The composite of mortality with the 12-month change in (i) left ventricular mass index (LVMI) by magnetic resonance imaging, and (ii) SF-36 RAND Physical Health Composite (PHC) are specified as co-primary outcomes. The seven main secondary outcomes are between group comparisons of: change in LVMI, change in PHC, change in Beck Depression Inventory score, change in Trail Making Test B score, change in pre-HD serum albumin, change in pre-HD serum phosphorus, and rates of non-access hospitalization or death. Changes in blood pressure and erythropoiesis will also be assessed. Safety outcomes will focus on vascular access complications and burden of treatment. Data will be obtained on the cost of delivering frequent HD compared to conventional HD. Efforts will be made to reduce bias, including blinding assessment of subjective outcomes. Because no large-scale randomized trials of frequent HD have been previously conducted, the first year has been designated a Vanguard Phase, during which feasibility of randomization, ability to deliver the interventions, and adherence will be evaluated.

Treatment of rat glomerular mesangial cell (GMC) cultures with pancreatic secreted phospholipase A(2) (sPLA(2)-IB) results in an enhanced expression of sPLA(2)-IIA and COX-2, possibly via binding to its specific M-type sPLA(2) receptor. In the current study, we have investigated the expression and regulation of sPLA(2)-IB and its receptor during glomerulonephritis (GN). In vivo we used the well-established rat model of anti-Thy 1.1 GN (anti-Thy 1.1-GN) to study the expression of sPLA(2)-IB and the M-type sPLA(2) receptor by immunohistochemistry. In addition, in vitro we determined the interkeukin (IL)-1beta-regulated mRNA and protein expression in primary rat glomerular mesangial and endothelial cells as well as in rat peripheral blood leukocytes (PBLs). Shortly after induction of anti-Thy 1.1-GN, sPLA(2)-IB expression was markedly upregulated in the kidney at 6-24 h. Within glomeruli, the strongest sPLA(2)-IB protein expression was detected on infiltrated granulocytes and monocytes. However, at the same time, the M-type receptor was also markedly upregulated on resident glomerular cells. In vitro, the most prominent cytokine-stimulated secretion of sPLA(2)-IB was observed in monocytes isolated from rat PBLs. Treating glomerular endothelial cells (GECs) with cytokines elicited only weak sPLA(2)-IB expression, but treatment of these cells with exogenous sPLA(2)-IB resulted in a marked expression of the endogenous sPLA(2)-IB. Mesangial cells did not express sPLA(2)-IB at all. The M-type sPLA(2) receptor protein was markedly upregulated on cytokine-stimulated mesangial and endothelial cells as well as on lymphocytes and granulocytes. During anti-Thy 1.1 rat GN, sPLA(2)-IB and the M-type sPLA(2) receptor are induced as primary downstream genes stimulated by inflammatory cytokines. Subsequently, both sPLA(2)-IB and the M-type sPLA(2) receptor are involved in the autocrine and paracrine amplification of the inflammatory process in different resident and infiltrating cells.

Background: Gender and body size have been associated with survival in hemodialysis populations. In recent observational studies, overall mortality was similar in men and women and higher in small patients. The effect of dialysis dose in each of these subgroups has not been tested in a clinical trial., Methods: The HEMO Study was a controlled trial of dialysis dose and membrane flux in 1846 hemodialysis patients followed up for 6.6 years in 15 centers throughout the United States. We examined the effect of dialysis dose on mortality and on selected secondary outcomes in subgroups of patients., Results: Adjusting for age only, overall mortality was lower in patients with higher body weight (P < 0.001), higher body mass index (P < 0.001), and higher body water content determined by the Watson formula (Vw) (P < 0.001), but was not associated with gender (P= 0.27). The RR of mortality comparing the high dose with the standard dose group was related to gender (P= 0.014). Women randomized to the high dose had a lower mortality rate than women randomized to the standard dose (RR = 0.81, P= 0.02), while men randomized to the high dose had a nonsignificant trend for a higher mortality rate than men randomized to the standard dose (RR = 1.16, P= 0.16). Analysis of both genders combined showed no overall dose effect (R = 0.96, P= 0.52), as reported previously. Vw was greater than 35 L in 84% of men compared with 17% of women. However, the RR of mortality for the high versus standard dose remained lower in women than in men after adjustment for the interaction of dose with Vw or with other size parameters, including weight and body mass index. Conversely, the dose effect was not significantly related to size parameters after controlling for the relationship of the dose comparison with gender., Conclusion: The data suggest that mortality and morbidity might be reduced by increasing the dialysis dose above the current standard in women but not in men. This effect was not explained by differences between men and women in age, race, or in several indices of body size. Because multiple comparisons were considered in this analysis, the role of gender on the effect of dialysis dose is suggestive and invites further study.

The present study was conducted to dissect the underlying mechanisms by which catecholamines protect cells against preservation injury. To this end, we firstly defined the cellular and molecular differences between protected and nonprotected cells and secondly defined the mediators that were involved in cold-induced damage. Cold storage of untreated human umbilical vein endothelial cells (HUVECs) resulted in profound cellular damage as assessed by lactate dehydrogenase (LDH) release and by morphological changes, e.g. cell size alterations and loss of cytoskeletal organization. Treatment of HUVECs with catecholamines before cold storage prevented cellular damage in a dose- and time-dependent fashion. Similar results were obtained with carvedilol or its hydroxylated derivative BM91.0228. Protection was not receptor-mediated and did not require de novo protein synthesis. The onset of protection occurred relatively quickly and the duration was long lasting. Addition of superoxide dismutase (SOD) to untreated HUVECs during cold preservation also was protective. Oxidation of catecholamines completely abrogated the protective effect of these compounds on cold-induced damage. Both at 4 degrees and 37 degrees C, catecholamines reduced the amount of reactive oxygen species (ROS) produced by HUVECs. In conclusion we have demonstrated that catecholamines protect cells against preservation injury either by scavenging of ROS or by inhibition of ROS production.

Objective: Development of leadership competencies has become a priority for many academic health science centers. However, traditional faculty development has focused almost exclusively on improving teaching skills. The process and outcomes of developing leadership skills for academic health science center faculty has not been extensively studied., Methods: The University of Nebraska Medical Center (UNMC) created a year-long course, called the Administrative Colloquium, as a means to enhance faculty leadership skills. Completion of the course required attendance at 8 half-day workshop sessions, each devoted to teaching a leadership competency (eg, leading with vision, managing change) and completing a project with a project report (oral or poster presentation). Course evaluation was multifaceted. Attendees were queried multiple times by a pre- and poststrategy and retrospective pre- and poststrategy concerning their perceptions about knowledge obtained during the course. Paired t testing was used to determine statistical differences between the mean pre- versus postvalues and the retrospective pre- versus postvalues. Project content was qualitatively analyzed for themes., Results: All comparisons of pre- and postdata and retrospective pre- and postdata were statistically significant (P <.05). Three themes arose from the analysis of projects: change, management, and interpersonal communications., Conclusions: The pre- and postknowledge data and the retrospective pre- and postknowledge data demonstrate that learning was significant as well as sustained. Qualitative analysis of the project content demonstrates that the participants were applying the course content to solving real-world problems. These results give preliminary support to the conclusion that the Administrative Colloquium has had an impact on faculty leadership development at UNMC.

The human intestinal absorption of 241 drugs was evaluated. Three main methods were used to determine the human intestinal absorption: bioavailability, percentage of urinary excretion of drug-related material following oral administration, and the ratio of cumulative urinary excretion of drug-related material following oral and intravenous administration. The general solvation equation developed by Abraham's group was used to model the human intestinal absorption data of 169 drugs we considered to have reliable data. The model contains five Abraham descriptors calculated by the ABSOLV program. The results show that Abraham descriptors can successfully predict human intestinal absorption if the human absorption data is carefully classified based on solubility and administration dose to humans., (Copyright 2001 Wiley-Liss, Inc.)

The Hemodialysis Study is a multicenter clinical trial of hemodialysis prescriptions for patients with end stage renal disease. Participants from over 65 dialysis facilities associated with 15 clinical centers in the United States are randomized in a 2 x 2 factorial design to dialysis prescriptions targeted to a standard dose or a high dose, and to either low or high flux membranes. The primary outcome variable is mortality; major secondary outcomes are defined based on hospitalizations due to cardiovascular or infectious complications, and on the decline of serum albumin. The Outcome Committee, consisting of study investigators, uses a blinded review system to classify causes of death and hospitalizations related to the major secondary outcomes. The dialysis dose intervention is directed by the Data Coordinating Center using urea kinetic modeling programs that analyze results from dialysis treatments to monitor adherence to the study targets, adjust suggested dialysis prescriptions, and assist in trouble-shooting problems with the delivery of dialysis. The study design has adequate power to detect reductions in mortality rate equal to 25% of the projected baseline mortality rate for both of the interventions.

The tremendous importance of cytokines to immune defensive systems suggests that they have been conserved through evolution. The existence of interleukin (IL)-1-like molecules in several invertebrate groups substantiates this hypothesis. To characterize further the relationship of invertebrate IL-1-like molecules, we have used competitive binding assays to show that invertebrate coelomocytes of the starfish Asterias forbesi possess an IL-1-specific binding protein. Competitive binding experiments used radiolabeled human IL-1alpha. IL-1 bound specifically to the coelomocytes by a single high-affinity binding site (K(d) = 8.72 x 10(-10)/M). There are approximately 6000 binding sites per cell. The specificity of the receptor was confirmed by demonstrating that, among a group of cytokines and lymphokines tested, only vertebrate IL-1- or echinoderm IL-1-like molecules and the vertebrate IL-1 receptor antagonist inhibit IL-1 binding. Treatment of coelomocytes (labeled with IL-1alpha) with bivalent water-soluble crosslinkers identified a membrane protein of approximately 70 kDa to which IL-1 is specifically crosslinked., (Copyright 2000 Academic Press.)

Background: This study was performed to develop an intensive care unit (ICU) admission risk score based on preoperative condition and intraoperative events. This score provides a tool with which to judge the effects of ICU quality of care on outcome., Methods: Data were collected prospectively on 4,918 patients (study group n = 2,793 and a validation data set n = 2,125) undergoing coronary artery bypass grafting alone or combined with a valve or carotid procedure between January 1, 1993, and March 31, 1995. Data were analyzed by univariate and multiple logistic regression with the end points of hospital mortality and serious ICU morbidity (stroke, low cardiac output, myocardial infarction, prolonged ventilation, serious infection, renal failure, or death)., Results: Eight risk factors predicted hospital mortality at ICU admission, and these factors and five others predicted morbidity. A clinical score, weighted equally for morbidity and mortality, was developed. All models fit according to the Hosmer-Lemeshow goodness-of-fit test. This score applies equally well to patients undergoing isolated coronary artery bypass grafting., Conclusions: This model is complementary to our previously reported preoperative model, allowing the process of ICU care to be measured independent of the operative care. Sequential scoring also allows updated prognoses at different points in the continuum of care.

The detection of overt albuminuria (> 300 mg/g creatinine) in the absence of azotemia was used to diagnose early nephropathy in 34 Pima Indians with NIDDM of 16 +/- 1 years duration. Differential solute clearances were performed serially to define the course of the glomerular injury over 48 months. At baseline, the GFR (107 +/- 5 ml/min), filtration fraction and sieving coefficients of relatively permeant dextrans (< 52 A) were all depressed below corresponding values in 20 normoalbuminuric Pima Indians with a similar duration of NIDDM. Over the ensuing 48 months the GFR (-34%) and filtration fraction (-13%) in the nephropathic patients declined further. The sieving coefficients of large, nearly impermeant dextrans (> 56 A radius) increased selectively and fractional clearances of albumin and IgG increased correspondingly by > 10-fold. Analysis of the findings with pore theory revealed: (1) a progressive decline in pore density and the ultrafiltration coefficient (Kf); and (2) broadening of glomerular pore-size distribution that resulted in greater prominence of large pores (> 70 A radius). We conclude that increasing loss of intrinsic ultrafiltration capacity is the predominant cause of the early and progressive decline in GFR that follows the development of nephropathy in NIDDM. We speculate that progressive impairment of barrier size-selectivity contributes to but does not fully account for the increasingly heavy proteinuria that is observed early in the course of this disorder.

Phagocytosis is the predominant defense mechanism of invertebrates. Here we show that phagocytosis by echinoderm bladder amoebocytes and tunicate granular amoebocytes can be enhanced by invertebrate interleukin-1-like molecules. As little as 5 ng/ml of invertebrate interleukin-1 produced a significant stimulation of echinoderm and tunicate amoebocyte phagocytosis. Stimulation of phagocytosis by echinoderm interleukin-1-like molecules was inhibited by antisera to vertebrate interleukin-1. Invertebrate interleukin-1 also acted as an opsonin when preincubated with erythrocytes or yeast. In addition, the cellular mechanisms of invertebrate phagocytosis were studied using pharmacologic agents to inhibit echinoderm amoebocyte phagocytosis. The energy requirements and involvement of cellular cytoskeletal elements in phagocytosis by bladder amoebocytes were similar to those of mammalian macrophages. These results demonstrate a role for interleukin-1 in invertebrate host defense mechanisms.

Exposure to HBO causes hypothermia, bradycardia, head weaving, resting tremor, piloerection, and straub tail in rats. These physiological and behavioral responses can also be evoked by selective activation of serotonin1A (5-HT1A) receptors. The purpose of the current study was to determine if hypothermia caused by HBO is due to increased activation of 5-HT1A receptors. The levels of brain biogenic amines were measured in brain regions of Sprague-Dawley (SD) rats exposed to HBO. Exposure to HBO caused an increase in the levels of 5-hydroxyindoleacetic acid (5-HIAA) in the striatum (92%, p < 0.05) and occipital-temporal cortex (116%, p < 0.05), but not in other brain regions. Exposure to HBO did not change the levels of tryptophan, serotonin (5-HT), other biogenic amines, or their metabolites. It is hypothesized that the Fawn Hood (FH) rat, which is reported to be resistant to hypothermia induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), has an abnormality of 5-HT1A receptor activity. Although the FH rat was more resistant to hypothermia induced by HBO than the SD rat, we were not able to confirm that this rat was resistant to hypothermia induced by 8-OH-DPAT. The 5-HT receptor antagonists, 1-(1H-Indol-4-yloxy)-3-[(1-methylethyl)amino]-2-propanol (Pindolol), 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl] piperazine hydrobromide (NAN-190), and methysergide, did not block hypothermia induced by HBO in SD rats. A series of control experiments were used to confirm that the antagonists blocked hypothermia induced by serotonin agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

The Modification of Diet in Renal Disease Trial is a multicenter randomized clinical trial for men and women aged 18-70 years with chronic renal disease who are not on dialysis and who have not had a kidney transplant. Study participants are randomized in a 2 x 2 factorial design to diets containing different amounts of protein and phosphorus and to two levels of blood pressure control. The prescribed modifications differ depending on the level of a patient's kidney function. The primary outcome variable to compare diet or blood pressure groups is each patient's slope (or the change) in glomerular filtration rate with time. This paper describes the study design with particular emphasis on sample size determination. Special statistical analysis issues that arise with slope as the outcome are also discussed.

We studied glucocorticoid receptor autoregulation and corticotropin response to dexamethasone in depressed patients and controls, attempting to control for the confounding effect of endogenous glucocorticoids. After depletion of endogenous cortisol, depressed patients showed an attenuated suppressibility of corticotropin by dexamethasone in the face of unchanged dexamethasone plasma levels. Beta-endorphin levels were strongly correlated with adrenocorticotropic hormone (ACTH) concentrations. Although metyrapone administration resulted in a marked rise of glucocorticoid receptor sites per cell in controls, this effect was not present in depressives. These data support the hypothesis of a decreased glucocorticoid receptor plasticity and a partial steroid resistance in depression.

Mediators released from injured human skin that initiate the inflammatory response have not been adequately identified. Organ culture of full-thickness skin explants enables us to do so, because injury to the skin can be made in vitro, eliminating the rapid leakage of serum and infiltration of leukocytes that occur in vivo. In our studies, the military vesicant sulfur mustard (SM) (10 microliters of a 0.01 to 1.0% dilution) was topically applied to injure the epidermis of the explant. Then, the explants were cultured in small Petri dishes, usually for 18 h at 36 degrees C, and the organ-culture fluids were assayed for various inflammatory mediators. We found that the culture fluids from SM-exposed and control explants contained similar amounts of angiotensin-converting enzyme, trypsin-like and chymotrypsin-like proteases, acid phosphatase, beta-glucuronidase, beta-galactosidase, lysozyme, deoxyribonuclease, ribonuclease, interleukin 1, and lactic dehydrogenase. However, the culture fluids from SM-exposed explants contained increased amounts of histamine and plasminogen-activating activity, and often prostaglandin E2, when compared to culture fluids from control explants. After 3 to 4 d in culture, full-thickness human skin explants, when exposed to 0.2% SM (but not when exposed to 1.0% SM), sometimes showed separation of the epidermis and increased collagenase activity (i.e., hydroxyproline release). Thus, histamine (from local mast cells), and prostaglandin E2 and plasminogen-activating activity (probably from both mast cells and epidermal cells) are apparently involved in early mediation of the inflammatory response.

A new high-performance liquid chromatographic technique has been developed to quantitate nonoxynol-9 in serum, urine, and vaginal fluid. The method is rapid, involves minimal sample preparation, and can be used to analyze a large number of biological fluid samples. The assay elutes a single nonoxynol-9 peak with no interfering components. This was accomplished using a 10-microns pelicular packed amine column, a normal-phase solvent system, and fluorescence detection. Nonoxynol-9 levels as low as 0.23 micrograms/mL in urine can be detected.

Microsomal preparations from adult male rat liver actively oxidized RU38486 into the 11 beta-monodemethylated, 11 beta-didemethylated and 17 alpha-hydroxylated derivatives, metabolites which are known to be formed in vivo. These oxidative reactions were inhibited at different degrees by P450 chemical inhibitors. Pretreatment of the animals by P450 mono-oxygenase prototype inducers led to drastic changes in RU38486 metabolization. Methylcholanthrene treatment carried out a significant decrease while phenobarbital markedly increased the metabolic activity of the liver microsomes. Moreover, antibodies to methylcholantrene-inducible P450 forms did not affect the metabolic activity while a complete blockade-of RU38486 oxidation was observed in the presence of antibodies to phenobarbital- inducible forms. The present results demonstrate that liver P450 mono-oxygenases are engaged in different oxidative steps of RU38486 metabolism and that phenobarbital-inducible but not methylcholanthrene-inducible P450 forms are active in RU38486 degradation.

Peptidoglycan (PG), an essential cell wall polymer of most bacteria, has been isolated from many species of spirochetes. Our interest in the host response to Borrelia burgdorferi led us to isolate and characterize its PG. Extracted cells were solubilized with warm 1% SDS followed by digestion with proteases. Amino acid analysis of the isolated PG demonstrated the presence of alanine, glycine, glutamic acid, and ornithine as occurs in other spirochetes and bacteria. Intense erythematous reactions were observed after id injection of 10 micrograms of PG into normal human skin. PG was not mitogenic for human peripheral blood mononuclear cells. Murine splenocytes of certain strains responded to the PG, but only at concentrations of 25 micrograms/ml or more. PG stimulated macrophages to produce interleukin 1. Sixteen micrograms of PG injected iv into rabbits produced biphasic fevers. These observations on the in vitro and in vivo activities associated with the cellular components of the B. burgdorferi spirochete give further insight to how a small number of invading organisms can cause a multisystemic disease such as Lyme disease.

Physiologic concentrations of human plasma very low density lipoproteins inhibit the DNA synthesis of lymphocytes stimulated by allogeneic cells or lectins. In this report we have compared the effects of isolated lipoproteins [very low density lipoproteins (VLDL), low density lipoproteins (LDL), and high density lipoproteins (HDL)] and lipoprotein-depleted plasma (LDP) on DNA synthesis by phytohemagglutinin-stimulated human lymphocytes. The relative potency for the inhibition of lymphocyte proliferation was VLDL greater than LDL greater than HDL greater than LDP. Fifty percent inhibition of DNA synthesis was observed at a VLDL protein concentration of 1.5--2.0 microgram/ml. We have further demonstrated the presence of specific receptors for VLDL on human lymphocytes. Native VLDL was more effective than LDL in competing for 125I-VLDL binding sites. Subsequent to binding to lymphocytes, 125I-VLDL was internalized and degraded to acid-soluble products. Based on a Scatchard analysis of VLDL binding at 4 degrees C, the number of VLDL receptors per lymphocyte was estimated at 28,000 +/- 1300. Based on an estimated mean binding affinity for the VLDL receptor complex at half saturation of approximately 8.8 X 10(7) liter/mole, it is estimated that 91% of lymphocyte VLDL receptors are occupied at physiologic VLDL concentrations in blood. Although the immune regulatory role of plasma lipoproteins is uncertain, we suggest tha VLDL and LDL-In may maintain circulating blood lymphocytes in a nonproliferative state via their respective cell receptor mechanisms.

It has been suggested that exposure to formaldehyde (FA) induces asthmatic symptomatology. We have previously studied healthy and asthmatic individuals and found that lung function was unaltered by controlled exposures to 2.0 ppm FA with and without mild exercise. Our present study extends these observations to a group of hospital laboratory workers routinely exposed to FA. Fifteen laboratory workers were exposed in double-blind, random sequence to 0 and 2 ppm FA for 40 min in an environmental chamber with temperature and relative humidity held constant at 23 degrees C and 50%, respectively. These exposures were repeated on two more occasions with a 10-min exercise regimen (450 kpm/min) after being in the chamber 5 min. In addition, a symptom diary and measurements of peak expiratory flow rate (PEFR) were recorded for 24 hr after exposure. Lung function remained unaltered for all 4 exposure days; e.g., mean FEV1.0 for the group did not change by more than 3% at any testing time on any exposure day. Also, there were no delayed obstructive changes as measured by PEFR recordings. Symptoms were mild and transient with unusual odor and eye irritation the most frequent complaint. No lower airway symptoms were reported. We conclude that this group of healthy laboratory workers did not experience any acute or delayed lung function changes from exposure to 2.0 ppm FA at rest and with exercise and that irritative symptoms were few.

Changes in symptoms and pulmonary function among asthmatic subjects in the general population remain poorly characterized. We studied 1,303 white residents aged seven years and older in Lebanon, Conn, a rural community largely unaffected by air pollution or major occupational exposures. These residents were examined in 1972 and again in 1978. There were 73 asthmatic subjects seen in 1972 who were followed. In addition, we identified 278 persons in 1972 who complained of wheezing who were also seen in 1978. Of the original asthmatic subjects, 50 (68 percent) were in remission; and from the original nonasthmatic population, 19 (1.4 percent) new asthmatic subjects were identified. Similarly, the condition of 215 (77 percent) of those who initially complained of wheeze had improved, whereas 56 (4.6 percent) of those initially studied either developed new wheeze or saw their wheezing worsen. When the groups of persons complaining of wheeze and the asthmatic subjects were analyzed for the presence of chronic bronchitis, we found a significant correlation between wheeze and chronic bronchitis in individuals aged 18 years and older (p less than 0.001) for both men and women, and a significant correlation (p less than 0.001) between asthma and chronic bronchitis in women aged 18 years and older. Loss of pulmonary function over time measured in terms of the forced expiratory volume in one second and the forced expiratory flow at 50 percent of total lung capacity was consistently greater for asthmatic adults than for nonasthmatic adults. Furthermore, when individuals were studied by the severity and duration of their asthmatic symptoms, a trend of worse pulmonary function was seen in those individuals with chronic asthma. We conclude that remission rates among asthmatic subjects and persons with wheeze are high in individuals aged seven years and older, that chronic bronchitis is frequently associated with wheezing and a history of asthma in adults, and that significant abnormalities in pulmonary function as well as accelerated loss of pulmonary function are associated with asthma.

Adherence to host cells by pathogenic bacteria is achieved through both specific and non-specific mechanisms. The former involve bacterial adhesin and corresponding cell receptors (Gibbons and Van Houte, 1980), while the second include electric charges and hydrophobicity of bacterial cell walls. In a previous study (Beck et al., 1988), we showed that these two cell surface characteristics vary during growth of Staphylococcus aureus in a manner which should promote adherence to host cells. The aims of the current study were to assess: (1) whether the same growth-related variations in surface properties were present in another bacterial species, Streptococcus pneumoniae; (2) whether the adherence of the two types of bacteria to epithelial cells was in fact different at different growth times; and (3) whether such differences were consistent with the observed surface properties.

Modifications in the surface charge and hydrophobicity of Staphylococcus aureus Oxford during growth were studied by analysing electrophoretic mobility and adherence to hydrocarbons (hexadecane), respectively. Bacterial concentration had no effect upon the measurements. Both surface charge and hydrophobicity varied during the exponential phase of growth (1 to 4 h): surface charge decreased significantly (p less than 0.001), while hydrophobicity increased (p less than 0.001). In the stationary phase (4 to 9 h), the surface charge increased significantly (p less than 0.001), whereas hydrophobicity showed no change. Cationized ferritin decreased the surface charge and had no effect on hydrophobicity. These results suggest that in S. aureus, different structures could be responsible for their surface charge and hydrophobic properties.