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Low-density polyethylene (LDPE) is among the most abundant synthetic plastics in the world, contributing significantly to the plastic waste accumulation problem. A variety of microorganisms, such as Cupriavidus necator H16, Pseudomonas putida LS46, and Pseudomonas chlororaphis PA2361, can form biofilms on the surface of LDPE polymers and cause damage to the exterior structure. However, the damage is not extensive and complete degradation has not been achieved. The changes in polymer structure were analyzed using Time-domain Nuclear Magnetic Resonance (TD-NMR), High-Temperature Size-Exclusion Chromatography (HT-SEC), Differential Scanning Calorimetry (DSC), and Gas Chromatography with a Flame Ionization Detector (GC-FID). Limited degradation of the LDPE powder was seen in the first 30 days of incubation with the bacteria. Degradation can be seen in the LDPE weight loss percentage, LDPE degradation products in the supernatant, and the decrease in the percentage of amorphous regions (from >47% to 40%). The changes in weight-average molar mass (Mw), number-average molar mass (Mn), and the dispersity ratio (Đ) indicate that the low-molar mass fractions of the LDPE were preferentially degraded. The results here confirmed that LDPE degradation is heavily dependent on the presence of amorphous content and that only the amorphous content was degraded via bacterial enzymatic action.

Purpose: To present primary and final analyses from the randomized, double-blind, placebo-controlled, phase III iNTEGRATE study, which evaluated the safety and efficacy of ibrutinib with prednisone in previously untreated patients with chronic graft-versus-host disease (cGVHD)., Methods: Patients (age ≥ 12 years) with newly diagnosed moderate or severe cGVHD, requiring systemic corticosteroid therapy, and with no prior systemic treatment for cGVHD were randomly assigned 1:1 to receive ibrutinib 420 mg once daily plus prednisone, starting at 1 mg/kg once daily or placebo plus prednisone. The primary end point was response rate at 48 weeks according to 2014 National Institutes of Health Consensus Development Project Criteria. Other end points included event-free survival, duration of response, time to withdrawal of immunosuppressants, improvement in Lee cGVHD Symptom Scale score, overall survival (OS), and safety., Results: Ninety-five and 98 patients enrolled in the ibrutinib-prednisone and placebo-prednisone arms, respectively. At 48 weeks, response rates were 41% (ibrutinib-prednisone) and 37% (placebo-prednisone; P = .54). At 33 months of follow-up, median duration of response was 19 months (ibrutinib-prednisone) and 10 months (placebo-prednisone; P = .10). Median event-free survival was 15 months (ibrutinib-prednisone) and 8 months (placebo-prednisone; hazard ratio, 0.76; 95% CI, 0.54 to 1.1; P = .11). Improvement in overall Lee cGVHD Symptom Scale was 43% (ibrutinib-prednisone) and 31% (placebo-ibrutinib; P = .07). Median OS was not reached in either arm. The 24-month Kaplan-Meier OS estimates were 80% for both arms (hazard ratio, 1.06; 95% CI, 0.59 to 1.90). Grade ≥ 3 serious adverse events occurred in 49% (ibrutinib-prednisone) and 47% (placebo-prednisone) of patients., Conclusion: There was no statistical difference observed in the primary and secondary end points with ibrutinib-prednisone treatment. No new safety signals were observed with ibrutinib treatment in previously untreated patients with cGVHD. The primary end point of iNTEGRATE was not met.

Axicabtagene ciloleucel (axi-cel) is a standard-of-care for patients with relapsed or refractory (r/r) large B cell lymphoma who have received 2 or more lines of prior therapy. Patients receiving axi-cel in the real world could have broader a demographic, disease, and treatment profile compared with that of the cohort in the pivotal ZUMA-1 trial. The present study was conducted to evaluate the outcomes of axi-cel therapy in the real-world setting. A total of 1297 patients receiving commercial axi-cel between 2017 and 2020 were selected from the Center for International Blood and Marrow Transplant Research's data registry, of whom 739 (57%) would have been ineligible for inclusion in the ZUMA-1 cohort. Efficacy and safety outcomes were described for the entire cohort and by ZUMA-1 eligibility. Their associations with age, Eastern Cooperative Oncology Group Performance Score, and comorbidities were evaluated using multivariable logistic and Cox regressions. At a median follow-up of 12.9 months, the overall response rate (ORR) was 73%, with a 56% complete response (CR) rate. Median overall survival (OS) and progression-free survival (PFS) were 21.8 months (95% confidence interval [CI], 17.4 to 28.8 months) and 8.6 months (95% CI, 6.5 to 12.1 months), respectively. Duration of response (DOR) was comparable in the ZUMA-1 ineligible patients and ZUMA-1 eligible patients (62% by 1 year [95% CI, 57% to 66%] versus 67% [95% CI, 62% to 72%]). Patients age ≥65 years had favorable ORR (odds ratio [OR], 1.39; 95% CI, 1.05 to 1.83) despite having a higher risk of cytokine release syndrome (CRS) (OR, 1.41; 95% CI, 1.02 to 1.94) and immune effector cell-associated neurotoxicity syndrome (ICANS) (OR, 1.77; 95% CI, 1.39-2.26). Eastern Cooperative Oncology Group Performance Score ≥2 was associated with inferior efficacy outcomes (OR for ORR, 0.32; 95% CI, 0.18-0.56; hazard ratio [HR] for OS, 3.27; 95% CI, 2.37 to 4.52) and higher incidence of ICANS (OR, 2.63; 95% CI, 1.40 to 4.93). The patients ineligible for ZUMA-1 still had a durable response with axi-cel. Elderly patients had favorable efficacy outcomes despite higher rates of CRS and ICANS. Patient selection for standard-of-care axi-cel should consider comorbidities and risk-to-benefit ratio rather than be based strictly on ZUMA-1 eligibility., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

A Ciboria sp. strain (Phylum Ascomycota) was isolated from hydrocarbon-polluted soil of an abandoned oil refinery in Italy. The strain was able to utilize diesel oil as a sole carbon source for growth. Laboratory-scale experiments were designed to evaluate the use of this fungal strain for treatment of the polluted soil. The concentration of total petroleum hydrocarbons (TPH) in the soil was 8,538 mg/kg. Mesocosms containing the contaminated soil were inoculated with the fungal strain at 1 or 7%, on a fresh weight base ratio. After 90 days of incubation, the depletion of TPH contamination was of 78% with the 1% inoculant, and 99% with the 7% inoculant. 16S rDNA and ITS metabarcoding of the bacterial and fungal communities was performed in order to evaluate the potential synergism between fungi and bacteria in the bioremediation process. The functional metagenomic prediction indicated Arthrobacter , Dietzia , Brachybacerium , Brevibacterium , Gordonia , Leucobacter , Lysobacter , and Agrobacterium spp. as generalist saprophytes, essential for the onset of hydrocarbonoclastic specialist bacterial species, identified as Streptomyces , Nocardoides , Pseudonocardia , Solirubrobacter , Parvibaculum , Rhodanobacter , Luteiomonas , Planomicrobium , and Bacillus spp., involved in the TPH depletion. The fungal metabolism accelerated the onset of specialist over generalist bacteria. The capacity of the Ciboria sp. to deplete TPH in the soil in treatment was also ascertained., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Becarelli, Chicca, La China, Siracusa, Bardi, Gullo, Petroni, Levin and Di Gregorio.)

The necrotrophic fungus Botrytis cinerea , is considered a major cause of postharvest losses in a wide range of crops. The common fungal extracellular membrane protein (CFEM), containing a conserved eight-cysteine pattern, was found exclusively in fungi. Previous studies in phytopathogenic fungi have demonstrated the role of membrane-bound and secreted CFEM-containing proteins in different aspects of fungal virulence. However, non-G protein-coupled receptor (non-GPCR) membrane CFEM proteins have not been studied yet in phytopathogenic fungi. In the present study, we have identified a non-GPCR membrane-bound CFEM-containing protein, Bcin07g03260, in the B. cinerea genome, and generated deletion mutants, ΔCFEM- Bcin07g03260 , to study its potential role in physiology and virulence. Three independent ΔCFEM- Bcin07g03260 mutants showed significantly reduced progression of a necrotic lesion on tomato ( Solanum lycopersicum ) leaves. Further analysis of the mutants revealed significant reduction (approximately 20-30%) in conidial germination and consequent germ tube elongation compared with the WT. Our data complements a previous study of secreted Δ CFEM1 mutants of B. cinerea that showed reduced progression of necrotic lesions on leaves, without effect on germination. Considering various functions identified for CFEM proteins in fungal virulence, our work illustrates a potential new role for a non-GPCR membrane CFEM in pathogenic fungi to control virulence in the fungus B. cinerea .

Campylobacter infection is one of the most common causes of bacterial gastroenteritis worldwide and a major global health threat due to the rapid development of antibiotic resistance. Currently, there are no vaccines approved to prevent campylobacteriosis, and rehydration is the main form of therapy. Secretory immunoglobulin A (SIgA) is the main antibody class found in mucous secretions, including human milk, and serves as the first line of defense for the gastrointestinal epithelium against enteric pathogens. In this study, we describe the prophylactic activity of orally delivered recombinant SIgA generated from two human monoclonal antibodies (CAA1 and CCG4) isolated for their reactivity against the flagellar-capping protein FliD, which is essential for bacteria motility and highly conserved across Campylobacter species associated with severe enteritis. In an immunocompetent weaned mouse model, a single oral administration of FliD-reactive SIgA CAA1 or CCG4 at 2 h before infection significantly enhances Campylobacter clearance at early stages post-infection, reducing the levels of inflammation markers associated with epithelial damage and polymorphonuclear (PMN) cells infiltration in the cecum lamina propria. Our data indicate that the prophylactic activity of CAA1 and CCG4 is not only dependent on the specificity to FliD but also on the use of the SIgA format, as the immunoglobulin G (IgG) versions of the same antibodies did not confer a comparable protective effect. Our work emphasizes the potential of FliD as a target for the development of vaccines and supports the concept that orally administered FliD-reactive SIgA can be developed to prevent or mitigate the severity of Campylobacter infections as well as the development of post-infection syndromes., (Copyright © 2020 Perruzza, Jaconi, Lombardo, Pinna, Strati, Morone, Seehusen, Hu, Bajoria, Xiong, Kumru, Joshi, Volkin, Piantanida, Benigni, Grassi, Corti and Pizzuto.)

Reconstruction of the irradiated perineum has posed a consistent reconstructive challenge historically. The evolution of reconstructive techniques must mirror advances in neoadjuvant treatment and surgery for low rectal cancer. The purpose of this study was to evaluate the perineal healing in a cohort of patients, of whom a majority had laparoscopic tumor excision and partial myocutaneous gluteal flap reconstruction. There were 11 patients in this cohort; 8 primary reconstructions and 3 salvage cases. Complete healing was measured as the cessation of all dressings. There were no returns to theater for flap-related surgery. Mean postreconstruction inpatient stay was 16.5 days. All patients healed completely. Mean time to healing was 42 days. This method has been successful for primary and salvage reconstruction in patients having laparoscopic or open surgery; thus, averting the major morbidity associated with failed reconstruction as reported for most of other reconstructive modalities in these patients.

Stroke is the third leading cause of death in the United States and the leading cause of disability. Stroke patients' outcomes are strongly determined by how long they remain untreated ("time is brain"). The Joint Commission's adoption of stroke performance improvement measures combined with the Centers for Medicare and Medicaid's more recent adoption in October 2009 make a systems approach to improving stroke outcomes a higher priority. As hospitals establish local and regional stroke care systems to meet these performance measures, treatment of emergent high blood pressure (BP) is a major consideration to improve rapid triage and management of acute stroke patients. Intravenous thrombolysis with tissue plasminogen activator (tPA) is a critical quality of care component for acute ischemic stroke (AIS) treatment, but its administration is contingent on BP management. For patients with AIS who are potentially eligible for tPA and patients with intracerebral hemorrhage, timely, controlled BP may improve patient outcomes. Appropriate BP management, however, is still controversial given the heterogeneity of stroke subtypes, the varying attributes of candidate antihypertensive agents, and both local and central hemodynamics. Additionally, organizational delivery system factors may be suboptimal at some hospitals. Under current hospital stroke performance measures, payment mechanisms, and emergency department throughput measures, the impact of BP management may become transparent to patients and payers, and have important consequences for hospital-derived stroke outcomes.

OBJECTIVE-To determine whether urine protein-to-creatinine (UP:C) ratio assessment provides an estimate of urine protein excretion (UPE) over a 24-hour period in horses and ponies, establish a preliminary UP:C ratio reference range, and determine UP:C ratio variation over time in healthy equids. ANIMALS-11 female horses and 6 female ponies. PROCEDURES-Urine was collected from all equids at 4-hour intervals for 24 hours. Total 24-hour UPE (mg of protein/kg of body weight) and UP:C ratio were determined; these variables were also assessed in aliquots of urine collected at 4-hour intervals. On 2 additional days, urine samples were also obtained from 6 horses (1 sample/horse/d) to determine day-to-day variation in UP:C ratio. Correlation between 4-hour or 24-hour UPE and UP:C ratio values was assessed. Reference ranges for 24-hour UPE, 24-hour UP:C ratio, and 4-hour UP:C ratios were calculated as central 95th percentiles of observed values. RESULTS-Mean 24-hour UPE (4.28 +/- 2.99 mg/kg) and 24-hour UP:C ratio (0.0 to 0.37) had excellent correlation (R = 0.826; P < 0.001) in both horses and ponies; analysis of 4-hour data also revealed good correlation (R = 0.782; P < 0.001) with these variables. Calculated UPE and UP:C ratio reference ranges were similar to established ranges in other species. Day-to-day variability in UP:C ratio was minimal, and all results were within the reference range calculated by use of the 24-hour urine samples. CONCLUSIONS AND CLINICAL RELEVANCE-Assessment of the UP:C ratio appears to be a reliable method for estimating 24-hour UPE in horses and ponies.

We evaluated 4 volume-based automatic image registration algorithms from 2 commercially available treatment planning systems (Philips Syntegra and BrainScan). The algorithms based on cross correlation (CC), local correlation (LC), normalized mutual information (NMI), and BrainScan mutual information (BSMI) were evaluated with: (1) the synthetic computed tomography (CT) images, (2) the CT and magnetic resonance (MR) phantom images, and (3) the CT and MR head image pairs from 12 patients with brain tumors. For the synthetic images, the registration results were compared with known transformation parameters, and all algorithms achieved accuracy of submillimeter in translation and subdegree in rotation. For the phantom images, the registration results were compared with those provided by frame and marker-based manual registration. For the patient images, the results were compared with anatomical landmark-based manual registration to qualitatively determine how the results were close to a clinically acceptable registration. NMI and LC outperformed CC and BSMI, with the sense of being closer to a clinically acceptable result. As for the robustness, NMI and BSMI outperformed CC and LC. A guideline of image registration in our institution was given, and final visual assessment is necessary to guarantee reasonable results.

The effect of gantry rotation on beam profiles of photon and electron beams is an important issue in quality assurance for radiotherapy. To address variations in the profiles of photon and electron beams at different gantry angles, a Dynamic Phantom scanner composed of a 20 x 12 x 6 cm3 scanning Lucite block was designed as a cross-beam-profile scanner. To our knowledge, differences between scanned profiles acquired at different gantry angles with a small size Lucite block and those acquired a full-size (60 x 60 x 50 cm3) water phantom have not been previously investigated. We therefore performed a feasibility study for a first prototype Dynamic Phantom scanner without a gantry attachment mount. Radiation beams from a Varian LINAC 21EX and 2100C were used. Photon beams (6 MV and 18 MV) were shaped by either collimator jaws or a Varian 120 Multileaf (MLC) collimator, and electron beams (6 MeV, 12 MeV, and 20 MeV) were shaped by a treatment cone. To investigate the effect on profiles by using a Lucite block, a quantitative comparison of scanned profiles with the Dynamic Phantom and a full-size water phantom was first performed at a 0 degrees gantry angle for both photon and electron beams. For photon beam profiles defined by jaws at 1.0 cm and 5.0 cm depths of Lucite (i.e., at 1.1 cm and 5.7 cm depth of water), a good agreement (less than 1% variation) inside the field edge was observed between profiles scanned with the Dynamic Phantom and with a water phantom. The use of Lucite in the Dynamic Phantom resulted in reduced penumbra width (about 0.5 mm out of 5 mm to 8mm) and reduced (1% to 2%) scatter dose beyond the field edges for both 6 MV and 18 MV beams, compared with the water phantom scanner. For profiles of the MLC-shaped 6 MV photon beam, a similar agreement was observed. For profiles of electron beams scanned at 2.9 cm depth of Lucite (i.e., at 3.3 cm depth of water), larger disagreements in profiles (3% to 4%) and penumbra width (3 mm to 4 mm out of 12 mm) were observed. Additional profiles with the gantry at 90 degrees and 270 degrees were performed for both MLC- and jaw-shaped photon beams and electron beams to evaluate the effect of gantry rotation. General good agreement is seen (less than 1 % variation) at all field sizes for collimator-shaped 6 MV and 18 MV photon beams. Similar variations observed for MLC-shaped photon beams indicate that the uncertainty in MLC position is similar to that for the collimator jaws. We conclude that the Dynamic Phantom scanner is a useful device for the routine quality assurance on beam profiles of photon beams and for constancy check on electron beams at various gantry angles. Caution should be taken when using this device to acquire basic electron dosimetry data.

Bone traps vary in design, although the effect of pore size on the nature of the debris collected in vivo has not yet been established. The aims of this study were 1) to compare the clinical performance of two bone collectors during implant surgery, ii) to establish the mass of tissue collected by each device, and iii) to characterize the nature of the collected debris. Thirty-eight patients (paired for implant site) were categorised into three clinical groups according to the site and the number of implants they were to receive. Patients underwent bone collection with the Frios bone trap or the Osseous Coagulum Trap according to a randomisation sequence. The samples were fixed in formalin, frozen, freeze-dried and weighed. Material from each sample was embedded in paraffin wax and stained with haematoxylin and eosin. All sections were examined by optical microscopy and the proportion of bone to coagulum was established histomorphometrically. During surgery, the Frios bone trap blocked once and the Osseous Coagulum Trap blocked 11 times. In all cases where blockage occurred, excess coagulum was apparent. All the samples that were collected by the Frios bone trap contained bone and coagulum, with a mean proportion of 90.6% bone. With regard to the Osseous Coagulum Trap, one sample contained no bone and two samples contained only trace amounts of bone; the remaining samples contained a mean proportion of 67.3% bone. Pore size affects both clinical performance and the histological composition of the debris collected, and this might have important implications if used as an augmentation material.

Background: In recent years, health and disease management has emerged as an effective means of delivering, integrating, and improving care through a population-based approach. Since 1997 the University of Pennsylvania Health System (UPHS) has utilized the key principles and components of continuous quality improvement (CQI) and disease management to form a model for health care improvement that focuses on designing best practices, using best practices to influence clinical decision making, changing processes and systems to deploy and deliver best practices, and measuring outcomes to improve the process. Experience with 28 programs and more than 14,000 patients indicates significant improvement in outcomes, including high physician satisfaction, increased patient satisfaction, reduced costs, and improved clinical process and outcome measures across multiple diseases. DIABETES DISEASE MANAGEMENT: In three months a UPHS multidisciplinary diabetes disease management team developed a best practice approach for the treatment of all patients with diabetes in the UPHS. After the program was pilot tested in three primary care physician sites, it was then introduced progressively to additional practice sites throughout the health system. The establishment of the role of the diabetes nurse care managers (certified diabetes educators) was central to successful program deployment. Office-based coordinators ensure incorporation of the best practice protocols into routine flow processes. A disease management intranet disseminates programs electronically. Outcomes of the UPHS health and disease management programs so far demonstrate success across multiple dimensions of performance-service, clinical quality, access, and value., Discussion: The task of health care leadership today is to remove barriers and enable effective implementation of key strategies, such as health and disease management. Substantial effort and resources must be dedicated to gain physician buy-in and achieve compliance. The challenge is to provide leadership support, to reward and recognize best practice performers, and to emphasize the use of data for feedback and improvement. As these processes are implemented successfully, and evidence of improved outcomes is documented, it is likely that this approach will be more widely embraced and that organizationwide performance improvement will increase significantly., Conclusions: Health care has traditionally invested extraordinary resources in developing best practice approaches, including guidelines, education programs, or other tangible products and services. Comparatively little time, effort, and resources have been targeted to implementation and use, the stage at which most efforts fail. CQI's emphasis on data, rapid diffusion of innovative programs, and rapid cycle improvements enhance the implementation and effectiveness of disease management.

Health and disease management, a clinical improvement process that integrates best practice principles in a comprehensive manner throughout the entire continuum of care, is likely to be the dominant style of health care delivery in the future. The goal of these programs is to eliminate or reduce unacceptable variations in cost and quality between various providers by developing guidelines that will achieve measurable outcomes for specific diseases. These protocols also emphasize wellness and disease prevention, coordinate resources across the entire continuum of care, and define interventions for the entire duration of the disease. Conditions most suited to this management strategy include diseases that are of high volume and cost, complex to manage, and present chronically over a long period of the patient's life. Such programs are developed by a multidisciplinary team that is also charged with obtaining buy-in and championing the program to their peers. Among the many components of a comprehensive health and disease management program, intensive education for patients and families and altering physician behavior to obtain compliance are key areas on which to focus. Hypertension is an ideal condition to manage in this way. It is frequently the most common reason for patients to be seen by a primary care provider, is an expensive disease to treat, and is an important cause of major organ damage from inadequate treatment. Successfully adopting a disease management model for hypertension treatment that will integrate all health care providers and offer intensive education of patients and providers to encourage adherence to the highly effective therapies currently available should afford a major opportunity for a dramatic reduction in complications and costs, with enhanced clinical outcomes and quality of life for these patients.

Hyperlipidemia so commonly complicates heavy proteinuria that it has come to be regarded as an integral feature of the nephrotic syndrome (NS). Characteristically, total plasma cholesterol and triglyceride levels are elevated, as are very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) cholesterol. Although high-density lipoprotein (HDL) concentrations may be normal, HDL subtypes are abnormally distributed, with a reduction of HDL2 and an increase in HDL3. In addition, lipoprotein (a) [Lp (a)] levels may be elevated. The mechanisms underlying these abnormalities are multifactorial, involving both increased rates of lipoprotein synthesis and defective clearance and catabolism of circulating particles. Although recent dietary and therapeutic studies have demonstrated that nephrotic hyperlipidemia can be effectively treated, the need for such intervention has not been clearly established. This pattern of lipoprotein abnormality is associated with an increased risk of cardiovascular disease in the general population, and several studies have suggested that nephrotic individuals are more likely to develop atherosclerosis. However, no prospective trials have evaluated the relationship between deranged lipid metabolism and coronary or cerebral artery disease in patients with NS. In addition, although recent experimental studies suggest that lipid abnormalities may accelerate renal injury and that lipid-lowering agents may protect renal function, there is little current evidence to suggest that such intervention is of value in preserving residual renal function in humans. Further studies are clearly required to assess the potential long-term benefits of lipid-lowering intervention in individuals with NS. In the meantime, based on data generated from other population groups, a rational approach to the clinical management of hyperlipidemia in these patients is presented.

Dialysis-amyloidosis (A beta 2M) is a recently recognized chronic complication in long-term dialysis patients, apparently effecting 5% to 10% of all dialysis patients. In 1985, Gejyo et al (Biochem Biophys Res Commun 129:701-706, 1085) and Shirahama et al (Lab Invest 53:705-709, 1985) identified beta 2-microglobulin (beta 2-M) as the major constituent protein of this unique type of systemic amyloidosis. The specific pathogenesis of A beta 2M remains unknown, although beta 2-M has been clearly identified as playing a central role as the amyloidogenic protein. To investigate the factors responsible for in vitro beta 2-M synthesis, we studied beta 2-M production by lymphocyte cultures obtained from dialysis patients and grown under a variety of different conditions, and compared the results to a control group of subjects with normal renal function. We could not demonstrate any stimulatory influence on beta 2-M synthesis by the hemodialysis treatment, the type of dialysis membrane used, or the clinical presence of A beta 2M. Rather, dialysis membranes, sterilized with ethylene oxide or gamma rays, added to the lymphocyte cultures exerted a strong dose-dependent inhibitory effect on beta 2-M synthesis. From the results of this study, we conclude that peripheral blood lymphocytes in uremic patients synthesize beta 2-M normally and that the direct interaction between circulating lymphocytes and the dialysis membrane that occurs during hemodialysis does not seem to contribute directly to beta 2-M synthesis.

The natriuretic peptide system, which comprises at least four related proteins: atrial natriuretic peptide; brain natriuretic peptide; C-type natriuretic peptide; and urodilatin, exerts important influences on central and renal hemodynamics and renal sodium excretion. Recent studies have examined the role of these peptides in the pathophysiology of edema formation in congestive heart failure, cirrhosis, and nephrotic syndrome and have explored the therapeutic value of manipulating their metabolic pathways. One striking feature appears common to all three states ie, a blunted response to the natriuretic effect of atrial natriuretic peptide, which becomes particularly severe in the late stages of each disease. However, whereas in congestive heart failure and cirrhosis the main mechanism responsible is enhanced proximal tubular reabsorption of sodium resulting in reduced distal sodium delivery to the major site of atrial natriuretic peptide action, in nephrotic syndrome a biochemical defect in the cellular response to atrial natriuretic peptide within the kidney is a more likely explanation. Most information regarding the efficacy of therapies that alter the metabolism or the local action of atrial natriuretic peptide pertain to congestive heart failure. However, continued investigation in this area may ultimately lead to interventions that play a valuable role in the future management of all three edematous states.

Reflex sympathetic dystrophy syndrome (RSDS), a complex clinical syndrome characterized by pain and swelling of an affected extremity, is most commonly seen after trauma. We report the case of a woman with diabetes mellitus and chronic renal failure who presented with RSDS 5 months after placement of an arteriovenous (AV) graft for hemodialysis. The temporal relationship between RSDS and the vascular surgery suggests AV graft placement as the precipitating event for the development of RSDS. Treatment with systemic corticosteroids successfully relieved the patient's symptoms. We believe that RSDS should be included in the differential diagnosis of unexplained limb pain and swelling after AV graft placement.

The National Cooperative Dialysis Study (NCDS) established the importance of the time-averaged concentration of blood urea nitrogen (BUN) (TACurea) as a determinant of morbidity among patients maintained on hemodialysis. Although urea is not itself toxic, it serves as a surrogate for those low-molecular weight products of protein catabolism that do contribute to uremic toxicity. The NCDS also reported an association between low protein catabolic rates (a measure of dietary protein intake) and increased morbidity, but the validity of this result has been questioned. On the basis of a retrospective re-analysis of the data, Gotch and Sargent have proposed following the normalized whole-body urea clearance, Kt/V, as a more fundamental index of the level of dialytic therapy. In this review, a comparison is made between these two measures of adequate dialysis, namely, midweek predialysis urea concentration and Kt/V. At least for the cellulosic membranes used in the NCDS, they seem to be equivalent. Furthermore, each prescription defines adequate nutrition as a dietary protein intake (DPI) of 1.0 g/kg/d. At this DPI, a time-averaged concentration of BUN of 17.9 mmol/L (50 mg/dL) (corresponding roughly to a midweek predialysis BUN of 21.4 to 28.6 mmol/L (60 to 80 mg/dL), as recommended by the NCDS, is equivalent to a Kt/V of 1.0, as recommended by Gotch and Sargent. Based on ease and accuracy of measurement, TACurea would seem the more reliable marker for monitoring the adequacy of dialysis. Extrapolation of the utility of TACurea and/or Kt/V to noncellulosic membranes remains to be established. Urea kinetic modeling constitutes a powerful mathematical tool for implementing these recommendations. Urea kinetic modeling may also be used as a means of monitoring DPI and thereby ensuring adequate nutrition.

Lymphocyte function as assessed by spontaneous cellular cytotoxicity (NK) and antibody-dependent cellular cytotoxicity (ADCC) was studied in a group of 23 patients with end-stage renal disease who were being maintained on haemodialysis. The mononuclear cells from 12 (50%) of these patients were markedly reduced in their ability to effect NK activity. When mononuclear cells from 13 patients were examined for ADCC activity, however, only two displayed reduced cytotoxicity. The remainder showed either normal or enhanced ADCC activity against erythrocyte targets. Five patients with consistently low NK cell function demonstrated a significantly enhanced ADCC function when compared with normal controls. Several patients were tested repeatedly over a period of 6 months and we found that these two mononuclear cell functions remained consistent during this time. A reduction in NK activity may reflect a lessened capability for immunosurveillance in these patients.

We have studied sodium retention during volume expansion in rats with autologous immune complex nephropathy (AICN), a model of nephrotic syndrome (NS) in which GFR after volume expansion was not different from that in adjuvant-injected controls (C). AICN rats developed heavy proteinuria (298 +/- 27 vs. less than 10 mg/day), hypoalbuminemia (2.14 +/- 0.15 vs. 3.08 +/- 0.12 g/100 ml) and hypercholesterolemia (181 +/- 22 vs. 58 +/- 4 mg/100 ml). After saline, there were no significant differences in blood pressure (119 +/- 2 vs. 114 +/- 2 mm Hg), renal plasma flow (4.9 +/- 0.41 vs. 4.1 +/- 0.28 ml/min), inulin clearance (1.37 +/- 0.06 vs. 1.55 +/- 0.10 ml/min), or SNGFR (47 +/- 2 vs. 53 +/- 4 nl/min). Sodium excretion, however, was significantly lower in NS rats (4.7 +/- 1.1 vs. 9.2 +/- 1.2 muEq/min). Proximal sodium reabsorption was decreased in NS rats (35 +/- 2 vs. 41 +/- 2%, 2.5 +/- 0.2 vs. 3.3 +/- 0.2 nEq/min). Sodium delivery into the loop, however, was equal in NS and C, since the slightly lower filtered load in NS rats offset the depression in proximal reabsorption. Sodium reabsorption by the loop and by the distal convoluted tubules were equal in NS and C. Thus, sodium delivered into the cortical collecting ducts was the same in both groups (0.33 +/- 0.17 vs. 0.34 +/- 0.07 nEq/min; 4.5 +/- 0.6% of filtered sodium vs. 4.4 +/- 0.3%). The percent of filtered sodium excreted in the urine, however, was significantly lower in the NS rats, 2.18 +/- 0.48% vs. 4.0 +/- 0.58%. We conclude that antinatriuresis in this model of NS is determined beyond the superficial late distal convoluted tubule. The inability to excrete the sodium load during volume expansion is due to either enhanced reabsorption by the collecting duct or to abnormal function in deep nephrons.

Renal kallikrein is present in human urine in both an active and an inactive form. Several previous studies have examined the response of active kallikrein excretion to alterations in sodium and water metabolism, but the response of inactive kallikrein has not been evaluated systematically. We have developed a method for determining inactive kallikrein in urine using two assays. Active kallikrein is measured using a kininogenase assay. Total (active plus inactive) kallikrein is measured using a direct RIA. Inactive kallikrein is calculated from the difference between active and total kallikrein excretion. We have used this technique to study the effect of alterations in sodium and water metabolism on kallikrein excretion. Acute volume expansion with saline and moderate acute or chronic increases in water intake did not alter the excretion of either active or inactive kallikrein. Dietary sodium restriction increased the excretion of total kallikrein by 30%; active kallikrein increased 82%, while inactive kallikrein excretion was found to be unchanged. Spironolactone reduced total kallikrein excretion in subjects on a low salt diet. Again, the change in excretion was entirely attributable to the active form of the enzyme. Total kallikrein excretion increased during the first 3 days of fludrocortisone administration in subjects on a high salt intake and then plateaued. Active kallikrein increased progressively throughout the 7-day study period. Inactive kallikrein increased during the first 4 days, then fell to control levels. Thus, mineralocorticoid initially stimulates the formation and/or release into urine of both active and inactive kallikrein. Later, reciprocal changes in active and inactive enzymes occur.

We report an asymptomatic man found to have simultaneous renal transport defects for magnesium and phosphate. Associated findings include gout, high frequency hearing loss, chronic elevations of SGOT and SGPT, metabolic bone disease, and hyperparathyroidism. The clinical expression of hyperparathyroidism was masked for 5 years by hypomagnesemia, and the patient became hypercalcemic only when magnesium levels were normalized by intravenous infusion. Both the phosphate and magnesium transport abnormalities persisted after parathyroidectomy. The many unique features of this case distinguish it from previously described disorders of magnesium or phosphate wasting.

We report a 52-year-old male renal transplant recipient who had three "rejection episodes." The first of these responded to conventional antirejection therapy; however, the next two episodes showed incomplete responses to treatment for rejection. At subsequent presentation with deteriorating renal function, ureteral obstruction was evident and was relieved with percutaneous antegrade balloon dilatation with a return of his plasma creatinine to normal. Obstruction of the ureter was a major component in our patient's course given the lack of response to conventional antirejection therapy and the normalization of renal function with relief of the documented ureteral stenosis. This case illustrates that ureteral obstruction can mimic rejection in the renal transplant recipient. Management of ureteral stenosis in transplant patients with percutaneous antegrade balloon dilatation appears to be an effective procedure and can supplant the need for open surgical procedures.

To assess the interaction between adrenergic activity and blood pressure regulation in patients with chronic renal failure, plasma norepinephrine (NE) and plasma renin activity (PRA) were measured before and after vigorous ultrafiltration. The significance of PRA was further assessed by angiotensin blockade with saralasin. Two patterns of response were defined: nine patients had low levels of PRA before and after hemodialysis. These patients showed a net fall in norepinephrine and no angiotensin dependence of any time. Failure to stimulate either PRA or norepinephrine was also observed during periods of marked hypotension. Seven other patients had higher PRA, which rose during hemodialysis. This was associated with an increase in NE and postdialysis angiotensin dependence. Patients experiencing hypotension in this group showed a sharp rise in NE, suggesting baroceptor-mediated adrenergic stimulation. In all patients sustaining hypotension during therapy, postdialysis PRA was closely correlated with NE. These results indicate that hemodialysis mobilizes the renin-angiotensin system to maintain hypertension in a greater proportion of dialysis patients than previously supposed and that impaired renin release following hypotension may represent uremic autonomic dysfunction.

The systemic and regional circulatory effects of angiotensin-converting enzyme inhibition were investigated in 30 normal subjects and in 36 patients with severe congestive heart failure. Regional blood flow was measured in individual patient groups. Cardiac index rose and systemic vascular resistance fell in normal subjects after angiotensin-converting enzyme inhibition. In the patients with heart failure, a similar rise in cardiac index and fall in systemic resistance occurred. In addition, right and left ventricular filling pressures decreased. The fall in systemic vascular resistance correlated with plasma renin activity (r = 0.57, p less than or equal to 0.001). Of the regional circulations investigated in normal subjects, only forearm blood flow increased after angiotensin-converting enzyme inhibition. Although over-all there was no change in renal or coronary blood flow, coronary flow dramatically increased in some patients and the increase in flow correlated with plasma renin activity (r = 0.939, p less than or equal to 0.001). In patients with heart failure, forearm, splanchnic, and coronary flow were unaffected by angiotensin-converting enzyme inhibition, whereas renal blood flow estimated from para-aminohippurate clearance increased 60 percent and accounted for 50 percent of the increase in cardiac output seen in these patients. Thus, redistribution of flow occurs in congestive heart failure with a significant reduction in the fraction flow to the kidneys when compared with normal flow. The contribution of the renin-angiotensin system to the regulation of regional blood flow is different in normal subjects and in patients with heart failure. Angiotensin-converting enzyme inhibition augments skeletal flow in normal subjects whereas it increases renal blood flow in patients with heart failure.

The acute effects of the angiotensin converting-enzyme inhibitor captopril on regional blood flow, renal hemodynamics and sodium excretion were studied in 12 patients with severe congestive heart failure. Converting-enzyme inhibition decreased systemic vascular resistance by 27% and increased cardiac index by 16%. Estimated hepatic blood flow decreased 17%, but renal blood flow increased 60%. The ratio of renal-systemic blood flow increased from 0.10 +/- 0.01 to 0.14 +/- 0.02 (p = 0.031). Although renal plasma flow increased from 202.8 +/- 28.8 to 323.7 +/- 42.7 ml/min (p less than 0.008), the glomerular filtration rate did not change significantly from the mean pretreatment value of 82.1 +/- 12.3 ml/min. The filtration fraction decreased from 41.3 +/- 3.8% to 33.4 +/- 4.5% (p = 0.050), while urinary sodium excretion doubled, from 34.5 +/- 9.6 to 68.2 +/- 19.6 muEq/min. The plasma renin activity increased from 12.6 +/- 5.0 to 29.9 +/- 8.4 ng/ml/hr (p = 0.030) as plasma aldosterone concentration decreased from 30.5 +/- 6.5 to 11.3 4/- 1.2 ng/dl (p = 0.010) and norepinephrine concentrations decreased from 774 +/- 105 to 618 +/- 85 pg/ml (p = 0.020). We conclude that converting-enzyme inhibition reverses renal vasoconstriction in congestive heart failure and redistributes regional blood flow. The natriuresis may be mediated by one or more of the following: improved renal plasma flow, reduction in filtration fraction, suppression of hyperaldosteronism, and lowering of circulatory catecholamine concentrations.

Anaphylaxis is a rare complication of hemodialysis. Unless there is a high index of suspicion, symptoms may not be immediately recognized as a manifestation of hypersensitivity and prompt attention may be delayed. To improve physician awareness of this problem we report a patient who developed a severe anaphylactic reaction within minutes of beginning dialysis. Review of the literature indicates that hypersensitivity reactions are most commonly associated with Cuprophan dialyzers. Although the etiology has not been established, recurrence can be prevented by selection of a different type of dialysis membrane.

We report a patient with compensated congestive heart failure who developed acute anuric renal failure immediately after indomethacin and triamterene had been added to the treatment regimen. Renal function failed to improve promptly with discontinuation of these medications, anuria persisting for 11 days. While it is well known that patients suffering from edematous states are prone to develop renal insufficiency when given nonsteroidal anti-inflammatory agents, it is not generally appreciated that the specific combination of prostaglandin inhibitors with triamterene may carry a particularly high risk of acute renal failure, even in euvolemic subjects.