Radionuclide synovectomy/synoviorthesis (RS) in patients with bleeding disorders: A review of patient and procedure demographics and functional outcomes in the ATHNdataset.

INTRODUCTION: Radionuclide synovectomy/synoviorthesis (RS) to manage proliferative synovitis in persons with bleeding disorders has been utilized for decades; however, aggregate US results are limited. AIM: To determine the prevalence of RS utilization, patient and procedure related demographics and functional outcomes in United States haemophilia treatment centres (HTCs). The ATHNdataset includes US patients with bleeding disorders who have authorized the sharing of their demographic and clinical information for research. METHODS: We performed a multi-institutional, observational cohort study utilizing this dataset through 2010. Cases treated with RS procedure were compared to controls within the dataset. Standard template for data collection included patient and procedure related demographics as well as functional outcomes including range of motion (ROM) of the affected joint. Normative age- and sex-matched control ROM was obtained from published data. RESULTS: In the ATHNdataset there were 19 539 control-patients and 196 case-patients treated with RS. Patients with severe haemophilia were more likely to have had RS compared to those with mild/moderate haemophilia, although the proportion of RS performed was similar between severe HA and HB. Inhibitory antibodies, HIV and hepatitis C infection were significantly more common in cases. There were 362 RS procedures captured with 94 cases having >1 RS procedures. CONCLUSIONS: Right-sided joint procedures were more prevalent than left-sided procedures. Overall, case-patients had worse joint ROM compared to control-patients and published normative values. Geographically, there was regional variation in RS utilization, as the Southeast region had the largest percent of case-patients.

Control of calcium carbonate nucleation and crystal growth by soluble matrx of oyster shell.

A calcium-binding soluble protein extracted from oyster shell suppresses calcium carbonate nucleation and decreases the rate of crystal growth in vitro. These findings suggest that soluble matrix may regulate shell growth.

TEM immunocytochemistry of a 48 kDa MW organic matrix phosphoprotein produced in the mantle epithelial cells of the Eastern oyster (Crassostrea virginica).

Immunohistochemical TEM of Eastern oyster (Crassostrea virginica) mantle epithelial cells using a polyclonal antibody to a gel purified 48 kDa MW oyster shell phosphoprotein revealed that it is phosphorylated in the Golgi, packaged into secretory vesicles and subsequently exocytosed across the apical membrane of specialized cells. These phosphoprotein producing cells are concentrated along the mantle side facing the shell, in the region of the outer mantle lobe. A layer of calcium enriched immuno-reactive mucous is associated with the apical microvilli of these cells. The 48 kDa phosphoprotein forms a component of the fibrous organic matrix and appears to be involved in calcium supply thus enabling crystal growth at the mineralization front.

Physician practices in the treatment of pulmonary embolism and deep venous thrombosis.

To quantify physician practices in the care of patients with presumed pulmonary embolism or deep venous thrombosis, we analyzed heparin sodium orders, the intensity of anticoagulation, and complications in 65 patients with the diagnosis of deep venous thrombosis or pulmonary embolism. All patients were given heparin, for a mean (+/- SEM) period of 8.8 +/- 0.4 days. A high percentage of patients (60%) did not have a single partial thromboplastin time (PTT) greater than 1.5 times control within the first 24 hours of heparin therapy. Not until day 8 were 90% of PTTs in therapeutic range. We identified five common practices that led to delays in achieving a PTT greater than 1.5 times the laboratory control: (1) failure to start heparin therapy at the time of initial clinical suspicion, (2) choice of a heparin sodium bolus (mean, 5861 +/- 365 U) and continuous infusion (1026 +/- 148 U/h) insufficient to elevate the PTT to greater than 1.5 times control, (3) delay in obtaining the first PTT (mean, 11.7 +/- 1 h after start of heparin therapy), (4) insufficient heparin dosing in response to a low PTT, and (5) excessive and prolonged reductions in heparin therapy in response to a PTT greater than three times control, leading to subtherapeutic levels in 56% of subsequent PTTs. We think that poor understanding of heparin kinetics, overcautious behavior of physicians, and high heparin requirements in this selected population account for the findings.

Use of pulse oximetry to recognize severity of airflow obstruction in obstructive airway disease: correlation with pulsus paradoxus.

STUDY OBJECTIVES: The purpose of this cross-sectional study was to confirm the observation that pulse oximetry tracing correlates with pulsus paradoxus, and is therefore a measure of the severity of air trapping in obstructive airway disease. DESIGN: Cross-sectional survey. SETTING: The ICU in a tertiary care academic hospital. PATIENTS: Twenty-six patients consecutively admitted to the ICU with obstructive airway disease, either asthma or COPD. MEASUREMENTS AND RESULTS: Forty-six percent of the study patients required mechanical ventilation, and 69% had an elevated pulsus paradoxus. We defined the altered pulse oximetry baseline tracing as the respiratory waveform variation (RWV). The RWV was measured in numerical form as the change in millimeters from the baseline. Pulsus paradoxus was significantly correlated with the RWV of the pulse oximetry tracing (p < 0.0001). An analysis of the respiratory variations in the pulse oximetry waveforms in obstructive lung disease patients reflects the presence and degree of auto-positive end-expiratory pressure (auto-PEEP; p < 0.0001). CONCLUSIONS: We describe the characteristic alterations in the pulse oximetry tracings that occur in the presence of pulsus paradoxus and auto-PEEP. Since pulse oximetry is available universally in ICUs and emergency departments, it may be a useful noninvasive means of continually assessing pulsus paradoxus and air trapping severity in obstructive airway disease patients.

A trial of antioxidants N-acetylcysteine and procysteine in ARDS. The Antioxidant in ARDS Study Group.

OBJECTIVE: To determine the levels of glutathione and cysteine in patients with ARDS and examine the effect of treatment with N-acetylcysteine (NAC) and L-2-oxothiazolidine-4-carboxylate (Procysteine; Clintec Technologies Inc; Chicago [OTZ]) on these levels and on common physiologic abnormalities, and organ dysfunction associated with ARDS. DESIGN: Randomized, double-blind, placebo-controlled, prospective clinical trial. SETTING: ICUs in five clinical centers in the United States and Canada. PATIENTS: Patients meeting a predetermined definition of ARDS and requiring mechanical ventilation. INTERVENTION: Standard care for ARDS and I.V. infusion, every 8 h for 10 days, of one of the following: NAC (70 mg/kg, n=14), OTZ (63 mg/kg, n=17), or placebo (n=15). MAIN RESULTS: Both antioxidants effectively repleted RBC glutathione gradually over the 10-day treatment period (47% and 49% increases from baseline values for NAC and OTZ, respectively). There was no difference in mortality among groups (placebo, 40%; NAC, 36%; OTZ, 35%). However, the number of days of acute lung injury was decreased and there was also a significant increase in cardiac index in both treatment groups (NAC/OTZ [+]14%; placebo [-]6%). CONCLUSIONS: Our findings suggest that repletion of glutathione may safely be accomplished with NAC or OTZ in patients with acute lung injury/ARDS. Such treatment may shorten the duration of acute lung injury, but larger studies are needed to confirm this.

Tumor necrosis factor's effects on lung mechanics, gas exchange, and airway reactivity in sheep.

The macrophage- and monocyte-produced cytokine tumor necrosis factor alpha (TNF alpha) has been proposed as a major mediator of endotoxin-induced injury. To determine if TNF alpha could reproduce the effects of endotoxin on the lung, we intravenously administered 10 micrograms/kg of human recombinant TNF alpha into five chronically instrumented unanesthetized sheep on two occasions to characterize the TNF alpha response and its reproducibility. We assessed changes in lung mechanics, pulmonary and systemic hemodynamics, gas exchange, and the number and type of peripheral blood leukocytes. We also determined airway reactivity by use of aerosolized histamine before and after TNF alpha infusion. Pulmonary arterial pressure (Ppa) peaked within 30 min of initiating the TNF alpha infusion [47.7 +/- 2.2 vs. 15.9 +/- 0.4 (SE) cmH2O at base line] and then returned toward base line over 4 h. There was a brief decline in left atrial pressure after TNF alpha. Pulmonary hypertension was accompanied by leukopenia, neutropenia, and increases in the alveolar-arterial O2 difference (AaDO2). Dynamic lung compliance (Cdyn) declined after TNF alpha, reaching a nadir within 15 min of the initiation of the TNF alpha infusion [0.045 +/- 0.007 vs. 0.093 +/- 0.007 (+/- SE) l/cmH2O at base line]. Resistance to airflow across the lung (RL) increased from 1.2 +/- 0.2 cmH2O.l-1.s at base line, peaking at 5.4 +/- 1.3 cmH2O.l-1.s 30 min after the start of the TNF alpha infusion. Alterations in Cdyn and RL persisted for 4 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Applications of molecular biology and biotechnology: antibody therapy of sepsis.

The use of antibody therapy for the treatment of infections and inflammatory disease is well established. Unfortunately, clinical studies of antiendotoxin and anti-TNF monoclonal antibodies have failed to show clear physiological or survival benefit. Little information is available regarding the effect of antibodies to cytokines other than TNF in human sepsis. Limited pre-clinical data indicate that IL-6 antibodies may abrogate the effects of endotoxin infusion, but no human studies have been performed. Although both monoclonal and polyclonal antibodies have the potential to protect septic humans, at this time it is the polyclonal antibodies that have shown the greatest promise. Each type of antibody possesses specific advantages and limitations, the ultimate effectiveness of which will need to be proven in large randomized clinical trials.

Diagnosis and therapy of acute respiratory distress syndrome in adults: an international survey.

In an attempt to identify the range of opinions influencing the diagnosis and therapy of patients with the adult respiratory distress syndrome (ARDS), a postal survey was mailed to 3,164 physician members of the American Thoracic Society Critical Care Assembly. The questionnaire asked opinions regarding the factors important in the diagnosis of ARDS and its treatment. Thirty-one percent of physicians surveyed responded within 4 weeks, the vast majority of which were board certified or eligible in Internal Medicine, Pulmonary Disease, and/or Critical Care Medicine. A known predisposing cause, measure of oxygenation efficiency, and a chest radiograph depicting pulmonary edema were reported to be the most important criteria for a clinical and research diagnosis of ARDS. Lung compliance and bronchoalveolar lavage neutrophil or protein content were reportedly less important. The initial treatment of patients with ARDS was reported to be most commonly accomplished using volume-cycled ventilation in the assist/control mode. Nearly half the responders reported using lower tidal volumes (5 to 9 mL/kg) than the traditionally recommended 10 to 15 mL/kg. Most respondents indicated they have intentionally allowed CO2 retention. On average, oxygen toxicity was thought to begin at an FIO2 between 0.5 and 0.6. It was reported that modest levels of positive end-expiratory pressure (PEEP) were used in incremental fashion as FiO2 requirements increased. Perceived indications for insertion of pulmonary artery catheters and compensation of the effects of PEEP on the pulmonary artery occlusion pressure varied widely among the responders. We conclude that reported practice patterns regarding the care of ARDS patients vary widely even within a relatively homogenous group of critical care practitioners.

Pseudogout presenting with low synovial fluid glucose: identification of crystals by gram stain.

A man developed acute monoarticular ankle arthritis caused by calcium pyrophosphate dihydrate (CPPD) crystals. The clinical syndrome resembled that of a pyogenic arthritis. Synovial fluid analysis revealed a glucose concentration of 13 mg/dL and 99,000 white blood cells/mm3. Only one other report of an extremely low synovial fluid glucose associated with pseudogout could be found. The diagnosis of pseudogout was initially suggested when rhomboidal forms were seen during synovial fluid Gram stain examination. Synovial fluid examination with polarized microscopy was initially negative, but revealed numerous CPPD crystals when repeated on the third hospital day. This case serves to illustrate how pseudogout can mimic pyogenic arthritis in both clinical presentation and low synovial fluid glucose concentration. The examination of Gram-stained synovial fluid can reveal the rhomboidal forms of CPPD crystals. The appearance of these crystals is documented in this report.

Nucleation and growth of calcite on native versus pyrolyzed oyster shell folia.

The thin sheets of calcite, termed folia, that make up much of the shell of an oyster are covered by a layer of discrete globules that has been proposed to consist of agglomerations of protein and mineral. Foliar fragments, treated at 475 degrees C for 36 h to remove organic matter, were imaged by atomic force microscopy (AFM) as crystals grew on the foliar surfaces in artificial seawater at calcite supersaturations up to 52-fold. Crystals were also viewed later by scanning electron microscopy. After pyrolysis, the foliar globules persisted only as fragile remnants that were quickly washed away during AFM imaging, revealing an underlying morphology on the foliar laths of a tightly packed continuum of nanometer-scale protrusions. At intermediate supersaturations, crystal formation was seen immediately almost everywhere on these surfaces, each crystal having the same distinctive shape and orientation, even at the outset with crystals as small as a few nanometers. In contrast, nucleation did not occur readily on non-pyrolyzed foliar surfaces, and the crystals that did grow, although slowly at intermediate supersaturations, had irregular shapes. Possible crystallographic features of foliar laths are considered on the basis of the morphology of ectopic crystals and the atomic patterns of various surfaces. A model for foliar lath formation is presented that includes cycles of pulsed secretion of shell protein, removal of the protein from the mineralizing solution upon binding to mineral, and mineral growth at relatively high supersaturation over a time frame of about 1 h for each turn of the cycle.

P2X7 purinoceptors contribute to the death of Schwann cells transplanted into the spinal cord.

The potential to use Schwann cells (SCs) in neural repair for patients suffering from neurotrauma and neurodegenerative diseases is well recognized. However, significant cell death after transplantation hinders the clinical translation of SC-based therapies. Various factors may contribute to the death of transplanted cells. It is known that prolonged activation of P2X7 purinoceptors (P2X7R) can lead to death of certain types of cells. In this study, we show that rat SCs express P2X7R and exposure of cultured SCs to high concentrations of ATP (3-5 mM) or a P2X7R agonist, 2'(3')-O-(4-benzoylbenzoyl)ATP (BzATP) induced significant cell death rapidly. High concentrations of ATP and BzATP increased ethidium uptake by SCs, indicating increased membrane permeability to large molecules, a typical feature of prolonged P2X7R activation. SC death, as well as ethidium uptake, induced by ATP was blocked by an irreversible P2X7R antagonist oxidized ATP (oxATP) or a reversible P2X7R antagonist A438079. oxATP also significantly inhibits the increase of intracellular free calcium induced by minimolar ATP concentrations. Furthermore, ATP did not cause death of SCs isolated from P2X7R-knockout mice. All these results suggest that P2X7R is responsible for ATP-induced SC death in vitro. When rat SCs were treated with oxATP before transplantation into uninjured rat spinal cord, 35% more SCs survived than untreated SCs 1 week after transplantation. Moreover, 58% more SCs isolated from P2X7R-knockout mice survived after being transplanted into rat spinal cord than SCs from wild-type mice. This further confirms that P2X7R is involved in the death of transplanted SCs. These results indicate that targeting P2X7R on SCs could be a potential strategy to improve the survival of transplanted cells. As many other types of cells, including neural stem cells, also express P2X7R, deactivating P2X7R may improve the survival of other types of transplanted cells.

Subcellular localization and characterization of HCO3(-)-ATPase from the mantle of the freshwater clam, Anodonta cataracta.

1. HCO3(-)-stimulated ATPase activity was demonstrated in mantle tissue of the freshwater clam, Anodonta cataracta. 2. Calcium (1 mM) slightly inhibited and SCN- completely inhibited HCO3(-)-stimulation of the enzyme. 3. ATPase activity had a Km of 6.8 mM for HCO3(-)-activation and was inhibited at HCO3(-)-concentrations greater than 20 mM. 4. Subcellular fractionation studies revealed the presence of both a mitochondrial and a non-mitochondrial HCO3(-)-ATPase.

Fatal hemoptysis: aortobronchial fistula as a preventable cause of death.

Hemoptysis as a result of leaking aortic aneurysms occurs rarely and has a high fatality rate. A case of chronic hemoptysis resulting from an aortobronchial fistula in a patient with an aortic prosthesis is reported. Hemoptysis, even when chronic, should prompt investigation of the possibility of a leaking graft in patients with prosthetic aortic grafts. Chest x-ray and bronchoscopy usually yield nonspecific findings. Aortography may demonstrate an aortic aneurysm and is the preferred diagnostic procedure; however, an aggressive surgical approach is often necessary.

New ways to reduce unnecessary variation and improve outcomes in the intensive care unit.

The care of critically ill patients and the advent of the modern day intensive care unit (ICU) present a large person power and cost burden to society. The high cost of critical care is attributed to high overhead expenses (eg, experienced staff and equipment), high resource utilization (eg, pharmaceutical resources, lab testing, imaging procedures), and high demand for services. Pathways to standardize numerous facets of patient care have been shown to improve the efficiency of delivery of care and to reduce resource utilization, and are becoming the most sought-after means of improving patient outcomes and reducing overall ICU expenditures. A number of large, randomized, prospective trials have demonstrated that protocol-based strategies can not only reduce variation and cost of ICU medicine but also improve morbidity and mortality of critically ill patients requiring ICU support. In this article, we discuss examples of these trials investigating four major areas of modern ICU medicine: ventilator management, ventilator weaning, sedation and analgesia, and blood transfusions.

Studies of an antiendotoxin antibody in preventing the physiologic changes of endotoxemia in awake sheep.

In sheep, endotoxin (LPS) causes pulmonary hypertension, hypoxemia, leukopenia, exudation of protein-rich lung lymph, reduced dynamic compliance (Cdyn), and increased resistance to airflow (RL), changes similar to those seen in human sepsis and sepsis-induced ARDS. We used well-described methods in the awake sheep-endotoxin model to evaluate the effectiveness of a commercially manufactured antibody to prevent the physiologic changes of endotoxemia. In awake sheep with chronic lung lymph fistulas, we used a whole-body plethysmograph to measure Cdyn, RL, and FRC. Pulmonary artery, left atrial, and systemic arterial pressures were recorded continuously. Arterial blood gases (for calculating AaPO2), leukocyte counts, and lymph samples were collected every 30 min. Animals received a 30-min (2 mg/kg) infusion of antiendotoxin antibody 4 h before LPS (0.75 micrograms/kg) challenge (n = 4), or were given a mixture of LPS (0.75 micrograms/kg) and antibody (2 mg/kg) that had been incubated in vitro at 37 degrees C for 30 min before infusion (n = 6). A control group given only 2 mg/kg of antibody (n = 4) showed no change in any measured parameter, whereas control animals receiving LPS alone (n = 6) exhibited a typical endotoxin response. In all animals receiving endotoxin, Cdyn declined by approximately 50% within 30 to 60 min, and RL increased approximately sixfold over a similar time course. Accompanying the abnormalities in lung mechanics were pulmonary hypertension, leukopenia, and widening of the AaPO2.(ABSTRACT TRUNCATED AT 250 WORDS)

Promotion and Inhibition of Calcium Carbonate Crystallization In Vitro by Matrix Protein From Blue Crab Exoskeleton.

Soluble organic matrix isolated from dorsal carapaces of the blue crab, Callinectes sapidus, inhibited CaCO3 crystallization when free in solution. Immobilized matrix complexes, prepared by crosslinking soluble matrix to decalcified crab carapace, promoted CaCO3 formation in that crystallization in the presence of the immobilized soluble matrix complexes began sooner than in solution controls. In the experimental treatments, deposition of crystals occured only within the complexes and not in the crystallization solutions. Chitin, a polymer of N-acetyl-D-glucosaminc, and chitosan, a deacetylated chitin, which are both insoluble products of the organic matrix of the crab carapace containing little to no matrix protein, did not promote CaCO3 crystallization. Complexes of immobilized polyanionic synthetic peptides on chitosan also promoted CaCO3 crystallization. Addition of a hydrophobic tail (Ala8) to the polyanionic peptide (Asp20) reduced the rate of promotion, possibly because the hydrophobic tail formed a diffusion barrier around crystal nuclei growth sites, suppressing interactions of nascent crystal nuclei with ions in the bulk solution.

Radiographic issues in adult respiratory distress syndrome.

Despite significant technical limitations, the portable chest radiograph remains the primary tool for radiographic evaluation of patients with the acute respiratory distress syndrome (ARDS). Using good-quality films, experienced observers usually can distinguish permeability-induced from nonpermeability-induced pulmonary edema. In patients with ARDS, the chest radiograph typically shows rapid dramatic deterioration within 24 hrs, as indicated by the development of patchy peripheral infiltrates. Radiographic density may increase in severity for 5 to 7 days, after which time, further deterioration usually signals the occurrence of another process (e.g., infection, fluid overload). In the period beyond 1 wk, where the radiograph usually remains relatively stable, the chest radiograph is most useful in detecting complications of therapy, predominantly barotrauma. The vast majority of survivors of ARDS show improvement in their radiographs within the first 10 to 14 days after the onset of illness. Failure to show improvement during this time is a poor prognostic factor. Computed tomography is a useful modality in patients with questionable chest radiograph findings, provided that the patients are stable enough to leave the ICU for evaluation.