XMetA, an allosteric monoclonal antibody to the insulin receptor, improves glycaemic control in mice with diet-induced obesity.

XMetA, a high-affinity, fully human monoclonal antibody, allosterically binds to and activates the insulin receptor (INSR). Previously, we found that XMetA normalized fasting glucose and glucose tolerance in insulinopenic mice. To determine whether XMetA is also beneficial for reducing hyperglycaemia due to the insulin resistance of obesity, we have now evaluated XMetA in hyperinsulinemic mice with diet-induced obesity. XMetA treatment of these mice normalized fasting glucose for 4 weeks without contributing to weight gain. XMetA also corrected glucose tolerance and improved non-high density lipoprotein cholesterol. These studies indicate, therefore, that monoclonal antibodies that allosterically activate the INSR, such as XMetA, have the potential to be novel agents for the treatment of hyperglycaemia in conditions associated with the insulin resistance of obesity.

Anatomical patterns and correlated MRI findings of non-perinatal hypoxic-ischaemic encephalopathy.

Non-perinatal hypoxic-ischaemic encephalopathy (HIE) has varying anatomical patterns dependent on the type of insult, the degree and duration of cerebral hypoxia, or presence and degree of hypoperfusion. Profound insults can affect the entire cerebral cortex or just the perirolandic cortex, the cerebellum and the deep grey matter structures. Less severe insults may affect only the watershed regions. The objective of this article is to review the anatomical patterns of non-perinatal HIEs by MRI.

Novel proximal 14q deletion: clinical and diffusion tensor imaging tractography findings in a patient with lissencephaly, agenesis of the corpus callosum, and septo-optic dysplasia.

We report the unique CNS findings in a patient with a proximal chromosome 14q interstitial deletion. Conventional MR imaging allowed the clear delineation of agenesis of the corpus callosum, SOD, and diffuse lissencephaly. DTI tractography played a significant role in the evaluation of the proximal 14q deletion-associated abnormalities, delineating the extent of the dysmorphic connections of the Probst bundles and clarifying that apparent areas of heterotopias were the corticospinal tracts.

Diffusion tensor MR imaging of cerebral gliomas: evaluating fractional anisotropy characteristics.

BACKGROUND AND PURPOSE: FA correlation to glioma tumor grade has been mixed if not disappointing. There are several potential underlying fundamental issues that have contributed to these results. In an attempt to overcome these past shortfalls, we evaluated characteristics of FA of the solid tissue components of gliomas, including whether high-grade gliomas have a greater variation of FA than low-grade gliomas. MATERIALS AND METHODS: Thirty-four patients with gliomas (9 grade II, 8 grade III, and 17 grade IV) underwent diffusion tensor imaging at 3T. Mean FA, maximum FA, and minimum FA values were measured within the solid tissue components of the tumors. The variations of FA were evaluated by determining the range of FA values and the maximum SDs of FA. The variations of FA values among different tumor grades were compared statistically. We also correlated FA variations with minimum FA and maximum FA. RESULTS: The maximum FA, FA range, and maximum SD for grade II tumors were significantly lower than those for grade III and IV tumors (P < .0001 ∼ P = .0164). A very good correlation of maximum FA to FA range (r = 0.931) and maximum SD (r = 0.889) was observed. CONCLUSIONS: The FA range and maximum SD appear useful for differentiating low- and high-grade gliomas. This analysis added value to the findings on conventional MR imaging. In addition, focal maximum FA is a key factor contributing to the larger FA variation within high-grade gliomas.

Level VI lymph node dissection for papillary thyroid cancer.

Papillary thyroid cancer (PTC) is the most common endocrine malignancy and commonly metastasizes to regional lymph nodes. Surgical treatment of cervical lymph nodes in PTC remains controversial. It has traditionally been accepted that regional lymph node metastases in PTC may increase local recurrence rates but do not ultimately affect survival. This conventional wisdom has been challenged by recent reports indicating that regional lymph node metastases do increase mortality. Thus, there has been renewed interest in operative control of nodal disease for PTC. A systematic review of central lymph node dissection (CLND) in the recent literature using evidence-based criteria permitted formation of the following five recommendations: 1) limited data suggest benefit with the addition of prophylactic CLND to thyroidectomy (grade C); 2) systematic compartment-oriented CLND may decrease recurrence of PTC and improve disease-specific survival (no grade); 3) the addition of CLND to total thyroidectomy can significantly reduce levels of serum thyroglobulin and increase rates of athyroglobulinemia (no grade); 4) there may be a higher rate of permanent hypoparathyroidism and unintentional permanent nerve injury when CLND is performed with total thyroidectomy than for total thyroidectomy alone (grade C); 5) reoperation in the central neck compartment for recurrent PTC may increase the risk of hypoparathyroidism and unintentional nerve injury when compared to total thyroidectomy with or without CLND, supporting a more aggressive initial operation by experienced endocrine surgeons (grade C). Taken together, these recommendations support the application of routine CLND at the initial operation for papillary thyroid cancer in expert hands.

Analysis of central nervous system vasculitis with diffusion-weighted imaging and apparent diffusion coefficient mapping of the normal-appearing brain.

BACKGROUND AND PURPOSE: Diffusion-weighted imaging (DWI) is a novel method of studying the brain that creates tissue contrast secondary to water diffusion. Central nervous system (CNS) vasculitis is a rare inflammatory disease that continues to be difficult to diagnose and evaluate with MR imaging. DWI with apparent diffusion coefficient (ADC) analysis may demonstrate abnormalities within the brain that would otherwise be undetected by conventional imaging, thus aiding in the diagnosis and evaluation of patients with CNS vasculitis. MATERIALS AND METHODS: A retrospective analysis was performed of patients who were diagnosed with CNS vasculitis and had undergone DWI. A total of 15 patients who had DWI with b = 1000 were analyzed. Regions of interest were drawn in the anterior, central, and posterior regions of white matter (WM) at 3 levels. Regions of interest were also drawn bilaterally in the caudate heads, putamina, thalami, posterior internal capsules, and the cerebellar WM. ADC values were measured and compared with 15 healthy controls who were matched for age, sex, and MR imaging scanner. RESULTS: There was a significant increase in the ADC values (P<.00625) for the anterior WM, central WM, thalami, and posterior internal capsules in patients with CNS vasculitis. CONCLUSION: Diffuse increase in water diffusion was present in the normal-appearing brain in patients with CNS vasculitis, and these abnormalities were not demonstrated by conventional MR imaging sequences. The detection and quantification of ADC abnormalities may provide useful diagnostic information for patients with CNS vasculitis.

Impact of the European Working Time Directive on the training of paediatric anaesthetists.

The European Working Time Directive and the New Deal have decreased the number of hours worked by anaesthetic trainees. We implemented the Working Time Directive in May 2004 and evaluated the effect of its implementation on training. During two 6-month periods, one before and one after the change, we determined the number of operating lists undertaken by each Specialist Registrar in Anaesthesia. After implementation of the Working Time Directive, the mean number of lists performed by Specialist Registrars decreased from 24 to 21 lists per registrar per month, a 13% decrease. Exposure to subspecialty lists was the same in both periods, but this was at the expense of general lists and those in remote locations. We conclude that the Working Time Directive has had a measurable impact on the training of paediatric anaesthetists, but that the significance of this change for clinical practice has not yet been measured.

Preoperative and intraoperative predictors of postoperative morbidity, poor graft function, and early rejection in 190 patients undergoing liver transplantation.

HYPOTHESIS: Preoperative and intraoperative variables predict in part adverse outcome after liver transplantation. DESIGN: Prospective, blinded, cohort study. SETTING: Tertiary care hospital. SUBJECTS: A total of 190 adult patients undergoing primary liver transplantation. MAIN OUTCOME MEASURE: Adverse outcome was prospectively defined as either in-hospital death or prolonged postoperative hospitalization (>14 days) associated with morbidity. Potential preoperative and intraoperative risk factors were collected. Associations were tested by univariate analysis followed by multivariate analysis in which preoperative factors were entered before intraoperative factors. RESULTS: Adverse outcome occurred in 44.7% of patients. Incidences of other complications were as follows: in-hospital mortality (8.4%), primary graft nonfunction (4.2%), poor early graft function (1.1%), and early rejection (31.2%). Univariate predictors of adverse outcome were United Network for Organ Sharing status (P =.003), Child-Turcotte-Pugh score (P =.02), POSSUM physiological score (P =.002), recipient age (P =.01), preoperative serum high-density lipoprotein cholesterol level (P =.03), preoperative serum creatinine level (P =.002), preoperative serum total IgG level (P =.004), duration in hospital preoperatively (P =.03), operative duration (P<.001), allogeneic erythrocyte transfusions (P<.001), total intraoperative fluids (P =.002), and use of inotropic agents (P =.01). In the final multivariate model, predictors of adverse outcome were United Network for Organ Sharing status (P =.03), recipient age (P =.002), and total intraoperative fluids (P =.04). Most patients who died or had a prolonged hospitalization exhibited dysfunction of more than 1 organ system, including pulmonary, renal, and infectious complications. CONCLUSIONS: Adverse outcome occurs frequently after liver transplantation, usually involves multiple organ systems, and is predicted in part by several preoperative and intraoperative factors.

Sulcal hyperintensity on fluid-attenuated inversion recovery mr images in patients without apparent cerebrospinal fluid abnormality.

OBJECTIVE: Failure to suppress cerebrospinal fluid (CSF) signal intensity (sulcal hyperintensity) on fluid-attenuated inversion recovery (FLAIR) images has been reported in patients with abnormal CSF, such as those with meningitis and subarachnoid hemorrhage. Our study investigates the clinical history and MR findings associated with sulcal hyperintensity on FLAIR images in patients without apparent CSF abnormality. SUBJECTS AND METHODS: Three hundred consecutive MR imaging examinations were prospectively screened for patients with sulcal hyperintensity on FLAIR images. Nine patients with clinical, CT, or laboratory evidence suggesting abnormal CSF were excluded. The distribution of sulcal hyperintensity on FLAIR images and associated abnormal enhancement were evaluated. The presence of the "dirty CSF" sign (mild increase in CSF signal on unenhanced T1-weighted images or mild decrease on T2-weighted images) in the corresponding hyperintense sulcus was also assessed. RESULTS: Twenty-six (8.9%) of the 291 patients had sulcal hyperintensity (16 focal, 10 diffuse) associated with 18 masses (6.1%) and eight vascular abnormalities (2.7%). Sulcal hyperintensity was frequently associated with the dirty CSF sign (69.2%) and abnormal contrast enhancement (overall, 96.2%; 88.5%, leptomeningeal; 53.8%, vascular enhancement). CONCLUSION: Our study shows that sulcal hyperintensity on FLAIR imaging can occur in patients without apparent CSF abnormality. Its frequent association with mass effect, vascular disease, abnormal vascular enhancement, and dirty CSF sign suggests that an increase in blood pool, a small amount of protein leakage, and the "flow-entering" phenomenon of the congested blood may contribute to sulcal hyperintensity on FLAIR images.

Geographic clustering of Pneumocystis carinii pneumonia in patients with HIV infection.

To detect whether there was geographic clustering of Pneumocystis carinii pneumonia cases among patients with human immunodeficiency virus (HIV) infection, we performed a retrospective analysis of a clinical database. The rates of pneumocystosis were analyzed by zip code zones for evidence of geographical clustering. During the study period, 118 patients at our AIDS Treatment Center had a first episode of P. carinii pneumonia. An analysis of the 24 zip code zones for which a P. carinii pneumonia rate was calculated (requiring a denominator of at least 10 known HIV- infected individuals residing in that zone) showed a trend toward geographic clustering (p = 0.07); when all 45 Cincinnati zip code zones were included in the analysis, clustering of cases was observed (p = 0. 02). By contrast, no clustering was observed for 52 HIV-infected control subjects with respiratory disease or for 960 HIV-infected patients treated at our center during the same time period. These data raise intriguing questions about exposure to exogenous sources of P. carinii and suggest the need for prospective studies.

Cervical spine: MR imaging techniques and anatomy.

MR imaging techniques of the cervical spine are reviewed. Cervical spine anatomy is described, with special attention given to the intervertebral disks, the arterial system, and the peripheral and central nervous systems. Anatomic structures are detailed on sagittal, axial, and coronal MR images.

Dissociation between the time course of ethanol and extracellular dopamine concentrations in the nucleus accumbens after a single intraperitoneal injection.

BACKGROUND: Dopamine release in the nucleus accumbens has been linked to the reinforcing effects of ethanol, but the time course or relationship of this response to ethanol concentrations in the brain has not been studied. METHODS: Various doses of ethanol (0-2.0 g/kg) were administered intraperitoneally to male Sprague Dawley rats, and dopamine and ethanol were simultaneously analyzed in dialysate samples from the nucleus accumbens. A separate study to compare the ethanol-induced dopamine response in male and female rats was carried out by using a 1 g/kg intraperitoneal dose of ethanol. RESULTS: In male rats, 1 and 2 g/kg ethanol significantly increased dialysate dopamine by 40% over basal, whereas 0.25 and 0.5 g/kg ethanol produced a nonsignificant 20% increase. Dialysate ethanol concentrations exhibited a curvilinear decline after reaching peak levels for the lower doses but showed a linear decrease after 1 and 2 g/kg. There was a dissociation between the time courses of extracellular dopamine and ethanol after 1 and 2 g/kg ethanol treatment. The dopamine response returned to basal within 90 min, whereas the ethanol concentrations remained elevated. In a separate study that compared male and female rats, the ratio of the dopamine response over basal to the dialysate ethanol concentrations was significantly decreased at 60 min after an injection of 1 g/kg. However, there were no differences between males and females. CONCLUSIONS: The dissociation between dopamine and ethanol levels may reflect the development of acute tolerance to ethanol-induced dopamine release in the nucleus accumbens within the time course of a single acute injection. Given the strong links between dopamine and ethanol reinforcement, our findings may be relevant for understanding the time course of ethanol's reinforcing effects in vivo.

Preoperative and postoperative endotoxemia in children with congenital heart disease.

STUDY OBJECTIVES: Recent data indicate that increases in inflammatory cytokines are seen in patients with diverse cardiac diseases. However, the primary stimulus for cytokine secretion during cardiac illness remains unknown. Since bacterial endotoxin is a potent inducer of cytokines, we determined the incidence, magnitude, and clinical relevance of endotoxemia in children with congenital heart disease before and after surgical repair. DESIGN: A prospective, observational study. SETTING: A large, urban, university-affiliated, tertiary-care children's hospital. PATIENTS: Thirty children with a variety of congenital heart defects (median age, 59 days; median weight, 4.0 kg) were sequentially enrolled. INTERVENTIONS: Blood was sampled prior to surgery, and at 1, 8, 24, 48, and 72 h following cardiopulmonary bypass. Assays included plasma endotoxin, lipopolysaccharide-binding protein (LBP), and interleukin-6 (IL-6). MEASUREMENTS AND RESULTS: Twenty-nine of 30 patients (96%) had evidence of endotoxemia during the study period. Twelve of the 30 patients (40%) were significantly endotoxemic prior to surgery. LBP, a plasma marker that responds to bacteria and endotoxin, rose significantly following cardiopulmonary bypass, as did the plasma levels of IL-6. Fifteen of 30 patients met prospectively defined criteria for experiencing a severe hemodynamic disturbance in their postoperative course. These patients had significantly higher preoperative plasma LBP (p < 0.02) and plasma endotoxin levels (p < 0.05), compared to patients with less-severely disturbed hemodynamics. Mortality was 25% in patients with preoperative endotoxemia, compared with no mortality in patients who were not endotoxemic before surgery (p = 0.05). CONCLUSIONS: These data demonstrate that endotoxemia in children with congenital heart disease is more common than previously suspected, and is associated with clinical outcomes. We conclude that clinical trials targeting endotoxin will be necessary to determine if endotoxin is a causal, etiologic agent in the disease process.

Current and future imaging of acute cerebral ischemia: assessment of tissue viability by perfusion imaging.

With the advances and availability of new imaging modalities, the role of imaging of acute stroke has been broadened from making diagnosis to providing valuable information for patient management. We need to have rapid diagnostic modalities that distinguish reversible ischemic tissue from irreversibly damaged tissue for successful thrombolytic therapy. Although diffusion imaging has been reported to have both high sensitivity and specificity for acute ischemia in clinical studies, previous reports do not conclude whether the diffusion abnormality is indicative of reversibly or irreversibly injured tissue. Perfusion imaging such as perfusion magnetic resonance imaging and single-photon emission computed tomography may have the potential for providing useful information that determines tissue viability and/or reversibility. Cerebral blood flow thresholds evaluated by pretreatment single-photon emission computed tomography provide important information that is potentially useful in the management of acute stroke patients with intra-arterial thrombolysis. Perfusion imaging, when combined with diffusion imaging, may thus be potentially useful in improving patient selection for thrombolytic therapy.

Depiction of intracranial vessels with MRA: utility of magnetization transfer saturation and gadolinium.

PURPOSE: The purpose of this work was to quantitate the individual and combined effects of magnetization transfer (MT) saturation and gadolinium (Gd) on the visualization of intracranial vessels with MR angiography (MRA). METHOD: Thirty-five subjects underwent two three-dimensional time-of-flight MRA sequences without and with MT and/or Gd. There were 14 MR angiograms without Gd or MT, 18 with MT only, 17 with Gd only, and 21 with both Gd and MT. On a projection image, a region of interest was drawn to delineate the arteries in the middle cerebral artery territory. The total area of blood vessels in the region of interest was calculated for each MR angiogram. Mean vessel areas for the four types of MRA were compared with analysis of variance. RESULTS: MRA with either MT or Gd alone showed significantly more vessel area than MRA without either (p < 0.05). MRA with MT alone and MRA with Gd alone were not different from each other (p = 0.29). The improvement in vessel area measured by using MT and Gd together was significantly more than expected from the cumulative improvement of adding each alone (p < 0.05). CONCLUSION: Combining MT and Gd synergistically improved the visualization of intracranial vessels on MRA.

Gender differences in blood levels, but not brain levels, of ethanol in rats.

Female rodents tend to drink more alcohol than males, a difference that emerges at puberty and appears to vary over the female estrous cycle. In addition, male and female rodents display different responses to alcohol; for example, female rats are reported to have faster elimination rates than males. We were interested in whether circulating ovarian hormones influence alcohol distribution to or elimination from the brain of rats, which might explain observed differences in drinking behavior. We administered 0.8 g/kg of ethanol via intraperitoneal injection to age-matched male and female Sprague-Dawley rats. Extracellular brain ethanol was sampled using microdialysis, and vascular ethanol concentrations were determined via tail blood collection, in two separate experiments. Ethanol pharmacokinetic parameters were calculated for both compartments. There were no differences in pharmacokinetic parameters due to gender or estrous cycle stage in brain ethanol concentration profiles. There were, however, differences in blood ethanol profiles: females showed faster elimination rates and a smaller area under the ethanol concentration versus time curve than males. In addition, the maximum concentration varied significantly across the estrous cycle. These results suggest that (1) circulating ovarian hormones do not influence alcohol distribution to the brain, but do influence distribution to more peripheral tissues such as the tail; and (2) apparent differences in tail blood alcohol levels may not reflect differences in brain levels.

Population pharmacokinetics and pharmacodynamics of the anti-CD11a antibody hu1124 in human subjects with psoriasis.

The pharmacokinetics of hu1124, a human anti-CD11a antibody, were investigated in human subjects with psoriasis. CD11a is a subunit of LFA-1, a cell surface molecule involved in T cell mediated immune responses. Subjects received a single dose of 0.03, 0.1, 0.3, 0.6, 1, 2, 3, or 10 mg/kg of hu1124 intravenously over 1-3 hr. Blood samples were collected at selected times from 60 min to 72 days after administration. Plasma samples were assayed for hu1124 by ELISA, and pharmacokinetic analyses were performed on the drug plasma concentrations. As the dose of hu1124 was increased, the clearance decreased from 322 ml/day per kg at 0.1 mg/kg to 6.6 ml/day per kg at 10 mg/kg of hu1124. The plasma hu1124 concentration-time profile suggested that the clearance of hu1124 was saturable above 10 micrograms/ml. In addition, treatment with hu1124 caused a rapid reduction in the level of CD11a expression on CD3-positive lymphocytes (T cells) to about 25% of pretreatment levels. Regardless of the hu1124 dose administered, cell surface CD11a remained at this reduced level as long as hu1124 was detectable (> 0.025 microgram/ml) in the plasma. When hu1124 levels fell below 3 micrograms/ml, the drug was rapidly cleared from the circulation and expression of CD11a returned to normal within 7-10 days thereafter. In vitro, half-maximal binding of hu1124 to lymphocytes was achieved at about 0.1 microgram/ml and saturation required more than 10 micrograms/ml. One of the receptor-mediated pharmacokinetic/pharmacodynamic models which was developed describes the dynamic interaction of hu1124 binding to CD11a, resulting in the removal of hu1124 from the circulation and reduction of cell surface CD11a. The model accounts for the continually changing number of CD11a molecules available for removing hu1124 from the circulation based on prior exposure of cells expressing CD11a to hu1124. In addition, the model also accounts for saturation of CD11a molecules by hu1124 at drug concentrations of approximately 10 micrograms/ml, thereby reducing the clearance rate of hu1124 with increasing dose.

Pharmacokinetics of a recombinant amino terminal fragment of bactericidal/permeability increasing protein (rBPI21) after liver surgery in rats and humans.

Major liver resections are associated with considerable morbidity and mortality. Gut-derived bacteria and bacterial endotoxin (LPS) are considered to play a central role in the pathophysiology of these complications. Like human BPI, rBPI21 binds to LPS from Gram-negative bacteria. By binding and clearing of LPS, rBPI21 can inhibit a number of endotoxin-induced humoral and cellular responses. Because of this capacity, rBPI21 could partially compensate for the loss of hepatic mononuclear phagocytic system function after liver resection. However, the liver is also thought to be an important organ for the clearance of BPI, and reduction of liver mass could result in a decreased clearance and exceedingly high plasma levels of rBPI21. In this study we therefore investigated the pharmacokinetics of rBPI21 in rats and in patients undergoing a major liver resection. Rats were administered an intravenous (i.v.) bolus of rBPI21 after undergoing a 60% or 80% hepatectomy (with sham-operated controls). Patients undergoing a hemihepatectomy and healthy volunteers received rBPI21 or placebo by continuous i.v. infusion for 48 h. Plasma concentrations were measured by sandwich ELISA. In rats, 60% hepatectomy did not consistently change the clearance of rBPI21, whereas 80% hepatectomy decreased the clearance of rBPI21 severalfold. In hemihepatectomized patients, the clearance of rBPI21 after major hepatectomy was also slower, when compared with healthy volunteers, but this difference had disappeared within 24 h. Our data indicate that the administration of rBPI21 in patients undergoing liver resection is well tolerated and does not result in exceedingly high plasma levels. Additional studies on the efficacy of rBPI21 in the prevention of complications after hepatectomy are needed.

Stability of hydrogels used in cell encapsulation: An in vitro comparison of alginate and agarose.

The present studies were undertaken to evaluate the in vitro gel stability of the hydrogels alginate and agarose. Gel strength (of alginate and agarose) and protein diffusion (of alginate only) were shown to correlate with gel stability and to be useful techniques to monitor gel stability over time. The gel strengths of alginate and agarose were followed for a 90-day period using gel strength as a measure of gel stability. The gel strength of agarose diminished in the presence of cells because the cells likely interfered with the hydrogen bond formation required for agarose gelation. In the presence of cells, the gel strength of agarose decreased by an average of 25% from time 0 to 60 days, thereafter maintaining that value to 90 days. The gel strength of calcium- or barium-crosslinked alginate decreased over 90 days, with an equilibrium gel strength being achieved after 30 days. The presence of cells did not further decrease alginate gel strength. The gel strengths of calcium- and barium-crosslinked alginates were similar at 60 days-350 +/- 20 g and 300 +/- 60 g, respectively-indicating equivalence in their stability. The stability of calcium-crosslinked sodium alginate gels over a 60-day time period was monitored by diffusion of proteins ranging in molecular weight from 14.5 to 155 kD. From these diffusion measurements, the average pore size of the calcium-crosslinked alginate gels was estimated, using a semi-empirical model, to increase from approximately 176 to 289 A over a period of 60 days. (c) 1996 John Wiley & Sons, Inc.

A phase I safety and pharmacokinetic study of a recombinant amino terminal fragment of bactericidal/permeability-increasing protein in healthy male volunteers.

A phase I pharmacokinetic and safety clinical trial of rBPI23, a recombinant amino terminal fragment of bactericidal/permeability-increasing protein, was conducted in healthy male volunteers. rBPI23 was administered as a 5 or 30 min infusion at doses of .1 to 1 mg/kg. The pharmacokinetics of rBPI23 in human subjects were described by a bi-exponential disposition function with evidence of concentration-dependent kinetics. The alpha half-life increased significantly with increasing dose, from 4-5 min at .1 mg/kg to 7-8 min at 1 mg/kg. The beta half-life varied between 18 and 29 min regardless of dose and the clearance varied from 5 to 10 mL/min/kg. Very little, if any, of the administered rBPI23 was excreted intact in the urine. Electrocardiograms, ionized calcium concentration, prothrombin and partial prothrombin times, hematologic parameters, and blood chemistries remained normal. Furthermore, no antibody response to rBPI23 was observed in any of the subjects.