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OBJECTIVES Renal replacement therapy may be required for acute kidney injury treatment in neonates with complex cardiac conditions. Continuous veno-venous hemofiltration is applied safely in this population but no published recommendations for dose prescription in neonates currently exist. The aim of our study was to evaluate the effects of a relatively small dialysis dose on critically ill neonates. DESIGN Retrospective analysis of clinical charts. SETTING Pediatric Cardiac ICU. PATIENTS Ten critically ill neonates with severe acute kidney injury were analyzed. The primary indication for continuous veno-venous hemofiltration initiation was severe fluid overload with oligoanuria. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS The median (range) age and weight were 3 days (1-12 d) and 2.6 kg (2.1-4.2 kg), respectively, whereas the median continuous veno-venous hemofiltration duration was 17 days (3-63 d). Median prescribed blood flow rate, replacement fluid rate, and net ultrafiltration rate were 12 mL/min (9-50 mL/min), 100 mL/hr (40-200 mL/hr), and 20 mL/hr (5-45 mL/hr), respectively. The median effluent-based continuous veno-venous hemofiltration dose was 35 mL/kg/hr (11-66 mL/kg/hr), whereas the median delivered daily Kt/V per session (24 hr) was 0.5 (0.01-1.8). However, for treatment sessions lasting less than or equal to 12 versus greater than or equal to 12 hours per session, the median prescribed effluent dose was 41 (11-66) and 32 (17-60) mL/kg/hr, respectively (p = 0.06), whereas the delivered creatinine daily Kt/V values were 0.3 (0.01-0.9) and 0.9 (0.5-1.8), respectively (p < 0.0001). An inverse correlation was found between delivered daily Kt/V and the blood concentration differences of both creatinine (r = -0.3; p = 0.0093) and urea (r = -0.3; p = 0.0028) measured at the end and the beginning of a 24-hour treatment. The decrease of creatinine concentration was significantly greater during 24-hour treatment sessions with a delivered daily Kt/V greater than 0.9 than during those with daily Kt/V less than 0.9. CONCLUSIONS Based on these findings, we propose on a provisional basis the use of daily Kt/V as a measure of continuous renal replacement therapy adequacy for critically ill neonates.

Toxin retention is felt to be a major contributor to the development of uremia in patients with advanced chronic kidney disease and end-stage renal disease (ESRD). Uremic retention compounds are classically divided into 3 categories: small solutes, middle molecules, and protein-bound toxins. Compounds comprising the first category, for which the upper molecular weight limit is generally considered to be 500 Da, possess a high degree of water solubility and minimal or absent protein binding. The second category of middle molecules has largely evolved now to be synonymous with peptides and proteins that accumulate in uremia. Although not precisely defined, low-molecular weight proteins as a class have a molecular weight spectrum ranging from approximately 500 to 60,000 daltons. The final category of uremic retention compounds is protein-bound uremic toxins (PBUTs). As opposed to the above small, highly water-soluble toxins, which are largely by-products of protein metabolism, PBUTs have diverse origins and possess chemical characteristics that preclude the possibility of circulation in an unbound form despite being of low molecular weight. This review is the first in a series of papers designed to provide the current state of the art for extracorporeal treatment of ESRD. Subsequent papers in this series will address membranes, mass transfer mechanisms, and future directions. For small solutes and middle molecules, particular emphasis is placed on the important clinical trials that comprise the evidence base regarding the influence of dialytic solute removal on outcome. Because such trials do not exist for PBUTs, the discussion here is instead focused on solute characteristics and renal elimination mechanisms.

Conventional hemodialysis remains an important renal replacement modality for critically ill patients with acute kidney injury. Because prescription of hemodialysis requires goals with regard to the rate and extent of solute and fluid removal, an understanding of the mechanisms by which solutes and fluid are removed during hemodialysis is necessary. This chapter provides an overview of basic mechanisms of solute and fluid transfer during conventional hemodialysis. The major characteristics of hollow fiber membranes influencing solute and water removal are discussed subsequently. Within this section, the chemical composition and physical characteristics of commonly used dialysis membranes and the features determining their solute and water permeability properties are reviewed. Flow distribution inside the dialyzer, internal filtration, and backfiltration phenomena are discussed in the last section of the chapter.

Importance The androgen receptor inhibitor enzalutamide prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC). In controlled clinical studies, 0.5% (10 of 2051) of patients experienced seizure, but patients with a history of or risk factors for seizure were excluded. Men with mCRPC and seizure risk factors have an estimated seizure rate of 2.8 per 100 patient-years without enzalutamide exposure. Objective To assess seizure incidence in patients with seizure risk factors who were receiving enzalutamide for mCRPC. Design, Setting, and Participants The UPWARD study (A Study to Evaluate the Potential Increased Risk of Seizures Among Metastatic Castration-Resistant Prostate Cancer Patients Treated With Enzalutamide) is an international, multicenter (73 sites in 20 countries), single-arm, open-label safety study in institutional practice. Data were collected from September 25, 2013, to February 1, 2016. Patients had at least 1 risk factor for seizure at baseline, including medications that lower seizure threshold, history of stroke, or history of seizure. Exclusion criteria included seizure (assessed by neurologic examination and history) requiring antiseizure medication within the past 12 months. Intervention Treatment with oral enzalutamide, 160 mg/d. Main Outcomes and Measures The primary end point was the proportion of evaluable patients with 1 or more independently confirmed seizures during the 4-month study period; evaluable patients were defined as those who had 3 months or more of treatment or 1 or more confirmed seizures during this treatment period. Results Of 423 patients with mCRPC receiving enzalutamide, 366 were evaluated. At baseline, risk factors for seizure included medications that lowered seizure threshold (242 of 423 patients [57.2%]), history of brain injury (112 [26.5%]), and history of cerebrovascular accident or transient ischemic attack (94 [22.2%]). Four of the 366 evaluable patients (1.1%) had at least 1 confirmed seizure within 4 months of enzalutamide initiation, and 3 (0.8%) additional patients experienced a seizure within 4 months following the 4-month study period. The incidence of confirmed seizure was 2.6 per 100 patient-years (7 seizures). Of the 423 patients receiving enzalutamide, 357 (84.4%) experienced at least 1 treatment-emergent adverse event (an adverse event temporally related to the study treatment); 141 (33.3%) had at least 1 serious treatment-emergent adverse event, and 29 (6.9%) had at least 1 drug-related serious adverse event. Thirty-eight deaths (9.0%) were reported during treatment or within 30 days of drug discontinuation; 4 were considered possibly drug related. Conclusions and Relevance Incidence of seizure is similar in patients with mCRPC and similar seizure risk factors with or without enzalutamide exposure. The risk profile presented, along with the previously established efficacy of enzalutamide, suggests that enzalutamide can benefit patients with a history of seizures or other predisposing factors, but each patient should be closely monitored for the duration of treatment.

Background: Docetaxel–prednisone (DP) is an approved therapy for metastatic castration-resistant prostate cancer (mCRPC). Orteronel (TAK-700) is an investigational, selective, non-steroidal inhibitor of 17,20-lyase, a key enzyme in androgenic hormone production. This phase 1/2 study evaluated orteronel plus DP in mCRPC patients. Methods: Adult men with chemotherapy-naive mCRPC, serum prostate-specific antigen (PSA) ≥5 ng/mL, and serum testosterone

Hemodialysis is a process of mass separation by a semipermeable membrane, utilized to cleanse blood from waste products retained in case of kidney failure. Traditionally, dialysis membranes have been classified based on composition and hydraulic conductance, creating the net differentiation between cellulosic versus non-cellulosic on one hand and low-flux versus high-flux on the other. With the evolution of biomaterials and improved spinning technology, new membranes have been introduced in the market with specific characteristics and refined individual properties. Therefore, we should consider new parameters to classify dialysis membranes including polymer blending, surface functionalization, molecular weight cut-off (MWCO), hydrophilic/hydrophobic properties, thickness and architecture, adsorption capacity, and electric potential. All these parameters may be utilized to characterize a membrane alone or in combination. Recently, a new parameter has been identified as an important element to characterize a new class of membranes. Beyond the classic MWCO describing the molecular weight at which the sieving value in pure convection = 0.1, the molecular weight retention onset (MWRO) is a new parameter that defines membrane sieving properties. The retention onset value is the molecular weight at which the sieving value = 0.9. The relationship between MWCO and MWRO describes the steepness of the sieving curve and the membrane pore size distribution with important consequences on the final mass separation process and solute removal.

Background: Increased expression and neomorphic mutations of the histone methyltransferase EZH2 are often observed in cancer, leading to repression of genes associated with apoptosis and differentiation. High EZH2 expression and low expression of EZH2 target genes in mCRPC correlate with poor prognosis. CPI-1205 is a potent, reversible, cofactor-competitive small molecule inhibitor of EZH2. Preclinical studies revealed that prostate cancer models dependent on androgen receptor signaling (ARS) are sensitive to EZH2 inhibition, and that CPI-1205, when combined with novel ARS inhibitors, results in synergistic cell growth inhibition (Bradley 2018). Here we report preliminary results from the Phase Ib component. Methods: In this multicenter Phase Ib/II study, patients (pts) with mCRPC previously treated with a novel ARS inhibitor were enrolled in different cohorts exploring two regimens of oral CPI-1205 on a continuous 28-day cycle: 800 mg TID or 400 mg BID with cobicistat, a CYP3A4 inhibitor, combined with the standard dose of E (160 mg QD) or standard dose of A/P (1000 mg QD/5 mg BID). Prior chemotherapy was allowed. The primary objective in Phase Ib is to determine safety, a recommended Phase II dose, pharmacokinetics (PK), and pharmacodynamics (PD). Results: As of 11/16/2018, 35 pts were enrolled in four cohorts (two cohorts of CPI-1205 + E; two cohorts of CPI-1205 + A/P) and were treated for ≥1 cycle. Age ranged from 55 to 90 years (median 72). 63% were ECOG 0 and 37% ECOG 1. 13 pts (37%) tested positive for ARV7. 21 pts (60%) had unfavorable circulating tumor cells (CTC) counts at baseline. 6 pts (17%) had prior taxane-based chemotherapy for mCRPC. 16 pts received CPI-1205 + E and 19 pts received CPI-1205 + A/P. Only 1 DLT (asymptomatic reversible ALT increase, Grade 4) was reported in the CPI-1205 + A/P + cobicistat. No serious AE related to the study drug was reported in any cohort. Overall, the commonly reported drug-related treatment-emergent adverse events (TEAEs ≥10%) were low-grade diarrhea (n= 11, 31%), fatigue and nausea (n= 9, 26% each), and decreased appetite (n=5, 14%). Grade ≥3 TEAEs were fatigue and elevated ALT (n=2, 6% each), and nausea, pruritus, hypokalemia, and muscular weakness (n=1, 3% each). 16 pts remain on treatment. Cases of PSA >80% reduction, CTC ≥30% reduction, and RECIST response were observed. Both CPI-1205 regimens resulted in significant target engagement (reduced H3K27me3 in PBMCs and CTCs). Patient sample analysis to maximize biomarker identification is ongoing. PK data will be presented. Conclusions: Both CPI-1205 800 mg PO TID and 400 mg PO BID plus cobicistat, combined with full doses of either E or A/P, are well tolerated, with acceptable safety. Encouraging clinical activity has been observed. CPI-1205 800 mg PO TID + E or A/P has been selected for phase 2 expansion, and patient enrollment is ongoing Citation Format: Mary-Ellen Taplin, Arif Hussain, Satish Shah, Neal D. Shore, William Jeffery Edenfield, Oliver A. Sartor, Luke T. Nordquist, Manish Agrawal, William Clark, David R. Wise, William K. Oh, Mark T. Fleming, James E. Butrynski, Gurkamal S. Chatta, Manojkumar Bupathi, Claudia Lebedinsky, Adrian Senderowicz, Jian Li, Gozde Colak, David Nash, Patrick Trojer, William D. Bradley, Jessica Piel, Emmanuel S. Antonarakis. Phase Ib results of ProSTAR: CPI-1205, EZH2 inhibitor, combined with enzalutamide (E) or abiraterone/prednisone (A/P) in patients with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT094.

A cadmium sulfide (CdS) passivation process was demonstrated for the first time on InGaAs/InP p-i-n mesa photodetectors. The passivated devices produced lower reverse bias leakage currents in comparison to devices that received only a thermally deposited SiO2 film. The subsequent deposition of SiO2 on the passivated devices produced virtually no change to the aforementioned leakage currents even after undergoing a 3-h, 300°C thermal treatment. In contrast, similar SiO2 capped devices, fabricated without the CdS passivating layer, show a large increase in leakage current when subjected to the same thermal cycle. Leakage current versus mesa diameter measurements suggest these results are due to reduce surface recombination at the exposed mesa sidewall. X-ray photoelectron spectroscopy (XPS) results indicate the S:Cd ratio of these films to be 0.77.

Hemodialyzers used for renal dialysis rely upon ultrafiltration to eliminate middle molecular-weight uremic solutes. It is valuable to measure the ultrafiltration rate locally to better understand dialyzer operation and to ensure there is no backfiltration of potential pyrogens into the patient’s blood stream. We used a magnetic resonance flow imaging method to measure the local variation of the ultrafiltration rate along the length of a SYNTRA·160 hemodialyzer. The technique uses magnetic resonance fourier velocity imaging (MRFVI) to determine the percentage of flow in different velocity ranges. From these velocity profiles we estimate the maximum flow velocity in the lumen of the dialyzer fibers. Assuming laminar flow with a parabolic flow profile we estimated the variation in the total volume flow rate at each location where images are made. The local ultrafiltration rate declined uniformly over the length of the dialyzer, and the total rate is in agreement with independent measurements of ultrafiltration rate using pure water.

In free space optical communication, photodetectors serve not only as communications receivers but as position sensitive detectors (PSD) for pointing, tracking, and stabilization. Typically, two separate detectors are utilized to perform these tasks but recent advances in the fabrication and development of large area, low noise avalanche photodiode (APD) arrays have enabled these devices to be used both as PSDs and as data communication receivers. This combined functionality allows for more flexibility and simplicity in optical assembly design without sacrificing the sensitivity and bandwidth performance of smaller, single element data receivers. This work presents a large area, five element concentric avalanche photodiode array rated for bandwidths beyond 1GHz with a measured carrier ionization ratio of approximately 0.2 at moderate APD gains. We discuss the integration of this array in a bi-static optical interrogator where it acts as a data receiver and provides position information for pointing and stabilization. In addition to front-end and digital electronics design, we also describe the optical assembly design and the development of a pointing and stabilization algorithm.

Effect of membrane composition and structure on solute removal and biocompatibility in hemodialysis. Significant changes in extracorporeal membranes have occurred over the past five decades in which hemodialysis (HD) has been available as a therapy for both acute renal failure (ARF) and end-stage renal disease (ESRD). For cellulosic membranes, these changes have included a reduction in thickness, hydroxyl group substitution, and an increase in pore size. These modifications have resulted in enhanced efficiency of small solute removal, a broader spectrum of overall solute removal, and an attenuation of complement activation in comparison to the thick, unsubstituted cellulosic membranes of low permeability used in the early days of HD therapy. Synthetic membranes, originally developed specifically for use in high-flux HD and hemofiltration, have also evolved during this same time period. In fact, the initially clear distinction between low-flux regenerated cellulosic and high-flux synthetic membranes has become blurred, as membrane formulators have developed products designed to appeal to enthusiasts for both membrane formats. The purpose of this review is to characterize both the solute removal and biocompatibility characteristics of dialysis membranes according to their composition (that is, polymeric makeup) and structure. In this regard, the manner in which membrane biocompatibility interacts with flux is highlighted.

CRRT efficiency and efficacy in relation to solute size. Removal of blood solutes in patients with decreased or absent glomerular filtration is the prime objective of continuous renal replacement therapies (CRRTs). However, because these blood solutes are of different molecular weights, factors such as the porosity and hydrophobicity of the filter membranes and the extracorporeal flow rates determine the CRRT that is the most effective filtration system. This article discusses both small and large solute removal, the interaction of convection and diffusion, and the potential for CRRTs to remove particular inflammatory mediators of acute renal failure.

One potential benefit of chronic hemodialysis (HD) regimens of longer duration or greater frequency than typical three-times-weekly schedules is enhanced solute removal over a relatively wide molecular weight spectrum of uremic toxins. This study assesses the effect of variations in HD frequency (F: per week), duration (T: min per treatment), and blood/dialysate flow rates (QB/QD: ml/min) on steady-state concentration profiles of five surrogates: urea (U), creatinine (Cr), vancomycin (V), inulin (I), and beta2-microglobulin (beta2M). The regimens assessed for an anephric 70-kg patient were: A (standard): F = 3, T = 240, QB = 350, QD = 600; B (daily/short-time): F = 7, T = 100, QB = 350, QD = 600; C/D/E (low-flow/long-time): F = 3/5/7, T = 480, QB = 300, QD = 100. HD was simulated with a variable-volume double-pool model, which was solved by numerical integration (Runge-Kutta method). Endogenous generation rates (G) for U, Cr, and beta2M were 6.25, 1.0, and 0.17 mg/min, respectively; constant infusion rates for V and I of 0.2 and 0.3 mg/min, respectively, were used to simulate middle molecule (MM) G values. Intercompartment clearances of 600, 275, 125, 90, and 40 ml/min were used for U, Cr, V, I, and beta2M, respectively, For each solute/regimen combination, the equivalent renal clearance (EKR: ml/min) was calculated as a dimensionless value normalized to the regimen A EKR, which was 13.4, 10.8, 6.6, 3.7, and 4.8 ml/min for U, Cr, V, I, and beta2M, respectively. For regimens B, C, D, and E, respectively, these normalized EKR values were U: 1.04, 0.96, 1.58, and 2.22; Cr: 1.03, 1.08, 1.80, and 2.55; V: 1.06, 1.32, 2.21, and 3.12; I: 1.05, 1.54, 2.57, and 3.62; beta2M: 1.00, 1.27, 1.73, and 2.19. The extent of post-HD rebound (%) was highest for regimens A and B, ranging from 16% (urea) to 50% (inulin), and lowest for regimen E, ranging from 6% (urea) to 28% (beta2M). The following conclusions can be made: (1) Relative to a standard three-times-weekly HD regimen of approximately the same total (weekly) treatment duration, a daily/short-time regimen results in modest (3 to 6%) increases in effective small solute and MM removal. (2) Relative to a standard three-times-weekly HD regimen, a three-times-weekly low-flow/long-time regimen results in comparable effective small solute removal and progressive increases in MM and beta2M removal. A daily low-flow/long-time regimen substantially increases the effective removal of all solutes.

The effects of bleach reprocessing on the performance of high-flux dialyzers have not been comprehensively characterized. We compared the effects of automated bleach/formaldehyde reprocessing on solute and hydraulic permeability for cellulose triacetate (CT190) and polysulfone (F80B) dialyzers using an in vitro model. Dialyzers were studied after initial blood exposure (R0) and after 1 (R1), 5 (R5), 10 (R10), and 15 (R15) reuse cycles. Ultrafiltration coefficient (K(uf)), serial clearances, and/or sieving coefficients (SCs) of urea, creatinine, vancomycin, inulin, myoglobin, and albumin were determined. Urea, creatinine, and vancomycin clearances and SCs did not significantly differ from R0 to R15 with either dialyzer. Inulin clearances and SC also did not significantly change from R0 to R15 for the CT190. However, these same values for the F80B significantly increased (P0.05). The inulin clearance and SC values for the CT190 dialyzer were significantly higher than those for the F80B at all stages except R15. Myoglobin clearances significantly increased over 15 reuses for both dialyzers (P0.01). However, CT190 myoglobin clearances were significantly higher at all stages (R0 = 37.7 +/- 9.7; R15 = 52.5 +/- 8.8 mL/min) than the F80B (R0 = negligible; R15 = 41.3 +/- 16.5 mL/min; P0.01). Albumin pre- and postdialysis SCs significantly increased for both dialyzers (P0.01). K(uf) for R0 and R15 were 52.3 +/- 3.3 and 52.6 +/- 7.6 mL/h/mm Hg for CT190 (P = not significant) and 48.8 +/- 4.4 and 87.3 +/- 7.0 mL/h/mm Hg for F80B (P0.0001). We conclude that bleach reprocessing significantly increases larger solute and hydraulic permeability of high-flux cellulosic and polysulfone dialyzers. This effect is more pronounced for the polysulfone membrane. Until 10 reuses or greater, the removal of solutes greater than 1,500 d is significantly compromised with the polysulfone dialyzer used in this study.

High-sensitivity photodetectors serve two purposes in free-space optical communication: data reception and position sensing for pointing, tracking, and stabilization. Two separate detectors are traditionally utilized to perform these tasks, but recent advances in the fabrication and development of large area, low-noise avalanche photodiode (APD) arrays have enabled these devices to be used both as position-sensitive detectors and communications receivers because of the conflicting performance criteria. Combining these functionalities allows for more flexibility and simplicity in optical assembly design without sacrificing the sensitivity and bandwidth performance of smaller, single-element data receivers. Beyond eliminating the need to separate the return beam into two separate paths, these devices enable implementation of adaptive approaches to compensate for focal plane beam wander and breakup, which is often seen in highly scintillated terrestrial and maritime optical links. While the Naval Research Laboratory and Optogration, Inc. have recently demonstrated the performance of single period, InAlAs/InGaAs APD arrays as combined data reception and tracking sensors, an impact-ionization-engineered epilayer design achieves even lower carrier ionization ratios by incorporating multiple multiplication periods engineered to suppress lower ionization rate carriers while enhancing the higher ionization rate carriers of interest. This work presents a three-period I2E concentric, five-element APD array rated for bandwidths beyond 1 GHz with measured carrier ionization ratios of 0.05 to 0.1 at moderate APD gains. The epilayer design of the device will be discussed along with initial device characterization and high-speed performance measurements.

Photodiode arrays are instrumental in providing pointing and tracking information for free space optical communication systems. Recent advances in the fabrication and development of low noise, high bandwidth avalanche photodiode (APD) arrays have enabled these devices to be used not only as position sensitive detectors (PSD) for tracking but also as communications receivers. In a collaborative effort with Optogration, Inc., the U.S. Naval Research Laboratory has developed avalanche photodiode arrays with three different geometries: a 3x3 square pixel array, a centered hexagonal pixel array, and a 5 pixel concentric array configuration with a center pixel and four periphery pixels. The characterization and performance of each array geometry will be described along with associated front-end and digital electronics. Design tradeoffs for maximizing the performance of a given array geometry will also be discussed.© (2012) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE). Downloading of the abstract is permitted for personal use only.

The effects of wood and cotton smoke and several known smoke components on the dynamic surface activity of pulmonary surfactant were characterized with a modified Wilhelmy balance. Surfactant was harvested by saline lavage from dog lungs, placed in the balance and a control surface tension/area isotherm (y-A) and surface tension at minimum area (control y/min = 6.6 +/- 1.6 dynes/cm) measured. Hysteresis area (HA), recruitment index (RI), and stability index (SI) were calculated. Following control measurements, smoke (wood or cotton) was gently blown over the surfactant in the balance. Similarly, each of the individual smoke components or Liquid smoke (prepared by bubbling wood smoke through saline) were injected onto the balance. Wood smoke significantly (P0.05) altered all surface properties measured, increasing ymin (22.0 +/- 1.6 dynes/cm) and decreasing HA, RI, and SI as compared to control; cotton smoke exposure had almost no effect on surfactant function. A supplementary dose of surfactant was added to the balance, following wood smoke exposure, which decreased ymin (9.4 +/- 2.6 dynes/cm, P = NS vs control) but not the other parameters to control. Acrolein, formaldehyde, and HCl had little effect on any of the surface properties measured whereas isobutyraldehyde and liquid smoke altered the y-A curve but did not increase ymin. These data demonstrate that wood but not cotton smoke inhibit surfactant function, however, surfactant function can be restored, following deactivation by smoke, suggesting that surfactant replacement therapy for victims of severe smoke inhalation may be of benefit.

Free space optical communication uses photode tectors for two purposes: as communicati ons receivers and, in the form of a quadrant cell or a position sensitive detector, for tracking. Generally two separate detectors are used. In this work we describe combining these functions into one device through the use of heterostructure avalanche photodiode (APD) arrays. Combined functionality more efficiently uses the available light and allows for large area communications detector arrays that maintain the bandwidth and sensitivity of smaller, single-element, devices. In this paper we describe a prototype 2x2 arrays and associated electronics and processing. The design tradeoffs in balancing both functions are explored and future geometries that are more effective than square arrays are described. Keywords : free-space laser communication, avalanche photodiod e arrays, position sensitive detector, quadrant cell 1. INTRODUCTION Photodetectors play an important role in the design and performance of a free space optical (FSO) communications system. Not only are photodetectors esse ntial in receiving transmitted data but they also provide valuable position information that can be used by a FSO communications system for pointing, tracking, and stabilization. The extent to which these systems can perform these tasks reliably hinges upon the sensitivity, bandwidth, and dynamic range of the system’s photodetector and accompanying front-end electroni cs. Typically, a position sensitive detector is used for tracking information while a separate, smaller active area and therefore, more sensitive and higher bandwidth photodetector is used as a data receive r. The simplicity, performance, and abund ant supply of PIN- based photodetectors combined with the relative immaturity of InGaAs aval anche photodiodes (APD) compared to their silicon-based counterparts made APD detectors a non-viable option for near-IR FSO systems in past years. Recently, advances in device fabrication coupled with more novel heterostructure designs have led to significant improvements in the performance of APDs [1]. In particular, important improvements have come in the form of reduced APD excess noise. In an ideal world, an APD would act as a PIN photodiode with significantly more gain. In actuality, the randomness of an avalanche event matched with very high operating gains means an additional source of noise compared to shot-noise limited PIN photodiodes. The APD excess noise factor, F , is a function of the effec tive carrier ionization ratio, k

The U.S. Naval Research Laboratory (NRL) is characterizing InGaAs avalanche photodiodes (APDs) with internal structures engineered to reduce dark counts and ionization coefficient ratio (keff). Recently, much progress has been made in the use of APDs in linear mode for photon counting applications.1 However, the best results in linear mode single photon counting in InGaAs devices have been obtained by cooling the devices well below 200 K to reduce dark current. The single photon counting capability is due to the high gain available in the tail of the APD gain distribution, and this high gain tail is enhanced by reducing the ionization ratio (keff) and dark noise.2 Since recent promising results in linear mode APD photon counting have involved engineering the APDs to reduce keff, it is likely that these devices will also perform much better than standard APDs in free space lasercomm applications at temperatures which can easily be reached by thermoelectric coolers, or even uncooled, due to the keff reduction. NRL has obtained several InGaAs APDs of both the standard design and of a new design using impact ionization engineering from OptoGration, Inc. of Wilmington, MA. Some results of characterization of these APDs will be presented.

In free space optical communication systems, atmospheric turbulence makes it very difficult to focus transmitted laser power onto small, low capacitance photodetectors. The obvious challenge, therefore, is to take advantage of larger area photodiodes without sacrificing a great deal of bandwidth and sensitivity in the process. In this work, we report on a high sensitivity, high speed adaptive avalanche photodetector array for free-space optical communication. The receiver consists of a 2×2 InGaAs APD array with each 100um element in the array having its own dedicated trans-impedance amplifier and buffering stage. The corresponding voltage outputs for each element are processed through a four channel digital, fast switching and summation circuit. The resulting signal is selectable to be either that of the element in the array with the greatest signal response or the sum of multiple or all channels. Design requirements, laboratory sensitivity measurements, and field testing results are presented.

The effect of high alveolar surface tension on alveolar epithelial permeability was studied in anesthetized closed-chest mongrel dogs. Alveolar surface tension was elevated by displacement of pulmonary surfactant from the alveolar hypophase by the aerosolized detergent dioctyl sodium sulfosuccinate (OT). After measurement of baseline hemodynamics, arterial blood gases, and airway pressure, the dogs were separated into groups: Group I inhaled a 1% solution of OT (15 mg/kg) in a vehicle of equal parts saline and ethanol; group II inhaled the same volume of vehicle without OT. The pulmonary clearance of technetium 99m diethylenetriamine-pentaacetic acid (99mTc-DTPA) (half-time in minutes) was studied immediately after aerosol (OT and vehicle) delivery and compared with that of historical control values. No change was seen in arterial blood gases and airway pressure after vehicle inhalation, whereas OT caused a marked fall in arterial oxygen tension and increase in airway pressure. Vehicle inhalation effected only a slight increase in DTPA clearance, whereas OT significantly reduced half-time over control and group II. These data suggest that high alveolar surface tension increases alveolar epithelial permeability.

Anesthetized dogs with thoracotomy were injected with Evans blue dye and were exposed acutely (5 min) to wood smoke inhalation. Thin slices from freeze-dried samples were photographed and assessed for periarterial and perivenous cuff area and for blue coloration with a score of 0 to 5. Bloodless extravascular lung water (EVLW) was also measured. The smoke-exposed animals were compared with controls and with animals exposed to alloxan or to high-pressure-induced pulmonary edema. EVLW at 2 h after smoke (6.46 +/- 0.80) was above control value (4.30 +/- 0.63) but not different from the alloxan (6.13 +/- 0.70) or high-pressure (6.88 +/- 1.30) groups. Despite the similarity in EVLW in the edematous lungs, there were marked differences in the intensity of blue color and size of cuffing around arteries and veins: the smoke, alloxan, and high-pressure groups had blue color scores of 1.0 +/- 0.1, 2.9 +/- 0.3, and 0.3 +/- 0.1, respectively. These scores indicated a large increase in microvascular permeability to proteins in the alloxan group, a moderate increase in the smoke group, and minimal change in the high-pressure group. The perivascular cuff area was largest in the alloxan group and moderate in the smoke and high-pressure groups. The cuff area was higher for arteries than for veins in all groups except the 0.5-h smoke group. We conclude that smoke inhalation causes a moderate increase in permeability and EVLW compared with alloxan. The extravascular lung water accumulates preferentially around the arteries, but the size of the perivascular cuff is not similar for all causes of pulmonary edema.

This paper presents results of three research and development efforts on the subject of avalanche photodiodes with InGaAs absorbers and InAlAs multiplication layers. The first portion of the paper presents results on 256x256 arrays of InAlAs-InGaAs APDs. These spanned more than 1.5 cm x 1.5 cm, had breakdown voltage variation of less than 2.5 volts and a dark current range between 1.5 and 3.5 nA at a gain of 10. The second portion of the paper presents single photon detection results of a receiver with a 50 micron aperture avalanche photodiode biased into sub-Geiger mode and a Maxim MAX3658 transimpedance amplifier. At temperatures of 200K and average avalanche gains approaching 1000 single photon detection efficiencies greater than 5% were observed with dark count rates of less than 500 kHz. At 175 K detection rates were as high as 14%. Finally, in the third portion of this paper, performance results of a novel impact ionization engineered InGaAs-InAlAs based avalanche photodiode are presented showing excess noise values lower than any previously published InGaAs based avalanche photodiode.

The U. S. Naval Research Laboratory (NRL) and OptoGration, Inc. have collaborated in the development and testing of large area, high speed InGaAs avalanche photodiode (APD) receivers for use in free-space lasercom systems. A 200 micron diameter InGaAs APD receiver has been tested in a free-space lasercom testbed and has demonstrated sensitivities of -42.4 dBm at 622 Mbps and -44.8 dBm at 155 Mbps. A 100 micron diameter receiver has been tested with a resulting sensitivity of -35.75 dBm at 2.4883 Gbps. These receivers are made possible due to OptoGration's capability to manufacture a large area, high speed InGaAs APD with an effective ionization ratio of < 0.2 and by matching the APD device with an appropriate transimpedance amplifier and limiting amplifier. Development and testing of the APD receivers will be described below.

For critically ill patients treated with continuous hemofiltration (HF), doses recently shown to improve survival can usually be achieved only in the pre-dilution mode. However, use of the pre-dilution mode results in reduced treatment efficiency, relative to post-dilution at the same ultrafiltration rate (Qf) and blood flow rate (Qb). The objective of this study is to determine the effect of Qf on removal parameters for solutes over a wide molecular weight spectrum in pre-dilution HF. Experiments were performed in an isovolemic, plasma-based pre-dilution system with Qb=200 ml/min. Removal parameters were measured for a 1.2 m2 polysulfone hemofilter (HF1200, Minntech) at Qf values of 20, 40, and 60 ml/min, corresponding to 17, 34 and 51 ml/h/kg for a 70 kg patient (N=3 hemofilters for each Qf). Clearance of urea and creatinine (small solute surrogates) was derived from plasma and ultrafiltrate concentrations at 30, 60, 120, 180, and 240 min while clearance of vancomycin and inulin (middle molecule surrogates) was estimated from changes in plasma concentrations over time. In addition, the sieving coefficient (SC) of vancomycin and inulin was measured at the same time points and at baseline (T=0 min). Our findings indicate pre-dilution had a predictable effect on clearance for each solute, as clearance increased linearly with Qf. Sieving coefficient values were not significantly influenced by either Qf or time and the equivalence of SC values in the middle molecule range suggest attenuation of secondary membrane effects. These data indicate filter performance can largely be preserved despite high Qf values by use of pre-dilution. Moreover, Qf appears to be a reasonable dose surrogate in pre-dilution HF.

III-V based single photon avalanche diodes (SPADs), avalanche photodiodes (APDs) operated in Geiger-mode, are ideally suited for ultra-weak signal detection in the near infrared for photon counting and photon timing applications. Spaceborne SPADs would provide a rugged, compact alternative to photomultiplier tubes with lower operating voltage requirements, stronger near-IR response, and the possibility for array implementation. Results from a performance characterization of an in-house fabricated In0.53Ga0.47As/InP SPAD are presented. Sensitivity (NEP) and timing resolution (δt) were investigated as a function of bias from T = 135 K to 165 K; an NEP ≈ 5 x 1015W/Hz1/2 at T = 150 K and δt ≈ 230 ps at T = 165 K were measured for λ = 1.55 μm light.

Molecular weight has traditionally been the parameter most commonly used to classify uremic toxins, with a value of approximately 500 Da frequently used as a demarcation point below which the molecular weights of small nitrogenous waste products fall. This toxin group, the most extensively studied from a clinical perspective, is characterized by a high degree of water solubility and the absence of protein binding. However, uremia is mediated by the retention of a plethora of other compounds having characteristics that differ significantly from those of the previously mentioned group. As opposed to the relative homogeneity of the nitrogenous metabolite class, other uremic toxins collectively are a very heterogeneous group, not only with respect to molecular weight but also other characteristics, such as protein binding and hydrophobicity. A recently proposed classification scheme by the European Uraemic Toxin Work Group subdivides the remainder of molecules into 2 categories: protein-bound solutes and middle molecules. For the latter group, the Work Group proposes a molecular weight range (500-60,000 Da) that incorporates many toxins identified since the original middle molecule hypothesis, for which the upper molecular weight limit was approximately 2,000 Da. In fact, low-molecular-weight peptides and proteins (LMWPs) comprise nearly the entire middle molecule category in the new scheme. The purpose of this article is to provide an overview of the middle molecule class of uremic toxins, with the focus on LMWPs. A brief review of LMWP metabolism under conditions of normal (and in a few cases, abnormal) renal function will be presented. The physical characteristics of several LMWPs will also be presented, including molecular weight, conformation, and charge. Specific LMWPs to be covered will include beta 2-microglobulin, complement proteins (C3a and Factor D), leptin, and proinflammatory cytokines. The article will also include a discussion of the treatment-related factors influencing dialytic removal of middle molecules. Once these factors, which include membrane characteristics, protein-membrane interactions, and solute removal mechanisms, are discussed, an overview of the different therapeutic strategies used to enhance clearance of these compounds is provided.

Background The investigational agent TAK-700 (orteronel) is a selective 17,20-lyase inhibitor that blocks androgen production. Since DP is currently standard chemotherapy in mCRPC, this phase 1/2 study examined TAK-700 + DP in men with mCRPC. Methods The primary phase 2 objective is tolerability of TAK-700 400 mg BID + D (75 mg/m q3w) + P (5 mg BID) in castrate men (testosterone [T] Results 24 men were treated: median age was 66 yrs (range 53–87), ECOG PS 0/1 (88%/12%). At baseline, median PSA was 47 ng/mL (4.5–813) and T was 7.2 ng/dL (3.2–13.8). At data cutoff, 15/24 men remained on study treatment. 22/24 men experienced a treatment-related AE. 3 men discontinued due to AEs (ALT increase, arthralgia, pneumonitis). 21 men (88%) had at least 1 Gr ≥3 AE (19 were drug-related). Drug-related Gr ≥3 AEs ≥10% were WBC decreased (29%); neutropenia (25%); decreased neutrophil count (25%); fatigue, and febrile neutropenia (each 13%). The most common drug-related SAE was febrile neutropenia (13%). As of cutoff, there were no on-study deaths. At 3 mo, PSA30, PSA50, and PSA90 rates in the PSA evaluable population were 59%, 50%, and 18%, respectively. Best PSA decline (median) was -76% (n = 22; -99 to +144%). Median T at 3 mo decreased to ≤0.2 ng/dL (0.3–10.6). Best ORR 50% (n = 10; 80% CI: 27,73; partial response in 5 of 10 evaluable men). Median time to PSA progression was 6.1 mo (95% CI: 4.6, not reached) and median time to radiologic progression was not reached. The Cmax of DP + TAK-700 was similar to that of DP alone. Conclusions TAK-700 400 mg BID + DP appears tolerable and shows androgen-lowering activity and strong PSA and partial tumor response in mCRPC. Plasma levels of D administered with TAK-700 + P were similar to published data on DP without TAK-700. Disclosure D.P. Petrylak: Consultant/Advisor: Amgen, Bayer, Pfizer, Ferring, Millennium, Novartis, Dendreon, Johnson & Johnson, Glaxo Smith Kline Research funding: Celgene, Dendreon, Sanofi, Pfizer, AstraZenca, Glaxo Smith Kline, Rogosen institute, Boehringer Ingelheim, W.R. Clark: Investigator for BMS, Millenium, Lily, Watson, Roll International, Astellas, E.I. Heath: Research funding: Millennium Pharmaceuticals, Ltd. W.K. Oh: Advisor/consultant: Amgen, Pfizer, Sanofi, Dendreon, Bellicum, and Medivation, D.B. Agus: Millenium Pharmaceuticals, Inc./Takeda Advisory Board, S. Moran: Employment: Millennium Pharmaceuticals, Inc. All other authors have declared no conflicts of interest.

Two increasingly common characteristics of the American chronic hemodialysis (HD) population, high hematocrit and large body size, may render the currently recommended adequacy targets difficult to achieve, even with very efficient dialyzers. In a group of patients with these characteristics, we assessed the ability of a new high efficiency dialyzer (PSN210; Baxter Healthcare Corporation) to achieve the currently recommended adequacy targets. Six patients (mean pre-HD weight and hematocrit, 90.3 +/- 18.0 kg and 0.40 +/- 0.03 kg, respectively) were evaluated. At prescribed blood and dialysate flow rates of 400 and 800 ml/min, respectively, and a mean treatment duration of 4 hrs, mean delivered urea Kt/V and reduction ratio (URR) were 1.38 +/- 0.25 and 0.73 +/- 0.07, respectively. For the same flow rates, whole blood clearances for urea, creatinine, and phosphate were 315 +/- 13, 246 +/- 28, and 260 +/- 27 ml/min, respectively. These data indicate this dialyzer has an efficient mass transfer design allowing adequate dialysis to be delivered even to very large patients under high efficiency conditions.

The recognition that both morbidity and mortality are is an additional (implied ) corollary of the steady-state inversely related to delivered haemodialysis (HD) dose assumption. For stable chronic HD patients, typical in end-stage renal disease ( ESRD) patients [1‐4] has normal protein catabolic rate (nPCR) values are in the substantially changed clinical practices in the US. 0.8‐1.2 g/kg/day range while normalized urea distriNumerous quantification techniques diVering greatly bution volume ( V ) is usually in the 0.55‐0.60 l/kg in complexity and sophistication are now used in range. ESRD patients. These techniques include the formal Typical values of both nPCR and V in ARF patients (variable-volume single pool: VVSP) urea kinetic diVer greatly from the above values reported for stable model [5], which requires three successive blood urea ESRD patients, as the clinical state of critically ill nitrogen (BUN ) determinations and a computer cap- ARF patients is inherently a non-steady-state situation. able of iterative calculations, and a number of simpler High rates of protein catabolism (>1.5 g/kg/day) and methods designed to be more ‘user-friendly’ to the generally large net nitrogen deficits (> 5g /day) are

Background. In comparison to conventional haemodialysis membranes, highly permeable membranes allow a broader spectrum of solute removal, including enhanced elimination of vancomycin (1448 Daltons). However, the mass transfer characteristics of vancomycin removal by highly permeable membranes have not been adequately assessed. An understanding of vancomycin's predominant dialytic mass transfer mechanism under a given set of operating conditions, including dialyser type and flow rates, may permit more accurate dosing of the drug. Methods. We performed a mass transfer analysis of vancomycin removal by a high-flux dialyser, cellulose triacetate (CT). In a cross-over fashion with a 3-week washout between treatments, eight subjects received vancomycin 1000 mg (1) during the last hour of CT haemodialysis; or (2) after dialysis. Serial urea and vancomycin serum concentrations were used to assess dialytic removal. Results. Dialysis removed 26.2% (mean; range 16-44%) of the administered vancomycin dose. While vancomycin removal and (Kt/V) urea were directly correlated (r=0.88; P

Epitaxial layer transfer was used to fabricate In/sub 0.53/Ga/sub 0.47/As-InP avalanche photodiodes on GaAs substrates. The photodiodes displayed a gain-bandwidth product of 80 GHz, dark current of 10.20 nA at 90% of the breakdown voltage, and responsivity of 5.9 A/W at 2 V below breakdown. Performance is comparable to standard devices fabricated on InP substrates, suggesting the transfer process does not degrade material quality.

59 Background: Orteronel is an investigational non-steroidal, selective inhibitor of 17,20-lyase, a key enzyme in the production of steroidal hormones. DP is currently an approved therapy in mCRPC; this phase 1/2 study examined orteronel + DP in men with mCRPC. Methods: Castrate men (testosterone [T] 2 q3w) + P (5 mg BID). The primary phase 2 objectives were tolerability, PK, serum PSA declines, and best PSA response. Secondary objectives included time to progression of PSA ± radiographic disease, response by RECIST 1.1. Results: At data cutoff (July 23, 2012), 24 men had been treated and 12 remained on study: median age was 66 yrs (n=24, range 53–87), ECOG PS 0/1 (88%/13%). At baseline, median PSA was 46 ng/mL (4.5–813) and T was 6.8 ng/dL (2.6–13.8). 9 men discontinued due to AEs (the most common was fatigue [13%]). All men reported at least 1 Gr ≥3 AE (23 were drug-related). Drug-related Gr ≥3 AEs ≥10% were neutropenia (38%); WBC decreased (25%); fatigue (21%); decreased neutrophil count (17%); blood alkaline phosphatase increased, and leukopenia (each 13%). The most common drug-related SAE was dehydration (13%). There were 2 on-study deaths, due to disease progression and respiratory distress, both considered unrelated to treatment. At 3 mo, PSA response was evaluable in 18 men; PSA30/50/90 rates were 83%/72%/28%. Best PSA decline (median) was -76% (n=23; -99 to +144%). Median T at 3 mo decreased to ≤0.2 ng/dL (0.3–10.6). Response was evaluable in 9 men; 5 achieved a PR; ORR was 56% (n=9; 80% CI: 30, 79). Median time to PSA progression was 6.1 mo (95% CI: 4.6, not reached); median time to radiologic progression was not reached. The Cmax of orteronel + DP was similar to that of DP alone with no evidence of DDI. Conclusions: Orteronel 400 mg BID + DP appears tolerable and shows androgen-lowering activity, and strong PSA and partial tumor response in mCRPC. There was no evidence of DDI between orteronel and DP. Updated data, including a detailed PK analysis, will be presented. Clinical trial information: NCT01084655.

Continuous veno-venous hemofiltration (CVVH) has been reported to provide beneficial effects during endotoxic shock. This experiment was designed to determine if selective removal of plasma mediators occurs during CVVH and if plasma concentrations of these mediators are reduced. A swine endotoxic-shock model with three groups was used (lipopolysaccharide (LPS) only (n = 6); LPS followed by CVVH (n = 6); and LPS followed by sham CVVH (n = 4). Plasma and filtrate samples were collected at frequent intervals for 5 h. Lactic acid (LA), eicosanoids [prostacyclin (6-keto PGF1 alpha), thromboxane (TxB2), and prostaglandin E2 (PGE2)] and tumor necrosis factor (TNF) were measured in plasma and filtrate. Plasma concentrations of 6-keto PGF1 alpha, TxB2, TNF, and LA were not significantly different in any group. LA, PGE2, 6-keto PGF1 alpha, and TXB2 concentrations were similar in filtrate and plasma. TNF did not move across the membrane into the filtrate, CVVH, as used in this experiment, did not significantly reduce plasma concentrations of any of these mediators.

Plasma protein adsorption to highly permeable hemodialysis membranes. Although membrane adsorption of plasma proteins is one of several factors determining the biocompatibility and mass transfer characteristics of a hemodialyzer, this process has not been evaluated rigorously. We performed an equilibrium and kinetic analysis of the binding of proteins of differing molecular weight to highly permeable membranes of differing hydrophobicity and surface change. Hydrophobic, anionic poly-acrylonitrile (PAN) and hydrophilic, uncharged cellulose triacetate (CT) membrane fragments were incubated in buffer containing radioiodinated β 2 -microglobulin (β 2 m) or bovine serum albumin (BSA). From an initial solution concentration of 50 mg/liter, both membranes adsorbed significantly more β 2 m than BSA at equilibrium (PAN, 352 ± 30 vs. 32.1 ± 2.4 ng; CT, 87.0 ± 0.6 vs. 30.8 ± 1.7 ng). These results were consistent with membrane pore exclusion of BSA. Comparison of the slopes of the equilibrium isotherm lines (concentration range, 0 to 220 mg/liter) showed the PAN binding affinity for β 2 m and BSA was 28 and 1.4 times that of CT, respectively. In kinetic studies, the approach to equilibrium versus (time) 1/2 was assessed. For all protein-membrane combinations, this relationship was linear, consistent with a diffusion-controlled process. This latter characteristic permitted the determination of β 2 m membrane diffusivity values for both PAN and CT, which were found to be 0.30 and 3.25 × 10 -7 cm 2 /sec, respectively. These data suggest membrane hydrophobicity more significantly influences the binding of low-molecular weight proteins than that of pore-excluded proteins. In addition, these results demonstrate electrostatic membrane-protein interactions may influence the kinetics of both the adsorption and transmembrane mass transfer of plasma proteins.

4656 Background: The investigational agent orteronel (ortl, TAK-700) is a selective 17,20-lyase inhibitor that blocks androgen production. Since DP is standard chemotherapy in mCRPC, this phase 1/2 study examined ortl + DP in men with mCRPC. Methods: The primary phase I objective was to determine the maximum dose of ortl 200–400 mg BID that can be administered safely with DP in castrate men (testosterone [T] 2 q3w) + P (5 mg BID) was started on d8 of cycle 1 (28 d); cycles ≥2 = 21 d. Results: 14 men, median age 68 yrs (range 53–81), ECOG PS 0/1 (71%/29%), median PSA 59.4 ng/mL (5.2–1052), T 8.1 ng/dL (1.2–16.7), 9 with measurable disease, were treated. Median ortl exposure was 33.3 wks (6.3–59); 6 and 8 men received ortl 200 and 400 mg BID + DP, in cohorts 1 and 2, respectively. No dose-limiting toxicities (DLTs) occurred in cohort 1 (2 x 3 pts); in cohort 2 (2 x 4 pts), 1 pt in group 1 had DLT (Gr3 related febrile neutropenia); no DLTs occurred in group 2. 3 pts discontinued due to AEs (2 D infusion reactions, 1 at each dose; 1 unrelated cardiorespiratory death at 200 mg). All men had at least 1 AE Gr ≥3 which were treatment-related in 11 men. The most common Gr ≥3 AEs were seen at both doses and included neutropenia 50% (n = 7), hyperglycemia 21% (n = 3), febrile neutropenia, infusion reaction, hyponatremia, decreased neutrophil count (2 each); at 400 mg only: fatigue, hypophosphatemia, and decreased WBC count (2 each). 7 men had serious AEs (SAEs), which were drug-related in 5. The most common SAE was febrile neutropenia in 2 men. At 3 mo, PSA50 and PSA90 rates were 86% and 36%, respectively; 12/14 men had a median PSA decline ≥70%; and median T declined to ≤0.2 ng/dL (0–10.7). The Cmax of D + ortl was similar to D alone. Conclusions: Ortl 200 mg and 400 mg BID + DP appears safe and tolerable with androgen-lowering activity at the maximum planned dose in mCRPC. There is no evidence of AE potentiation when ortl is administered with DP. The phase II portion of the study will use ortl 400 mg BID + DP.

The study of the mechanism of cell-mediated cytotoxicity received renewed interest with the introduction of a rather elegant and simple model: exocytosis of toxin-containing granules from cytotoxic effector cells upon encounter with and activation by their specific target cells (Dennert and Podack, 1983; Henkart et al., 1984; Podack and Konigsberg, 1984; Young and Cohn, 1986). A pore-forming protein, perforin (also called cytolysin), was identified first in the cytoplasmic granules of natural killer (NK) cells, and subsequently in cytotoxic T lymphocytes (CTL). Binding of CTL and NK cells to their target cells is proposed to trigger a degranulation event, releasing perforin monomers which assemble in the presence of Ca2+ into complement-like pore structures that insert into the target membrane, thereby causing damage to the target cell. Initially it seemed that this model could adequately account for the known features of antigen-specific, CTL-mediated cytotoxicity. That perforin exists is beyond question, the gene having been cloned and sequenced by several laboratories. A role for perforin in cell-mediated cytolysis has been greatly strengthened by recent antisense (AchaOrbea et al., 1990) and gene transfection (Shiver and Henkart, 1991) experiments.

This technique is useful for a number of purposes. Antibodies to either the T-cell receptor (TCR) or to the associated CD-3 molecules are effective, and antibodies such as class I or CD-8 are good controls. We have used this method quite successfully to induce CTL degranulation. It also causes cells to release tumor necrosis factor-α (TNF-α), if they produce it. CTLs stimulated by TCR or CD-3 antibody on plates also show greatly enhanced lysis of specific and nonspecific target cells.

This technique is very useful for redirected lysis of target cells which are otherwise not recognized by a particular CTL. Target cells are derivatized with antibody specific either for the α- or β-chain of the T-cell receptor (TCR), or for a member of the CD-3 complex of TCR-associated proteins. Useful control antibodies are class I or CD-8, neither of which should induce target cell lysis.

Urea kinetic analysis allows for the calculation of the urea distribution volume and urea generation rate. This method was employed in patients with acute renal failure managed by continuous venovenous hemofiltration (CVVH). Based on serial serum urea nitrogen concentration measurements, each patient's treatment course consisted of both steady state and non-steady state periods. Thirteen data sets were obtained from 11 critically ill patients treated with CVVH. The duration of therapy was 9.5 +/- 7.5 days (mean +/- SD). Serum urea nitrogen concentration fell from 114 +/- 32 mg/dl to a steady state value of 79 +/- 17 mg/dl (p < 0.0005). The urea distribution volume was 0.55 +/- 0.11 L/kg (range 0.29-0.73), and the urea generation rate 11.7 +/- 3.1 mg urea N/min (range 7.1-17.3). The steady state serum urea nitrogen concentration had a linear relationship to the rate of urea generation (r = 0.92). Urea kinetic analysis permitted the simultaneous determination of the urea generation rate and distribution volume, on an individualized basis, in patients with acute renal failure treated with CVVH.

Design and performance characteristics of InGaAs/InP avalanche photodiodes which have been optimi7.ed for use in eye­ safe rangefinding applications are desaibed. The devices have diameters ranging from 85 to 350 µm. The use of a ball lens mounted on a bade-entry version of the 200 µm diameter APD Oextends its useful diameter up to 500 µm for most applications. For a 350 µm diameter APD, operating at 23°C, and biased to achieve a responsivity of 10 A/W at 1540 nm, typical dark current and noise are, respectively, 150 nA and 1.5 pA/lHz. In addition to room temperature performance characteristics, reduced noise and dark current at lower temperatures are reported for the various device types mounted on single stage thermoelectric coolers. In general, operation of the devices cooled also makes possible the use of higher gains - frequently as high as 2.5 - while still maintaining acceptable levels of noise and dark current. In particular, a typical 85 µm. diameter APD, operating at O"C, has noise less than 0.8 pA/./Hz when biased to operate at a 1540 nm responsivity of 20 A/W.