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Biomedical subjects

S J Updike

Publications and source records attributed to S J Updike.

At least 19 recordsLinked to original sources

Massive rhabdomyolysis and multiple organ dysfunction syndrome caused by leptospirosis.

We report a case of leptospiral infection in a 63-year-old man who acquired the infection while swimming in canals and streams in Hawaii. The patient's course was atypical in that he was anicteric and had no evidence of meningitis when he presented with fever, rapidly progressive and severe rhabdomyolysis, thrombocytopenia, acute renal failure, and respiratory distress syndrome. Although he recovered after a protracted illness, he required major life support, including mechanical ventilation and hemodialysis. Initial antimicrobial therapy was designed to cover major bacterial and atypical pathogens, including leptospires. An in-depth work-up for causes of this catastrophic illness confirmed acute leptospirosis. Although rare, leptospirosis is a potentially lethal infection classically associated with hepatitis, azotemia, and meningitis. Most patients experience self-limited illness, with fever, myalgias, and malaise followed by an immune-mediated aseptic meningitis. A small proportion develop shock and multiple organ dysfunction. Whereas myalgias are ubiquitous in leptospiral infection, and most patients show mildly elevated muscle enzymes, life-threatening rhabdomyolysis is rare. This atypical case is reported to urge clinicians to consider leptospirosis in the evaluation of a patient with cryptogenic sepsis who develops multiple organ dysfunction associated with rhabdomyolysis. Appropriate antimicrobial therapy, with penicillin or doxycycline, can be life-saving.

Hawaii↗

A subcutaneous glucose sensor with improved longevity, dynamic range, and stability of calibration.

OBJECTIVE: To evaluate the lifetime, response time, linearity, glucose range, and calibration stability of two different types of continuous glucose sensor implants in a dog model. RESEARCH DESIGN AND METHODS: Glucose sensors based on the enzyme electrode principle that are coupled to a radio transmitter were evaluated on the bench top, sterilized, and then implanted subcutaneously in nondiabetic mongrel dogs. A multichannel radio receiver and PC data processor were used to record the sensor glucose data. Initial early reliable sensor responsivity was recognized by a vigorous hyperglycemic excursion after an intramuscular injection of glucagon. Periodically the dogs were made temporarily diabetic by blocking pancreatic insulin secretion by subcutaneous injection of a synthetic somatostatin (octreotide). By using exogenous insulin injection followed by intravenous glucose infusion, glucose levels were manipulated through the entire clinical range of interest: 2.2-38.9 mmol/l (40-700 mg/dl). Every 5-10 min, reference blood glucose samples were obtained and run in our hospital clinical laboratory. The glucose sensor data was evaluated by linear least squares optimization and by the error grid method. RESULTS: Beginning as early as postimplant day 7, the in vivo performances of sensors were evaluated by using glucose infusion studies performed every 1-4 weeks. Bench-top and in vivo 90% response-time sensors were in the range of 4-7 min during sensor lifetime. Best-performing sensors from both types are summarized as follows. The earlier-stage technology was less linear with a dynamic range of no more than 22 mmol/l glucose, had a best-case recalibration interval of 18 days, and had a maximum lifetime of 94 days. The improved later-stage technology sensors, which were constructed with the addition of bioprotective and angiogenic membranes, were linear over the full extended range of clinical interest (2.2-38.9 mmol/l [40-700 mg/dl glucose]), had a best-case recalibration interval of 20 days, and had a maximum lifetime of >160 days. CONCLUSIONS: Stable clinically useful sensor performance was demonstrated as early as 7 days after implantation and for a sensor lifetime of 3-5 months. This type of subcutaneous glucose sensor appears to be promising as a continuous and painless long-term method for monitoring blood glucose. Specifically sensors with top-layer materials that stimulate angiogenesis at the sensor/tissue interface may have better dynamic measurement range, longer lifetimes, and better calibration stability than our previously reported sensors.

Animals↗

Prediction of pocket-portable and implantable glucose enzyme electrode performance from combined species permeability and digital stimulation analysis.

Development of enzyme electrode sensors can be facilitated by the use of computer simulation modeling techniques. In this work, the model accounts for contacting solution effects, changes in species diffusion and partition coefficients across multiple membrane layer interfaces, cofactor limitation effects, enzyme loading, enzyme kinetics and decay, and other variations in electrode layer geometry. Experimentally determined single species membrane permeabilities are included in the digital simulations to predict the performance characteristics of a multilayered glucose oxidase based enzyme electrode. Information obtained includes range of sensor linearity under different substrate and cofactor concentration combinations, sensor time response and output as permeability parameters and enzyme loading are varied, sensor washout and interference effects, and prediction of decay of sensor enzyme concentration and resultant estimated sensor lifetime as a function of contacting solution conditions and sensor permeability.

Biosensing Techniques↗

A telemetry-instrumentation system for monitoring multiple subcutaneously implanted glucose sensors.

An implantable potentiostat-radiotelemetry system for in vivo sensing of glucose is described. An enzyme electrode sensor measures the oxidation current of hydrogen peroxide formed by the stoichiometric conversion of glucose substrate and oxygen cofactor in an immobilized glucose oxidase layer. The sensor current is converted to a frequency and transmitted at programmable intervals (4, 32, 256 s) to a remote receiver. Low power CMOS circuitry is employed and device operation for up to 1.5 years is predicted using two series connected 250 mAh lithium cells. Crystal controlled RF frequencies uniquely identify each sensor allowing over 10 sensors within the same 10 m radius. A custom interface card allows a PC to program the receiver and handle the transmitted sensor data using software written in Microsoft C and QuickBasic. Software control allows on-the-fly sensor addition or subtraction to the sensor group being monitored. Over 10 sensors can be tracked long-term using the longest transmit interval, or four sensors can be tracked during short-term infusion studies when the transmit interval is reduced to 4 s. The design, construction, operation, and performance of the system hardware and software are described and evaluated.

Animals↗

Evaluation of a subcutaneous glucose sensor out to 3 months in a dog model.

OBJECTIVE: To advance the feasibility of an implantable long-term glucose sensor with bioprotective sensor membranes and test protocols using a somatostatin analog (octreotide). RESEARCH DESIGN AND METHODS: Implantable sensors were constructed with one of eight bioprotective membranes and screened in vitro for stable response to glucose. Sensors were implanted subcutaneously into nondiabetic mongrel dogs and monitored at 4-min intervals via radiotelemetry. When implanted sensor responses showed evidence of tracking blood glucose after glucagon challenge (8-21 days postimplant), a glucose infusion protocol was used to assess performance. Sensor data were collected every 4 s after octreotide inhibition of endogenous insulin release. Reference plasma glucose samples were taken every 4-10 min. RESULTS: Preimplant in vitro testing of sensors verified linearity to 33.3 mM glucose and response times to 90% of equilibrium in 2-7 min. Ten implanted sensors tracked glucose for 20-114 days, during which 25 separate glucose infusion studies were conducted. The resulting regression data yielded a mean slope of 0.99 +/- 0.06, an intercept of 0.24 +/- 0.53 mM glucose, and a correlation coefficient 0.98 +/- 0.01. Long-term sensor stability was not judged adequate for clinical application, although two sensors tracked within +/- 15% for 33 and 42 days. In vivo oxygen delivery was shown to affect sensor performance. On explant, two of eight tested bioprotective membranes were found to be biostable and to fully protect the sensor's enzyme membrane. The foreign body capsule was adequately vascularized adjacent to the sensor up to 91 days postimplant. Sensor units eventually failed because of electronic problems (package leakage) or because of biodegradation or biofouling of test bioprotective membranes. CONCLUSION: Further development of this type of sensor may provide diabetic patients with a better means of monitoring blood glucose.

Animals↗

Preparation of flexible models of hollow gastrointestinal organs.

Flexible models of hollow gastrointestinal organs can be easily prepared by coating air-dried organs with a commercially available clear plastic compound. The plastic infiltrates the full thickness of organ walls to support and protect internal as well as external structures. Models are flexible, resistant to fluids, and lightweight. This plasticizing technique is particularly useful for the preservation and study of large animal gastrointestinal tracts.

Animals↗

Fascial compartments of the equine crus.

The deep fascia of the equine crus was dissected grossly and separated into 2 layers, the superficial and deep laminae of the deep fascia. Attachments of these fascial laminae to the tibia and fibula formed 5 separate osteofascial compartments: cranial, lateral, caudal deep, caudal intermediate, and caudal superficial. Cranial tibial vessels and the deep peroneal nerve entered the cranial compartment through separate fascial hiatuses; this may predispose the equine crus to the occurrence of compartmental syndromes with clinically recognizable neural deficits.

Animals↗

Entrapment of L-asparaginase in red blood cells. A strategy to improve treatment of acute lymphoblastic leukemia.

Autologous red blood cells were loaded with L-asparaginase and injected intravenously into monkeys. A single dose of 1850 IU/Kg suppressed plasma asparagine for 19 days compared to 10 days for the same dose injected free in solution. Rabbit antisera to asparaginase was used to passively immunize guinea-pigs. These animals were then challenged with RBC-entrapped asparaginase versus asparaginase free in solution. RBC entrapment allowed a ten fold greater dose of asparaginase before anaphylaxis became a problem. RBC entrapment prolongs the duration of action of asparaginase and offers protection against anaphylaxis. Clinical trial in patients with acute lymphoblastic leukemia is recommended.

Anaphylaxis↗

Facilitating intensive conventional insulin management using a manually operated syringe injector.

A manually operated 3-ml insulin catheter and syringe injector system was evaluated in 26 insulin-dependent ketosis-prone patients for a mean of 11 months per patient. Eighteen patients had normal kidney function, 5 had renal insufficiency (plasma creatinine 2.0-4.8 mg/dl) and 3 had successful kidney transplants. Regular insulin was infused 15-30 min before each meal. The subcutaneous route of delivery was used in all patients except the 3 renal transplant patients who received regular insulin intraperitoneally through a chronically placed intraperitoneal microbore catheter. Basal insulinization was obtained using subcutaneous long-acting insulin. Blood glucose control improved in all 3 groups of patients. Mean blood glucose decreased from 203 +/- 10-118 +/- 3 SEM; hemoglobin A1 decreased from 12.5 +/- 0.4-9.2 +/- 0.25 SEM (normal range 5-9%). We conclude that a manually operated syringe injector can be used to make multiple dose insulin management less painful and more convenient. The injector can be worn and activated beneath clothing and also worn while showering or swimming. Yet it can be removed while sleeping, when sexually active or when engaged in strenuous athletic activity.

Adolescent↗

Functional anatomy of the equine tarsocrural collateral ligaments.

Equine tarsocrural collateral ligaments (CL) were dissected grossly. The areas of attachment and fiber arrangements were described for the long lateral CL, long medial CL, 3 short lateral CL, and 3 short medial CL. Sequential cutting of CL in any order indicated that the short medial CL were responsible for the snap-joint phenomenon observed at the equine tarsocrural joint.

Animals↗

Infusion of red blood cell-loaded asparaginase in monkey. Immunologic, metabolic, and toxicologic consequences.

In order to evaluate enzyme loading of RBCs as a drug delivery system, the antitumor agent asparaginase was loaded into the erythrocytes of nine monkeys at three different doses and autologously injected back into these animals. Nine control monkeys were also once injected intravenously at the same doses of enzyme, but the enzyme was free in solution rather than entrapped in RBCs. The RBCs and asparaginase were labeled with 51Cr and 125I, respectively. The circulating half-life of the enzyme-loaded, resealed RBCs was 7 days, as compared to 9 days in the control RBCs. Beginning at 5 days, circulating enzyme activity was several orders of magnitude higher in the monkeys injected with RBC-loaded asparaginase than in controls. Targeting of drug-loaded RBCs into the spleen and liver was apparent. Suppression of the serum substrate level of asparaginase in the monkeys treated with the single intravenous injection of RBCs loaded with asparaginase was 20 days, which was twice as long as the suppression in the control monkeys. Production of anti-asparaginase antibody was shown to reach a higher level and persist longer in the monkeys with RBC-entrapped asparaginase. Evidence was also obtained showing that entrapping asparaginase in RBCs protects against anaphylaxis in the guinea pig. Thus this drug delivery system is also proposed as a strategy to avoid life-threatening allergic reactions. Advantages and limitations of RBC loading as a drug delivery system are discussed.

Amylases↗

Renal preservation resistance: evidence against myogenic vasoactive factors.

Vasoconstriction is believed to be a dominant cause of high perfusion resistance during kidney preservation at low temperatures. An experiment was performed to study the effects of hypothermia on vasoactivity. Measurements were made on an apparatus that permitted perfusion resistance to be compared simultaneously in two isolated kidneys at different temperatures. With perfusion temperature serving as the variable, the vascular responses to several vasoactive agents were measured. Hypothermia diminished or altered the vascular responses to the agents. For example, no vasoconstriction was observed with Angiotensin II, dopamine, acetylcholine, or BaCl2 and no vasodilation was observed with papaverine or bradykinin in the hypothermic kidney. A significantly altered response was observed with norepinephrine. The responses were reversible upon return to normothermia. From these data, we conclude that myogenic vasoconstriction plays a questionable role in producing the elevated perfusion resistance observed in some hypothermic kidneys.

Acetylcholine↗