Measurement of glucose in diabetic subjects using noninvasive transdermal extraction.

Results from the Diabetes Care and Complications Trial show that tight blood glucose control significantly reduces the long-term complications of diabetes mellitus. In that study, frequent self-testing of glucose and insulin administration resulted in a significant reduction in long-term complications. This protocol, however, also resulted in a threefold increase in the frequency of hypoglycaemic incidents. Currently, self-testing requires a drop of blood for each measurement. The pain and inconvenience of self-testing, along with the fear and danger of hypoglycaemia has led to poor patient acceptance of a tight control regimen, despite the clear long-term advantages. A continuously worn, noninvasive method to periodically measure glucose would provide a convenient and comfortable means of frequent self-testing. A continuously worn device could also alert the user of low glucose levels, thereby reducing the incidence of hypoglycaemia. Guy et al. demonstrated a noninvasive method to transport glucose through the skin using low-level electrical current. To provide a quantitative measurement, the flux of glucose extracted across the skin must correlate with serum glucose in a predictive manner. The results presented here show a quantitative relationship between serum and transdermally extracted glucose in diabetics.

Correlation of fingerstick blood glucose measurements with GlucoWatch biographer glucose results in young subjects with type 1 diabetes.

OBJECTIVE: The purpose of this study was to compare measurements of glucose obtained via iontophoretic extraction with the GlucoWatch automatic glucose biographer (Cygnus, Inc., Redwood City, CA) with capillary blood glucose values that were determined 1) in a controlled outpatient clinic setting and 2) in a home setting. RESEARCH DESIGN AND METHODS: There were 76 GlucoWatch biographers used on 28 different young adults (21 women and 7 men) with type 1 diabetes (age 30.9 +/- 6.9 years and duration of diabetes 18.4 +/- 8.1 years [mean +/- SD]) in a controlled outpatient clinic setting. Some subjects participated on multiple days. Subjects wore two GlucoWatch biographers, each on the forearm (ventral aspect). Comparisons were made to HemoCue blood glucose analyzer (Aktiebolgat Leo, Helsingborg, Sweden) capillary blood glucose measurements. In addition, GlucoWatch biographers (one each day for 3 consecutive days) were used by 12 subjects (8 women, 4 men) in a home setting. Comparisons were made to capillary blood glucose values determined using the One Touch Profile meter (Johnson & Johnson, New Brunswick, NJ). RESULTS: GlucoWatch biographer glucose values correlated well with capillary blood glucose values determined using the HemoCue analyzer in the clinic setting (r = 0.90, 1,554 paired data points) and using the One Touch Profile meter in the home setting (r = 0.85, 204 paired data points). When 36 subjects wore two biographers simultaneously, the correlation between the two biographers was r = 0.94. The error grid analysis demonstrated that > 96% of biographer glucose values determined in the clinic or home setting were in the clinically acceptable A and B regions. CONCLUSIONS: This study confirms the accuracy and precision of glucose values as determined using the GlucoWatch biographer in clinic and home settings.

Detection of hypoglycemia with the GlucoWatch biographer.

OBJECTIVE: Hypoglycemia is a common acute complication of diabetes therapy. The GlucoWatch biographer provides frequent and automatic glucose measurements with an adjustable low-glucose alarm. We have analyzed the performance of the biographer low-glucose alarm relative to hypoglycemia as defined by blood glucose < or = 3.9 mmol/l. RESEARCH DESIGN AND METHODS: The analysis was based on 1,091 biographer uses from four clinical trials. which generated 14,487 paired (biographer and blood glucose) readings. RESULTS: The results show that as the low-glucose alert level of the biographer is increased, the number of true positive alerts (alarm sounds and blood glucose < or = 3.9 mmol/l) and false positive alerts (alarm sounds but blood glucose >3.9 mmol/l) increased. When analyzed as a function of varying low-glucose alert levels, the results show receiver operator characteristic curves consistent with a highly useful diagnostic tool. Setting the alert level from 1.1 to 1.7 mmol/l above the level of concern is likely to optimize the trade-off between true positives and false positives for each user. When the same blood glucose data are analyzed for typical monitoring practices (two or four measurements per day), the results show that fewer hypoglycemic events are detected than those detected with the biographer.

Analysis of hemangiopericytic meningiomas by immunohistochemistry, electron microscopy and cell culture.

Intracranial hemangiopericytic meningiomas (HM) from seven patients were examined by immunostaining, transmission electron microscopy (TEM), scanning electron microscopy (SEM) and cell culture. Positive staining for Factor VIII-related antigen was restricted to capillary endothelial cells. There was no reaction with anti-glial fibrillary acidic protein (GFAP) serum or anti-S-100 protein serum. In these neoplasms TEM displayed extracellular basement membrane-like material (BMLM), cytoplasmic intermediate filaments (IF) associated with a dense body, dilated rough-surfaced endoplasmic reticulum containing BMLM, a small area of interdigitation of cell membranes, and a unique intercellular punctate or linear density. By SEM these tumors had intercellular shell-like or reticular structures and irregularly branched capillaries which were compressed by ellipsoidal- or carrot-shaped tumor cells. Short-term monolayer culture showed rapid and vigorous growth of tumor cells, and the formation of pseudolumens but not of whorls. The TEM of cultured cells also showed cytoplasmic IF associated with the dense body. By SEM the cultured cells were flat and had a discoid nucleus with conspicuous nucleolar hillocks. Our results show that HM are mainly poorly specialized mesenchyme-related tumors of the meninges; some possess a potential for aggressive growth and some for differentiation into smooth muscle cells. Further study is needed to determine their histogenesis.

Future directions in biomaterials.

Biomaterials have made a great impact on medicine. However, numerous challenges remain. This paper discusses three representative areas involving important medical problems. First, drug delivery systems; major considerations include drug-polymer interactions, drug transformation, diffusion properties of drugs and, if degradation occurs, of polymer degradation products through polymer matrices developing a more complete understanding of matrix degradation in the case of erodible polymers and developing new engineered polymers designed for specific purposes such as vaccination or pulsatile release. Second, cell-polymer interactions, including the fate of inert polymers, the use of polymers as templates for tissue regeneration and the study of polymers which aid cell transplantation. Third, orthopaedic biomaterials, including basic research in the behaviour of chondrocytes, osteocytes and connective tissue-free interfaces and applied research involving computer-aided design of biomaterials and the creation of orthopaedic biomaterials.

In vitro degradation of porous poly(L-lactic acid) foams.

This study investigated the in vitro degradation of porous poly(L-lactic acid) (PLLA) foams during a 46-week period in pH 7.4 phosphate-buffered saline at 37 degrees C. Four types of PLLA foams were fabricated using a solvent-casting, particulate-leaching technique. The three types had initial salt weight fraction of 70, 80, and 90%, and a salt particle size of 106-150 microm, while the fourth type had 90% initial weight fraction of salt in the size range 0-53 microm. The porosities of the resulting foams were 0.67, 0.79, 0.91, and 0.84, respectively. The corresponding median pore diameters were 33, 52, 91, and 34 microm. The macroscopic degradation of PLLA foams was independent of pore morphology with insignificant variation in foam weight, thickness, pore distribution, compressive creep behavior, and morphology during degradation. However, decrease in melting temperature and slight increase in crystallinity were observed at the end of degradation. The foam half-lives based on the weight average molecular weight were 11.6+/-0.7 (70%, 106-150 microm), 15.8+/-1.2 (80%, 106-150 microm), 21.5+/-1.5 (90%, 106-150 microm), and 43.0+/-2.7 (90%, 0-53 microm) weeks. The thicker pore walls of foams prepared with 70 or 80% salt weight fraction as compared to those with 90% salt weight fraction contributed to an autocatalytic effect resulting in faster foam degradation. Also, the increased pore surface/volume ratio of foams prepared with salt in the range 0-53 microm enhanced the release of degradation products thus diminishing the autocatalytic effect and resulting in slower foam degradation compared to those with salt in the range 106-150 microm. Formation and release of crystalline PLLA particulates occurred for foams fabricated with 90% salt weight fraction at early stages of degradation. These results suggest that the degradation rate of porous foams can be engineered by varying the pore wall thickness and pore surface/volume ratio.

In vitro and in vivo degradation of porous poly(DL-lactic-co-glycolic acid) foams.

This study investigated the in vitro degradation of porous poly(DL-lactic-co-glycolic acid) (PLGA) foams during a 20-week period in pH 7.4 phosphate-buffered saline (PBS) at 37 degrees C and their in vivo degradation following implantation in rat mesentery for up to 8 weeks. Three types of PLGA 85 : 15 and three types of 50 : 50 foams were fabricated using a solvent-casting, particulate-leaching technique. The two types had initial salt weight fraction of 80 and 90%, and a salt particle size of 106-150 microm, while the third type had 90% initial weight fraction of salt in the size range 0-53 microm. The porosities of the resulting foams were 0.82, 0.89, and 0.85 for PLGA 85 : 15, and 0.73, 0.87, and 0.84 for PLGA 50 : 50 foams, respectively. The corresponding median pore diameters were 30, 50, and 17 microm for PLGA 85: 15, and 19, 17, and 17 microm for PLGA 50 : 50. The in vitro and in vivo degradation kinetics of PLGA 85: 15 foams were independent of pore morphology with insignificant variation in foam weight, thickness, pore distribution, compressive creep behavior, and morphology during degradation. The in vitro foam half-lives based on the weight average molecular weight were 11.1 +/- 1.8 (80%, 106-150 microm), 12.0 +/- 2.0 (90%, 106-150 microm), and 11.6 +/- 1.3 (90%, 0-53 microm) weeks, similar to the corresponding values of 9.4 +/- 2.2, 14.3 +/- 1.5, and 13.7 +/- 3.3 weeks for in vivo degradation. In contrast, all PLGA 50 : 50 foams exhibited significant change in foam weight, water absorption, and pore distribution after 6-8 weeks of incubation with PBS. The in vitro foam half-lives were 3.3 +/- 0.3 (80%, 106-150 microm), 3.0 +/- 0.3 (90%, 106-150 microm), and 3.2 +/- 0.1 (90%, 0-53 microm) weeks, and the corresponding in vivo half-lives were 1.9 micro 0.1, 2.2 +/- 0.2, and 2.4 +/- 0.2 weeks. The significantly shorter half-lives of PLGA 50: 50 compared to 85: 15 foams indicated their faster degradation both in vitro and in vivo. In addition, PLGA 50: 50 foams exhibited significantly faster degradation in vivo as compared to in vitro conditions due to an autocatalytic effect of the accumulated acidic degradation products in the medium surrounding the implants. These results suggest that the polymer composition and environmental conditions have significant effects on the degradation rate of porous PLGA foams.

Clinical evaluation of the GlucoWatch biographer: a continual, non-invasive glucose monitor for patients with diabetes.

A device providing frequent, automatic, and non-invasive glucose measurements for persons with diabetes has been developed: the GlucoWatch biographer. This device extracts glucose through intact skin via reverse iontophoresis where it is detected by an amperometric biosensor. The biographer can provide glucose readings every 20 min for 12 h. The performance of this device was evaluated in two large clinical studies in a controlled clinical environment (n=231), and the home environment (n=124). Accuracy of the biographer was evaluated by comparing the automatic biographer readings to serial finger-stick blood glucose (BG) measurements. Biographer performance was comparable in both environments. Mean difference between biographer and finger-stick measurements was -0.01 and 0.26 mmol l(-1) for the clinical and home environments, respectively. The mean absolute value of the relative difference was 1.06 and 1.18 mmol l(-1) for the same studies. Correlation coefficient (r) between biographer and finger-stick measurements was 0.85 and 0.80 for the two studies. In both studies, over 94% of the biographer readings were in the clinically acceptable A+B region of the Clarke Error Grid. A slight positive bias is observed for the biographer readings at low BG levels. Biographer accuracy is relatively constant over all rates of BG changes, except when BG decreases more than 10 mmol l(-1) h(-1), which occurred for only 0.2% of points in the home environment study. Biographer precision, as measured by CV%, is approx. 10%. Skin irritation, characterized by erythema and edema, was either non-existent or mild in >90% of subjects and resolved in virtually all subjects without treatment in several days.

Effect of acetaminophen on the accuracy of glucose measurements obtained with the GlucoWatch biographer.

BACKGROUND: Improved glycemic control significantly reduces long-term microvascular complications of diabetes mellitus associated with chronic hyperglycemia. The GlucoWatch biographer is designed to facilitate intensive diabetes management by providing automatic, frequent, and noninvasive glucose readings up to three times per hour for as long as 12 hours. METHODS: The device extracts glucose through intact skin using reverse iontophoresis and measures the extracted glucose with an electrochemical biosensor. A clinical trial was performed to assess the effect of acetaminophen, a potential interference for traditional blood glucose meters, on the accuracy of the GlucoWatch biographer in adult subjects with diabetes (n = 18). One thousand milligram doses of acetaminophen were administered to subjects in two groups: one to achieve Cmax (peak acetominophen concentration) at the time of biographer calibration and the other to achieve Cmax during the measurement period. The biographer readings were compared to serial fingerstick blood glucose measurements. RESULTS: Time profiles over 9 hours show close tracking of the biographer glucose results with fingerstick blood glucose measurements for all groups. The mean difference between the two measurements is between 8 and 12 mg/dL for all groups. The mean absolute value of the relative difference is less than 20%, and more than 93% of the points were in the clinically acceptable (A+B) region of the Clarke Error Grid. No statistically significant differences were found for any accuracy measurement across all groups. CONCLUSIONS: The GlucoWatch Biographer provides frequent measurements of glucose over a 12-hour period with high accuracy. No effect of therapeutic dosage of acetaminophen on the accuracy of the glucose readings was found.

A new generic column switching system for quantitation in cassette dosing using LC/MS/MS.

Cassette dosing is a method in which multiple drugs are administered to a single animal at the same time, and the plasma concentrations of the individual compounds are simultaneously determined. This method enables high-throughput rapid screening for pharmacokinetic assessment of new drug candidates. An available gradient method was modified for cassette dosing analysis to attain the advantages of high sensitivity and applicability to a wide range of compounds. However, two problems arose; (1). the time-consuming optimization of mobile phases for each compound group, which limited applicability and (2). the remarkable suppression of ionization by polyethyleneglycol, which is commonly used in intravenous administration. To resolve these problems, a new column switching method was established to attain wider applicability and avoid the ionization suppression. This column switching system is very simple because the trap column and the analytical column are specified and the mobile phase is selected from only two species. Method optimization requires only the selection of the mobile phase and takes only a few hours. About 200 compounds, which were administered as about 50 cassettes, were analyzed using this column switching system. Assay validation of one cassette was carried out, and good accuracy and precision were obtained. About 90% of the compounds could be determined within 20% bias. These results showed that this new column switching system for cassette dosing is accurate enough for the screening of drug candidates and offers wide applicability for various compounds. This system was shown to be very useful for the determination of cassette dosing samples, containing multiple compounds.

Radiosensitive craniopharyngiomas: the role of radiosurgery.

Clinical characteristics of radiosensitive craniopharyngiomas and histologically identical tumours were re-evaluated from among 53 patients. There were 9 squamous cell type and 3 mixed type tumours. Early effects of radiosurgery for two recent cases are reported. Radiosurgery may have an important role to play in the treatment of craniopharyngiomas, especially of the squamous cell type.

Endobronchial metastasis from prostate cancer.

We describe a case of endobronchial metastasis from prostate cancer originally diagnosed as primary bronchogenic carcinoma. We conducted a sleeve lobectomy and determined a final diagnosis using a serumprostate-specific antigen and immunohistochemical studies.