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J K Sherwood

Publications and source records attributed to J K Sherwood.

11 recordsLinked to original sources
PubMed2001

Effect of pore size and void fraction on cellular adhesion, proliferation, and matrix deposition.

The aim of this study was to determine the influence of two key scaffold design parameters, void fraction (VF) and pore size, on the attachment, growth, and extracellular matrix deposition by several cell types. Disc-shaped, porous, poly(-lactic acid) (L-PLA) scaffolds were manufactured by the TheriForm solid free-form fabrication process to generate scaffolds with two VF (75% and 90%) and four pore size distributions (< 38, 38-63, 63-106, and 106-150 microm). Microcomputed tomography analysis revealed that the average pore size was generally larger than the NaCl used, while VF was at or near the designated percentage. The response of three cell types-canine dermal fibroblasts (DmFb), vascular smooth muscle cells (VSMC), or microvascular epithelial cells (MVEC)-to variations in architecture during a 4-week culture period were assessed using histology, metabolic activity, and extracellular matrix deposition as comparative metrics. DmFb, VSMC, and MVEC showed uniform seeding on scaffolds with 90% VF for each pore size, in contrast to the corresponding 75% VF scaffolds. DmFb showed the least selectivity for pore sizes. VSMC displayed equivalent cell proliferation and matrix deposition for the three largest pore sizes. MVEC formed disconnected webs of tissue with sparse extracellular matrix at 90% VF and >38 to 150 microm; however, when cultured on scaffolds with pores formed with salt particles of <38 microm, MVEC formed a multilayered lining on the scaffolds surface. Culture data from scaffolds with a 75% VF suggests that the structural features were unsuitable for tissue formation. Hence, there were limits of acceptable scaffold architecture (VF, pore size) that modulated in vitro cellular responses.

Animals↗
PubMed2000

Long-term vaginal antibody delivery: delivery systems and biodistribution.

Topical delivery systems can provide prolonged delivery of antibodies to the vaginal mucosal surface for long-term protection against infectious diseases. We examined the biodistribution of antibodies during 30 days of vaginal antibody delivery in mice. Different antibody preparations (including monoclonal IgG and IgM, as well as several different (125)I-labeled IgGs) were administered by polymer vaginal rings, which were designed to provide continuous antibody delivery. Antibody concentrations remained high in the vaginal secretions for up to 30 days after disk insertion; radiolabeled antibody was also found, at approximately 100 times lower concentration, in the blood and other tissues. The measured concentrations agreed reasonably well with a simple pharmacokinetic model, which was used to calculate mucosal and systemic concentrations as a function of antibody delivery and elimination rates. Results from the model were consistent with previously reported antibody pharmacokinetic measurements: the half-life for antibody elimination for the vagina was approximately 3 h; the half-life for IgG(1) clearance from the blood was >1 day; and the overall permeability constant for vaginal uptake of IgG was approximately 0.01 to 0.03 h(-1). These results provide important information for the design of controlled antibody delivery devices for vaginal use, and suggest that high-dose, long-term vaginal administration of antibodies may be a reasonable approach for achieving sustained mucosal and systemic antibody levels.

Administration, Intravaginal↗
PubMed1998

Topical antibody delivery systems produce sustained levels in mucosal tissue and blood.

Immunity at mucosal surfaces, which are ports of entry for many pathogens, is essential in preventing infections. But most current strategies for passive immunization involve injection of antibodies for systemic, not mucosal, protection. We measured mucosal and systemic antibody levels after controlled topical delivery to the vagina. Poly(ethylene-co-vinyl acetate) disks containing 125I-labeled monoclonal IgG or anti-lactate dehydrogenase-C4 antibodies were placed in the vaginas of mice. High antibody levels (0.26-12 micrograms/ml) were maintained at the mucosal surface for 7 days after disk insertion. Antibody molecules also penetrated into the vaginal epithelium, presumably by diffusing through the extracellular space, and entered the circulation. Biologically active antibodies were detected in the blood. The antibody concentration in the blood was approximately 1% of the concentration in the vagina. Although the permeability of the epithelium to macro-molecules is low, high concentrations were maintained at the luminal surface for an extended period, permitting substantial systemic uptake of antibody.

Administration, Intravaginal↗
PubMed1996

Controlled release of antibodies for long-term topical passive immunoprotection of female mice against genital herpes.

Current methods for sexually transmitted diseases (STD) prophylaxis, which can be disruptive and inconvenient, must be used before each act of sexual intercourse, so a method that provides protection over the course of many acts is desirable. We used a mouse model of vaginally-transmitted herpes simplex virus 2 (HSV-2) infection to test polymeric controlled-release devices for sustained passive immunoprotection. Vaginal disks were prepared by dispersing a monoclonal antibody to HSV-2 (III-174) within a matrix of poly(ethylene-co-vinyl acetate); these disks released 2 to 40 micrograms/day of antibody into buffered water. When disks were placed in the vagina, large amounts of III-174 (5 to 3,000 ng) were recovered from the vaginal fluid over the next 8 days. Mice were vaginally challenged with 10 ID50 of HSV-2 either 3 or 7 days after disk placement; no mice receiving III-174 disks became infected, while 65% of control mice receiving identical disks with nonspecific IgG did. Controlled-release disks with III-174 provided significant protection against HSV-2 infection (p < 0.005). This new technology for long-term STD prophylaxis should increase user compliance, a factor limiting the efficacy of current methods.

Administration, Intravaginal↗
PubMed1996

Residence half-life of IgG administered topically to the mouse vagina.

Antibodies delivered directly to the vagina can provide passive immunoprotection against pregnancy and sexually transmitted disease. The duration of protection is limited by the residence time of the antibodies in the vagina; to our knowledge such residence times have not been reported. We investigated the time-course of disappearance of IgG delivered to the mouse vagina using three different methods to monitor the amount of administered IgG remaining in the vagina: gamma counting of 125I-IgG, viral neutralization of unlabeled monoclonal anti-herpes virus IgG2a, and ELISA of biotinylated IgG. The test IgG was delivered to the vagina in saline and recovered by lavage. All three methods yielded similar results, suggesting that the residence half-life is not significantly affected by the volume administered, phase of the estrous cycle, or labeling of IgG. In awake mice, a significant fraction of IgG disappeared with a relatively short half-life, (t1/2)alpha, of 0.7 +/- 0.1 h; but this rapid (alpha phase) decrease did not occur in anesthetized mice, suggesting that the movements of awake mice expel some of the test IgG-saline solution from the vagina. Over the next 25 h, the test IgG disappeared with a residence half-life, (t1/2)beta, of 5 +/- 2 h. We believe this slow elimination of IgG may depend on the rate that mucus secretions are shed from the vagina.

Administration, Topical↗
PubMed1992

Controlled antibody delivery systems.

We have developed methods for controlling the release of antibodies (Ab) from biocompatible polymers. Human Ab, human Ab fragments, and mouse monoclonal antibody (mAb) directed against human chorionic gonadotropin (anti-hCG) were incorporated into matrices of poly(ethylene-co-vinyl acetate), which is stable in biological environments. Human Ab and bovine gamma-globulin were also incorporated in biodegradable matrices of a poly-anhydride copolymer composed of a stearic acid dimer and sebacic acid. Abs were slowly released from all the polymeric carriers during 30 days of continuous immersion in buffered saline. The ability of anti-hCG to bind antigen was retained following release from EVAc matrices. Only minor Ab aggregation was observed following release from either polymer. Polymeric delivery systems, similar to those described here, may become an important element in the delivery of mAbs to humans for immunoprotection against infectious diseases or the delivery of mAb-conjugates for immunotherapy against cancer.

Anhydrides↗
PubMed1986

Hyperparathyroid crisis reviewed: a role for parenteral cimetidine?

Hyperparathyroid crisis secondary to primary hyperparathyroidism has variously been described as hypercalcemic crisis, parathyroid storm, and parathyroid intoxication as well as other equally descriptive terms. Whatever the nomenclature, all emphasize the seriousness and urgency of the condition. Although fewer than 200 cases have been described since the first report by Hanes in 1939, it is generally agreed that hyperparathyroid crisis is more prevalent than commonly appreciated. The signs and symptoms of the syndrome are believed due not only to the presence of hypercalcemia, but to the toxic effects of parathormone as well. Its wide, but nonspecific clinical spectrum makes it easily confused with other causes of rapidly fatal cardiovascular or renal disease. The mortality in untreated cases is essentially 100 per cent. With combined medical-surgical treatment, it is still reported as high as 60 per cent. Three patients with severe hyperparathyroid syndrome are reported. Effective control of both hypercalcemia and the toxic effects of acute hyperparathyroid crisis was achieved with the use of parenteral cimetidine. Definitive surgical removal of a solitary parathyroid adenoma was performed in all three patients. The intimate relationship of the bioavailability of cimetidine and its effect in primary hyperparathyroidism is clearly demonstrated. An analogy to the use of cimetidine in Zollinger-Ellison syndrome is made. Both are endocrinopathies that require doses of cimetidine in excess of that normally considered therapeutic for peptic ulcer disease. The signs and symptoms of hyperparathyroid crisis as well as current modalities of treatment are reviewed. It is concluded that parenteral cimetidine is an important aid in the management of acute hyperparathyroid syndromes secondary to primary hyperparathyroidism.

Adult↗
PubMed1983

The preoperative use of cimetidine as a means of preventing symptomatic hypocalcemia following a parathyroid operation.

Cimetidine has been shown to lower circulating PTH levels effectively by causing an intraglandular rearrangement of PTH peptides in human parathyroid tissue in instances of primary hyperparathyroidism. A state of "euparathyroidism" is established. It has been statistically found at a 98.7 per cent confidence level that preoperative treatment with cimetidine effectively prevents symptomatic hypocalcemia postoperatively after parathyroid operations. It is anticipated that cimetidine has provided a tool for the in depth exploration of parathyroid disease.

Adenoma↗
PubMed1980

Effect of cimetidine on circulating parathyroid hormone in primary hyperparathyroidism.

In twelve patients with primary hyperparathyroidism the raised parathyroid hormone (PTH) levels consistently returned to normal with cimetidine ("Tagamet"), 300 mg four times a day, orally. As PTH levels returned to normal, signs and symptoms improved. Reduction of hypercalcaemia varied with the time, dose, and route of administration of cimetidine. Whenever cimetidine was discontinued, there was a rebound of PTH levels to approximately twice the initial value, which suggests that cimetidine blocks the synthesis and/or secretion of parathyroid hormone, so that parathyroid hormone or its precursor accumulates in the gland. A solitary parathyroid adenoma has been confirmed surgically in the five patients so far operated on. In all surgical patients the PTH levels were brought to normal by cimetidine preoperatively; these levels were maintained postoperatively. The adenomas were unusually large, firm, and congested; there was no atrophy of the rest of the glands. These last two observations further support our hypothesis that cimetidine blocks the synthesis or release of parathyroid hormone; they also support the concept that in primary hyperparathyroidism the parathyroid adenoma becomes autonomous or there is an abnormal hormone.

Adenoma↗