Microfabricated microneedles: a novel approach to transdermal drug delivery

Although modern biotechnology has produced extremely sophisticated and potent drugs, many of these compounds cannot be effectively delivered using current drug delivery techniques (e.g., pills and injections). Transdermal delivery is an attractive alternative, but it is limited by the extremely low permeability of skin. Because the primary barrier to transport is located in the upper 10-15 micron of skin and nerves are found only in deeper tissue, we used a reactive ion etching microfabrication technique to make arrays of microneedles long enough to cross the permeability barrier but not so long that they stimulate nerves, thereby potentially causing no pain. These microneedle arrays could be easily inserted into skin without breaking and were shown to increase permeability of human skin in vitro to a model drug, calcein, by up to 4 orders of magnitude. Limited tests on human subjects indicated that microneedles were reported as painless. This paper describes the first published study on the use of microfabricated microneedles to enhance drug delivery across skin.     

Oscillations of two competing microbial populations in configurations of two interconnected chemostats

It is known that, when two microbial populations competing for a single rate-limiting nutrient are grown in a spatially uniform environment, such as a single chemostat, with competition being the only interaction between them, they cannot coexist, but eventually one of the two populations prevails and the other becomes extinct. Spatial heterogeneity has been suggested as a means of obtaining coexistence of the two populations. A configuration of two interconnected chemostats is a simple model of a spatially heterogeneous environment. It has been shown that, when Monod's model is used for the specific growth rates of the two populations, steady-state coexistence can be obtained in such systems for wide ranges of operating conditions. In the present work, we study a model of microbial competition in configurations of interconnected chemostats and we show that, if a substrate inhibition model is used for the specific growth rates of the two populations, coexistence in a periodic state is also possible. The analysis of the model is done by numerical bifurcation theory methods.     

Multiple splice variants of phosphodiesterase PDE4C cloned from human lung and testis

Four closely related cyclic-nucleotide specific phosphodiesterase (PDE4) genes have been identified in both humans and rats: PDE4A, 4B, 4C and 4D. We have now cloned cDNAs for multiple splice variants of human PDE4C. Two splice variants, PDE4C-791 and PDE4C-426, were isolated from a fetal lung library. The longest open reading frame (ORF) of 791 amino acids (aa) is encoded by PDE4C-791, which is similar to a recently described cDNA [Engels, P., Sullivan, M., Muller, T. and Lubbert, H. FEBS Lett. 358 (1995) 305-10], except that an alternative 5'-end sequence upstream of the first methionine extends the PDE4C-791 ORF by 79 aa. The PDE4C-426 variant contains 3 insertions that are located 5' to the catalytic domain and encode several in-frame stop codons. The predicted 426 aa protein initiates at a methionine 365 aa within PDE4C-791. A baculovirus clone starting at this methionine expressed an enzymatically active protein. Two additional splice variants, PDE4C-delta54 and PDE4C-delta109, were found in testis mRNA. PDE4C-delta54 contained a novel 5'-end region and a deletion of 162 nt; the predicted protein deletes 54 aa from the amino-terminal region. The PDE4C-delta54 protein produced in baculovirus-infected cells was enzymatically active and sensitive to PDE4-specific inhibitors. The PDE4C-delta109 protein is similar to PDE4C-delta54 but has an additional 55 aa deleted in the catalytic domain; it lacked enzymatic activity. Analysis of uncloned total mRNA from 4 tissue sources by polymerase chain reaction (PCR) confirmed the presence of mRNAs with the two deletions and three insertions that we observed in cDNA clones. The PDE4C-delta54 variant was found only in testis and the 5'-extended region of PDE4C-791 was seen only in lung and the melanoma cell line G361. Hence, tissue-specific expression of various PDE4C isoforms should be considered in understanding how these gene products modulate cellular responses to cAMP.     

Comparative studies of specific acquired systemic tolerance induced by intrathymic inoculation of a single synthetic Wistar-Furth (RT1U) allo-MHC class I (RT1.AU) peptide or WAG (RT1U)-derived class I peptide

Research on public opinion has seldom been incorporated into the debate about appropriate coverage of mental health and substance abuse treatment services in health insurance plans. However, several surveys have been conducted to probe for voters' awareness of and attitudes toward persons with mental illness and insurance coverage of their treatment needs. Given the current debate over mandating parity for coverage of mental health and substance abuse treatment services, these data promise to be particularly useful to politicians and health policy analysts. The author reviews reports of survey research conducted between 1989 and 1994 to assess American voters' support for expansions of mental health and substance abuse treatment coverage, including their knowledge about the origins and implications of mental illness and their willingness to pay for more generous benefits. The results suggest widespread support for such benefit expansions, but voters express concern about potential increases in their taxes or in their health insurance premiums. To facilitate the passage of meaningful reforms for mental health and substance abuse treatment benefits, policy makers must present realistic estimates of the costs of such expansions and of the benefits to be delivered to those in need.     

Subcongenic analysis of the Idd13 locus in NOD/Lt mice: evidence for several susceptibility genes including a possible diabetogenic role for beta 2-microglobulin

Although they share approximately 88% of their genome with NOD mice including the H2g7 haplotype, NOR mice remain free of T cell-mediated autoimmune diabetes (IDDM), due to non-MHC genes of C57BLKS/J (BKS) origin. NOR IDDM resistance was previously found to be largely controlled by the Idd13 locus within an approximately 24 cM segment on Chromosome 2 encompassing BKS-derived alleles for H3a, B2m, Il1, and Pcna. NOD stocks carrying subcongenic intervals of NOR Chromosome 2 were utilized to more finely map and determine possible functions of Idd13. NOR- derived H3a-Il1 (approximately 6.0 cM) and Il1-Pcna (approximately 1.2 cM) intervals both contribute components of IDDM resistance. Hence, the Idd13 locus is more complex than originally thought, since it consists of at least two genes. B2m variants within the H3a-Il1 interval may represent one of these. Monoclonal Ab binding demonstrated that dimerizing with the beta 2m(a) (NOD type) vs beta 2m(b) isoform (NOR type) alters the structural conformation, but not total expression levels of H2g7 class I molecules (e.g. Kd, Db). Beta 2m-induced alterations in H2g7 class I conformation may partially explain findings from bone marrow chimera analyses that Idd13 modulates IDDM development at the level of non-hematopoietically derived cell types controlling selection of diabetogenic T cells and/or pancreatic beta cells targeted by these effectors. Since trans-interactions between relatively common and functionally normal allelic variants may contribute to IDDM in NOD mice, the search for Idd genes in humans should not be limited to functionally defective variants.     

Long-term results from metacarpophalangeal arthroplasty

The authors have been using Swanson's prostheses for MP joint replacement in rheumatoid arthritis since 1968. After thirteen years of experience, they present an analysis of these prostheses from a clinical and radiological point of view. 88 joints replacements in 20 patients are reviewed. These operations were performed between 1968 and 1976. The average follow-up is nine years. The authors compare their results with those obtained in a previous study made in 1975. They show that a replacement arthroplasty with a Swanson type prosthesis, imparts considerable benefits to the patient in the form of complete disappearance of pain, improvement in function, and a more normal looking hand, in spite of radiologic deterioration.