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Biomedical subjects

C Merrill

Publications and source records attributed to C Merrill.

At least 19 recordsLinked to original sources
PubMed2001

Immunoglobulin binding properties of the Prosorba immunadsorption column in treatment of rheumatoid arthritis.

Studies of the humoral effects of the Prosorba column were conducted in conjunction with the Phase 3 trial of Prosorba versus sham therapy for rheumatoid arthritis (RA). When perfused with normal human plasma in vitro, Prosorba bound predominantly IgG with a maximal capacity of approximately 462 g of Ig per Prosorba column, equal to about 1.5% of circulating IgG. Prosorba treatment did not alter the concentrations of albumin, IgG, IgM, and IgA in 3 RA patients, except for a small dilutional effect. Kinetic studies demonstrated that Prosorba removed IgG > IgM, IgA, and IgM rheumatoid factor (RF) during the initial moments of apheresis and almost exclusively IgM RF after 15 min. No net protein removal occurred at > or = 60 min. Mean values of circulating immune complexes (CICs) were not significantly decreased by 12 weekly treatments. Complement was activated by the apheresis system upstream of the Prosorba column without changing C3 or C4 levels. We conclude that the Prosorba mechanism of action in RA is not bulk removal of Ig, but might involve modification of the CIC repertoire and could include, but not be limited to, effects related to complement activation.

Antigen-Antibody Complex↗
PubMed1999

Truncated RanGAP encoded by the Segregation Distorter locus of Drosophila.

Segregation Distorter (SD) in Drosophila melanogaster is a naturally occurring meiotic drive system in which the SD chromosome is transmitted from SD/SD+ males in vast excess over its homolog owing to the induced dysfunction of SD+-bearing spermatids. The Sd locus is the key distorting gene responsible for this phenotype. A genomic fragment from the Sd region conferred full distorting activity when introduced into the appropriate genetic background by germline transformation. The only functional product encoded by this fragment is a truncated version of the RanGAP nuclear transport protein. These results demonstrate that this mutant RanGAP is the functional Sd product.

Animals↗
PubMed1999

Anti-adhesion molecule therapy as an interventional strategy for autoimmune inflammation.

Functional inactivation of leukocyte adhesion molecules has been used to intervene in the development of tissue injury in experimental models of postperfusion infarction as well as autoimmune inflammation. We investigated the use of humanized monoclonal antibodies (mAb) against CD18 in the treatment of five patients with vasculitic tissue injury sufficient to threaten infarction or gangrene. The treatment was monitored in three ways: (i) whole-body gamma camera scintiscanning of autologous indium-labeled PMN, (ii) an index of the therapeutic inhibition of adhesion derived from comparison pre, during, and post mAb treatment of the ability of patients' PMN to be aggregated after activation by fMLP, and (iii) flow cytometric analysis of PMN CD18 expression. Four of five patients given anti-CD18 at 20 mg/day for up to 3 weeks showed prompt clinical improvement, with healing of the ulceration and restoration of limb function within 4 weeks, which was sustained. The fifth patient, who was not doing well clinically, decided to withdraw from all active treatment: at autopsy there was no evidence of the underlying vasculitis evident pretreatment. Our findings suggest that anti-adhesion molecule treatment might be an effective immediate treatment in severe vasculitis especially when tissue viability is threatened by progressive infarction and/or development of gangrene.

Aged↗
PubMed1998

Male sterility and meiotic drive associated with sex chromosome rearrangements in Drosophila. Role of X-Y pairing.

In Drosophila melanogaster, deletions of the pericentromeric X heterochromatin cause X-Y nondisjunction, reduced male fertility and distorted sperm recovery ratios (meiotic drive) in combination with a normal Y chromosome and interact with Y-autosome translocations (T(Y;A)) to cause complete male sterility. The pericentromeric heterochromatin has been shown to contain the male-specific X-Y meiotic pairing sites, which consist mostly of a 240-bp repeated sequence in the intergenic spacers (IGS) of the rDNA repeats. The experiments in this paper address the relationship between X-Y pairing failure and the meiotic drive and sterility effects of Xh deletions. X-linked insertions either of complete rDNA repeats or of rDNA fragments that contain the IGS were found to suppress X-Y nondisjunction and meiotic drive in Xh-/Y males, and to restore fertility to Xh-/T(Y;A) males for eight of nine tested Y-autosome translocations. rDNA fragments devoid of IGS repeats proved incapable of suppressing either meiotic drive or chromosomal sterility. These results indicate that the various spermatogenic disruptions associated with X heterochromatic deletions are all consequences of X-Y pairing failure. We interpret these findings in terms of a novel model in which misalignment of chromosomes triggers a checkpoint that acts by disabling the spermatids that derive from affected spermatocytes.

Animals↗
PubMed1996

Rapid resolution of chronic colitis in the cotton-top tamarin with an antibody to a gut-homing integrin alpha 4 beta 7.

BACKGROUND & AIMS: Integrins play diverse roles in cellular actions and signalling in the immune system. In the context of mucosal immune responses, the integrin alpha 4 beta 7 has received particular attention because of its intimate involvement in lymphocyte recruitment to normal gastrointestinal mucosa and associated lymphoid tissue. The aim of this study was to determine the functional relevance of alpha 4 beta 7 in the pathogenesis of colonic inflammatory disease using the colitic cotton-top tamarin, an animal model of human ulcerative colitis. METHODS: Chronically colitic cotton-top tamarins were given either a cross-reactive monoclonal antibody to human alpha 4 beta 7 or an irrelevant control monoclonal antibody. The animals were then evaluated clinically and mucosal biopsy specimens assessed by histological and quantitative morphometric analysis. RESULTS: A blocking monoclonal antibody to alpha 4 beta 7 integrin ameliorated inflammatory activity and rapidly improved stool consistency when administered to chronically colitic animals. Furthermore, using morphometric analysis of biopsy specimens, antibody therapy reduced the mucosal density of alpha 4 beta 7+ lymphocytes and alpha 4 beta 7 neutrophils and macrophages. CONCLUSIONS: These results suggest that the alpha 4 beta 7 integrin represents a novel, potentially organ-specific therapeutic target for the treatment of inflammatory bowel disease.

Animals↗
PubMed1993

Clinicopathologic study of the effect of radial tears and loop fixation on intraocular lens decentration.

PURPOSE: The purpose of this study is to determine the effect of loop fixation and anterior capsular tears on intraocular lens (IOL) decentration. METHODS: A retrospective measurement of IOL decentration was performed on 144 human eyes with posterior chamber (PC) IOLs obtained after death. RESULTS: Decentration in eyes with asymmetrical bag-sulcus fixation (mean +/- standard deviation, 0.64 +/- 0.39 mm) was significantly higher than eyes with symmetrical fixation. In the presence of radial tears, symmetrically fixated IOLs in either the capsular bag or the ciliary sulcus decentered to a similar degree, 0.35 +/- 0.25 mm and 0.4 +/- 0.26 mm, respectively. The least decentration was observed with capsular fixation and no radial tears (0.18 +/- 0.09 mm). This was significantly less decentration than with any other form of fixation in the presence of radial tears. CONCLUSION: This study shows that capsular fixation with no radial tears, as can be achieved by using the continuous curvilinear capsulorhexis, is associated with the least decentration.

Adult↗
PubMed1991

Acute dependence on depressant drugs is determined by common genes in mice.

Withdrawal seizure prone (WSP) and withdrawal seizure resistant (WRS) mice were genetically selected to express severe or mild handling-induced convulsions (HIC), respectively, after cessation of chronic ethanol (EtOH) vapor inhalation. The studies reported here tested WSP and WSR mice to determine whether elevated HIC were seen after administration of acute doses of several drugs that depress central nervous system activity. The drugs tested were EtOH, pentobarbital, t-butanol, acetaldehyde, and diazepam. All drugs initially suppressed HIC in WSP mice. This suppression was followed by an exacerbation of HIC, suggestive of a state of rebound central nervous system hyperexcitability during acute withdrawal. Susceptibility to acute withdrawal seizures was clearly under genetic control, since WSR mice did not display acute withdrawal HIC to any appreciable extent. Acute EtOH withdrawal seizures did not require testing WSP mice repeatedly, as they could be seen upon a single HIC test 8 hr after EtOH injection. Results with acetaldehyde and t-butanol suggest that the formation of acetaldehyde may be sufficient, but is not necessary for the elicitation of acute EtOH withdrawal. Earlier studies had found that WSP mice displayed more severe withdrawal HIC than WSR mice after chronic treatment with t-butanol, phenobarbital, nitrous oxide, or diazepam. The genetic predisposition to chronic EtOH withdrawal HIC in WSP mice generalized to all central nervous system depressants acutely tested, suggesting that acute and chronic withdrawal to all these drugs is largely under the control of a common group of genes.

Acetaldehyde↗
PubMed1990

Effect of chronic ivermectin treatment on GABA receptor function in ethanol withdrawal-seizure prone and resistant mice.

Ivermectin, a potent, effective anthelmintic, is easy to administer, has a broad spectrum of action and a wide safety margin. However, no testing has been done in hosts genetically selected for seizure susceptibility which may be more sensitive to the effects of ivermectin than other animals. This was done in the present experiments with seizure prone and seizure resistant mice infested with Syphacia obvelata (pinworm). These subjects were treated daily with oral ivermectin in their drinking water every other week for six weeks, for a total of 21 days. The treatment cleared the mice of the pinworm infestation, but did not alter the seizure susceptibility or binding parameters of [3H]flunitrazepam in either of the selected lines.

Animals↗
PubMed1988

Effects of ageing and long-term subcultivation on collagen lattice contraction and intra-lattice proliferation in three rat cell types.

Many cells can contract a hydrated collagen lattice when seeded within one, reorganizing the collagen fibrils into a compact structure by tractional forces exerted during cell movement and translocation. The effects of ageing on this tractional-motility property of cells was examined for three cell types from adult Fischer 344 male rats: skin fibroblasts, aortic smooth muscle cells, and dedifferentiated chondrocytes. All cell types at low population doubling levels (PDL less than 10) contracted collagen lattices, though with different proficiencies (smooth muscle cells greater than dedifferentiated chondrocytes greater than skin fibroblasts). There was no significant difference in contraction ability of cell isolates of the same type obtained from 4-month and 24-30-month animals. Cells that had been subcultivated extensively (PDLs of 50-110) retained contractional ability. The cell types proliferated within lattices to varying extents, and there was no correlation between a cell type's extent of proliferation in a lattice and its proliferation in monolayer culture. That lattice contraction ability is preserved intact with ageing in three cell types suggests that the tractional forces exerted by cells on a collagen matrix in vitro may have a significant role in adult life in vivo.

Aging↗
PubMed1984

Collagen biosynthesis by cells in a tissue equivalent matrix in vitro.

Collagen biosynthesis by fibroblasts and subsequent processing and polymerization have been studied in conventional monolayer cultures and in a new model system in vitro in which cells organize into a tissue like structure. While the bulk of the newly made collagen becomes tightly and selectively bound to the matrix of the tissue equivalent model, in monolayer cultures most of the collagen passes into the culture medium. Collagen biosynthesis appears to be regulated differently in cells of the tissue equivalent model as compared with monolayered cells. In the former there is a 6- to 8-fold decrease in collagen output even though overall protein synthesis per unit of DNA is twice as great as in monolayered cells. Cells grown in tissue lattices exhibit much higher collagenolytic activity than cells in monolayer suggesting the model may also be of special use for studying collagen turnover and matrix remodeling.

Cell Line↗
PubMed1983

Cyclic variations in sensitivity to X-irradiation during meiosis in Saccharomyces cerevisiae.

Cyclic variation in mutation induction and lethality was found following X-irradiation during meiosis in Saccharomyces cerevisiae. An enhanced mutagenic response was found in meiotic G1 phase cells in comparison to cells later in meiosis, similar to the response shown during mitosis, but meiotic G1 phase cells appeared more resistant to the lethal effects of X-irradiation than mitotic G1 phase cells. Resistance to the lethal effects of X-rays was found during meiotic DNA synthesis in the strain SK1, which may indicate the operation of a sister-chromatid exchange repair mechanism. A difference was found between gene conversion which appeared to be at a maximum by the end of meiotic DNA synthesis and reciprocal recombination, which could be induced up to prophase I.

DNA Repair↗
PubMed1983

Endogenous peroxidases in normal human dermis: a marker of fibroblast differentiation.

Incubation of unfixed and unfrozen slices of normal human skin allows visualization of a peroxidase activity associated with the perinuclear envelope and with the endoplasmic reticulum of resident dermal macrophages, dermal mastocytes, and also of some dermal fibroblasts. No peroxidase activity can be detected in fibroblasts cultivated in monolayer, while 80% of fibroblasts in an "in vitro" collagen lattice, called a dermal equivalent, express a peroxidase activity in the perinuclear envelope and the endoplasmic reticulum. Hence expression of this peroxidase activity in normal human skin fibroblasts serves as a marker of fibroblast differentiation and seems to depend on an interaction to fibroblast with the elements of a three-dimensional matrix.

Adult↗
PubMed1983

The reconstitution of living skin.

A living-skin equivalent useful as a skin replacement and as a model system for basic studies has been fabricated and tested extensively. It consists of two components: (1) a dermal equivalent made up of fibroblasts in a collagen matrix that is contracted and modified by the resident cells, and (2) an epidermis that develops from keratinocytes "plated" on the dermal equivalent. A multilayered keratinizing epidermis with desmosomes, tonofilaments, and hemidesmosomes forms. Basement lamella formation occurs within 2 weeks in vitro when rat cells are used. With human cells, crypt or pseudofollicular morphogenesis is observed in vitro within 3 weeks after plating cells on the dermal equivalent. Autografts and isografts of rat-skin equivalents made with cultured cells from biopsies are rapidly vascularized, block wound contraction, and persist essentially for the lifespan of the host. Seven to 9 days after grafting, donor cells become activated biosynthetically and mitotically. By 1 year, the dermal population decreases to a normal level and the matrix has been extensively remodeled. The grafts remain free of hair and sebaceous glands. Grafts to rats have been in place for over 2 years. Now, allografts of dermal equivalents have been made across a major histocompatibility barrier and are not rejected. The persistence of cellular elements of the grafts is monitored by use of a genetic marker. Challenge of the allograft with a second skin-equivalent graft after 1 month does not result in rejection of the original graft or of the second skin-equivalent graft. We propose that allografts of tissue equivalents are tolerated because cells with class II antigens are selected against during in vitro cultivation and are excluded from the graft. Thus the fabrication of skin-equivalent tissues or of other equivalent tissues with parenchymal cells that do not bear class II antigens may render transplants of such tissues immunologically acceptable despite the presence of allogeneic cells. The capacity to graft across major histocompatibility barriers using living tissue equivalents may have important clinical significance.

Animals↗
PubMed1981

Regulation of proliferation of fibroblasts of low and high population doubling levels grown in collagen lattices.

While IMR 90 and AG 1519 fibroblasts of low and high population doubling levels grow to confluency when plated on plastic surfaces, they cease to divide within four days when incorporated into collagen lattices. Growth inhibition in the lattices is not due to exhaustion of the medium or isotope, or to contact inhibition; nor is it due to impermeability of the lattice to the materials in the medium. While cells in a lattice arrest in G0, this state is reversible when cells are permitted to leave the lattice and populate a plastic substrate. We conclude that fibroblasts in tissue-like lattices may be responsive to some of the same controls as cells in connective tissues.

Animals↗