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Biomedical subjects

D M Phillips

Publications and source records attributed to D M Phillips.

At least 19 recordsLinked to original sources
PubMed2005

The limitation of acute necrosis in retro-patellar cartilage after a severe blunt impact to the in vivo rabbit patello-femoral joint.

We have previously shown that surface lesions and acute necrosis of chondrocytes are produced by severe levels of blunt mechanical load, generating contact pressures greater than 25 MPa, on chondral and osteochondral explants. We have also found surface lesions and chronic degradation of retro-patellar cartilage within 3 years following a 6J impact intensity with an associated average pressure of 25 MPa in the rabbit patello-femoral joint. We now hypothesized that cellular necrosis is produced acutely in the retro-patellar cartilage in this model as a result of a 6J impact and that an early injection of the non-ionic surfactant, poloxamer 188 (P188), would significantly reduce the percentage of necrotic cells in the traumatized cartilage. Eighteen rabbits were equally divided into a 'time zero' group and two other groups carried out for 4 days. One '4 day' group was administered a 1.5 ml injection of P188 into the impacted joint immediately after trauma, while the other was injected with a placebo solution. Impact trauma produced surface lesions on retro-patellar cartilage in all groups. Approximately 15% of retro-patellar chondrocytes suffered acute necrosis in the 'time zero' and '4-day no poloxamer' groups. In contrast, significantly fewer cells (7%) suffered necrosis in the poloxamer group, most markedly in the superficial cartilage layer. The use of P188 surfactant early after severe trauma to articular cartilage may allow sufficient time for damaged cells to heal, which may in turn mitigate the potential for post-traumatic osteoarthritis. Additional studies are needed to improve the efficacy of this surfactant and to determine the long-term health of joint cartilage after P188 intervention.

Acute Disease↗
PubMed2001

Comparison of microbicides for efficacy in protecting mice against vaginal challenge with herpes simplex virus type 2, cytotoxicity, antibacterial properties, and sperm immobilization.

BACKGROUND: Currently, a number of different over-the-counter spermicides and potential microbicides under development are in various phases of clinical trials. It is difficult to know how the various formulations would compare with each other or how efficacious they would be because no existing microbicides are commercially available. GOAL: To evaluate, in a standardized manner, various parameters of potential microbicides. STUDY DESIGN: In an effort to make a comprehensive comparison, several potential microbicides and over-the-counter vaginal products were assayed for their efficacy in protecting mice from infection by herpes simplex virus type 2 (HSV-2), for their cytotoxicity to human vaginal epithelial cells, for their effect on the growth rate of L acidophilus, and for their spermicidal activity. Test formulations were K-Y Plus, Gynol II, Advantage S, Replens, BufferGel, No Fertil, Carrageenan, and PC-550. Additionally, several formulations were evaluated for their use as a possible placebo in microbicide clinical trials. RESULTS: The formulations tested fell into three categories of efficacy in protecting mice from HSV-2 infection. The most efficacious were Carraguard and PC-550. All the other test formulations except methyl cellulose afforded varying degrees of protection against herpes simplex virus-2 infection. It was found that formulations containing the surfactant N9 had a cytotoxic effect on human vaginal cells, inhibited the growth rate of L acidophilus, and exhibited spermicidal activity. In addition, it was found that Replens, BufferGel, No Fertil, and the Carbopol formulation might have some effect on sperm motility. Also, K-Y Jelly significantly inhibited the growth rate of L acidophilus. CONCLUSION: Evaluating formulations under the same testing conditions can help to distinguish among potential formulations that are likely to show promise as safe and effective microbicides.

Animals↗
PubMed2000

Nonoxynol-9 causes rapid exfoliation of sheets of rectal epithelium.

Nonoxynol-9 (N-9) containing spermicides and other N-9 containing products are commonly used as lubricants during rectal intercourse. We have previously demonstrated that rectal application of N-9 products in mice can cause exfoliation of epithelial cells, increasing the probability of infection by HSV-2. To determine if N-9-containing products would have a similar effect on the rectal epithelium in humans, the application of K-Y Plus and ForPlay, both over-the-counter (OTC) N-9 products, were compared to the application of two formulations, carrageenan and methyl cellulose, that do not contain N-9. The effects of each formulation were evaluated in 4 human participants. Light and electron microscope examination of rectal lavage specimens collected 15 min post application of N-9 products revealed the presence of sheets of epithelium. Each sheet contained hundreds of epithelial cells that included columnar and goblet cells, varieties of cells typical of rectal epithelial morphology. Sheets of epithelium were not observed in rectal lavage specimens collected 8 to 12 hr post N-9 product use or in either of the timed lavages involving non-N-9 containing formulations. In addition, no sheets of epithelial cells were observed in the baseline lavage specimens. We conclude that the rectal use of N-9-containing products causes a rapid exfoliation of extensive areas of the rectal epithelium. Exfoliation of the epithelium is no longer observed at 8 hr. It is reasonable to assume that the loss of the protective epithelium would render a person more at risk for infection by HIV and other sexually transmitted pathogens. We, therefore, caution against the use of N-9-containing products during rectal intercourse.

Adult↗
PubMed2000

A randomized phase II trial comparing two different sequence combinations of autologous vaccine and human recombinant interferon gamma and human recombinant interferon alpha2B therapy in patients with metastatic renal cell carcinoma: clinical outcome and analysis of immunological parameters.

PURPOSE: The clinical observation of spontaneous regression in patients with renal cell carcinoma (RCC) and the response to various immunotherapeutic therapies strongly suggest a role for the host immune system in this disease. Prior studies showed that sequential administration of interferon (IFN) gamma and IFN alpha to RCC patients was safe. Clinical responses as well as immune changes in the peripheral blood mononuclear cell compartment were observed. Autologous tumor cell vaccines (AV) have also demonstrated activity in renal cell carcinoma. We hypothesize that the addition of AV to sequential IFN gamma and a therapy might improve the tumor-specific immune response by providing an appropriate source of antigen in the appropriate cytokine environment. To our knowledge, this is the first trial using AV combined with IFN alpha and IFN gamma. The purpose of this study was to evaluate the feasibility of manufacturing and administering (AV) from resected tumor samples, and administration of AV with combination IFN gamma and IFN alpha therapy. Finally, the impact on immunological parameters of these treatment options was assessed. MATERIALS AND METHODS: Patients with metastatic RCC were randomly assigned to receive AV plus bCG along with a sequential administration of IFN gamma and a either together or after initiation of vaccine. Toxicity and clinical responses were evaluated. Modulations of the immune system were investigated by analyzing phenotype, cytokine mRNA expression, T cell proliferation and cytotoxicity in the peripheral blood mononuclear cell compartment. RESULTS: Fourteen patients with metastatic renal cell carcinoma were enrolled in this study; 9 were available for response evaluation. In a 70 day period, 3 (33%) showed mixed responses, 5 (56%) stable disease and 1 (11%) progression of disease. Toxicities were consistent with previous clinical reports. In the flow-cytometry phenotype analysis, stimulation of distinct subsets of circulating T-lymphocytes and a decrease of CD8+ T cell subsets was demonstrated. T-cell proliferation to allogeneic tumor cell stimulation improved following treatment. IL-4 and IL-5 mRNA levels were reduced in all patients after treatment. Patients who responded to treatment did not produce any IL-4 mRNA at all, before or after treatment. CONCLUSIONS: AV with IFNgamma and IFNalpha therapy might induce a MHC class-mediated cytotoxic T lymphocyte (CTL) response. We suggest that adequate therapy might direct T cell response toward a Th1 type response. We hypothesize a state of improved immune readiness in patients who might eventually respond to immunotherapy.

Adult↗
PubMed1999

School problems and the family physician.

Children with school problems pose a challenge for the family physician. A multidisciplinary team of professionals can most appropriately assess and manage complex learning problems, which are often the cause of poor school performance. The family physician's primary role in this process is to identify or exclude medical causes of learning difficulties. An understanding of the complicated nature of school problems, the methods used to assess, diagnose and treat them, and the resources available to support the child and family are essential to successful management. Various references and resources are helpful for a more in-depth study of specific school problems.

Adolescent↗
PubMed1999

An investigation of the latency period between sperm oolemmal adhesion and oocyte penetration.

In clinical studies of the ability of capacitated human sperm to penetrate zona-free hamster eggs, we have previously observed that the ratio of oolemmal adherent to penetrating sperm varied between men. Sperm incorporation did not occur immediately following gamete adhesion and not all adherent sperm penetrated the egg. To further investigate this phenomenon, comparisons were made of the kinetics of gamete adhesion, membrane fusion, and sperm incorporation of capacitated mouse and human spermatozoa by zona-free hamster eggs and of mouse sperm by zona-free mouse and hamster eggs. Eggs were inseminated with either capacitated human or mouse sperm or combinations of both, washed out of sperm suspension after initial gamete adherence, and further incubated in sperm-free medium. Gamete membrane fusion was judged by dye transfer of Hoechst 33342 and sperm entry of the cortical ooplasm by observation of expanded sperm heads within acridine orange stained eggs. Oolemmal adherent mouse and human sperm fused with and penetrated zona-free hamster eggs at different times whether eggs were inseminated in parallel or with combinations of sperm of both species. Oolemmal adherent mouse sperm penetrated zona-free hamster eggs prior to their penetration of zona-free mouse eggs. Ultrastructural studies of zona-free human eggs inseminated with human sperm confirmed prior observations with hamster eggs that only acrosome-reacted human sperm adhere to the oolemma. These results have lead us to postulate that sperm entry into the egg may occur through a "zipper" mechanism involving the ligation of local gamete receptors similar to the incorporation of target particles by phagocytes and suggest that not all oolemmal adherent human sperm are capable of being incorporated although they have undergone an acrosome reaction.

Animals↗
PubMed1999

Pushing the frontiers of science--the Population Council's Microbicide Basic Science Network on vaginal microbicide research.

Microbicides are the new frontier of products for the prevention of sexually transmitted infections (STIs). Twelve years ago, scientists realized that existing spermicides had some anti-microbial activity and perhaps could be improved or reformulated with new compounds to provide a complete barrier against STIs. However, the development and successful marketing of an effective, non-toxic, convenient and affordable vaginal microbicide that women can use on a long-term basis hinges on a close collaboration between research institutions and the pharmaceutical industry. The Population Council has recently taken the first step in instituting a multifaceted strategy for the development of a microbicide by establishing the Microbicide Basic Science Network, comprising of scientists with diverse backgrounds and expertize.

Anti-Infective Agents↗
PubMed1998

Breast cancer in older women.

The American Geriatric Society currently recommends screening mammography for women up to 85 years of age whose life expectancy is three years or longer. The value of clinical breast examinations in older women needs further study. Total mastectomy and partial mastectomy with postoperative radiation therapy yield similar results in localized breast cancer. Postoperative irradiation may be avoided in women with small tumors (2.5 cm or less in diameter) who have undergone quadrantectomy. Lymph node dissection is important for tumor staging but significantly increases the risks and morbidity of surgery. Lymph node mapping may obviate the need for lymphadenectomy in many older women. Adjuvant hormonal therapy for at least two years appears to be beneficial in all women with hormone-receptor-rich tumors. Adjuvant chemotherapy is indicated in women with lymph node involvement or high-risk tumors with no lymph node involvement. Unless life-threatening metastases are present, hormonal therapy is the first approach to metastatic cancer. Chemotherapy is indicated if endocrine therapy is unsuccessful or life-threatening metastases are present. Most chemotherapy regimens appear to be well tolerated, even by women over 70 years of age. Special treatment should be employed for metastases to tumor sanctuaries (i.e., brain, eyes), the long bones, the spine and the chest wall.

Aged↗
PubMed1998

Structure-based design of peptides that recognize the CD4 binding domain of HIV-1 gp120.

DESIGN: Envelope protein-specific antiviral peptides, called mucibodies, that can specifically recognize and bind to the surface unit protein gp120 of HIV-1 were designed. The initial mucibody binding target was the V3 loop of HIV-1 gp120. Here, the gp120-CD4 binding domain was chosen as the site of mucibody binding. The CD4 binding domain of gp120 is known to be a conformational epitope and is involved in the earliest events of viral entry into many cells. METHODS: The design of the mucibody antivirals was based on previous observations that antibody complementarity determining regions (CDR) are generally similar to the repeating loops or knob structures found in the 20-residue tandem repeat domain of human mucin MUC1. The heavy chain CDR3 from the bacteriophage display antibody b12 was used to construct two mucibodies, b12-CDR1 and b12-26. RESULTS: Peptides corresponding to three tandem repeats were shown to bind directly to the CD4 binding domain of HIV-1 gp120 in a solid-phase enzyme-linked immunosorbent assay. These mucibody peptides also disrupted the gp120-CD4 interaction in a solution-phase inhibition assay. Finally, mucibodies neutralized primary and laboratory macrophage-tropic isolates of HIV-1. CONCLUSIONS: There is a potential for medical use of these peptides as topical vaginal microbicides in preventing HIV-1 transmission during sexual contact. These results also suggest that multivalent, non-immunogenic binding proteins of virtually any specificity could be constructed for use in therapeutic applications involving infectious diseases and immune system dysfunction.

Anti-HIV Agents↗
PubMed1998

Sulfated polysaccharides block chlamydia infection in vitro, but do not protect mice from vaginal inoculation.

There is considerable interest in developing a vaginal product that women could use to protect themselves from sexually transmitted pathogens, including chlamydia. It has been suggested that sulfated polysaccharides would be effective in a prophylactic product because they have been shown to block infection of cultured cells by sexually transmitted pathogens, including chlamydia. In order to compare in vitro findings with animals, we placed sulfated polysaccharides into the vaginae of mice prior to inoculation with chlamydia. The surfactant nonoxynol 9 (N9) was used as a positive control as it has been previously shown to protect mice from infection by chlamydia. In this study, N9 also protected the mice from infection. However, sulfated polysaccharides which had been shown to be efficacious in vitro did not block infection.

Animals↗
PubMed1998

Nonoxynol-9 enhances rectal infection by herpes simplex virus in mice.

Pretreating the rectum of mice with nonoxynol-9 (N9) or spermicides containing N9 before infecting via the rectal route with herpes simplex virus 2 (HSV-2) increased the likelihood of infection and shortened the time until infection. Microscopic analysis indicated that N9 rapidly caused exfoliation of the rectal epithelium, exposing the underlying connective tissue. These findings suggest that use of N9-containing products during rectal intercourse may increase the risk of infection with HSV-2 or other sexually transmitted pathogens.

Animals↗
PubMed1998

Ultrastructure of the murine cervix following infection with Chlamydia trachomatis.

We have used electron microscopy to follow the course of Chlamydia trachomatis infection in the mouse cervix. Although numerous elementary bodies (EBs) were observed on the surface of epithelial cells, evidence of coated pits or entry of EBs into epithelial cells were rarely observed. After 2 days postinoculation, inclusions contained numerous reticulate bodies (RBs) and a few intermediate forms (IBs). At 4 days postinoculation, microvilli were no longer present on infected cells and inclusions had often ruptured and released chlamydiae into the cytoplasm of the cells. Aberrant and miniature RBs, similar to those which have been described in in vitro models for persistence, were observed. Unlike the case in vitro where inclusion cause rupture of the cell, infection in vivo may result in rupture of inclusions within the cytoplasm of infected cells. Our observations also suggest that persistent chlamydia can form in some of the cells of the cervical epithelium that are infected by the initial inoculation.

Animals↗
PubMed1998

Electron microscopy: use of transmission and scanning electron microscopy to study cells in culture.

Standard techniques for electron microscopy were developed for tissues dissected from animals. Optimal methods for electron microscopy of cells in culture are different. This chapter describes methods for processing cells grown on plastic or in suspension. Both transmission and scanning electron microscopy are discussed. The focus is on the procedures for fixation, dehydration, embedding, and staining, which will help the reader to obtain superior electron micrographs of cultured cells.

Animals↗
PubMed1998

Breast cancer.

Infiltrating ductal carcinoma is the most common form of breast cancer, and major risk factors are nonmodifiable. Current screening recommendations offer the best chance of early diagnosis. Staging takes into account the size of primary tumor, number of positive lymph nodes at surgery, and location of distant metastases. Treatment options include various combinations of surgical procedures, radiotherapy, chemotherapy, and endocrine therapy.

Breast Neoplasms↗
PubMed1998

CAT-transfected epithelial cells provide evidence for a CD4 independent pathway of HIV infection.

Several laboratories have presented evidence that HIV can productively infect CD4- cell lines. However, this data could be challenged on the basis that the target cells may express low levels of the CD4 receptor. In addition, it could be argued that assays might be detecting residual virus. In the case of cell-mediated infection, it is possible that virus detected in assays could be secreted from HIV-infected donor cells rather than the target CD4- cells. In this report we describe a CD4- epithelial cell line which has been transfected with a plasmid containing the chloramphenicol acetyltransferase (CAT) gene ligated to the HIV LTR. CAT-ELISA and immunocytochemistry indicate that target cells synthesize CAT after exposure to HIV-infected primary activated peripheral blood mononuclear cells (PBMC). Results correlate very well with p24 ELISA assays. Infection of epithelia by primary NSI strains of HIV can be blocked by patient antisera or by certain sulfated polysaccharides. Since the CAT assay is not dependent on virus production, the data reported here confirm that CD4- epithelial cells derived from the human cervix can be productively infected by HIV. The observations also support the theory that sexual transmission of HIV could be initiated by infection of genital tract epithelia. Furthermore, the findings support the suppositions that sexual transmission of HIV could be prevented by antibodies to HIV or alternately by a topical formulation containing certain sulfated polysaccharides.

Animals↗