Biomedical subjects
Publications and source records attributed to Michael Smith.
An evidence-based systematic review including scientific evidence, expert opinion, folkloric precedent, history, pharmacology, kinetics/ dynamics, interactions, adverse effects, toxicology, and dosing.
Attempts to study renal angiogenesis have been hampered by the lack of an appropriate model. Here we present data on a successful ex vivo culture of renal medullary explants in three-dimensional collagen 1 or Matrigel lattices and characterize the dynamics of capillary formation by sprouting endothelial cells. Initially, endothelial cells represented 71 +/- 3% among the sprouting cells, but within a week growing capillaries were comprised exclusively of endothelial cells. The quantitative analysis showed that the number of sprouting capillaries progressively increased until 12 days in culture, after which capillaries underwent involution. Occasional formation of glomeruloid bodies was noted. Capillaries were characterized by a well-defined lumen, whereas glomeruloid bodies showed cellular debris occupying the luminal space. In view of the existing controversy regarding angiogenic competence in diabetic nephropathy, we applied this ex vivo culture system to Zucker diabetic rat model of diabetes mellitus. Comparative analysis of capillary sprouting in Zucker diabetic fat and lean nondiabetic control rats showed no differences in angiogenic properties of renal explants obtained at the age of 11 weeks. However, when kidneys were obtained from rats at age of 21 weeks, the capillary sprouting was significantly reduced in Zucker diabetic rats compared to age-matched lean rats. The rate of capillary involution was unaffected in Zucker diabetic rats. In conclusion, the data presented herein delineate the first successful ex vivo model of angiogenesis initiated from the renal medullary explants of adult rats and provide evidence of impaired angiogenesis in Zucker diabetic rats with the established, but not with incipient diabetes mellitus.
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Fenugreek has a long history of medical uses in Ayurvedic and Chinese medicine, and has been used for numerous indications, including labor induction, aiding digestion, and as a general tonic to improve metabolism and health. Preliminary animal and human trials suggest possible hypoglycemic and antihyperlipidemic properties of oral fenugreek seed powder.
Many patients with cancer use complementary and alternative medical (CAM) therapies. Physicians need authoritative information on CAM therapies to responsibly advise patients who seek these interventions. This article summarizes current evidence on the efficacy and safety of selected CAM therapies that are commonly used by patients with cancer. The following major categories of interventions are covered: dietary modification and supplementation, herbal products and other biological agents, acupuncture, massage, exercise, and psychological and mind-body therapies. Two categories of evidence on efficacy are considered: possible effects on disease progression and survival and possible palliative effects. In evaluating evidence on safety, two types of risk are considered: the risk for direct adverse effects and the risk for interactions with conventional treatments. For each therapy, the current balance of evidence on efficacy and safety points to whether the therapy may be reasonably recommended, accepted (for example, dietary fat reduction in well-nourished patients with breast or prostate cancer), or discouraged (for example, high-dose vitamin A supplementation). This strategy allows the development of an approach for providing responsible, evidence-based, patient-centered advice to persons with cancer who seek CAM therapies.
BACKGROUND: Imiquimod 5% topical cream is an immune response modifier that induces interferon alpha and interleukin-12, and exhibits antiviral and tumor-inhibiting properties. It is currently available for treatment of genital and perianal warts. Three randomized, open-label or assessor-blinded, placebo-controlled studies were carried out to assess its safety on normal white skin exposed to ultraviolet radiation (UVR). METHODS: Healthy white volunteer adult subjects between the ages of 18 and 60 years with skin types I, II or III (Fitzpatrick Scale, US Federal Register 43:38260, 1978) were invited to participate. Imiquimod 5% cream (each dose approximately 0.1-0.2 ml) was compared with placebo cream. Two preliminary studies assessed the potential photosensitizing properties of the drug, and the third study added measurement of sunburn cell counts (SBC) and deoxyribonucleic acid (DNA) pyrimidine dimer (PD) formation. The three studies were: a 6-week standard photocontact allergenicity bioassay; a 4-day standard phototoxicity bioassay; and a 4-week photodamage study using biopsy sample analyses to determine SBC or PD frequency. RESULTS: Imiquimod had no detectable potential for inducing either photocontact allergy (n=115) or phototoxicity (n=20). The final study further assessing photodamage potential of imiquimod included 44 subjects. There were no significant differences between imiquimod vs. the control (no drug+UVB) for SBC counts (mean 0.88 vs. 0.93), or PD frequency (mean 60.86 vs. 70.03). CONCLUSIONS: Results from the two preliminary safety studies suggest that imiquimod 5% cream does not possess a detectable photosensitizing potential in humans. Furthermore, topical imiquimod did not enhance UVR-induced damage to epidermal cells or DNA.
A physical map of a genome is an essential guide for navigation, allowing the location of any gene or other landmark in the chromosomal DNA. We have constructed a physical map of the mouse genome that contains 296 contigs of overlapping bacterial clones and 16,992 unique markers. The mouse contigs were aligned to the human genome sequence on the basis of 51,486 homology matches, thus enabling use of the conserved synteny (correspondence between chromosome blocks) of the two genomes to accelerate construction of the mouse map. The map provides a framework for assembly of whole-genome shotgun sequence data, and a tile path of clones for generation of the reference sequence. Definition of the human-mouse alignment at this level of resolution enables identification of a mouse clone that corresponds to almost any position in the human genome. The human sequence may be used to facilitate construction of other mammalian genome maps using the same strategy.
Selectin ligands are glycan structures that participate in leukocyte trafficking and inflammation. At least 6 ST3Gal sialyltransferases (I-VI) have been identified that may contribute to selectin ligand formation. However, it is not known which of these sialyltransferases are involved in vivo and whether they may differentially regulate selectin function. We have produced and characterized mice genetically deficient in ST3Gal-I, ST3Gal-II, ST3Gal-III, and ST3Gal-IV. Unlike mice bearing severe defects in selectin ligand formation, there was no finding of leukocytosis with these single ST3Gal deficiencies. Among neutrophils, only ST3Gal-IV was found to play a role in the synthesis of selectin ligands. In vitro rolling of marrow-derived neutrophils on E- or P-selectins presented by Chinese hamster ovary cells was reduced in the absence of ST3Gal-IV. However, in a tumor necrosis factor alpha (TNF-alpha)-induced inflammation model in vivo, no defect among P-selectin ligands was observed. Nevertheless, the number of leukocytes rolling on postcapillary venules in an E-selectin-dependent manner was decreased while E-selectin-dependent rolling velocity was increased. We propose that multiple ST3Gal sialyltransferases contribute to selectin ligand formation, as none of these ST3Gal deficiencies recapitulated the degree of E- and P-selectin ligand deficit observed on neuraminidase treatment of intact neutrophils. Our findings indicate a high degree of functional specificity among sialyltransferases and a substantial role for ST3Gal-IV in selectin ligand formation.
BACKGROUND: Nausea and vomiting during pregnancy (NVP) affects two-thirds of pregnant women to varying degrees and over the years many modalities have been used to try to alleviate this often debilitating condition. There is a paucity of information in the literature about the use or efficacy of complementary and alternative medicine (CAM) for the treatment of this condition that affects so many women. Our primary objective was to examine the prevalence of CAM usage by women suffering from NVP. Our secondary objective was to ascertain if women had any supervision in the use of these treatments. METHODS: Women who called The Motherisk NVP helpline, were asked after the counseling session to complete a questionnaire, which included demographic data as well as information about their CAM use. RESULTS: Seventy women completed the questionnaire. 61% reported using CAM therapies, of which the three most popular were: ginger, vitamin B6 and acupressure. 21% of those who reported using CAM, had consulted CAM practitioners, 8% their physicians or pharmacists and 71% discussed the usage with family, friends and other allied health professionals. Women who did not use CAM stated they would probably use these modalities if there was more information about the safety in pregnancy. CONCLUSION: Pregnant women with NVP are mirroring the trend in the general population of the use of CAM. They are also using CAM therapies with little supervision from practitioners experienced in the use of these modalities.
The World Wide Web is increasingly important for medical education. Internet served pages may also be used on a local hard disk or CD-ROM without a network or server. This allows authors to reuse existing content and provide access to users without a network connection. CD-ROM offers several advantages over network delivery of Web pages for several applications. However, creating Web pages for CD-ROM requires careful planning. Issues include file names, relative links, directory names, default pages, server created content, image maps, other file types and embedded programming. With care, it is possible to create server based pages that can be copied directly to CD-ROM. In addition, Web pages on CD-ROM may reference Internet served pages to provide the best features of both methods.
The membrane epithelial mucin MUC1 is expressed at the luminal surface of most simple epithelial cells, but expression is greatly increased at lactation and in most breast carcinomas. The increase in level of expression of MUC1 in breast cancer is accompanied by changes in the profile of glycosyl transferases involved in the synthesis of the O-glycans attached to the MUC1 core protein. The cancer-associated mucin is therefore structurally different from the normal mucin, and expresses novel B cell epitopes. MUC1 antibodies are used for in vivo targeting of breast and ovarian tumors, and there is considerable interest in MUC1 as a possible target antigen for the immunotherapy of breast cancer. The different glycoforms can affect cell interactions differently, depending on whether specific interactions with lectins occur. In the absence of such lectin interactions, the long sialylated and negatively charged molecule can inhibit intercellular interactions between other cell surface molecules. The potential role of the different components of the immune system in MUC1 responses are discussed within the framework of how to develop logical strategies for designing clinical studies.
Herpes simplex virus type-1 (HSV-1) has been demonstrated as a potentially useful gene delivery vector for gene therapy due to its high efficiency of in vivo transduction. The helper virus-dependent, HSV- 1 amplicon vectors were developed for easier operation and their larger capacity. In this study, the herpes simplex virus type-1 thymidine kinase (HSVtk) gene was cloned into the pHE700 amplicon vector to make an HE7tk vector and used for in vivo gene delivery. Human melanoma xenografts were established in athymic nude mice. Tumors were injected directly with HE7tk vector alone, HE7tk vector followed by ganciclovir (GCV), or a pHE700 amplicon vector carrying a green fluorescent protein (HE7GFP) gene followed by GCV. Efficient HSVtk transgene expression was found in the tumor 3 days after injection. Animals transduced with HE7tk followed by GCV had minimal tumor growth (P < .01 ). Animals that received either HE7tk vector without GCV or HE7GFP vector with GCV had some reduction in tumor growth compared to animals that were injected with buffer only. These data indicate that replication-defective HSV-1 amplicon vectors can be used effectively to deliver transgenes into solid tumors in vivo.
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OBJECTIVE: We assessed the effect of a social work liaison program on caregiver outcomes for families caring for people with brain injury. DESIGN: All telephone calls received by the team were entered into a standardized log form to record topics raised by caregivers. MAIN OUTCOME MEASURES: We compared the experience of this cohort of traumatic brain injury (TBI) caregivers with the experience of an earlier cohort by use of standard measures of caregiver mental health. Because patients in the cohort had mixed etiologies, we also examined the experience of caregivers according to type of brain injury, comparing cerebrovascular accident with TBI patients. RESULTS: The social work liaison program offered benefit to caregivers on burden, satisfaction, and mastery outcomes. CONCLUSIONS: This research suggests that a relatively low-cost, nonintensive intervention may offer substantial benefit to families caring for people with brain injury.
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Present strategies for control of herpes genitalis recurrences require multiple daily doses of antiviral medication. Imiquimod, an immune response modifier, induces alpha interferon and interleukin-12; application in the presence of local herpes antigens during a recurrence may augment herpes simplex virus (HSV)-specific cell-mediated immunity. To test this theory, we performed a randomized, double-blind, placebo-controlled study of imiquimod 5% cream to assess safety and efficacy for decreasing recurrences. Patients with six or more recurrences of herpes genitalis per year applied study cream (imiquimod or placebo) to lesions one, two, or three times per week for 3 weeks for each recurrence during a 16-week treatment period. This was followed by a 16-week observation period. Of 124 patients randomized to the study, 103 completed the treatment period and 93 completed the observation period. The median times to first genital herpes recurrence were 53 days for those receiving placebo (n = 30) and 54, 60, and 64 days for those receiving imiquimod one time per week (n = 34), two times per week (n = 32), and three times per week (n = 28), respectively. The median annualized recurrence rates during the treatment period were 3.8, 4.9, 3.2, and 3.1, respectively. There were no statistically significant differences in the time to first recurrence or in the annualized recurrence rate between the imiquimod and placebo groups in either the treatment or the observation period. A trend in increased rates of local adverse events at the application site and a delay in lesion healing with more frequent dosing suggested a pharmacologic effect. Although clinical efficacy has been observed for imiquimod in other conditions in which a TH1-type immune response may be beneficial, including other viral infections such as those caused by human papillomavirus, no apparent effect on the short-term natural history of herpes genitalis recurrences was observed.
Destruction of lung elastin is critical for development of emphysema associated with chronic obstructive pulmonary disease (COPD). Lung macrophages release elastolytic enzymes, including matrix metalloproteinase (MMP)-9, along with tissue inhibitors of MMP (TIMP). We examined the production and activity of macrophage-derived MMP-9 and TIMP-1 from alveolar macrophages (AM) from smokers with COPD, healthy smokers (HS), and nonsmokers (NS). AM were stimulated with either lipopolysaccharide (LPS), interleukin (IL)-1 beta, or cigarette smoke-conditioned culture medium (CSM). AM from patients with COPD released greater amounts of MMP-9 with greater enzymatic activity than HS and NS. In contrast, AM from NS released more TIMP-1 than cells from HS and subjects with COPD. LPS and IL-1 beta caused a dose-dependent increase in MMP-9 release and activity, together with increased levels of TIMP-1. Dexamethasone prevented the increase in MMP-9 release, and increased TIMP-1 release. CSM increased MMP-9 and TIMP-1 release from AM of all groups. Dexamethasone decreased CSM-stimulated MMP-9 release, but had no effect on MMP-9 activity This study suggests that macrophages might be important in the development of COPD because these cells exhibit increased levels of elastolytic activity.