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Biomedical subjects

S Bain

Publications and source records attributed to S Bain.

At least 19 recordsLinked to original sources
PubMed2004

HER-2 overexpression is an independent marker of poor prognosis of advanced primary ovarian carcinoma: a multicenter study of the GINECO group.

BACKGROUND: Despite numerous studies, no biological marker has been identified that accurately predicts prognosis of advanced ovarian cancer. Tumors from a homogeneous population of 117 patients with a stage III/IV ovarian cancer, enrolled in a multicenter prospective GINECO clinical trial were analyzed retrospectively. PATIENTS AND METHODS: All patients received the same platinum-based combination therapy and were followed-up for a median of 68 months. Tumor expression of Ki67, BCL-2, BAX, P53 or c-erbB-2 proteins was evaluated immunohistochemically on paraffin-embedded tissues and their prognostic impact analyzed. RESULTS: The median rate of Ki67-positive nuclear area was 30%. BCL-2, BAX and P53 proteins were expressed in 52, 54 and 71% of the tumors, respectively, while HER-2 protein was overexpressed in 16%. Only HER-2 overexpression was significantly associated with shorter progression-free survival and overall survival. According to our multivariate analysis, the HER-2 prognostic impact was independent of classical clinical prognostic factors. CONCLUSION: HER-2 appeared to influence the outcome of advanced ovarian cancer patients included in a clinical trial with prolonged follow-up, thereby suggesting that HER-2 is a potential target for treatment of this cancer.

Adult↗
PubMed2002

Mechanical strain, induced noninvasively in the high-frequency domain, is anabolic to cancellous bone, but not cortical bone.

Departing from the premise that it is the large-amplitude signals inherent to intense functional activity that define bone morphology, we propose that it is the far lower magnitude, high-frequency mechanical signals that continually barrage the skeleton during longer term activities such as standing, which regulate skeletal architecture. To examine this hypothesis, we proposed that brief exposure to slight elevations in these endogenous mechanical signals would suffice to increase bone mass in those bones subject to the stimulus. This was tested by exposing the hind limbs of adult female sheep (n = 9) to 20 min/day of low-level (0.3g), high-frequency (30 Hz) mechanical signals, sufficient to induce a peak of approximately 5 microstrain (micro epsilon) in the tibia. Following euthanasia, peripheral quantitative computed tomography (pQCT) was used to segregate the cortical shell from the trabecular envelope of the proximal femur, revealing a 34.2% increase in bone density in the experimental animals as compared with controls (p = 0.01). Histomorphometric examination of the femur supported these density measurements, with bone volume per total volume increasing by 32% (p = 0.04). This density increase was achieved by two separate strategies: trabecular spacing decreased by 36.1% (p = 0.02), whereas trabecular number increased by 45.6% (p = 0.01), indicating the formation of cancellous bone de novo. There were no significant differences in the radii of animals subject to the stimulus, indicating that the adaptive response was local rather than systemic. The anabolic potential of the signal was evident only in trabecular bone, and there were no differences, as measured by any assay, in the cortical bone. These data suggest that subtle mechanical signals generated during predominant activities such as posture may be potent determinants of skeletal morphology. Given that these strain levels are three orders of magnitude below strains that can damage bone tissue, we believe that a noninvasive stimulus based on this sensitivity has potential for treating skeletal complications such as osteoporosis.

Animals↗
PubMed2001

Anabolism. Low mechanical signals strengthen long bones.

Although the skeleton's adaptability to load-bearing has been recognized for over a century, the specific mechanical components responsible for strengthening it have not been identified. Here we show that after mechanically stimulating the hindlimbs of adult sheep on a daily basis for a year with 20-minute bursts of very-low-magnitude, high-frequency vibration, the density of the spongy (trabecular) bone in the proximal femur is significantly increased (by 34.2%) compared to controls. As the strain levels generated by this treatment are three orders of magnitude below those that damage bone tissue, this anabolic, non-invasive stimulus may have potential for treating skeletal conditions such as osteoporosis.

Adaptation, Physiological↗
PubMed2001

Alternative medicine use in HIV-positive men and women: demographics, utilization patterns and health status.

Between 1995 and 1997, 1,675 HIV-positive men and women using complementary and alternative medicine (CAM) were enrolled into the Bastyr University AIDS Research Center's Alternative Medicine Care Outcomes in AIDS (AMCOA) study. Funded by the National Institutes of Health (NIH) Office of Alternative Medicine (OAM) and National Institute of Allergy and Infectious Diseases (NIAID), the AMCOA study collected information on participant demographics, health status and use of conventional and CAM therapies. Participants from 46 states completed a baseline questionnaire, while additional clinical information (such as CD4 count and HIV-RNA viral load) was obtained from laboratory records. AMCOA participants reported using more than 1,600 different types of CAM therapies (1,210 CAM substances, 282 CAM therapeutic activities and 119 CAM provider types) for treating HIV/AIDS. Approximately two-thirds (63% n = 1,054) of the AMCOA cohort reported using antiretroviral drug therapy (ART) during the six-months previous to completing the baseline questionnaire, while 37% (n = 621) indicated they were not using ART. Of those not using ART, 104 subjects reported never having used any conventional medications for their HIV and 12 subjects used only non-prescription diarrhoea medications. The most frequently reported CAM substances were vitamin C (63%), multiple vitamin and mineral supplements (54%), vitamin E (53%) and garlic (53%). CAM provider types most commonly consulted by the AMCOA cohort were massage therapists (49%), acupuncturists (45%), nutritionists (37%) and psychotherapists (35%). CAM activities most commonly used were aerobic exercise (63%), prayer (58%), massage (53%) and meditation (46%). The choice of CAM therapies among the AMCOA cohort does not appear to be solely based on scientific evidence of efficacy of individual therapies. The majority of AMCOA subjects could be characterized as using integrated medicine, since an overwhelming proportion of the cohort consult with both conventional and CAM providers and use both conventional and CAM medications, yet few subjects reported that their conventional and CAM providers work as a team. These data and this cohort set the stage for conducting studies of health status changes associated with specific CAM therapies.

Acupuncture Therapy↗
PubMed2001

A combination of subtherapeutic doses of chemically modified doxycycline (CMT-8) and a bisphosphonate (clodronate) inhibits bone loss in the ovariectomized rat: a dynamic histomorphometric and gene expression study.

Recent studies have demonstrated that tetracyclines can reduce bone loss in the ovariectomized (OVX) rat model of osteoporosis. In the current study, a non-antimicrobial, chemically modified doxycycline (CMT-8), alone or in combination with a bisphosphonate (Clodronate), was evaluated in this model. Forty-two, 6month old, female rats were randomly assigned to the following groups, (6/ group): a) sham/vehicle, b) OVX/vehicle; c) OVX/1 mg/day CMT-8; d) OVX/2 mg/day CMT-8, e) OVX/1 mg/week Clodronate; and f) OVX/1 mg/day CMT-8 + 1 mg/week Clodronate, CMT-8 was administered by oral gavage, Clodronate injected S/C. Following sham surgery or OVX, the rats were treated for 90 days with CMT-8 or vehicle alone, injected at three different times with fluorochrome labels, the rats were sacrificed, and the tibiae excised for analysis by dynamic bone histomorphometry. Femurs were aseptically removed and analyzed for collagen, collagenase and osteopontin mRNAs by Northern and dot blot analysis. As expected, OVX decreased trabecular bone volume (BV/TV by 73.8% vs. sham p<.01), and also reduced trabecular thickness, numbers, and increased spacing. Bone loss in the OVX animals was partially prevented with either 2 mg/day CMT-8 or 1 mg/wk Clodronate (p<.01), while the 1 mg/day CMT-8 had no effect. Interestingly, the efficacy of the combination therapy of CMT-8 and Clodronate was significantly better than either treatment by itself, maintaining bone mass and structural indices at levels identical to sham values. OVX rats mRNA for collagen, collagenase and osteopontin were elevated indicating high-turnover bone loss. Only COMBO therapy significantly reduced the collagenase and osteopontin mRNA. In summary, CMT-8 mono-therapy (2 mg) alone partially inhibited bone loss in this animal model of osteoporosis. However, 1 mg/day (CMT-8) monotherapy had no effect on bone loss or bone mRNA levels and when combined with Clodronate, interacted to increase efficacy. Thus, a combination of a suboptimal dose of CMT-8 and a bisphosphonate appears to increase the amount of bone by suppressing resorption in a model of osteoporosis.

Animals↗
PubMed2000

Synthesis and pharmacology of a novel pyrrolo[2,1,5-cd] indolizine (NNC 45-0095), a high affinity non-steroidal agonist for the estrogen receptor.

1-Ethyl-2-(4-hydroxyphenyl)pyrrolo[2,1,5-cd]indolizine (NNC 45-0095) is a novel compound which represents the parent pharmacophore structure of a series of pyrrolo[2,1,5-cd]indolizine derivatives with mixed estrogen agonist/antagonist properties. NNC 45-0095 binds with high affinity to the estrogen receptor (IC50=9.5 nM) and exhibits full protection of bone loss in the ovariectomized mouse model for post-menopausal osteoporosis.

Animals↗
PubMed1999

RANK is essential for osteoclast and lymph node development.

The physiological role of the TNF receptor (TNFR) family member, RANK, was investigated by generating RANK-deficient mice. RANK(-/-) mice were characterized by profound osteopetrosis resulting from an apparent block in osteoclast differentiation. RANK expression was not required for the commitment, differentiation, and functional maturation of macrophages and dendritic cells from their myeloid precursors but provided a necessary and specific signal for the differentiation of myeloid-derived osteoclasts. RANK(-/-) mice also exhibited a marked deficiency of B cells in the spleen. RANK(-/-) mice retained mucosal-associated lymphoid tissues including Peyer's patches but completely lacked all other peripheral lymph nodes, highlighting an additional major role for RANK in lymph node formation. These experiments reveal that RANK provides critical signals necessary for lymph node organogenesis and osteoclast differentiation.

Animals↗
PubMed1999

A chemically modified nonantimicrobial tetracycline (CMT-8) inhibits gingival matrix metalloproteinases, periodontal breakdown, and extra-oral bone loss in ovariectomized rats.

Estrogen deficiency in the postmenopausal (PM) female is the major cause of osteoporosis and may contribute to increased periodontal disease, including alveolar bone loss, seen in these women. In the current study, an animal model of PM osteoporosis, the OVX adult female rat, was studied to determine: (i) the relationship between periodontal breakdown and skeletal bone loss, and (ii) the effect of CMT-8 on gingival collagenase and bone loss. OVX rats were daily gavaged with CMT-8 (1, 2, or 5 mg/rat) for 28 or 90 days; non-OVX rats and those gavaged with vehicle alone served as controls. Elevated collagenase activity, assessed using [3H-methyl] collagen as substrate in the presence or absence of APMA, was seen in the gingiva of the OVX rats, and CMT-8 therapy suppressed this effect. Western blot revealed a similar pattern for MMP-8 and MMP-13 concentrations. The changes in the gingival collagenase activity paralleled changes in periodontal bone loss, which, in turn, reflected trabecular bone density changes. Preliminary studies on PM humans administered sub-antimicrobial tetracycline as a matrix metalloproteinase inhibitor are under way.

Alveolar Bone Loss↗
PubMed1997

High resolution characterization of an interstitial deletion of less than 1.9 Mb at 4p16.3 associated with Wolf-Hirschhorn syndrome.

Wolf-Hirschhorn syndrome (WHS) caused by 4p16.3 deletions comprises growth and mental retardation, distinct facial appearance and seizures. This study characterized a subtle interstitial deletion of 4p16.3 in a girl with mild retardation and possessing facial traits characteristic of WHS. The patient had generalized seizures in conjunction with fever at 3 and 5 years of age. Fluorescence in situ hybridization (FISH) with a series of markers in the 4p16.3 region showed that the interstitial deletion in this patient was between the probes D4S96 and D4S182, enabling the size of the deletion to be estimated as less than 1.9 Mb. This is the smallest interstitial deletion of 4p16.3 which has been reported. The patient contributes to a refinement of the phenotypic map of the WHS region in 4p16.3. The critical region for the characteristic facial changes of WHS, failure to thrive and developmental delay is now localized to a region of less than 700 kb. The mental retardation of this patient was mild suggesting that small interstitial deletion may have less severe phenotypic consequences.

Child, Preschool↗
PubMed1997

Tetracycline prevents cancellous bone loss and maintains near-normal rates of bone formation in streptozotocin diabetic rats.

The skeletal consequences of streptozotocin-induced (STZ) diabetes in the rat are characterized by decreased bone formation and, consequently, reductions in bone mass. Given the ability of tetracyclines to inhibit the breakdown of connective tissue collagen in experimental diabetes (and in other diseases), we examined the potential of this drug to prevent the osteopenia associated with STZ diabetes. To evaluate drug efficacy, the cortical and trabecular bone histomorphometry were analyzed and compared between vehicle-treated control and diabetic rats and control and diabetic rats treated orally with 20 mg/day of minocycline, a semisynthetic tetracycline. In addition, blood and urine glucose, body weight change, tibia lengths, cortical bone densities, and bone ash content were compared. At the end of the 26 day experimental period, diabetic (D) and minocycline-treated diabetic (MTD) rats were polyuric with reduced body weights and significantly elevated blood and urinary glucose levels (p < 0.01). Compared to control (C) and minocycline-treated control (MTC) animals, the periosteal and cancellous bone formation in the D rats had virtually ceased (p < 0.001), and the cancellous bone mass in the tibial metaphysis was reduced 47% (p < 0.01). In contrast, bone formation rates in the MTD animals were increased compared to the D rats (p < 0.001), while cancellous bone areas in the MTD animals were essentially equivalent to those observed in the C and MTC groups. Moreover, growth plate thickness, reduced 43% in the D rats, was preserved in the diabetic animals treated with minocycline. These results demonstrate that minocycline treatment of the streptozotocin diabetic rat maintains normal bone formation, normalizes growth plate thickness, and prevents cancellous bone loss.

Administration, Oral↗
PubMed1997

Evidence by allelic association-dependent methods for a type 1 diabetes polygene (IDDM6) on chromosome 18q21.

Type 1 diabetes is a common polygenic disease. Fine mapping of polygenes by affected sibpair linkage analysis is not practical and allelic association or linkage disequilibrium mapping will have to be employed to attempt to detect founder chromosomes. Given prior evidence of linkage of the Jk-D18S64 region of chromosome 18q12-q21 to type 1 diabetes, we evaluated the 12 informative microsatellite markers in the region for linkage with disease by the transmission disequilibrium test (TDT) in a UK data set of type 1 diabetic families (n = 195). Increased transmission of allele 4 of marker D18S487 to affected children was detected (P = 0.02). Support for this was extended in a total of 1067 families from four different countries by isolating, and evaluating by the TDT, two novel microsatellites within 70 kb of D18S487. Evidence for linkage and association was P = 5 x 10(-5) and 3 x 10(-4), respectively. There was no evidence for increased transmission of associated alleles to nonaffected siblings. Analysis of an additional 390 families by the TDT did not extend the evidence further, and reduced support in the total 1457 families to P = 0.001 for linkage and P = 0.003 for association. However, evidence for linkage by affected sibpair allele sharing was strong (P = 3.2 x 10(-5)) in the second data set. Heterogeneity in TDT results between data sets was, in part, accounted for by the presence of more than one common disease-associated haplotype (allelic heterogeneity) which confounds the analysis of individual alleles by the TDT. Guidelines for strategies for the mapping of polygenes are suggested with the emphasis on collections of large numbers of families from multiple populations that should be as genetically homogeneous as possible.

Adolescent↗
PubMed1997

Evidence for a type 1 diabetes susceptibility locus (IDDM10) on human chromosome 10p11-q11.

A region of linkage to type 1 diabetes has been defined on human chromosome 10p11-q11 (IDDM10; P = 0.0007) using 236 UK and 76 US affected sibpairs and a 1 cM resolution microsatellite marker map. Analysis by the transmission disequilibrium test (TDT) in 1159 families with at least one diabetic child, from the UK, the US, Norway, Sardinia and Italy provided additional support for linkage at D10S193 (P = 0.006, Pc = 0.17). Notably, 5.1 cM distal to D10S193, marker D10S588 also provided positive TDT results (P = 0.009, Pc = 0.25) but the allele under analysis was also preferentially transmitted to nonaffected siblings (P = 0.0008, Pc = 0.02). This allele was positively associated in an independent UK case control study and, importantly, was neutrally transmitted in control CEPH families. These results suggest a type 1 diabetes susceptibility locus on chromosome 10p11-q11 (provisionally designated IDDM10) and demonstrate the necessity of analysis of non affected siblings in disease families, as well as analysis of control families.

Adolescent↗
PubMed1997

The molecular basis of the Kidd blood group polymorphism and its lack of association with type 1 diabetes susceptibility.

The Kidd blood group locus encodes a urea transporter which is expressed on human red cells and in the kidney. This gene is located on chromosome 18q12, and evidence for linkage and association with type 1 diabetes mellitus has been reported. To investigate this further, the genetic basis for the blood group Jk(a)/Jk(b) polymorphism was first determined by sequencing reverse-transcribed reticulocyte RNAs from Jk(a+b-) and Jk(a-b+) donors. The Jk(a)/Jk(b) polymorphism was caused by a transition (G838A), resulting in a Asp280Asn amino acid substitution and an MnlI restriction fragment length polymorphism (RFLP). Using the MnlI RFLP, we found that the Jk(a)/Jk(b) polymorphism was not in linkage disequilibrium with type 1 diabetes in 228 multiplex UK and US families tested.

Adolescent↗
PubMed1997

The functional block of TNF but not of IL-6 prevents bone loss in ovariectomized mice.

Considerable evidence supports the hypothesis that estrogen prevents bone loss by blocking the bone marrow cell production of pro-osteoclastogenic cytokines. However, controversy remains on the role of candidate factors, such as tumor necrosis factor (TNF) and interleukin-6 (IL-6). To investigate the contribution of these cytokines to the pathogenesis of ovariectomy (OVX)-induced bone loss, OVX mice were treated with either TNF binding protein (TNFbp), an inhibitor of TNF, the anti-(IL-6) antibody (Ab) 20F3, or estrogen for the first 2 weeks after surgery. OVX caused a rapid decrease in trabecular bone volume (TBV) and an increase in in vivo bone resorption, as assessed by bone histomorphometry. Treatment with TNFbp completely prevented bone loss and the increase in both osteoclast formation and bone resorption induced by OVX, but had no effects in sham-operated controls. In contrast, treatment with anti-IL-6 antibody failed to prevent bone loss, and the increase in bone resorption and osteoclastogenesis induced by OVX. These data demonstrate that in nongenetically manipulated mice, the estrogen-regulated cytokine that plays a central role in the mechanism by which estrogen deficiency causes bone loss is not IL-6, but rather TNF.

Animals↗
PubMed1997

A scientific plan for the evaluation of alternative medicine in the treatment of HIV/AIDS.

The Bastyr University AIDS Research Center was established in October 1994 through a 3-year cooperative grant with the Office of Alternative Medicine, National Institutes of Health. The mission of the Center is to (1) describe forms and patterns of use of alternative medical therapies for HIV infection and AIDS prescribed by practitioners and self-administered by HIV-positive patients in the United States, (2) screen and evaluate therapies for HIV/AIDS from five program areas of alternative medicine, and (3) provide consultation and support in the scientific evaluation of alternative therapies. To meet these goals, the Center has established a network of cooperating alternative medicine clinics and is recruiting HIV-positive men and women who are using alternative medicine to participate in the study. It is collecting data every 6 months from 1500 HIV-positive patients throughout the United States and has created a centralized database to compare outcomes (CD4+ lymphocytes, HIV RNA, CDC class progression, weight, quality of life, and survival) for a variety of alternative therapies. The Center will determine whether patients who use both conventional medicine and alternative medicine have different outcomes from patients who use only conventional medicine. The occurrence of AIDS-related opportunistic infections and neoplasms in HIV-positive patients who are using specific alternative therapies will be compared with the incidence in those who use other medical treatment. This article describes the scientific plan for the study.

Acquired Immunodeficiency Syndrome↗