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Biomedical subjects

R Smith

Publications and source records attributed to R Smith.

At least 145 records · Page 8Linked to original sources
PubMed2001

Local delivery of human tissue kallikrein gene accelerates spontaneous angiogenesis in mouse model of hindlimb ischemia.

BACKGROUND: Human tissue kallikrein (HK) releases kinins from kininogen. We investigated whether adenovirus-mediated HK gene delivery is angiogenic in the context of ischemia. METHODS AND RESULTS: Hindlimb ischemia, caused by femoral artery excision, increased muscular capillary density (P:<0.001) and induced the expression of kinin B(1) receptor gene (P:<0.05). Pharmacological blockade of B(1) receptors blunted ischemia-induced angiogenesis (P:<0.01), whereas kinin B(2) receptor antagonism was ineffective. Intramuscular delivery of adenovirus containing the HK gene (Ad. CMV-cHK) enhanced the increase in capillary density caused by ischemia (969+/-32 versus 541+/-18 capillaries/mm(2) for control, P:<0.001), accelerated blood flow recovery (P:<0.01), and preserved energetic charge of ischemic muscle (P:<0.01). Chronic blockade of kinin B(1) or B(2) receptors prevented HK-induced angiogenesis. CONCLUSIONS: HK gene delivery enhances the native angiogenic response to ischemia. Angiogenesis gene therapy with HK might be applicable to peripheral occlusive vascular disease.

Adenoviridae↗
PubMed2001

Corticotropin-releasing hormone-binding protein in primates.

In humans, placental corticotropin-releasing hormone (CRH) production has been linked to the determination of gestational length, and a late gestational fall in CRH-binding protein (CRH-BP) has been linked to the onset of parturition. Expression of placental CRH mRNA is limited to primates, and only in man has a circulating CRH-BP been described. As the fall in CRH-BP in late gestation has been associated with parturition in humans, we sought to determine whether a CRH-BP circulated in the plasma of other primates. It is unclear whether maternal plasma CRH concentrations are elevated in New World monkeys and prosimians. We have therefore performed CRH plasma measurements in the blood of pregnant marmosets, in several species of lemur, and in pregnant and fetal rhesus monkeys as a positive control. Using gel chromatography, CRH-BP was detected in the human, gorilla, chimpanzee, orangutan, gibbon, macaque, squirrel monkey, and marmoset, but was absent in the mandrill, spider monkey, and lemur. CRH was detected in the plasma of pregnant marmosets and rhesus monkeys. CRH was also detected in the fetal rhesus monkey, but at lower concentrations than in maternal plasma. CRH immunoreactivity was not detectable in the plasma of pregnant lemurs or in extracts of lemur placenta. In conclusion, a circulating binding protein for CRH exists in all species of apes but occurs variably among New World and Old World monkeys and is absent in lemurs. The variable occurrence of the CRH-BP does not support a role for this protein in the mechanism of parturition in primates. Maternal CRH is elevated in the pregnant marmoset and rhesus, and may play a role in the pregnancy of New and Old World monkeys.

Animals↗
PubMed2001

Combination angiostatin and endostatin gene transfer induces synergistic antiangiogenic activity in vitro and antitumor efficacy in leukemia and solid tumors in mice.

Angiostatin and endostatin are potent endothelial cell growth inhibitors that have been shown to inhibit angiogenesis in vivo and tumor growth in mice. However, tumor shrinkage requires chronic delivery of large doses of these proteins. Here we report synergistic antitumor activity and survival of animals when these factors are delivered in combination to tumors by retroviral gene transfer. We have demonstrated this efficacy in both murine leukemia and melanoma models. Complete loss of tumorigenicity was seen in 40% of the animals receiving tumors transduced by the combination of angiostatin and endostatin in the leukemia model. The synergy was also demonstrated in vitro on human umbilical vein endothelial cell differentiation and this antiangiogenic activity may suggest a mechanism for the antitumor activity in vivo. These findings imply separate pathways by which angiostatin and endostatin mediate their antiangiogenic effects. Together, these data suggest that a combination of antiangiogenic factors delivered by retroviral gene transfer may produce synergistic antitumor effects in both leukemia and solid tumors, thus avoiding long-term administration of recombinant proteins. The data also suggest that novel combinations of antiangiogenic factors delivered into tumors require further investigation as therapeutic modalities.

Angiogenesis Inhibitors↗
PubMed2001

Prediction of osteoporotic fractures by bone densitometry and COLIA1 genotyping: a prospective, population-based study in men and women.

Osteoporosis is a common disease with a strong genetic component, characterized by reduced bone mineral density and increased fracture risk. Although the genetic basis of osteoporosis is incompletely understood, previous studies have identified a polymorphism affecting an Sp1 binding site in the COLIA1 gene that predicts bone mineral density and osteoporotic fractures in several populations. Here we investigated the role of COLIA1 genotyping and bone densitometry in the prediction of osteoporotic fractures in a prospective, population-based study of men (n = 156) and women (n = 185) who were followed up for a mean (+/- SEM) of 4.88+/-0.03 years. There was no significant difference in bone density, rate of bone loss, body weight, height, or years since menopause between the genotype groups but women with the 'ss' genotype were significantly older than the other genotype groups (p = 0.03). Thirty-nine individuals sustained 54 fractures during follow-up and these predominantly occurred in women (45 fractures in 30 individuals). Fractures were significantly more common in females who carried the COLIA1 's' allele (p = 0.001), although there was no significant association between COLIA1 genotype and the occurrence of fractures in men. Logistic regression analysis showed that carriage of the COLIA1 's' allele was an independent predictor of fracture in women with an odds ratio (OR) [95% CI] of 2.59 [1.23-5.45], along with spine bone mineral density (OR = 1.57 [1.04-2.37] per Z-score unit) and body weight (OR = 1.05 [1.01-1.10] per kilogram). Moreover, bone densitometry and COLIA1 genotyping interacted significantly to enhance fracture prediction in women (p = 0.01), such that the incidence of fractures was 45 times higher in those with low BMD who carried the 's' allele (24.3 fractures/100 patient-years) compared with those with high BMD who were 'SS' homozygotes (0.54 fracture/100 patient-years). We conclude that in our population, COLIA1 genotyping predicts fractures independently of bone mass and interacts with bone densitometry to help identify women who are at high and low risk of sustaining osteoporotic fractures.

Absorptiometry, Photon↗
PubMed2001

Anatomic study of the tricuspid valve in children.

We performed an anatomic study of the right atrioventricular valve in children under one year of age using a conservative method of dissection of the heart valve. The main aspects studied were the number of cusps and their morphometric characteristics, such as the width of the base and the depth of the cusps. Other parameters studied were the number of papillary muscles, number of tendinous cords, and diameter of the fibrous ring and the last one were divided in three regions, anterior, posterior and septal for localization of cusps. Our results showed that the number of cusps varied from two to four. Three cusps was the commonest finding and the fourth cusp, if present, was classified as anterolateral in location. The anterior and septal cusps had bases bigger than those of the posterior and anterolateral cusps; the septal cusp was deeper than the others; and the number of tendinous cords was greater for the anterior and septal cusps than for the posterior and anterolateral cusps. In addition, the posterior region showed great variability: in 35.7% it was occupied by undeveloped valve tissue and the posterior valve in these cases was located anteriorly.

Cadaver↗
PubMed2001

Choriocapillaris photodynamic therapy using indocyanine green.

PURPOSE: To evaluate the potential of photodynamic therapy using indocyanine green for occlusion of choroidal neovascularization, the authors studied efficiency and collateral damage of photodynamic therapy-induced photothrombosis in the rabbit choriocapillary layer. METHODS: Fundus photography, fluorescein angiography, and light and transmission electron microscopy were used to study the efficiency of photodynamic therapy-induced photothrombosis using indocyanine green as the photosensitizer, and to assess the resultant collateral damage. The delivery system consisted of a modified infrared diode laser tuned to 810 nm, near the maximum absorption peak of indocyanine green. RESULTS: Choriocapillary occlusion was achieved at indocyanine green doses of 10 and 20 mg/kg and a radiant as low as 6.3 J/cm(2). When photodynamic therapy was performed with indocyanine green doses of 10 mg/kg, damage to the neural retina was minimal. Only inner photoreceptor segments showed degeneration, probably secondary to choroidal ischemia. Bruch membrane remained intact. Retinal pigment epithelium was invariably damaged, as seen with other photosensitizers. Temporary occlusion of large choroidal vessels occurred at both dye doses. CONCLUSIONS: In this experimental study, photodynamic therapy using indocyanine green and 810-nm light irradiation produced endothelium-bound intraluminal photothrombosis, with preservation of the retinal architecture and minimal loss of visual cells. Membrane targetability, hydrophilic and fluorescent properties, and activation at 805 nm suggest indocyanine green as a potential photosensitizer for choroidal neovascularization. These combined considerations point toward further study of photodynamic therapy using indocyanine green for the treatment of choroidal vascular disease.

Animals↗
PubMed2001

Solid-state NMR structure determination of melittin in a lipid environment.

Solid-state (13)C NMR spectroscopy was used to investigate the three-dimensional structure of melittin as lyophilized powder and in ditetradecylphosphatidylcholine (DTPC) membranes. The distance between specifically labeled carbons in analogs [1-(13)C]Gly3-[2-(13)C]Ala4, [1-(13)C]Gly3-[2-(13)C]Leu6, [1-(13)C]Leu13-[2-(13)C]Ala15, [2-(13)C]Leu13-[1-(13)C]Ala15, and [1-(13)C]Leu13-[2-(13)C]Leu16 was measured by rotational resonance. As expected, the internuclear distances measured in [1-(13)C]Gly3-[2-(13)C]Ala4 and [1-(13)C]Gly3-[2-(13)C]Leu6 were consistent with alpha-helical structure in the N-terminus irrespective of environment. The internuclear distances measured in [1-(13)C]Leu13-[2-(13)C]Ala15, [2-(13)C]Leu13-[1-(13)C]Ala15, and [1-(13)C]Leu13-[2-(13)C]Leu16 revealed, via molecular modeling, some dependence upon environment for conformation in the region of the bend in helical structure induced by Pro14. A slightly larger interhelical angle between the N- and C-terminal helices was indicated for peptide in dry or hydrated gel state DTPC (139 degrees -145 degrees ) than in lyophilized powder (121 degrees -139 degrees ) or crystals (129 degrees ). The angle, however, is not as great as deduced for melittin in aligned bilayers of DTPC in the liquid-crystalline state (approximately 160 degrees ). The study illustrates the utility of rotational resonance in determining local structure within peptide-lipid complexes.

Carbon Isotopes↗
PubMed2001

Candidate gene analysis in premature pubarche and adolescent hyperandrogenism.

OBJECTIVE: To identify genetic markers associated with premature pubarche in children and hyperandrogenism in adolescent girls. DESIGN: Association study. SETTING: Academic research environment. PATIENT(S): Forty children with premature pubarche (PP), 29 adolescent girls with hyperandrogenism (HA), and 15 healthy control women. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Genetic variations at five loci selected because of known associations with hyperandrogenism, insulin resistance, hyperinsulinemia, or obesity. RESULT(S): Heterozygosity for CYP21 mutations was identified in 14 of 40 (35%) PP, 8 of 29 (28%) HA, and 1 of 30 (3%) controls. Heterozygosity for HSD3B2 variants was identified in 3 of 40 (7.5%) PP, 5 of 29 (17%) HA, and 0/15 controls. Among the PP, 11 of 80 (14%), 5 of 80 (6%), and 7 of 80 (9%) alleles showed the IRS-1, GRL, and ADRB3 variants, respectively. Among the HA, 5 of 58 (8.6%), 3 of 58 (5%), and 6 of 58 (10%) alleles showed the IRS-1, GRL, and ADRB3 variants, respectively. Among the control participants, variant allele frequency was 1 of 30 (3.3%) for IRS-1, 2 of 30 (6.6%) for GRL, and 2 of 30 (6.6%) for ADRB3. CONCLUSION(S): Our findings suggest that the development of PP and HA can be associated with the occurrence of multiple sequence variants at five susceptibility loci, especially steroidogenic enzyme genes. This approach offers a novel paradigm to investigate and identify the genetic factors relevant to polycystic ovary syndrome.

3-Hydroxysteroid Dehydrogenases↗
PubMed2001

Coordination of the ankle joint complex during walking.

A simple model of the joint between the leg and the rearfoot is that of two hinges each with one degree of freedom. The superior hinge at the talocrural joint caters for most of the sagittal plane motion due to its mediolateral orientation. Motion in the transverse and coronal planes is largely taken up by the subtalar joint which has an inclination of 42 degrees to the transverse plane and deviates 23 degrees to the medial side. It could be expected from the orientation of this joint that rearfoot motion in the coronal plane (inversion/eversion) would be tightly coupled to motion in the transverse plane (adduction/abduction). A simple, non-viscous mechanical hinge joint would produce an in-phase, fixed gain relationship between inversion/eversion and adduction/abduction. This relation could be adequately quantified by Pearson's product moment correlation (r(P)). In contrast, muscular control of the joint, which introduces visco-elastic elements and time-delayed control lines and feedback loops, could be characterised by more complex phase and gain relations among the frequency components of the signals. These relations can be characterised by a transfer function relation (gain and phase angle) computed using a dynamic analysis. In the present study, both Pearson's correlation and linear systems analysis were employed. For 43 normal adults, five trials of one walking stride (stance and swing phases) were videographed at 30 Hz with three markers placed on each of the leg and rearfoot. Using inversion/eversion as the input and adduction/abduction as the output, the proportion of the total variance accounted for by a dynamic relation was measured by the coherence square function, which is analogous to the correlation squared (r(P)(2)). The mean r(P)(2) was 0.26, whereas the mean overall coherence was 0.62, thus accounting for more than twice the variance. This result suggests that while there may be a degree of simple mechanical coupling between inversion/eversion and adduction/abduction during walking, the major control is via muscular and/or visco-elastic passive elements.

Adult↗
PubMed2001

The regulation of human corticotrophin-releasing hormone gene expression in the placenta.

Corticotrophin-releasing hormone (CRH) is a 41 amino acid neuropeptide that is expressed in the hypothalamus and the human placenta. Placental CRH production has been linked to the determination of gestational length in the human. Although encoded by a single copy gene, CRH expression in the placenta is regulated differently to the hypothalamus. Glucocorticoids stimulate CRH promoter activity in the placenta but inhibit it's activity in the hypothalamus, via mechanisms involving different regions of the CRH promoter. We discuss how various stimuli alter CRH promoter activity and why these responses are unique to the placenta.

Corticotropin-Releasing Hormone↗
PubMed2001

The regulation of human corticotrophin-releasing hormone gene expression in the placenta.

Corticotrophin-releasing hormone (CRH) is a 41 amino acid neuropeptide that is expressed in the hypothalamus and the human placenta. Placental CRH production has been linked to the determination of gestational length in the human. Although encoded by a single copy gene, CRH expression in the placenta is regulated differently to the hypothalamus. Glucocorticoids stimulate CRH promoter activity in the placenta but inhibit it's activity in the hypothalamus, via mechanisms involving different regions of the CRH promoter. We discuss how various stimuli alter CRH promoter activity and why these responses are unique to the placenta.

Corticotropin-Releasing Hormone↗
PubMed2001

Regional differences in the expression of corticostriatal synaptic plasticity.

Field recordings of responses to activation of corticostriatal afferents were made in coronally sectioned rat brain slices. Each recording site was categorized according to its medial to lateral and rostral to caudal position to investigate anatomical differences in synaptic plasticity. Individual responses were highly variable exhibiting extremes of tetanus induced depression and potentiation. Consequently, averaging masked the capacity of these synapses to express long-term forms of plasticity. Block of GABA(A) inhibition and elimination of dopaminergic input with 6-hydroxydopamine lesions both acted to increase the expression of potentiation, but again considerable variability was observed. Separation of recordings into medial and lateral groups revealed clear anatomical trends which contributed to the variability observed in the total sample. Paired-pulse, post-tetanic and long-term potentiation was greater in medial than in lateral groups in normal artificial cerebral spinal fluid. Similar tendencies were seen after block of GABA(A) receptors with bicuculline. 6-Hydroxydopamine lesions in combination with bicuculline treatment reduced medial to lateral differences. Factoring in medial to lateral trends revealed block of GABA(A) receptor mediated inhibition had its greatest effect on medial corticostriatal responses and 6-hydroxydopamine lesions had their greatest effect on lateral responses. From these data we suggest anatomical variation in striatal circuitry may underlie regional differences in synaptic plasticity evoked by corticostriatal activation.

Action Potentials↗
PubMed2001

The coming-out process and its adaptational and health-related associations among gay, lesbian, and bisexual youths: stipulation and exploration of a model.

A model is proposed and explored that links the coming-out process to the psychological functioning (i.e., self-esteem and distress) and sexual behaviors of gay, lesbian, and bisexual youths recruited from gay-focused community-based and college organizations in New York City. The coming-out process is multidimensional, consisting, as defined here, of involvement in gay/lesbian activities, attitudes toward homosexuality, comfort with homosexuality, self-disclosure of sexual identity to others, and sexual identity. The coming-out dimensions were related to self-esteem, distress, and unprotected sexual behaviors. In addition, the relations between the coming-out dimensions and unprotected sexual behaviors were explained by psychological functioning. In particular, limited involvement in gay/lesbian activities was associated with more unprotected sex. Negative attitudes toward homosexuality were related directly to more unprotected sex, and they were related indirectly to more unprotected sex by means of increasing emotional distress. These and other findings have implications for designing preventive interventions to increase the youths' psychological functioning and reduce their unprotected sexual behaviors.

Adolescent↗
PubMed2001

Statin-AE: a novel angiostatin-endostatin fusion protein with enhanced antiangiogenic and antitumor activity.

The combination of angiostatin and endostatin has been shown to have synergistic antiangiogenic and antitumor effects when the genes for these proteins are delivered to tumor cells by retroviral gene transfer. Here we report the construction of a murine angiostatin-endostatin fusion gene (Statin-AE) which shows enhanced antiangiogenic activity on human umbilical vein endothelial cell (HUVEC) tube formation in vitro compared with angiostatin or endostatin alone. Similarly, the fusion gene demonstrates antiangiogenic effects in vivo and antitumor activity in a B16F10 melanoma model when co-delivered by retroviral packaging cell inoculation in mice. The fusion gene demonstrates significantly greater inhibition of tumor growth compared with angiostatin, endostatin or the combination of genes.

Amino Acid Sequence↗