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Biomedical subjects

G N Smith

Publications and source records attributed to G N Smith.

At least 37 records · Page 2Linked to original sources
PubMed2001

Oral tolerance induction by type V collagen downregulates lung allograft rejection.

Immunization with specific proteins or peptides has been used to induce immunologic tolerance to allografts other than the lung. Recently, we have reported that the immune response to lung alloantigen also involves an immune response to type V collagen [col(V)]. The purpose of the current study was to determine if oral administration of col(V) to lung allograft recipients before transplantation downregulates acute rejection episodes. The data show that, compared with controls, col(V)-fed recipients had fewer polymorphonuclear cells and lymphocytes in allograft bronchoalveolar lavage fluid, and reduced rejection pathology. Data showing that col(V)- fed allograft recipients had diminished delayed-type hypersensitivity (DTH) responses to donor alloantigens suggest that feeding col(V) prevented allograft rejection by inducing tolerance to donor antigens. Systemic production of transforming growth factor (TGF)-beta, interleukin (IL)-4, or IL-10 has been reported to be a mechanism for oral tolerance-induced suppression of immune responses. Feeding col(V) induced upregulated production of TGF-beta, but not IL-4 or IL-10 in serum. Neutralizing TGF-beta recovered the DTH response to donor antigen in tolerant allograft recipients. Collectively, these data show that oral administration of col(V) is a novel approach to induce immunologic tolerance to lung allografts, and that TGF-beta contributed to suppression of the rejection response.

Adaptation, Physiological↗
PubMed2001

An MRI study of basal ganglia volumes in first-episode schizophrenia patients treated with risperidone.

OBJECTIVE: The basal ganglia may contribute to extrapyramidal movement disorders, affective disturbances, and cognitive deficits in schizophrenia. Basal ganglia volumes are putatively affected by antipsychotic medications. The purpose of this study was to determine the long-term effects of risperidone treatment in a cohort of first-episode patients with schizophrenia. METHOD: The subjects were 30 patients with first-episode schizophrenia, 12 patients chronically treated with typical antipsychotics, and 23 healthy comparison subjects. They were scanned by magnetic resonance imaging at baseline. The first-episode patients received 1 year of continuous risperidone treatment, after which they and the comparison subjects were rescanned. Caudate, putamen, and globus pallidus volumes were determined from coronal images. RESULTS: The baseline caudate, putamen, and globus pallidus volumes were significantly larger in the chronically treated patients than in the untreated first-episode subjects and comparison subjects. These volumes did not differ between the first-episode patients and healthy comparison subjects. Basal ganglia volumes were unchanged after 1 year of exposure to risperidone in the first-episode subjects. Extrapyramidal movement disorders were present in the majority of chronically treated patients and more than one-third of the never-medicated first-episode patients at baseline. CONCLUSIONS: This group of first-episode patients did not exhibit abnormalities of basal ganglia volumes, nor were basal ganglia volumes affected by exposure to risperidone. Movement disorders were observed in both first-episode and chronically treated patients, suggesting effects of both illness and medications.

Adult↗
PubMed2001

Effect of intraarticular hyaluronan injection on synovial fluid hyaluronan in the early stage of canine post-traumatic osteoarthritis.

OBJECTIVE: To determine how the quantity and molecular weight of synovial fluid hyaluronan (HA) within the synovial fluid (SF) of osteoarthritis (OA) joints is affected by intraarticular injection of HA. METHODS: Dogs in which OA was induced by transection of the anterior cruciate ligament received 5 weekly injections of HA (1.5 x 10(6) Da) in saline (10 mg/0.67 ml) or an equal volume of saline into the operated knee, beginning the day after surgery. Immediately before each injection, SF was aspirated and the volume of SF and the concentration of HA was measured (uronic acid), and the molecular weight of the HA in each sample was estimated by electrophoresis in agarose. RESULTS: The volume of SF in the unstable knee increased after surgery, and the molecular weight decreased from approximately 2.5 x 10(6) Da to approximately 2 x 10(6) Da. Injection of HA did not affect the volume of SF or average molecular weight of HA in samples obtained immediately before each injection or at the end of the experiment, 12 weeks after surgery. The SF HA concentration fell from a baseline value of 2.3 +/- 0.1 mg/ml to 1.1 +/- 0.2 mg/ml the day after surgery and remained low throughout the course of injections. The HA concentration 12 weeks after surgery in the HA injected knees was approximately 40% lower than the preoperative value, although it increased slightly relative to saline injected knees (1.4 +/- 0.3 vs 1.1 +/- 0.01 mg/ml, respectively; p = 0.04). CONCLUSION: Intraarticular injection of HA did not alter the volume of SF or molecular weight of HA in SF of OA canine knees, nor did it restore the HA concentration to that of normal canine SF.

Adjuvants, Immunologic↗
PubMed2000

Atomic force microscopy-based detection of binding and cleavage site of matrix metalloproteinase on individual type II collagen helices.

Type II tropocollagen molecules were reacted with matrix metalloproteinase 8 (MMP-8) and the binding sites as well as the cleavage site of MMP-8 were detected on individual molecules using atomic force microscopy (AFM). Approximately 300-nm-long coiled-coil tropocollagen molecules were straightened and immobilized on an atomically flat surface for detection by AFM. The direct visualization of individual collagen molecules revealed heterogeneous characteristics of MMP-8:collagen complexes. We observed that there existed multiple MMP-8 nonspecific binding sites on the collagen molecules, but cleavage always took place at a unique site. When collagen molecules, straightened and immobilized on the surface, were reacted with MMP-8, a site of cleavage appeared as a gap in stretched molecules. This is the first report to visually show direct collagenase:collagen interactions using AFM. The described AFM-based analysis has potential as a protein analysis tool for understanding a complex mechanism of enzyme:substrate interactions.

Animals↗
PubMed2000

Heme oxygenase activity in term human placenta.

Carbon monoxide (CO) is a novel gaseous chemical messenger, formed during heme oxygenase (HO)-catalysed oxidation of heme. CO is proposed to play a key role(s) in cell function in many organ systems, including vasodilator action in the cardiovascular system. Recently, it has been demonstrated that there is expression of HO protein in the human placenta and this appears to have a regulatory role in placental perfusion. The objective of the present study was to determine HO enzymatic activity in vitro in five different regions of term human placenta. HO activity was determined in the microsomal fraction of tissue homogenate by measuring the rate of formation of CO from heme, using a gas-chromatographic method. HO activity, expressed as nmol CO formed/g tissue wet weight/h, was higher (P< 0.05) in the chorionic plate, chorionic villi, basal plate and chorio-decidua compared with the amnion. The finding that HO enzymatic activity is present in different regions of term human placenta supports the concept that the heme-CO (HO) pathway plays a complementary role with the L -arginine-nitric oxide (nitric oxide synthase) pathway in the regulation of placental haemodynamics.

Amnion↗
PubMed2000

Type V collagen modulates alloantigen-induced pathology and immunology in the lung.

Perivascular and peribronchiolar tissues are targets of the immune response during lung allograft rejection. Collagen type V (col[V]) is located within these tissues. Col(V) may be major histocompatibility complex (MHC)-like, and MHC-derived peptides have been used to induce immunologic tolerance and prevent rejection in allografts other than the lung. The current study tests the hypothesis that col(V) could be used to downregulate immune responses to lung alloantigen in vivo. We developed a murine model in which instillations of allogeneic bronchoalveolar lavage (BAL) cells (C57BL/6, I-a(b), H-2(b)) into lungs of BALB/c mice (I-a(d), H-2(d)) induce histology similar to grades 1 and 2 acute lung allograft rejection, apoptosis of airway epithelium and vascular endothelium, and upregulate tumor necrosis factor (TNF)-alpha production locally. The current study reports that instillations of col(V) into lungs before allogeneic BAL cells prevent development of rejection pathology and apoptosis, downregulate alloantigen-induced T-lymphocyte proliferation, and abrogate local TNF-alpha production. In addition, instillation of col(V)-pulsed autologous BAL cells into lungs of mice primed with allogeneic BAL cells perpetuates rejection pathology. Collectively, these data show that col(V) is a novel antigen involved in the rejection process, and suggest that col(V) could be used to modulate the rejection response to lung allografts.

Animals↗
PubMed1999

Diacerhein treatment reduces the severity of osteoarthritis in the canine cruciate-deficiency model of osteoarthritis.

OBJECTIVE: To determine if diacerhein protects against the early stages of joint damage in a canine model of osteoarthritis (OA). METHODS: OA was induced in 20 adult mongrel dogs by transection of the anterior cruciate ligament of the left knee. Beginning the day after surgery, dogs in the active treatment group were dosed twice a day with capsules of diacerhein, providing a total daily dose of 40 mg/kg, for 32 weeks. Dogs in the control group received placebo capsules on the same schedule. Pathology in the unstable knee was assessed arthroscopically 16 weeks after surgery and by direct observation when the dogs were killed 32 weeks after surgery. The severity of gross joint pathology was recorded, and samples of the medial femoral condyle cartilage and the synovial tissue adjacent to the central portion of the medial meniscus were collected for histologic evaluation. Water content and uronic acid concentration of the articular cartilage from the femoral condyle were determined, and collagenolytic activity in extracts of cartilage pooled from the medial and lateral tibial plateaus was assayed against 14C-labeled collagen fibers. RESULTS: Diacerhein treatment slowed the progression of OA, as measured by grading of gross changes in the unstable knee at arthroscopy 16 weeks after cruciate ligament transection (P = 0.04) and at the time the animals were killed, 32 weeks after surgery (P = 0.05). However, 32 weeks after ACL transection, the mean proteoglycan concentration and water content of the OA cartilage and the level of collagenolytic activity in extracts of the cartilage were not significantly different in the diacerhein treatment group than in the placebo treatment group. CONCLUSION: Diacerhein treatment significantly reduced the severity of morphologic changes of OA compared with placebo. These findings support the view that diacerhein may be a disease-modifying drug for OA.

Animals↗
PubMed1999

Differential patterns of response to doxycycline and transforming growth factor beta1 in the down-regulation of collagenases in osteoarthritic and normal human chondrocytes.

OBJECTIVE: To investigate the ability of doxycycline, transforming growth factor beta1 (TGFbeta1), and phorbol myristate acetate (PMA) to modulate collagenase synthesis in osteoarthritic (OA) chondrocytes. METHODS: Levels of fibroblast collagenase (matrix metalloproteinase 1 [MMP-1]), neutrophil collagenase (MMP-8), and collagenase 3 (MMP-13) proteins and messenger RNA (mRNA) were measured in chondrocytes isolated from involved and uninvolved areas of OA cartilage and from normal human chondrocytes, after treatment with doxycycline, TGFbeta1, and PMA. RESULTS: Chondrocytes isolated from cartilage immediately adjacent to the OA lesion had, on average, 1.8-3.9-fold higher basal levels of MMP mRNA. These cells down-regulated collagenase proteins and mRNA upon incubation with TGFbeta1. In contrast, chondrocytes from areas located more distant from the macroscopic lesion increased MMP-13 mRNA, while MMP-1 and MMP-8 decreased after stimulation with TGFbeta1. Discoordinate regulation was observed after stimulation with PMA, with an increase in MMP-1 and MMP-8 but a decrease in MMP-13. Incubation of OA chondrocytes with doxycycline (1-10 microg/ml), at pharmacologically achievable levels, decreased levels of mRNA of all 3 collagenases, but not G3PDH. In addition, doxycycline inhibited the increase in mRNA for these enzymes in normal chondrocytes stimulated with tumor necrosis factor alpha. CONCLUSION: These findings suggest that regulation of MMP-1, MMP-8, and MMP-13 in OA chondrocytes, although mediated by differing pathways, can be decreased by treatment with doxycycline at low concentrations. Our data provide a rationale for the use of doxycycline in the treatment of OA.

Aged↗
PubMed1999

Specificity of inhibition of matrix metalloproteinase activity by doxycycline: relationship to structure of the enzyme.

OBJECTIVE: To investigate the inhibition of matrix metalloproteinase 1 (MMP-1), MMP-8, and MMP-13 by doxycycline, and to determine whether the variable hemopexin-like domain of each MMP was responsible for the differences in susceptibility to doxycycline inhibition among these collagenases. METHODS: Recombinant human MMP-1 (collagenase 1), MMP-8 (collagenase 2), and MMP-13 (collagenase 3), truncated forms of MMP-8 and MMP-13 lacking the hemopexin-like domain, and a mutant form of truncated MMP-13 were used in these studies. The activity of the full-length MMP in the presence of doxycycline was tested against type II collagen, a natural substrate for the enzymes. A small peptolide substrate was used to determine which structural features of the MMPs were related to sensitivity to doxycycline inhibition. RESULTS: The activity of MMP-13 and MMP-8 against type II collagen was inhibited by 50-60% by 30 microM doxycycline, while that of MMP-1 was inhibited only 18% by 50 microM doxycycline. In contrast, in experiments with the peptolide substrate, neither full-length nor truncated MMP-13 was inhibited until the concentration of the drug exceeded 90 microM. MMP-8 and truncated MMP-8 were sensitive to inhibition by 30 microM doxycycline, while MMP-1 was slightly inhibited (14%) by 90 microM doxycycline. For MMP-8, inhibition was reversible upon dilution and was independent of the order in which the reagents were added. Kinetic analysis of the inhibition constant (K(i)) of MMP-8 (K(i) = 36 microM) and truncated MMP-8 (K(i) = 77 microM) indicated that inhibition was noncompetitive. CONCLUSION: Significant inhibition of MMP-13 and MMP-8 activity against collagen occurred in vitro at concentrations that were near the concentrations achieved in serum after oral dosing. Studies with truncated enzymes and 2 substrates suggest that doxycycline disrupts the conformation of the hemopexin-like domain of MMP-13 and the catalytic domain of MMP-8.

Amino Acid Sequence↗
PubMed1999

Changes in homocysteine levels during normal pregnancy.

OBJECTIVE: The objective of this study was to determine the changes in total plasma homocysteine concentration that occur during normal pregnancy. STUDY DESIGN: In this cross-sectional study homocysteine was measured in 155 normal women in the first, second, and third trimesters and in nonpregnant controls. In addition, albumin, serum B12, serum folate, and red blood cell folate concentrations were measured and correlated to homocysteine values. RESULTS: The mean homocysteine concentration (in micromoles per liter) was 5.6 (95% confidence interval 3.9-7.3) at 8-16 weeks' gestation, 4.3 (95% confidence interval 3.5-5.3) at 20-28 weeks' gestation, 5.5 (95% confidence interval 3.3-7.5) at 36-42 weeks' gestation, and 7.9 (95% confidence interval 6.2-9.6) in the nonpregnant control group. Homocysteine was significantly lower in all 3 trimesters of pregnancy compared with nonpregnant controls (P <.001). Homocysteine levels were directly correlated with albumin levels, which decreased during pregnancy. Homocysteine concentrations were decreased in subjects taking folic acid supplementation. CONCLUSION: Serum concentrations of homocysteine decrease during pregnancy. This occurs in association with the physiologic fall in albumin during pregnancy, as well as with folic acid supplementation.

Adult↗
PubMed1999

Randomised, double-blind, placebo controlled pilot study assessing nitroglycerin as a tocolytic.

Thirty-three women in preterm labour were randomised in a double-blind fashion to receive either transdermal nitroglycerin (n = 17) or placebo (n = 16). Both groups had significant (P < 0.001) change in the cervix prior to randomisation. The primary outcome measure was delivery within 48 hours of randomisation. Fewer women randomised to nitroglycerin treatment (6/17) were delivered within 48 hours, compared with the placebo treatment (10/16) (RR 0.56, 95% CI 0.27 to 1.19). This pilot study lends support to two case series published that suggest that transdermal nitroglycerin may be promising as a safe, effective means for tocolysis.

Administration, Cutaneous↗
PubMed1998

Effect of intraarticular hyaluronan injection in experimental canine osteoarthritis.

OBJECTIVE: To determine if intraarticular injections of hyaluronan (HA) protect against the early stages of joint damage in a canine model of osteoarthritis (OA). METHODS: OA was induced in adult mongrel dogs by transection of the anterior cruciate ligament of the left knee. One group of dogs (n=7) was treated with 5 weekly injections of HA (MW 1,500,000) into the operated knee beginning 1 day after ligament transection. The control group (n=6) was injected with saline on the same schedule. Twelve weeks after surgery, all dogs were killed, the severity of pathologic changes of OA was graded, and composition of the cartilage and extent of aggregation of proteoglycans (PGs) synthesized in vitro by cartilage slices were determined. RESULTS: All dogs showed gross morphologic changes typical of OA in the unstable knee. The severity of joint pathology in HA-treated dogs was comparable with that in the saline-injected controls. In OA cartilage from the saline-treated group, the mean uronic acid concentration was 30-60% greater than that in the contralateral knee. In sharp contrast, the uronic acid concentration in OA cartilage from the HA-treated dogs was 10-30% lower than that in cartilage from the contralateral knee (P=0.02 and P=0.03, respectively, for samples from the medial and lateral femoral condyle). The extent of aggregation of PG synthesized in vitro by cartilage from HA-injected animals was similar to that synthesized by cartilage from the saline-injected dogs. CONCLUSION: In this canine model of OA, the series of intraarticular injections of HA did not alter development of osteophytosis or fibrillation. However, the PG concentration of cartilage in the OA knee was significantly reduced by this treatment, suggesting that HA therapy might adversely affect the biomechanical properties of the cartilage.

Animals↗
PubMed1998

Obstetric complications, treatment response and brain morphology in adult-onset and early-onset males with schizophrenia.

BACKGROUND: Substantial variability in age at onset of illness and course of illness exists between patients with schizophrenia. Recent studies suggest that age at illness onset may be useful in defining biologically and clinically distinct subgroups of patients. METHODS: Two hundred and ten males with schizophrenia were classified as early-onset or adult-onset according to their age at first hospitalization. Birth history, clinical functioning and treatment response was assessed in a subgroup of patients. Brain anatomy was assessed from CT scans in all patients and in 32 non-psychiatric control subjects. RESULTS: Patients with an early-onset were likely to have a history of obstetric complications, a poor response to neuroleptic treatment, and showed no relationship between ventricle size and duration of illness. Adult-onset patients were less likely to have obstetric complications, more likely to respond to treatment in the first years of illness, and showed an association between brain structure and duration of illness. CONCLUSIONS: The distinction between early- and adult-onset patients may have important aetiological and treatment implications.

Adolescent↗
PubMed1998

An open comparison of clozapine and risperidone in treatment-resistant schizophrenia.

BACKGROUND: Clozapine and risperidone are used in treatment-resistant schizophrenia. At present, there are few reported comparisons of these drugs in this population. We report on a consecutive series of treatment-resistant schizophrenics given either clozapine or risperidone in open clinical trials. METHOD: Subjects were treated with clozapine (n = 57) or risperidone (n = 29). Pretreatment GAF, CGI, and PANSS scores did not differ between the groups, nor did demographic variables including age, age at first hospitalization, years ill, number of previous hospitalizations, or gender. The mean treatment trial was 12.1 weeks, with mean doses of clozapine 420 mg, and risperidone 7.75 mg. The length of the trial did not differ significantly between the groups. Response was taken to be a 20% decrease in the PANSS score. RESULTS: Using repeated measures ANOVA, PANSS total scores (F = 5.3, p = 0.02) and positive subscore (F = 7.4, p = 0.008) showed greater improvement in the clozapine group than the risperidone group, while other PANSS subscores showed a trend toward greater improvement with clozapine. The PANSS-derived factors of excitement (F = 6.7, p = 0.01), psychosocial withdrawal (F = 3.8, p = 0.05), and psychomotor retardation (F = 3.9, p = 0.05) improved more in the group treated with clozapine. The GAF (F = 10.9, p = 0.0014), CGI (F = 11.5, p = 0.0011), and CGI improvement (p = 0.0001) scores also improved more in the clozapine group. Of the clozapine group, 25 (44%) responded, while 8 (28%) of the risperidone group responded to treatment. DISCUSSION: Clozapine had better efficacy in subjects with treatment-resistant schizophrenia compared to risperidone, although risperidone appears to yield better response rates than those previously reported for typical antipsychotics. Double-blind, controlled trials of risperidone are needed to establish its efficacy in treatment-resistant schizophrenia.

Adult↗
PubMed1998

Use of nitroglycerin for uterine relaxation.

Data from human and experimental animal research indicate that nitric oxide (NO), a novel messenger, formed during the nitric oxide synthase-catalyzed oxidation of L-arginine to L-citrulline, is involved in maintaining normal uterine tone during gestation. There are demonstrated and potential benefits of manipulating the L-arginine-NO system during pregnancy. Several recent case reports and case series have described the effective use of nitroglycerin (GTN), a NO donor compound, antenatally, intrapartum, and postpartum for acute uterine relaxation. Therapeutic indications for GTN range from facilitating external cephalic version, difficult vaginal or cesarean section delivery, and manual exploration of the uterus, to its use as a tocolytic. The intravenous regimen of GTN required to obtain the desired degree of uterine relaxation is extremely variable; intravenous bolus doses of 50 micrograms to 500 micrograms GTN with up to three repeated injections of 50 micrograms to 250 micrograms have been reported. Other methods of GTN administration include transdermal patches and sublingual spray. GTN, when used in low doses, may provide safe and effective uterine relaxation with no clinically apparent fetal or maternal adverse effects. However, clinical trials with use of objective methods of evaluating uterine tone and comparing GTN to other tocolytic agents are required before widespread use in advocated.

Animals↗
PubMed1998

Oral administration of doxycycline reduces collagenase and gelatinase activities in extracts of human osteoarthritic cartilage.

OBJECTIVE: To determine whether oral administration of doxycycline in clinically relevant doses will suppress activities of collagenase and gelatinase in extracts of human osteoarthritic (OA) cartilage. METHODS: Femoral heads were obtained from 21 patients undergoing arthroplasty for endstage hip OA. Activities of collagenase and gelatinase were measured in extracts of the OA cartilage from patients who received doxycycline, 100 mg bid or qam for 5 days before surgery (n = 5 and n = 6, respectively), 200 mg as a single dose 3 days before surgery (n = 4); or no doxycycline (n = 6). RESULTS: Five days of doxycycline treatment, in a dose of either 100 mg bid or 100 mg qam, inhibited gelatinase activity in the cartilage extracts (p = 0.003, 0.008, respectively). The bid dose also inhibited collagenase activity (p = 0.002), but inhibition of collagenase with 100 mg qam did not quite reach statistical significance (p = 0.055), in comparison with the values for the untreated OA controls. The single 200 mg dose, given 3 days before procurement of the cartilage, was ineffective in inhibiting metalloproteinase activity. CONCLUSION: Oral administration of doxycycline significantly inhibited collagenase and gelatinase activity in human OA cartilage. The effective dose is likely to be well tolerated during chronic administration, e.g., in a clinical trial to assess the potential of the drug to modify cartilage breakdown in OA.

Administration, Oral↗