Biomedical subjects

David A Young

Publications and source records attributed to David A Young.

30 records · Page 2Linked to original sources

PubMed2003

Intrauterine growth restriction, preeclampsia, and intrauterine mortality at high altitude in Bolivia.

Infant mortality and stillbirth rates in Bolivia are high and birth weights are low compared with other South American countries. Most Bolivians live at altitudes of 2500 m or higher. We sought to determine the impact of high altitude on the frequency of preeclampsia, gestational hypertension, and other pregnancy-related complications in Bolivia. We then asked whether increased preeclampsia and gestational hypertension at high altitude contributed to low birth weight and increased stillbirths. We performed a retrospective cohort study of women receiving prenatal care at low (300 m, Santa Cruz, n = 813) and high altitude (3600 m, La Paz, n = 1607) in Bolivia from 1996 to 1999. Compared with babies born at low altitude, high-altitude babies weighed less (3084 +/- 12 g versus 3366 +/- 18 g, p < 0.01) and had a greater occurrence of intrauterine growth restriction [16.8%; 95% confidence interval (CI): 14.9-18.6 versus 5.9%; 95% CI: 4.2-7.5; p < 0.01]. Preeclampsia and gestational hypertension were 1.7 times (95% CI: 1.3-2.3) more frequent at high altitude and 2.2 times (95% CI: 1.4-3.5) more frequent among primiparous women. Both high altitude and hypertensive complications independently reduced birth weight. All maternal, fetal, and neonatal complications surveyed were more frequent at high than low altitude, including fetal distress (odds ratio, 7.3; 95% CI: 3.9-13.6) and newborn respiratory distress (odds ratio, 7.3; 95% CI: 3.9-13.6; p < 0.01). Hypertensive complications of pregnancy raised the risk of stillbirth at high (odds ratio, 6.0; 95% CI: 2.2-16.2) but not at low altitude (odds ratio, 1.9; 95% CI: 0.2-17.5). These findings suggest that high altitude is an important factor worsening intrauterine mortality and maternal and infant health in Bolivia.

Adult↗

PubMed2003

The comparative role of activator protein 1 and Smad factors in the regulation of Timp-1 and MMP-1 gene expression by transforming growth factor-beta 1.

The balance between matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), is pivotal in the remodeling of extracellular matrix. TGF-beta has profound effects on extracellular matrix homeostasis, in part via its ability to alter this balance at the level of gene expression. The intracellular signaling pathways by which TGF-beta mediates its actions include the Smad pathway, specific to the TGF-beta superfamily, but also, for example, mitogen-activated protein kinase pathways; furthermore, cross-talk between the Smads and other signaling pathways modifies the TGF-beta response. The reciprocal effect of TGF-beta on the expression of Timp-1 and MMP-1 supports its role in matrix anabolism, yet the mechanisms by which TGF-beta induces Timp-1 and represses induced MMP-1 have remained opaque. Here, we (i) investigate the mechanism(s) by which TGF-beta1 induces expression of the Timp-1 gene and (ii) compare this with TGF-beta1 repression of phorbol ester-induced MMP-1 expression. We report that the promoter-proximal activator protein 1 (AP1) site is essential for the response of both Timp-1 and MMP-1 to TGF-beta (induction and repression, respectively). c-Fos, JunD, and c-Jun are essential for the induction of Timp-1 gene expression by TGF-beta1, but these AP1 factors transactivate equally well from both Timp-1 and MMP-1 AP1 sites. Smad-containing complexes do not interact with the Timp-1 AP1 site, and overexpression of Smads does not substitute or potentiate the induction of the gene by TGF-beta1; furthermore, Timp-1 is still induced by TGF-beta1 in Smad knockout cell lines, although to varying extents. In contrast, Smads do interact with the MMP-1 AP1 site and mediate repression of induced MMP-1 gene expression by TGF-beta1.

Animals↗

PubMed2003

Different immunosuppressive regimens and recurrence of primary sclerosing cholangitis after liver transplantation.

Primary sclerosing cholangitis (PSC) is the fourth leading diagnosis in liver transplant recipients in the United States. The disease is known to recur in 15% to 30% of liver transplant recipients. We set out to investigate how different immunosuppression regimens affected natural history of PSC after liver transplantation at our center. We reviewed records of all patients who underwent a liver transplantation at our institution in between 1988 and 2000 and had a diagnosis of PSC at the time of liver transplantation. Primary sclerosing cholangitis recurred in 15 of 71 patients (21.1%) who had complete records and survived more than 30 days after liver transplantation. Although recurrence of primary sclerosing cholangitis was most often seen (but not statistically significantly so) in patients who received maintenance corticosteroids, the time to recurrence was not significantly different between those who were treated with maintenance, those who were not successfully weaned, and those who successfully weaned off corticosteroids within 3 months after liver transplantation. Orthoclone (OKT3) therapy (Ortho-Biotech, Inc., Raritan, NJ) was associated with a higher risk of primary sclerosing cholangitis recurrence (29% versus 10%, P <.05). Recurrence was not influenced by immunosuppression with either cyclosporine or tacrolimus. Coexistent inflammatory bowel disease was a cause of failure to wean off corticosteroids, was associated with a shorter time to recurrence of sclerosing cholangitis, and was responsible for significant comorbidity (colon cancer in 7.3%). Primary sclerosing cholangitis recurrence is commonly seen after liver transplantation. More immunosuppression seems to be detrimental to the outcome of our patients with sclerosing cholangitis: use of OKT3 was associated with a greater incidence of recurrence. Length of corticosteroid use did not affect timing or risk of recurrence, and because it has been proven that early corticosteroid withdrawal after liver transplantation is beneficial, we continue to recommend this practice.

Adult↗

PubMed2003

Relations between exhaled nitric oxide and measures of disease activity among children with mild-to-moderate asthma.

OBJECTIVE: Exhaled nitric oxide (FE(NO)) was evaluated in children with asthma after 4 to 6 years of treatment with budesonide, nedocromil, or albuterol as needed. STUDY DESIGN: FE(NO), spirometry, total eosinophil count, and serum eosinophil cationic protein levels were obtained from 118 children at the Denver site of the Childhood Asthma Management Program upon completion of treatment and after a 2- to 4-month washout. RESULTS: Budesonide-treated patients had significantly lower median (1st, 3rd quartile) FE(NO) (21.5 [13.2, 84.4] vs 62.5 [26.2, 115.0] ppb, P <.01) and eosinophil cationic protein levels (17.4 [10.1, 24.3] vs 24.0 [15.4, 33.9] mg/dL, P =.05) compared with placebo, whereas no differences were noted between nedocromil and placebo groups. After washout, FE(NO) levels were similar between the three treatments. FE(NO) levels significantly correlated with degree of bronchial hyperresponsiveness, bronchodilator reversibility, allergen skin prick tests, serum IgE, and total eosinophil count. FE(NO) levels were also higher in patients with nocturnal symptoms and in patients requiring beta-agonist use at least once weekly. CONCLUSIONS: Budesonide therapy was more effective than nedocromil in reducing FE(NO). Unfortunately, the effects of long-term budesonide were not sustained after its discontinuation. FE(NO) may be a complementary tool to current practice guidelines in assessing asthma control and medication response.

Anti-Asthmatic Agents↗

PubMed2002

An enhancer complex confers both high-level and cell-specific expression of the human type X collagen gene.

Type X collagen expression is restricted to hypertrophic chondrocytes in the endochondral growth plate. Transient transfection of reporter constructs containing the human collagen X promoter into primary growth plate chondrocytes identified a cis-acting positive regulatory DNA element(s) that has cell-specific enhancer properties and binds a nuclear protein expressed specifically in growth plate chondrocytes. Functional disruption of this region results in a significant reduction in the activation of reporter gene transcription. The identified enhancer is a major element controlling both high-level and cell-specific expression of type X collagen gene.

Base Sequence↗

PubMed2002

Chronic hypoxia opposes pregnancy-induced increase in uterine artery vasodilator response to flow.

We tested the hypotheses that pregnancy increases the uterine artery (UA) vasodilator response to flow and that this increase is impaired under conditions of chronic hypoxia (30 days, simulated elevation 3,960 m). UA were isolated from 24 normoxic or chronically hypoxic midpregnant guinea pigs and studied with the use of pressure myography. Normoxic pregnancy increased UA flow vasodilator response and protected against a rise in wall shear stress (WSS). Chronic hypoxia opposed these effects, prompting vasoconstriction at high flow and increasing WSS above levels seen in normoxic pregnant UA. The nitric oxide synthase inhibitor N(G)-nitro-l-arginine (l-NNA) eliminated the pregnancy-associated increase in flow vasodilation in normoxic UA, suggesting that increased nitric oxide production was responsible. The considerable residual vasodilation after nitric oxide synthase and cyclooxygenase inhibition implicated endothelial-derived hyperpolarizing factor (EDHF) as an additional contributor to flow vasodilation. l-NNA increased flow vasodilation in UA from chronically hypoxic animals, suggesting that chronic hypoxia may have lowered EDHF or elevated peroxynitrite production. In conclusion, flow is an important physiological vasodilator for the acute and more chronic UA dimensional changes required to increase uteroplacental blood flow during normal pregnancy. Chronic hypoxia may be a mechanism that opposes the pregnancy-associated rise in UA flow vasodilation, thereby increasing the incidence of preeclampsia and intrauterine growth restriction at a high altitude.

Altitude↗

PubMed2002

Identification of an initiator-like element essential for the expression of the tissue inhibitor of metalloproteinases-4 (Timp-4) gene.

We have used real-time quantitative reverse transcriptase PCR (TaqMan) to quantify the expression of the four tissue inhibitor of metalloproteinases (Timp) genes in mouse tissues during development and in the adult. Among the four Timp genes, Timp-4 shows the most restricted pattern of expression, with highest RNA levels in brain, heart and testes. These data indicate that in the brain, Timp-4 transcripts are temporally regulated during development, becoming more abundant than those of the other Timps after birth. Cloning of the Timp-4 gene confirmed a five-exon organization resembling that of Timp-2 and Timp-3, and like all Timps, Timp-4 is located within an intron of a synapsin gene. Ribonuclease protection analysis and 5'-rapid amplification of cDNA ends PCR identified multiple transcription starts for Timp-4 from brain and heart mRNA. The promoter region of Timp-4 was functional in transient transfection analysis in mouse C3H10T1/2 fibroblasts, where it directed basal expression that was non-inducible by serum. The TATA-less promoter contains consensus motifs for Sp1 and an inverted CCAAT box upstream of an initiator-like element that is in close proximity to a transcription start site. Mutation of the CCAAT box caused a 2-fold increase in reporter expression. More significantly, mutation of the Sp1 motif or initiator-like element almost completely abolished reporter expression. This first functional characterization of the Timp-4 promoter shows it to be distinct from other members of the Timp family and provides insights into potential mechanisms controlling the tight spatio-temporal expression pattern of the gene.

5' Untranslated Regions↗

PubMed2002

Increased hippocampal volume in schizophrenics' parents with ancestral history of schizophrenia.

OBJECTIVE: Decreased hippocampal volume is one of the hypothesized pathological features of schizophrenia, but it is not known if this abnormality is familially transmitted. The aim of this study was to measure the hippocampal volume of the parents of schizophrenic probands, in relationship to the apparent transmission of genetic risk. METHOD: Eighteen subjects from families consisting of a schizophrenic proband and two clinically unaffected parents were studied. Probands were compared to six control subjects, matched for age, sex, and educational level. The six families were selected so that only one parent had an ancestral family history of schizophrenia. The volumes of both hippocampi were measured by magnetic resonance imaging and adjusted for age and whole brain volume. RESULTS: The total hippocampal volumes of the parents with ancestral family history of schizophrenia were significantly larger than those of their schizophrenic offspring. CONCLUSIONS: This study suggests that decreased hippocampal volume in schizophrenia is not a familially transmitted abnormality. Rather, it appears that clinically unaffected parents who transmit apparent genetic risk for schizophrenia may have increased hippocampal volume, which may be a protective factor against the illness.

Adolescent↗

PubMed2002

Osmium has the lowest experimentally determined compressibility.

On the basis of high pressure diamond-anvil compression studies for the precious metals Ru, Ir, and Os we report the surprising discovery that metallic osmium has a lower compressibility than covalently bonded diamond. We also find that Ir and Ru are as incompressible as Re. In addition, we have performed first principles calculations that confirm the trend in the measured transition metal compressibilities.

Journal Article↗

PubMed2002

Laser-tattoo removal--a study of the mechanism and the optimal treatment strategy via computer simulations.

BACKGROUND AND OBJECTIVE: The physical mechanisms for laser-tattoo interactions and the tattoo particle breakup process are not well understood. This study investigates whether the mechanism of the breakup process can be identified via computer simulations and proposes a treatment strategy that can potentially minimize the collateral damage to the surrounding tissues. Note that the "removal" of tattoo particles is defined here as breakup of particles into smaller ones with sizes approaching or smaller than the visible wavelength of light so that they become less visible. STUDY DESIGN/MATERIALS AND METHODS: The radiation-hydrodynamics code LATIS is used for the modeling. We first identify the magnitude of the tensile stress generated inside graphite tattoo particles as functions of laser pulse length and particle size. We then calculate the relationship between the surface laser fluence (defined as the time integrated energy flux) and the tensile strength of the tattoo particle at a given depth. RESULTS: If the laser pulse length is sufficiently short, strong acoustic waves with tensile strengths exceeding the fracture thresholds for graphite are generated. The strength of the wave decreases with particle size and increases as the laser pulse length decreases. Simulation results are in general agreement with clinical studies. Although temperatures of the tattoo particles never reach the melting point, a cavitation bubble around the particle can be formed. The steam generated can get into the cracked particles and induce steam-carbon reactions. Laser energy density decreases rapidly with the skin depth. Therefore, the minimum surface laser fluence, for a given pulse length, required for breaking up tattoo particles at a given skin depth, increases with particle depth. CONCLUSIONS: Computer simulations confirm that the breakup of tattoo particles is photoacoustic. For the same amount of laser energy, a shorter pulse is more efficient. The optimal pulse length is approximately 10-100 picosecond to minimize the laser fluence and the collateral damage. It is more difficult to break up the smallest tattoo particles that have diameters smaller than 10 nm; however, smaller particles are less important because they are less visible. Tissue surrounding the tattoo particles can be damaged by cavitation bubbles. These bubbles could be the cause of the empty vacuoles in the ash-white lesions throughout the dermis seen after treatment. Steam-carbon reactions can be induced. Particles then become grossly transparent because of this reaction. Different laser intensity should be used for pigments at different depths in order to minimize the collateral damage to the dermis.

Computer Simulation↗

PubMed2002

Predictors of protocol adherence in a pediatric asthma clinical trial.

BACKGROUND: Declining protocol adherence can threaten the validity of a clinical trial. OBJECTIVE: We sought to explore patient and family factors important for protocol adherence in the 133 patients followed at one of the 8 Childhood Asthma Management Program (CAMP) clinical centers. Difficulties with timely return of diary cards (diary card problem), with keeping or frequently rescheduling appointments (appointment problem), and with commitment to all aspects of the trial (commitment problem) were tracked prospectively during the treatment phase of CAMP, which ranged from 20 to 40 months at the time of the analysis. METHODS: We performed a cross-sectional analysis. RESULTS: During the course of this investigation, no St Louis CAMP patients dropped out of the study, although signs of eroding participation were observed in 44% of patients. For this cross-sectional analysis, the percentage of patients exhibiting protocol-adherence problems was greater the longer patients had been in the trial: 33.3% at 20 to 25 months, 39.5% at 26 to 30 months, 51.4% at 31 to 35 months, and 69.2% at 36 to 40 months (P <.01). The diary card problem was present in 22.2% of the patients enrolled in the trial for 20 to 25 months compared with 66.7% for patients enrolled for 36 to 40 months (P <.005). Appointment and commitment problems were present in smaller percentages of patients and did not change by time in the trial (P =.41 and.22, respectively). A logistic regression analysis of demographic characteristics indicated that age at randomization and time in the trial were significant factors: for every 2-year increase in age, a child was twice as likely to have a commitment problem (odds ratio [OR], 1.96; 95% CI, 1.50-2.57), and for each additional 5 months of participation in the study, a child was twice as likely to have a diary card problem (OR, 1.91; 95% CI, 1.76-2.07). There was no influence of family income, patient race, or patient sex on the occurrence of any of the 3 protocol-adherence problems. A similar analysis of psychologic characteristics of the child and family indicated (1) a 2-fold increase in the risk of a diary card problem with a 10% increase in the percentage of total commissions on the attention scale of the Gordon Diagnostic Study (OR, 2.18; 95% CI, 2.02-2.35), (2) a 2-fold decrease in the risk of an appointment problem with a 10-unit increase in the Child Manifest Anxiety Scale (OR, 0.46; 95% CI, 0.44-0.49), (3) a 2-fold decrease in risk of an appointment problem with a 10-unit increase in the cohesion subscale of the Family Environment Scale (OR, 0.58; 95% CI, 0.55-0.60), and (4) a 5-fold decrease in the risk of a commitment problem with a 10-unit increase in the Child Depression Index score (OR, 0.21; 95% CI, 0.18-0.24). CONCLUSIONS: Adherence and retention problems commonly occur in longer clinical trials. CAMP patients and families were selected in part on the basis of likelihood of being able to participate in the trial to enhance the conclusions of the trial. Despite this selection process, adherence problems were noted. Problems increased with duration of participation, increasing child age, and the presence of less family cohesion or attention problems in the child. In contrast, the presence of mild emotional distress (anxiety and depression) in the child was associated with fewer protocol-adherence problems. Incorporating procedures that help anticipate and identify adherence problems early might improve continued participation in all aspects of a trial and even retention in long-term clinical trials.

Adolescent↗

PubMed2002

Smoking cessation in pregnancy: failure of an HMO pilot project to improve guideline implementation.

This pilot project investigated whether a system introduced by a health maintenance organization (HMO) could encourage obstetric providers to implement smoking-cessation guidelines in their offices. Staff from participating offices was trained in cessation counseling and paid $150 for each pregnant smoker counseled. Data were collected from chart review from participating physicians and a telephone survey of all HMO members giving birth before and after program implementation. Eighteen physician practices participated, representing 27 office sites and 80 physicians. Sixty-six staff members were trained in cessation counseling. Chart review revealed that identification of smoking status increased from 90% to 96% (p=0.03), but documentation of advice to quit worsened (62% vs. 24%, p=0.03). The HMO received claims for counseling from four pregnant smokers out of the 21 identified on chart review. The telephone survey revealed a similar prevalence of current smokers in the baseline and post-intervention samples (15% vs. 13%) but more former smokers (11% vs. 22%) in the follow-up. For the HMO as a whole, fewer smokers reported being advised to quit in the follow-up survey (86% vs. 65%). Few smokers reported being counseled to quit at baseline or follow-up (11% vs. 3%). None of the smokers who received obstetric care from a pilot group physician reported awareness of the smoking-cessation benefit despite the placement of brochures in participating offices advertising the program. This pilot project to reimburse for cessation counseling did not increase smoking-cessation advice or counseling in participating physician's offices. Smoking-cessation counseling worsened across the entire HMO obstetric community during the intervention. A more comprehensive systems approach and a larger HMO market share or a partnership among multiple HMOs may be required to increase smoking-cessation guideline implementation.

Adult↗