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Biomedical subjects

D W Green

Publications and source records attributed to D W Green.

At least 19 recordsLinked to original sources

Novel osteoinductive biomimetic scaffolds stimulate human osteoprogenitor activity--implications for skeletal repair.

The development of new bone formation strategies offers tremendous therapeutic implications in a variety of musculoskeletal diseases. One approach involves harnessing the regenerative capacity of osteoprogenitor bone cells in combination with biomimetic scaffolds generated from appropriate scaffold matrices and osteoinductive factors. The aims of our study were to test the efficacy of two innovative osteoinductive agents: the osteoblast stimulating factor-1 (osf-1), an extracellular matrix-associated protein, and osteoinductive extracts of Saos-2 cells on human osteoprogenitor cells. Saos-2 extracted osteoinductive factors significantly stimulated alkaline phosphatase specific activity in basal and osteogenic conditions. Osf-1 significantly stimulated chemotaxis, total colony formation, alkaline phosphatase-positive colony formation, and alkaline phosphatase specific activity at concentrations as low as 10 pg/ml compared with control cultures. Osteoinductive factors present in Saos-2 cell extracts and osf-1 promoted adhesion, migration, expansion, and differentiation of human osteoprogenitor cells on 3-D scaffolds. The successful generation of 3-D biomimetic structures incorporating osf-1 or osteoinductive factors from Saos-2 cells indicates their potential for de novo bone formation that exploits cell-matrix interactions.

Aged↗

The choice of inhalation anaesthetic for major abdominal surgery in children with liver disease.

Many children with liver disease undergo major abdominal surgery. Maintenance of anaesthesia is thus an important consideration in this surgical population. Despite a comprehensive and painstaking review of the literature, a sound evidence base, on which a choice of inhalation anaesthetic may be made, is lacking due to limited research in these patients. Differences between the more recent agents such as isoflurane, sevoflurane and desflurane are minor. Sevoflurane is favoured in paediatric practice for gaseous induction, but desflurane or isoflurane are marginally the preferred agents for maintenance of anaesthesia in children with liver disease undergoing major abdominal surgery. However, on the evidence that exists, much of it admittedly in animals and in adults, all three are preferable to halothane in this group of patients. More work is needed in this area before sound conclusions can be drawn and one agent proved to be definitely superior to the others.

Abdomen↗

Suppression of beta-catenin inhibits the neoplastic growth of APC-mutant colon cancer cells.

Mutations involving the adenomatous polyposis coli (APC) tumor suppressorgene/beta-catenin signaling pathway have been identified in the majority of colon carcinomas. However, the role of aberrant beta-catenin signaling in the neoplastic growth of APC-mutant colon cancer cells has not been directly studied. To address this question, antisense oligonucleotides have been used to specifically down-regulate beta-catenin expression in APC-mutant human colon carcinoma cells. Antisense-mediated suppression of beta-catenin inhibits the in vitro proliferation, anchorage-independent growth, and cellular invasiveness of APC-mutant human colon carcinoma cells. The systemic administration of beta-catenin antisense oligonucleotides down-regulates beta-catenin expression in vivo in human colon cancer xenografts in nude mice. Such treatment inhibits the tumorigenic growth of colon cancer xenografts and can completely eradicate tumors in some treated animals. These studies formally demonstrate the critical role of beta-catenin signaling in the neoplastic growth of APC-mutant colon cancer cells and suggest that strategies targeting beta-catenin may be of use in the therapy of colon cancer.

Animals↗

Beta-catenin antisense treatment decreases beta-catenin expression and tumor growth rate in colon carcinoma xenografts.

BACKGROUND: Loss of the adenomatous polyposis coli (APC) tumor suppressor gene plays a significant role in colorectal carcinogenesis. One function of the APC gene product is to regulate beta-catenin, a protein that plays a role in cell adhesion and also regulates the activity of certain transcription factors. To more precisely delineate the role of beta-catenin signaling in colon cancer growth, we treated mice bearing APC-mutant SW480 colon cancer xenografts with antisense oligonucleotides (ODNs) directed against beta-catenin mRNA and examined effects on beta-catenin expression and tumor growth. METHODS: Balb/C nude mice underwent subcutaneous injection of 1 x 10(6) SW480 cells to establish tumor xenografts. In one experiment, tumors were allowed to grow for 7 days, after which time animals were randomized to undergo daily intraperitoneal injections of either antisense beta-catenin ODN at doses of 5, 10, or 20 mg/kg, scrambled sequence beta-catenin ODN control, or saline control for 7 days. Tumors were excised and homogenized, and tumor lysates subjected to gel electrophoresis and Western blotting for beta-catenin protein quantification. In a second experiment, tumor-bearing animals began receiving daily intraperitoneal injections of either antisense beta-catenin ODN at doses of 5, 10, or 20 mg/kg, scrambled sequence beta-catenin ODN control, or saline control. Tumor growth was quantitated by measuring tumor volumes twice weekly. A third experiment evaluated the antitumor effects of daily bolus dosing versus continuous infusion of beta-catenin antisense ODNs (20 mg/kg). RESULTS: Treatment of APC-mutant colorectal carcinoma xenografts with beta-catenin antisense resulted in a dose-dependent down-regulation in beta-catenin protein expression as shown by Western blotting. Treatment of tumor-bearing mice with antisense directed at beta-catenin also demonstrated a dose-dependent inhibition of tumor growth. There appears to be little difference in the antitumor effects of antisense ODNs administered by continuous infusion or bolus dosing schedules. CONCLUSIONS: beta-Catenin expression plays a critical role in the tumorigenic growth of APC-mutant colon cancer xenografts. Strategies targeting beta-catenin, including the use of antisense ODNs, may be of use in the treatment of human colon cancer.

Animals↗

Contingency, causation, and adaptive inference.

In contingency judgment tasks involving 2 event types, individuals weight the a and b cells of a 2 x 2 contingency table more than the c and d cells. Some theorists have argued that they can provide normative justifications for this weighting and that the weighting reflects simple heuristics that are adaptive in the real world. The authors show that, to avoid error, individual judgments about real contingencies should be more subtle than these supposedly adaptive heuristics allow.

Bayes Theorem↗

Understanding microworlds.

Little is known about how individuals understand change in complex systems. In the natural world, for instance, the effects of change need to be understood in terms of two-way (interdependent) causal processes. Based on subject's ratings of the causal likelihood that a given change will yield a target effect and on subjects' ratings of the impact of a given change on specified populations in a microworld, White (1997, 2000) argued that individuals in fact understand change in terms of one-way causal processes and assume that causal effects decline with distance from the source of the change. An alternative view is that the ratings reflect individuals' mental simulations of change as elicited by the tasks. Experiments 1 and 2 confirm that such ratings are task dependent and that individuals make no general assumption that causal effects decrease with distance. Experiment 3 shows that when required to explain a pattern of change in the size of a population individuals can construct two-way causal explanations consistent with this mental simulation proposal.

Adolescent↗

Medical complications in scoliosis surgery.

Several medical complications can occur after scoliosis surgery in children and adolescents. They include the syndrome of inappropriate antidiuretic hormone; pancreatitis; cholelithiasis; superior mesenteric artery syndrome; ileus; pnemothorax; hemothorax; chylothorax; and fat embolism. This review focuses on the pathophysiology, diagnosis, and treatment of the various conditions that occur after correction of spinal deformity. Attention is given to recent literature specifically related to scoliosis surgery. Surgical complications like urinary tract infection, wound infection, and hardware failure will not be addressed.

Adolescent↗

HER2/neu antisense targeting of human breast carcinoma.

Overexpression of the HER2/neu oncogene is observed in approximately 30% of human breast carcinoma specimens. HER2/neu overexpression is a negative prognostic factor in breast cancer patients. Cancer cells that overexpress HER2/neu may also be less sensitive to chemotherapy. In order to further define mechanisms by which HER2/neu overexpression drives neoplastic cell growth and chemoresistance, antisense oligonucleotides (ODNs) have been utilized to selectively down-regulate HER2/neu expression in human breast cancer cells. Such antisense ODNs suppress HER2/neu mRNA and protein levels in a dose-dependent, sequence-specific manner. Down-regulation of HER2/neu expression in HER2/neu overexpressing breast cancer cells inhibits cell cycle progression in G0/G1 and results in apoptotic cell death. In tissue culture studies, combined treatment of HER2/ neu overexpressing breast cancer cells with HER2/neu antisense ODNs and conventional chemotherapeutic agents results in synergistic inhibition of cancer cell growth and activation of apoptotic cell death mechanisms. These studies have been extended to demonstrate synergistic antitumor effects following systemic treatment with antisense ODNs plus doxorubicin in nude mice bearing human breast carcinoma xenografts. Collectively these findings demonstrate that HER2/neu overexpression stimulates anti-apoptotic cell survival mechanisms and suggest that HER2/neu antisense ODNs may be of use in cancer therapeutics.

Animals↗

The IF(1) inhibitor protein of the mitochondrial F(1)F(0)-ATPase.

Recent studies on the IF(1) inhibitor protein of the mitochondrial F(1)F(0)-ATPase from molecular biochemistry to possible pathophysiological roles are reviewed. The apparent mechanism of IF(1) inhibition of F(1)F(0)-ATPase activity and the biophysical conditions that influence IF(1) activity are summarized. The amino acid sequences of human, bovine, rat and murine IF(1) are compared and domains and residues implicated in IF(1) function examined. Defining the minimal inhibitory sequence of IF(1) and the role of conserved histidines and conformational changes using peptides or recombinant IF(1) is reviewed. Luft's disease, a mitochondrial myopathy where IF(1) is absent, is described with respect to IF(1) relevance to mitochondrial bioenergetics and clinical observations. The possible pathophysiological role of IF(1) in conserving ATP under conditions where cells experience oxygen deprivation (tumor growth, myocardial ischemia) is evaluated. Finally, studies attempting to correlate IF(1) activity to ATP conservation in myocardial ischemic preconditioning are compared.

Adenosine Triphosphate↗

Nucleated red blood cells in healthy infants of women with gestational diabetes.

OBJECTIVE: To evaluate whether absolute nucleated red blood cell (RBC) counts are elevated in large-for-gestational-age (LGA) infants of women with gestational diabetes compared with appropriate-for-gestational-age (AGA) infants of women with or without gestational diabetes. METHODS: We compared absolute nucleated RBC counts during the first 12 hours of life in three groups of term, vaginally delivered infants, LGA infants of women with gestational diabetes (n = 20), AGA infants of women with gestational diabetes (n = 20), and AGA infants of nondiabetic women (n = 30). We excluded infants of women with hypertension, smoking, alcohol or drug abuse, and those with fetal heart rate abnormalities in labor, low Apgar scores, hemolysis, blood loss, or chromosomal anomalies. RESULTS: There were no significant differences among groups in gestational age, gravidity, parity, maternal analgesia, 1- and 5-minute Apgar scores, and lymphocyte counts. Corrected white blood cell counts and hematocrit were significantly higher in LGA infants of women with gestational diabetes than in the other groups. The median nucleated RBC count was significantly higher in LGA infants of women with gestational diabetes (0.56 x 10(9)/L, range 0-1.8 x 10(9)/L) than AGA infants of women with gestational diabetes (0.13 x 10(9)/L, range 0-0.65 x 10(9)/L) and controls (0.0005 x 10(9)/L, range 0-0.6 x 10(9)/L) (P < .001). Multiple regression analysis showed that absolute nucleated RBC count was significantly correlated with birth weight (or macrosomia) and maternal diabetic status (r2 = .25, P < .001 for the multiple regression, contribution of birth weight r2 = .19, and diabetes r2 = .06). CONCLUSION: At birth, term LGA infants born to women with gestational diabetes had higher absolute nucleated RBC counts compared with AGA infants born to women with gestational diabetes and controls.

Birth Weight↗

Congenital scoliosis.

Congenital scoliosis is a deformity of the developing spine that results from defects in vertebral development. The developmental etiologies may be classified as either a failure of formation, a failure of segmentation, or a mixture of these two modes of maldevelopment. Early detection and close surveillance of congenital scoliosis is critical, as a rapidly progressive curve may lead to significant deformity, pulmonary restriction, and neurologic problems if not treated. Early surgical treatment is often necessary for rapidly progressive curves.

Cervical Vertebrae↗

Anaesthesia, perioperative management and outcome of correction of extrahepatic biliary atresia in the infant: a review of 50 cases in the King's College Hospital series.

Extrahepatic biliary atresia (EHBA) is an uncommon condition presenting in the first few weeks of life. It has an incidence of 0. 5-1 per 10 000 live births and is the end result of a destructive inflammatory process involving the extrahepatic biliary system of unknown aetiology occurring in utero. The net result is neonatal jaundice due to bile stasis, with subsequent hepatocellular damage and cirrhosis. In the untreated, patient death is inevitable within 2 years. Precise diagnosis (or exclusion) of EHBA in the persistently jaundiced infant must be made urgently and major surgery (hepatic portoenterostomy: Kasai procedure) carried out as soon as possible, preferably before 6-8 weeks of age. This review is concerned with anaesthesia for correction of EHBA in 50 consecutive patients and also outlines the experience gained in the largest European centre for correction of EHBA where the number of cases now approaches 500.

Anesthesia↗

The modified Fontan procedure: morphometry and surgical implications.

BACKGROUND: The modified Fontan procedure for patients with only one well-formed ventricle is now widely regarded as palliative, not curative. METHODS: To improve the surgical management and postoperative follow-up of such patients, a morphometric study of 33 postmortem cases was done. RESULTS: The three main causes of death were congestive heart failure (82%), arrhythmias (12%), and central nervous system dysfunction (6%). The cross-sectional area of the Fontan anastomosis (FA) relative to the systemic venous area (SVA) and relative to the body surface area (BSA) revealed that the Fontan pathway was often obstructive. The mean FA/SVA index was 73% less than normal: 0.54 +/- 0.22, range 0.13 to 0.98. The mean FA/BSA index was 70% less than normal: 143.52 +/- 50.01 mm2/M2, range 55.09 to 261.67 mm2/M2. CONCLUSIONS: The main surgical challenge is to minimize or eliminate prepulmonary stenosis. Although significant postoperative obstruction was often not evident hemodynamically because of small or absent gradients, the presence of important obstruction of the Fontan pathway was clearly revealed by morphometry.

Adolescent↗

Nucleated red blood cells in infants of smoking mothers.

OBJECTIVE: To evaluate whether the absolute nucleated red blood cell (RBC) count is elevated in term, appropriate for gestational age (AGA) infants born to smoking women. METHODS: We compared absolute nucleated RBC counts taken during the first 12 hours of life in two groups of term, vaginally delivered, AGA infants, one group born to mothers who smoked during pregnancy (n = 30) and the other born to mothers who did not smoke (n = 30). We excluded infants of women with diabetes, hypertension, or alcohol or drug abuse, and infants with heart rate abnormalities, hemolysis, blood loss, or chromosomal anomalies. RESULTS: There were no differences between the groups in birth weight, gestational age, maternal age, gravidity, parity, maternal analgesia during labor, 1- and 5-minute Apgar scores, corrected white blood cell counts, lymphocyte counts, or hematocrits. The median absolute nucleated RBC count in infants of smoking mothers was 0.5 x 10(9)/L (range 0 to 5.0) versus 0.0005 x 10(9)/L (range 0 to 0.6) in nonsmoking controls (P < .002). Regression analysis that included Apgar scores, gestational age, and number of cigarettes smoked per day showed a significant correlation of absolute nucleated RBC count only with the number of cigarettes smoked per day (P < .001). CONCLUSION: At birth, term AGA infants born to smoking mothers have increased circulating absolute nucleated RBC counts compared with controls. The absolute nucleated RBC count in newborns correlates with the number of cigarettes smoked during pregnancy.

Adult↗