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Biomedical subjects

M Wong

Publications and source records attributed to M Wong.

At least 91 records · Page 5Linked to original sources
PubMed2000

5' phospholipid phosphatase SHIP-2 causes protein kinase B inactivation and cell cycle arrest in glioblastoma cells.

The tumor suppressor protein PTEN is mutated in glioblastoma multiform brain tumors, resulting in deregulated signaling through the phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB) pathway, which is critical for maintaining proliferation and survival. We have examined the relative roles of the two major phospholipid products of PI3K activity, phosphatidylinositol 3,4-biphosphate [PtdIns(3,4)P2] and phosphatidylinositol 3,4,5-triphosphate [PtdIns(3,4,5)P3], in the regulation of PKB activity in glioblastoma cells containing high levels of both of these lipids due to defective PTEN expression. Reexpression of PTEN or treatment with the PI3K inhibitor LY294002 abolished the levels of both PtdIns(3, 4)P2 and PtdIns(3,4,5)P3, reduced phosphorylation of PKB on Thr308 and Ser473, and inhibited PKB activity. Overexpression of SHIP-2 abolished the levels of PtdIns(3,4,5)P3, whereas PtdIns(3,4)P2 levels remained high. However, PKB phosphorylation and activity were reduced to the same extent as they were with PTEN expression. PTEN and SHIP-2 also significantly decreased the amount of PKB associated with cell membranes. Reduction of SHIP-2 levels using antisense oligonucleotides increased PKB activity. SHIP-2 became tyrosine phosphorylated following stimulation by growth factors, but this did not significantly alter its phosphatase activity or ability to antagonize PKB activation. Finally we found that SHIP-2, like PTEN, caused a potent cell cycle arrest in G(1) in glioblastoma cells, which is associated with an increase in the stability of expression of the cell cycle inhibitor p27(KIP1). Our results suggest that SHIP-2 plays a negative role in regulating the PI3K-PKB pathway.

3T3 Cells↗
PubMed2000

A comparison of the effects of raloxifene and estrogen on bone in postmenopausal women.

Raloxifene HCl, a selective estrogen receptor modulator, has been shown to increase bone mineral density (BMD) and decrease biochemical markers of bone turnover in postmenopausal women without stimulatory effects on the breast and uterus. However, it is not known whether the changes in BMD and bone turnover are associated with changes at the tissue level, nor how changes with raloxifene compare with estrogen. In this randomized, double blind study, we evaluated the effects of raloxifene (Evista, 60 mg/day) or conjugated equine estrogens (CEE; Premarin, 0.625 mg/day) on bone architecture, bone turnover, and BMD. Iliac crest bone biopsies were obtained at baseline and at the end of the study after double tetracycline labeling and were analyzed for standard histomorphometric indexes. Serum and urinary biochemical markers of bone turnover were measured at baseline and at 4, 10, 18, and 24 weeks of treatment. Total body, lumbar spine, and hip BMD were measured at baseline and at the end of the study by dual energy x-ray absorptiometry. Activation frequency and bone formation rate/bone volume were significantly decreased from baseline in the CEE, but not in the raloxifene, group. Bone mineralization did not change in either group. Most markers of bone resorption and formation decreased in both groups, but to a greater degree in the CEE group (P < .05). Total body and lumbar spine BMD increased from baseline in both groups, with a greater increase in the CEE group (P < 0.05). Hip BMD significantly increased from baseline in the raloxifene group, but the change was not different from that in the CEE group. These results suggest that raloxifene reduces bone turnover and increases bone density, although to a lesser extent than CEE. Thus, raloxifene is an alternative to CEE for the prevention and treatment of osteoporosis in postmenopausal women.

Aged↗
PubMed2000

Raloxifene: a new choice for treating and preventing osteoporosis.

Selective estrogen receptor modulators (SERMs) are a new class of drugs that provide a new option for addressing the health challenges of postmenopausal women. This review discusses the proposed mechanism of action of SERMs and describes clinical findings on raloxifene, a SERM now available for treating and preventing osteoporosis.

Aged↗
PubMed2000

Motor benefit from levodopa in spastic quadriplegic cerebral palsy.

We report on a 16-year-old girl with spastic quadriplegic cerebral palsy associated with premature birth and typical periventricular leukomalacia, who had a dramatic improvement in motor function after treatment with carbidopa/levodopa. Kinematic and electromyographic analyses of reaching movements demonstrate that levodopa decreased muscle co-contraction, decreased unwanted movements, and improved her ability to maintain a steady arm posture. These findings suggest that levodopa be considered as an adjunct therapy for the treatment of spastic quadriplegic cerebral palsy.

Adolescent↗
PubMed2000

Leptin in cerebrospinal fluid from children: correlation with plasma leptin, sexual dimorphism, and lack of protein binding.

BACKGROUND: Previous studies in adults have established that leptin is present at very low concentrations in cerebrospinal fluid (CSF), but few data exist concerning CSF leptin in children. Current evidence suggests that CSF leptin concentrations interact with hypothalamic centers controlling food intake. Serum leptin concentrations manifest a sexual dimorphism that arises during puberty. METHODS: Leptin concentrations were determined in CSF from 42 pre- and postpubertal children who had been objectively classified into non-neurological disease or aseptic meningitis groups. Multivariate analysis of the dependence of CSF leptin on gender, pubertal state, body mass index (BMI), presence of aseptic meningitis, and CSF protein concentration was performed. RESULTS: CSF leptin concentrations correlated with log-transformed plasma leptin concentrations in concomitantly collected samples (r = 0.582; P = 0.029). BMI and gender were significant determinants of CSF leptin in postpubertal children, but only BMI was significant in prepubertal children. Analysis with HPLC to separate protein-bound and free forms of leptin found only free leptin in CSF. CONCLUSIONS: CSF leptin concentrations in children reflect plasma leptin concentrations, including the advent of sexual dimorphism at puberty. Only free leptin is detectable in CSF, suggesting that it is the biologically active form.

Adolescent↗
PubMed2000

Assessment of the child with recurrent respiratory infections.

BACKGROUND: Children with atopy, daycare attendance, crowding or exposure to cigarette smoke are predisposed to recurrent respiratory infection. The young child who 'is always sick' is a common problem, creating concern for their parents and doctors. OBJECTIVE: To outline an approach for determining which children with recurrent respiratory infections are normal, which have an allergic disorder and which have an underlying immune or other problem. DISCUSSION: The majority of children with recurrent respiratory tract infections are normal, however, it is important to consider atopy and underlying immunodeficiency. In those children where there are features suggesting an underlying immunological disorder, specialist assessment is warranted.

Air Pollutants↗
PubMed2000

Prophylactic esmolol infusion for the control of cardiovascular responses to extubation after intracranial surgery.

INTRODUCTION: Emergence from general anaesthesia and extubation are often accompanied by significant surges in heart rate and blood pressure. To document these changes and the efficacy of low-dose beta-blocker infusions in ameliorating these rises, we undertook a descriptive dose-ranging study comparing the use of esmolol to placebo in patients emerging from neuro-anaesthesia. MATERIALS AND METHODS: Thirty-six patients undergoing intracranial surgery were randomised to receive saline, esmolol 100 micrograms/kg/min or 200 micrograms/kg/min infusions. The number of patients developing severe hypertension or tachycardia in each group was compared using Fisher's exact test. RESULTS: Systolic blood pressure (SBP) and heart rate (HR) increased in all 3 groups during emergence and peaked at extubation. The proportion of patients with severe tachycardia or hypertension was reduced from 92% in the placebo group to 40% (P = 0.02) and 8% (P = 0.001) in the low and intermediate dose esmolol groups, respectively. Results were better in the intermediate dose group but the difference was not statistically significant. Two patients from the esmolol infusion groups required supplemental medication for bradycardia. CONCLUSION: Severe hypertension or tachycardia occurs in 92% of patients during extubation following neuro-anaesthesia and warrants the consideration of routine prophylaxis. Prophylactic esmolol infusion for the control of haemodynamic disturbances during extubation is feasible and safe. A modest level of obtundation is evident at 100 micrograms/kg/min but a rate of 200 micrograms/kg/min may prove to be more effective.

Adrenergic beta-Antagonists↗
PubMed2000

Validation studies in epidemiology: the relative precision of different designs.

BACKGROUND: In epidemiological studies, estimation of disease exposure associations will be biased if the exposure is measured with error. In previous papers, we considered the validity of an estimator of the correction factor under a variety of assumptions. In particular, in both univariate and bivariate cases, we considered the error in estimating the correction factor induced by incorrect assumptions on the independent errors of repeated measures, or of different types of measures. METHOD: We concentrate our discussion in this paper on the optimal design of the validation study based on the asymptotic variance of the estimate of the correction factor. Only the univariate situation is considered. We also present an example to illustrate the importance of suitable design. RESULTS: The value of a good biomarker is demonstrated again.

Bias↗
PubMed2000

Guide to safe prescribing.

In this article, we examine the common errors in prescribing medications and analyze the steps clinicians can take to develop and maintain good prescribing habits. Advanced practice nurses are encouraged to develop a personal formulary by using reliable resources and to use this formulary to write error-free prescriptions.

Drug Prescriptions↗
PubMed1999

Neurologic complications of pediatric lung transplantation.

OBJECTIVE: To report neurologic complications in a large population of pediatric lung transplantation patients. METHODS: A retrospective review of the first 135 patients to undergo lung transplantation at St. Louis Children's Hospital from July 1990 to December 1997. RESULTS: Sixty-one (45%) patients had neurologic complications. The most common presenting symptoms were seizures (27%), followed by encephalopathy, headache, depression, and focal neurologic deficits. Cyclosporine toxicity (7%) and hypoxia-ischemia (7%) constituted the most commonly identified etiologies, followed by stroke, metabolic, and infectious causes. Risk factor analysis found that patients with interstitial lung disease had a higher frequency of hypoxic-ischemic events and patients with seizures had significantly elevated trough cyclosporine levels. Patients with stroke and hypoxia had a poor neurologic prognosis, whereas patients with cyclosporine toxicity uniformly had a good outcome. CONCLUSIONS: Neurologic complications occur frequently after lung transplantation in pediatric patients, with seizures being the most common presenting symptom. Except in patients with stroke and hypoxia, prognosis is generally favorable. Seizures not accompanied by an irreversible structural etiology are unlikely to require long-term treatment with antiepileptic medications. Cyclosporine neurotoxicity typically resolves without requiring discontinuation of immunosuppressive therapy.

Adolescent↗
PubMed1999

Essential role for oncogenic Ras in tumour maintenance.

Advanced malignancy in tumours represents the phenotypic endpoint of successive genetic lesions that affect the function and regulation of oncogenes and tumour-suppressor genes. The established tumour is maintained through complex and poorly understood host-tumour interactions that guide processes such as angiogenesis and immune sequestration. The many different genetic alterations that accompany tumour genesis raise questions as to whether experimental cancer-promoting mutations remain relevant during tumour maintenance. Here we show that melanoma genesis and maintenance are strictly dependent upon expression of H-RasV12G in a doxycycline-inducible H-Ras12G mouse melanoma model null for the tumour suppressor INK4a. Withdrawal of doxycycline and H-RasV12G down-regulation resulted in clinical and histological regression of primary and explanted tumours. The initial stages of regression involved marked apoptosis in the tumour cells and host-derived endothelial cells. Although the regulation of vascular endothelial growth factor (VEGF) was found to be Ras-dependent in vitro, the failure of persistent endogenous and enforced VEGF expression to sustain tumour viability indicates that the tumour-maintaining actions of activated Ras extend beyond the regulation of VEGF expression in vivo. Our results provide genetic evidence that H-RasV12G is important in both the genesis and maintenance of solid tumours.

Animals↗
PubMed1999

Stimulation of aggrecan synthesis in cartilage explants by cyclic loading is localized to regions of high interstitial fluid flow.

Chondrogenesis in cartilage development and repair and cartilage degeneration in arthritis can be regulated by mechanical-load-induced physical factors such as tissue deformation, interstitial fluid flow and pressure, and electrical fields or streaming potentials. Previous animal and tissue explant studies have shown that time-varying dynamic tissue loading can increase the synthesis and deposition of matrix molecules in an amplitude-, frequency-, and spatially dependent manner. To provide information on the cell-level physical factors which may stimulate chondrocytes to increase production and export of aggrecan, the main proteoglycan component of the cartilage matrix, we characterized local changes in aggrecan synthesis within cyclically loaded tissue explant disks and compared those changes to values of predicted local physical factors. Aggrecan synthesis following a 23-h compression/radiolabel protocol was measured with a spatial resolution of approximately 0.1 mm across the 1.5-mm radius of explanted disks using a quantitative autoradiography method. A uniform stimulation of aggrecan synthesis was observed at an intermediate frequency of 0.01 Hz, while, at a higher frequency of 0.1 Hz, stimulation was only seen at peripheral radial positions. Profiles of radial solid matrix deformation and interstitial fluid pressure and velocity predicted to be occurring across the radius of the disk during sinusoidal loading were estimated using a composite poroelastic model. Tissue regions experiencing high interstitial fluid velocities corresponded to those displaying increased aggrecan synthesis. These results reinforce the role of load-induced flow of interstitial fluid in the stimulation of aggrecan production during dynamic loading of cartilage.

Aggrecans↗
PubMed1999

Viral oncogenes accelerate conversion to immortality of cultured conditionally immortal human mammary epithelial cells.

Our recent studies on the process of immortalization of cultured human mammary epithelial cells (HMEC) have uncovered a previously undescribed, apparently epigenetic step, termed conversion. When first isolated, clonally derived HMEC lines of indefinite lifespan showed little or no telomerase activity or ability to maintain growth in the presence of TGFbeta. Cell populations whose mean terminal restriction fragment length had declined to <3 kb also exhibited slow heterogeneous growth, and contained many non-proliferative cells. With continued passage, these conditionally immortal cell populations very gradually converted to a fully immortal phenotype of good growth+/-TGFbeta, expression of high levels of telomerase activity, and stabilization of telomere length. We now show that exposure of the early passage conditionally immortal 184A1 HMEC line to the viral oncogenes human papillomavirus type 16 (HPV16)-E6, -E7, or SV40T, results in either immediate (E6) or rapid (E7; SV40T) conversion of these telomerase negative, TGFbeta sensitive conditionally immortal cells to the fully immortal phenotype. Unlike conditional immortal 184A1, the HPV16-E7 and SV40T exposed cells were able to maintain growth in TGFbeta prior to expression of high levels of telomerase activity. A mutated HPV16-E6 oncogene, unable to inactivate p53, was still capable of rapidly converting conditional immortal 184A1. Our studies provide further evidence that the transforming potential of these viral oncogenes may involve activities beyond their inactivation of p53 and pRB functions. These additional activities may greatly accelerate a step in HMEC immortal transformation, conversion, that would be rate-limiting in the absence of viral oncogene exposure.

Antigens, Polyomavirus Transforming↗
PubMed1999

Treatment of postmenopausal women with osteoporosis or low bone density with raloxifene. Raloxifene Study Group.

Raloxifene, a selective estrogen receptor modulator (SERM), has been shown to improved bone mineral density (BMD) and serum lipid profiles in healthy postmenopausal women. The objective of this study was to examine the effects of raloxifene on BMD, biochemical markers of bone metabolism and serum lipids in postmenopausal women with low bone density or osteoporosis. This Phase II, multicenter, 24-month, double-masked study assessed the efficacy and safety of raloxifene in 129 postmenopausal women (mean age +/- SD: 60.2 +/- 6.7 years) with osteoporosis or low bone density (baseline mean lumbar spine BMD T-score: -2.8). Women were randomly assigned to one of three treatment groups: placebo, 60 mg/day raloxifene-HCl (RLX 60) or 150 mg/day raloxifene-HCL (RLX 150) and concomitantly received 1000 mg/day calcium and 300 U/day vitamin D3. At 24 months, BMD was significantly increased in the lumbar spine (+3.2%), femoral neck (+2.1%), trochanter (+2.7%) and total hip (+1.6%) in the RLX 60 group compared with the placebo group (p < 0.05). The RLX 150 group had increases in BMD similar to those observed with RLX 60. A greater percentage of raloxifene-treated patients, compared with those receiving placebo, had increased BMD (p < 0.05). Serum bone-specific alkaline phosphatase activity, serum osteocalcin, and urinary type I collagen:creatinine ratio were significantly decreased in the RLX-treated groups, compared with the placebo group (p < 0.01). RLX 60 treatment significantly decreased serum levels of triglycerides, and total- and LDL-cholesterol levels (p < 0.01). The rates of patient discontinuation and adverse events were not significantly different among groups. In this study, raloxifene increased bone density, decreased bone turnover, and improved the serum lipid profile with minimal adverse events, and may be a safe and effective treatment for postmenopausal women with osteoporosis or low bone density.

Aged↗
PubMed1999

Linkage analysis of candidate myelin genes in familial multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system. A complex genetic etiology is thought to underlie susceptibility to this disease. The present study was designed to analyze whether differences in genes that encode myelin proteins influence susceptibility to MS. We performed linkage analysis of MS to markers in chromosomal regions that include the genes encoding myelin basic protein (MBP), proteolipid protein (PLP), myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMGP), and myelin oligodendrocyte glycoprotein (MOG) in a well-characterized population of 65 multiplex MS families consisting of 399 total individuals, 169 affected with MS and 102 affected sibpairs. Physical mapping data permitted placement of MAG and PLP genes on the Genethon genetic map; all other genes were mapped on the Genethon genetic map by linkage analysis. For each gene, at least one marker within the gene and/or two tightly linked flanking markers were analyzed. Marker data analysis employed a combination of genetic trait model-dependent (parametric) and model-independent linkage methods. Results indicate that MAG, MBP, OMGP, and PLP genes do not have a significant genetic effect on susceptibility to MS in this population. As MOG resides within the MHC, a potential role of the MOG gene could not be excluded.

DNA Primers↗