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Biomedical subjects

S Wong

Publications and source records attributed to S Wong.

At least 55 records · Page 3Linked to original sources
PubMed2001

The outbreak of West Nile virus infection in the New York City area in 1999.

BACKGROUND: In late August 1999, an unusual cluster of cases of meningoencephalitis associated with muscle weakness was reported to the New York City Department of Health. The initial epidemiologic and environmental investigations suggested an arboviral cause. METHODS: Active surveillance was implemented to identify patients hospitalized with viral encephalitis and meningitis. Cerebrospinal fluid, serum, and tissue specimens from patients with suspected cases underwent serologic and viral testing for evidence of arboviral infection. RESULTS: Outbreak surveillance identified 59 patients who were hospitalized with West Nile virus infection in the New York City area during August and September of 1999. The median age of these patients was 71 years (range, 5 to 95). The overall attack rate of clinical West Nile virus infection was at least 6.5 cases per million population, and it increased sharply with age. Most of the patients (63 percent) had clinical signs of encephalitis; seven patients died (12 percent). Muscle weakness was documented in 27 percent of the patients and flaccid paralysis in 10 percent; in all of the latter, nerve conduction studies indicated an axonal polyneuropathy in 14 percent. An age of 75 years or older was an independent risk factor for death (relative risk adjusted for the presence or absence of diabetes mellitus, 8.5; 95 percent confidence interval, 1.2 to 59.1), as was the presence of diabetes mellitus (age-adjusted relative risk, 5.1; 95 percent confidence interval, 1.5 to 17.3). CONCLUSIONS: This outbreak of West Nile meningoencephalitis in the New York City metropolitan area represents the first time this virus has been detected in the Western Hemisphere. Given the subsequent rapid spread of the virus, physicians along the eastern seaboard of the United States should consider West Nile virus infection in the differential diagnosis of encephalitis and viral meningitis during the summer months, especially in older patients and in those with muscle weakness.

Adolescent↗
PubMed2001

Superinduction of TNF-alpha and IL-6 in macrophages by vomitoxin (deoxynivalenol) modulated by mRNA stabilization.

Vomitoxin (VT or deoxynivalenol), a trichothecene, superinduces proinflammatory cytokine gene expression in vitro and in vivo. To better understand the underlying molecular mechanisms for this observation, post-transcriptional effects of VT on TNF-alpha and IL-6 gene expression were studied in lipopolysaccharide (LPS)-stimulated macrophage RAW 264.7 cells. VT was found to enhance both TNF-alpha and IL-6 protein secretion in the presence of LPS. Upon addition of the transcriptional inhibitor, 5,6-dichloro-1-beta-D-ribofuranosyl benzimidazole (DRB), secretion of both cytokines was inhibited. Using Northern analysis, the mRNA stabilities of TNF-alpha and IL-6 were studied in DRB-treated cells exposed to VT and LPS in both asynchronous and delayed synchronous modes. In the asynchronous model, cells were first incubated with LPS for 2 h, and then the medium was removed and replaced with medium containing DRB and VT. In the delayed synchronous model, cells were pretreated with LPS for 2 h and then DRB and VT were added to the culture. TNF-alpha and IL-6 mRNA were rapidly stabilized by VT (100 and 250 ng/ml) in both asynchronous and delayed synchronous models. In the asynchronous model, TNF-alpha mRNA half-life was 25 min but this was extended in the presence of 100 and 250 ng/ml of VT to >3 h. VT also extended half-lives of IL-6 mRNA from 60 min to >3 h. In the delayed synchronous model, the half-lives for TNF-alpha and IL-6 mRNA of 1.3 and 1.5 h, respectively, were extended to >3 h upon incubation with 100 and 250 ng/ml VT. These results suggest that post-transcriptional control via enhancement of mRNA stability is likely to contribute to proinflammatory cytokine superinduction in macrophages by VT and other trichothecenes.

Analysis of Variance↗
PubMed2001

Linking the Rb and polycomb pathways.

Polycomb group (PcG) proteins associate to form complexes that repress Hox genes, thereby imposing the patterning of Hox expression required for development. However, these proteins have a second Hox-independent role in regulating cell proliferation. Our results suggest that association between Rb and PcG proteins forms a repressor complex that blocks entry of cells into mitosis. Also, we provide evidence that Rb colocalizes with nuclear PcG complexes and is important for association of PcG complexes with nuclear targets. The Rb-PcG complex may provide a means to link cell cycle arrest to differentiation events leading to embryonic pattern formation.

Alcohol Oxidoreductases↗
PubMed2001

Transplantation of IL-2-mobilized autologous peripheral blood progenitor cells for adults with acute myelogenous leukemia in first remission.

In order to improve leukemia-free survival we evaluated the feasibility and efficacy of autologous transplantation of interleukin-2 (IL-2)-mobilized peripheral blood progenitor cells for adult patients with acute myelogenous leukemia in first remission. Forty-nine consecutive patients (median age 49, range 21-70) with acute myelogenous leukemia in first remission were enrolled on a study of high-dose cytarabine/mitoxantrone consolidation chemotherapy with post-recovery IL-2 used as a method of in vivo purging for the purpose of autologous peripheral blood progenitor cell transplantation. A median of 2.08 x 10(6) CD34+ peripheral blood progenitor cells/kg were infused 1 day after preparative conditioning with 11.25 Gy total body irradiation and cyclophosphamide (120 mg/kg). Forty-one patients received myeloablative chemoradiotherapy followed by the infusion of IL-2-mobilized autologous peripheral blood progenitor cells. The median times to both neutrophil and platelet recovery were 16 days (range, 2-43) and 23 days (8-318+ days), respectively. Twenty-seven patients remain alive with 24 in continued first complete remission. Median remission duration for all eligible patients is 8 months, and actuarial leukemia-free survival is 49+/-15%. The actuarial risk of relapse is 43+/-16%. Toxicity of autologous peripheral blood progenitor cell transplant included treatment-related death in three patients and serious organ toxicity in 12. Advanced age was a negative prognostic factor for leukemia-free survival. Results were compared to an age-matched historical control treated with autologous transplantation of chemotherapy-mobilized progenitor cells; no significant difference in favor of IL-2 mobilization could be demonstrated. Our results demonstrate that autologous transplantation of IL-2-mobilized peripheral blood progenitor cells is feasible in an unselected population of adult patients with acute myelogenous leukemia in first remission with minimal toxicity but no clear evidence of benefit in leukemia-free survival.

Adult↗
PubMed2001

Morphologic features of the rheumatic mitral regurgitant valve by three-dimensional echocardiography.

BACKGROUND: Rheumatic fever remains a significant worldwide cause of mitral regurgitation (MR). We describe morphologic features of the rheumatic MR valve by quantitative 3-dimensional (3D) echocardiography. METHODS: Eight healthy subjects and 16 patients with less than moderate (n = 7) or more than or equal to moderate (n = 9) rheumatic MR underwent 3D echocardiography by use of freehand transthoracic scanning. Left ventricular (LV) borders, mitral chordae, papillary muscles and annuli were traced at end-diastole (ED) and end-systole (ES) with LV surfaces and mitral annulus reconstructed in 3D. Regional LV function was quantified by myocardial thickening. Regional LV shape was assessed by alignment of diseased ED endocardial surfaces to a reference normal surface. RESULTS: In the diseased group, LVs were more spheric and had regional shape abnormality in the area of anterior papillary muscle attachment. LV volumes, ejection fraction, and regional function in the areas of papillary attachment were not different. Mitral annular length and area were increased and correlated with LVED volume but were no different in height, sphericity, or beat-to-beat deformity. Chordal and papillary muscle lengths were not reduced. The interchordal angle (between the anterior and posterior chordae) was more acute in MR. CONCLUSION: Alterations in LV geometry and mitral apparatus morphologic features contribute to rheumatic regurgitant disease. Consequent changes include malalignment of the papillary muscles and a narrowed interchordal angle that is opposite to the widening seen in MR from dilated cardiomyopathy. We hypothesize that leaflet involvement with retraction causes increased tension on the chordae, a reduction in the interchordal angle, and a consequent coaptation defect.

Adolescent↗
PubMed2001

Stability of dopamine and epinephrine solutions up to 84 hours.

OBJECTIVES: The current practice of preparing fresh dopamine and epinephrine solutions every 24 hrs may lead to hemodynamic instability caused by the interruption of infusions with each change. We determined the stability of these catecholamines over an 84-hr period and whether stability was enhanced by dextrose-containing solutions. SETTING: Tertiary care teaching hospital. DESIGN: The stability of dopamine and epinephrine, each at three commonly used concentrations, was studied in three vehicles (10 gm/dl dextrose in water [D10W], 5 gm/dl dextrose in water [D5W], and 0.9% NaCl in water [NS]). To mimic clinical conditions, solutions were placed on syringe pumps infusing continuously into a closed system at ambient temperature for 84 hrs. MEASUREMENTS: Concentrations of dopamine in mg/ml and epinephrine in microg/ml were measured by high-performance liquid chromatography at 0, 24, 36, 48, 72, and 84 hrs. RESULTS: Dopamine and epinephrine concentrations did not change over the 84-hr period regardless of the vehicles in which the drugs were prepared. CONCLUSIONS: Clinically relevant concentrations of dopamine and epinephrine remain stable in dextrose- and saline-containing solutions for >or=84 hrs. These data suggest that solutions of these catecholamines may safely be used in clinical practice beyond the currently recommended 24 hrs.

Journal Article↗
PubMed2001

Dendritic cell activation and cytokine production induced by group B Neisseria meningitidis: interleukin-12 production depends on lipopolysaccharide expression in intact bacteria.

Interactions between dendritic cells (DCs) and microbial pathogens are fundamental to the generation of innate and adaptive immune responses. Upon stimulation with bacteria or bacterial components such as lipopolysaccharide (LPS), immature DCs undergo a maturation process that involves expression of costimulatory molecules, HLA molecules, and cytokines and chemokines, thus providing critical signals for lymphocyte development and differentiation. In this study, we investigated the response of in vitro-generated human DCs to a serogroup B strain of Neisseria meningitidis compared to an isogenic mutant lpxA strain totally deficient in LPS and purified LPS from the same strain. We show that the parent strain, lpxA mutant, and meningococcal LPS all induce DC maturation as measured by increased surface expression of costimulatory molecules and HLA class I and II molecules. Both the parent and lpxA strains induced production of tumor necrosis factor alpha (TNF-alpha), interleukin-1alpha (IL-1alpha), and IL-6 in DCs, although the parent was the more potent stimulus. In contrast, high-level IL-12 production was only seen with the parent strain. Compared to intact bacteria, purified LPS was a very poor inducer of IL-1alpha, IL-6, and TNF-alpha production and induced no detectable IL-12. Addition of exogenous LPS to the lpxA strain only partially restored cytokine production and did not restore IL-12 production. These data show that non-LPS components of N. meningitidis induce DC maturation, but that LPS in the context of the intact bacterium is required for high-level cytokine production, especially that of IL-12. These findings may be useful in assessing components of N. meningitidis as potential vaccine candidates.

Acyltransferases↗
PubMed2001

Detection and characterization of porcine endogenous retrovirus in porcine plasma and porcine factor VIII.

The pig genome contains porcine endogenous retroviruses (PERVs) capable of infecting human cells. Detection of infectious retrovirus in porcine peripheral blood mononuclear cells and endothelial cells suggested to us that pig plasma is likely to contain PERV. Both PERV env sequences and viral reverse transcriptase (RT) activity were detected in all plasma samples isolated from four NIH minipigs. To detect infectious virus from plasma, we performed a culture assay using three cell lines of feline, swine, and human origin that had previously been shown to be permissive for PERV. Infectious virus was successfully cultured from all four NIH minipig plasmas on the swine cell line ST-IOWA. Using RT-PCR with env-specific primers, we could detect expression of PERV class C envelope in the supernatant of ST-IOWA cells that had been exposed to each pig plasma. We next examined a pig plasma derivative, Hyate:C (porcine factor VIII), and found evidence of PERV particles, since all six lots examined were positive for PERV RNA and RT activity. However, infectious virus could not be detected in clinical lots of Hyate:C, suggesting that the manufacturing process might reduce the load of infectious virus to levels below detectable limits of the assay. Detection of infectious virus in porcine plasma confirms and extends the previous findings that certain porcine cells express PERV when manipulated in vitro and clearly demonstrates that there are porcine cells that express infectious PERV constitutively in vivo.

Animals↗
PubMed2001

Intrahepatic genetic inoculation of hepatitis C virus RNA confers cross-protective immunity.

Naturally occurring hepatitis C virus (HCV) infection has long been thought to induce a weak immunity which is insufficient to protect an individual from subsequent infections and has cast doubt on the ability to develop effective vaccines. A series of intrahepatic genetic inoculations (IHGI) with type 1a HCV RNA were performed in a chimpanzee to determine whether a form of genetic immunization might stimulate protective immunity. We demonstrate that the chimpanzee not only developed protective immunity to the homologous type 1a RNA after rechallenge by IHGI but was also protected from chronic HCV infection after sequential rechallenge with 100 50% chimpanzee infectious doses of a heterologous type 1a (H77) and 1b (HC-J4) whole-virus inoculum. These results offer encouragement to pursue the development of HCV vaccines.

Amino Acid Sequence↗
PubMed2001

Transcriptional regulation of oxytocin receptor by interleukin-1beta and interleukin-6.

The up-regulation of oxytocin (OT) receptors in late pregnancy results principally from increased synthesis of messenger RNA. The 5'-flanking region of the human OT receptor gene contains several putative binding sites for nuclear factor-interleukin-6 (NF-IL6), also known as CAAT/enhancer binding protein-beta. This trans-acting factor modulates the expression of genes involved in acute inflammatory responses. Proinflammatory cytokines, such as IL-1beta or IL-6, have been implicated as mediators in both preterm and term labor, particularly in association with intrauterine infection. We hypothesized that IL-1beta and IL-6 induce OT receptor gene expression in human myometrial cells, and this is mediated by NF-IL6 and cognate response elements in the 5'-flanking region of the OT receptor gene. Contrary to the hypothesis, both IL-1beta and IL-6 treatment resulted in a significant decrease in OT receptor messenger RNA measured by ribonuclease protection analysis. Using electrophoretic mobility shift assay, we have shown that NF-IL6 is present at low levels that appear to be increased after treatment with either IL-1beta or IL-6. Using deletion analysis and functional transfection studies in HeLa cells, we demonstrated that the OT receptor gene promoter displays constitutive basal activity and is negatively regulated by both IL-1beta and IL-6. This suppressive ability of IL-1beta and IL-6 depends on the -1203/-722 region of the OT receptor promoter, which contains binding sites for NF-IL6, acute phase response element, and NF-kappaB. Our findings suggest a role for IL-1beta and IL-6 in the transcriptional regulation of the human OT receptor gene.

5' Untranslated Regions↗
PubMed2001

Glioblastoma multiforme occurring in a patient treated with gamma knife surgery. Case report and review of the literature.

Stereotactic radiosurgery is being increasingly advocated as the primary modality for treatment of vestibular schwannomas (VS). This modality has been shown to arrest tumor growth, with few associated short-term morbidities, and with possibly better hearing and facial nerve preservation rates than microsurgery. Radiation-induced oncogenesis has long been recognized, although stereotactic radiosurgery de novo induction of a secondary tumor has never been clearly described. The authors report on a patient with a VS who did not have neurofibromatosis Type 2 and who underwent gamma knife surgery (GKS). This patient required microsurgical removal of the VS within 8 months because of development of a tumor cyst with associated brainstem compression and progressive hydrocephalus. The operation resulted in clinical stabilization and freedom from tumor recurrence. Seven and a half years after undergoing GKS, the patient presented with symptoms of raised intracranial pressure. Magnetic resonance imaging demonstrated a new ring-enhancing lesion in the inferior temporal lobe adjacent to the area of radiosurgery, which on craniotomy was confirmed to be a glioblastoma multiforme (GBM). Despite additional conventional external-beam radiation to the temporal lobe, the GBM has progressed. Whereas this first reported case of a GBM within the scatter field of GKS does not conclusively prove a direct causal link, it does fulfill all of Cahan's criteria for radiation-induced neoplasia, and demands increased vigilance for the potential long-term complications of stereotactic radiosurgery, and reporting of any similar cases.

Brain Neoplasms↗
PubMed2001

West Nile virus envelope protein: role in diagnosis and immunity.

The role of antibodies to the West Nile virus envelope (E) protein in serodiagnosis and protection was examined. The E protein was expressed and purified in recombinant form. Antibodies to the E protein were detected in patients with West Nile virus infection. Passive immunization with rabbit anti-E protein sera also partially protected mice from challenge with West Nile virus. The humoral response to the West Nile virus E protein is therefore useful as an aid in the diagnosis and may also play a role in immunity to infection.

Animals↗
PubMed2000

Chloride channel activity of ClC-2 is modified by the actin cytoskeleton.

The chloride channel ClC-2 has been implicated in essential physiological functions, including cell-volume regulation and fluid secretion by specific epithelial tissues. Although ClC-2 is known to be activated by hyperpolarization and hypo-osmotic shock, the molecular basis for the regulation of this channel remains unclear. Here we show in the Xenopus oocyte expression system that the chloride-channel activity of ClC-2 is enhanced after treatment with the actin-disrupting agents cytochalasin and latrunkulin. These findings suggest that the actin cytoskeleton normally exerts an inhibitory effect on ClC-2 activity. An inhibitory domain was previously defined in the N-terminus of ClC-2, so we sought to determine whether this domain might interact directly with actin in binding assays in vitro. We found that a glutathione S-transferase fusion protein containing the inhibitory domain was capable of binding actin in overlay and co-sedimentation assays. Further, the binding of actin to this relatively basic peptide (pI 8.4) might be mediated through electrostatic interactions because binding was inhibited at high concentrations of NaCl with a half-maximal decrease in signal at 180 mM NaCl. This work suggests that electrostatic interactions between the N-terminus of ClC-2 and the actin cytoskeleton might have a role in the regulation of this channel.

Actins↗
PubMed2000

Nrg-1 belongs to the endothelial differentiation gene family of G protein-coupled sphingosine-1-phosphate receptors.

The previously cloned rat nerve growth factor-regulated G protein-coupled receptor NRG-1 (Glickman, M., Malek, R. L., Kwitek-Black, A. E., Jacob, H. J., and Lee N. H. (1999) Mol. Cell. Neurosci. 14, 141-52), also known as EDG-8, binds sphingosine-1-phosphate (S1P) with high affinity and specificity. In this paper we examined the signal transduction pathways regulated by the binding of S1P to EDG-8. In Chinese hamster ovary cells heterologously expressing EDG-8, S1P inhibited forskolin-induced cAMP accumulation and activated c-Jun NH2-terminal kinase. Surprisingly, S1P inhibited serum-induced activation of extracellular regulated protein kinase 1 and 2 (ERK1/2). Treatment with pertussis toxin, which ADP-ribosylates and inactivates G(i), blocked S1P-mediated inhibition of cAMP accumulation, but had no effect on c-Jun NH2-terminal kinase activation or inhibition of ERK1/2. The inhibitory effect of S1P on ERK1/2 activity was abolished by treatment with orthovanadate, suggesting the involvement of a tyrosine phosphatase. A subunit selective [35S] guanosine 5'-3-O-(thio)triphosphate binding assay demonstrates that EDG-8 activated G(i/o) and G12 but not Gs and G(q/11) in response to S1P. In agreement, EDG-8 did not stimulate phosphoinositide turnover or cAMP accumulation. The ability of S1P to induce mitogenesis in cells expressing the EDG-1 subfamily of G protein-coupled receptors is well characterized. In contrast, S1P inhibited proliferation in Chinese hamster ovary cells expressing EDG-8 but not empty vector. The antiproliferative effect, like S1P-mediated ERK1/2 inhibition, was orthovanadate-sensitive and pertussis toxin-insensitive. Our results indicate that EDG-8, a member of the EDG-1 subfamily, couples to unique signaling pathways.

Cell Division↗
PubMed2000

BCR/ABL inhibition by an escort/phosphatase fusion protein.

Cellular transformation by the BCR/ABL oncogene depends on the ABL-encoded tyrosine kinase activity. To block BCR/ABL function, we created a unique tyrosine phosphatase by fusing the catalytic domain of SHP1 (SHP1c) to the ABL binding domain (ABD) of RIN1, an established binding partner and substrate for c-ABL and BCR/ABL. This fusion construct (ABD/SHP1c) binds to BCR/ABL in cells and functions as an active phosphatase. ABD/SHP1c effectively suppressed BCR/ABL function as judged by reductions in transformation of fibroblast cells, growth factor independence of hematopoietic cell lines, and proliferation of primary bone marrow cells. In addition, the leukemogenic properties of BCR/ABL in a murine model system were blocked by coexpression of ABD/SHP1c. Both the "escort" function provided by ABD and the inhibitor function provided by the phosphatase of SHP1c were necessary for effective BCR/ABL interference. Expression of ABD/SHP1c also reversed the transformed phenotype of K562, a human leukemia-derived cell line. These results have direct implications for leukemia therapeutics and suggest an approach to block aberrant signal transduction in other pathologies through the use of appropriately designed escort/inhibitors.

Animals↗
PubMed2000

High-sensitivity stark spectroscopy obtained by surface plasmon resonance measurement.

The effect (Stark effect) of an applied electric field on the electronic states of molecular adsorbates was studied by measuring surface plasmon resonance (SPR) as a function of the wavelength of the incident light that excites the SPR. Using the Kramers-Kronig relation, Stark spectra comparable to those obtained with conventional methods were extracted from the electric field-induced SPR angular shift for several organic adsorbates. Because this method relies on detecting the SPR angular shift that can be measured precisely, high-sensitivity Stark spectroscopy can be achieved. In addition, the adsorbate coverage information can be determined from the SPR angular shift upon molecular adsorption.

Electricity↗
PubMed2000

Are hereditary hemochromatosis mutations involved in Alzheimer disease?

Mutations in the class I-like major histocompatibility complex gene called HFE are associated with hereditary hemochromatosis (HHC), a disorder of excessive iron uptake. We screened DNA samples from patients with familial Alzheimer disease (FAD) (n = 26), adults with Down syndrome (DS) (n = 50), and older (n = 41) and younger (n = 52) healthy normal individuals, for two HHC point mutations-C282Y and H63D. Because the apolipoprotein E (ApoE) E4 allele is a risk factor for AD and possibly also for dementia of the AD type in DS, DNA samples were also ApoE genotyped. Chi-squared analyses were interpreted at the 0.05 level of significance without Bonferroni corrections. In the pooled healthy normal individuals, C282Y was negatively associated with ApoE E4, an effect also apparent in individuals with DS but not with FAD. Relative to older normals, ApoE E4 was overrepresented in both males and females with FAD, consistent with ApoE E4 being a risk factor for AD; HFE mutations were overrepresented in males and underrepresented in females with FAD. Strong gender effects on the distribution of HFE mutations were apparent in comparisons among ApoE E4 negative individuals in the FAD and healthy normal groups (P < 0.002). Our findings are consistent with the proposition that among ApoE E4 negative individuals HFE mutations are predisposing to FAD in males but are somewhat protective in females. Further, ApoE E4 effects in our FAD group are strongest in females lacking HFE mutations. Relative to younger normals there was a tendency for ApoE E4 and H63D to be overrepresented in males and underrepresented in females with DS. The possibility that HFE mutations are important new genetic risk factors for AD should be pursued further.

Adult↗