Biomedical subjects

James Wang

Publications and source records attributed to James Wang.

11 recordsLinked to original sources

PubMed2006

Efficacy and duration of effect of extended-release dexmethylphenidate versus placebo in schoolchildren with attention-deficit/hyperactivity disorder.

OBJECTIVE: The aim of this study was to assess changes in symptomatology of attention-deficit/ hyperactivity disorder (ADHD) with extended-release dexmethylphenidate (d-MPHER) versus placebo in a laboratory classroom setting. METHODS: This double-blind, placebo-controlled, crossover study randomized 54 children 6-12 years of age, stabilized on methylphenidate 20-40 mg/day. Patients participated in a practice day, then received 5 days of treatment with d-MPH-ER 20 mg/day or placebo. After a 1-day wash-out, they returned to the classroom and received 1 dose of their assigned treatment. Evaluations occurred predose and at postdose hours 1, 2, 4, 6, 8, 9, 10, 11, and 12. Children were then crossed over to the alternate treatment, using identical protocol. Primary efficacy variable was the Swanson, Kotkin, Agler, M-Flynn, and Pelham rating scale (SKAMP)-Combined scores, and primary analysis time point was 1 hour postdose; secondary efficacy variables over 12 hours included SKAMP-Attention and -Deportment scores and written math test results. Safety was assessed by adverse event (AE) recording following each period. Vital signs were recorded at each visit; laboratory tests were conducted at screening and final visit. RESULTS: D-MPH-ER 20 mg/day showed a significant advantage over placebo as early as 1 hour postdose on SKAMP-Combined scores (p < 0.001). When analyzing the entire sample of 54 children, d-MPH-ER maintained significant superiority over placebo from hours 1 through 12 (p-values ranged from < 0.001 to 0.046). D-MPH-ER was well tolerated, with no severe AEs reported. CONCLUSIONS: D-MPH-ER is safe and effective and improves classroom attention, deportment, and performance in children with ADHD.

Aptitude Tests↗

PubMed2006

Overuse of antihypertensives in patients with acute ischemic stroke.

BACKGROUND: The Stroke Council of the American Heart Association/American Stroke Association (AHA/ASA) recommends conservative management of hypertension (HTN) during acute ischemic stroke (AIS), although clinicians often manage blood pressure more aggressively. Our hypothesis was that aggressive management of HTN in patients with AIS is associated with hypotensive events and worsened neurologic outcomes. METHODS: The study was a retrospective, observational cohort of patients who were admitted to the hospital with AIS. Classification of neurologic outcomes was based on nurses' neurologic assessments and were categorized as "worsened," "stayed the same," or "improved." The accuracy of these assessments was verified by review of physician's progress notes. Management of arterial HTN was recorded in all patients. RESULTS: Fifty medical records of patients with AIS who met inclusion criteria were reviewed. While only 22% of patients met the AHA/ASA criteria for hypertension treatment, 98% of the cohort were given antihypertensive therapy. Relative hypotension occurred in 64% of treated patients. Absolute hypotension associated with antihypertensive medications was uncommon but did occur in 2 of 15 patients who experienced neurologic worsening (13%), in 1 of 28 (3%) of patients who stayed the same, and in none of those who improved. Blood pressure was reduced excessively in all 11 of the patients who met AHA/ASA guidelines for treatment. CONCLUSIONS: Adherence to AHA/ASA guidelines for HTN management during AIS was poor. Initiation or intensification of antihypertensive drugs was not associated with worsened neurologic outcomes. Furthermore, relative hypotension, absolute hypotension and excessive reductions in blood pressure were not associated with worsened neurologic outcomes.

Aged↗

PubMed2005

Tech: a RhoA GEF selectively expressed in hippocampal and cortical neurons.

Recent studies implicating the Rho family of small G proteins in the regulation of neuronal morphology have focused attention on identifying key components of Rho signaling pathways in neurons. To this end, we have conducted studies aimed at defining the localization and function of Tech, a Rho guanine nucleotide exchange factor (GEF) family member that is highly enriched in brain. We have found that Tech is selectively expressed in cortical and hippocampal neurons with prominent Tech immunostaining apparent in the cell bodies and dendrites of these cells. In vitro studies with prototypical members of the major Rho subfamilies, RhoA, Rac1 and Cdc42, indicate that Tech binds selectively to and activates RhoA. To assess whether Tech may be involved in the regulation of neuronal morphology, we examined the effects of Tech constructs on the morphology of cortical neurons grown in primary culture. We found that a constitutively active Tech construct, Tech 245DeltaC, decreases the number of dendritic processes present on these neurons. This reduction appears to be mediated by activation of RhoA as it is blocked by insertion of a point mutation into the DH domain of Tech which blocks its ability to activate RhoA or coexpression of a dominant negative RhoA construct. As Tech protein levels increase during post-natal development and remain at peak levels into adulthood, these results indicate that Tech regulates RhoA signaling pathways in developing and mature forebrain neurons.

Animals↗

PubMed2004

Endotoxin inhibits intestinal epithelial restitution through activation of Rho-GTPase and increased focal adhesions.

Diseases of gut inflammation such as neonatal necrotizing enterocolitis (NEC) result after an injury to the mucosal lining of the intestine, leading to translocation of bacteria and endotoxin (lipopolysaccharide). Intestinal mucosal defects are repaired by the process of intestinal restitution, during which enterocytes migrate from healthy areas to sites of injury. In an animal model of NEC, we determined that intestinal restitution was significantly impaired compared with control animals. We therefore sought to determine the mechanisms governing enterocyte migration under basal conditions and after an endotoxin challenge. Here we show that the cytoskeletal reorganization and stress fiber formation required for migration in IEC-6 enterocytes requires RhoA. Enterocytes were found to express the endotoxin receptor Toll-like receptor 4, which served to bind and internalize lipopolysaccharide. Strikingly, endotoxin treatment significantly inhibited intestinal restitution, as measured by impaired IEC-6 cell migration across a scraped wound. Lipopolysaccharide was found to increase RhoA activity in a phosphatidylinositol 3-kinase-dependent manner, leading to an increase in phosphorylation of focal adhesion kinase and an enhanced number of focal adhesions. Importantly, endotoxin caused a progressive, RhoA-dependent increase in cell matrix tension/contractility, which correlated with the observed impairment in enterocyte migration. We therefore conclude that endotoxin inhibits enterocyte migration through a RhoA-dependent increase in focal adhesions and enhanced cell adhesiveness, which may participate in the impaired restitution observed in experimental NEC.

Animals↗

PubMed2004

(2-amino-phenyl)-amides of omega-substituted alkanoic acids as new histone deacetylase inhibitors.

A variety of omega-substituted alkanoic acid (2-amino-phenyl)-amides were designed and synthesized. These compounds were shown to inhibit recombinant human histone deacetylases (HDACs) with IC(50) values in the low micromolar range and induce hyperacetylation of histones in whole cells. They induced expression of p21WAF1/Cip1 and caused cell-cycle arrest in human cancer cells. Compounds in this class showed efficacy in human tumor xenograft models.

Amides↗

PubMed2004

Thrombotic microangiopathy (TMA) and stroke due to human herpesvirus-6 (HHV-6) reactivation in an adult receiving high-dose melphalan with autologous peripheral stem cell transplantation.

We report an adult autologous stem cell transplant (ASCT) patient who developed transplant-associated thrombotic microangiopathy (TMA) due to human herpesvirus-6 (HHV-6) reactivation. A 58-year-old female with Stage IIIA IgGkappa multiple myeloma received a melphalan (200 mg/m2) ASCT with discharge home after resolution of ASCT-related toxicities. She presented on D+20 with dyspnea, rash, and fever to 105 degrees F, followed by worsening dyspnea, hypotension, and capillary leak. Mental status (MS) changes were noted on D+23, but head CT and EEG were unremarkable. On D+29, a generalized seizure occurred with decline in platelet count and haptoglobin. TMA was noted on peripheral blood smear and therapeutic plasma exchange (TPE) was initiated on D+31. Lumbar puncture (LP) revealed CSF protein 74 mg/dL and white blood count 7,000/mm3 with 74% lymphocytosis. TPE was continued without improvement in her MS or thrombocytopenia despite improvement in microangiopathy. An MRI of the brain showed a left hippocampus abnormality, and an EEG was consistent with encephalopathy. Serum polymerase chain regimen (PCR) was negative for CMV, HSV1, and HSV2 but was strongly positive for HHV-6. Repeat LP protein was 597 mg/dL. Foscarnet was initiated, and cerebrospinal fluid (CSF) PCR for HHV-6 revealed 1,400 DNA copies/mL. Her MS greatly improved within 48 hr of antiviral therapy, serum HHV-6 became negative, and TPE was tapered without recurrence of her TMA. TMA with HHV-6 reactivation is likely an underdiagnosed entity. Given its fulminant course and favorable response to therapy, HHV-6 reactivation should be considered a potential etiology in patients with TMA after ASCT.

Antineoplastic Agents, Alkylating↗

PubMed2004

Detection of BRAF mutation on fine needle aspiration biopsy specimens: a new diagnostic tool for papillary thyroid cancer.

Numerous biomolecular markers have been studied to improve the accuracy of fine needle aspiration biopsy (FNAB) in the diagnostic and prognostic evaluation of thyroid tumors, but none of them has yet become clinically useful. The recently discovered BRAF mutation, which occurs specifically in papillary thyroid cancers (PTC) with a high prevalence and is associated with poor clinicopathological outcomes, has the potential to be a useful diagnostic and prognostic marker for PTC. In the present study, we investigated whether detection of BRAF mutation on FNAB specimens was technically possible and could be used as an adjunct diagnostic tool with routine FNAB. Evaluation of a new colorimetric mutation detection method demonstrated 100% sensitivity and 100% specificity in comparison with conventional DNA sequencing as the "gold standard" in a large pool of DNA samples from various primary thyroid tumor specimens and cell lines. We found this novel technique even more sensitive in detecting BRAF mutation on FNAB specimens than conventional sequencing. In a series of 48 patients undergoing thyroidectomy, mostly for thyroid cancer or for suspicion of cancer, we performed preoperative FNAB and, using the colorimetric mutation detection method, identified BRAF mutation on the cytological specimens. Prospective analysis showed that 50% of the nodules that proved to be PTC on surgical histopathology were correctly diagnosed by BRAF mutation analysis on FNAB specimens; there were no false positive findings. Thus, we have demonstrated the usefulness of BRAF mutation detection on FNAB specimens that can help diagnose and identify those PTC patients who may need more aggressive surgical treatment and vigilant clinical monitoring.

Biomarkers, Tumor↗

PubMed2003

Identification of endothelial cell genes by combined database mining and microarray analysis.

Vascular endothelial cells maintain the interface between the systemic circulation and soft tissues and mediate critical processes such as inflammation in a vascular bed-selective fashion. To expand our understanding of the genetic pathways that underlie these specific functions, we have focused on the identification of novel genes that are differentially expressed in all endothelial cells, as well as restricted groups of this cell type. Virtual subtraction was conducted employing gene expression data deposited in public databases and 384 genes identified. These genes were spotted on custom microarrays, along with 288 genes identified through subtraction cloning from TGF-beta-stimulated endothelial cells. Arrays were evaluated with RNA samples representing endothelial cells cultured from four vascular sources and five non-endothelial cell types. These studies identified 64 pan-endothelial markers that were differentially expressed with at least a threefold difference (range 3- to 55-fold). In addition, differences in gene expression profiles among endothelial cells from different vascular beds were identified. Validation of these findings was performed by RNA blot expression studies, and a number of the novel genes were shown to be expressed under angiogenic conditions in the developing mouse embryo. The combined tools of database mining and transcriptional profiling thus provide expanded knowledge of endothelial cell gene expression and endothelial cell biology.

Adult↗

PubMed2003

MRI features of intramedullary spinal cord ependymomas.

BACKGROUND AND PURPOSE: To assess the magnetic resonance (MR) imaging characteristics of spinal intramedullary ependymomas. METHODS: MR images were obtained from 60 patients with spinal intramedullary ependymomas. All patients were treated surgically, and pathological diagnoses were confirmed. MR images of ependymomas and associated cysts were correlated with surgical findings. RESULTS: Among 60 cases of intramedullary ependymomas, 39 were cervical and 11 thoracic, and 10 were located at the conus medullaris and filum terminale. The lesions measured 1 to 10 vertebral segments in length along the neuraxis, with a mean length of 3.7 segments. All tumors had slightly hyperintense signals on T2-weighted MR images. Clear tumor margins were seen in 77% of patients; 75% had uniform contrast enhancement. Rostral and caudal cysts were seen in 90% of all patients; all cysts were hypointense on T1-weighted images and hyperintense on T2-weighted images. The rostral cysts were 1 to 5 segments in length and caudal cysts 2 to 10 segments in length. CONCLUSION: Ependymomas occur most often at the upper cord rather than in the conus medullaris and filum terminale. Of the cervical and thoracic ependymomas, most were cellular or epithelial types. Papillary ependymomas occurred exclusively in the conus medullaris and filum terminale. Rostral and caudal cysts are frequently associated with intramedullary ependymomas. Clear tumor margins, more uniform enhancement, and central locations can help differentiate ependymomas from other intramedullary spinal cord tumors.

Adult↗

PubMed2002

Synthesis of 5,6-dihydro-11H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidine-N-cyanoguanidine derivatives as inhibitors of ras farnesyl protein transferase.

A series of novel N-cyanoguanidine tricyclic farnesyl protein transferase (FPT) inhibitors was prepared. Replacement of a piperidine amide-group with a N-cyanoguanidine functionality increased FPT activity. X-ray crystal structure determination of 42 complexed with FPT revealed differences in the interactions of the amide and N-cyanoguanidine groups with the protein.

Alkyl and Aryl Transferases↗

PubMed2002

A novel doxycycline-inducible system for the transgenic analysis of mammary gland biology.

Normal developmental events such as puberty, pregnancy, and parity influence the susceptibility of the mammary gland to tumorigenesis in both humans and rodent model systems. Unfortunately, constitutive transgenic mouse models that rely on mammary-specific promoters to control transgene expression have limited utility for studying the effect of developmental events on breast cancer risk since the hormonal signals governing these events also markedly influence transgene expression levels. A novel transgenic mouse system is described that uses the MMTV-LTR to drive expression of the reverse tetracycline-dependent transactivator rtTA. Transgenic mice expressing rtTA in the mammary epithelium were crossed with reporter lines bearing tet operator-controlled transgenes. We tested the ability to spatially, temporally, and quantitatively control reporter gene expression after administration of doxycycline to bitransgenic mice. Transgene expression using this system can be rapidly induced and deinduced, is highly mammary specific, can be reproducibly titrated over a wide range of expression levels, and is essentially undetectable in the uninduced state. Homogeneous transgene expression throughout the mammary epithelium can be achieved. This system permits transgene expression to be restricted to any desired stage of postnatal mammary gland development. We have developed a mammary-specific, doxycycline-inducible transgenic mouse model for studying the effect of mammary gland development on transgene-mediated phenotypes. Unlike other mammary-specific, transgenic systems that have been described, this system combines spatially homogeneous transgene expression in the mammary epithelium during puberty, pregnancy, lactation, and involution with the use of an orally administered, inexpensive, and widely available inducing agent. This system offers new opportunities for the transgenic analysis of mammary gland biology in vivo.

Animals↗