Biomedical subjects
Publications and source records attributed to D Solomon.
The design, synthesis, and preliminary evaluation of the first example of synthetic pentasaccharide (1) that shows marked rate enhancement and specificity for the hydrolysis of GTP to GDP and orthophosphate (OP) are reported. At the concentration ratios of GTP/1 = 3.6 and GTP/Mg(2+) = 1 (pH 7.1, 50 degrees C), a rate enhancement of about 500-fold was obtained.[reaction: see text]
A beta-xylosidase from Bacillus stearothermophilus T-6 assigned to the uncharacterized glycosyl hydrolase family 52 was cloned, overexpressed in Escherichia coli and purified. The enzyme showed maximum activity at 65 degrees C and pH 5.6-6.3. The stereochemistry of the hydrolysis of p-nitrophenyl beta-D-xylopyranoside was followed by 1H-nuclear magnetic resonance. Time dependent spectrum analysis showed that the configuration of the anomeric carbon was retained, indicating that a retaining mechanism prevails in family 52 glycosyl hydrolases. Sequence alignment and site-directed mutagenesis enabled the identification of functionally important amino acid residues of which Glu337 and Glu413 are likely to be the two key catalytic residues involved in enzyme catalysis.
BACKGROUND: More than 2 million U.S. women receive an equivocal cervical cytologic diagnosis (atypical squamous cells of undetermined significance [ASCUS]) each year. Effective colposcopy triage strategies are needed to identify the minority of women who have clinically significant disease while avoiding excessive follow-up evaluation for others. METHODS: The ASCUS/LSIL (i.e., low-grade squamous intraepithelial lesion) Triage Study (ALTS) is a multicenter, randomized trial comparing the sensitivity and specificity of the following three management strategies to detect cervical intraepithelial neoplasia grade 3 (CIN3): 1) immediate colposcopy (considered to be the reference standard), 2) triage to colposcopy based on human papillomavirus (HPV) results from Hybrid Capture 2(TM) (HC 2) and thin-layer cytology results, or 3) triage based on cytology results alone. This article summarizes the cross-sectional enrollment results for 3488 women with a referral diagnosis of ASCUS. All statistical tests are two-sided. RESULTS: Among participants with ASCUS, the underlying prevalence of histologically confirmed CIN3 was 5.1%. Sensitivity to detect CIN3 or above by testing for cancer-associated HPV DNA was 96.3% (95% confidence interval [CI] = 91.6% to 98.8%), with 56.1% of women referred to colposcopy. Sensitivity of a single repeat cytology specimen with a triage threshold of HSIL or above was 44.1% (95% CI = 35.6% to 52.9%), with 6.9% referred. Sensitivity of a lower cytology triage threshold of ASCUS or above was 85.3% (95% CI = 78.2% to 90.8%), with 58.6% referred. CONCLUSIONS: HC 2 testing for cancer-associated HPV DNA is a viable option in the management of women with ASCUS. It has greater sensitivity to detect CIN3 or above and specificity comparable to a single additional cytologic test indicating ASCUS or above.
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OBJECTIVE: A number of studies have suggested that lithium may be particularly effective in reducing suicide risks among patients with major affective disorders. The design of many of these studies left them open to biases associated with treatment compliance, however. METHOD: Subjects were drawn from a naturalistic, long-term follow-up of patients with major affective disorders. Fifteen who committed suicide while receiving somatotherapy where matched to non-suicidal patients who were similarly receiving somatotherapy at the same point in follow-up. The same procedure was followed for 41 patients who made a serious suicide attempt during follow-up. RESULTS: Six (40.0%) of the patients who committed suicide, and eight (53.3%) of their controls, were thought to have been taking lithium in the preceding week. Among attempters and their controls, nine (22.0%) and eight (19.5%), respectively, were taking lithium. CONCLUSION: These results do not support previous suggestions that lithium has uniquely antisuicidal properties. Other existing datasets should be explored with this design to establish whether lithium does, or does not, offer special protection against suicide.
The molecular signals required for initiating myelination and maintenance of the myelin internode are not known. Several growth factor families have been implicated in promoting oligodendrocyte survival or differentiation and may have consequences on formation of myelin. We developed a reliable assay for detecting ensheathment of neurites by oligodendrocytes in spinal cord explants. This system was used to assay the effect of selected growth factors on myelin internode formation. We examined the influence on myelination of the polypeptide growth factors neuregulin (NRG), platelet-derived growth factor (PDGF), leukemia inhibitory factor (LIF), and the thyroid hormone T(3). We found that NRG, PDGF, and T(3) treatments enhanced myelination while LIF treatment inhibited it. We furthermore found that the most potent combination of factors to enhance myelination was NRG and T(3). Our results demonstrate that the role of growth factors on CNS myelination can be reliably studied in a controlled in vitro environment and that the impact of individual or combinations of growth factors on myelination cannot be predicted by their known effects on oligodendrocyte survival, proliferation, or differentiation.
Cytologic detection of high-grade squamous intraepithelial lesions (HSILs) is critical to cervical cancer prevention. Therefore, identifying "equivocal HSIL" (ASCUS [atypical squamous cells of undetermined significance]-H) may be useful. Accordingly, we compared findings associated with "equivocal low-grade SIL" (ASCUS-L), ASCUS-H, and HSIL using data from the ASCUS LSIL (low-grade squamous intraepithelial lesion) Triage Study. The frequency of oncogenic human papillomavirus (HPV) DNA detection and underlying lesions cervical intraepithelial neoplasia (CIN) 2 or worse or CIN 3 or worse in women with ASCUS-H was intermediate between that of ASCUS-L and HSIL. Oncogenic HPV DNA was associated with 85.6% of ASCUS-H ThinPreps and 69.8% of ASCUS-H smears. Histopathologic lesions CIN 2 or worse were associated with 40.5% of ASCUS-H ThinPreps and 27.2% of ASCUS-H smears (mostly CIN 3). Nevertheless, numerically more lesions CIN 2 or worse were preceded by ASCUS-L than by ASCUS-H because ASCUS-L was more common. ASCUS-H is an uncommon interpretation that derives clinical usefulness from its high positive predictive value for lesions CIN 2 or worse.
The GALEN technology has matured over more than a decade of use. We describe a set of software tools and associated methodologies that together are supporting ontological engineering in a production, rather than a research setting.
Glioblastomas are highly vascular malignant brain tumors that often overexpress vascular endothelial growth factor (VEGF). They also frequently overexpress epidermal growth factor receptor (EGFR) and contain regions of hypoxia, both conditions that can induce VEGF. We examined VEGF regulation in U87 MG human glioblastoma cells and in U87/T691 cells, a clonal derivative that contains a truncated erbB2/Neu receptor that interferes with EGFR signaling through the formation of nonfunctional heterodimeric receptor complexes. U87/T691 cells contained approximately one-half as much VEGF mRNA as did U87 MG cells under normoxic conditions (21% oxygen). Pharmacological inhibition of EGFR, Ras, or PI(3) kinase, but not MAP kinase, led to a significant decrease in VEGF mRNA levels in U87 MG cells. VEGF promoter activity in transient transfections was decreased by either pharmacological or genetic inhibition of EGFR, Ras, or phosphatidylinositol 3'-kinase [PI(3) kinase]. However, inhibition of PI(3) kinase or EGFR did not completely abolish induction of VEGF mRNA by hypoxia (0.2% oxygen). Likewise, VEGF mRNA expression was induced 3-fold by hypoxia in EGFR-inhibited U87/T691 cells, comparable with the fold induction seen in parental U87 MG cells, although the absolute level of message under hypoxia was higher in U87 MG cells. In transient transfections, a luciferase reporter construct containing a 1.2-kb fragment of the VEGF promoter, lacking the known hypoxic-responsive element (HRE), showed up-regulation after EGF stimulation to the same degree as the full-length, 1.5-kb VEGF promoter construct retaining the HRE. Furthermore, activity of the HRE-deleted, 1.2-kb promoter luciferase reporter was down-regulated by PI(3) kinase inhibition. Therefore, in glioblastoma cells, transcriptional regulation of the VEGF promoter by EGFR appears to involve Ras/PI(3) kinase and to be distinct from signals induced by hypoxia.
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BACKGROUND: Studies of family history and lithium response in patients with bipolar affective disorder have produced mixed results, but the majority have shown relationships between the presence of affective disorder among relatives and positive responses to lithium in probands. The analysis presented here sought to confirm and to further characterize such relationships. METHODS: Subjects described here participated in a long-term, prospective follow-up; had a history of Research Diagnostic Criteria manic disorder or schizoaffective disorder, manic type; and took lithium for periods of 26 weeks or longer. The majority participated in a family study in which first-degree relatives were directly interviewed. Morbidity during lithium and during anticonvulsant trials was quantified in alternative ways, as were the risks among first-degree relatives for bipolar I and nonbipolar affective disorders. RESULTS: Familial loading for bipolar affective disorder was not associated with better outcomes during lithium treatment. Rather, the presence of major depressive disorder (MDD) among relatives was associated with slower improvement during acute treatment and with higher symptom levels during continuing treatment. Findings for morbidity during anticonvulsant treatment were similar. The patients who experienced symptom persistence with lithium did so as well during periods of anticonvulsant treatment and during periods without thymoleptics. CONCLUSIONS: A family history of MDD may have an enduring and negative prognostic significance that manifests across treatment conditions. Though difficult to reconcile with several earlier studies, these findings invite replication and further exploration.
Both hypoxia and overexpression of the urokinase plasminogen activator receptor (uPAR) are associated with a poor clinical outcome in human cancers. Hypoxia has been shown to induce uPAR expression in breast cancer cells and to increase their invasion through Matrigel, a phenomenon which can be blocked using an anti-uPAR antibody. We examined expression of uPAR mRNA in MCF7 human breast carcinoma cells under hypoxia and found that an increase in the level of the message could be detected at 1% oxygen but was most marked at 0.2 or 0.05% oxygen with an induction of 9- to 20-fold over baseline. To determine whether changes in RNA stability contributed to this dramatic increase, we used actinomycin D to inhibit transcription and found that the half-life of the message was much longer under hypoxic conditions (approximately 10 h) than during reoxygenation (approximately 2 h). Transient transfections using a luciferase reporter construct containing 2 kbp of the mouse uPAR promoter showed that promoter activity increased up to 5-fold after exposure to 0.2% oxygen. Thus, hypoxic induction of the uPAR message in MCF7 cells is due to both mRNA stabilization and increased transcriptional activation.
Benign paroxysmal positional vertigo can be diagnosed with great certainty, and treated effectively at the bedside using one of the canalith repositioning procedures described in this paper. This treatment has been shown effective in properly controlled trials, has a rational basis, and has minimal risk.
This article presents the anatomy and physiology of the balance system focusing on the daily use of the system in normal individuals to accomplish the major goals of the system. These goals include perceptions of movement and orientation, control of eye movements for clear visualization of the world, and control of upright stance during static and dynamic tasks. When discussing various pathologies and the assessment and treatment options available, the information provided sets the foundation on which the remainder of the articles are built.
A patient's dizziness can be caused by a peripheral vestibular disorder, VIIIth nerve compression, brain stem ischemia, or cerebellar stroke. Clues from the history and physical examination are mentioned, and diagnostic entities, such as demyelination, cerebrovascular disease, migraine, Arnold-Chiari malformation, cerebellar degeneration, and neoplastic disease are discussed. Treatment options are outlined so that therapeutic and diagnostic trials can be initiated. Guidelines are offered for when to image the brain or posterior circulation vasculature and when a patient with acute vertigo should be admitted for observation.
Bipolar disorder has been conceptualized as an outcome of dysregulation in the behavioral activation system (BAS), a brain system that regulates goal-directed activity. On the basis of the BAS model, the authors hypothesized that life events involving goal attainment would promote manic symptoms in bipolar individuals. The authors followed 43 bipolar I individuals monthly with standardized symptom severity assessments (the Modified Hamilton Rating Scale for Depression and the Bech-Rafaelsen Mania Rating Scale). Life events were assessed using the Goal Attainment and Positivity scales of the Life Events and Difficulties Schedule. As hypothesized, manic symptoms increased in the 2 months following goal-attainment events, but depressed symptoms were not changed following goal-attainment events. These results are congruent with a series of recent polarity-specific findings.
One of the signs of the cerebellar ocular motor syndrome is the inability to maintain horizontal and vertical fixation. Typically, in the presence of cerebellar atrophy, the eyes show horizontal gaze-evoked and vertical downbeat nystagmus. We investigated whether or not the cerebellar ocular motor syndrome also includes a torsional drift and, specifically, if it is independent from the drift in the horizontal-vertical plane. The existence of such a torsional drift would suggest that the cerebellum is critically involved in maintaining the eyes in Listing's plane. Eighteen patients with cerebellar atrophy (diagnosis confirmed by magnetic resonance imaging) were tested and compared with a group of normal subjects. Three-dimensional eye movements (horizontal, vertical, and torsional) during attempted fixations of targets at different horizontal and vertical eccentricities were recorded by dual search coils in a three-field magnetic frame. The overall ocular drift was composed of an upward drift that increased during lateral gaze, a horizontal centripetal drift that appeared during lateral gaze, and a torsional drift that depended on horizontal eye position. The vertical drift consisted of two subcomponents: a vertical gaze-evoked drift and a constant vertical velocity bias. The increase of upward drift velocity with eccentric horizontal gaze was caused by an increase of the vertical velocity bias; this component did not comply with Listing's law. The horizontal-eye-position-dependent torsional drift was intorsional in abduction and extorsional in adduction, which led to an additional violation of Listing's law. The existence of torsional drift that is eye-position-dependent suggests that the cerebellum is critically involved in the implementation of Listing's law, perhaps by mapping a tonic torsional signal that depends on the direction of the line of sight. The magnitude of this signal might reflect the difference in torsional eye position between the torsional resting position determined by the mechanics of the eye plant and the torsional position required by Listing's law.