Circle of Willis: evaluation by computed tomography angiography with different concentration of contrast media.
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Brain↗
Biomedical subjects
R Kay
Publications and source records attributed to R Kay.
Lfc and Lsc oncoproteins represent two new guanine nucleotide exchange factors for the Rho GTP-binding protein.
Lfc and Lsc are two recently identified oncoproteins that contain a Dbl homology domain in tandem with a pleckstrin homology domain and thus share sequence similarity with a number of other growth regulatory proteins including Dbl, Tiam-1, and Lbc. We show here that Lfc and Lsc, like their closest relative Lbc, are highly specific guanine nucleotide exchange factors (GEFs) for Rho, causing a >10-fold stimulation of [3H]GDP dissociation from Rho and a marked stimulation of GDP-[35S]GTPgammas (guanosine 5'-O-(3-thiotriphosphate) exchange. All three proteins (Lbc, Lfc, and Lsc) are able to act catalytically in stimulating the guanine nucleotide exchange activity, such that a single molecule of each of these oncoproteins can activate a number of molecules of Rho. Neither Lfc nor Lsc shows any ability to stimulate GDP dissociation from other related GTP-binding proteins such as Rac, Cdc42, or Ras. Thus Lbc, Lfc, and Lsc appear to represent a subgroup of Dbl-related proteins that function as highly specific GEFs toward Rho and can be distinguished from Dbl, Ost, and Dbs which are less specific and show GEF activity toward both Rho and Cdc42. Consistent with these results, Lbc, Lfc, and Lsc each form tight complexes with the guanine nucleotide-depleted form of Rho and bind weakly to the GDP- and GTPgammaS-bound states. None of these oncoproteins are able to form complexes with Cdc42 or Ras. However, Lfc (but not Lbc nor Lsc) can bind to Rac, and this binding occurs equally well when Rac is nucleotide-depleted or is in the GDP- or GTPgammaS-bound state. These findings raise the possibility that in addition to acting directly as a GEF for Rho, Lfc may play other roles that influence the signaling activities of Rac and/or coordinate the activities of the Rac and Rho proteins.
3T3 Cells↗
Cross-linking the murine heat-stable antigen induces apoptosis in B cell precursors and suppresses the anti-CD40-induced proliferation of mature resting B lymphocytes.
The murine heat-stable antigen (HSA) is a glycosyl-phosphatidylinositol-linked cell surface protein which has been implicated in cellular adhesion processes, the co-stimulation of CD4+ T cells, and B cell memory. We have recently demonstrated a significant reduction in pro-B and pre-B lymphocytes in transgenic mice that overexpress HSA. We now report that cross-linking HSA with the M1/69 monoclonal antibody induces the apoptosis of cultured B cell precursors in a stomal cell and cytokine-independent manner and that sensitivity to HSA-mediated cell death increases with developmental maturity. The cross-linking of HSA does not induce apoptosis in mature splenic B cells, but instead inhibits their ability to proliferate in response to anti-CD40 + IL-4. Taken together, these data implicate HSA as a potent negative regulator of B cell development and activation.
Animals↗
Expression cloning of lsc, a novel oncogene with structural similarities to the Dbl family of guanine nucleotide exchange factors.
In a screen for genes with oncogenic potential expressed by the murine B6SUtA1 myeloid progenitor cell line, we isolated a 2. 5-kilobase pair cDNA whose expression causes strong morphological transformation and deregulated proliferation of NIH 3T3 cells. The transforming cDNA encodes a truncated protein (designated Lsc) with a region of sequence similarity to the product of the lbc oncogene. This region includes the tandem Dbl homology and pleckstrin homology domains that are hallmarks of the Dbl-like proteins, a family of presumptive or demonstrated guanine nucleotide exchange factors that act on Rho family GTPases. Lsc requires intact Dbl homology and pleckstrin homology domains for its oncogenic activity. The transforming activity of Lsc in NIH 3T3 cells is reduced by cotransfection with p190 (a GTPase activating protein for Rho family GTPases) and the Rho family dominant-negative mutants RhoA(19N), CDC42(17N), and Rac1(17N). These results indicate a role for the Rho family of GTPases in mediating the transforming activity of Lsc and are consistent with the exchange specificities that have been attributed to Dbl family members. The lsc gene is expressed in a variety of tissues and is particularly abundant in hemopoietic tissues (thymus, spleen, and bone marrow). Lsc is a member of a growing family of proteins that may function as activators of Rho family GTPases in a developmental or tissue-specific manner.
3T3 Cells↗
Reduction of early B lymphocyte precursors in transgenic mice overexpressing the murine heat-stable antigen.
To study the role of the murine heat-stable Ag (HSA) in lymphocyte maturation, we generated transgenic mice in which the HSA cDNA was under the transcriptional control of the TCR V beta promoter and Ig mu enhancer. The HSA transgene was expressed during all stages of B lymphocyte maturation. Expression was first detected in the earliest lymphoid-committed progenitors, which normally do not express HSA, and subsequently reached the highest levels in pro- and pre-B cells. In bone marrow, the number of IL-7-responsive clonogenic progenitors was < 4% of normal, whereas the frequency of earlier B lymphocyte-restricted precursors, detectable as Whitlock-Witte culture-initiating cells, was normal. Pro- and pre-B cells detected by flow cytometry were reduced by approximately 50% relative to controls. Mature splenic B cells were also reduced but to a lesser extent than in marrow, and their response to LPS stimulation was impaired. Reconstitution of SCID and BALB/c-nu/nu mice with HSA transgenic marrow indicated that the perturbations in B lymphopoiesis were not caused by a defective marrow microenvironment or by abnormal T cells. Our previous studies showed elevated HSA expression throughout thymocyte development, which resulted in a profound depletion of CD4+CD8+ double-positive and single-positive thymocytes. Together, these results indicate that HSA levels can determine the capacity of early T and B lymphoid progenitors to proliferate and survive. Therefore, HSA could serve as an important regulator during the early stages of B and T lymphopoiesis.
Animals↗
Treating bulimia nervosa in primary care: a pilot study.
OBJECTIVE: To develop and evaluate a simplified and condensed cognitive behavioral treatment for bulimia nervosa suitable for use in primary care. METHOD: Once developed, the treatment was tested on a consecutive series of 11 patients. RESULTS: Six patients did well, 3 were nonresponders, and in the other 2 external events interfered with progress. DISCUSSION: This form of treatment may benefit a significant proportion of those patients with bulimia nervosa who are seen in primary care. It can be administered by nonspecialist therapists.
Adolescent↗
Selective liver enzyme induction by carbamazepine and phenytoin in Chinese epileptics.
OBJECTIVE: Anticonvulsant drugs are known inducers of cytochrome P450 liver enzymes and it has been suggested that this induction increases susceptibility to paracetamol-induced hepatotoxicity. METHODS: We measured the percentage urinary recovery of paracetamol and its metabolites after a dose of 20 mg kg-1, and the excretion of 6 beta-hydroxycortisol as a ratio to urinary free cortisol (6 beta OHF/F) in Chinese epileptic patients maintained on long-term therapy with carbamazepine (n = 6) or phenytoin (n = 6). RESULTS: Compared to the healthy controls (n = 20), patients on phenytoin had significantly lower recoveries of mercapturic acid, cysteine and sulphate metabolites, but a higher recovery of glucuronide metabolites of paracetamol. The recoveries of paracetamol metabolites in patients on carbamazepine were not different from controls. In contrast, the 6 beta OHF/F was significantly higher in patients on carbamazepine (3-fold) or phenytoin (2-fold) compared to controls. Healthy control Chinese subjects metabolised paracetamol in a similar way to that reported in Caucasians, indicating that the risk for hepatotoxicity would be the same. Our findings in a group of Chinese patients on phenytoin were also similar to those previously reported in Caucasians on this drug. The apparent differences in the pattern of isoenzyme induction between the groups on phenytoin and carbamazepine require verification in larger studies. The data do not suggest an increased risk of paracetamol-induced hepatotoxicity in Chinese patients on anticonvulsants.
Acetaminophen↗
The spectrum of ureteropelvic junction obstructions occurring in duplicated collecting systems.
The authors reviewed four cases of ureteropelvic junction obstruction (UPJ) in duplicated systems. Associated abnormalities included contralateral duplication, vesicoureteral reflux, and a case of ipsilateral upper pole ectopic ureter with a dysplastic upper pole moiety. Surgical management included dismembered pyeloplasty, ureteral reimplantation, end-to-side pyeloureterostomy to the upper-pole ureter, and upper-pole heminephrectomy with lower-pole dismembered pyeloplasty. UPJ obstructions occurring in duplicated systems often are associated with other anomalies.
Child, Preschool↗
Putaminal and thalamic hemorrhage in ethnic chinese living in Hong Kong.
BACKGROUND: Hemorrhagic stroke is very common in the Chinese population, and it is one of the leading causes of mortality in Chinese communities. The risk factors to explain this high incidence are unknown. It is the purpose of this study to look into the features of hemorrhagic stroke in the Hong Kong Chinese. METHODS: We conducted a prospective hospital-based study in which 60 consecutive Chinese patients with computed tomography diagnosis of putaminal or thalamic hemorrhage were included. Their demographic and clinical data were collected and analyzed. RESULTS: Two major findings evolved from the present study. (1) Unlike the Western studies, the majority of our patients were about a decade younger; (2) 50% of the patients had previously diagnosed hypertension, but only 20% of these patients were compliant with their antihypertensive medication. Our results also suggested that low admission Glasgow Coma Scale scores, large hematoma size, and the presence of intraventricular blood were associated with poor outcomes. CONCLUSIONS: This study concludes that hemorrhagic stroke is indeed a serious health problem in Hong Kong. Simple measures, such as improvement of health education and the primary care system in the management of hypertension, would help to reduce the incidence of hemorrhagic stroke.
Adult↗
Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: a meta-analysis of placebo-controlled trials.
Meta-analysis of four double-blind, randomized, placebo-controlled trials of oral acyclovir (800 mg five times daily) for the treatment of herpes zoster was conducted to provide definitive assessments of the effect of acyclovir on the resolution of zoster-associated pain. The studies involved a total of 691 patients, and the analysis was performed on an intent-to-treat basis. A range of milestones of pain cessation were evaluated by means of Cox regression models with adjustment for relevant prognostic factors. The proportion of patients with postherpetic neuralgia at 3 and 6 months was also determined. Advancing age and more severe pain at presentation were associated with more prolonged pain. Acyclovir was clearly shown to accelerate pain resolution by all of the measures employed. Benefit was especially evident in patients 50 years of age or older. Fewer acyclovir recipients had postherpetic neuralgia at 3 or 6 months. Overall, the reductions of pain duration and prevalence were approximately twofold.
Acyclovir↗
Motor neuron disease in Hong Kong Chinese: epidemiology and clinical picture.
This study documents the clinical features, incidence and prevalence of motor neuron disease (MND) in Hong Kong Chinese. Patients with MND who were alive between 1989 and 1992 were recruited by retrieval of medical records from the four major hospitals in Hong Kong, and by referral of neurologists, neurosurgeons and medical consultants. Mortality statistics was provided by the Census and Statistics Department. A total of 84 cases were identified with a male preponderance of 1.98:1. The average annual period incidence was 0.31/100,000 and the point prevalence on December 31, 1992, was 0.95/100,000. The mean age at onset was 55.5 years (range 19-81) with a peak observed from 55 to 65 years. The clinical features are similar to other reported series of MND. The incidence and mortality of MND in Hong Kong are therefore lower than the worldwide figures of 2.0/100,000 and 1.5/ 100,000, respectively.
Adult↗
Variability of magnetic resonance angiography and computed tomography angiography in grading middle cerebral artery stenosis.
BACKGROUND AND PURPOSE: Magnetic resonance angiography and computed tomography angiography are new, noninvasive methods to provide images of the cerebral vasculature. The reliability of magnetic resonance angiography and computed tomography angiography when used to grade middle cerebral artery stenosis remains to be established. We sought to study the interobserver and intraobserver variabilities of magnetic resonance angiography and computed tomography angiography in grading middle cerebral artery stenosis. METHODS: A total of 50 middle cerebral arteries in 25 patients were studied with magnetic resonance angiography and computed tomography angiography. All patients had a history of ischemic stroke. The films were read independently by two observers on separate occasions. Films were shown again to the same observer 4 weeks after the first reading. The degree of middle cerebral artery stenosis was categorized into four grades: normal/mild, moderate, severe, and occluded. The interobserver and intraobserver variabilities were calculated by the kappa statistic method. RESULTS: Interobserver variability for grading middle cerebral artery stenosis was good (kappa = 0.78) for magnetic resonance angiography and moderate (kappa = 0.51) for computed tomography angiography. There was perfect agreement between two observers in 86% of the vessels shown in magnetic resonance angiography and in 76% of the vessels shown in computed tomography angiography. Intraobserver variability for both imaging methods was good, with the kappa value in the range of 0.70 to 0.76. CONCLUSIONS: Our results suggest that according to our protocol, magnetic resonance angiography is more reliable than computed tomography angiography in grading middle cerebral artery stenosis.
Adult↗
Apolipoprotein E genotype and Alzheimer's disease in Hong Kong elderly Chinese.
We studied the apolipoprotein E (apoE) allele frequencies in 65 Chinese patients with late-onset Alzheimer's disease (AD) and 82 age- and sex-matched controls. The apoE epsilon 4 allele frequency was significantly higher in the AD group than in the control group (0.169 versus, p < 0.01). There were five homozygotes for epsilon 4 in the AD group but none among the controls. The odds ratio for AD was 1.6 for epsilon 4 heterozygotes. The age at onset was lower in the presence of the epsilon 4 allele and higher with the epsilon 2 allele, although neither of these differences reached statistical significance. The association between apoE alleles and AD previously reported in Caucasian populations was also present in this reports of lower prevalence of AD compared with the prevalence of multi-infarct dementia.
Aged↗
Low-molecular-weight heparin for the treatment of acute ischemic stroke.
BACKGROUND: Despite doubts about their efficacy and concern about their safety, antithrombotic agents are often used to treat acute ischemic stroke. Recent experience in patients with other thromboembolic disorders suggests that low-molecular-weight heparin, which requires only subcutaneous administration once or twice daily, may be more effective and safer than standard (unfractionated) heparin. METHODS: We conducted a randomized, double-blind, placebo-controlled trial comparing two dosages of low-molecular-weight heparin with placebo in the treatment of ischemic stroke. Patients were randomly assigned within 48 hours of the onset of symptoms to receive high-dose nadroparin (4100 anti-factor Xa IU twice daily), low-dose nadroparin (4100 IU once daily), or placebo subcutaneously for 10 days. The primary measure of outcome was death or dependency regarding activities of daily living six months after randomization. Secondary outcomes were death, hemorrhagic transformation of the infarction, and other complications at 10 days, and death or dependency at 3 months. RESULTS: A total of 2750 patients were screened for the study. Among 312 patients randomized, 306 had outcomes that were analyzed at six months. Forty-five patients (45 percent) in the high-dose group, 53 patients (52 percent) in the low-dose group, and 68 patients (65 percent) in the placebo group died or became dependent. There was a significant dose-dependent effect among the three study groups in favor of low-molecular-weight heparin (P = 0.005 by the chi-square test for trend). No significant differences among the groups in the occurrence of secondary outcomes were observed at 10 days. CONCLUSIONS: For patients with ischemic stroke treated within 48 hours of the onset of symptoms, low-molecular-weight heparin was effective in improving outcomes at six months.
Activities of Daily Living↗
Expression cloning of lfc, a novel oncogene with structural similarities to guanine nucleotide exchange factors and to the regulatory region of protein kinase C.
In order to identify cDNAs that can induce oncogenic transformation, a retroviral vector was used to transfer a library of cDNAs from the murine 32D hemopoietic cell line into NIH 3T3 fibroblasts. We have identified and recovered a provirus containing a 1.8-kilobase pair cDNA whose expression causes morphological transformation in NIH 3T3 cells. The transforming cDNA contains a complete open reading frame that encodes a protein (designated Lfc) with a region of sequence similarity to the product of the lbc oncogene. This region includes a domain that is characteristic of the CDC24 family of guanine nucleotide exchange factors in tandem with a pleckstrin homology (PH) domain. The Lfc protein is distinguished from Lbc by a 150-amino acid NH2-terminal extension that contains a cysteine- and histidine-rich domain similar to the diacylglycerol-binding site (zinc butterfly) found in protein kinase C. NH2- and COOH-terminal deletion analysis revealed that both the PH and putative guanine nucleotide exchange factor domains are required, but the zinc butterfly is dispensable, for transformation. Although the removal of the PH domain of the Lfc protein completely eliminated its ability to transform NIH 3T3 cells, replacement of this domain with an isoprenylation site restored all of its transforming activity. This suggests that a PH domain-dependent recruitment of the Lfc protein to the cellular membrane is a necessary step for cellular transformation. The lfc gene is expressed in a broad range of tissues as well as in a variety of hemopoietic and non-hemopoietic cell lines. Lfc appears to be a new member of a growing family of proteins that are likely to act as activators of Ras-like proteins in a developmental or cell-lineage specific manner.
3T3 Cells↗
Retroviral transduction and oncogenic selection of a cDNA encoding Dbs, a homolog of the Dbl guanine nucleotide exchange factor.
A retroviral vector was used to transfer a large library of cDNAs from the 32D murine hemopoietic cell line to NIH3T3 fibroblasts, for the purpose of selecting cDNAs that induce oncogenic transformation. One highly transformed colony arising in the infected NIH3T3 cell culture contained a provirus with a 1900 bp cDNA insert. After recovery and reincorporation into a retroviral vector, this cDNA induced rapid morphological transformation and proliferation when expressed in NIH3T3 or C3H10T1/2 fibroblast cell lines. The transforming cDNA encoded a protein, designated Dbs, which had a region of high sequence similarity to the Dbl proto-oncogene. This region included motifs characteristic of the CDC24 family of guanine nucleotide exchange factors, and an adjacent pleckstrin homology domain. Dbs was distinguished from Dbl by an N-terminal extension and the presence of an SH3 domain at its C terminus. Deletions of the Dbs-encoding cDNA demonstrated that transformation of NIH3T3 cells required intact exchange factor and pleckstrin homology domains, but did not require the SH3 domain. In contrast to Dbl, the N-terminal sequences of Dbs did not suppress its transforming activity. The Dbs gene was expressed at low levels in several murine hemopoietic cell lines and in thymus and spleen, and at higher levels in other tissues, particularly in brain. Dbs may be one of a large family of exchange factors which provide cell-type specific pathways for regulating proliferating via the activation of Ras-like proteins.
3T3 Cells↗
Cerebral microembolism detected by transcranial Doppler during percutaneous transvenous mitral commissurotomy.
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Adult↗
How should zoster trials be conducted?
In 1994, an international group of interested clinicians and biostatisticians met to discuss the design of clinical trials in herpes zoster. They agreed that trials in herpes zoster should have prospectively agreed definitions of all outcome measures and plans for data analysis. In immunocompetent individuals, in whom pain is the major outcome measure, trials should only include patients over the age of 50 years, and for those recruited within 72 h of rash onset, should be designed to demonstrate superiority of any new therapy over existing antivirals. The primary endpoint should be time to cessation of pain for at least 4 weeks and, for the purposes of statistical analysis of its duration, the pain associated with herpes zoster ought to be considered as a continuum. All other variables, including the incidence of post-herpetic neuralgia and effects upon quality of life should be considered as secondary end-points. Evaluation of treatment effects on primary endpoints should be based upon an intent-to-treat (ITT) analysis and subgroup analysis should be used only to support the findings of the ITT analysis. These elements of good study design should be borne in mind in the evaluation of current and future trails of antiviral drugs in herpes zoster.
Clinical Trials as Topic↗