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Biomedical subjects

K Chu

Publications and source records attributed to K Chu.

At least 19 recordsLinked to original sources
PubMed2006

Increased response to morphine in mice lacking protein kinase C epsilon.

The protein kinase C (PKC) family of serine-threonine kinases has been implicated in behavioral responses to opiates, but little is known about the individual PKC isozymes involved. Here, we show that mice lacking PKCepsilon have increased sensitivity to the rewarding effects of morphine, revealed as the expression of place preference and intravenous self-administration at very low doses of morphine that do not evoke place preference or self-administration in wild-type mice. The PKCepsilon null mice also show prolonged maintenance of morphine place preference in response to repeated testing when compared with wild-type mice. The supraspinal analgesic effects of morphine are enhanced in PKCepsilon null mice, and the development of tolerance to the spinal analgesic effects of morphine is delayed. The density of mu-opioid receptors and their coupling to G-proteins are normal. These studies identify PKCepsilon as a key regulator of opiate sensitivity in mice.

Animals↗
PubMed2003

Diffusion-weighted MR findings in isolated angiitis of the central nervous system (IACNS).

OBJECTIVES: To describe the diffusion-weighted MR (DWI) findings of isolated angiitis of the central nervous system (IACNS) and narrow the differential diagnosis. METHODS: The DWI findings of two IACNS patients. Apparent diffusion coefficient (ADC) values were measured in the abnormal lesions, and DWI and T2-weighted MR images were visually inspected. RESULTS: IACNS was diagnosed based on clinical history, MR findings and cerebral angiographic findings. DWI showed hyperintense lesions with heterogeneous ADC values (287-1359 x 10(-6) mm2/s), which indicate the coexistence of cytotoxic and vasogenic oedema. CONCLUSIONS: The findings suggest that the various stages of inflammatory process with ischaemia might exist in IACNS and allow a differentiation from the usual arterial ischaemic infarction. DWI with ADC map can be a useful non-invasive diagnostic test increasing specificity in the diagnosis of IACNS, combined with conventional MRI and cerebral angiography.

Adult↗
PubMed2001

Cerebral venous thrombosis associated with tentorial subdural hematoma during oxymetholone therapy.

Androgen was reported to cause cerebral venous thrombosis (CVT) during replacement therapy for aplastic anemia. Oxymetholone, a synthetic androgen analogue, has been widely used in the treatment of aplastic anemia. A 40-year-old woman with aplastic anemia visited our hospital because of severe headache, nausea, vomiting, blurred vision and diplopia for a period of 1 month. She had taken oxymetholone for 2 years. Neurological examination revealed bilateral papilledema and bilateral sixth nerve palsies. Brain magnetic resonance imaging (MRI), performed at the time of admission, demonstrated left-sided tentorial SDH, and focal cerebral thrombosis of the left superficial sylvian vein and sigmoid sinus. MR venography revealed multiple irregularities in the superior sagittal sinus and left transverse sinus. CVT with tentorial subdural hematoma (SDH) caused by oxymetholone was strongly suggested. Oxymetholone was immediately discontinued, and her symptoms and signs disappeared. Because of the thrombocytopenia, anticoagulation was not started. She was discharged and visited the outpatient clinic without neurological symptoms for 6 months. This report supports the cautions given about the risk of CVT with oxymetholone supplementation in aplastic anemia. To the best of our knowledge, this is the first report of CVT associated with tentorial SDH that was probably caused by oxymetholone.

Adult↗
PubMed2001

The role of structure, energy landscape, dynamics, and allostery in the enzymatic function of myoglobin.

The grail of protein science is the connection between structure and function. For myoglobin (Mb) this goal is close. Described as only a passive dioxygen storage protein in texts, we argue here that Mb is actually an allosteric enzyme that can catalyze reactions among small molecules. Studies of the structural, spectroscopic, and kinetic properties of Mb lead to a model that relates structure, energy landscape, dynamics, and function. Mb functions as a miniature chemical reactor, concentrating and orienting diatomic molecules such as NO, CO, O(2), and H(2)O(2) in highly conserved internal cavities. Reactions can be controlled because Mb exists in distinct taxonomic substates with different catalytic properties and connectivities of internal cavities.

Allosteric Regulation↗
PubMed2001

Regulation of human coagulation factor X gene expression by GATA-4 and the Sp family of transcription factors.

Serine protease factor Xa plays a critical role in the coagulation cascade. Zymogen factor X is synthesized and modified in the liver. To understand the mechanisms governing the liver-specific expression of factor X, the proximal promoter of human factor X was previously characterized. Two crucial cis elements at -73 and -128 and their cognate binding proteins, HNF-4 and NF-Y, respectively, were identified. In this report, studies are extended to 3 additional cis elements within the factor X promoter. Using gel mobility shift assays, the liver-enriched protein GATA-4 was identified as the protein binding to the GATA element at -96. GATA-4 transactivates the factor X promoter 28-fold in transient transfection experiments. It was also determined that the Sp family of transcription factors binds 2 DNase I-footprinted sites at -165 and -195. Disruption of Sp protein binding at either site reduces the promoter activity by half. Simultaneous disruption of both sites reduces the promoter activity 8-fold. This is the first report indicating the involvement of GATA-4 in the regulation of clotting factor expression. These observations provide novel insight into mechanisms by which the vitamin K-dependent coagulation factors are regulated.

3T3 Cells↗
PubMed2001

Posttranslational modifications of recombinant myotube-synthesized human factor IX.

Recent data demonstrate that the introduction into skeletal muscle of an adeno-associated viral (AAV) vector expressing blood coagulation factor IX (F.IX) can result in long-term expression of the transgene product and amelioration of the bleeding diathesis in animals with hemophilia B. These data suggest that biologically active F.IX can be synthesized in skeletal muscle. Factor IX undergoes extensive posttranslational modifications in the liver, the normal site of synthesis. In addition to affecting specific activity, these posttranslational modifications can also affect recovery, half-life in the circulation, and the immunogenicity of the protein. Before initiating a human trial of an AAV-mediated, muscle-directed approach for treating hemophilia B, a detailed biochemical analysis of F.IX synthesized in skeletal muscle was carried out. As a model system, human myotubes transduced with an AAV vector expressing F.IX was used. F.IX was purified from conditioned medium using a novel strategy designed to purify material representative of all species of rF.IX in the medium. Purified F.IX was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), N-terminal sequence analysis, chemical gamma-carboxyglutamyl analysis, carbohydrate analysis, assays for tyrosine sulfation, and serine phosphorylation, and for specific activity. Results show that myotube-synthesized F.IX has specific activity similar to that of liver-synthesized F.IX. Posttranslational modifications critical for specific activity, including removal of the signal sequence and propeptide, and gamma-carboxylation of the N-terminal glutamic acid residues, are also similar, but carbohydrate analysis and assessment of tyrosine sulfation and serine phosphorylation disclose differences. In vivo experiments in mice showed that these differences affect recovery but not half-life of muscle-synthesized F.IX.

1-Carboxyglutamic Acid↗
PubMed2001

Diffusion-weighted magnetic resonance in cerebral venous thrombosis.

BACKGROUND: Cerebral venous thrombosis (CVT) is a cause of stroke with obscure pathophysiologic properties that differ from arterial stroke. Its main mechanisms of pathophysiology are the breakdown of the blood-brain barrier and the coexistence of cytotoxic and vasogenic edema. However, conventional magnetic resonance imaging (MRI) cannot differentiate between vasogenic and cytotoxic edema. OBJECTIVES: To describe the diffusion-weighted imaging (DWI) findings and characterize the clinical applications of DWI in CVT. SETTING: A tertiary referral center, neurology department. DESIGN AND METHODS: From November 1998 to March 2001, 14 patients (5 men, 9 women; mean age, 43 +/- 10 years) with CVT underwent DWI, conventional MRI, MR venography, or conventional cerebral angiography. Abnormal findings on DWI and conventional MRI indicated the necessity of MR venography and conventional angiography to confirm the diagnosis of CVT. Apparent diffusion coefficient (ADC) values were measured in all of the abnormal lesions with visual inspection of DWI and T2-weighted echo planar imaging. RESULTS: Findings on DWI were grouped according to 3 patterns: (1) Heterogeneous signal intensity (SI) (10 patients) showed mixed bright high SI and low SI and the corresponding ADC values were inversely correlated to the DWI SI. The areas of prominent low SI on DWI were reversed with adequate treatment on follow-up MRI in 1 patient. (2) Multifocal high SI (3 patients) was similar to that observed in acute arterial stroke. The corresponding ADC values were decreased and DWI was performed in the acute stages. (3) Intravascular clot with high SI was found with (1 patient, also in heterogeneous SI group) or without (1 patient) parenchymal lesions. In 1 patient, DWI demonstrated T2-negative and fluid attenuated inversion recovery-negative lesions without correlative symptoms. CONCLUSIONS: These data suggest that DWI with ADC maps can be used to discriminate between types of edema for tissue viability and to provide information about stages and diagnostic clues in CVT.

Acute Disease↗
PubMed2001

Diffusion-weighted magnetic resonance imaging in nonconvulsive status epilepticus.

BACKGROUND: In human and experimental models, diffusion-weighted magnetic resonance imaging (DWI) findings in status epilepticus (SE) have been reported to show that apparent diffusion coefficients are reduced during the initial phase and normalized or increased in the later phase of prolonged SE. This effect is caused by cytotoxic edema induced by excitotoxicity. In humans, only focal DWI abnormalities have been reported in partial SE. OBJECTIVES: To report and discuss the DWI findings suggesting diffuse neuronal injury in a patient with nonconvulsive SE. DESIGN AND METHODS: A 56-year-old man was admitted because of changing levels of consciousness over 3 days. On admission he was comatose. He had nystagmoid eye movement, forced eye blinking, and oroalimentary automatism. The results of a search for possible infectious and metabolic etiologies were negative, and electroencephalographic findings showed continuous, semirhythmic, bifrontal sharp waves of 2 Hz. Phenytoin and midazolam hydrochloride were infused to alleviate the seizure activities. He underwent DWI initially (3 days after the onset of seizure) and at the 5-month follow-up. SETTING: The neurology department of a tertiary referral center. RESULTS: During SE, DWI findings showed marked, diffuse gyriform cortical hyperintensity throughout the brain. The apparent diffusion coefficient decreased in the corresponding areas, especially in the occipital lobes. Findings from T2-weighted magnetic resonance imaging showed the intense cortical hyperintensity with gyral swelling and no involvement of brainstem, basal ganglia, thalamus, and white matter. The follow-up DWI findings showed marked atrophy and hypointensity in the corresponding regions. The apparent diffusion coefficient increased in the corresponding regions. CONCLUSIONS: Diffusion-weighted imaging in our patient indicated that the magnetic resonance imaging abnormalities of the affected cortex were due to cytotoxic edema caused by neuronal excitotoxicity during prolonged SE. Diffusion-weighted imaging can be used in the localization of seizure focus for predicting the prognosis of the affected tissue and for researching the basic pathophysiology of SE.

Brain↗
PubMed2001

Modulation of human cytomegalovirus immediate-early gene enhancer by mitogen-activated protein kinase kinase kinase-1.

The immediate-early (IE) promoter of human cytomegalovirus (HCMV) constitutes a primary genetic switch, which determines the progression of viral infection. Earlier reports by others have shown mitogen-activated protein kinase kinase kinase-1 (MEKK1) to be able to up-regulate HCMV-IE promoter through downstream mitogen-activated protein kinase (MAPK) pathways. However, we noticed that the activation of the HCMV-IE promoter by constitutively active MEKK1 (MEKK1-TRU) might not be through the MAPK pathways. Using a HCMV-IE enhancer/promoter (- 522 to + 72) driving a luciferase reporter, we demonstrated that the downstream MAPK activation actually repressed the up-regulation of the promoter by MEKK1 in CHO-K1 and human 293 cells. We further found that the up-regulation of HCMV-IE promoter by MEKK1 could be in great extent suppressed by over-expression of IkappaBalpha. Deletion of the NFkappaB/rel sites in the HCMV-IE enhancer region by mutagenesis proportionally reduced the transcriptional activation by MEKK1-TRU, whereas deletion of the ATF/CREB binding sites or cyclic AMP response elements (CRE) had no effects. Furthermore, the NFkappaB/rel deletion mutant also showed repression on the basic transcription activity of the HCMV-IE promoter. Our results indicate that the NFkappaB/rel sites are not only responsible for the modulation of HCMV-IE enhancer activity by MEKK1 but also control the basic transcription activity of the HCMV-IE promoter. On the other hand, the four consensus CRE sites were found to have no function in the activation of the promoter by MEKK1.

Animals↗
PubMed2001

Case of essential palatal tremor: atypical features and remarkable benefit from botulinum toxin injection.

We describe a 21-year-old man with essential palatal tremor. The patient had rhythmic contractions not only of tensor veli palatini but also of facial, lingual, temporalis, pharyngeal, and neck muscles. He had some voluntary control of palatal tremor and ear clicks. He was treated with 5 units of botulinum toxin-A (BOTOX) injected into each tensor veli palatini, and had complete resolution of all the symptoms.

Adult↗
PubMed2001

Risk and prevention of anti-factor IX formation in AAV-mediated gene transfer in the context of a large deletion of F9.

The safety of several gene therapy approaches for treatment of the severe, X-linked bleeding disorder hemophilia is currently being evaluated in early phase clinical trials. One strategy seeks to correct deficiency of functional coagulation factor IX (hemophilia B) by intramuscular (IM) administration of an adeno-associated viral (AAV) vector. A potentially serious complication of any treatment for hemophilia is formation of inhibitory antibodies against the coagulation factor protein, a risk that increases in the setting of null mutations in the factor IX gene (F9). Here, we describe hemophilia B mice with a large F9 deletion that form inhibitors within 1 to 2 months after IM administration of an AAV vector expressing mouse F9 or after repeated intravenous infusion of mouse F9 concentrate. In both cases, inhibitors are primarily IgG1 immunoglobulins representing a Th2-driven humoral immune response. We further demonstrate that anti-mouse F9 antibody formation in the gene-based approach can be reduced by transient immune modulation at the time of vector administration. Moreover, this maneuver resulted in complete absence of anti-mouse F9 and sustained expression of functional mouse F9 in some hemophilia B mice, particularly in those animals treated with the immunosuppressive drug cyclophosphamide. These data have direct relevance for design of clinical trials and strategies aimed at avoiding immune responses against a secreted transgene product.

Animals↗
PubMed2001

Diffusion-weighted MR findings of central pontine and extrapontine myelinolysis.

Diffusion-weighted MR (DWI) can detect changes in water diffusion associated with cellular dysfunction, which enables the differentiation of cytotoxic edema from vasogenic edema. In this study on DWI findings in central pontine (CPM) and extrapontine myelinolysis (EPM), DWI showed high signal intensities in the bilateral pons, midbrain, and genu of the corpus callosum. The corresponding apparent diffusion coefficient values were rather low. This suggests that cytotoxic edema does in fact exist in CPM and EPM and that DWI can be useful in the rapid diagnosis and prediction of the various types of edema occurring in active demyelinating diseases.

Aged↗
PubMed2001

Abdominal injury and the seat-belt sign.

OBJECTIVE: To report on: 1. Prevalence of seat-belt sign in motor vehicle accident victims with abdominal injuries; 2. Prevalence of intestinal injuries in patients with seat-belt sign; and 3. Spectrum of abdominal injuries in a population with high usage of three-point restraints. METHODS: A retrospective chart review was conducted in an adult tertiary-referral hospital from January 1992 to August 1998. Patients were identified from International Classification of Disease-9 codes for abdominal wall and intra-abdominal injuries. RESULTS: The seat-belt sign was present in 60/99. The proportion of intestinal injuries in patients with and without seat-belt sign were 9/60 and 0/39, respectively (P = 0.01). In the 25 patients with intra-abdominal injuries, there were 10 hepatic, 8 splenic, 9 intestinal and 4 retroperitoneal injuries. CONCLUSION: The seat-belt sign is indicative of an increased risk of intestinal injury, which is difficult to detect with no single test providing reliable diagnosis. Other intra-abdominal and retroperitoneal injuries may also occur, which are more readily diagnosed on computed tomography scan or focused abdominal utlrasound when available, but are no more frequent in patients with the seat-belt sign than those without.

Abdominal Injuries↗
PubMed2001

Encephalitis associated with motor polyneuropathy.

We describe three patients with acute encephalitis and motor-dominant polyneuropathy. All three patients were in their middle age and presented with features of encephalopathy with flu like illness. Cerebrospinal fluid (CSF) studies showed lymphocytic pleocytosis with increased protein. Brain magnetic resonance imagings (MRIs) showed symmetric high signal intensities in bilateral mesial temporal lobes and bilateral thalami in all patients. All three patients became quadriplegic and areflexic within two hospital days (HDs) and electrophysiologic studies revealed motor polyneuropathy. Viral or atypical bacterial infection was suspected, but no causative agent could be found. One patient expired on the twentieth hospital day, and the other two patients showed no or little improvement. To our knowledge, this combination of acute encephalitis with motor polyneuropathy has not been reported.

Adult↗
PubMed2001

Emergency department anaphylaxis: A review of 142 patients in a single year.

BACKGROUND: There are few data on the incidence, clinical features, and management of patients with acute anaphylaxis presenting to the emergency department. We investigated all presentations to one department during the course of a year to improve current awareness of this medical emergency. OBJECTIVE: The purpose of the study was to describe the clinical features, management, and outcome of anaphylaxis presentations to a single Australian adult emergency department in a single year, 1998-1999. METHODS: This was a retrospective, case-based study of adult patients (>or=13 years of age) attending a single emergency department in Brisbane, Australia, during the year 1998-1999. The medical records of 304 patients satisfying the relevant discharge diagnostic codes were studied. We determined incidence, sex ratio, age, clinical features, management, disposal, asthma prevalence, and causes in patients presenting with acute allergic reactions and anaphylaxis. RESULTS: In all, 162 emergency department patients with acute allergic reactions and 142 emergency department patients with anaphylaxis, including 60 whose anaphylaxis was severe, were seen during the year, for an anaphylaxis presentation incidence of 1 in 439. One patient died; this gave a case fatality rate of 0.70%. Cutaneous features were present in 94% of the patients with anaphylaxis. Of those with severe anaphylaxis, 35% had dizziness/syncope before hospital presentation, 25% laryngeal edema, and 21.7% systolic hypotension on hospital presentation. A cause was recognized in 73% of the anaphylaxis cases; most commonly, the causative agent was a drug, insect venom, or food. Adrenaline was used in 57% of the severe cases before hospital presentation or in the hospital. The emergency department alone definitively cared for 94% of all patients, though only 43% severe anaphylaxis cases were referred for follow-up. CONCLUSION: The emergency department anaphylaxis presentation incidence of 1 in 439 cases is greater than previously recognized, though death remains rare. In three fourths of cases, a precipitant was identified, a fact that emphasizes the need for a detailed initial history. Definitive management in the emergency department alone is possible in most cases, provided that the appropriate use of adrenaline and the need for allergy clinic follow-up are appreciated.

Adolescent↗
PubMed2001

Older patients' utilisation of emergency department resources: a cross-sectional study.

A cross-sectional study was conducted to investigate older patients' utilisation of emergency department resources. Patients aged > or = 65 years, compared with adults < 65 years, were more likely to be triaged to higher clinical urgency categories. They have a higher hospital admission rate and longer length-of-stay even after adjusting for triage category. Patients > or = 80 years, compared with 65-79 years, were more likely to be triaged to higher urgency categories. These groups had similar hospital admission rates and lengths-of-stay. Patients > or = 65 years presented in similar numbers during office-hours and after-hours, but after-hours attendances were more likely to be triaged to higher urgency categories. The greater emergency department resource utilisation by older people has implications for the provision of health services in an aging population.

Aged↗