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Biomedical subjects

J D Lee

Publications and source records attributed to J D Lee.

At least 19 recordsLinked to original sources
PubMed2003

The cerebrovascular response to traditional acupuncture after stroke.

Acupuncture is useful in treating the nausea and vomiting related to chemotherapy, adult postoperative surgery pain and postoperative dental pain. We obtained single-photon emission computed tomography (SPECT) brain perfusion images of six patients with middle cerebral artery occlusion obtained before and after acupuncture and compared the changes in regional cerebral blood flow (rCBF) to those in normal control. Images were obtained before and after acupuncture at six traditional acupoints (LI 4, 10, 11, 15 and 16 and TE5) in the affected arm. The baseline image was subtracted from the postacupuncture image, to produce a subtraction image displaying only voxels with values >2 SD from the mean and those voxels were coregistered to the baseline SPECT or T2-weighted MRI. Similar images were obtained before and after acupuncture of eight normal volunteers. Statistical parametric mapping with a threshold of P =0.001 and a corrected P of 0.05 was performed for group comparison between postacupuncture and baseline SPECT. Focally increased CBF was seen in all patients especially in the hypoperfused zone surrounding the ischaemic lesion, the ipsilateral or contralateral sensorimotor area, or both. Normal subjects showed increased rCBF mainly in the parahippocampal gyrus, premotor area, frontal and temporal areas bilaterally and ipsilateral globus pallidus. Acupuncture stimulation after stroke patients appears to activate perilesional or use-dependent reorganised sites and might be a way of looking at brain reorganisation.

Acupuncture Therapy↗
PubMed2003

Thyrotoxic autoimmune encephalopathy: a repeat positron emission tomography study.

Thyroid related autoantibodies have been related to the development of encephalopathy, known as Hashimoto's encephalopathy. However, their relation with the encephalopathy occurring in patients with Graves' disease has not been well established. The case is reported of a 51 year old woman presenting with subacute progressive dementia with evidence of hyperthyroidism. She had Graves' disease associated with high titres of thyroid related autoantibodies. Her encephalopathy was not improved by antithyroid drugs, but promptly responded to corticosteroid treatment, and stabilised with a gradual reduction of thyroid related autoantibody titres. Brain positron emission tomography initially showed a diffuse and multifocal cerebral hypometabolism with subsequent normalisation on her clinical recovery, which was consistent with the acute and reversible cerebral inflammation probably mediated by autoimmune mechanisms.

Autoantibodies↗
PubMed2003

Primary human parvovirus B19 infection in an HIV infected patient on highly active antiretroviral therapy.

Adults developing primary human parvovirus B19 (B19) infection may present with arthralgia, fever, and maculopapular rash. Recovery is linked to the development of specific neutralising antibodies. In immunosuppressed patients, including those with HIV infection, such humoral responses are impaired and severe chronic bone marrow suppression and arthritis may occur.

AIDS-Related Opportunistic Infections↗
PubMed2001

Strong spin-fluctuation effects on the photoemission line shape in the normal state of high-T(c) cuprates.

We have studied the quasiboson model for photoemission from cuprates in the normal state, where quasiparticles are coupled to collective spin excitations strongly enhanced near momentum (pi,pi). The present model has a benefit to describe the observed crossover from the overdoped to the underdoped cases because it is in principle an infinite-order theory in the limit of narrow bandwidth. The anomalous dependences of the photoemission line shape on the momentum and hole concentration are consistently understood within the model with no adjustable parameter except for a doping-independent coupling constant.

Journal Article↗
PubMed2001

Extracellular signal regulated kinase 5 (ERK5) is required for the differentiation of muscle cells.

Extracellular signal regulated kinase 5 (ERK5) is a novel member of the mitogen-activated protein kinase (MAPK) family with a poorly defined physiological function. Since ERK5 and its upstream activator MEK5 are abundant in skeletal muscle we examined a function of the cascade during muscle differentiation. We show that ERK5 is activated upon induction of differentiation in mouse myoblasts and that selective activation of the pathway results in promoter activation of differentiation-specific genes. Moreover, myogenic differentiation is completely blocked when ERK5 expression is inhibited by antisense RNA. Thus, we conclude that the MEK5/ERK5 MAP kinase cascade is critical for early steps of muscle cell differentiation.

Animals↗
PubMed2001

Ubiquitination-dependent mechanisms regulate synaptic growth and function.

The covalent attachment of ubiquitin to cellular proteins is a powerful mechanism for controlling protein activity and localization. Ubiquitination is a reversible modification promoted by ubiquitin ligases and antagonized by deubiquitinating proteases. Ubiquitin-dependent mechanisms regulate many important processes including cell-cycle progression, apoptosis and transcriptional regulation. Here we show that ubiquitin-dependent mechanisms regulate synaptic development at the Drosophila neuromuscular junction (NMJ). Neuronal overexpression of the deubiquitinating protease fat facets leads to a profound disruption of synaptic growth control; there is a large increase in the number of synaptic boutons, an elaboration of the synaptic branching pattern, and a disruption of synaptic function. Antagonizing the ubiquitination pathway in neurons by expression of the yeast deubiquitinating protease UBP2 (ref. 5) also produces synaptic overgrowth and dysfunction. Genetic interactions between fat facets and highwire, a negative regulator of synaptic growth that has structural homology to a family of ubiquitin ligases, suggest that synaptic development may be controlled by the balance between positive and negative regulators of ubiquitination.

Animals↗
PubMed2001

Sightless has homology to transmembrane acyltransferases and is required to generate active Hedgehog protein.

Proteins of the Hedgehog (Hh) family act as important developmental signals in a variety of species [1]. Hh proteins are synthesized as full-length precursors that are autocatalytically cleaved by their C-terminal domains to release the signaling N-terminal domains [2]. The addition of a cholesterol molecule to the C terminus of the signaling domain is concomitant with cleavage [3]. Vertebrate Sonic hedgehog (Shh) proteins have also been shown to acquire a fatty acid chain on the N-terminal cysteine of this domain [4], which is required for a subset of their in vivo functions [5, 6]. A mutation of the corresponding cysteine in Drosophila Hh transforms it into a dominant-negative protein [6]. We have identified a novel gene, sightless (sit), which is required for the activity of Drosophila Hh in the eye and wing imaginal discs and in embryonic segmentation. sit acts in the cells that produce Hh, but does not affect hh transcription, Hh cleavage, or the accumulation of Hh protein. sit encodes a conserved transmembrane protein with homology to a family of membrane-bound acyltransferases. The Sit protein could act by acylating Hh or by promoting other modifications or trafficking events necessary for its function.

Acylation↗
PubMed2001

An acylatable residue of Hedgehog is differentially required in Drosophila and mouse limb development.

The Drosophila Hedgehog protein and its vertebrate counterpart Sonic hedgehog are required for a wide variety of patterning events throughout development. Hedgehog proteins are secreted from cells and undergo autocatalytic cleavage and cholesterol modification to produce a mature signaling domain. This domain of Sonic hedgehog has recently been shown to acquire an N-terminal acyl group in cell culture. We have investigated the in vivo role that such acylation might play in appendage patterning in mouse and Drosophila; in both species Hedgehog proteins define a posterior domain of the limb or wing. A mutant form of Sonic hedgehog that cannot undergo acylation retains significant ability to repattern the mouse limb. However, the corresponding mutation in Drosophila Hedgehog renders it inactive in vivo, although it is normally processed. Furthermore, overexpression of the mutant form has dominant negative effects on Hedgehog signaling. These data suggest that the importance of the N-terminal cysteine of mature Hedgehog in patterning appendages differs between species.

Acylation↗
PubMed2001

BMK1 mediates growth factor-induced cell proliferation through direct cellular activation of serum and glucocorticoid-inducible kinase.

Activation of the mammalian mitogen-activated protein kinase known as BMK1 is required for growth factor-induced cell proliferation. To understand the mechanism by which BMK1 mediates this cellular response, this kinase was used as bait in a yeast two-hybrid-based library screening. Here, we report the identification of serum and glucocorticoid-inducible kinase (SGK) as a cellular protein that physically interacts with BMK1. During growth factor-induced cell stimulation, BMK1 activates SGK by phosphorylation at serine 78. This BMK1-mediated phosphorylation event is necessary for the activation of SGK and, more importantly, for cell proliferation induced by growth factors.

Cell Division↗
PubMed2001

Nitric oxide synthase activity in peripheral polymorphonuclear leukocytes in patients with chronic congestive heart failure.

Increased activity of inducible nitric oxide synthase (NOS) has been found in cardiac tissue and in skeletal muscle from patients with chronic congestive heart failure (CHF). There have been few reports investigating NOS activity in other organs or in peripheral blood cells from patients with chronic CHF. To examine whether NOS activities in peripheral polymorphonuclear leukocytes (PML) are increased in patients with chronic CHF and to determine whether a correlation exists between disease severity and NOS activity in PML of patients with chronic CHF, we assessed the levels of NOS activity in PML by measuring the capacity of isolated PML to convert 3H-L-arginine to 3H-L-citrullin in 70 Japanese patients with chronic CHF and in 24 age-matched healthy volunteers. The levels of NOS activity in PML were significantly greater in patients with chronic CHF than in healthy volunteers (18.0 +/- 0.6% vs 11.5 +/- 0.3%, p <0.01). NOS activity in PML was increased with the severity of New York Heart Association functional class. Among the various neurohumonal factors, the plasma levels of interleukin-6, atrial natriuretic peptide, and norepinephrine showed independent and significant positive relations with levels of NOS activity in PML. Thus, we demonstrated that NOS activity in PML was elevated in patients with chronic CHF in relation to the severity of heart failure, circulating proinflammatory cytokines, and neurohormonal factors.

Adult↗
PubMed2001

Molecular cloning of mouse ERK5/BMK1 splice variants and characterization of ERK5 functional domains.

The mitogen-activated protein kinases (MAPKs) play important roles in regulation of cell growth and survival. Human MAPK 5 (ERK5) or Big MAP kinase 1 (BMK1) is a recently cloned member of the MAPK family. To identify ERK5-related kinases, we searched the GenBanktrade mark expressed sequence tag (EST) data base for mouse cDNAs with homology to human ERK5. A full-length mouse cDNA that was highly homologous to the human ERK5 was identified. Further analysis of ERK5 polymerase chain reaction products generated from mouse embryo cDNA yielded three mouse ERK5 cDNAs (mERK5a, mERK5b, and mERK5c). Sequence analysis showed that these cDNAs are alternative splice products of the mouse ERK5 gene. Interestingly, expressed mERK5b and mERK5c act as dominant negative inhibitors based on inhibition of mERK5a kinase activity and mERK5a-mediated MEF2C transactivation. However, the physiological significance of mERK5b and mERK5c is not fully understood. Further investigation using these mouse ERK5 splice variants and other constructed mutants identified functional roles of several regions of mERK5, which appear to be important for protein-protein interaction and intracellular localization. Specifically, we found that the long C-terminal tail, which contains a putative nuclear localization signal, is not required for activation and kinase activity but is responsible for the activation of nuclear transcription factor MEF2C due to nuclear targeting. In addition, the N-terminal domain spanning amino acids (aa) 1-77 is important for cytoplasmic targeting; the domain from aa 78 to 139 is required for association with the upstream kinase MEK5; and the domain from aa 140-406 is necessary for oligomerization. Taken together, these observations indicate that ERK5 is regulated by distinct mechanisms determined by its unique structure and presumably the presence of multiple splice variants.

Alternative Splicing↗
PubMed2001

Src and multiple MAP kinase activation in cardiac hypertrophy and congestive heart failure under chronic pressure-overload: comparison with acute mechanical stretch.

Activation of members of the mitogen-activated protein (MAP) kinase family and their downstream effectors has been proposed to play a key role in the pathogenesis of cell survival, ischaemic preconditioning, cardiac hypertrophy and heart failure. This study investigated the responses of Src kinase and multiple MAP kinases during the transition from compensated pressure-overload hypertrophy to decompensated congestive heart failure. Extracellular signal-regulated protein kinase (ERK) 1/2, p38, and Src were activated by chronic pressure-overload and their activity was sustained for 8 weeks after aortic banding. In contrast, while p90 ribosomal S6 kinase (90RSK) and big MAP kinase 1 (BMK1) were activated in compensated hypertrophy, their activities were significantly decreased in hearts with heart failure. No changes were found in C-Jun NH2 terminal kinase (JNK) activity after aortic banding. These data suggest that differential activation of MAP kinase family members may contribute to the transition from compensated to decompensated hypertrophy. We also examined acute effects of mechanical stretch on the activation of these kinases in normal and hypertrophied hearts. In the isolated coronary-perfused heart, a balloon in the left ventricle was inflated to achieve minimum end-diastolic pressure of 25 mmHg for 10-20 min. In normal guinea pig hearts, stretch activated ERK1/2, p90RSK, p38, Src, and BMK1 but not JNK. However in hypertrophied hearts, further activation of these kinases was not observed by acute mechanical stretch. Mechanical stretch-induced activation of ERK1/2 and p38 kinase in normal hearts was attenuated significantly by a protein kinase C inhibitor, chelerythrine. We demonstrate that ERK1/2, p90RSK, p38, Src, and BMK1 are activated by chronic pressure-overload and by acute mechanical stretch. These data suggest that Src, BMK1 and p90RSK play a role as novel signal transduction pathways leading to cardiac hypertrophy. In addition, the differential inhibition of p90RSK and BMK1 in hearts with congestive heart failure suggests the specific role of these two kinases to maintain cardiac function under chronic pressure-overload.

Alkaloids↗
PubMed2001

Src family kinase and adenosine differentially regulate multiple MAP kinases in ischemic myocardium: modulation of MAP kinases activation by ischemic preconditioning.

Recent studies suggest that ischemia activates Src and members of the mitogen-activated protein (MAP) kinase superfamily and their downstream effectors, including big MAP kinase 1 (BMK1) and p90 ribosomal S6 kinase (p90RSK). It has also been reported that adenosine is released during ischemia and involved in triggering the protective mechanism of ischemic preconditioning. To assess the roles of Src and adenosine in ischemia-induced MAP kinases activation, we utilized the Src inhibitor PP2 (4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine) and the adenosine receptor antagonist 8-(p-sulfophenyl) theophylline (SPT) in perfused guinea pig hearts. PP2 (1 microm) inhibited ischemia-induced Src, BMK1 and JNK activation but not JAK2 and p38 activation. SPT inhibited ischemia-mediated p38 and JNK activation. These results demonstrate that Src family kinase and adenosine regulate MAP kinases by parallel pathways. Preconditioning significantly improved both recovery of developed pressure and dp/dt in isolated guinea pig hearts. Since the protective effect of preconditioning was blocked by PP2 (1 microm) and SPT (50 microm), we next investigated the regulation of Src, MAP kinases and p90RSK during preconditioning. The activity and time course of ERK1/2 was not changed, but p90RSK activation by reperfusion was completely inhibited by preconditioning. In contrast, the activation by ischemia of Src, BMK1, p38 and JNK was significantly faster in preconditioned hearts. Maximal BMK1 activation by ischemia was also significantly enhanced by preconditioning. These data suggest important roles for Src family kinases and adenosine in mediating preconditioning, and suggest specific roles for individual MAP kinases in preconditioning.

Adenosine↗
PubMed2001

Copper-62 ATSM as a hypoxic tissue tracer in myocardial ischemia.

Copper-62 labeled diacetyl-bis(N4-methylthiosemicarbazone) (62Cu-ATSM) has been proposed as a generator produced positron-emitting tracer for hypoxic tissue imaging. To clarify the usefulness of 62Cu-ATSM for myocardial ischemia, 62Cu-ATSM PET was performed in 7 patients with coronary artery disease. Increased myocardial uptake of 62Cu-ATSM was observed (myocardium/blood ratio: 3.09) in one patient with unstable angina, who had increased 18F-fluorodeoxyglucose (18F-FDG) uptake under the fasting condition. The other 6 patients, who were clinically stable, did not have increased 62Cu-ATSM uptake, although abnormal 18F-FDG uptake was seen in 4 patients. This preliminary study suggests that 62Cu-ATSM is a promising PET tracer for hypoxic imaging in acute ischemia.

Aged↗
PubMed2001

Myocardial FDG-PET examination during fasting and glucose loading states by means of a one-day protocol.

We propose a new method to measure the myocardial FDG uptake during fasting and glucose loading in one day, a myocardial FDG-PET one-day protocol, with both 2- and 3-dimensional data acquisition (2D and 3D) without background activity subtraction. To confirm it, we evaluated the effect of scatter correction in the 2D and 3D modes of a PET scanner both in phantom and patient studies. In the phantom study, we used a cardiac phantom with six divided chambers and two cylindrical phantoms placed as the activity outside the field of view. Each chamber was filled with a different concentration of F- 18 solution. Regions of interest (ROI) were placed on a polar map generated from reconstructed images and were compared to the concentration of the solution in each chamber in both 2D and 3D. In the patient study, 10 non-diabetic patients with coronary artery disease were studied. Each patient received a myocardial FDG study during fasting (F) and glucose loading (L). L images with background subtraction (Lsub(+)) and without background subtraction (Lsub(-)) were compared by polar map analysis. The ROI counts for the true activity in 2D and 3D demonstrated a linear relationship, and quite similar slopes were observed (0.72 in 2D, 0.69 in 3D). The background fraction in Lsub(-) was 3.59+/-1.83%. There were significant differences between Lsub(-) or Lsub(+) and F in both normal and ischemic myocardium. Scatter correction was successfully performed in both 2D and 3D modes. Background activity is thought to be negligible and this proposed method is simple touse in measuring the myocardial FDG uptake in one day.

Aged↗
PubMed2001

Clinical significance of reverse redistribution on resting thallium-201 imaging in patients with vasospastic angina.

To evaluate the clinical significance of reverse redistribution (RR) of resting 201Tl single photon emission computed tomography (SPECT) in patients with vasospastic angina (VSA), we performed left ventriculography, coronary angiography and resting 201Tl-SPECT in 22 patients with VSA. Left ventriculography showed abnormal wall motion in 17 of 22 patients (77%) and 37 of 154 segments. Thirty-one of these 37 segments (84%) were within the area perfused by coronary arteries showing acetylcholine-induced vasospasm. On 201Tl images, abnormal findings were observed in 11 of 22 patients (50%), and among them, 7 patients (32%) had RR. Seven of 37 segments (19%) having abnormal regional wall motion had RR of 201TI, and in 6 of these 7 segments (86%), accumulation of 123I-BMIPP was found to be reduced. We conclude that repetitive brief myocardial ischemia may cause myocardial injuries in patients with VSA, and that the presence of RR of 201Tl indicates the presence of myocardial injury in these patients.

Acetylcholine↗
PubMed2001

A phase I/IIa study on intra-articular injection of holmium-166-chitosan complex for the treatment of knee synovitis of rheumatoid arthritis.

Previous animal studies have established that the intra-articular injection of holmium-166-chitosan complex (DW-166HC) causes effective necrosis of the inflamed synovium with litle leakage of radioactivity from the injected joint. Based on these findings, we conducted a phase I/IIa study to examine the biodistribution of DW-166HC and to assess the safety of DW-166HC for the treatment of knee synovitis in patients with rheumatoid arthritis (RA). A total of 16 patients [1 man, 15 women; median age 49 (range 36-65) years] who had RA knee synovitis refractory to disease-modifying anti-rheumatic drug treatments of > 3 months' duration were randomly assigned to three treatment groups with different radiation doses of DW-166HC: 370 MBq (n = 6), 555 MBq (n = 5) and 740 MBq (n = 5). In each treatment group, blood and urine radioactivity were analysed by beta counter and biodistribution of the injected DW-166HC was evaluated using a gamma scan camera. Clinical assessment was done according to three variables (evaluation method): knee joint pain (visual analogue scale), range of motion (goniometry) and joint swelling (circumference of knee joint). The duration of follow-up observation was 3 months. Following the intra-articular injection of DW-166HC, the blood radioactivity was little changed from the baseline measurement and the accumulated radioactivity excreted in urine was minimal. Gamma scan study indicated that most of the injected radiochemical was localized within the injected joint cavity, and the extra-articular leakage was negligible at 24 h after the injection: brain, 0.3%; lung, 0.6%; abdomen, 0.7%; and pelvis, 0.8%. Major adverse events were transient post-injection knee joint pain and swelling. These results suggest that DW-166HC might be a safe agent for radiation synovectomy, particularly for the treatment of knee synovitis of RA, and further trials in a larger patient population are warranted to evaluate the therapeutic efficacy of DW-166HC.

Adult↗