Biomedical subjects

P Chen

Publications and source records attributed to P Chen.

At least 217 records · Page 12Linked to original sources

PubMed1999

Identification of neuronal input to the arcuate nucleus (ARH) activated during lactation: implications in the activation of neuropeptide Y neurons.

Activation of the neuropeptide Y (NPY) neuronal system in the arcuate nucleus of the hypothalamus (ARH) during lactation in the rat is likely due to the neural impulses arising from the suckling stimulus. However, the afferent neuronal input to the ARH that is activated during lactation and is responsible for activation of NPY neurons is currently unknown. Previously, using cFos as a marker for neuronal activation, we identified several brain areas in the lactating animals that were activated by the suckling stimulus. Thus, the objective of the present study was to determine if these activated areas observed in the lactating animals project directly into the ARH. The retrograde tracer, fluorogold (FG), was injected into the ARH on day 4 postpartum. Chronically suckled rats were then deprived of their eight-pup litters on day 9 postpartum, and 48 h later, the pups were returned to the females to reinitiate the suckling stimulus for 90 min to induce cFos expression. The animals were then perfused and the brains were subjected to double-label immunohistochemistry to visualize both FG- and cFos-positive cells. Substantial FG/cFos double-labeled cells were found in forebrain regions, including the medial preoptic area, periventricular preoptic area, bed nucleus of the stria terminalis, and the medial amygdala, and in brainstem regions including the lateral parabrachial nucleus, peripeduncular area and ventrolateral medulla. The results of the present study demonstrate that specific areas in the brain are activated during lactation and send direct projections to the ARH. Thus, these areas are potentially important candidates for mediating the activation of the NPY neuronal system in the ARH during lactation.

Animals↗

PubMed1999

RNA antisense abrogation of MAT1 induces G1 phase arrest and triggers apoptosis in aortic smooth muscle cells.

The human MAT1 gene (ménage à trois 1) is an assembly factor and a targeting subunit of cyclin-dependent kinase (CDK)-activating kinase. The novel mechanisms by which MAT1 forms an active CDK-activating kinase and determines substrate specificity of CDK7-cyclin H are involved in the cell cycle, DNA repair, and transcription. Hyperplasia of vascular smooth muscle cells (SMC) is a fundamental pathologic feature of luminal narrowing in vascular occlusive diseases, and nothing is yet known regarding the cell cycle phase specificity of the MAT1 gene in its involvement in SMC proliferation. To investigate such novel regulatory pathways, MAT1 expression was abrogated by retrovirus-mediated gene transfer of antisense MAT1 RNA in cultured rat aortic SMCs. We show that abrogation of MAT1 expression retards SMC proliferation and inhibits cell activation from a nonproliferative state. Furthermore, we have demonstrated that these effects are due to G1 phase arrest and apoptotic cell death. Our studies indicate a link between cell cycle control and apoptosis and reveal a potential mechanism for coupling the regulation of MAT1 with G1 exit and prevention of apoptosis.

Animals↗

PubMed1999

Altered cytochrome c display precedes apoptotic cell death in Drosophila.

Drosophila affords a genetically well-defined system to study apoptosis in vivo. It offers a powerful extension to in vitro models that have implicated a requirement for cytochrome c in caspase activation and apoptosis. We found that an overt alteration in cytochrome c anticipates programmed cell death (PCD) in Drosophila tissues, occurring at a time that considerably precedes other known indicators of apoptosis. The altered configuration is manifested by display of an otherwise hidden epitope and occurs without release of the protein into the cytosol. Conditional expression of the Drosophila death activators, reaper or grim, provoked apoptogenic cytochrome c display and, surprisingly, caspase activity was necessary and sufficient to induce this alteration. In cell-free studies, cytosolic caspase activation was triggered by mitochondria from apoptotic cells but identical preparations from healthy cells were inactive. Our observations provide compelling validation of an early role for altered cytochrome c in PCD and suggest propagation of apoptotic physiology through reciprocal, feed-forward amplification involving cytochrome c and caspases.

Animals↗

PubMed1999

Transforming growth factor-beta1 polarizes murine hematopoietic progenitor cells to generate Langerhans cell-like dendritic cells through a monocyte/macrophage differentiation pathway.

We have recently demonstrated that CD11b-/dullCD11c+ and CD11b+hiCD11c+ dendritic cell (DC) precursor subsets represent two distinct DC differentiation pathways from murine bone marrow lineage-phenotype negative (Lin-)c-kit+ hematopoietic progenitor cells (HPCs) stimulated with granulocyte-macrophage colony-stimulating factor (GM-CSF) + stem cell factor (SCF) + tumor necrosis factor alpha (TNFalpha). We show here that transforming growth factor-beta1 (TGF-beta1) significantly inhibits the generation of these CD11b-/dullCD11c+ and CD11b+hiCD11c+ DC precursors. Phenotypically, this inhibitory effect was accompanied by markedly suppressed expression of Ia and CD86 antigens as well as major histocompatibility complex (MHC) class II transactivator (CIITA) and CC-chemokine receptor 7 (CCR7) mRNAs in Lin-c-kit+ HPC cultures stimulated with GM-CSF + SCF + TNFalpha at day 6. TGF-beta1 could also suppress mature DC differentiation from CD11b+hiCD11c+ DC precursors, but not the differentiation from CD11b-/dullCD11c+ DC precursors. In the absence of TNFalpha, TGF-beta1 markedly suppressed the expression of CIITA and CCR7 mRNAs in GM-CSF + SCF-stimulated Lin-c-kit+ HPCs at either day 6 or day 12 and induced the differentiation solely into monocytes/macrophages as evident in morphology, active phagocytic, and endocytic activities. These cells expressed high levels of F4/80 and E-cadherin antigens, but low or undetectable levels of Ia, CD86, and CD40 molecules. However, upon the stimulation with TNFalpha + GM-CSF, these cells could further differentiate into mature DCs expressing high levels of Ia and E-cadherin, characteristics for Langerhans cells (LCs), and gained the capacity of enhancing allogenic MLR. Taken together, all of these findings suggest that TGF-beta1 polarizes murine HPCs to generate LC-like DCs through a monocyte/macrophage differentiation pathway.

Animals↗

PubMed1999

HIV-1 tat protein induces the production of interleukin-8 by human brain-derived endothelial cells.

This study focused on the role of the HIV-derived viral protein, tat, in activating central nervous system (CNS)-derived endothelial cells (EC) to produce interleukin-8 (IL-8), a stimulator and chemoattractant for neutrophils and lymphocytes. Human CNS-EC treated with tat (100 ng/ml) demonstrated a 2 to 3 fold upregulation in IL-8 mRNA and protein. Tumor necrosis factor-alpha (TNF) and tat were found to act additively in upregulating IL-8 production. In contrast, transforming growth factor beta (TGF beta), appeared to down modulate tat-induced IL-8 production. These data suggest that extracellular tat, especially in the presence of TNF, may be responsible for the local production of IL-8.

Acquired Immunodeficiency Syndrome↗

PubMed1999

Chk1 complements the G2/M checkpoint defect and radiosensitivity of ataxia-telangiectasia cells.

Cells from patients with the human genetic disorder ataxia-telangiectasia (A-T) are defective in the activation of cell cycle checkpoints in response to ionizing radiation damage. In order to understand the role of ATM in checkpoint control we investigated whether Schizosaccaromyces pombe chk1, a protein kinase implicated in controlling the G2 DNA damage checkpoint, might alter the radiosensitive phenotype in A-T cells. The fission yeast chkl gene was cloned into an EBV-based vector under the control of a metallothionein promoter and transfected into A-T lymphoblastoid cells. Induction of chk1 enhanced the survival of an A-T cell line in response to radiation exposure as determined by cell viability and reduction of radiation-induced chromosome aberrations. This can be accounted for at least in part by the restoration of the G2 checkpoint to chk1 expressing cells. There was no evidence that chk1 expression corrected either the G1/S checkpoint or radioresistant DNA synthesis in S phase in these cells. These results suggest that chk1 when overexpressed acts downstream from ATM to restore the G2 checkpoint in these cells and correct the radiosensitive phenotype. These data allow us to dissociate individual checkpoint events and relate them to the radiosensitive phenotype in A-T cells.

Ataxia Telangiectasia↗

PubMed1999

Effect of the compression ratio on properties of lung surfactant (bovine lipid extract surfactant) films.

Using axisymmetric drop shape analysis (ADSA) and a captive bubble technique, the properties of lung surfactant (BLES) films under different compression ratios (i.e. the ratio of maximum to minimum surface area of the bubble) were investigated. In particular, the effect of the compression ratio of the films on the shape of the volume area surface tension-time (VAST) graphs and on the shape of the surface tension relative area (gamma-A ) graphs was examined at the air-liquid interface. Under relatively low compression ratios of the films, the VAST and gamma-A graphs indicate that the cycling is reversible (i.e. the gamma-A graphs are identical for expansion and compression). When the compression ratio of the films increases, failure tends to occur when the surface film can not support the increasing surface pressure, causing a hysteresis loop in the gamma-A graph. It was also found that low surface tension (i.e. below 5 mJ/m2) at the interface could be attained with a 30% compression ratio and collapse of the films always occurs near or below 1 mJ/m2.

Adsorption↗

PubMed1999

The temporal relationship between depressive symptoms and dementia: a community-based prospective study.

BACKGROUND: The temporal relationship between the appearance of depressive symptoms and the clinical onset of dementia and Alzheimer disease was evaluated in a community sample. METHODS: An original sample of 1366 subjects aged 65 years or older, selected randomly from a rural Pennsylvania community, was cognitively screened at study entry and every 2 years thereafter. A subset of 954 survivors of this cohort without dementia was screened for depressive symptoms at the second and subsequent data-collection waves. A "depression cluster" was identified by the presence of 5 or more depressive symptoms, including depressed mood, at the time of screening. Cognitively impaired subjects and a sample of unimpaired controls underwent standardized clinical evaluation to determine the presence of incident dementia (by DSM-III-R criteria) and probable or possible Alzheimer disease (by criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association) and to estimate the clinical onset of dementia symptoms. RESULTS: A highly increased probability of the depression cluster developing existed among subjects following the onset of dementia (15.4% [6/39]) and Alzheimer disease (17.6% [6/34]) compared with subjects without dementia (3.2% [23/712]). The odds ratios, after adjustment for age, sex, education level, and self reported memory loss, for the development of depression were 6.5 (95% confidence interval, 2.2-19.1) in subjects with Alzheimer disease and 5.2 (95% confidence interval, 1.8-15.2) in subjects with overall dementia. Depressive symptoms did not confer a significantly increased relative risk of dementia (1.27; 95% confidence interval, 0.55-2.93) or Alzheimer disease (1.28; 95% confidence interval, 0.51-3.20). CONCLUSION: Depressive symptoms appeared to be early manifestations, rather than predictors, of Alzheimer disease in this community sample.

Aged↗

PubMed1999

Irradiation of the tumor bed alone after lumpectomy in selected patients with early-stage breast cancer treated with breast conserving therapy.

BACKGROUNDS AND OBJECTIVES: We present the interim findings of our in-house protocol treating the tumor bed alone after lumpectomy with low-dose-rate (LDR) interstitial brachytherapy in selected patients with early-stage breast cancer treated with breast conserving therapy (BCT). METHODS: From 1 March 1993 through 1 January 1995, 50 women with early-stage breast cancer were entered into a protocol of tumor bed irradiation alone using an interstitial LDR implant. Patients were eligible if their tumor was an infiltrating ductal carcinoma < or =3 cm in diameter, surgical margins were clear by at least 2 mm, the tumor did not contain an extensive intraductal component, the axilla was surgically staged with < or =3 nodes involved with cancer, and a postoperative mammogram was performed. Implants were positioned using a template guide delivering 50 Gy over 96 hr to the lumpectomy bed plus a 1-2-cm margin. Local control, cosmetic outcome, and complications were assessed. RESULTS: Patients ranged in age from 40 to 84 years (median, 65). The median tumor size was 10 mm (range, 1-25). Seventeen of 50 patients (34%) had well-differentiated tumors, 22 (44%) had moderately differentiated tumors, and in 11 (22%) the tumor was poorly differentiated. Forty-five patients (90%) were node-negative while five (10%) had 1-3 positive nodes. A total of 23 (46%) patients were placed on tamoxifen and 3 (6%) received adjuvant systemic chemotherapy. No patient was lost to follow-up. The median follow-up for surviving patients is 47 months (range, 37-59). No patient has experienced a local, regional, or distant failure. Three patients have died at 19, 33, and 39 months after treatment. All were without clinical evidence of recurrent disease and all deaths were unrelated to treatment. Good-to-excellent cosmetic results have been observed in 49 of 50 patients (98%) (median cosmetic follow-up was 44 months with a range of 19-59). No patient has experienced significant sequelae related to their implant. CONCLUSIONS: Interim results with treatment of the tumor bed alone with an LDR interstitial implant appear promising. Long-term follow-up of these patients and additional studies will be necessary to establish the equivalence of this treatment approach compared to standard BCT.

Adult↗

PubMed1999

The evolutionary history of carbamoyltransferases: A complex set of paralogous genes was already present in the last universal common ancestor.

Forty-four sequences of ornithine carbamoyltransferases (OTCases) and 33 sequences of aspartate carbamoyltransferases (ATCases) representing the three domains of life were multiply aligned and a phylogenetic tree was inferred from this multiple alignment. The global topology of the composite rooted tree (each enzyme family being used as an outgroup to root the other one) suggests that present-day genes are derived from paralogous ancestral genes which were already of the same size and argues against a mechanism of fusion of independent modules. A closer observation of the detailed topology shows that this tree could not be used to assess the actual order of organismal descent. Indeed, this tree displays a complex topology for many prokaryotic sequences, with polyphyly for Bacteria in both enzyme trees and for the Archaea in the OTCase tree. Moreover, representatives of the two prokaryotic Domains are found to be interspersed in various combinations in both enzyme trees. This complexity may be explained by assuming the occurrence of two subfamilies in the OTCase tree (OTC alpha and OTC beta) and two other ones in the ATCase tree (ATC I and ATC II). These subfamilies could have arisen from duplication and selective losses of some differentiated copies during the successive speciations. We suggest that Archaea and Eukaryotes share a common ancestor in which the ancestral copies giving the present-day ATC II/OTC beta combinations were present, whereas Bacteria comprise two classes: one containing the ATC II/OTC alpha combination and the other harboring the ATC I/OTC beta combination. Moreover, multiple horizontal gene transfers could have occurred rather recently amongst prokaryotes. Whichever the actual history of carbamoyltransferases, our data suggest that the last common ancestor to all extant life possessed differentiated copies of genes coding for both carbamoyltransferases, indicating it as a rather sophisticated organism.

Amino Acid Sequence↗

PubMed1999

Homocysteine metabolism in cardiovascular cells and tissues: implications for hyperhomocysteinemia and cardiovascular disease.

We have determined the activity and protein levels of CBS in a number of cardiovascular cells and tissues by direct enzyme assay and Western blot analysis, respectively. We have also determined the activity of BHMT in these same tissues and cells and have come to the conclusion that neither enzyme is expressed. This results suggests that in the human cardiovascular system homocysteine metabolism is limited to the remethylation pathway catalyzed by MS. Thus, hyperhomocysteinemia in conjunction with a limited metabolic capacity for homocysteine in the cardiovascular system could result in cellular dysfunction.

Animals↗

PubMed1999

Intrathecal substance P-induced thermal hyperalgesia and spinal release of prostaglandin E2 and amino acids.

Substance P is an important neuromediator in spinal synaptic transmission, particularly in processing nociceptive afferent information. The effects of substance P are mediated by activation of the neurokinin 1 receptor. Evidence has suggested that excitatory amino acids such as glutamate, and prostaglandins including prostaglandin E2 are involved in the enhanced spinal excitability and hyperalgesia produced by spinal substance P. In the present study, we have demonstrated that intrathecal injection of substance P (20 nmol) in rats chronically implanted with intrathecal dialysis catheters induced a decrease in thermal paw withdrawal latency (before: 10.4+/-0.3 s; after 7.6+/-0.6 s), which was accompanied by an increase in prostaglandin E2 (362+/-37% of baseline), glutamate (267+/-84%) and taurine (279+/-57%), but not glycine, glutamine, serine or asparagine. Intrathecal injection of artificial cerebrospinal fluid had no effect upon the behavior or release. Substance P-induced thermal hyperalgesia and prostaglandin E2 release were significantly attenuated by a selective neurokinin 1 receptor antagonist RP67580, but not by an enantiomer RP68651. However, substance P-induced release of glutamate and taurine was not reduced by treatment with RP67580. SR140333, another neurokinin 1 receptor antagonist, displayed the same effects as RP67580 (i.e. block of thermal hyperalgesia and prostaglandin E2 release, but not release of amino acids). These results provide direct evidence suggesting that the spinal substance P-induced thermal hyperalgesia is mediated by an increase in spinal prostaglandin E2 via activation of the neurokinin 1 receptor. These findings define an important linkage between small afferents, sensory neurotransmitter release and spinal prostanoids in the cascade of spinally-mediated hyperalgesia. The evoked release of glutamate is apparently not a result of activation of neurokinin 1 receptors. Accordingly, consistent with other pharmacological data, acute spinal glutamate release does not contribute to the hyperalgesia induced by activation of spinal neurokinin 1 receptors.

Amino Acids↗

PubMed1999

Neural populations in the rat forebrain and brainstem activated by the suckling stimulus as demonstrated by cFos expression.

During lactation in the rat, the suckling stimulus plays an important role in mediating alterations in hypothalamic neuroendocrine function associated with lactation. To provide the basis for understanding the neural circuitry that may transmit suckling-induced signals into the hypothalamus, the present study used the expression of the immediate-early gene product, cFos protein, as a marker for neuronal activation to identify neural populations in the brain of lactating female rats activated by the suckling stimulus. In addition, cFos expression induced by the exteroceptive sensory stimuli (olfactory, auditory, visual) associated with pup exposure alone was also determined. Thus, cFos patterns in response to the physical suckling stimulus, which would include exteroceptive sensory stimuli associated with pup exposure, were compared with the patterns induced in response to pup exposure alone, so that neuronal populations specifically activated by the suckling stimulus could be identified. After 90 min of suckling, several forebrain areas, including the lateral septum, medial preoptic area, periventricular preoptic area and supraoptic nucleus of hypothalamus, showed a significant increase in cFos expression, compared with non-suckled controls and pup exposure animals. In addition, in the bed nucleus of stria terminalis, the medial amygdala and several cortical areas, cFos-positive cells were found in both suckling and pup exposure animals. In the brainstem, the suckling stimulus induced a significant increase in cFos expression in the ventrolateral medulla, locus coeruleus, lateral parabrachial nucleus, lateral and ventrolateral portions of the caudal part of the periaqueductal gray, and caudal portion of the paralemniscal nucleus, compared with non-suckled controls and pup exposure animals. As expected, in several areas related with sensory input, such as reticular formation and pontine nucleus, cFos expression was found in both suckling and pup exposure animals. Moreover, when double-label immunocytochemistry was used to identify cFos- and catecholamine-positive neurons in the brainstem, it was found that catecholamine-positive neurons in the ventrolateral medulla and locus coeruleus showed a significant increase in cFos expression in response to suckling compared with non-resuckled and pup-exposure groups. Using cFos expression as a marker for neuronal activation, the present studies identified the neural populations in the brain that are activated by the suckling stimulus. By comparing the pattern of cFos expression observed in response to pup exposure alone or the suckling stimulus, the present studies differentiated the neural populations activated by the physical suckling stimulus from the populations activated by the exteroceptive sensory stimuli associated with pup exposure. These suckling-activated areas are likely candidates for playing an important role in transmitting the effects of the suckling stimulus into the hypothalamus to regulate neuroendocrine alterations associated with lactation.

Animals↗

PubMed1999

Flow injection with chemical reaction interface-isotope ratio mass spectrometry: an alternative to off-line combustion for detecting low levels of enriched 13C in mass balance studies.

We have evaluated the potential of flow injection chemical reaction interface isotope-ratio mass spectrometry to replace radioactive labeling techniques in material balance studies. A sample is flow injected and transmitted through a desolvation system followed by combustion to form 13CO2 with a microwave-powered chemical reaction interface. We can detect trace amounts of a 13C-labeled drug (3'-azido-3'-deoxythymidine, AZT) in urine or feces. Our ability to quantify less than 100 ng/mL of excess 13C (approximately 1 microgram/mL of 13C-labeled AZT) from a sample equivalent to 10 microL of urine is superior to previous detection limits for 13C in urine that use off-line combustion methods. Parallel studies using 14C-labeled AZT showed that our stable isotope method provides comparable percent excretion data for urine and feces. These results support previous findings that mass balance studies could be carried out with isotope-ratio mass spectrometer, here using doses as low as 1-2 mg/kg.

Algorithms↗

PubMed1999

Study of binding of 12(S)-hydroxy-5(Z),8(Z),10(E), 14(Z)-eicosatetraenoic acid to bovine serum albumin using dynamic surface tension measurements.

In a recent paper,(1) we demonstrated that molecular interactions between biopolymers and other smaller molecules can be detected by means of dynamic surface tension measurements. In the present paper, we demonstrate that the same methodology can be employed for investigating dose effects and specificity of molecular interactions. Three similar lipids were chosen for this study: 12(S)-hydroxy-5(Z), 8(Z),10(E),14(Z)-eicosatetraenoic acid (12(S)-HETE-free acid), methyl 12(S)-hydroxy-5(Z),8(Z),10(E),14(Z)-eicosatetraenoate (12(S)-HETE-methyl ester), and 5(Z),8(Z),11(Z), 14(Z)-eicosatetraenoic acid (arachidonic acid-free acid). These substances were added to a fatty acid free bovine serum albumin (BSA) aqueous solution at different lipid concentrations. The characteristic tension response indicates that molecular interactions between 12(S)-HETE-free acid and BSA exist. The detected interactions are concentration dependent: at a molecular ratio of lipid to protein of 1:1, the binding of 12(S)-HETE-free acid to BSA is hydrophobic in nature; at the molecular ratio of lipid to protein of 10:1, a secondary binding occurs and is hydrophilic in nature. Similar molecular interactions were not detected between 12(S)-HETE-methyl ester or arachidonic acid-free acid and BSA, indicating that the interactions between 12(S)-HETE-free acid and BSA are specific. As an independent means, surface elasticity is used to probe the molecular interactions at the interface. In the case of 12(S)-HETE-free acid but not its methyl ester or arachidonic acid, distinct higher surface elasticities were observed at lipid concentrations in excess of a molecular ratio of lipid to protein of 1:1. This finding reinforces the above stipulations.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗

PubMed1999

Expression of chicken gizzard RLC complements the cytokinesis and developmental defects of Dictyostelium RLC null cells.

Dictyostelium RLC null cells have defects in cytokinesis and development that can be rescued by expression of either the wild type Dictyostelium RLC or an RLC mutant that cannot be phosphorylated by MLCK (S13A) (Ostrow et al., 1994). The wild type and S13A mutant LCs rescued the cells equally well, despite the fact that RLC phosphorylation increases purified Dictyostelium myosin's activity 5-fold. In this report, we assess the ability of foreign RLCs to rescue the RLC null phenotype. The RLC from smooth muscle myosin, whose activity is tightly controlled by phosphorylation, rescued the null cell phenotype. The purified hybrid myosin had an activity and motility comparable to phosphorylated Dictyostelium myosin. In contrast, cells expressing skeletal muscle RLC were deficient in cytokinesis and development, despite having an activity and motility similar to that of myosin with the unposphorylatable S13A mutant RLC. Neither foreign LC was phosphorylated when expressed in Dictyostelium. These results suggest that the level of actin-activated ATPase activity and motility is not the sole determinant of proper myosin function in vivo. Other heavy chain/light chain interactions, which occur only with the native RLC and smooth muscle RLC, appear to be necessary for optimal function.

Amino Acid Sequence↗

PubMed1999

Dark is a Drosophila homologue of Apaf-1/CED-4 and functions in an evolutionarily conserved death pathway.

Here we identify a new gene, dark, which encodes a Drosophila homologue of mammalian Apaf-1 and Caenorhabditis elegans CED-4, cell-death proteins. Like Apaf-1, but in contrast to CED-4, Dark contains a carboxy-terminal WD-repeat domain necessary for interactions with the mitochondrial protein cytochrome c. Dark selectively associates with another protein involved in apoptosis, the fly apical caspase, Dredd. Dark-induced cell killing is suppressed by caspase-inhibitory peptides and by a dominant-negative mutant Dredd protein, and enhanced by removal of the WD domain. Loss-of-function mutations in dark attenuate programmed cell deaths during development, causing hyperplasia of the central nervous system, and other abnormalities including ectopic melanotic tumours and defective wings. Moreover, ectopic cell killing by the Drosophila cell-death activators, Reaper, Grim and Hid, is substantially suppressed in dark mutants. These findings establish dark as an important apoptosis effector in Drosophila and raise profound evolutionary considerations concerning the relationship between mitochondrial components and the apoptosis-promoting machinery.

Amino Acid Sequence↗

PubMed1999

Effect of acute high dose dobutamine administration on serum thyrotrophin (TSH).

OBJECTIVE: The interpretation of thyroid function tests in the setting of severe illness is often complicated by concomitant drug administration which may independently produce changes in thyroid hormone concentrations or even secondary hypothyroidism. Although the effects of dopamine on TSH are well established, the effects of dobutamine, another drug commonly used in the setting of severe illness, on TSH are unknown. The aim of the study was to establish the effect(s) of acute high dose dobutamine on serum TSH concentration. DESIGN AND PATIENTS: Thirty subjects undergoing dobutamine stress echocardiogram were compared to twenty controls. Serum TSH was determined between the hours of 0800 and 1000 h at baseline, at maximum dobutamine infusion (20-50 micrograms/kg/min and 15 minutes after stopping dobutamine. MEASUREMENTS: Serum TSH concentration was measured using a third generation chemiluminescent assay. RESULTS: TSH concentration decreased with time in both dobutamine and control subjects and there was an additional statistically significant effect of dobutamine treatment to decrease TSH. TSH concentration remained within the normal range in all subjects who started with normal TSH concentration and remained above normal in the three dobutamine-treated subjects with elevated TSH at baseline. The dobutamine-associated decrease in TSH was still present 15 minutes after discontinuing dobutamine. CONCLUSIONS: These results indicate that acute high dose dobutamine lowers TSH by an unknown mechanism. Additional study with prolonged dobutamine infusion is needed to establish the steady state level and physiological consequences of dobutamine-inhibited TSH.

Adrenergic beta-Agonists↗