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Biomedical subjects

D Lang

Publications and source records attributed to D Lang.

At least 19 recordsLinked to original sources
PubMed1995

Prostacyclin aerosol in an infant with pulmonary hypertension.

Prostacyclin aerosol (100 ng/kg.min) caused selective pulmonary vasodilation without causing systemic hypotension in an infant with idiopathic pulmonary hypertension. Cardiac index increased suggesting improved right ventricular function. CONCLUSION Aerosolized prostacyclin causes selective pulmonary vasodilation and may thereby improve systemic haemodynamics in infants with primary pulmonary hypertension. Because of the lack of known toxicity and the uncomplicated mode of administration it may be a useful alternative to inhaled nitric oxide.

Aerosols↗
PubMed1995

Late effects of anthracycline therapy in childhood in relation to the function of the heart at rest and under physical stress.

To evaluate the long-term effects of anthracyclines on the myocardium of the young child we examined 34 patients who had been treated with anthracyclines in childhood. In addition to anthracycline, the patients were treated with other potentially cardiotoxic substances within the framework of different protocols. The mean cumulative anthracycline dose was 128.6 mg/m2, the average age at onset of chemotherapy 4.2 years, and the time interval after discontinuation of treatment 9.0 years. The cardiological examination consisted of a physical examination, electrocardiography and echocardiography, including Doppler and bio-impedance cardiography. The patients were studied at rest and after physical exercise with a cycle ergometer test in a supine position. The results of the physical examination, the electrocardiogram at rest and the 24 h Holter monitoring were normal. The left ventricular enddiastolic diameter, shortening fraction, velocity of fibre shortening (VCF), the diastolic flow profile at the mitral valve level and the cardiac stroke volume at rest were also normal. However, the shortening fraction (SF) was below the margin of 2 standard deviations in two patients and the VCF in three patients. There was a significant reduction in septal thickness, (-1.4 SD, P < 0.0004), in the width of left ventricular posterior wall (-1.5 SD, P > 0.0002) and in the left ventricular myocardial mass (-0.76 SD, P = 0.0042). Physical working capacity was normal. Immediately after physical stress the expected rise of SF and VCF did not occur and the SF fell below the values at rest. In comparison to a healthy control group the SF and the VCF were markedly decreased (P > 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Molecular species analysis of 1,2-diglycerides on phorbol ester stimulation of LA-N-1 neuroblastoma cells during proliferation and differentiation.

1,2-Diacyl-sn-glycerol (DAG) is a product of cell activation that has emerged as an important intracellular messenger whose primary function appears to be the activation of protein kinase C. They originate by the activation of phospholipases, which hydrolyze different phospholipids depending on the external stimulus and the nature of the cells, leading to the production of different molecular species. In the present study the quantitative changes in the total mass and the molecular species of DAG formed on phorbol ester (12-O-tetradecanoyl-phorbol 13-acetate) stimulation were investigated in proliferating and retinoic acid (RA)-differentiated human LA-N-1 cells. The TPA treatment of both cell types elicited an increase in the total amount of DAG. The increase was biphasic; i.e., an initial peak at 2-5 min was followed by a sustained increase that persisted for > 30 min. The analysis of the molecular species of DAG and phospholipids showed that in proliferating LA-N-1 cells, the DAG increase corresponds to the production of mainly saturated/monounsaturated (16:0-18:1, 18:0-18:1) and saturated/saturated (16:0-16:0, 16:0-18:0) species, suggesting that they originate essentially from the hydrolysis of phosphatidylcholine. In contrast, RA-differentiated cells responded to TPA treatment by increasing the level of saturated/polyunsaturated (16:1-22:6, 18:0-22:6, 16:0-20:4, 18:0-20:4) and monounsaturated/monounsaturated (18:1-18:1) species, suggesting mainly a phosphatidylethanolamine origin. These findings indicate that the treatment of LA-N-1 cells with TPA generates different molecular species of DAG depending on their physiological state. These observations suggest in turn that different phospholipases are activated by TPA in proliferating and RA-differentiated cells.

Cell Differentiation↗
PubMed1995

Chemopreventive activity of Oltipraz against N-nitrosobis(2-oxopropyl)amine (BOP)-induced ductal pancreatic carcinoma development and effects on survival of Syrian golden hamsters.

The synthetic dithiolethione Oltipraz has marked cancer chemopreventive and phase II enzyme inducing activity in various animal carcinogenesis models, but has not been examined in any animal models of ductal pancreatic cancer relevant to the human disease. The chemopreventive potential of Oltipraz on pancreatic tumor incidence and multiplicity was examined in the N-nitrosobis(2-oxopropyl)-amine (BOP)-induced ductal pancreatic adenocarcinoma model in Syrian hamsters. Animals were maintained on control semipurified diets or semipurified diets containing 300 and 600 mg/kg Oltipraz beginning 2 weeks prior to BOP initiation and throughout the 26 week study. Oltipraz at 300 mg/kg had no effect on the incidence or multiplicity of preneoplastic, neoplastic or metastatic lesions, while at 600 mg/kg dietary Oltipraz the incidence of pancreatic adenocarcinomas was reduced significantly (P < or = 0.05) compared to BOP-treated controls. Dietary Oltipraz at both doses had a significant influence on reducing mortality and morbidity in tumor-bearing animals with metastatic disease. At 26 weeks, total hepatic glutathione-S transferase (GST) activity and GST mu activity were elevated significantly in Oltipraz-treated animals, while total pancreatic GST activity was reduced, albeit not significantly. Serum lipase activity, a marker for pancreatic damage, exhibited a progressive decline in BOP-treated animals administered Oltipraz compared to BOP-treated controls at 12 weeks of the study; by week 26, lipase activity was comparable in all groups and reduced compared to activity at week 12. Positive nuclear immunostaining for the p53 tumor suppressor protein, a hallmark of human pancreatic cancer and a transient response to DNA damage, was observed in only a small percentage of BOP-induced pancreatic lesions and was not influenced Oltipraz administration. Further chemoprevention and pharmacologic studies of Oltipraz in relevant animal models of ductal pancreatic cancer could provide a foundation for future studies in human populations at potential risk for pancreatic cancer.

Animals↗
PubMed1995

Functional interaction between the human cytomegalovirus 86-kilodalton IE2 protein and the cellular transcription factor CREB.

The 86-kDa IE2 protein (IE86) of human cytomegalovirus (HCMV) has been described as a promiscuous transactivator of viral, as well as cellular, gene expression. Investigation of the mechanism used by IE86 to activate gene expression from the early UL112/113 promoter of HCMV revealed the existence of three binding sites for IE86 located between nucleotides -290 and -120 relative to the transcriptional start site (H. Arlt, D. Lang, S. Gebert, and T. Stamminger, J. Virol. 68:4117-4125, 1994). As shown previously, deletion of these target sites resulted in a reduction of IE86-mediated transactivation by approximately 70%. The remaining promoter, however, could still be stimulated about 40-fold, indicating the presence of an additional responsive element within these sequences. Here, we provide evidence that a binding site for the cellular transcription factor CREB can also act as a target for IE86 transactivation. By DNase I protection analysis, a binding sequence for CREB could be detected between nucleotides -78 and -56 within the respective promoter region. After in vitro mutagenesis of this CREB-binding site within the context of the entire UL112/113 promoter, a marked reduction in transactivation levels was evident. Moreover, when individual CREB-binding sites were positioned upstream of a minimal, TATA box-containing UL112/113 promoter, they were able to confer strong IE86 responsiveness, whereas a mutated sequence did not exert any effect. In far Western blot and pull-down experiments, a direct interaction of IE86 with the cellular transcription factor CREB could be observed. The in vivo relevance of this in vitro interaction was confirmed by using various GAL4 fusion proteins in the presence or absence of IE86 which revealed a strong activation only in the presence of both a GAL4-CREB fusion and IE86. This shows that at least one specific member of the ATF/CREB family of transcription factors is involved in mediating transactivation by the HCMV IE86 protein.

Base Sequence↗
PubMed1995

Endothelial inhibition of myofilament calcium response in intact cardiac myocytes.

Recent studies suggest that factors released by endothelial cells can modify contraction of isolated cardiac preparations. We compared the effects of 1) coronary effluent collected from Langendorff-perfused rat hearts and 2) cultured vascular endothelial cell superfusate on isolated fura 2-loaded rat ventricular cardiac myocytes. Coronary and cultured cell effluent produced similar effects. Isotonic contraction amplitude was reduced by 31.6 +/- 2.6 and 70.2 +/- 9.1%, respectively; myocyte diastolic length increased by 0.8 +/- 0.2 and 1.5 +/- 0.4 microns, and time to 50% relaxation fell by 6.2 +/- 1.8 and 10.1 +/- 2.0% (all P < 0.05; n = 29 and 15 myocytes, respectively). A small fall in the amplitude of the intracellular Ca2+ transient was observed (8.5 +/- 1.5 and 10.9 +/- 3.5%, respectively; both P < 0.01), insufficient to account for the reduction in twitch amplitude. In intact myocytes tetanized in the presence of thapsigargin, the steady-state myofilament response to Ca2+ was reduced by coronary and cultured cell effluent. These results suggest that both coronary endothelial cells in situ and cultured endothelial cells tonically release a factor(s) that reduces myofilament Ca2+ response.

Actin Cytoskeleton↗
PubMed1995

Prolonged akinetic mutism due to multiple sclerosis.

A 25-year-old woman with multiple sclerosis and an affective disorder probably secondary to MS presented with multiple neurological signs and symptoms suggestive of active MS, most prominently akinetic mutism. Spinal fluid analysis and MRI supported a diagnosis of active MS. SPECT and EEG were nonspecifically abnormal. After 6 weeks of severe akinetic mutism refractory to one ECT treatment and trials of steroids and stimulants, the patient recovered spontaneously over a 2-month period. An acute brainstem lesion seen on MRI may explain this patient's akinetic mutism.

Adult↗
PubMed1994

Minor groove contacts are essential for an interaction of the human cytomegalovirus IE2 protein with its DNA target.

The 86 kDa immediate early-2 protein (IE2, IE86) of human cytomegalovirus (HCMV) is a multifunctional polypeptide that can regulate gene expression both positively and negatively. In particular, it represses its own mRNA synthesis by binding directly to a sequence element, termed cis repression signal (CRS), that is located between the TATA box and the transcriptional start site of the major IE enhancer/promoter of HCMV. Here, we provide evidence that IE86, unlike most sequence-specific DNA-binding proteins, interacts primarily within the minor groove of the DNA helix. This was shown by hydroxyl radical and methylation interference assays. In addition, binding studies with inosine-substituted oligonucleotides which have an altered major groove morphology without changing the surface of the minor groove, confirmed the results obtained in interference analyses. This establishes IE86 as a member of a small group of DNA binding proteins that interact with A - T rich sequences within the minor groove and which also includes the TATA-box binding protein TBP. Remarkably, IE86 and TBP are able to bind simultaneously in an immediate vicinity at the major IE enhancer/promoter of HCMV. As minor groove binding proteins are known to bend DNA heavily this could contribute to the observed negative regulation of transcription by IE86.

Antigens, Viral↗
PubMed1994

Monocyte activation for enhanced tumour necrosis factor-alpha and interleukin 6 production during chronic renal allograft rejection.

To evaluate the contribution of immune mechanisms in the initiation and progression of chronic renal allograft rejection we investigated monocyte-derived cytokine synthesis in vitro in 16 patients with histologically proven chronic rejection; 22 transplant patients with stable function served as controls. Basal tumour necrosis factor-alpha (TNF-alpha) production, measured by L 929 bioassay, was low and not significantly different in both groups. By triggering TNF-alpha formation in vitro by lipopolysaccharide (LPS), high concentrations of TNF-alpha (155.1 +/- 243.0 ng/ml) were measured in monocyte cultures from chronic rejection patients which greatly exceeded the TNF-alpha levels of 11.5 +/- 14.5 ng/ml in the control group. Measurement of interleukin 6 (IL-6) levels by enzyme immunoassay gave similar results, with significantly higher IL-6 concentrations in LPS-triggered monocyte cultures from chronic rejection compared with stable function patients. Additional stimulation of LPS-treated monocytes with interferon-gamma (IFN-gamma) as a priming agent enhanced TNF-alpha formation in stable function patients and, in contrast, slightly reduced monokine formation in chronic rejection patients, which suggests that in this group a high activation level of monocytes has already been reached in vivo by T cell factors such as IFN-gamma. Treatment of monocyte cultures in vitro with prednisolone reduced TNF-alpha formation differently in most but not all cultures from chronic rejection and stable function patients; thus this in vitro test system might be helpful in predicting the benefit of an intensified immunosuppressive regimen for chronic rejection patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Identification of binding sites for the 86-kilodalton IE2 protein of human cytomegalovirus within an IE2-responsive viral early promoter.

The 86-kDa IE2 protein (IE86) of human cytomegalovirus (HCMV) can act as both an activator and a repressor of gene expression. The mechanisms for both of these functions are not well defined. It has recently been demonstrated that this protein has sequence-specific DNA binding properties: it interacts directly with a target sequence that is located between the TATA box and the cap site of its own promoter. This sequence, termed the CRS (cis repression signal) element, is required for negative autoregulation of the IE1/IE2 enhancer/promoter by IE2. We demonstrate now that binding of this protein to DNA is not confined to this site but occurs also within an early promoter of HCMV that has previously been shown to be strongly IE2 responsive. By DNase I protection analysis using a purified, procaryotically expressed IE2 protein, we could identify three binding sites within the region of -290 to -120 of the UL112 promoter of HCMV. Competition in DNase I protection experiments as well as gel retardation experiments showed that the identified binding sites are specific and have high affinity. Deletion of IE2 binding sites from this promoter reduced the level of transactivation; however, the remaining promoter could still be stimulated about 40-fold. Constructs in which IE2 binding sites were fused directly to the TATA box of the UL112 promoter did not reveal a significant contribution of these sequences to transactivation. However, if an IE2 binding site was reinserted upstream of nucleotide -117 of the UL112 promoter, an increase in transactivation by IE2 was obvious, whereas a mutated sequence could not mediate this effect. This finding suggests that DNA-bound IE2 can contribute to transactivation but seems to require the presence of additional transcription factors. Moreover, a comparison of the detected IE2 binding sites could not detect a strong homology, suggesting that this protein may be able to interact with a broad spectrum of different target sequences.

Base Sequence↗
PubMed1994

Post-traumatic amnesia: still a valuable yardstick.

Records of coma and post-traumatic amnesia (PTA) were collected for a group of 38 patients with closed head injury. The results confirmed earlier studies indicating that patients may have short or negligible coma but report prolonged PTA. Comparison of eight patients with prolonged PTA (> 7 days) and short coma (< 6 hours) with the rest of the group on MRI in the acute stage showed that these patients had significantly more extensive hemispheric damage. In the group as a whole both coma and PTA were related to the number of areas in central brain structures in which lesions were detected, but only PTA was significantly related to the number of hemispheric areas in which lesions were found. It is concluded that although both coma and PTA are related to brain damage they reflect disparate patterns of lesions. Assessment of PTA can thus provide additional information concerning severity of injury.

Adolescent↗
PubMed1994

Differential effects of insulin-like growth factor I and platelet-derived growth factor on growth response, matrix formation, and cytosolic free calcium of glomerular mesangial cells of spontaneously hypertensive and normotensive rats.

In this study, we compared the cellular functions of cultured glomerular mesangial cells (MC) from spontaneously hypertensive rats (SHR) and from normotensive Wistar-Kyoto rats (WKY) in response to the growth factors insulin-like growth factor I (IGF-I) and platelet-derived growth factor (PDGF). IGF-I and PDGF at a concentration above 2 ng/ml and a combination of both tested growth factors exerted a highly elevated growth response of SHR MC versus WKY MC. The total RNA synthesis induced by IGF-I and PDGF was increased in SHR MC as compared with WKY MC, while the overall protein synthesis showed no differences between both strains. Analysis of cell-associated fibronectin accumulation and incorporation of proline into collagenous proteins revealed an enhanced basal and PDGF-stimulated matrix formation of SHR MC which was not dependent on the increased production of autocrine matrix-stimulatory mediators by SHR MC. Changes of cytosolic free calcium - [Ca2+]i - could not be correlated with the enhanced responsiveness of SHR MC to the tested growth factors. The described differences of cellular functions between SHR and WKY MC may contribute to pronounced glomerular alterations such as glomerulosclerosis seen in primary and secondary forms of hypertension.

Animals↗
PubMed1994

[Sinus node dysfunction in children without heart defect].

Sinus node dysfunction (SND) is a rare cause of bradycardia in children without structural heart disease. The clinical and diagnostic findings in 4 children with this condition are described. Two of them presented with symptoms, in one arrhythmias had been noted before birth, and a routine physical examination had revealed bradycardia in another. Age at onset of either clinical symptoms or bradycardia ranged from 0 to 11 1/2 years. Routine and 24-h-electrocardiograms showed atrioventricular junctional rhythms with minimal rates of 25/min and episodes of asystole with a maximal duration of 10.3 s. Other electrocardiographic abnormalities such as first degree atrioventricular block, ventricular extrasystoles or tachycardia were common findings. Electrophysiological studies were performed in 3 cases and confirmed the diagnosis of SND. A permanent pacemaker was inserted in 2 children; medical treatment did not have any long-term effect. During a follow-up period of 5 to 13 years there were no complications. In summary, SND in childhood can be assessed by Holter monitoring with high reliability. Electrophysiological studies are not necessary and of limited value. Therapeutic policies and prognostic statements are difficult to establish due to the small number of cases so far described. Permanent cardiac pacing, however, is unavoidable in symptomatic children.

Bradycardia↗
PubMed1994

Development of infant botulism in a 3-year-old female with neuroblastoma following autologous bone marrow transplantation: potential use of human botulism immune globulin.

Infant botulism is a rare disease caused by the release of toxin produced in the intestinal tract by Clostridium botulinum. The disease primarily affects infants under 1 year of age. We report a 3-year-old child with stage IV neuroblastoma who developed symptoms of progressive motor weakness, bulbar palsy and respiratory failure 42 days after autologous BMT. The diagnosis of infant botulism was established by identifying botulism toxin in the stool. Human botulism immune globulin (HBIG) was administered. Following the diagnosis, the patient made significant recovery over the next 7 weeks and was successfully extubated from mechanical ventilation. However, her neuroblastoma eventually recurred and she subsequently died of progressive disease. Although the etiology of the development of infant botulism in this case following autologous BMT still remains unclear, alteration of the intestinal microbial environment from gut sterilization and laminar airflow room isolation or, alternatively, immune suppression during pre- and post-autologous BMT and activation of endogenous spores may have contributed to the development of this disease. The use of HBIG in children with botulism over 1 year of age may be beneficial.

Bone Marrow Transplantation↗
PubMed1993

Plasma L-arginine levels in a rabbit model of hypercholesterolaemia.

A novel method for the quantitation of L-arginine in plasma samples has been developed, based on the technique of enantiomer labelling coupled to the capillary gas chromatographic separation of amino acids. Using this technique plasma L-arginine levels have been measured in rabbits fed a 1% cholesterol-containing diet and compared with rabbits fed a standard diet. Blood cholesterol levels were significantly elevated in the rabbits fed cholesterol but no significant difference was found in plasma L-arginine levels between the cholesterol-fed and control animals. No D-arginine was found in any of the plasma samples. It is concluded that the impairment in endothelium-dependent relaxation previously described in this animal model of hypercholesterolaemia is not due to deficiency of plasma L-arginine.

Animals↗
PubMed1993

Platelet-activating factor antagonism attenuates platelet and neutrophil activation and reduces myocardial injury during coronary reperfusion.

Platelet-activating factor (PAF) is known to be synthesized during tissue reperfusion and to be involved in the activation of platelets and neutrophils in inflammatory processes. The hypothesis of the present study is that PAF is central in the pathophysiology of myocardial reperfusion and that specific PAF receptor antagonism may reduce myocardial reperfusion injury. Utilizing an intact sheep model that involved a 90-min occlusion of the mid-left anterior descending coronary artery followed by 6 hr of reperfusion, a study group that received a specific PAF receptor antagonist (L-659,989, 5 mg/kg) 10 min before reperfusion was compared to a control group that received a saline placebo (n = 8 in each group). Coronary sinus platelet aggregating activity and neutrophil oxidative burst were studied by standard platelet aggregometry and the 2',7'-dichlorofluorescein flow cytometric assay, respectively. Left coronary flow and left ventricular functions measured as peak +/- dp/dt and stroke work were analyzed. The extent of myocardial infarction at the end of 6 hr of reperfusion was measured by standard histochemical stainings. The results demonstrated that platelets were hyperaggregable and that neutrophil oxidative burst was increased in the myocardial compartment during the first 3 hr of coronary reperfusion after 90 min of ischemia. The administration of the PAF antagonist immediately before reflow effectively prevented the activation of platelets and neutrophils. This was associated with significantly improved coronary reflow and ventricular function during the observed reperfusion period and with reduced myocardial infarct measured at 6 hr of reperfusion. We conclude that the use of a specific PAF receptor antagonist, L-659,989, immediately before controlled coronary reflow attenuated the activation of platelets and neutrophils that occurred during reperfusion. These anti-platelet and anti-neutrophil effects together with the inhibition of the known direct deleterious effects of PAF on the myocardium translated into improved ventricular function and reduced myocardial infarct.

Adenosine Diphosphate↗
PubMed1993

Induction of a calcium-independent NO synthase by hypercholesterolaemia in the rabbit.

Endothelium-dependent and -independent relaxation of aortic ring preparations was assessed and nitric oxide (NO) synthase activity measured in the lung, and cerebellum of cholesterol-fed and normal rabbits. Endothelium-dependent relaxation of acetylcholine and ATP was depressed while that to the calcium ionophore, A23187, was unaltered in the cholesterol-fed group. Relaxation to sodium nitroprusside was however greater in aortae from the cholesterol-fed animals. Neither Ca(2+)-dependent nor Ca(2+)-independent NO synthase activity could be detected in aortae or hearts taken from either group of animals. Activity of both enzymes was unaltered in cerebellae from both groups of animals. Activity of the Ca(2+)-independent enzyme was however significantly greater (ca. 2 fold) in lungs from the cholesterol-fed rabbits though the activity of the Ca(2+)-dependent NO synthase was not significantly altered. This finding may account for the increased production of nitrogen oxides previously observed in this model of hypercholesterolaemia.

Amino Acid Oxidoreductases↗