Pentoxifylline and intravenous gamma globulin combination therapy for acute Kawasaki disease

We compared the efficacy of oral administration of pentoxifylline (PTX) and intravenous infusions of gamma globulin (IVGG) combination therapy with that of IVGG in reducing the frequency of coronary-artery lesions (CAL) in children with Kawasaki disease (KD), in a randomized trial. All patients with KD received acetylsalicylic acid (30 mg/kg per day), until the 30th day, after the onset of fever, followed by daily acetylsalicylic acid at a dose of 3-5 mg/kg per day there-after, and intravenous IVGG, 200 mg/kg per day, for 5 consecutive days. In addition, patients randomly assigned to PTX and IVGG combination therapy groups received oral PTX at a dosage of 10 mg/kg per day (low-dose) or 20 mg/kg per day (high-dose), in three divided doses until the 30th day. Patients with KD were all free from CAL prior to treatment. We assessed the presence of CAL by two-dimensional echocardiography which was also done prior to treatment and then twice a week after hospital admission. We detected CAL in 3 of 18 patients (16.7%) in the IVGG therapy group, as compared with 2 of 18 patients (11.1%) in the low-dose PTX and IVGG combination therapy group. There were no significant differences between the two groups. In the next study, we detected CAL in 3 of 21 patients (14.3%) in the IVGG therapy group, as compared with none of 22 patients (0%) in the high-dose PTX and IVGG combination therapy group (ntent/uv7k41n32k142704/xxlarge967.gif" alt="chi" align="MIDDLE" BORDER="0">² = 6.4, P < 0.02). No adverse side-effects were observed in 79 patients with KD.     

次声刺激后大鼠下丘神经型一氧化氮合成酶阳性神经元FOS蛋白的表达

目的　研究次声对下丘的作用机制。方法　用抗 Ｆ Ｏ Ｓ 蛋白和抗神经型一氧化氮合成酶（ｎｃ Ｎ Ｏ Ｓ） 免疫组织化学方法,将大鼠暴露于８ Ｈｚ 、１２０ ｄ Ｂ 的次声中,持续２ 小时,观察下丘 Ｆ Ｏ Ｓ 蛋白的表达情况及其与ｎｃ Ｎ Ｏ Ｓ 阳性神经元的关系。结果　在下丘出现大量 Ｆ Ｏ Ｓ 样及散在的ｎｃ Ｎ Ｏ Ｓ 样免疫反应阳性神经元,且部分ｎｃ Ｎ Ｏ Ｓ阳性神经元的胞核同时呈 Ｆ Ｏ Ｓ 染色阳性,这种 Ｆ Ｏ Ｓ／ｎｃ Ｎ Ｏ Ｓ 双标记神经元约占 Ｆ Ｏ Ｓ 阳性神经元总数的１０ ％ 。结论　部分ｎｃ Ｎ Ｏ Ｓ 神经元参与对次声刺激的反应。     

A healthcare staff decision model considering the effects of staff cross‐training

In this study a staff planning model for a health service clinic has been developed and validated using an example case of a health service clinic. The primary purpose of this research is to develop a representative staff planning model which balances the cost and benefits of staff task flexibility through crossntent/n6804320lj426g05/xxlarge8208.gif" alt="dash" align="MIDDLE" BORDER="0">training for a healthcare facility. Additionally, legal requirements for task substitution in the healthcare industry have been considered in the model.     

Dysphagia in Parkinson's disease: Pharyngeal manometry and fiberoptic endoscopic evaluation

ObjectiveDysphagia is a common symptom in Parkinson's disease (PD) and it represents a negative prognostic factor because of its complications. This study is to evaluate pharyngeal dysphagia for boluses of various consistencies with Fiberoptic Endoscopic Evaluation of Swallowing (FEES) and Pharyngeal High-Resolution Manometry (PHRM) in a group of PD patients, making a comparison between the information provided by the two exams.MethodsGroup of 20 patients affected by PD was selected and initially subjected to a qualitative evaluation of the swallowing performing FEES. Subsequently, they were evaluated by PHRM to identify quantitative measures associated with pressures expressed by pharyngeal organs during swallowing. Values obtained in the study group were compared with those recorded in a group of 20 healthy subjects.ResultsStudy showed that Pmax (the maximum pressure elicited by the single pharyngeal muscle structures involved in swallowing) was significantly lower than the control group (p<0.05) for all the boluses and consistency tested, in particular for the Tongue base and the Cricopharyngeal muscle. Pmean pre-swallowing pressure (represents the mean value of a contraction in which basal and maximal pressure where normally calculated) was significantly higher compared to normal subjects for the Tongue base and the Cricopharyngeal muscle (p<0.05). Mean intra-swallowing pressure was higher for the Velopharynx and the Cricopharyngeal muscle, but lower for the tongue base. Pmax and Pmean at PHRM were altered independently to the degree of dysphagia detected at FEES, and they did not correlate either with the location of the residue or with the type of bolus. Images displayed at the FEES, found the corresponding biomechanical explanations in the PHRM, which also allowed us to quantify the extent of the dysfunction, through the calculation of the pressures generated in the various structures studied.ConclusionPHRM is particularly useful in the early detection of dysphagia, when FEES may still show no evidence of abnormal swallowing.     

保存时间及温度对血清标本补体C_3和CH50测定结果的影响

目的 了解保存时间及温度对补体活性的影响。方法:用单向琼脂扩散法和非离心单管法对不同温度和时间下标本的C_3含量及CH50进行测定。结果与结论:血清补体C_5含量在室温下24h、4C下4dC、-10C和-20C下8d内无显著变化;CH50在室温下12h、4C下24h,-10C和-20C下8d内CH50无明显变化。     

N-nitro- -arginine methylester is protective against ethanol-induced gastric damage in cholestatic rats

In this study the effect of nitric oxide (NO) synthesis inhibition on ethanol-induced gastric damage was evaluated in bile duct-ligated, sham-operated and unoperated rats. The animals were injected intraperitoneally with saline, -arginine (200 mg/kg) or N^G-nitro- -arginine methylester ( -NAME) in doses of 5, 15 and 30 mg/kg, 30 min before ethanol administration. The animals were killed 1 h after ethanol administration and their stomachs were removed for measurement of gastric mucosal damage. The results showed that -NAME significantly enhanced the development of gastric mucosal lesions in sham-operated and unoperated rats, while in bile duct-ligated animals, -NAME decreased and -arginine enhanced the potentiation of ethanol-induced gastric mucosal damage. The plasma level of nitrite and nitrate was also measured and was significantly higher in bile duct-ligated rats than in control groups. The results suggest that inhibition of NO synthase with -NAME has different effects on ethanol-induced gastric damage in cholestatic groups and in normal rats and that these effects can be explained by overproduction of NO in bile duct-ligated animals.     

Animal models of Parkinson's disease: An empirical comparison with the phenomenology of the disease in man

Summary Animal models are an important aid in experimental medical science because they enable one to study the pathogenetic mechanisms and the therapeutic principles of treating the functional disturbances (symptoms) of human diseases. Once the causative mechanism is understood, animal models are also helpful in the development of therapeutic approaches exploiting this understanding. On the basis of experimental and clinical findings. Parkinson's disease (PD) became the first neurological disease to be treated palliatively by neurotransmitter replacement therapy.The pathological hallmark of PD is a specific degeneration of nigral and other pigmented brainstem nuclei, with a characteristic inclusion, the Lewy body, in remaining nerve cells. There is now a lot of evidence that degeneration of the dopaminergic nigral neurones and the resulting striatal dopamine-deficiency syndrome are responsible for its classic motor symptoms akinesia and bradykinesia. PD is one of many human diseases which do not appear to have spontaneously arisen in animals. The characteristic features of the disease can however be more or less faithfully imitated in animals through the administration of various neurotoxic agents and drugs disturbing the dopaminergic neurotransmission.The cause of chronic nigral cell death in PD and the underlying mechanisms remain elusive. The partial elucidation of the processes underlie the selective action of neurotoxic substances such as 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), has however revealed possible molecular mechanisms that give rise to neuronal death. Accordingly, hypotheses concerning the mechanisms of these neurotoxines have been related to the pathogenesis of nigral cell death in PD.The present contribution starts out by describing some of the clinical, pathological and neurochemical phenomena of PD. The currently most important animal models (e.g. the reserpine model, neuroleptic-induced catalepsy, tremor models, experimentally-induced degeneration of nigro-striatal dopaminergic neurons with 6-OHDA, methamphetamine, MPTP, MPP⁺, tetrahydroisoquinolines, ntent/ml2vm278q58n34j5/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-carbolines, and iron) critically reviewed next, and are compared with the characteristic features of the disease in man.     

Degradation Kinetics of BMP 777, an Elastase Inhibitor

Purpose. The objective was to evaluate the degradation profile of the elastase inhibitor DMP 777 and lay the foundation for formulation development. Methods. The pK_a was determined by potentiometric titration in mixed-aqueous solvents. The degradation kinetics were studied as a function of pH, buffer concentration, ionic strength, methanol concentration and temperature using a stability-indicating HPLC assay. The degradation products were identified by LC-MS, NMR, and by comparison with authentic samples. Results. The pK_a for the protonated piperazine nitrogen was estimated to be 7.04. The pH-rate profile is described by specific acid-, water-, and specific base-catalyzed pathways. The pH of maximum stability is in the range of 4 to 4.5 where water is the principal catalyst in the reaction. Buffer catalysis, primary salt effects and medium effects were observed. The proposed mechanism for acid catalyzed degradation is the rarely observed A_AL1 which involves alkyl-nitrogen heterolysis. The driving force for the reaction appears to lie in the stability of the benzylic carbocation. The proposed mechanism for base catalyzed degradation is B_AC2 which involves ntent/n0130x329j066j67/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-lactam ring opening. The ntent/n0130x329j066j67/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-lactam ring of DMP 777, a monolactam, appears to be as reactive as that in benzylpenicillin in the k _OH controlled region where a similar mechanism of hydrolysis should be operative. A contributing factor to this increased reactivity may lie in the reduced basicity of the ntent/n0130x329j066j67/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-lactam nitrogen making it a good leaving group. Conclusions. The degradation profile indicates that development of a solution dosage form of DMP 777 with adequate shelf-life stability at room temperature is feasible.     

Specific inhibition of epidermal growth factor receptor tyrosine kinase by 4-anilinoquinazolines

Summary Since the mitogenic action of EGF is mediated by ligand-induced autophosphorylation of the EGF receptor (EGFR), and EGFR is commonly overexpressed in solid human tumours, inhibitors of receptor tyrosine kinase activity (RTK) could prove to be effective antitumour agents. Screening of a compound library using an EGF-RTK enzyme prepared from human tumour derived A431 cells identified a series of potent (IC₅₀<1µM) enzyme inhibitors. These inhibitors are quinazolines bearing a variety of substituted anilines at the 4-position. The most potent 4-anilinoquinazolines (IC₅₀ ntent/n7282658137366r1/xxlarge8773.gif" alt="cong" align="MIDDLE" BORDER="0"> 20nM) have small non-polar meta substituents on the aniline ring, and are competitive with ATP and non-competitive with substrate. The growth inhibitory activity of these agents was assessed in vitro using KB cells (human oral squamous tumour) grown in the absence or presence of EGF. A selected compound, 4-(3-chloroanilino)quinazoline (CAQ), inhibited EGF-stimulated growth in a concentration dependent manner and complete blockade was observed at concentrations (1–10 µM) which had no effect on basal growth. Selectivity of growth inhibition by CAQ was further exemplified in IGF1-stimulated KB cells where no effect was detected at concentrations which completely blocked EGF-stimulated growth. Similarly, CAQ blocked TGFntent/n7282658137366r1/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-stimulated growth in MCF-7 human breast cancer cells without affecting insulin-stimulated growth. These studies define a novel class of EGF-RTK inhibitors which are also potent and selective inhibitors of EGF-stimulated human tumour cell growthin vitro. Presented at the symposium "New Approaches in the Therapy of Breast Cancer", Georgetown University Medical Center, Washington DC, October 1994, generously supported by an education grant from Bristol-Myers Squibb.     

The stereoisomers of 17α-[123I]iodovinyloestradiol and its 11α-methoxy derivative evaluated for their oestrogen receptor binding in human MCF-7 cells and rat uterus,and their distribution in immature rats

We studied the potential of both stereoisomers of 17ntent/n21350p04763v267/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-[¹²³I]iodovinyloestradiol (E- andZ-[¹²³I]IVE) and of 11ntent/n21350p04763v267/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-methoxy-17ntent/n21350p04763v267/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-[¹²³I]iodovinyloestradiol (E-andZ-[¹²³I]MIVE) as suitable radioligands for the imaging of oestrogen receptor(ER)-positive human breast tumours. The 17ntent/n21350p04763v267/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-[¹²³I]iodovinyloestradiols were prepared stereospecifically by oxidative radio-iododestannylation of the corresponding 17ntent/n21350p04763v267/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-tri-n-butylstannylvi-nyloestradiol precursors. Competitive binding studies were performed in order to determine the relative binding affinity (RBA) of the unlabelled 17ntent/n21350p04763v267/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-iodovinyloes-tradiols for the ER in both human MCF-7 breast tumour cells and rat uterine tissue, compared with that of diethylstilboestrol (DES). Target tissue uptake, retention and uptake selectivity of their¹²³I-labelled analogues were studied in immature female rats. All four 17ntent/n21350p04763v267/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-iodovi-nyloestradiols showed high affinity for the ER in human MCF-7 cells, as well as rat uterus. Their RBA for the ER showed the following order of decreasing potency: RBA of DES >Z-IVE >Z-MIVE >E-MIVE ntent/n21350p04763v267/xxlarge8805.gif" alt="ge" align="MIDDLE" BORDER="0">E-IVE. Neither of these 17ntent/n21350p04763v267/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-iodovinyloestradiols showed any significant binding to the sex hormone binding globulin in human plasma. The biodistribution studies showed ER-mediated uptake in the uterus, ovaries and pituitary, that ofE- andZ-[¹²³I]MIVE being higher than that ofE- andZ-[¹²³I]IVE. High target-to-non-target tissue uptake ratios, especially at longer periods after injection (up to 24 h), were exhibited by both isomers of [¹²³I]MIVE. The uterus-to-blood uptake ratio was higher for^E-[¹²³I]MIVE. However, the uterus-to-fat uptake ratio appeared to be higher for theZ-isomer of [¹²³I]MIVE, especially at 24 h after injection. Metabolic properties and temperature effects, which play a more important role in vivo, probably cause the discrepancies seen between in vitro and in vivo binding results. On the basis of their in vitro binding properties and in vivo distribution characteristics we conclude thatE- andZ-[¹²³I]MIVE could be suitable radioligands for the diagnostic imaging of ER in human breast cancer. Therefore, further studies with these radioligands in mature normal and tumour-bearing rats are warranted.