Percutaneous transluminal coronary angioplasty in a child with Kawasaki disease

A successful attempt at percutaneous transluminanl coronary angioplasty (PTCA) to relieve stenosis of the mid-portion of the left anterior descending artery was achieved in a 6-year 9-month old boy who had multiple coronary aneurysms and stenosis due to Kawasaki disease. Despite the progression of coronary stenosis he had been well except for the perfusion defect of the anterior wall of myocardium on 99mTc-MIBI SPECT with dipyridamole infusion until PTCA was carried out after 4-year 4-months of the onset of illness. The area of stenosis was 70% before PTCA and 20% after PTCA. No restenosis at the site of PTCA was observed on follow-up angiography at 26 months after PTCA. This successful attempt may indicate that this procedure should be considered early in subclinical stenosis to prevent ischemic cardiac damage.     

Transgenic knockout mice exclusively expressing human hemoglobin S after transfer of a 240-kb betas-globin yeast artificial chromosome: A mouse model of sickle cell anemia

Sickle cell anemia (SCA) and thalassemia are among the most common genetic diseases worldwide. Current approaches to the development of murine models of SCA involve the elimination of functional murine alpha- and beta-globin genes and substitution with human alpha and betas transgenes. Recently, two groups have produced mice that exclusively express human HbS. The transgenic lines used in these studies were produced by coinjection of human alpha-, gamma-, and beta-globin constructs. Thus, all of the transgenes are integrated at a single chromosomal site. Studies in transgenic mice have demonstrated that the normal gene order and spatial organization of the members of the human beta-globin gene family are required for appropriate developmental and stage-restricted expression of the genes. As the cis-acting sequences that participate in activation and silencing of the gamma- and beta-globin genes are not fully defined, murine models that preserve the normal structure of the locus are likely to have significant advantages for validating future therapies for SCA. To produce a model of SCA that recapitulates not only the phenotype, but also the genotype of patients with SCA, we have generated mice that exclusively express HbS after transfer of a 240-kb betas yeast artificial chromosome. These mice have hemolytic anemia, 10% irreversibly sickled cells in their peripheral blood, reticulocytosis, and other phenotypic features of SCA.     

Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis

Triacylglycerols are quantitatively the most important storage form of energy for eukaryotic cells. Acyl CoA:diacylglycerol acyltransferase (DGAT, EC 2.3.1.20) catalyzes the terminal and only committed step in triacylglycerol synthesis, by using diacylglycerol and fatty acyl CoA as substrates. DGAT plays a fundamental role in the metabolism of cellular diacylglycerol and is important in higher eukaryotes for physiologic processes involving triacylglycerol metabolism such as intestinal fat absorption, lipoprotein assembly, adipose tissue formation, and lactation. DGAT is an integral membrane protein that has never been purified to homogeneity, nor has its gene been cloned. We identified an expressed sequence tag clone that shared regions of similarity with acyl CoA:cholesterol acyltransferase, an enzyme that also uses fatty acyl CoA as a substrate. Expression of a mouse cDNA for this expressed sequence tag in insect cells resulted in high levels of DGAT activity in cell membranes. No other acyltransferase activity was detected when a variety of substrates, including cholesterol, were used as acyl acceptors. The gene was expressed in all tissues examined; during differentiation of NIH 3T3-L1 cells into adipocytes, its expression increased markedly in parallel with increases in DGAT activity. The identification of this cDNA encoding a DGAT will greatly facilitate studies of cellular glycerolipid metabolism and its regulation.     

Pharmacology of the spinal adenosine receptor which mediates the antiallodynic action of intrathecal adenosine agonists

The effects of intrathecally delivered adenosine agonists on allodynia induced by L5/L6 spinal nerve ligation in rats with lumbar intrathecal catheters were examined. Tactile allodynia was assessed by measuring the threshold for evoking withdrawal of the lesioned hind paw with calibrated von Frey hairs. Intrathecal administration of the A1 adenosine selective agonist, N6-(2-phenylisopropyl)-adenosine R-(-)isomer (R-PIA), produced a dose-dependent (0.3-3 nmol; ED50 = 0.6 nmol) antiallodynic action and evoked a delayed motor weakness at a dosage of 30 nmol. Intrathecal administration of the A2 adenosine selective agonist, CGS 21680 {2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamido adenosine hydrochloride}, also produced a dose-dependent reduction in allodynia (2-40 nmol; ED50 = 15 nmol), but this effect was associated at 40 nmol after a short interval with prominent hind limb weakness. Intrathecal pretreatment with A1/A2 adenosine antagonists, caffeine (20 mumol) and 8-sulfophenyltheophylline (60 nmol), blocked antiallodynic actions of R-PIA (1 nmol) and CGS 21680 (40 nmol). Intrathecal pretreatment with the A1 adenosine-selective antagonist, 8-cyclopentyl-1,3-dimethylxanthine (3 nmol), blocked the antiallodynic effect of R-PIA (1 nmol), but even a dose as high as 10 nmol did not block the effect of CGS 21680 (40 nmol). The A2 adenosine-selective antagonist, 3, 7-dimethyl-1-propargylxanthine (3 nmol), prevented the antiallodynic effects of R-PIA (1 nmol) and CGS 21680 (40 nmol). Pretreatment with caffeine (20 mumol), 8-sulfophenyltheophylline (60 nmol) and 3,7-dimethyl-1-propargylxanthine (3 nmol) prevented the motor dysfunction induced by R-PIA (30 nmol) and CGS 21680 (40 nmol), but 8-cyclopentyl-1,3-dimethylxanthine (3 or 10 nmol) did not. Based on these effects, we hypothesize that the antiallodynic effects are mediated through the activation of spinal A1 adenosine receptors and motor dysfunction effects are mediated through A2 adenosine receptors.     

Role of intermediate filaments in migration, invasion and metastasis

The expression of intermediate filament proteins is remarkably tissue-specific which suggests that the intermediate filament (IF) type(s) present in cells is somehow related to their biological function. However, in some cancers-particularly malignant melanoma and breast carcinoma, there is a strong indication that vimentin and keratin IFs are coexpressed, thus presenting as a dedifferentiated or interconverted (between epithelial and mesenchymal) phenotype. In this review, two in vitro models are presented which recapitulate the interconverted phenotype in human melanoma and breast carcinoma, and allow, for the first time, unique observations to be made with respect to the role of IFs in cancer progression. These studies have provided direct evidence linking overexpression of keratin IFs in human melanoma with increased migratory and invasive activity in vitro, which can be down-regulated by substituting dominant-negative keratin mutants. Overexpression of vimentin IFs in the breast carcinoma model leads to augmentation of motility and invasiveness in vitro, which can be transiently down-regulated by treatment with antisense oligonucleotides to vimentin. Additional experimental evidence suggests that the mechanism(s) responsible for the differential expression of metastatic properties associated with the interconverted phenotype rest(s) in the unique interaction, either direct or indirect, of IFs with specific integrins interacting with the extracellular matrix. In this review, we discuss the observations derived from the human melanoma and breast carcinoma models to address the hypothesis that the ability to coexpress vimentin and keratins confers a selective advantage to tumor cells in their interpretation of and response to signaling cues from the extracellular matrix. The ramifications of these observations are discussed with respect to the patholophysiology of the respective in situ tumors.     

Synthesis and in vivo evaluation of a 99m/99Tc-DADT-benzovesamicol: a potential marker for cholinergic neurons

Fifty-six asthmatics from an asthma ward or from an asthma out-patient clinic were challenged with two low concentrations (0.03 and 0.012 mg) of metacholine chloride in order to assess the relationship between pronounced hyper-responsiveness and asthma severity in a clinical setting. Only inhaled bronchodilators were stopped before challenge. Asthma severity was assessed retrospectively and prospectively on the basis of treatment, number of days in hospital, intensive care, number of emergency visits and days on sick-leave. The results show that pronounced hyper-responsiveness (n = 28) is not associated with asthma severity. It is concluded that a single simplified test of pronounced bronchial hyper-responsiveness, performed without taking into consideration the actual state of the disease and without stopping all medication, is of no help in identifying the patients with the clinically most severe asthma and worst prognosis.     

Pelvic floor function in multiple sclerosis

The aim of this study was to define pelvic floor function in patients with multiple sclerosis and bowel dysfunction, either incontinence (MSI) or defecation difficulties without incontinence (MSC). Normal controls and patients with idiopathic neurogenic faecal incontinence without multiple sclerosis (FI, disease controls) were also studied. Thirty eight multiple sclerosis patients (20 incontinent, 18 incontinent) 73 normal controls, and 91 FI patients were studied. The FI group showed the characteristic combined sensorimotor deficit previously described in these patients of low resting and voluntary contraction and pressures, increased sensory threshold to mucosal stimulation, and increased pudendal nerve terminal motor latencies and fibre densities. MSI patients had significantly lower anal resting pressures (80 (30-140) cm H2O, median (range) v 98 (30-200), normal controls, p = 0.002) and both MSC and MSI patients had significantly lower anal maximum voluntary contraction pressures (65 (0-260) cm H2O, MSC and 25 (0-100), MSI v 120 (30-300), normal controls, p = < 0.0004) and higher external anal sphincter fibre densities (1.7 (1.1-2.6), MSC and 1.7 (1.1-2.4), MSI v 1.5 (1.1-1.75), normal controls, p < 0.006) compared with normal controls but pudendal nerve terminal motor latencies were similar and no sensory deficit was found. This contrasted with the idiopathic faecal incontinent patients who, in addition to significantly higher fibre densities (1.8 (1.1-3), p = 0.001) had increased pudendal latencies (2.5 (1.1-5.5) mS v 2.08 (1.4-2.6), p = 0.001) compared with normal controls. The idiopathic faecal incontinent group had significantly lower resting anal pressures (50 (10-160) cm H2O, p=0.02) than the MSI group. Comparison with the incontinent and continent multiple sclerosis groups showed that incontinence was associated with lower voluntary anal contraction pressures (25 (0-100) v 65 (0-260), p=0.03) but that there were no other differences between these two groups. Pelvic floor function is considerably disturbed in multiple sclerosis, showing muscular weakness with preservation of peripheral motor nerve conduction, providing indirect evidence that this is mainly a result of lesions within the central nervous system.     

Attenuation of alcohol intake by ibogaine in three strains of alcohol-preferring rats

Alcohol-preferring (P), Fawn-Hooded (FH) and alcohol-accepting (AA) rats were injected intraperitoneally (IP) or subcutaneously (SC) with different doses (10, 30, and 60 mg/kg) of Ibogaine or vehicle. In a separate experiment, FH rats were administered intragastrically (IG) with either 60 mg/kg of Ibogaine or vehicle for 5 days. In addition, the effects of Ibogaine on blood alcohol concentrations were measured. Our data show that, contrary to the SC administration of Ibogaine, IP administration of the agent significantly and dose-dependently reduced alcohol intake in these rats. Subchronic IG administration of 60 mg/kg of Ibogaine into FH rats significantly reduced alcohol intake without the development of tolerance or a significant effect on food or water intake. A single IP injection of 60 mg/kg Ibogaine into FH rats did not affect the blood alcohol levels. These results show that Ibogaine when injected IP or IG, but not SC, can significantly reduce alcohol intake without an effect on blood alcohol concentrations or food intake. These findings may suggest the involvement of Ibogaine's metabolite(s) in reducing alcohol intake. Although the neuronal mechanism(s) of action of Ibogaine on the regulation of alcohol intake is not fully understood, it is speculated that Ibogaine or its metabolite(s) exerts its attenuating effect on alcohol intake by modulating neurotransmitters/neuromodulators proposed to be involved in regulation of alcohol consumption.     

In situ control of atomic-scale Si layer with huge strain in the nanoheterostructure NiSi/Si/NiSi through point contact reaction

Nanoheterostructures of NiSi/Si/NiSi in which the length of the Si region can be controlled down to 2 nm have been produced using in situ point contact reaction between Si and Ni nanowires in an ultrahigh vacuum transmission electron microscope. The Si region was found to be highly strained (more than 12%). The strain increases with the decreasing Si layer thickness and can be controlled by varying the heating temperature. It was observed that the Si nanowire is transformed into a bamboo-type grain of single-crystal NiSi from both ends following the path with low-activation energy. We propose the reaction is assisted by interstitial diffusion of Ni atoms within the Si nanowire and is limited by the rate of dissolution of Ni into Si at the point contact interface. The rate of incorporation of Ni atoms to support the growth of NiSi has been measured to be 7 x 10(-4) s per Ni atom. The nanoscale epitaxial growth rate of single-crystal NiSi has been measured using high-resolution lattice-imaging videos. On the basis of the rate, we can control the consumption of Si and, in turn, the dimensions of the nanoheterostructure down to less than 2 nm, thereby far exceeding the limit of conventional patterning process. The controlled huge strain in the controlled atomic scale Si region, potential gate of Si nanowire-based transistors, is expected to significantly impact the performance of electronic devices.