Coronary endothelium-protective effects of defibrotide in ischaemia and reperfusion

Summary Defibrotide is known to enhance prostacyclin (PGI₂) release from the vascular endothelium. We investigated the vasoactive effects of defibrotide in isolated rat hearts perfused at constant flow subjected to ischaemia and reperfusion. Defibrotide at 10^–7 or 100 g/ml did not exert any direct vasoactive effect on normal rats hearts. However, ischaemia and reperfusion resulted in an impaired vasodilation to acetylcholine, an endothelium-dependent vasodilator. In contrast, the vasodilator response to the endothelium-independent dilator, nitroglycerin, was unaffected. Defibrotide, at 10^–7 or 100 g/ml, markedly restored the vasodilation to acetylcholine 10^–7 nmol/l to 1 mol/l (P < 0.01) without influencing the vasodilator response to nitroglycerin (2 to 200 g/1). Haemoglobin (150 nmol/l) inhibited the dilation to acetylcholine in response to defibrotide. However, no evidence of (PGI₂) release was observed with acetylcholine-induced vasodilation in the presence or absence of defibrotide. Additionally, 10–100 g/ml of defibrotide did not significantly decrease superoxide radicals generated by a xanthine-xanthine oxidase synthetic system under conditions in which superoxide dismutase was effective. Thus, defibrotide appears to exert an endothelium-protective effect preserving endothelium-derived relaxing factor (EDRF) without directly scavenging free signals.Supported in part by Research Grant No. HL-25575 from the National Heart, Lung and Blood Institute of the NIH Send offprint requests to A. M. Lefer at the above address     

Gerstmann-Sträussler-Scheinker disease showing β-protein type cerebellar and cerebral amyloid angiopathy

Cerebral amyloid angiopathy is observed in several brain degenerative disorders, but this pathological condition has received little attention in Gerstmann-Sträussler-Scheinker disease (GSS). We report a 69-year-old man who showed the cardinal features of GSS together with typical and extensive congophilic angiopathy. Immunohistochemical studies revealed that the vast majority of the amyloid plaques present in the brain of this patient were consistently labeled by anti-prion protein (PrP) antibody. Double immunostaining disclosed many additional -protein immunoreactive plaque-like lesions, including a special type of hybrid plaque with colocalization of PrP and -protein (-PrP). The vascular amyloid deposits seen in both the cerebellum and cerebrum were immunoreactive only to anti--protein antibody. It seems likely that the extensive deposition of -protein amyloid (including brain vascular amyloidosis) seen in this and other similar cases is part of pathology of GSS, although the possibility that this finding is due to ageing or concomitant Alzheimer's disease cannot be completely ruled out.Supported by a research grant from the Intractable Disease Division, Ministry of Health and Welfare, Primary Amyloidosis Research Committee, Japan     

Quantitative analysis of cerebral microvascular hemodynamics with T2-weighted dynamic MR imaging

The purpose of this study was to quantify cerebral microvascular hemodynamics with T2-weighted dynamic susceptibility contrast-enhanced magnetic resonance imaging (DSC-MRI) using a half-Fourier acquisition single-shot turbo spin-echo (HASTE) sequence. We performed T2-weighted DSC-MRI with HASTE sequence in 19 normal subjects. After bolus injection of gadopentetate dimeglumine, HASTE images of two sections were acquired for the simultaneous creation of concentration-time curves in the internal carotid artery and in brain tissue. Absolute regional cerebral blood volume (rCBV), regional cerebral blood flow (rCBF), and mean transit time (MTT) values of brain tissue were calculated on a base of the indicator dilution theory, and all values were corrected on the assumption that rCBF of white matter is constant in 22 mL/100 g tissue/min without age-dependent alteration. A decrease in rCBV and rCBF of gray matter was age dependent, while rCBV of white matter did not show significant change with aging. The mean rCBF value in gray matter was 37.3 +/- 8.4 mL/100 g tissue/min. The mean rCBV value was 4.1 +/- 0.8 mL/100 g tissue in gray matter and 2.9 + 0.4 mL/100 g tissue in white matter. The rCBV and rCBF values of gray and white matter obtained from T2-weighted DSC-MRI with HASTE sequence were slightly lower than the published data calculated by gradient-echo sequence. We were able to perform absolute quantifications of the capillary blood volume and flow, using a HASTE sequence, which would not have been possible with a gradient-echo sequence. This technique provides a new method for estimating cerebral microvascular hemodynamics.     

A case of well-differentiated, fetal-type hepatoblastoma with very low serum alpha-fetoprotein

Serum alpha-fetoprotein (AFP) is elevated in 96.6% of infants and children with hepatoblastoma and hepatocarcinoma. Serum AFP was of normal level in only one case of immature-type hepatoblastoma, and very low in only one case of fetal-type hepatoblastoma among 43 cases reviewed in 1986. Recently, a case of hepatoblastoma with very low serum AFP was encountered in the authors' surgical department. In October 1998, a 55-month-old girl was admitted. Her birth weight was 717 g. A large space-occupying lesion (SOL) located in the left lobe of the liver was seen by magnetic resonance imaging (MRI), and her serum AFP level was 322 ng/mL with a subfractionation pattern of the "benign liver disease" type based on reactivity with lens culnaris hemagglutinin and concanavalin A. The patient underwent successful left lobectomy, and histological examination showed that the tumor, weighing 268 g, was hepatoblastoma of the well-differentiated, fetal type. Immunohistochemistry findings for AFP were negative. A hepatic mass in infants and children with low serum AFP level indicates the presence of either well-differentiated or immature hepatoblastoma, or fibrolamellar hepatocellular carcinoma. Subfractionation of AFP may contribute to the differential diagnosis of these subtypes.     

The renal lesions that develop in neonatal mice during angiotensin inhibition mimic obstructive nephropathy

BACKGROUND: Inhibition of angiotensin action, pharmacologically or genetically, during the neonatal period leads to renal anomalies involving hypoplastic papilla and dilated calyx. Recently, we documented that angiotensinogen (Agt -/-) or angiotensin type 1 receptor nullizygotes (Agtr1 -/-) do not develop renal pelvis nor ureteral peristaltic movement, both of which are essential for isolating the kidney from the high downstream ureteral pressure. We therefore examined whether these renal anomalies could be characterized as "obstructive" nephropathy. METHODS: Agtr1 -/- neonatal mice were compared with wild-type neonates, the latter subjected to surgical complete unilateral ureteral ligation (UUO), by analyzing morphometrical, immunohistochemical, and molecular indices. Agtr1 -/- mice were also subjected to a complete UUO and were compared with wild-type UUO mice by quantitative analysis. To assess the function of the urinary tract, baseline pelvic and ureteral pressures were measured. RESULTS: The structural anomalies were qualitatively indistinguishable between the Agtr1 -/- without surgical obstruction versus the wild type with complete UUO. Thus, in both kidneys, the calyx was enlarged, whereas the papilla was atrophic; tubulointerstitial cells underwent proliferation and also apoptosis. Both were also characterized by interstitial macrophage infiltration and fibrosis, and within the local lesion, transforming growth factor-beta 1, platelet-derived growth factor-A and insulin-like growth factor-1 were up-regulated, whereas epidermal growth factor was down-regulated. Moreover, quantitative differences that exist between mutant kidneys without surgical obstruction and wild-type kidneys with surgical UUO were abolished when both underwent the same complete surgical UUO. The hydraulic baseline pressure was always lower in the pelvis than that in the ureter in the wild type, whereas this pressure gradient was reversed in the mutant. CONCLUSION: The abnormal kidney structure that develops in neonates during angiotensin inhibition is attributed largely to "functional obstruction" of the urinary tract caused by the defective development of peristaltic machinery.     

Lactonamycin, a new antimicrobial antibiotic produced by Streptomyces rishiriensis MJ773-88K4. II. Structure determination.

The absolute structure of a new antibiotic lactonamycin is described. The NMR studies deduced one of four possible structures for the aglycon attached by a rhodinose through glycosidic bond. The stereochemistry of the sugar obtained by an acid hydrolysis was determined to be L-form by measuring optical rotation. The stereochemistry of the aglycon was determined by X-ray crystallographic analysis.     

Minimal synaptic delay in the saccadic output pathway of the superior colliculus studied in awake monkey

The synaptic organization of the saccade-related neuronal circuit between the superior colliculus (SC) and the brainstem saccade generator was examined in an awake monkey using a saccadic, midflight electrical-stimulation method. When microstimulation (50–100 A, single pulse) was applied to the SC during a saccade, a small, conjugate contraversive eye movement was evoked with latencies much shorter than those obtained by conventional stimulation. Our results may be explained by the tonic inhibition of premotor burst neurons (BNs) by omnipause neurons that ceases during saccades to allow BNs to burst. Thus, during saccades, signals originating from the SC can be transmitted to motoneurons and seen in the saccade trajectory. Based on this hypothesis, we estimated the number of synapses intervening between the SC and motoneurons by applying midflight stimulation to the SC, the BN area, and the abducens nucleus. Eye position signals were electronically differentiated to produce eye velocity to aid in detecting small changes. The mean latencies of the stimulus-evoked eye movements were: 7.9±1.0 ms (SD; ipsilateral eye) and 7.8±0.9 ms (SD; contralateral eye) for SC stimulation; 4.8±0.5 ms (SD; ipsilateral eye) and 5.1±0.7 ms (SD; contralateral eye) for BN stimulation; and 3.6±0.4 ms (SD; ipsilateral eye) and 5.2±0.8 ms (SD; contralateral eye) for abducens nucleus stimulation. The time difference between SC- and BN-evoked eye movements (about 3 ms) was consistent with a disynaptic connection from the SC to the premotor BNs.     

Clinical application of intrathecal lidocaine administration in surgery of the descending thoracic aorta

We studied the protective effects of intrathecally administered lidocaine against ischemic spinal cord injury during surgery. Seven patients (mean age 63.7 years, malefemale=61) with descending thoracic aortic aneurysms underwent reconstructive surgery. Following intrathecal lidocaine administration (10 ml), the operation was performed under femorofemoral bypass with an oxygenator. The aorta was cross-clamped at the distal end of the descending thoracic aorta and the proximal end of the lesions. The cross-clamping time was 47.1±23.3 minutes (mean ± SD). The operative procedure was total replacement of the descending thoracic aorta in five cases and patch closure in two. There were no operative deaths but paraparesis developed in two cases of total replacement. Neurological deficit was transient and disappeared in one case. In the other case, with 88 minutes of normothermic aortic cross-clamping, paraparesis gradually improved but was persistent after 7 months of follow-up. Graft anastomosis at the distal aortic arch was time consuming in this case and presumably caused prolonged spinal cord ischemia. Intrathecal administration of lidocaine was likely to reduce ischemic spinal cord injury and increase tolerance of the spinal cord to ischemia caused by prolonged aortic cross-clamping. This method was considered to provide a useful assistance to expand the safety limit of spinal cord ischemia in surgical reconstruction of the descending thoracic aorta requiring aortic occlusion. Tissue protective effects of intrathecal lidocaine administration may be further augmented by combining with deep hypothermia.