Vasodilator agents and supracollicular transection fail to inhibit cortical spreading depression in the cat

It remains an open question as to whether cortical spreading depression (CSD) is the pathophysiological correlate of the neurological symptoms in migraine with aura. In the experimental animal, CSD is an electrophysiological phenomenon mainly mediated via NMDA receptors. However, according to case reports in humans, visual aura in migraine can be alleviated by vasodilator substances, such as amyl nitrite and isoprenaline. There is also circumstantial evidence that brainstem nuclei (dorsal raphe nucleus and locus coeruleus) may play a pivotal role in the initiation of aura. In this study, CSD was elicited in alpha-chloralose anesthetized cats by cortical needle stab injury and monitored by means of laser Doppler flowmetry. Topical application of isoprenaline (0.1-1%) and amyl nitrite (0.05%) onto the exposed cortex had no effect on the elicitation or propagation of CSD. Also, after supracollicular transection, subsequent CSDs showed no differences in the speed of propagation and associated flow changes. We conclude from these data that--given CSD probably exists in humans during migraine--spreading neurological deficits during migraine aura are independent of brainstem influence and have a primarily neuronal rather than vascular mechanism of generation.     

The role of previously unmeasured organic acids in the pathogenesis of severe malaria

IntroductionSevere falciparum malaria is commonly complicated by metabolic acidosis. Together with lactic acid (LA), other previously unmeasured acids have been implicated in the pathogenesis of falciparum malaria.MethodsIn this prospective study, we characterised organic acids in adults with severe falciparum malaria in India and Bangladesh. Liquid chromatography-mass spectrometry was used to measure organic acids in plasma and urine. Patients were followed until recovery or death.ResultsPatients with severe malaria (n=138), uncomplicated malaria (n=102), sepsis (n=32) and febrile encephalopathy (n=35) were included. Strong ion gap (mean±SD) was elevated in severe malaria (8.2 mEq/L±4.5) and severe sepsis (8.6 mEq/L±7.7) compared with uncomplicated malaria (6.0 mEq/L±5.1) and encephalopathy (6.6 mEq/L±4.7). Compared with uncomplicated malaria, severe malaria was characterised by elevated plasma LA, hydroxyphenyllactic acid (HPLA), α-hydroxybutyric acid and β-hydroxybutyric acid (all P<0.05). In urine, concentrations of methylmalonic, ethylmalonic and α-ketoglutaric acids were also elevated. Multivariate logistic regression showed that plasma HPLA was a strong independent predictor of death (odds ratio [OR] 3.5, 95 % confidence interval [CI] 1.6–7.5, P=0.001), comparable to LA (OR 3.5, 95 % CI 1.5–7.8, P=0.003) (combined area under the receiver operating characteristic curve 0.81).ConclusionsNewly identified acids, in addition to LA, are elevated in patients with severe malaria and are highly predictive of fatal outcome. Further characterisation of their sources and metabolic pathways is now needed.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-1023-5) contains supplementary material, which is available to authorized users.     

Calcium loading, calcium accumulation, and associated cardiovascular risks in dialysis patients

Calcium and phosphate imbalances are important mutable risk factors for cardiovascular disease in chronic kidney disease (CKD). Nearly all dialysis patients require phosphate binders. These include traditional calcium-based compounds and, more recently, the calcium-free, metal-free, non-absorbed agent, sevelamer hydrochloride. Both binder types reduce serum phosphorus, but differ with respect to calcium load and metabolism. Absorption from calcium-based agents very likely promotes positive total calcium balance in many patients. Positive calcium balance is inappropriate in adults and may promote or accelerate soft-tissue and vascular calcification even in the absence of hypercalcemia. Calcium accumulation in heart and vascular tissues contributes to rapidly progressive cardiovascular calcification - a strong predictor of cardiovascular and all-cause mortality in stage 5 CKD. More than two-thirds of stage 5 CKD patients have calcification scores above the 75th percentile for matched controls -- scores associated with extremely high risk of cardiovascular events and death.     

Genetic factors affecting the consistency and magnitude of changes in plasma cholesterol in response to dietary challenge

We examined the role of common genetic variation in determining the consistency and magnitude of change in plasma total cholesterol (TC) levels in response to two separate changes from a high-saturated (SFA) to a low-saturated/high-polyunsaturated-fat (PUFA) diet, in a group of free-living healthy men and women. Consistent responders were defined as those whose mean difference in the change in TC was within one SD of the mean for all participants, and the remainder were defined as variable responders. DNA was obtained from 55 individuals and genotype determined at the apolipoprotein (apo) B locus (signal peptide, SP), apoCIII (C1100-T) and lipoprotein lipase (LPL) gene loci (HindIII). In the 38 consistent responders, the apoBSP24 allele was significantly more common than in the 17 individuals with a variable response (0.29 vs. 0.12; p < 0.05). No other polymorphism showed a significant frequency difference between groups. In the group as a whole, the correlation between the change in TC level in response to the first and second dietary change was 0.28 (p = 0.05), but those with one or more apoB SP24 alleles and those with the apoCIII genotype CC had a significantly higher correlation than those with other genotypes (0.46 (p = 0.05) vs. 0.12 (NS) and 0.31 (p = 0.05) vs. 0.02 (NS), respectively). In the group as a whole, mean response left TC 10% higher on the SFA than on the PUFA diet, and neither apoB nor apoCIII genotypes affected the magnitude of this response. However, individuals with the LPL HindIII genotype H+ H+ had a significantly smaller change in mean TC in response to diet than those with one or more H- allele (9.3% vs. 14.4%; p = 0.03). Thus variation at the apoB and apoCIII loci affects the consistency of response to change in dietary fat content, while variation at the LPL gene locus affects magnitude of response.      

Neuropeptides in migraine and cluster headache

The cerebral circulation is invested by a rich network of neuropeptide Y (NPY) and noradrenaline containing sympathetic nerve fibers in arteries, arterioles and veins. However, the nerve supply of vasoactive intestinal peptide (VIP), substance P (SP) and calcitonin gene-related peptide (CGRP) containing fibers is sparse. While noradrenaline and NPY cause vasoconstriction, VIP, SP and CGRP are potent vasodilators. Stimulation of the trigeminal ganglion in cat and man elicits release of SP and CGRP. Subjects with spontaneous attacks of migraine show release of CGRP in parallel with headache. Cluster headache patients have release of CGRP and VIP during bouts. Treatment with sumatriptan aborts headache in migraine and cluster headache as well as the concomitant peptide release.     

Confirmation of hepatitis C infection: a comparison of five immunoblot assays

BACKGROUND: Recently, new immunoblot assays for the detection of antibodies to hepatitis C virus (HCV) became available. STUDY DESIGN AND METHODS: The performance of five confirmatory anti-HCV immunoblot assays was studied with samples with known HCV antibody and HCV RNA status. The assays were a third-generation strip recombinant immunoblot assay (RIBA-3, Chiron Corp., Emeryville, CA), a second-generation HCV blot (DB-2 blot, Diagnostic Biotechnology, Singapore), the Wellcozyme HCV Western blot (Murex blot, Murex Diagnostics, Dartford, UK), an immunodot HCV assay (Matrix, Abbott Laboratories, Chicago, IL), and the third-generation HCV line immunoassay (Liatek-III, Organon Teknika, Boxtel, The Netherlands). RESULTS: Sensitivity on samples from 48 HCV RNA-positive, second-generation RIBA (RIBA-2)-positive persons and specificity on samples from 31 low-risk donors was 96 percent or better for all assays. The sensitivity on 31 HCV RNA-positive, RIBA-2- indeterminate samples was as follows: Liatek-III, 94 percent; RIBA-3, 90 percent; Murex blot, 61 percent; Matrix, 55 percent; and DB-2 blot, 39 percent. In testing 39 HCV RNA-negative, RIBA-2-indeterminate donor samples, the percentage found to be negative was Liatek-III, 77 percent; RIBA-3, 67 percent; Murex blot, 49 percent; DB-2 blot, 33 percent; and Matrix, 15 percent. The order of sensitivity on four HCV seroconversion series was (from high to low): RIBA-3, Liatek-III, DB-2 blot, Murex blot, and Matrix; the differences were small. CONCLUSION: Detection of HCV antibodies was not refined by the addition of new HCV antigens (NS5, E2/NS1), but by improved classical antigens (core, NS3, NS4). Replacement of the commonly used RIBA-2 will resolve the status of a high proportion of RIBA-2-indeterminate samples.     

重组犬钩虫分泌蛋白抗血清的免疫反应性

目的　分析重组犬钩虫分泌蛋白抗血清与钩虫不同种、期抗原的免疫反应性。　方法　用微型垂直电泳槽进行 SDS- PAGE,以低分子量标准蛋白作参照。EL IB试验 :以重组犬钩虫分泌蛋白 - 1(Ac- r Asp- 1)或重组犬钩虫分泌蛋白 - 2 (Ac- r Asp- 2 )免疫鼠血清作第一抗体 ,羊抗鼠 Ig G- HRP作第二抗体 ,用 Western blotting发光底物试剂反应 ,全自动摄影 ,按照底片中显示带的位置测出相应分子量。　结果与结论　 Ac- r Asp- 1组分为 45k Da,其免疫血清能识别犬钩虫第 期幼虫 (Ac- L3)抗原和 Ac- r Asp- 1,不与十二指肠钩虫成虫 (Ad- A)、十二指肠钩虫第 期幼虫 (Ad- L3)、美洲钩虫成虫 (Na- A)、犬钩虫成虫 (Ac- A)、巴西日圆线虫成虫 (Nb- A)抗原和 Ac- r Asp- 2起反应 ;Ac- r Asp- 2组分为 2 4k Da,其免疫血清能识别 Ad- A、Ad- L3、Na- A、Ac- A、Ac- L3抗原和 Ac- r Asp- 2 ,不与Nb- A抗原和 Ac- r Asp- 1起反应。     

Development of a marrow transplant regimen for acute leukemia using targeted hematopoietic irradiation delivered by 131I-labeled anti-CD45 antibody, combined with cyclophosphamide and total body irradiation

In an attempt to decrease the relapse rate after bone marrow transplantation (BMT) for advanced acute leukemia, we initiated studies using 131I-labeled anti-CD45 antibody (BC8) to deliver radiation specifically to hematopoietic tissues, followed by a standard transplant preparative regimen. Biodistribution studies were performed in 23 patients using 0.5 mg/kg trace 131I-labeled BC8 antibody. The BC8 antibody was cleared rapidly from plasma with an initial disappearance half-time of 1.5 +/- 0.2 hours, presumably reflecting rapid antigen- specific binding. The mean radiation absorbed doses (cGy/mCi131I administered) were as follows: marrow, 7.1 +/- 0.8; spleen, 10.8 +/- 1.4; liver, 2.7 +/- 0.2; lungs, 2.1 +/- 0.1; kidneys, 0.7 +/- 0.1; and total body, 0.4 +/- 0.03. Patients with acute myelogenous leukemia (AML) in relapse had a higher marrow dose (11.4 cGy/mCi) than those in remission (5.2 cGy/mCi; P = .001) because of higher uptake and longer retention of radionuclide in marrow. Twenty patients were treated with a dose of 131I estimated to deliver 3.5 Gy (level 1) to 7 Gy (level 3) to liver, with marrow doses of 4 to 30 Gy and spleen doses of 7 to 60 Gy, followed by 120 mg/kg cyclophosphamide (CY) and 12 Gy total body irradiation (TBI). Nine of 13 patients with AML or refractory anemia with excess blasts (RAEB) and two of seven with acute lymphocytic leukemia (ALL) are alive disease-free at 8 to 41 months (median, 17 months) after BMT. Toxicity has not been measurably greater than that of CY/TBI alone, and the maximum tolerated dose has not been reached. This study demonstrates that with the use of 131I-BC8 substantially greater doses of radiation can be delivered to hematopoietic tissues as compared with liver, lung, or kidney, which may improve the efficacy of marrow transplantation.