Combined oral lysine acetylsalicylate and metoclopramide in the acute treatment of migraine: a multicentre double-blind placebo-controlled study

This multicentre, double-blind, randomized, placebo-controlled, parallel study was designed to evaluate the efficacy of combined oral lysine acetylsalicylate and metoclopramide (LAS-MCP) in the acute treatment of migraine attacks. A total of 266 patients, 18–65 years old, with two to six attacks of migraine with or without aura (IHS criteria) per month were included. The patients had to treat two migraine attacks with LAS-MCP (1620 mg lysine acetylsalicylate-the equivalent of 900 mg aspirin- combined with 10 mg metoclopramide) or placebo. The main outcome measure was headache relief (reduction in headache severity from grade 3 or 2-severe or moderate-to grade 1 or 0-mild or none) 2 h after treatment. LAS-MCP was superior to placebo for headache relief (56% vs 28%) and for the following secondary outcome measures: complete headache relief (18% vs 7%; p < 0.001), nausea (28% vs 44%; p < 0.001), vomiting (3% vs 11%; p = 0.001), use of rescue medication (47% vs 68%; p < 0.001), global efficacy judged as good or excellent (32% vs 14%; p < 0.001). The tolerability was considered as good in 94% of treated attacks in both groups. Combined oral lysine acetylsalicylate and metoclopramide is an effective and well-tolerated acute treatment of migraine attacks.     

Effective removal of copper by plasma exchange in fulminant Wilson's disease

BACKGROUND: Patients who present with fulminant hepatic failure due to Wilson's disease may develop hemolytic anemia and renal insufficiency. In this entity, acute hepatocellular necrosis triggers the release of copper ions into the circulation, which leads to toxic effects on red cell metabolic pathways and hemolysis. STUDY DESIGN AND METHODS: The utility of therapeutic plasma exchange to rapidly remove copper and reduce toxic serum copper levels was studied in two patients with fulminant Wilson's disease. RESULTS: Intensive plasma exchange using fresh-frozen plasma replacement removed substantial amounts of copper from the hypercupremic patients, resulting in a rapid reduction in serum copper levels and decreased hemolysis. The net copper removal was proportional to the serum level, ranging from 7,000 to 11,800 micrograms per procedure in one patient and from 3,700 to 6,800 micrograms in the other. CONCLUSION: Plasma exchange allows a rapid reduction in elevated serum copper levels in patients with fulminant Wilson's disease. This leads to an amelioration of hemolytic anemia and provides clinical stabilization until liver transplantation can be performed.     

The effect of sterilization on transforming growth factor beta isolated from demineralized human bone

Growth factors have been identified as the primary cause of osteoinduction in bone healing. Transforming growth factor beta (TGF- beta) has been shown to promote bone formation and is present in bone in high quantities. The aims of the present study were to isolate TGF- beta from human bone, demonstrate its biologic activity, and analyze the effects of conventional sterilization techniques on activity. Bone, obtained from femoral heads of five patients (mean age, 70 years) was ground, demineralized, and freeze-dried, and samples from each patient were divided into three groups: no treatment, sterilization with 1.60 to 1.94 Mrad of 60Co irradiation, and sterilization with ethylene oxide (ETO). Carrier-free recombinant TGF-beta control was also treated and was totally inactivated by ETO but not by irradiation (p < 0.01). TGF- beta activity in demineralized bone was not significantly diminished (p > 0.1) by either sterilization procedure, and substantial amounts of active TGF-beta were recovered in all bone samples: 1.04 +/− 0.77 ng per mg of protein in irradiated samples, 0.67 +/− 0.26 ng per mg in ETO- treated samples, and 1.04 +/− 0.33 in untreated samples, respectively (mean +/− SD). Although a recent report demonstrated that the osteoinductive activity of bone morphogenetic protein in bone powder is diminished considerably by ETO and by 2.5 Mrad of irradiation sterilization of bone powder, these data demonstrate that TGF-beta activity, with its osteoinductive properties, was not destroyed in more coarsely ground, demineralized bone by ETO or by lower doses of irradiation. These findings support the use of human bone allografts in clinical instances involving impaired bone formation.     

Translocation breakpoints are clustered on both chromosome 8 and chromosome 21 in the t(8;21) of acute myeloid leukemia

The t(8;21)(q22;q22) is consistently associated with acute myeloid leukemia (AML) M2. Recent data have suggested that breakpoints on chromosome 21 are clustered within a single intron of a novel gene, AML1, just downstream of a region of homology to the runt gene of D melanogaster. In this report, we confirm rearrangement at the same location in at least 12 of 18 patients with t(8;21). Furthermore, we have isolated recombinant clones spanning the breakpoint regions on both the der(8) and the der(21) from one patient. By using a chromosome 8 probe derived from these clones, we show that t(8;21) breakpoints are also clustered on chromosome 8.     

Open-access transvaginal sonography in women of reproductive age with abnormal vaginal bleeding: a descriptive study in general practice

Background

Diagnostic ultrasonography is used by GPs in approximately 10% of patients of reproductive age with abnormal vaginal bleeding. Transvaginal sonography is recommended as a first-line diagnostic instrument for assessing uterine pathology.

Aim

To assess if findings resulting from openaccess sonography were in agreement with the GPs’ working hypotheses and if these findings contributed to GPs’ management.

Design and setting

Prospective observational cohort study of GPs working in the health district of the Academic Medical Center, Amsterdam and their patients consulting with abnormal vaginal bleeding.

Method

Data on patients’ history, GPs’ primary working hypotheses, and intended management were recorded. After sonography, GPs recorded their actual management.

Results

A total of 122 patients were included by 18 GPs from June 2003 to December 2004. Data from 89 patients were available for analysis. The GPs’ working hypotheses implied ‘no structural pathology’ in 65/89 patients, and ‘fibroids’ in 24/89 patients. Sonographic findings were confirmed in 50/65 patients where ‘no structural pathology’, and in 14/24 of those where ‘fibroids’ were expected. Initially, GPs had intended to refer nine patients to a gynaecologist. Actual management after sonographic assessment was watchful waiting or drug therapy in 57/89 patients. Eighty-nine per cent of these patients had normal sonographic findings. The actual referral rate rose to 27/89 patients. In 17 referred patients, sonographic findings were suggestive of intracavitary abnormalities.

Conclusion

Open-access sonography contributed to more accurate diagnoses and improved GPs’ management of women with abnormal vaginal bleeding.     

Chromosomal deletion unmasking a recessive disease: 22q13 deletion syndrome and metachromatic leukodystrophy

A deletion on one chromosome and a mutant allele on the other may cause an autosomal recessive disease. We report on two patients with mental retardation, dysmorphic features and low catalytic activity of arylsulfatase A. One patient had a pathogenic mutation in the arylsulfatase A gene ( ARSA ) and succumbed to metachromatic leukodystrophy (MLD). The other patient had a pseudoallele, which does not lead to MLD. The presenting clinical features and low arylsulfatase A activity were explained, in each patients, by a deletion of 22q13 and, thereby, of one allele of ARSA .     

Directed epitope delivery across the Escherichia coli outer membrane through the porin OmpF

The porins OmpF and OmpC are trimeric β-barrel proteins with narrow channels running through each monomer that exclude molecules > 600 Da while mediating the passive diffusion of small nutrients and metabolites across the Gram-negative outer membrane (OM). Here, we elucidate the mechanism by which an entire soluble protein domain (> 6 kDa) is delivered through the lumen of such porins. Following high-affinity binding to the vitamin B(12) receptor in Escherichia coli, the bacteriocin ColE9 recruits OmpF or OmpC using an 83-residue intrinsically unstructured translocation domain (IUTD) to deliver a 16-residue TolB-binding epitope (TBE) in the center of the IUTD to the periplasm where it triggers toxin entry. We demonstrate that the IUTD houses two OmpF-binding sites, OBS1 (residues 2-18) and OBS2 (residues 54-63), which flank the TBE and bind with K(d)s of 2 and 24 μM, respectively, at pH 6.5 and 25 oC. We show the two OBSs share the same binding site on OmpF and that the colicin must house at least one of them for antibiotic activity. Finally, we report the structure of the OmpF-OBS1 complex that shows the colicin bound within the porin lumen spanning the membrane bilayer. Our study explains how colicins exploit porins to deliver epitope signals to the bacterial periplasm and, more broadly, how the inherent flexibility and narrow cross-sectional area of an IUP domain can endow it with the ability to traverse a biological membrane via the constricted lumen of a β-barrel membrane protein.     

Factors influencing the regional haemodynamic responses to methanandamide and anandamide in conscious rats

Background and purpose:

In vitro evidence suggests that metabolism of anandamide by cyclooxygenase-2 (COX-2) may be more important when the primary metabolic pathway [i.e. fatty acid amide hydrolase (FAAH)] is inhibited. Thus, the first aim of the present study was to assess the effects of COX-2 and/or FAAH inhibition, on the cardiovascular actions of anandamide. The second aim was to compare the effects of anandamide with those of the metabolically stable analogue (i.e. methanandamide) and investigate mechanisms involved in responses to the latter in conscious rats.

Experimental approach:

Rats were chronically instrumented for recording blood pressure, heart rate and renal, mesenteric and hindquarters vascular conductances in the freely moving state.

Key results:

Inhibition of FAAH with URB597 (cyclohexycarbamic acid 3′-carbamoyl-biphenyl-3-yl-ester) augmented the haemodynamic actions of anandamide, but there was no effect of COX-2 inhibition with parecoxib, either in the absence or the presence of URB597. Methanandamide caused CB₁ receptor-mediated renal and mesenteric vasoconstriction and evoked β₂-adrenoceptor-mediated hindquarters vasodilatation.

Conclusions and implications:

No evidence for an involvement of COX-2 in the systemic cardiovascular actions of anandamide could be demonstrated. Vasoconstrictor actions of methanandamide were shown to involve CB₁ receptors, whereas no involvement of CB₁ receptors in such actions of anandamide has been shown. However, β₂-adrenoceptor-mediated hindquarters vasodilatation, independent of CB₁ receptors, observed here with methanandamide, has previously been seen with anandamide and differs from previous results with other synthetic cannabinoids for which the response was CB₁ receptor-dependent. Thus, mechanisms underlying the cardiovascular actions of endocannabinoids and synthetic analogues appear to be agonist-specific.     

Ectopic expression of rhombotin-2 causes selective expansion of CD4-CD8- lymphocytes in the thymus and T-cell tumors in transgenic mice

Although the proto-oncogene rhombotin-2 (RBTN-2) is widely expressed in most tissues, it is not expressed in T cells. We investigated the potential for overexpression of RBTN-2 to cause tumors in T cells and other tissues by constructing transgenic mice that expressed RBTN-2 under control of the metallothionein-1 promoter. Despite overexpression of RBTN-2 in all tissues, transgenic mice developed T-cell tumors only, thus indicating that tumorigenesis caused by RBTN-2 is T-cell-specific. Thymic tumors were found between 37 and 71 weeks and were invariably associated with metastasis to nonlymphoid organs. Thymuses from apparently healthy transgenic mice were also examined. In some mice there was an 10-fold increase in the CD4-CD8- thymocyte subset, yet the total number of thymocytes was the same as that in wild-type mice. Thymic homeostasis was maintained by a compensatory reduction in the CD4+CD8+ subset. The expansion of CD4-CD8- thymocytes was associated with increased expression of RBTN-2 and with increased cell proliferation. No differences were found in the proportion of thymocytes undergoing apoptosis in transgenic mice. Furthermore, RBTN-2- induced expansion of CD4-CD8- cells did not block differentiation of these cells. Thymuses with 30% CD4-CD8- cells were essentially monoclonal, indicating that all thymic immunophenotypes were derived from a single clone. Overall, our data are consistent with the following scenario: (1) RBTN-2 expression in T cells causes selective and polyclonal proliferation of CD4-CD8- thymocytes accompanied by a compensatory decrease in other thymocyte subsets; (2) a clone with growth advantage and differentiation potential is selected and populates the thymus; and (3) this clone eventually breaches homeostasis of the thymus, accompanied or followed by metastasis to other organs.