Alpha thalassaemia mental retardation (ATR-X): an atypical family

A novel form of severe, X linked mental retardation associated with alpha thalassaemia (ATR-X syndrome) has recently been described. Two affected cousins are described, one of whom has an unusually mild haematological phenotype. HbH inclusions, which are the hallmark of this disease, were only detected in the peripheral red blood cells after repeated observations.     

Behavioural effects of phenobarbitone and phenytoin in small children

Mothers of 56 children under 2 years old taking phenobarbitone and mothers of 55 children taking phenytoin recorded on questionnaires changes they had noted in the children's behaviour 3 and 9 weeks after starting the drug. Severe behavioural disturbance was noted by many, but the pattern and incidence was similar to that recorded by the mothers of 50 children starting a placebo, and we attribute it to the effect of a recent hospital admission. There was a small improvement in the behaviour of 20% of children who had been taking phenobarbitone for a year when they stopped it, but in this age group the disturbance caused by phenobarbitone did not appear to have been great.     

Spectrum of mutations in the fumarylacetoacetate hydrolase gene of tyrosinemia type 1 patients in northwestern Europe and Mediterranean countries

Hereditary tyrosinemia type 1 (HT1) is a rare metabolic disease caused by a deficient activity of the enzyme fumarylacetoacetase (FAH). To investigate the molecular heterogeneity of tyrosinemia, the geographic distribution and the genotype–phenotype relationship, we have analyzed the FAH genotype of 25 HT1 patients. Mutation screening was performed by PCR amplification of exons 1-14 of the FAH gene, followed by SSCP analysis and direct sequencing of the amplified exons. Fourteen different mutations were found, of which seven were novel, viz. Three missense mutations (G158D, P261L, F405H), a deletion of three nucleotides causing a deletion of serine (DEL366S) and three splice site mutations: IVS2+1(g-t), IVS6-1(g-c), IVS8-1(g-c). The splice site mutations IVS6-1(g-t) and IVS12+5(g-a) were frequently found in countries around the Mediterranean and northerwestern Europe, respectively. No clear correlation between the genotype and the three major HT1 subtypes could be established. Hum Mutat 12:19–26, 1998. © 1998 Wiley-Liss, Inc.     

Anterior cruciate ligament tears: MR imaging compared with arthroscopy and clinical tests

Seventy-nine magnetic resonance (MR) studies of the knee were reviewed in an evaluation of the ability of MR imaging to demonstrate arthroscopically proved anterior cruciate ligament (ACL) tears. MR findings were also compared with the findings of two commonly applied clinical tests of ACL instability: the Lachman test and the anterior drawer test. The sensitivity of MR imaging was 94% (17 of 18), compared with 78% (14 of 18) for the anterior drawer test and 89% (16 of 18) for the Lachman test. The specificity was 100% for all three. Three MR criteria were applied: irregularity or a wavy contour of the anterior margin of the ligament, high-signal-intensity change within the substance of the ligament on T2-weighted images, and discontinuity of that substance. The sagittal T2-weighted image was especially helpful, producing an "arthrographic" effect, in which the anterior margin of the ACL is outlined by high-signal-intensity joint fluid. By demonstrating ACL and other extrameniscal lesions, MR imaging may help clarify the mechanisms of knee injury.     

Liver volume measurement: reason of the difference between in vivo CT-volumetry and intraoperative ex vivo determination and how to cope it

Purpose

Volumetric assessment of the liver regularly yields discrepant results between pre- and intraoperatively determined volumes. Nevertheless, the main factor responsible for this discrepancy remains still unclear. The aim of this study was to systematically determine the difference between in vivo CT-volumetry and ex vivo volumetry in a pig animal model.

Material and Methods

Eleven pigs were studied. Liver density assessment, CT-volumetry and water displacement volumetry was performed after surgical removal of the complete liver. Known possible errors of volume determination like resection or segmentation borders were eliminated in this model. Regression analysis was performed and differences between CT-volumetry and water displacement determined.

Results

Median liver density was 1.07 g/ml. Regression analysis showed a high correlation of r² = 0.985 between CT-volumetry and water displacement. CTvolumetry was found to be 13% higher than water displacement volumetry (p < 0.0001).

Conclusion

In this study the only relevant factor leading to the difference between in vivo CT-volumetry and ex vivo water displacement volumetry seems to be blood perfusion of the liver. The systematic difference of 13 percent has to be taken in account when dealing with those measures.     

The influence of HAART on the efficacy and safety of pegylated interferon and ribavirin therapy for the treatment of chronic HCV infection in HIV-positive individuals

Objective

This study was performed to investigate the impact of HAART versus no HAART and nucleoside free versus nucleoside containing HAART on the efficacy and safety of pegylated interferon and ribavirin therapy for the treatment of chronic HCV infection in HIV/HCV co-infected patients. In addition a control group of HCV mono-infected patients undergoing anti-HCV therapy was evaluated.

Methods

Multicenter, partially randomized, controlled clinical trial. HIV-negative and -positive patients with chronic HCV infection were treated with pegylated interferon alfa-2a and ribavirin (800 - 1200 mg/day) for 24 - 48 weeks in one of four treatment arms: HIV-negative (A), HIV-positive without HAART (B) and HIV-positive on HAART (C). Patients within arm C were randomized to receive open label either a nucleoside containing (C1) or a nucleoside free HAART (C2).

Results

168 patients were available for analysis. By intent-to-treat analysis similar sustained virological response rates (SVR, negative HCV-RNA 24 weeks after the end of therapy) were observed comparing HIV-negative and -positive patients (54% vs. 54%, p = 1.000). Among HIV-positive patients SVR rates were similar between patients off and on HAART (57% vs. 52%, p = 0.708). Higher SVR rates were observed in patients on a nucleoside free HAART compared to patients on a nucleoside containing HAART, though confounding could not be ruled out and in the intent-to-treat analysis the difference was not statistically significant (64% vs. 46%, p = 0.209).

Conclusions

Similar response rates for HCV therapy can be achieved in HIV-positive and -negative patients. Patients on nucleoside free HAART reached at least equal rates of sustained virological response compared to patients on standard HAART.     

Mitogenic properties of a bispecific single-chain Fv-Ig fusion generated from CD2-specific mAb to distinct epitopes [In Process Citation]

The combination of anti-CD2 mAb 9.6 and 9-1, specific for distinct epitopes, induces proliferation of resting human T cells. The mitogenic activity of this mAb mixture depends upon accessory cells and the 9-1 mAb Fc domain. To further study the functional properties of these mAb, their variable regions were cloned and expressed as monospecific single- chain Fv (scFv) proteins fused to the human IgG1 Fc domain (scFvIg). A novel bispecific scFvIg was constructed by cloning the two monospecific scFv binding sites in tandem, with the 9.6 scFv placed N-terminal to the 9-1 scFvIg. Monospecific scFvIg binding to CD2 was comparable to that of the corresponding parental mAb, while the bispecific scFvIg exhibited binding activity similar to that of the 9-1 scFvIg. The combination of 9.6 scFvIg and 9-1 mAb was mitogenic, whereas mixtures including the 9-1 scFvIg were non-stimulatory, confirming the unique properties of the 9-1 IgG3 Fc. Without the IgG3 tail, the bispecific 9.6/9-1 scFvIg was directly mitogenic and was a more potent mitogen than the mAb mixture, but was accessory cell dependent. Unlike the combination of mAb, the bispecific reagent did not directly mobilize calcium in T cells. In comparison to the mAb mixture, bispecific 9.6/9- 1 scFvIg-mediated stimulation of a mixed lymphocyte reaction was significantly more resistant to inhibition of the CD28 co-stimulatory pathway by the inhibitor CTLA-4-Ig. These results show that expression of the 9.6 and 9-1 binding sites together on a bispecific scFvIg increased the mitogenic properties of the mAb and altered the degree of accessory cell signals required for T cell activation.