Perceived benefit after participating in positive or negative/neutral heart failure trials: the patients' perspective

BACKGROUND: Clinical trials, the gold standard for the evaluation of new therapeutic strategies, may prove a drug to be beneficial, harmful or neutral according to its effect on the end-point(s) under study. AIMS: To study the reaction and perspective of the patients participating in a clinical heart failure trial, particularly in relation to whether the trial subsequently proved to be positive, negative or neutral. METHODS: Anonymous self-completed questionnaire was sent to 78 and returned by 70 consecutive patients 1--6 months after participating in six clinical heart failure trials. The trial was neutral or negative regarding the primary end-point in four (47 patients) of the six studies (MACH-1 trial of mibefradil, REACH trial of bosentan, CASCO trial of calcium sensitizer, ecadotril trial of neutral endopeptidase inhibitor) and positive in two (23 patients) (ICARUS Israel carvedilol study, exercise study of candesartan cilexetil). RESULTS: Most patients reported subjective global clinical benefit (78% for positive, 74% for negative or neutral trial, NS) after participating in a clinical trial. After adjustment for age, sex, level of education, previous research, perceived comprehension, and treatment allocation (active drug/placebo) in a stepwise regression model, perceived global improvement was greater in older patients (P=0.02), after participation in a positive trial (P=0.05) and in females (P=0.07). The major reason given by the patient for perceived clinical improvement was better follow-up, some believed it was due to change in medication, particularly those who had participated in a positive trial. CONCLUSIONS: More than 70% of patients participating in clinical trials of new drugs for heart failure reported perceived global improvement. Clinical improvement was greater in, but not limited to, patients who participated in positive trials. These salutary findings support the continued recruitment of patients to clinical heart failure trials.     

Haemostasis contact system and fibrinolysis in hereditary angioedema (C1-inhibitor deficiency)

Factors of the classical complement pathway, the contact system and fibrinolysis were evaluated both with functional and immunochemical methods, in patients with inherited deficiency of C1-inhibitor. Evaluations were performed under basal conditions, during acute attacks and during prophylaxis with low doses of anabolic steroids. Patients in the basal state showed no significant abnormalities of any of the parameters that we investigated. During acute attacks a slightly reduced prekallikrein concentration was registered. During treatment with low doses of danazol and stanozolol, protein C and plasminogen were found to be increased. Our data suggest that C1-inhibitor deficiency per se does not lead to a derangement of the fibrinolysis and coagulation contact system, and that the kinin system may be involved during acute attacks of angioedema.     

Axons of callosal neurons bifurcate transiently at the white matter before consolidating an interhemispheric projection

The main alternative output routes of adult cortical axons are the internal capsule and the corpus callosum. How do callosal axons choose their trajectories? We hypothesized that bifurcation followed by elimination of one branch is a developmental strategy for accomplishing this aim. Using embryonic and postnatal mice, we labelled cortical projecting neurons and quantified their axonal bifurcations in correlation with the mediolateral position of their somata. Bifurcating axons were numerous in the younger brains but declined during further development. Most bifurcating axons pertained to neurons located in the dorsolateral cortex. Moreover, callosal neurons bifurcate more often than subcortically projecting cells. We then quantified bifurcations formed by dissociated green fluorescent cells plated onto cortical slices. Cells grown over dorsolateral cortex bifurcated more often than those grown over medial cortex, irrespective of their positional origin in the donor. Removal of intermediate targets from the slices prevented bifurcation. We concluded that transient bifurcation and elimination of the lateral branch is a strategy employed by developing callosal axons in search of their targets. As cell body position and intermediate targets determine axon behaviour, we suggest that bifurcations are regulated by cues expressed in the environment.     

Effect of testosterone metabolites on ABC half-transporter relative gene expression in X-linked adrenoleukodystrophy

Summary X-linked adrenoleukodystrophy (X-ALD) is an inherited neurodegenerative disorder associated with reduced very long-chain fatty acid β-oxidation, mainly affecting the nervous system, the adrenal cortex and the testes. The clinical manifestations of hypogonadism, alopecia and the impairment of the enzyme 5α-reductase, which converts testosterone into dihydrotestosterone, clearly point to an involvement of androgens in this pathology. The disease is characterized by mutations in the ABCD1 gene, which codes for the peroxisomal ABC half-transporter ALDP, and by a broad range of clinical manifestations. The altered function of ALDP can be compensated by the overexpression of proteins belonging to the same family of ABC half-transporters. A promising therapeutic approach is represented by the activation of these proteins by specific agonists. In this study we evaluated the effect of the testosterone metabolite dihydrotestosterone (DHT) and 5α-androstan-3α,17β-diol (3α-diol) on the expression of the ABC half-transporters encoded by the ABCD2 and ABCD3 genes, in fibroblasts drawn from controls and from two affected brothers. The two patients presented the same mutation in exon 9 but had different clinical manifestations, one patient being asymptomatic and the second one severely affected. When the cells were stimulated with testosterone metabolites, only the severely affected patient showed a significant increase in ABCD2 mRNA levels, while the ABCD3 expression remained unchanged in both patients. Electronic Supplementary Material The online version of this article (doi:) contains supplementary material, which is available to authorized users. Online citation: JIMD Short Report #062 (2007) Online     

Borderline mental development in a congenital disorder of glycosylation (CDG) type Ia patient with multisystemic involvement (intermediate phenotype)

Summary CDG Ia (phosphomannomutase deficiency) has a wide clinical spectrum with the most severe affected patients having multisystemic disease in addition to severe nervous system involvement. We report a patient with CDG Ia and an intermediate phenotype due to mild neurological impairment and borderline cognitive abilities despite the occurrence of typical extraneurological symptoms. These included liver involvement, coagulopathy and failure to thrive with enteropathy. Genotype analyses showed that he was compound heterozygous for T237R/C241S mutations. This observation underlines that the CDG Ia clinical spectrum may include intraindividual variability that might reflect different degrees of glycosylation abnormalities among distinct body compartments. CDG Ia should be considered in cases of unexplained liver involvement and/or enteropathy in patients with mild developmental delay and subtle neurological signs. Electronic Supplementary Material Supplementary material is available for this article at Communicating editor: Verena Peters     

Primary nodal marginal zone B-cell lymphoma: clinical features and prognostic assessment of a rare disease

This study defined the clinical features and assessed the prognosis of 47 patients (17 males, 30 females, median age 63 years) with primary nodal marginal zone B-cell lymphoma. Forty-five per cent had stage IV disease. Hepatitis C virus serology was positive in 24%. According to the Follicular Lymphoma International Prognostic Index (FLIPI), 33% were classified as low-risk, 34% as intermediate-risk, and 33% as high-risk. The 5-year overall survival (OS) was 69%. In univariate analysis worse OS was associated with: FLIPI (P = 0.02), age > 60 years (P = 0.05) and raised lactate dehydrogenase (P = 0.05). In multivariate analysis, only FLIPI predicted a worse OS (P = 0.02).     

Genetic alterations in mouse medulloblastomas and generation of tumors de novo from primary cerebellar granule neuron precursors

Mice lacking p53 and one or two alleles of the cyclin D-dependent kinase inhibitor p18(Ink4c) are prone to medulloblastoma development. The tumor frequency is increased by exposing postnatal animals to ionizing radiation at a time when their cerebella are developing. In irradiated mice engineered to express a floxed p53 allele and a Nestin-Cre transgene, tumor development can be restricted to the brain. Analysis of these animals indicated that inactivation of one or both Ink4c alleles did not affect the time of medulloblastoma onset but increased tumor invasiveness. All such tumors exhibited complete loss of function of the Patched 1 (Ptc1) gene encoding the receptor for sonic hedgehog, and many exhibited other recurrent genetic alterations, including trisomy of chromosome 6, amplification of N-Myc, modest increases in copy number of the Ccnd1 gene encoding cyclin D1, and other complex chromosomal rearrangements. In contrast, medulloblastomas arising in Ptc1(+/-) mice lacking one or both Ink4c alleles retained p53 function and exhibited only limited genomic instability. Nonetheless, complete inactivation of the wild-type Ptc1 allele was a universal event, and trisomy of chromosome 6 was again frequent. The enforced expression of N-Myc or cyclin D1 in primary cerebellar granule neuron precursors isolated from Ink4c(-/-), p53(-/-) mice enabled the cells to initiate medulloblastomas when injected back into the brains of immunocompromised recipient animals. These "engineered" tumors exhibited gene expression profiles indistinguishable from those of medulloblastomas that arose spontaneously. These results underscore the functional interplay between a network of specific genes that recurrently contribute to medulloblastoma formation.     

Bicommissural neurones in the cerebral cortex of developing hamsters.

The trajectory, developmental time course, and origin of callosal fibres that recross through the anterior commissure were studied in developing hamsters, using carbocyanines in fixed brains on different ages. The bicommissural fibres were found in hamsters from E15 through P7, but disappeared after P7. By double labelling it was found that the neurones of origin of these bicommissural fibres were located in the lateral cortex within the region where the callosal zone of origin overlaps that of the anterior commissure. From these experiments, it was concluded that the axons of a group of cells in the lateral cortex of developing rodents are branched and grow transiently through both the callosum and the anterior commissure.     

Decreased bone speed of sound in children with growing pains measured by quantitative ultrasound

OBJECTIVE: The most common cause of recurring childhood musculoskeletal pain is termed growing pains (GP). We hypothesized that GP may represent a local overuse syndrome and therefore may be associated with decreased bone speed of sound (SOS) measured by quantitative ultrasound (US). METHODS: We studied 39 children with GP. Bone SOS was measured by US in both mid-tibial and radius bones according to a validated protocol. Unpaired Student t test was used to compare patients and norms of healthy controls. RESULTS: Tibial SOS was significantly reduced in children with GP compared to controls (Z score -0.546 for boys and -0.891 for girls; p = 0.004, p < 0.001, respectively). Radius SOS was significantly reduced only in girls with GP (Z score -0.692, p = 0.006). No correlation was found between bone SOS and various demographic and clinical factors besides the child's ethnicity and body mass index. CONCLUSION: Bone SOS was significantly reduced in children with GP, especially in painful tibial regions. GP may represent a local overuse syndrome.