Phase I trial of the polyelectrolyte carbetimer administered i.v. once every four weeks

Summary Carbetimer, a new synthetic low molecular weight polyelectrolyte with a novel structure displayed antitumor activiy in a number of animal tumor model systems and in vitro investigations. Based on these findings it was brought to a phase I clinical trial in patients with advanced malignant disease after failure of conventional treatment or with no conventional treatment available. Forty-eight patients received 98 courses. The schedule was a one hour i.v. infusion every four weeks. The starting dose was 180 mg/m² and dose escalation was performed according to a modified Fibonacci formula up to 16,690 mg/m². At least three patients were treated at each dose level and each patient was eligible to receive repeat courses at the same dose, until progressive disease or dose-limiting toxicity intervened. No hematological toxicity was encountered. Some adverse effects such as reversible proteinuria, hypercalcaemia, pain at infusion site, nausea and vomiting and fatigue were seen partly in a dose-related manner but did not represent the maximum tolerated dose (MTD). The limiting toxicity at the highest dose level of 16,690 mg/m² consisted of ocular symptoms (light flashes) accompanied by a modest decrease of blood pressure and nausea or vomiting during a one hour infusion. 16,690 mg/m²/1 hour was considered the MTD. There were four deaths on study, all considered diseaserelated. Fourteen patients had stable disease for more than two courses, which, however, could also be explained by the natural course of disease. No clear-cut antitumor responses were noted in our study center.The recommended dose for phase II trials derived from our results is 12,550 mg/m²/2 hours. However, with regard to experiences in other phase I studies, the subsequent phase II studies will be performed with a dose of 6,500 mg/m².     

Gap-junctional coupling between neutrophils and endothelial cells: a novel modulator of transendothelial migration

Communication between leukocytes and endothelial cells is crucial for inflammatory reactions. Paracrine cross-talk and outside-in signaling (via adhesion molecules) have been characterized as communication pathways to date. As leukocytes and endothelial cells express connexins, we considered intercellular communication via gap junctions an intriguing additional concept. We found that gap-junctional coupling between neutrophils and endothelium occurred in a time-dependent, bidirectional manner and was facilitated by adhesion. After blockade of connexins, transmigration of neutrophils through the endothelial layer was enhanced, and the barrier function of cell monolayers was reduced during transmigration. Tumor necrosis factor alpha decreased coupling. In the presence of connexins, transmigration of neutrophils did not alter permeability. Thus, neutrophils couple to endothelium via gap junctions, functionally modulating transmigration and leakiness. Gap-junctional coupling may be a novel way of leukocyte-endothelial communication.     

Head circumference of children with Williams-Beuren syndrome

Head circumference is considered an important parameter of brain growth and development. Syndrome-specific standards for head circumference in Williams-Beuren syndrome (WBS) are not available to date, although mental retardation is a leading manifestation in the syndrome. Therefore, we investigated head growth in 63 girls (251 measurements) and 88 boys (298 measurements) with WBS between birth and adulthood. Most measurements in both sexes were from the first 4 years of life (n = 162 in girls and n = 189 in boys). Mean (±SD) head circumference at birth was 33.39 ± 1.38 cm and 34.02 ± 1.44 cm for term girls and boys, respectively. Although head growth in WBS girls and boys was at a slower velocity, the pattern of head circumference was similar to that in the normal population. After the age of 3 months, head circumference started to fall below the normal mean in girls (0.5–2 cm). In boys, mean head circumference was below the normal mean already at 1 month of age (2 cm). The deficit increased to 3 cm from 6 months to 4 years. Adult OFC was 52.85 ± 1.75 cm (n = 16) compared to 55.70 ± 1.83 cm (n = 46; P < 0.00001) in WBS women and 55.51 ± 1.68 cm (n = 30) compared to 57.87 ± 1.29 cm (n = 31; P < 0.00001) in WBS men. During development, microcephaly is only seen in about one third of WBS patients. © 1994 Wiley-Liss, Inc.     

Microdissection genotyping of mixed glial and primitive neuroectodermal central nervous system neoplasm

A 22-year-old man with previous radiation treatment for childhood astrocytoma underwent resection of a right parietooccipital lesion. Histopathology revealed a malignant neoplasm with areas of astrocytic and primitive neuroectodermal components. To resolve the relationship and cellular origin, representative tissue was microdissected from several targets, obtaining a balanced mixture of each element. Nonneoplastic brain parenchyma was separately microdissected to determine polymorphic marker informativeness and to serve as an internal negative control. Despite the relatively small quantity of tissue removed for each microdissection target, sufficient material was available for reliable, balanced, polymerase chain reaction-format genotyping encompassing a panel of tumor suppressor genes and genetic loci associated with these forms of neoplasia. The findings revealed distinct discordant genotypic profiles for each of the neoplastic components. The efficacy of the approach used for molecular analysis of this complex neoplasm and the implication of the genotypic findings are discussed.     

No evidence for involvement of the calpain-10 gene 'high-risk' haplotype combination for non-insulin-dependent diabetes mellitus in early onset obesity

In light of evidence of linkage of obesity to chromosome 2q31-q37, we hypothesized that the calpain-10 gene 'high-risk' haplotype combination for non-insulin-dependent diabetes mellitus (NIDDM) is involved in early onset obesity. We screened the NIDDM 'high-risk'-haplotype combination formed by the alleles 112 and 121 of the polymorphisms UCSNP-43, -19, and -63 in 166 families consisting of an extremely obese child or adolescent (mean BMI percentile: 99.3+/-1.38), one or more obese sibs (mean BMI percentile: 97.42+/-2.88), and both of their parents. Genotyping for three calpain-10 gene polymorphisms was performed by polymerase chain reaction (PCR) with (a) length polymorphism detection (UCSNP-19) or (b) allele-specific PCR (UCSNP-43 and -63). To allow for correct haplotype assignment all individuals were additionally genotyped for two microsatellite markers (D2S125 and D2S2338). We followed a hierarchical test procedure. As the first step, model-free linkage analysis was performed using maximum likelihood binomial statistics. The second stage consisted of a one-sided asymptotic pedigree disequilibrium test for the UCSNP-43 and on an exploratory level for the other SNP-markers and all haplotypes formed by the three SNPs. The final stage investigated the reported haplotype combination. We failed to detect an initial linkage of obesity to this region (LOD score <0.4). All subsequent exploratory analyses were negative. Our analysis of the relationship between the NIDDM 'high-risk' haplotype combination and extreme early onset obesity revealed no evidence for linkage and association.     

Central and peripheral psychophysiological responses to trauma-related cues in subclinical posttraumatic stress disorder: a pilot study

This study examined verbal-subjective, peripheral and central physiological responses of motor vehicle accident (MVA) survivors with subclinical posttraumatic stress disorder (PTSD), without PTSD symptoms as well as healthy controls. Seven persons of each group were exposed to positive, neutral, accident-related and negative, non-accident-related slides. The verbal-subjective ratings of the slides did not differ between the groups. In contrast to the verbal ratings of the trauma-related materials, the behavioral and physiological responses showed a remarkable dissociation from these reports. The startle responses were enhanced to accident-related slides only in the PTSD group and MVA survivors with PTSD had a significantly lower response to the neutral slides than MVA survivors without PTSD. P200 was lower to positive, neutral and negative slides in the PTSD group compared to both other groups. The late positive complex showed no group-related effects. The data suggest that traumatized persons with PTSD show exaggerated emotional responses to trauma-related stimuli and reduced cognitive responses to several types of stimuli that may interfere with the extinction of the emotional trauma memory.     

Sputum microbiome profiles identify severe asthma phenotypes of relative stability at 12 to 18 months

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Overrepresentation of genetic variation in the AnkyrinG interactome is related to a range of neurodevelopmental disorders

Upon the discovery of numerous genes involved in the pathogenesis of neurodevelopmental disorders, several studies showed that a significant proportion of these genes converge on common pathways and protein networks. Here, we used a reversed approach, by screening the AnkyrinG protein-protein interaction network for genetic variation in a large cohort of 1009 cases with neurodevelopmental disorders. We identified a significant enrichment of de novo potentially disease-causing variants in this network, confirming that this protein network plays an important role in the emergence of several neurodevelopmental disorders.Subject terms: Genetics research, Neurological disorders