Characterizing the phenotypic manifestations of MFN2 R104W mutation in Charcot-Marie-Tooth type 2

Mutations of the mitofusin 2 (MFN2) gene have been reported to be the most common cause of the axonal form of Charcot Marie Tooth disease (CMT). The aim of this study was to describe a de novo MFN2 p.R104W mutation and characterize the associated phenotype. We screened the entire coding region of MFN2 gene and characterized its clinical phenotype, nerve conduction studies and sural nerve biopsy. Neuropsychological tests and brain MRI were also performed. A de nova mutation was found in exon 4 (c.310C > T; p.R104W). In addition to a severe and early onset axonal neuropathy, the patient presented learning problems, obesity, glucose intolerance, leukoencephalopathy, brain atrophy and evidence of myelin involvement and mitochondrial structural changes on sural nerve biopsy. These results suggest that MFN2 p.R104W mutation is as a hot-spot for MFN2 gene associated to a large and complex range of phenotypes. (C) 2011 Elsevier B.V. All rights reserved.

Phenotypic and molecular characterization of recent and archived Erysipelothrix spp. isolated from Brazilian swine

One hundred fifty-one Erysipelothrix spp. isolates from Brazilian swine were characterized by serotyping, determination of antimicrobial susceptibility, amplified fragment length polymorphism (AFLP), and pulsed-field gel electrophoresis (PFGE). Among all isolates, 139 were classified in 18 different serotypes and serotype 2b was the most frequent. The susceptibility profiles of the isolates were very similar among each other, which did not permit subtyping Erysipelothrix spp. isolates by the antimicrobial susceptibility testing. Despite the fact that AFLP and PFGE provided the same discriminatory index (0.98), PFGE was more discriminatory than AFLP, given the types of groups it generates. Regardless the technique employed (AFLP or PFGE), no discrimination between recent and historical isolates was established, neither a fixed epidemiologic pattern for their grouping was observed. Nevertheless, AFLP could be an interesting alternative for discriminating the Erysipelothrix species, while PFGE could be an indication for discerning this bacterium according to the serotypes. (C) 2011 Elsevier Inc. All rights reserved.

Phenotypic and genetic analyses of a short measure of psychosis-proneness in a large-scale Australian twin study

Previous genetic analyses of psychosis proneness have been limited by their small sample size. For the purposes of large-scale screening, a 12-item questionnaire was developed through a two-stage process of reduction from the full Chapman and Chapman scales. 3685 individuals (including 1438 complete twin pairs) aged 18–25 years and enrolled in the volunteer Australian Twin Registry returned a mail questionnaire which included this psychosis proneness scale and the Eysenck Personality Questionnaire. Despite the brevity of the questionnaire, item and factor analysis identified four unambiguous and essentially uncorrelated scales. There were (1) Perceptual Aberration – Magical Ideation; (2) Hypomania – Impulsivity/Nonconformity; (3) Social Anhedonia and (4) Physical Anhedonia. Model-fitting analyses showed additive genetic and specific environmental factors were sufficient for three of the four scales, with the Social Anhedonia scale requiring also a parameter for genetic dominance. There was no evidence for the previously hypothesised sex differences in the genetic determination of psychosis-proneness. The potential value of multivariate genetic analysis to examine the relationship between these four scales and dimensions of personality is discussed. The growing body of longitudinal evidence on psychosis-proneness suggests the value of incorporating this brief measure into developmental twin studies.

Structure-hepatic disposition relationships for cationic drugs in isolated perfused rat livers: Transmembrane exchange and cytoplasmic binding process

This work studied the structure-hepatic disposition relationships for cationic drugs of varying lipophilicity using a single-pass, in situ rat liver preparation. The lipophilicity among the cationic drugs studied in this work is in the following order: diltiazem. propranolol. labetalol. prazosin. antipyrine. atenolol. Parameters characterizing the hepatic distribution and elimination kinetics of the drugs were estimated using the multiple indicator dilution method. The kinetic model used to describe drug transport (the two-phase stochastic model) integrated cytoplasmic binding kinetics and belongs to the class of barrier-limited and space-distributed liver models. Hepatic extraction ratio (E) (0.30-0.92) increased with lipophilicity. The intracellular binding rate constant (k(on)) and the equilibrium amount ratios characterizing the slowly and rapidly equilibrating binding sites (K-S and K-R) increase with the lipophilicity of drug (k(on) : 0.05-0.35 s(-1); K-S : 0.61-16.67; K-R : 0.36-0.95), whereas the intracellular unbinding rate constant (k(off)) decreases with the lipophilicity of drug (0.081-0.021 s(-1)). The partition ratio of influx (k(in)) and efflux rate constant (k(out)), k(in)/k(out), increases with increasing pK(a) value of the drug [from 1.72 for antipyrine (pK(a) = 1.45) to 9.76 for propranolol (pK(a) = 9.45)], the differences in k(in/kout) for the different drugs mainly arising from ion trapping in the mitochondria and lysosomes. The value of intrinsic elimination clearance (CLint), permeation clearance (CLpT), and permeability-surface area product (PS) all increase with the lipophilicity of drug [CLint (ml . min(-1) . g(-1) of liver): 10.08-67.41; CLpT (ml . min(-1) . g(-1) of liver): 10.80-5.35; PS (ml . min(-1) . g(-1) of liver): 14.59-90.54]. It is concluded that cationic drug kinetics in the liver can be modeled using models that integrate the presence of cytoplasmic binding, a hepatocyte barrier, and a vascular transit density function.

Saturable dose-response relationships for melphalan in melanoma treatment by isolated limb infusion in the nude rat

Nude rats bearing melanomas on their hindlimbs were treated by isolated limb infusion (ILI) with increasing doses (7.5-400 mug/ml) of melphalan. The response of tumours to treatment at the end of the observation period was graded, according to diameter, as complete response (CR), partial response (PR), no change (NC) or progressive disease (PD). No linear relationship between the dose of melphalan and the tumour response was observed. All doses above a threshold of 15 mug/ml achieved a PR or CR. The achievement of CR was not related to increased dose. Two major implications arise from this work. Firstly, the typically two-to three-fold increase in cytotoxic drug concentration given in high dose chemotherapy compared with standard drug concentration may not be sufficient to produce the expected increase in tumour response and possibly survival, and the controversial results of high dose chemotherapy in different studies may thus be explained. Secondly, since an increase in melphalan dose above a certain threshold does not greatly increase tumour response, the use of combination therapies would seem to be more likely to be effective than increased chemotherapeutic drug doses in achieving better tumour responses.

Tormopsolus attenuatus n. sp (Digenea : Acanthocolpidae) from Seriola hippos (Perciformes : Carangidae), Western Australia, with some observations on the relationships in the genus

A new acanthocolpid, Tormopsolus attenuatus n. sp., is described from the carangid Seriola hippos from waters off the coast of SW Australia. A cladistic analysis of the genus using 31 morphological and metrical characters indicates that the closest species is T. asiatica Parukhin, 1976 status amend. (previously T. orientalis asiatica). T. attenuatus differs from T. asiatica in its smaller overall dimensions, more attenuated outline, relatively shorter post-testicular region, vitelline interruption at the level of the ovary, papillae on the oral sucker and, possibly, much longer genital atrium. Other similar species, T. orientalis Yamaguti, 1934 and T. medius Reimer, 1983, differ in having interruptions of the vitelline fields at the level of both testes and at the level of the ovary.

The Relationships between West Nile and Kunjin Viruses

Until recently, West Nile (WN) and Kunjin (KUN) viruses were classified as distinct types in the Flavivirus genus. However, genetic and antigenic studies on isolates of these two viruses indicate that the relationship between them is more complex. To better define this relationship, we performed sequence analyses on 32 isolates of KUN virus and 28 isolates of WN virus from different geographic areas, including a WN isolate from the recent outbreak in New York. Sequence comparisons showed that the KUN virus isolates from Australia were tightly grouped but that the WN virus isolates exhibited substantial divergence and could be differentiated into four district groups. KUN virus isolates from Australia were antigenically homologous and distinct from the WN isolates and a Malaysian KUN virus. Our results suggest that KUN and WN viruses comprise a group of closely related viruses that can be differentiated into subgroups on the basis of genetic and antigenic analyses.

Phylogenetic relationships of Trypanosoma chelodina and Trypanosoma binneyi from Australian tortoises and platypuses inferred from small subunit rRNA analyses

Trypanosome infections are often difficult to detect by conventional microscopy and their pleomorphy often confounds differential diagnosis. Molecular techniques are now being used to diagnose infections and to determine phylogenetic relationships between species. Complete small subunit rRNA gene sequences were determined for isolates of Trypanosoma chelodina from the Brisbane River tortoise (Emydura signata), the saw-shelled tortoise (Elseya latisternum), and the eastern snake-necked tortoise (Chelodina longicollis) from southeast Queensland, Australia. Partial sequence data were also obtained for T. binneyi from a platypus (Ornithorhynchus anatinus) from Tasmania. Phylogenetic relationships between T. chelodina, T. binneyi and other species were examined by maximum parsimony and likelihood methods. The Australian tortoise and platypus trypanosomes did not exhibit any close phylogenetic relationships with those of mammals, reptiles or amphibians, but were closely related to each other, and to fish trypanosomes. This contra-indicates their co-evolution with their vertebrate hosts but does not exclude co-evolution with different groups of invertebrate vectors, notably insects and leeches.

Pyramidal neurones in macaque visual cortex: Interareal phenotypic variation of dendritic branching patterns

The basal dendritic arbors of over 500-layer III pyramidal neurones of the macaque cortex were compared by fractal analyses, which provides a measure of the space filling (or branching pattern) of dendritic arbors. Fractal values (D) of individual cells were compared between the cytochrome oxidase (CO)-rich blobs and CO-poor interblobs, of middle and upper layer III, and between sublaminae, in the primary visual area (Vi). These data were compared with those in the CO compartments in the second visual area (V2), and seven other extrastriate cortical areas. (V4, MT, LIP, 7a, TEO, TE and STP). There were significant differences in the fractal dimensions, and therefore the dendritic branching patterns, of cells in striate and extrastriate areas. Of the 55 possible pairwise comparisons of fractal dimension of neurones in different cortical areas (or CO compartments), 39 proved to be significantly different. The markedly different morphologies of pyramidal cells in the different cortical areas may be one of the features that determine the functional signatures of these cells by influencing the number of inputs received by, and propagation of potentials through, their dendritic arbors.

Relationships between non-occupational cadmium exposure and expression of nine cytochrome P450 forms in human liver and kidney cortex samples

This study was undertaken to assess associations between age, gender, cigarette smoke and non-workplace cadmium exposure, and liver pathology and inter-individual variation in cytochrome P450 (CYP) expression in human tissues. Autopsy specimens of twenty-eight Queensland residents whose ages ranged from 3 to 89 years were analyzed for the presence of nine CYP protein isoforms by immunoblotting. All subjects were Caucasians and their liver cadmium contents ranged from 0.11 to 3.95 kg/g wet weight, while their kidney cadmium contents were in the range of 2 to 63 mug/g wet weight. CYP1A2, CYP2A6, CYP2D6, CYP3A4, and CYP3A5 were detected in liver but not in kidney, and CYP1A1 and CYP1B1 were not found in liver or kidney. Lowered liver CYP2C8/19 protein contents were found to be associated with liver pathology. Importantly, we show elevated levels of CYP2C9 protein to be associated with cadmium accumulation in liver. No mechanism that explains this association is apparent, but there are two possibilities that require further study. One is that variation in CYP2C9 protein levels may be, in part, attributed to an individual's non-workplace exposure to cadmium, or an individual's CYP2C9 genotype may be a risk factor for cadmium accumulation. A positive correlation was found between liver CYP3A4 protein and subject age. Levels of liver CYPIA2 protein, but not other CYP forms, were increased in people more exposed to cigarette smoke, but there was no association between CYPIA2 protein and cadmium. CYP2A6 protein was found in all liver samples and CYP2A6 gene typing indicated the absence of CYP2A6 null allele (CYP2A6(D)) in this sample group, confirming very low prevalence of homozygous CYP2A6(D) in Caucasians. CYP2A6 gene types W/W, WIC, and CIC were not associated with variations in liver microsomal CYP2A6 protein. CYP2D6 protein was absent in all twenty-five kidney samples tested but was detectable in liver samples of all but two subjects, indicating the prevalence of the CYP2D6 null allele (CYP2D6(D)) in this sample group to be about 7%, typical of Caucasian populations. (C) 2001 Elsevier Science Inc. All rights reserved.

Trade relationships between the Gulf Cooperation Council and the European Union

This paper examines the trade relationship between the Gulf Cooperation Council (GCC) and the European Union (EU). A simultaneous equation regression model is developed and estimated to assist with the analysis. The regression results, using both the two stage least squares (2SLS) and ordinary least squares (OLS) estimation methods, reveal the existence of feedback effects between the two economic integrations. The results also show that during times of slack in oil prices, the GCC income from its investments overseas helped to finance its imports from the EU.