Disruption of NaS1 sulfate transport function in mice leads to enhanced acetaminophen-induced hepatotoxicity

Sulfate is required for detoxification of xenobiotics such as acetaminophen (APAP), a leading cause of liver failure in humans. The NaS1 sulfate transporter maintains blood sulfate levels sufficiently high for sulforiation reactions to work effectively for drug detoxification. In the present study, we identified two loss-of-function polymorphisms in the human NaS1 gene and showed the Nas1-null mouse to be hypersensitive to APAP hepatotoxicity. APAP treatment led to increased liver damage and decreased hepatic glutathione levels in the hyposulfatemic Nas1-null mice compared with that in normosulfatemic wild-type mice. Analysis of urinary APAP metabolites revealed a significantly lower ratio of APAP-sulfate to APAP-glucuronide in the Nas1-null mice. These results suggest hyposulfatemia increases sensitivity to APAP-induced hepatotoxicity by decreasing the sulfonation capacity to metabolize APAP. In conclusion, the results of this study highlight the importance of plasma sulfate level as a key modulator of acetaminophen metabolism and suggest that individuals with reduced NaS1 sulfate transporter function would be more sensitive to hepatotoxic agents.

The effects of moderate and low levels of acoustic overstimulation on stereocilia and their tip links in the guinea pig

Guinea pigs were exposed to pure tones of 10 kHz at intensities between 98 and 115 dB SPL for 5-30 min, to produce varying degrees of acoustic trauma. Changes in auditory thresholds were measured electrophysiologically, and the animals were immediately fixed for scanning electron microscopy. Correlation between morphological changes to the hair bundle and losses in threshold, showed that with the smallest degrees of trauma (98 dB SPL for 15 min, mean maximum threshold loss of 22 dB), damage was confined to a small stretch of inner hair cells (IHC), with only subtle changes to the stereocilia of the outer hair cells (OHC). At exposure intensities greater than 102 dB SPL (duration: 15 min) the IHC stereocilia in the centre of the lesion were always substantially disarrayed. Substantial damage to the OHC bundles was seen only with exposures above 110 dB SPL(duration: greater than or equal to 5 min), producing threshold losses of 50 dB or more. Tip links were lost only where the stereocilia were disarrayed. It is concluded that the tip links are not the most vulnerable components of the cochlear hair cell, but that relatively low levels of acoustic stimulation can cause significant damage to the stereociliary bundle of the IHCs.

Phylogenetic relationships and uncertain taxonomy of Pedomicrobium species

The phylogenetic relationships among the species of the genus Pedomicrobium were studied by comparing their 16S rRNA sequences, The Pedomicrobium species form a coherent phylogenetic cluster within the genera of the hyphal budding bacteria in the alpha-Proteobacteria. The sequences of two strains of Pedomicrobium australicum were obtained from DNAs extracted from nonviable freeze-dried cells, which are the only source of material available, and were found to be almost identical (level of similarity, 99.9%), Overall, the Pedomicrobium species are closely related, with sequence similarities ranging from 96.2 to 99.9%, Pedomicrobium manganicum is phylogenetically the most distantly related species and exhibits the lowest similarity (96.2%) with Pedomicrobium americanum, Australian isolate Pedomicrobium sp, strain ACM 3067, P, americanum, and P, australicum are all very highly related, with similarities greater than 99%, Pedomicrobium sp, strain ACM 3067 is most closely related to P, australicum (level of similarity, 99.6%) and P, americanum (99.4%), These manganese-oxidizing species are more closely related to the iron-oxidizing species Pedomicrobium ferrugineum than to the other manganese-oxidizing species, P, manganicum. Taxonomic uncertainties resulting from the loss of the type culture of P, australicum are discussed.

Direct visualisation of B-1 inhomogeneity by flip angle dependency

Inhomogeneities in the spatial distribution of the excitatory Radio Frequency (RF) field, are still a dominant source of artifacts and loss of signal to noise ratio in MR imaging experiments, A number of strategies have been proposed to quantify this distribution, However, in this technical note we present a relatively simple MR imaging procedure which can be used to visualise RF inhomogeneities directly either by means of the magnitude or the phase of an image. To visualise the RF field distribution in both the inner and outer volumes of the coil, we have performed experiments in which the entire coil is submerged in a non-conducting fluid, To the best of our knowledge this strategy has not been used previously in order to evaluate coil performance, Finally, we demonstrate that the method is sensitive enough to reveal the effects of the sample properties on the effective RF wavelength of the transmitted field. (C) 1997 Elsevier Science Inc.

Population structure of Phytophthora cinnamomi in South Africa

Phytophthora cinnamomi isolates collected from 1977 to 1986 and 1991 to 1993 in two regions in South Africa were analyzed using isozymes. A total of 135 isolates was analyzed for 14 enzymes representing 20 putative loci, of which four were polymorphic. This led to the identification of nine different multilocus isozyme genotypes. Both mating types of P. cinnamomi occurred commonly in the Cape region, whereas, predominantly, the A2 mating type occurred in the Mpumalanga region of South Africa. A2 mating type isolates could be resolved into seven multilocus isozyme genotypes, compared with only two multilocus isozyme genotypes for the A1 mating type isolates. Low levels of gene (0.115) and genotypic (2.4%) diversity and a low number of alleles per locus (1.43) were observed for the South African P. cinnamomi population. The genetic distance between the Cape and Mpumalanga P. cinnamomi populations was relatively low (D-m = 0.165), and no specific pattern in regional distribution of multilocus isozyme genotypes could be observed. The genetic distance between the ''old'' (isolated between 1977 and 1986) and ''new'' (isolated between 1991 and 1993) P. cinnamomi populations from the Cape was low (D-m = 0.164), indicating a stable population over time. Three of the nine multilocus isozyme genotypes were specific to the ''old'' population, and only one multilocus isozyme genotype was specific to the ''new'' population. Significant differences in allele frequencies, a high genetic distance (D-m = 0.581) between the Cape A1 and A2 mating type isolates, significant deviations from Hardy-Weinberg equilibrium, a low overall level of heterozygosity, and a high fixation index (0.71) all indicate that sexual reproduction occurs rarely, if at all, in the South African P. cinnamomi population.

Functional asymmetries in the movement kinematics of patients with Tourette's syndrome

Objectives-This study adopted a concurrent task design and aimed to quantify the efficiency and smoothness of voluntary movement in Tourette's syndrome via the use of a graphics tablet which permits analysis of movement profiles. In particular, the aim was to ascertain whether a concurrent task (digit span) would affect the kinematics of goal directed movements, and whether patients with Tourette's syndrome would exhibit abnormal functional asymmetries compared with their matched controls. Methods-Twelve patients with Tourette's syndrome and their matched controls performed 12 vertical zig zag movements, with both left and right hands (with and without the concurrent task), to large or small targets over long or short extents. Results-With short strokes, controls showed the predicted right hand superiority in movement time more strongly than patients with Tourette's syndrome, who instead showed greater hand symmetry with short strokes. The right hand of controls was less force efficient with long strokes and more force efficient with short strokes, whereas either hand of patients with Tourette's syndrome was equally force efficient, irrespective of stroke length, with an overall performance profile similar to but better than that of the controls' left hand. The concurrent task, however, increased the force efficiency of the right hand in patients with Tourette's syndrome and the left hand in controls. Conclusions-Patients with Tourette's syndrome, compared with controls, were not impaired in the performance of fast, goal directed movements such as aiming at targets; they performed in certain respects better than controls. The findings clearly add to the growing literature on anomalous lateralisation in Tourette's syndrome, which may be explained by the recently reported loss of normal basal ganglia asymmetries in that disorder.

The chemistry of 5-oxodihydroisoxazoles .19. The synthesis and photolysis of N-thioacylisoxazol-5(2H)-ones

5-Oxodihydroisoxazoles react with thiocarbonyl chlorides to afford N-thioacylisoxazol-5(2H)-ones which lose carbon dioxide under photochemical conditions and undergo intramolecular cyclisation of the iminocarbene to afford thiazoles, However, in some cases loss of carbon dioxide is accompanied by loss of sulfur, giving 1,3-oxazin-6-ones.

Property rights of landholders in non-captive wildlife and prospects for conservation

In order to reduce the rate of human-induced biodiversity loss of wild species, it has become increasingly important to stem this loss on private and tribal lands and to find effective policies to do this. Some writers believe that granting landholders commercial property rights in wildlife might be effective in dealing with this matter and result in the sustainable use of wildlife. This paper explores this view using economic theory. In doing so, it takes into account the total economic valuation concept. While granting of commercial property rights is found to be effective for conserving some species, it is predicted to be a complete failure as a means of conserving other species. In addition, particular attention is given to the economics of the utilisation and conservation of non-captive fugitive (or mobile) wildlife. The economic theory involved is contrasted and compared with that for the exploitation of open-access resources.

Anisotropy-based performance analysis of linear discrete time invariant control systems

The anisotropic norm of a linear discrete-time-invariant system measures system output sensitivity to stationary Gaussian input disturbances of bounded mean anisotropy. Mean anisotropy characterizes the degree of predictability (or colouredness) and spatial non-roundness of the noise. The anisotropic norm falls between the H-2 and H-infinity norms and accommodates their loss of performance when the probability structure of input disturbances is not exactly known. This paper develops a method for numerical computation of the anisotropic norm which involves linked Riccati and Lyapunov equations and an associated special type equation.

Methylation of O-6-methylguanine DNA methyltransferase characterizes a subset of colorectal cancer with low-level DNA microsatellite instability

The significance of low-level DNA microsatellite instability (MSI-L) is not well understood. K-ras mutation is associated with MSI-L colorectal cancer and with the silencing of the DNA repair gene O-6-methylguanine DNA methyltransferase (MGMT) by methylation of its promoter region. MGMT methylation was studied in sporadic colorectal cancers stratified as DNA microsatellite instability-high (n = 23), MSI-L (n = 44), and microsatellite-stable (n = 23). Methylation-specific PCR was used to detect MGMT-promoter hypermethylation in 3 of 23 (13%) microsatellite instability-high, in 28 of 44 (64%) MSI-L, and in 6 of 23 (26%) microsatellite-stable cancers (P = 0.0001). K-ras was mutated in 20 of 29 (69%) methylated MSI-L cancers and in 2 of 15 (13%) unmethylated MSI-L cancers (P = 0.001), indicating a relationship between MGMT-methylation and mutation of K-ras. Loss of nuclear expression of MGMT was demonstrated immunohistochemically in 23 of 31 (74%) cancers with methylated MGMT and in 10 of 49 (20%) cancers with nonmethylated MGMT (P < 0.0001). Loss of expression of MGMT was also demonstrated in 9 of 31 serrated polyps. Silencing of MGMT may predispose to mutation by overwhelming the DNA mismatch repair system and occurs with greatest frequency in MSI-L colorectal cancers.

Back, chest and abdominal pain: How good are spinal signs at identifying musculoskeletal causes of back, chest or abdominal pain?

Background: Spinal signs found in association with atypical chest and abdominal pain may suggest the pain is referred from the thoracic spine. However, the prevalence of such signs in these conditions has rarely been compared with that in those without pain. In this study, the prevalence of spinal signs and dysfunction in patients with back, chest and abdominal pain is compared with that in pain free controls. The aim of the study is to determine the significance of spinal findings in patients with such pain. Methods: A general practitioner blinded to the patients' histories performed a cervical and thoracic spinal examination on general practice patients with back, chest and/or abdominal pain and on controls without pain. Thoracic intervertebral dysfunction was diagnosed on the basis of movement and palpation findings. Results: Seventy three study patients plus 24 controls, were examined. For cervical spinal signs, pain in the back, chest and/or abdomen was associated with pain with active movements and overpressure at end range and with loss of movement range. For thoracic spinal signs, this association held for pain with active movements and overpressure, but not with loss of movement range. The prevalence of thoracic intervertebral dysfunction was 25.0% in controls, 65.5% with chest/abdominal pain, 72.0% with back pain and 79.0% with back pain with chest/abdominal pain. This prevalence was higher with chest pain than with abdominal pain. Conclusions: The results show an association, but not a causal link between thoracic intervertebral dysfunction and atypical chest/abdominal pain. A spinal examination should be performed routinely assessing these conditions. The minimum examination for the detection of intervertebral dysfunction is testing for pain with spinal movements and palpation for tenderness. The interpretation of positive signs requires knowledge of their prevalence in pain free controls and in patients with visceral disease

Selective down-regulation of the astrocyte glutamate transporters GLT-1 and GLAST within the medial thalamus in experimental wernicke's encephalopathy

Although earlier studies on thiamine deficiency have reported increases in extracellular glutamate concentration in the thalamus, a vulnerable region of the brain in this disorder, the mechanism by which this occurs has remained unresolved. Treatment with pyrithiamine, a central thiamine antagonist, resulted in a 71 and 55% decrease in protein levels of the astrocyte glutamate transporters GLT-1 and GLAST, respectively, by immunoblotting in the medial thalamus of day 14 symptomatic rats at loss of righting reflexes. These changes occurred prior to the onset of convulsions and pannecrosis. Loss of both GLT-1 and GLAST transporter sites was also confirmed in this region of the thalamus at the symptomatic stage using immunohistochemical methods. In contrast, no change in either transporter protein was detected in the non-vulnerable frontal parietal cortex. These effects are selective; protein levels of the astrocyte GABA transporter GAT-3 were unaffected in the medial thalamus. In addition, astrocyte-specific glial fibrillary acidic protein (GFAP) content was unchanged in this brain region, suggesting that astrocytes are spared in this disorder. Loss of GLT-1 or GLAST protein was not observed on day 12 of treatment, indicating that down-regulation of these transporters occurs within 48 h prior to loss of righting reflexes. Finally, GLT-1 content was positively correlated with levels of the neurofilament protein alpha -internexin, suggesting that early neuronal drop-out may contribute to the down-regulation of this glutamate transporter and subsequent pannecrosis. A selective, focal loss of GLT-1 and GLAST transporter proteins provides a rational explanation for the increase in interstitial glutamate levels, and may play a major role in the selective vulnerability of thalamic structures to thiamine deficiency-induced cell death.

Tissue-specific induction of SOCS gene expression by PRL

The mechanisms whereby tissue sensitivity to PRL is controlled are not well understood. Here we report that expression of mRNA and protein for members of the SOCS/CIS/JAB family of cytokine signaling inhibitors is increased by PRL administration in ovary and adrenal gland of the lactating rat deprived of circulating PRL and pups for 24 h but not in mammary gland. Moreover, suckling increases SOCS mRNA in the ovary but not in the mammary gland of pup-deprived rats. Deprivation of PRL and pups for 48 h allows the mammary gland to induce SOCS genes in response to PRL administration, and this is associated with a decrease in basal SOCS-3 mRNA and protein expression to the level seen in other tissues, suggesting that SOCS-3 induced refractoriness related to filling of the gland. In reporter assays, SOCS-1, SOCS-3, and CIS, but not SOCS-2, are able to inhibit transactivation of the STAT 5-responsive beta -lactoglobulin promoter in transient transfection assays. Moreover, suckling results in loss of ovarian and adrenal responsiveness to PRL administered 2 h after commencement of suckling, as determined by STAT 5 gel shift assay. Immunohistochemistry was used to localize the cellular sites of SOCS-3 and CIS protein expression in the ovary and adrenal gland. We propose that induced SOCS-1, SOCS-3, and CIS are actively involved in the cellular inhibitory feedback response to physiological PRL surges in the corpus luteum and adrenal cortex during lactation, but after pup withdrawal, the mammary gland is rendered unresponsive to PRL by increased levels of SOCS-3.

First published record of the pathogenic monogenean parasite Neobenenenia melleni (Capsalidae) from Australia

The monogenean Neobenedenia melleni (Mac- Callum, 1927) Yamaguti 1963 is a well-known and virulent pathogen in culture conditions recorded from the skin of many teleost fish species worldwide. Until now, N. melleni has not been reported from wild or cultured fish in Australian waters. This study documents a recent outbreak of N. melleni that occurred on Lates calcarifer (barramundi) cultivated in sea cages in Hinchinbrook Channel between Hinchinbrook Island and mainland Queensland, Australia, which resulted in the loss of 200 000 fish (50 tonnes). The origin of this outbreak is unclear because N. melleni has not been recorded from any wild host species in Australia and strict quarantine regulations exclude the possibility of its introduction on imported fish. We propose that N. melleni occurs naturally on wild populations of some teleost species in Australian waters and that the few surveys of wild fish conducted along the eastcoast have failed to report this species. The possibility that uncharacteristically low water temperatures led to the outbreak is discussed.

The use of F-19 NMR for new structure determination in the radiolysis of FEP

The radiation chemistry of poly(tetrafluoroethylene-co-perfluoropropylene), FEP, with a mole fraction of tetrafluoroethylene, TFE, of 0.90 has been studied under vacuum using Co-60 gamma -radiation over absorbed dose ranges up to 3.0 MGy. The radiolysis temperatures were 300, 363, 423 and 523 K. New structure formation in the copolymers was analyzed by solid-state F-19 NMR. The new structures formed in the copolymers have been identified and the G-values for the formation of new -CF3 groups was 2.2 at the lower temperatures and increased to 2.9 at 523 K. The G-value for the loss of original -CF3 groups was approximate to1.0 at all temperatures. At the lower temperatures there was a net loss of -CF-groups on irradiation, G(CF) of -1.3, -0.9 and -0.5 at 300, 363 and 423 K, respectively, but at 523 K there was a net gain with G(CF) equal to 0.8. (C) 2001 Elsevier Science B.V. All rights reserved.