Distribution of C-14 Cylindrospermopsin in vivo in the mouse

Radiolabelled C-14 cylindrospermopsin (CYN) has been prepared and used to investigate the distribution and excretion of CYN in vivo in male Quackenbush mice. At a dose of 0.2 mg/kg (i.e., approx. median lethal dose) the following mean (SID) urinary and faecal recoveries (cumulative) were obtained, respectively: (0-6 hours, n = 4) 48.2 (29.3)%, 11.9 (21.4)%; (0-12 hours, n = 12) 66.0 (27.1)%, 5.7 (5.6)%; (0-24 hours, n = 12) 68.4 (26.7)%, 8.5 (8.1)%. Mean (SD) recoveries from livers at 6 hours were 20.6 (6.4)% (n = 4), at 48 hours 13.1 (7.7)% (n = 8), and 5-7 days were 2.1 (2.1)% (n = 8). A substantial amount (up to 23%) can be retained in the liver for up to 48 hours with a lesser amount retained in the kidneys. The excretion patterns show substantial interindividual variability between predominantly faecal or urinary excretion, but these patterns are not related in any simple manner to the outcome in terms of toxicity. There is at least one methanol-extractable metabolite as well as a nonmethanol-extractable metabolite in the liver. The methanol-extractable metabolite was not found in the kidney and is more hydrophilic than CYN itself on reverse phase. (C) 2001 by John Wiley & Sons, Inc.

Analytical validation for a series of marker compounds used to assess renal drug elimination processes

Renal drug elimination is determined by glomerular filtration, tubular secretion, and tubular reabsorption. Changes in the integrity of these processes influence renal drug clearance, and these changes may not be detected by conventional measures of renal function such as creatinine clearance. The aim of the current study was to examine the analytic issues needed to develop a cocktail of marker drugs (fluconazole, rac-pindolol, para-aminohippuric acid, sinistrin) to measure simultaneously the mechanisms contributing to renal clearance. High-performance liquid chromatographic methods of analysis for fluconazole, pindolol, para-aminohippuric acid, and creatinine and an enzymatic assay for sinistrin were developed or modified and then validated to allow determination of each of the compounds in both plasma and urine in the presence of all other marker drugs. A pilot clinical study in one volunteer was conducted to ensure that the assays were suitable for quantitating all the marker drugs to the sensitivity and specificity needed to allow accurate determination of individual renal clearances. The performance of all assays (plasma and urine) complied with published validation criteria. All standard curves displayed linearity over the concentration ranges required, with coefficients of correlation greater than 0.99. The precision of the interday and intraday variabilities of quality controls for each marker in plasma and urine were all less than 11.9% for each marker. Recoveries of markers (and internal standards) in plasma and urine were all at least 90%. All markers investigated were shown to be stable when plasma or urine was frozen and thawed. For all the assays developed, there were no interferences from other markers or endogenous substances. In a pilot clinical study, concentrations of all markers could be accurately and reproducibly determined for a sufficient duration of time after administration to calculate accurate renal clearance for each marker. This article presents details of the analytic techniques developed for measuring concentrations of marker drugs for different renal elimination processes administered as a single dose to define the processes contributing to renal drug elimination.

Cavity QED analog of the harmonic-oscillator probability distribution function and quantum collapses

We establish a connection between the simple harmonic oscillator and a two-level atom interacting with resonant, quantized cavity and strong driving fields, which suggests an experiment to measure the harmonic-oscillator's probability distribution function. To achieve this, we calculate the Autler-Townes spectrum by coupling the system to a third level. We find that there are two different regions of the atomic dynamics depending on the ratio of the: Rabi frequency Omega (c) of the cavity field to that of the Rabi frequency Omega of the driving field. For Omega (c)

Assessment and management of dysphagia following pharyngolaryngectomy with free jejunal interposition: A series of eight case studies

The physiological and structural deficits contributing to swallowing complications in the pharyngolaryngectomy patient population are not homogeneous. Consequently, a team approach, involving medical investigations as well as clinical and radiological assessments of swallowing, is necessary to facilitate diagnosis of the underlying impairment and assist the medical/surgical and speech pathology team members in the process of individualizing the management plan for each patient. In the present study, the clinical assessment and management of eight pharyngolaryngectomy patients who presented with a decline in swallowing function unrelated to immediate postsurgical effects or direct effects of radiotherapy are reported. Clinical and radiological investigations revealed a heterogeneous group of factors contributing to their swallowing impairments and disability levels, including difficulty with graft and anastomotic patency and graft motility, impaired lingual coordination, increased bolus transit time, nasal and oral regurgitation, patient distress, and recurrence. Variation between the cases supported the need for differential intervention and management plans for all eight patients. Ratings of perceived swallowing disability, handicap, and well-being/distress levels at initial assessment and again six months following dysphagia intervention revealed a pattern of reduced levels of impairment, functional disability, and overall patient distress levels following informed intervention. The present case study data highlights the key role thorough clinical and radiological investigations play in the process of diagnosing the factors contributing to dysphagia and guiding the management of the resultant swallowing disability in the pharyngolaryngectomy population.

Subtropical drosophilids in Australia can be characterized by adult distribution across vegetation type and by height above forest floor

Understanding the pattern in which adult drosophilids of different species are distributed across and within different vegetation types is necessary for accurate interpretation of their local ecology and diversity. Such studies have been conducted mainly in temperate regions, and there is no basis for extrapolating their conclusions to tropical areas. This study describes the vertical distribution (0-20 m) of drosophilids attracted to banana baits in five different vegetation types in subtropical eastern Australia including open woodland, and rain-forest types. The distribution of most of the 15 common species could be characterized three-dimensionally by vegetation type and height above forest floor. Only one species, Scaptodrosophila lativittata, was common in all vegetation types and it was a canopy species in rain forests and a ground-level species in open woodland. Vertical distribution of some species clearly matched that of their larval hosts, but it did not in others. For example, the fungivore Leucophenga scutellata was mostly trapped well above the forest floor, yet it breeds at ground level, suggesting behavioural mode can influence vertical distributions. We conclude that the vertical dimension, although still poorly understood in relation to drosophilid habitats, needs to be taken into account when conducting and interpreting studies aimed at understanding drosophilid populations and communities in the subtropics.

Liquid distribution in wet granulation: dimensionless spray flux

This study investigates binder distribution in wet granulation and focuses on the nucleation zone, which is the area where the liquid binder and powder surface come into contact and form the initial nuclei. An equipment independent parameter, dimensionless spray flux Psi (a), is defined to characterise the most important process parameters in the nucleation process: solution flowrate, powder flux, and binder drop size. Ex-granulator experiments are used to study the relationship between dimensionless spray flux, process variables and the coverage of binder fluid on the powder surface. Lactose monohydrate powder on a variable speed riffler passed under a flat spray once only. Water and 7% HPC solution at two spray pressures were used as binders. Experiments with red dye and image analysis demonstrate that changes in dimensionless spray flux correlate with a measurable difference in powder surface coverage. Nucleation experiments show that spray flux controls the size and shape of the nuclei size distribution. At low Psi (a), the system operates in the drop controlled regime, where one drop forms one nucleus and the nuclei size distribution is narrow. At higher Psi (a), the powder surface cakes creating a broader size distribution. For controlled nucleation with the narrowest possible size distribution, it is recommended that the dimensionless spray flux be less than 0.1 to be in the drop-controlled regime. (C) 2001 Elsevier Science S.A. All rights reserved.

Begging and food distribution in crimson rosella (Platycercus elegans) broods: why don't hungry chicks beg more?

Altricial nestlings solicit food by begging and engaging in scramble competition. Solicitation displays can thus signal both hunger and competitive ability. I examined nestling solicitation and parental responses in crimson rosellas (Platycercus elegans), a species in which parents engage in complex patterns of food allocation and appear to control the distribution of food. By manipulating the hunger of individual chicks and entire broods, I assessed how chick behaviours and parental food allocation varied with hatching rank, level of hunger, and intensity of nestling competition. Last-hatched chicks begged more than first-hatched chicks irrespective of individual hunger levels. The two parents combined fed individually hungry chicks more, but mothers and fathers varied in their responses to begging chicks: fathers fed last-hatched chicks in proportion to their begging intensity, whereas mothers fed chicks equally. Since fathers generally allocate more food to first-hatched chicks, fathers appear to use begging rates to adjust food allocation to non-preferred chicks within the brood. When I manipulated brood hunger levels, begging rates increased for first- and last-hatched chicks suggesting that chick begging rates are sensitive to the level of competition. This study shows that begging by rosella chicks does not correlate with hunger in a straightforward way and that the primary patterns of food allocation by parents art: not influenced by chick begging. Thus the benefits of increased begging may be limited for nestlings in this species.

Spatial distribution and developmental appearance of postjunctional P2X(1) receptors on smooth muscle cells of the mouse vas deferens

P2X(1)-type purinoceptors, have been shown to mediate fast transmission between sympathetic varicosities and smooth muscle cells in the mouse vas deferens but the spatial organization of these receptors on the smooth muscle cells remains inconclusive. Voltage clamp techniques were used to estimate the amplitudes of spontaneous excitatory junction currents (SEJCs) in cells of the vas deferens longitudinal smooth muscle layer. These currents involved the activation of about 6% of the P2X-type channels present on the cell, as compared to whole cell currents produced when isolated smooth muscle cells were exposed to maximal concentrations of either ATP or alpha,beta -MeATP. Immunofluorescence staining of the vas deferens with antibodies against P2X(1) receptor showed a diffuse, grainy distribution over the entire membrane of each smooth muscle cell. Anti-P2X(1) staining was not markedly clustered beneath anti-SV2-stained sympathetic varicosities. Similar results were obtained for cells in the urinary bladder. During development, P2X(1) mRNA was detected as early as embryonic day 15 (E15). Increasing intensities of diffuse immunostaining for P2X(1) were observed in the walls of the bladder, tail artery, and aorta from E15 until 6 weeks postnatal. The vas deferens showed increasing intensities of diffuse staining of its smooth muscle layers between 2 and 6 weeks postnatal, consistent with the time-course of development of fast purinergic transmission described previously. Together, the results suggest that the response of smooth muscle of the vas deferens to ATP released from sympathetic varicosities relies on rapidly desensitizing P2X(1) receptors, distributed diffusely across the smooth muscle cell surface. Synapse 42:1-11, 2001. (C) 2001 Wiley-Liss, Inc.

Habitat complexity, spatial interference, and "minimum risk distribution": a framework for population stability

In the past century, the debate over whether or not density-dependent factors regulate populations has generally focused on changes in mean population density, ignoring the spatial variance around the mean as unimportant noise. In an attempt to provide a different framework for understanding population dynamics based on individual fitness, this paper discusses the crucial role of spatial variability itself on the stability of insect populations. The advantages of this method are the following: (1) it is founded on evolutionary principles rather than post hoc assumptions; (2) it erects hypotheses that can be tested; and (3) it links disparate ecological schools, including spatial dynamics, behavioral ecology, preference-performance, and plant apparency into an overall framework. At the core of this framework, habitat complexity governs insect spatial variance. which in turn determines population stability. First, the minimum risk distribution (MRD) is defined as the spatial distribution of individuals that results in the minimum number of premature deaths in a population given the distribution of mortality risk in the habitat (and, therefore, leading to maximized population growth). The greater the divergence of actual spatial patterns of individuals from the MRD, the greater the reduction of population growth and size from high, unstable levels. Then, based on extensive data from 29 populations of the processionary caterpillar, Ochrogaster lunifer, four steps are used to test the effect of habitat interference on population growth rates. (1) The costs (increasing the risk of scramble competition) and benefits (decreasing the risk of inverse density-dependent predation) of egg and larval aggregation are quantified. (2) These costs and benefits, along with the distribution of resources, are used to construct the MRD for each habitat. (3) The MRD is used as a benchmark against which the actual spatial pattern of individuals is compared. The degree of divergence of the actual spatial pattern from the MRD is quantified for each of the 29 habitats. (4) Finally, indices of habitat complexity are used to provide highly accurate predictions of spatial divergence from the MRD, showing that habitat interference reduces population growth rates from high, unstable levels. The reason for the divergence appears to be that high levels of background vegetation (vegetation other than host plants) interfere with female host-searching behavior. This leads to a spatial distribution of egg batches with high mortality risk, and therefore lower population growth. Knowledge of the MRD in other species should be a highly effective means of predicting trends in population dynamics. Species with high divergence between their actual spatial distribution and their MRD may display relatively stable dynamics at low population levels. In contrast, species with low divergence should experience high levels of intragenerational population growth leading to frequent habitat-wide outbreaks and unstable dynamics in the long term. Six hypotheses, erected under the framework of spatial interference, are discussed, and future tests are suggested.

Alcoholic liver disease: A clinical series in an Australian private practice

Background and Aim: The published literature on alcoholic liver disease (ALD) in Australia lacks a large clinical series out of private practice as distinct from hospital-based hepatology referral units. This series describes the presentation and clinical features of ALD in a consecutive series out of metropolitan private practice in Australia. Methods: A retrospective descriptive study by case-note review found 297 cases of ALD at a Brisbane practice over 20 years. The main outcome measures were: clinical features and stage at presentation, reasons for referral, and the predictive value of aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio. Results: Most patients (57.9%) had no symptoms of liver disease and 29 patients (9.8%) had neither symptoms nor signs. Cirrhosis was found in 41% of patients and hepatitis-fibrosis was found in 26% of patients. The male to female (M: F) ratio was 4.7:1. The AST/ALT ratio was not reliably predictive of ALD stage. The average reported daily alcohol intake was 131 g. Females drank less on average and presented a more vigorous clinical picture. Conclusions: This series presents the spectrum of ALD in a metropolitan Australian private practice. Many patients are asymptomatic on presentation. All heavy drinkers should be targeted for early investigation without waiting for volunteered symptoms or abnormal physical signs. The male to female ratio in ALD is higher than hitherto reported. The AST/ALT ratio is not generally applicable in the staging of ALD. The differences from hospital series data suggest the demography and epidemiology of ALD in Australia are incomplete, and further study is warranted. (C) 2001 Blackwell Science Asia Pty Ltd.

Nuclear PTEN expression and clinicopathologic features in a population-based series of primary cutaneous melanoma

Germline mutations of the PTEN tumor-suppressor gene, on 10q23, cause Cowden syndrome, an inherited hamartoma syndrome with a high risk of breast, thyroid and endometrial carcinomas and, some suggest, melanoma. To date, most studies which strongly implicate PTEN in the etiology of sporadic melanomas have depended on cell lines, short-term tumor cultures and noncultured metastatic melanomas. The only study which reports PTEN protein expression in melanoma focuses on cytoplasmic expression, mainly in metastatic samples. To determine how PTEN contributes to the etiology or the progression of primary cutaneous melanoma, we examined cytoplasmic and nuclear PTEN expression against clinical and pathologic features in a population-based sample of 150 individuals with incident primary cutaneous melanoma. Among 92 evaluable samples, 30 had no or decreased cytoplasmic PTEN protein expression and the remaining 62 had normal PTEN expression. In contrast, 84 tumors had no or decreased nuclear expression and 8 had normal nuclear PTEN expression. None of the clinical features studied, such as Clark's level and Breslow thickness or sun exposure, were associated with cytoplasmic PTEN expressional levels. An association with loss of nuclear PTEN expression was indicated for anatomical site (p = 0.06) and mitotic index (p = 0.02). There was also an association for melanomas to either not express nuclear PTEN or to express p53 alone, rather than both simultaneously (p = 0.02). In contrast with metastatic melanoma, where we have shown previously that almost two-thirds of tumors have some PTEN inactivation, only one-third of primary melanomas had PTEN silencing. This suggests that PTEN inactivation is a late event likely related to melanoma progression rather than initiation. Taken together with our previous observations in thyroid and islet cell tumors, our data suggest that nuclear-cytoplasmic partitioning of PTEN might also play a role in melanoma progression. (C) 2002 Wiley-Liss, Inc.