Integration of Peripheral and Glandular Regulation of Triiodothyronine Production by Thyrotropin in Untreated and Thyroxine-Treated Subjects.

The objective of the study was to evaluate the roles of central and peripheral T3 regulation. In a prospective study involving 1,796 patients, the equilibria between FT3 and TSH were compared in untreated and L-T4-treated patients with varying functional states, residual thyroid secretory capacities and magnitudes of TSH stimulation. T3 concentrations were stable over wide variations in TSH levels (from 0.2 to 7 mU/l) and endogenous T4 production in untreated patients, but unbalanced in L-T4-treated athyreotic patients where T3 correlated with exogenous T4 supply. T3 stability was related to TSH-stimulated deiodinase activity by clinical observation, as predicted by theoretical modelling. Deiodinase activity in treated patients was reduced due to both diminished responsiveness to TSH and lack of thyroidal capacity. Deiodinase activity was increased in high thyroid volume, compared to lower volumes in euthyroid patients (<5 ml, p<0.001). While deiodinase differed between euthyroid and subclinically hypothyroid patients in high volume, 26.7 nmol/s (23.6, 29.2), n=214 vs. 28.9 nmol/s (26.7, 31.5), n=20, p=0.02, it was equivalent between the 2 functional groups in low volume, 23.3 nmol/s (21.3, 26.1), n=117 vs. 24.6 nmol/s (22.2, 27.5), n=38, p=0.22. These findings suggest that the thyroid gland and peripheral tissues are integrated in the physiological process of T3 homeostasis in humans via a feed-forward TSH motif, which coordinates peripheral and central regulatory mechanisms. Regulatory and capacity deficiencies collectively impair T3 homeostasis in L-T4-treated patients.

Skeletal findings in the first 12 months following initiation of glucocorticoid therapy for pediatric nephrotic syndrome.

UNLABELLED: Incident vertebral fractures and lumbar spine bone mineral density (BMD) were assessed in the 12 months following glucocorticoid initiation in 65 children with nephrotic syndrome. The incidence of vertebral fractures was low at 12 months (6 %) and most patients demonstrated recovery in BMD Z-scores by this time point. INTRODUCTION: Vertebral fracture (VF) incidence following glucocorticoid (GC) initiation has not been previously reported in pediatric nephrotic syndrome. METHODS: VF was assessed on radiographs (Genant method); lumbar spine bone mineral density (LS BMD) was evaluated by dual-energy X-ray absorptiometry. RESULTS: Sixty-five children were followed to 12 months post-GC initiation (median age, 5.4 years; range, 2.3-17.9). Three of 54 children with radiographs (6 %; 95 % confidence interval (CI), 2-15 %) had incident VF at 1 year. The mean LS BMD Z-score was below the healthy average at baseline (mean ± standard deviation (SD), -0.5 ± 1.1; p = 0.001) and at 3 months (-0.6 ± 1.1; p < 0.001), but not at 6 months (-0.3 ± 1.3; p = 0.066) or 12 months (-0.3 ± 1.2; p = 0.066). Mixed effect modeling showed a significant increase in LS BMD Z-scores between 3 and 12 months (0.22 SD; 95 % CI, 0.08 to 0.36; p = 0.003). A subgroup (N = 16; 25 %) had LS BMD Z-scores that were ≤-1.0 at 12 months. In these children, each additional 1,000 mg/m(2) of GC received in the first 3 months was associated with a decrease in LS BMD Z-score by 0.39 at 12 months (95 % CI, -0.71 to -0.07; p = 0.017). CONCLUSIONS: The incidence of VF at 1 year was low and LS BMD Z-scores improved by 12 months in the majority. Twenty-five percent of children had LS BMD Z-scores ≤-1.0 at 12 months. In these children, LS BMD Z-scores were inversely associated with early GC exposure, despite similar GC exposure compared to the rest of the cohort.

Advantages of using development models of the carrion beetles Thanatophilus micans (Fabricius) and T. mutilatus (Castelneau) (Coleoptera: Silphidae) for estimating minimum post mortem intervals, verified with case data.

Some beetles are as useful as blow flies for estimating the minimum post mortem interval (PMImin) or time since death. Examples include Thanatophilus micans (Fabricius) and Thanatophilus mutilatus (Castelneau), two geographically and ecologically overlapping African beetles. Molecular means of identifying these species, descriptions of their natural history, thermal summation models for the development of each species, and a case in which T. micans was recovered are presented. These beetles colonise bodies soon after death, their development spans more time than that of flies, and they may be little affected by maggot-generated heat. From an experimental perspective, they can be reared individually, which allows the identification of sick individuals and has analytical advantages relative to fly larvae that must be reared in groups. Estimating minimum post mortem intervals for both species using the case data strongly suggests that developmental models parameterised for one species should not be used to make forensic estimates for closely related species for which no specific model is available and emphasises the need for correct identifications.

Resprouting as a key functional trait: how buds, protection and resources drive persistence after fire.

Resprouting as a response to disturbance is now widely recognized as a key functional trait among woody plants and as the basis for the persistence niche. However, the underlying mechanisms that define resprouting responses to disturbance are poorly conceptualized. Resprouting ability is constrained by the interaction of the disturbance regime that depletes the buds and resources needed to fund resprouting, and the environment that drives growth and resource allocation. We develop a buds-protection-resources (BPR) framework for understanding resprouting in fire-prone ecosystems, based on bud bank location, bud protection, and how buds are resourced. Using this framework we go beyond earlier emphases on basal resprouting and highlight the importance of apical, epicormic and below-ground resprouting to the persistence niche. The BPR framework provides insights into: resprouting typologies that include both fire resisters (i.e. survive fire but do not resprout) and fire resprouters; the methods by which buds escape fire effects, such as thick bark; and the predictability of community assembly of resprouting types in relation to site productivity, disturbance regime and competition. Furthermore, predicting the consequences of global change is enhanced by the BPR framework because it potentially forecasts the retention or loss of above-ground biomass.

The development of bone mineral lateralization in the arms.

UNLABELLED: Bone mineral content (BMC) is known to be greater in the dominant arm after the age of 8 years. We studied a group of children and found that BMC sidedness gradually increased up to the age of 6 years and then remained stable into late adolescence. INTRODUCTION: Bone mineral content (BMC) exhibits sidedness in the arms after the age of 8 years, but it is not known whether BMC is greater in the dominant arm from birth or whether lateralization develops in early childhood. To address this, we examined bone mineral status in relation to handedness and age. METHODS: Subjects (N = 158) were children recently initiating glucocorticoids for underlying disease (leukemia 43 %, rheumatic conditions 39 %, nephrotic syndrome 18 %). Handedness was determined by questionnaire and BMC by dual-energy X-ray absorptiometry. RESULTS: Median age was 7.2 years (range, 1.5 to 17.0 years), 49 % was male, and the spine BMD Z-score was -0.9 (SD, 1.3). By linear regression, BMC sidedness in the arms was significantly related to age (r = 0.294, p = 0.0005). Breakpoint analysis revealed two lines with a knot at 6.0 years (95 % CI, 4.5-7.5 years). The formula for the first line was: dominant:nondominant arm BMC ratio = 0.029 × age [in years] + 0.850 (r = 0.323, p = 0.017). The slope of the second line was not different from 0 (p = 0.332), while the slopes for the two lines were significantly different (p = 0.027). CONCLUSIONS: These results show that arm BMC sidedness in this patient group develops up to age 6 years and then remains stable into late adolescence. This temporal profile is consistent with mechanical stimulation of the skeleton in response to asymmetrical muscle use as handedness becomes manifest.

Flower orientation and corolla length as reproductive barriers in the pollinator-driven divergence of Erica shannonea and Erica ampullacea.

A variety of reproductive barriers can enable reproductive isolation and stable coexistence of plant species. Differing floral traits might play an important role in reproductive isolation imposed by pollinators. Such shifts in pollinator use have been hypothesized to contribute to the radiation of Erica (Ericaceae) in the Cape Floristic Region, South Africa. The sister species Erica shannonea and Erica ampullacea co-occur and overlap in flowering phenology. Both have unscented long-tubed flowers consistent with adaptations for pollination by long-proboscid flies (LPFs), but differences in flower orientation and corolla tube length are indicative of a shift in pollinator species. We conducted controlled pollination experiments and pollinator observations to determine the breeding system and pollinators of the two species. Both species are self-incompatible and require pollinator visits for seed production, suggesting that pollinators could strongly influence flower evolution. The horizontally orientated flowers of E. shannonea were found to be pollinated by Philoliche rostrata (Tabanidae), which has a long, fixed forward-pointing proboscis, while the vertically upright orientated flowers of E. ampullacea were found to be pollinated by Prosoeca westermanni (Nemestrinidae), which has a shorter proboscis that can swivel downwards. The nemestrinid fly's proboscis is too short to access the nectar in the relative long-tubed flowers of E. shannonea and the tabanid fly's proboscis cannot swivel down to access the upright flowers of E. ampullacea. Consequently, these traits are likely to act as reproductive barriers between the two Erica species and thereby might have contributed to speciation and enable stable coexistence.

Skeletal findings in children recently initiating glucocorticoids for the treatment of nephrotic syndrome.

SUMMARY: Eighty children with nephrotic syndrome underwent lumbar spine densitometry and vertebral morphometry soon after glucocorticoid initiation. We found an inverse relationship between glucocorticoid exposure and spine areal bone mineral density (BMD) Z-score and a low rate of vertebral deformities (8%). INTRODUCTION: Vertebral fractures are an under-recognized complication of childhood glucocorticoid-treated illnesses. Our goal was to study the relationships among glucocorticoid exposure, lumbar spine areal BMD (LS BMD), and vertebral shape in glucocorticoid-treated children with new-onset nephrotic syndrome. METHODS: Lateral thoracolumbar spine radiography and LS BMD were performed in 80 children with nephrotic syndrome (median age 4.4 years; 46 boys) within the first 37 days of glucocorticoid therapy. Genant semiquantitative grading was used as the primary method for vertebral morphometry; the algorithm-based qualitative (ABQ) method was used for secondary vertebral deformity analysis. RESULTS: Six of the 78 children with usable radiographs (8%; 95% confidence interval 4 to 16%) manifested a single Genant grade 1 deformity each. All deformities were mild anterior wedging (two at each of T6, T7, and T8). Four of the 78 children (5%; 95% confidence interval 2 to 13%) showed one ABQ sign of fracture each (loss of endplate parallelism; two children at T6 and two at T8). Two of the children with ABQ signs also had a Genant grade 1 deformity in the same vertebral body. None of the children with a Genant or ABQ deformity reported back pain. An inverse relationship was identified between LS BMD Z-score and glucocorticoid exposure. CONCLUSIONS: Although we identified an inverse relationship between steroid exposure and LS BMD soon after glucocorticoid initiation for childhood nephrotic syndrome, there was only a low rate of vertebral deformities. The clinical significance of these findings requires further study.

Are the eucalypt and non-eucalypt components of Australian tropical savannas independent?

Eucalypts (Eucalyptus and Corymbia spp.) dominate (>60%) the tree biomass of Australia's tropical savannas but account for only a fraction (28%) of the tree diversity. Because of their considerable biomass and adaptation to environmental stressors, such as fire, the eucalypts may drive tree dynamics in these savannas, possibly to the exclusion of non-eucalypts. We evaluated whether the eucalypt and non-eucalypt components in tropical savannas are dependent so that changes in one component are matched by opposite trends in the other. Using tree inventory data from 127 savanna sites across the rainfall and fire frequency gradients, we found that eucalypt and non-eucalypt basal area and species richness had a negative relationship. This relationship was maintained across the rainfall gradient, with rainfall having a positive effect on the basal area and species richness of both components, but with a greater effect in non-eucalypts. Fire frequency negatively affected basal area, but not species richness, although basal area and species richness of eucalypts and non-eucalypts did not differ in their response to fire. Rainfall appears to set the upper bounds to woody biomass in these mesic savannas, while fire maintains woody biomass below carrying capacity and facilitates coexistence of the components. The magnitude of the component responses, particularly for non-eucalypts, is determined by rainfall, but their dependence is likely due to their differential response to both rainfall and fire, but not to competition for resources. Thus, while eucalypts dominate biomass overall, at high rainfall sites non-eucalypt basal area and diversity are highest, especially where fire frequency is low.

Areal and volumetric bone mineral density changes after renal transplantation in children: a longitudinal study.

INTRODUCTION: The effect of renal transplantation on areal bone mineral density (aBMD) in children has previously been studied. However, most previous reports did not include estimation of volumetric bone mineral density (vBMD) or analyze longitudinal data in these patients. In addition, updated reference standards for aBMD in children have recently been made available. METHODS: This retrospective study describes the longitudinal effect of renal transplantation on aBMD and vBMD in a cohort of 40 pediatric kidney transplant recipients. Lumbar spine aBMD measurements were obtained using dual-energy X-ray absorptiometry prior to transplant and yearly thereafter. vBMD values and z-scores were estimated as described in the most recently published references. RESULTS: A significant decrease in average aBMD and vBMD z-scores was observed within 1 year posttransplant, which did not recover during follow-up. The negative effect of transplantation on vBMD was blunted and vBMD z-scores were higher compared to aBMD. Linear mixed-effects model analysis demonstrated that lumbar spine aBMD and vBMD z-scores were inversely related to yearly prednisone dose (g/m2) but this effect was diminished as glomerular filtration rate was increased. CONCLUSIONS: Bone mineral density was negatively affected by renal transplantation in this cohort of pediatric patients. Estimation of vBMD appears to be appropriate for interpretation of the BMD changes occurring after renal transplant in children. The inverse relation between BMD z-scores and yearly prednisone dose suggests that ongoing posttransplant corticosteroid therapy may be responsible for the negative effect of transplantation on bone mineral density in this cohort.

Baited traps may be an alternative to conventional pesticides in integrated crop management of chicory (Compositae) in South Africa.

Chicory, Chicorium intybus L. (Compositae), is a major field crop in the Eastern Cape Province of South Africa. Several pests feed on the leaves of the plant, resulting in reduced yield. The most important of these are the noctuid moths Helicoverpa armigera (Hübner), Chrysodeixis acuta (Walker), and Trichoplusia orichalcea (F.). The use of attract-and-kill traps offers an alternative to broad-based insecticides in the control of these species. Three fields were treated with normal insecticides and three fields with yellow-baited traps. Eight additional traps were placed in each field, with half of the traps containing the insecticide 2,2-dichlorovinyl dimethyl phosphate (dichlorvos) and half without dichlorvos; and half yellow and half green. Total moth numbers and nonphytophage diversity were measured from these eight traps. Although no differences in H. armigera or T. orichalcea catches were observed between insecticide- and trap-treated fields, numbers of C. acuta and the total number of moths were significantly higher in insecticide-treated fields. Yellow traps containing dichlorvos contained more moths than yellow traps without dichlorvos, or green traps with dichlorvos, or green traps without dichlorvos; but they also contained more nonphytophagous insects. Yellow traps also enhanced the catches of thrips on card traps associated with them. These results offer an opportunity for the South African chicory industry to reduce pesticide applications and thus mitigate environmental impacts.

Style polymorphism in Linum (Linaceae): a case of Mediterranean parallel evolution?

Heterostyly is a sex polymorphism that has challenged evolutionary biologists ever since Darwin. One of the lineages where heterostyly and related stylar conditions appear more frequently is Linum (Linaceae). This group is particularly suitable for testing competing hypotheses about ancestral and transitional stages on the evolutionary building up of heterostyly. We generated a phylogeny of Linum based on extensive sampling and plastid and nuclear DNA sequences, and used it to trace the evolution of character states of style polymorphism. We also revised available data on pollination, breeding systems, and polyploidy to analyse their associations. Our results supported former phylogenetic hypotheses: the paraphyly of Linum and the non-monophyly of current taxonomic sections. Heterostyly was common in the genus, but appeared concentrated in the Mediterranean Basin and the South African Cape. Ancestral character state reconstruction failed to determine a unique state as the most probable condition for style polymorphism in the genus. In contrast, approach herkogamy was resolved as ancestral state in some clades, giving support to recent hypotheses. Some traits putatively related to heterostyly, such as life history and polyploidy, did show marginal or non-significant phylogenetic correlation, respectively. Although pollinator data are limited, we suggest that beeflies are associated with specific cases of heterostyly. The consistent association between style polymorphism and heteromorphic incompatibility points to ecological factors as drivers of the multiple evolution of style polymorphism in Linum. Albeit based on limited evidence, we hypothesised that specialised pollinators and lack of mating opportunities drive evolution of style polymorphism and loss of the polymorphism, respectively.

Pollination and breeding system of the enigmatic South African parasitic plant Mystropetalon thomii (Mystropetalaceae): rodents welcome, but not needed.

Unrelated plants adapted to particular pollinator types tend to exhibit convergent evolution in floral traits. However, inferences about likely pollinators from 'pollination syndromes' can be problematic due to trait overlap among some syndromes and unusual floral architecture in some lineages. An example is the rare South African parasitic plant Mystropetalon thomii (Mystropetalaceae), which has highly unusual brush-like inflorescences that exhibit features of both bird and rodent pollination syndromes. We used camera traps to record flower visitors, quantified floral spectral reflectance and nectar and scent production, experimentally determined self-compatibility and breeding system, and studied pollen dispersal using fluorescent dyes. The dark-red inflorescences are usually monoecious, with female flowers maturing before male flowers, but some inflorescences are purely female (gynoecious). Inflorescences were visited intensively by several rodent species that carried large pollen loads, while visits by birds were extremely rare. Rodents prefer male- over female-phase inflorescences, likely because of the male flowers' higher nectar and scent production. The floral scent contains several compounds known to attract rodents. Despite the obvious pollen transfer by rodents, we found that flowers on both monoecious and gynoecious inflorescences readily set seed in the absence of rodents and even when all flower visitors are excluded. Our findings suggest that seed production occurs at least partially through apomixis and that M. thomii is not ecologically dependent on its rodent pollinators. Our study adds another species and family to the growing list of rodent-pollinated plants, thus contributing to our understanding of the floral traits associated with pollination by non-flying mammals.

RNA synthesis and the accumulation of guanine nucleotides during growth shift down in the blue-green alga Anacystis nidulans.

Shift down of growth rate in the blue-green alga Anacystis nidulans by reduction of the incident light intensity produced a reduction in the rate of stable RNA accumulation which was correlated with increased concentrations of three phosphorylated compounds, two of which were identified as guanosine 5'-diphosphate-3'-diphosphate (ppGpp) and guanosine 5'-triphosphate3'-diphosphate (pppGpp). The step also causes a large but transient increase in the concentration of GTP. Stable RNA fails to accumulate for a considerable length of time after the concentrations of ppGpp and pppGpp have fallen, suggesting the involvement of another mechanism in the control of stable RNA accumulation.

Reference range for thyrotropin. Post hoc assessment.

UNLABELLED: Setting the reference range for thyrotropin (TSH) remains a matter of ongoing controversy. PATIENTS, METHODS: We used an indirect method to determine the TSH reference range post hoc in a large sample. A total of 399 well characterised subjects showing no evidence of thyroid dysfunction were selected for definition of the TSH reference limits according to the method of Katayev et al.. To this end, the cumulative frequency was plotted against the individual logarithmic TSH values. Reference limits were calculated by extrapolating the middle linear part of the regression line to obtain the cut-offs for the 95% confidence interval. We also examined biological variation in a sample of 65 subjects with repeat measurements to establish reference change values (RCVs). RESULTS: Based on these, the reference interval obtained by the novel technique was in close agreement with the conventionally established limits, but differed significantly from earlier recommendations. DISCUSSION: Following unverified recommendations could result in a portion of patients with subclinical thyroid dysfunctions being missed, an important consideration in a setting with a high prevalence of thyroid autonomy. CONCLUSION: Indirect post hoc verification of reference intervals from a large retrospective sample is a modern approach that gives plausible results. The method seems particularly useful to assess the adequacy and performance of reference limits reported or established by others in a particular setting. The present data should encourage re-evaluation of reference systems on a broader scale.

Itraconazole cyclodextrin solution: the role of in vitro susceptibility testing in predicting successful treatment of HIV-related fluconazole-resistant and fluconazole-susceptible oral candidosis.

OBJECTIVES: This study assessed the ability of in vitro susceptibility testing of clinical Candida isolates to predict in vivo response to itraconazole cyclodextrin solution. METHODS: One hundred specimens were obtained from HIV-positive patients with oral thrush, of which 72 speciments were from patients who were clinically unresponsive to fluconazole at standard doses and had fluconazole-resistant isolates in vitro. Susceptibility to itraconazole was assessed by measuring the relative growth of an isolate in liquid medium containing a single concentration of itraconazole and then expressing growth in itraconazole as a percentage of growth in antifungal-free medium. RESULTS AND CONCLUSIONS: Where specimens yielded only one isolate, a cut-off relative growth in itraconazole of 68% discriminated between isolates from patients failing to respond clinically to itraconazole solution and those from patients successfully treated with the preparation (specificity 100%; sensitivity 88%). The presence of mixed infection reduced the predictive accuracy of the test. Only 30% of fluconazole-resistant isolates were cross-resistant to itraconazole. No isolates were resistant to itraconazole but susceptible to fluconazole. Non-response to itraconazole solution was attributed to resistant yeast infection in the majority of cases, and this susceptibility method accurately identified specimens from patients unlikely to respond to the drug.

Clinically significant azole cross-resistance in Candida isolates from HIV-positive patients with oral candidosis.

OBJECTIVES: To determine the proportion of fluconazole-resistant Candida albicans isolates that have clinically significant cross-resistance to itraconazole or ketoconazole, that is sufficient to result in failure of these agents at their standard doses (200 and 400 mg daily for 7 days, respectively). METHODS: Seven hundred C. albicans isolates from HIV-positive patients with oral candidosis underwent susceptibility testing using a relative growth method, for which cut-off values corresponding to clinical drug failure have been established. RESULTS: A total of 431 isolates were fully azole-susceptible and three main resistance patterns were detected: isolates resistant to fluconazole alone (n = 100); isolates resistant to fluconazole and ketoconazole but susceptible to itraconazole (n = 94); and isolates resistant to all three drugs (n = 50). No isolates were consistently resistant to ketoconazole without being fluconazole-resistant, and no itraconazole resistance was detected without ketoconazole resistance. Resistance to fluconazole alone was more common in specimens obtained soon after first clinical fluconazole failure, whereas specimens from patients with a longer history of fluconazole-unresponsive candidosis were more likely to be infected with cross-resistant isolates. Median days of prior azole exposure and cumulative fluconazole dose were significantly less for those with isolates resistant to fluconazole alone than for those with ketoconazole cross-resistant isolates, who had received less azole therapy and smaller cumulative fluconazole doses than those with isolates cross-resistant to all three drugs (although not statistically significant). After the diagnosis of fluconazole-unresponsive candidosis, increasing cumulative doses of itraconazole solution were associated with increasing likelihood of cross-resistance. CONCLUSIONS: Clinically significant cross-resistance to other azoles may occur in fluconazole-resistant isolates of C. albicans, although initially most isolates are not cross-resistant and the detection of cross-resistant isolates is associated with a history of greater prior azole exposure. Patients who have been treated for fluconazole-resistant candidosis for longer and with greater cumulative doses of itraconazole solution tend to become infected with increasingly cross-resistant isolates of C. albicans.

Itraconazole versus ketaconazole in the treatment of oral and oesophageal candidosis in patients infected with HIV.

To determine the efficacy and toxicity of two systemically active antifungal agents in the treatment of buccal and oesophageal candidiasis 111 HIV-infected patients with microscopically-confirmed candidiasis were randomized to receive either 200 mg itraconazole once a day or 200 mg ketoconazole twice a day for 28 days in a double blind study. After 1 week of treatment, 75 and 82% of the patients on itraconazole and ketoconazole, respectively, had responded clinically. After 4 weeks of treatment, this had risen to 93% in each group. One patient discontinued itraconozole because of toxicity (rash), five patients discontinued ketaconazole (two nausea, two hepatotoxicity and one rash). Despite successful clinical and mycological clearance, 80% patients had a further episode of candidosis within the next 3 months.

Treatment of HIV-related fluconazole-resistant oral candidosis with D0870, a new triazole antifungal.

OBJECTIVES: To evaluate the efficacy and tolerance of D0870 in the treatment of HIV-related fluconazole-resistant oro-oesophageal candidosis. DESIGN: Multicentre open study. PATIENTS: HIV-seropositive patients with oro-oesophageal candidosis despite at least 7 days of treatment with fluconazole at doses of 100 mg per day or more. METHODS: Patients received an initial dose of D0870 (150 mg), then 25 mg per day for 6 days. Symptoms and signs of candidosis were compared at entry and on days 3 and 7 of treatment. At each visit, samples were taken for safety monitoring and for in vitro susceptibility testing of Candida isolates. Limited pharmacokinetic samples were taken on days 1 and 7. RESULTS: Of 26 evaluable patients, 16 showed partial improvement, nine showed no improvement, and only one had full clearance of thrush by day 7. In vitro testing of the cleared patient's isolate suggested that it was susceptible to fluconazole. Symptoms of dysphagia cleared in 14 and improved in five of the 22 patients with presumptive oesophageal involvement at entry. Pharmacokinetic measurement showed wide variability in maximum D0870 levels recorded on day 1 (range, 0.07-0.34 mg/l) and susceptibility testing of isolates also showed a range of minimal inhibitory concentration values to D0870 (range, < 0.06-8 mg/l; median, 0.25 mg/l). When these data were combined with clinical response there was a strong suggestion that lack of symptomatic improvement was related to low plasma D0870 levels or to the presence of less D0870-susceptible isolates. Six patients were noted to have a fall in haemoglobin, three of whom were receiving concomitant therapy known to suppress bone marrow. Three patients reported headaches as adverse events that were attributed to study medication, but D0870 was well tolerated overall. CONCLUSIONS: D0870 shows promise in the treatment of fluconazole-resistant oro-oesophageal candidosis and was well tolerated, although efficacy in this difficult-to-treat patient group was probably limited due to the inadequate plasma levels achieved in this pilot study with the low doses of D0870 administered.

Approaches to short-acting neuromuscular blocking agents: nonsymmetrical bis-tetrahydroisoquinolinium mono- and diesters.

Nonsymmetrical bisquaternary mono- and diesters combining the potency-enhancing properties of the (1R)-laudanosinium group with a second unhindered quaternary ammonium moiety have been studied as a means of promoting short action with high-potency neuromuscular block. Atracurium-related nonsymmetrical diesters showed high potency, freedom from vagal blockade at neuromuscular blocking doses, and short action. Nonsymmetrical monoesters were short acting but showed varying degrees of vagal block.

Selective inhibition of adenylyl cyclase by octopamine via a human cloned alpha 2A-adrenoceptor.

1. In this study we have compared the abilities of the enantiomers of the structural isomers of the phenolamines, octopamine and synephrine, and the catecholamines, noradrenaline and adrenaline, to couple selectively a human cloned alpha 2A-adrenoceptor, stably expressed in a Chinese hamster ovary (CHO) cell line, to G-protein linked second messenger pathways mediating an increase and a decrease in cyclic AMP production. 2. The catecholamines couple the alpha 2A-adrenoceptor to both an increase and a decrease in the rate of cyclic AMP production. In the absence of pertussis toxin pretreatment both catecholamines tested showed a dose-dependent decrease with a maximum at 100 nM. After pertussis toxin pretreatment they both produced a dose-dependent increase in cyclic AMP production with a maximum at 10 microM. 3. The phenolamines, octopamine and synephrine were only able to couple the alpha 2A-adrenoceptor to a dose-dependent decrease in cyclic AMP production at concentrations up to 1 mM, with the synephrine isomers being more potent than the corresponding octopamine isomers. The meta-isomers of both phenolamines were more potent than the corresponding para-isomers and the (-)-enantiomers were more potent than the (+)-enantiomers. Thus, (-)-meta-synephrine [(-)-phenylephrine] was the most effective isomer tested with an observable decrease occurring between 100 nM and 1 microM. 4. The effects of octopamine and the catecholamines on the decrease in cyclic AMP production were additive at submaximal concentrations, whilst octopamine reduced the stimulant effect of submaximal concentrations of noradrenaline on cyclic AMP production after pertussis toxin pretreatment. 5. The time courses of the inhibitory effects of both meta-octopamine and noradrenaline were parallel and peaked after a 1 min exposure to the agonist. In contrast, the stimulant effects of noradrenaline after pertussis toxin pretreatment were of a much slower time course with a maximum effect occurring after a 5 min incubation period. 6. Since octopamine and synephrine occur naturally in, and are co-released with catecholamines from, mammalian tissues, the results of the present study suggest that the human cloned alpha 2A-adrenoceptor can be coupled selectively by different endogenous agonists to G-protein pathways mediating the regulation of adenylyl cyclase activity.