Natural and experimental tests of trophic cascades: gray wolves and white-tailed deer in a Great Lakes forest.

Herbivores can be major drivers of environmental change, altering plant community structure and changing biodiversity through the amount and species of plants consumed. If natural predators can reduce herbivore numbers and/or alter herbivore foraging behavior, then predators may reduce herbivory on sensitive plants, and a trophic cascade will emerge. We have investigated whether gray wolves (Canis lupus) generate such trophic cascades by reducing white-tailed deer (Odocoileus virginianus) herbivory on saplings and rare forbs in a northern mesic forest (Land O' Lakes, WI). Our investigation used an experimental system of deer exclosures in areas of high and low wolf use that allowed us to examine the role that wolf predation may play in reducing deer herbivory through direct reduction in deer numbers or indirectly through changing deer behavior. We found that in areas of high wolf use, deer were 62 % less dense, visit duration was reduced by 82 %, and percentage of time spent foraging was reduced by 43 %; in addition, the proportion of saplings browsed was nearly sevenfold less. Average maple (Acer spp.) sapling height and forb species richness increased 137 and 117 % in areas of high versus low wolf use, respectively. The results of the exclosure experiments revealed that the negative impacts of deer on sapling growth and forb species richness became negligible in high wolf use areas. We conclude that wolves are likely generating trophic cascades which benefit maples and rare forbs through trait-mediated effects on deer herbivory, not through direct predation kills.

First Report of Syzygites megalocarpus (Mucorales) Web Mold on the Commercial Portabella Button Mushroom Agaricus bisporus in North America.

Agaricus bisporus (Lange) Imbach mushrooms, which are cultivated commercially under environmentally controlled conditions, are the most valuable crop in Pennsylvania. In August 2011, we first observed a mucoraceous mold colonizing primordia and mature basidiocarps of a new brown portabella strain of A. bisporus at two commercial mushroom farms in Chester County, PA. This strain is a hybrid between a commercial strain producing white basidiocarps and a brown wild type isolate of A. bisporus. Mushrooms mature in weekly "flushes". By third flush, 25% of the production surface at both farms was colonized by a fast growing mycelium that was initially white, subsequently yellow to golden brown, and finally grayish. Mushrooms colonized by the mold showed pitting, discoloration, and necrosis. Two pure cultures of the mold were obtained by the hyphal tip method from mature, necrotic basidiocarps at each farm. These isolates were accessioned in the ARS Culture Collection (NRRL, Peoria, IL) as NRRL 54814 to 54815 and 54818 to 54819. The cultures produced abundant aerial sporangiophores that branched dichotomously on potato dextrose agar. Light microscopic examination revealed that each branch terminated in a globose, multispored sporangium with a conspicuous columella. Individual cultures of NRRL 54818 and 54819 produced large (175 to 250 × 200 to 250 µm), barrel-shaped, dark brown to black zygosporangia between opposed suspensors, indicating they were homothallic. Morphological and cultural characteristics of the mold matched the description of Syzygites megalocarpus (3), a member of the Mucorales reported to colonize diverse, mostly fleshy basidiomycetes (2), including cultivated matsutake (Tricholoma matsutake) in Korea (1). Molecular phylogenetic confirmation of the morphological identification was obtained by PCR amplifying and sequencing domains D1 and D2 at the 5' end of the nuclear ribosomal large subunit (LSU rDNA). The four isolates shared an identical LSU rDNA allele. A search of the NCBI nucleotide database, using a partial LSU rDNA sequence from NRRL 54814 as the BLAST query, revealed that it shared 99.5% identity with AF157216.1, a reference isolate of S. megalocarpus NRRL 6288 (3). To assess whether cultures of S. megalocarpus could induce the disease, caps of portabella and white button mushrooms were inoculated with 3.7 × 106 sporangiospores. When incubated in moist chambers at 21 to 22°C with a 12-h photoperiod, disease symptoms developed in 2 to 3 days on portabella that included discoloration and pitting at the site of inoculation. S. megalocarpus was reisolated from the symptomatic mushrooms and produced a colony identical to the original. By comparison, white button mushrooms inoculated with S. megalocarpus, using the same method, only showed minor pitting and discoloration. Disease symptoms were not observed on mushrooms inoculated with water as a negative control. Although development of new commercial varieties derived using "wild" genetically diverse stocks is an effective way to introduce desirable traits into cultivated mushrooms, it carries the risk of introducing new diseases into the industry. References: (1) K.-H. Ka et al. Korean J. Mycology 27:345, 1999. (2) R. L. Kovacs and W. J. Sundberg. Trans. Il. State Acad. Sci. 92:181, 1999. (3) K. O'Donnell. Zygomycetes in culture. Palfrey Contributions in Botany. No. 2. Department of Botany, University of Georgia, Athens, 1979.

Histological, cytological and biochemical alterations induced by microcystin-LR and cylindrospermopsin in white mustard (Sinapis alba L.) seedlings.

This study compares the histological, cytological and biochemical effects of the cyanobacterial toxins microcystin-LR (MCY-LR) and cylindrospermopsin (CYN) in white mustard (Sinapis alba L.) seedlings, with special regard to the developing root system. Cyanotoxins induced different alterations, indicating their different specific biochemical activities. MCY-LR stimulated mitosis of root tip meristematic cells at lower concentrations (1 µg ml-1) and inhibited it at higher concentrations, while CYN had only inhibitory effects. Low CYN concentrations (0.01 µg ml-1) stimulated lateral root formation, whereas low MCY-LR concentrations increased only the number of lateral root primordia. Both inhibited lateral root development at higher concentrations. They induced lignifications, abnormal cell swelling and inhibited xylem differentiation in roots and shoots. MCY-LR and CYN induced the disruption of metaphase and anaphase spindles, causing altered cell divisions. Similar alterations could be related to decreased protein phosphatase (PP1 and PP2A) activities in shoots and roots. However, in vitro phosphatase assay with purified PP1 catalytic subunit proved that CYN in contrast to MCY-LR, decreased phosphatase activities of mustard in a non-specific way. This study intends to contribute to the understanding of the mechanisms of toxic effects of a protein phosphatase (MCY-LR) and a protein synthesis (CYN) inhibitory cyanotoxin in vascular plants.

Habitat selection of resident and non-resident gray wolves: implications for habitat connectivity.

Habitat selection studies facilitate assessing and predicting species distributions and habitat connectivity, but habitat selection can vary temporally and among individuals, which is often ignored. We used GPS telemetry data from 96 Gray wolves (Canis lupus) in the western Great Lakes region of the USA to assess differences in habitat selection while wolves exhibited resident (territorial) or non-resident (dispersing or floating) movements and discuss implications for habitat connectivity. We used a step-selection function (SSF) to assess habitat selection by wolves exhibiting resident or non-resident movements, and modeled circuit connectivity throughout the western Great Lakes region. Wolves selected for natural land cover and against areas with high road densities, with no differences in selection among wolves when resident, dispersing, or floating. Similar habitat selection between resident and non-resident wolves may be due to similarity in environmental conditions, when non-resident movements occur largely within established wolf range rather than near the periphery or beyond the species range. Alternatively, non-resident wolves may travel through occupied territories because higher food availability or lower human disturbance outweighs risks posed by conspecifics. Finally, an absence of differences in habitat selection between resident and non-resident wolf movements may be due to other unknown reasons. We recommend considering context-dependency when evaluating differences in movements and habitat use between resident and non-resident individuals. Our results also provide independent validation of a previous species distribution model and connectivity analysis suggesting most potential wolf habitat in the western Great Lakes region is occupied, with limited connectivity to unoccupied habitat.

The relation between sunscreen layer thickness and vitamin D production after ultraviolet B exposure: a randomized clinical trial.

BACKGROUND: Sunscreens absorb ultraviolet B (UVB) and it is a major concern that sunscreen use may lead to vitamin D deficiency. OBJECTIVES: To investigate the relation between the amount of sunscreen applied and the vitamin D serum level in humans after UVB exposure under controlled conditions. METHODS: Thirty-seven healthy volunteers with fair skin types were randomized to receive an inorganic sunscreen with sun protection factor (SPF) 8 of 0 mg cm(-2) , 0.5 mg cm(-2) , 1 mg cm(-2) , 1.5 mg cm(-2) , or 2 mg cm(-2) thickness on the upper body, approximately 25% of the body area. Participants were irradiated with a fixed UVB dose of 3 standard erythema doses 20 min after sunscreen application. This procedure was repeated four times with a 2- to 3-day interval. Blood samples were drawn before the first irradiation and 3 days after the last to determine the serum vitamin D level expressed as 25-hydroxyvitamin D(3) [25(OH)D]. RESULTS: The vitamin D serum level increased in an exponential manner with decreasing thickness of sunscreen layer in response to UVB exposure. For all thicknesses of sunscreen, the level of 25(OH)D increased significantly after irradiation (P<0.05), except for the group treated with 2 mg cm(-2) , in which the increase in 25(OH)D was not statistically significant (P=0.16). CONCLUSIONS: Vitamin D production increases exponentially when thinner sunscreen layers than recommended are applied (<2 mg cm(-2) ). When the amount of sunscreen and SPF advised by the World Health Organization are used, vitamin D production may be abolished. Re-evaluation of sun-protection strategies could be warranted.

Distribution model transferability for a wide-ranging species, the Gray Wolf.

Using existing data can be a reliable and cost-effective way to predict species distributions, and particularly useful for recovering or expanding species. We developed a current gray wolf (Canis lupus) distribution model for the western Great Lakes region, USA, and evaluated the spatial transferability of single-state models to the region. This study is the first assessment of transferability in a wide-ranging carnivore, as well as one of few developed for large spatial extents. We collected 3500 wolf locations from winter surveys in Minnesota (2017-2019), Wisconsin (2019-2020), and Michigan (2017-2020). We included 10 variables: proportion of natural cover, pastures, and crops; distance to natural cover, agriculture, developed land, and water; major and minor road density; and snowfall (1-km res.). We created a regional ensemble distribution by weight-averaging eight models based on their performance. We also developed single-state models, and estimated spatial transferability using two approaches: state cross-validation and extrapolation. We assessed performance by quantifying correlations, receiver operating characteristic curves (ROC), sensitivities, and two niche similarity indices. The regional area estimated to be most suitable for wolves during winter (threshold = maximum sensitivity/specificity) was 106,465 km2 (MN = 48,083 km2, WI = 27,757 km2, MI = 30,625 km2) and correctly predicted 88% of wolf locations analyzed. Increasing natural cover and distance to crops were consistently important for determining regional and single-state wolf distribution. Extrapolation (vs. cross-validation) produced results with the greatest performance metrics, and were most similar to the regional model, yet good internal performance was unrelated to greater extrapolation performance. Factors influencing species distributions are scale-dependent and can vary across areas due to behavioral plasticity. When extending inferences beyond the current occurrence of individuals, assessing variation in ecology such as habitat selection, as well as methodological factors including model performance, will be critical to avoid poor scientific interpretations and develop effective conservation applications. In particular, accurate distribution models for recovering or recovered carnivores can be used to develop plans for habitat management, quantify potential of unoccupied habitat, assess connectivity modeling, and mitigate conflict, facilitating long-term species persistence.

Follow-up of dysfunctional bladder and rectum after surgery of a deep infiltrating rectovaginal endometriosis.

PURPOSE: The radical surgery of the deep infiltrating endometriosis of the rectovaginal septum and the uterosacral ligaments with or without bowel resection can cause a serious damage of the pelvic autonomic nerves with urinary retention and the need of self-catheterization. Major goal of this review article is to compare different surgical techniques of deep infiltrating endometriosis and their follow-up results. METHODS: The research strategy included the online search of databases [MEDLINE, EMBASE, SCOPUS] for the diagnosis of deep infiltrating endometriosis with the indication of an operative resection. The outcome of the follow-up terms were noticed and compared. RESULTS: All in all, 16 trials could be identified with included follow-up. In all patients at least single-sided resection of the uterosacral ligaments were performed. Follow-up was heterogeneous in all trials ranging from 1 to 92 months. Postoperative symptoms, such as dysmenorrhoea, pelvic pain, and dyspareunia were commonly described in the majority of trials. Nevertheless, a tendency towards lower comorbidity after nerve sparing resection of endometriosis could be observed. CONCLUSION: Identification of the inferior hypogastric nerve and plexus was feasible in the minority of trials. In comparison with non-nerve-sparing surgical technique, no cases of bladder self-catheterization for a long or even life time was observed, confirming the importance of the nerve-sparing surgical procedure.

Seasonality of spina bifida in Northern Germany.

PURPOSE: To verify a seasonal variation in the incidence of spina bifida and thus to identify possible environmental triggers leading to its developement. METHODS: An interdisciplinary approach has been taken to develop a better understanding of spina bifida through collaborative efforts from investigators specializing in genetics, fetal pathology, paediatrics, neuro-surgery and prenatal ultrasonographic diagnosis. All pregnancies with fetal spina bifida were retrospectively analyzed from May 1 1993 through May 1 2010 at Luebeck University Fetal Health Center. Results were used to construct a model to predict the occurrence of fetal spina bifida based on seasonal variation and environmental influence reflected by climatic changes and environmental pollution. Furthermore, data were categorized in respect to the date of conception and subdivided into date of conception during summer (April-September) and winter months (October-March). RESULTS: Neither a seasonal distribution of conception for fetuses with spina bifida in the defined time frame could be verified nor a relevant influence of the analyzed environmental factors on the prevalence of spina bifida could be proved. The incidence of spina bifida has remained relatively stable within the last 17 years at 2.5 per 1,000 screened pregnancies. CONCLUSION: Since we were unable to demonstrate a relationship between seasonal variation and certain environmental factors on the incidence of fetal spina bifida, other factors should be investigated for a possible association with the onset of fetal spina bifida.

Clothing reduces the sun protection factor of sunscreens.

BACKGROUND: Individuals are recommended to wait for 20 min following sunscreen application before dressing. However, this is probably seldom done in daily life, and therefore we investigated how dressing earlier than 20 min after application affected the sun protection factor (SPF). OBJECTIVES: To determine the SPF of a sunscreen applied at different amounts at 4, 8 and 20 min before dressing. METHODS: An organic sunscreen was used on the backs of 22 healthy volunteers. Before SPF testing, participants wore a cotton T-shirt for 60 min after the test areas had been uncovered for 4, 8 or 20 min after sunscreen application. The SPF was also tested on unclothed skin. RESULTS: The median SPF was 11.7 (2 mg cm(-2)), 5.7 (1 mg cm(-2)) and 3.3 (0.5 mg cm(-2)) for unclothed skin, and 8.1 (2 mg cm(-2)), 4.8 (1 mg cm(-2)) and 2.2 (0.5 mg cm(-2)) following an interval of 8 min before dressing. The SPF was similar for time intervals of 20 and 8 min when the amount was 1 mg cm(-2) (P = 0.48) and 2 mg cm(-2) (P = 0.56). For 0.5 mg cm(-2) there was no difference between skin clothed after 20 min and unclothed skin (P = 0.19), nor between skin clothed after 4 min and after 8 min (P = 0.28). CONCLUSIONS: When sunscreens are applied at amounts of 1 and 2 mg cm(-2) the time between sunscreen application and dressing can be as little as 8 min. When less sunscreen is used the SPF is insensitive to the length of time between application and dressing.

Cylindrospermopsin and microcystin-LR alter the growth, development and peroxidase enzyme activity of white mustard (Sinapis alba L.) seedlings, a comparative analysis.

This work focuses on the comparative analysis of the effects of two cyanobacterial toxins of different chemical structure cylindrospermopsin (CYN) and microcystin-LR (MC-LR) on the white mustard (Sinapis alba L.) seedlings. Both cyanotoxins reduced significantly the fresh mass and the length of cotyledons, hypocotyls and main roots of seedlings in a concentration dependent manner. For various mustard organs the 50% inhibitory concentration values (IC50) of growth were between 3-5 µg ml(-1) for MC-LR and between 5-10 µg ml-1 for CYN, respectively. Cyanotoxins altered the development of cotyledons, the accumulation of photosynthetically active pigments and anthocyanins. Low MC-LR concentrations (0.01 and 0.1 µg ml(-1)) stimulated anthocyanin formation in the cotyledons but higher than 1 µg ml(-1) MC-LR concentrations strongly inhibited it. The CYN treated chlorotic cotyledons were violet coloured in consequence of high level of anthocyanins, while MC-LR induced chlorosis was accompanied by the appearance of necrotic patches. Necrosis and increases of peroxidase enzyme activity (POD) are general stress responses but these alterations were characteristic only for MC-LR treated mustard plants. These findings provide experimental evidences of developmental alterations induced by protein synthesis and protein phosphatase inhibitory cyanotoxins (CYN and MC-LR) in a model dicotyledonous plant.

Mortality of a large wide-ranging mammal largely caused by anthropogenic activities.

With efforts to restore large mammal populations following extirpations, it is vital to quantify how they are impacted by human activities and gain insights into population dynamics in relation to conservation goals. Our objective was to characterize cause-specific mortality of black bears (Ursus americanus) throughout their range. We first quantified cause-specific mortality for 247 black bears in one harvested and two non-harvested populations. We then simulated a small recolonizing population with and without anthropogenic mortality. Lastly, we conducted a meta-analysis of all published black bear mortality studies throughout North America (31 studies of 2630 bears). We found anthropogenic mortality was greater than natural mortality, non-harvest anthropogenic mortality (e.g. poaching, defense of property, etc.) was greater in non-harvested populations, and harvesting was one of the major causes of mortality for bears throughout their range. Our simulation indicated that removing anthropogenic mortality increased population size by an average of 23% in 15 years. We demonstrated that bears are exposed to high levels of anthropogenic mortality, and the potential for human activities to slow population growth in expanding populations. Management and conservation of wide-ranging mammals will depend on holistic strategies that integrate ecological factors with socio-economic issues to achieve successful conservation and coexistence.

Maternal smoking promotes chronic obstructive lung disease in the offspring as adults.

INTRODUCTION: In utero and/or childhood environmental tobacco smoke exposure is well known to adversely affect lung function and to depreciate child's health in many ways. Fewer studies have assessed the long-term effects on COPD development and disease severity in later adulthood. METHODS: COPD patients were interviewed using a structured questionnaire regarding their personal as well as the smoking habits of their parents. Data were compared with the disease history, e.g. COPD exacerbation rate, and their lung function data. RESULTS: Between 2003 and 2004 COPD patients were recruited a) in a private practice specialized in pulmonary medicine (n = 133) and b) in a hospital (n = 158). 75% of their fathers and only 15.4 of all mothers smoked regularly. COPD patients from smoking mothers had lower FEV1 predicted than those raised in household without maternal smoking exposure: 39.4 +/- 9.5% vs. 51.9 +/- 6.0% (P = 0.037). Fathers had no effect on FEV1 regardless if they are smokers or non-smokers. Rate of severe exacerbations requiring hospitalization remained unaffected by parental second hand smoke exposure. CONCLUSION: Maternal smoking negatively affects lung function of their offspring even in late adulthood when they develop COPD. It even aggravates the cumulative effect of active cigarette consumption. Clinical course of the COPD remained unaffected.

[Prevention of complications in twin gestations and pregnancies after assisted reproduction]. / Risikoprävention bei Geminigraviditäten und Schwangerschaften nach assistierter Reproduktion.

BACKGROUND: Twin pregnancies and gestations after assisted reproductive therapy (ART) are of special obstetric significance with regard to their associated risks. However, little is known about preventive approaches specifically evaluated for these constellations. METHODS: A selective literature search was conducted to examine possible preventive approaches for complications such as hypertensive disorders, anaemia, gestational diabetes, prematurity, and others, seen significantly more often in twin gestations and pregnancies after ART. RESULTS: For both constellations, preventive approaches are not specifically evaluated for the majority of complications. For some preventive methods a possible detrimental effect cannot even be ruled out. CONCLUSIONS: The knowledge about specific preventive approaches against complications in twin pregnancies and gestations after ART is scarce. More prospective trials are urgently needed to assess the risks and benefits of prophylactic approaches for these risk constellations.

[Spontaneously conceived twins and twins after ART: are there any differences regarding direct financial costs of delivery]. / Gibt es einen Unterschied der direkten Entbindungskosten bei spontan eingetretener Zwillingsgravidität und Gemini nach Kinderwunschbehandlung?

BACKGROUND: Healthcare expenditures are rising steadily. There are no data on delivery expenses of twin pregnancies. This study aims to provide data on expenses of twin deliveries and to compare expenditures of deliveries after spontaneous conception with deliveries after infertility treatment. PATIENTS AND METHODS: Retrospective cohort-analysis on obstetrical data of twin deliveries at the Department of Obstetrics and Gynaecology of the University Hospital Schleswig-Holstein, Campus Luebeck between January 2000 and December 2008. A comparison of delivery expenses of spontaneous twin pregnancies and after infertility treatment. RESULTS: Patients delivering twins after infertility treatment stay 1.1 days longer at the hospital, are 2.5 years older and the number of previous pregnancies and deliveries are significantly lower compared to women after spontaneous conception of twins. In our setting fetal outcome (weeks of gestation, birthweight, APGAR, umbilical arterial pH, admission to neonatal intensive care unit etc.) and other maternal data (maternal height, maternal weight, length of surgery etc.) were not significantly different. The prolonged time spent in hospital leads to a 250 Euro higher expense per patient. DISCUSSION: Additional expenses of twin deliveries after assisted reproduction are due to a longer stay at the hospital. This prolonged stay of an average of 1.1 days was not obvious to medical reasons. Main delivery expenses for the substantial outcome-parameters are not significantly different between both groups.

[Parental smoking and passive smoke exposure in childhood promotes the COPD exacerbation rate]. / Einfluss einer elterlichen Passivrauchexposition im Kindes- und Jugendalter auf Lungenfunktion und Exazerbationsrate bei COPD-Patienten.

INTRODUCTION: Smoking parents are the main source of passive smoke exposure in childhood. Only few studies have assessed the effect of maternal or paternal cigarette smoke exposure in childhood on the development and severity of COPD. PATIENTS AND METHODS: We recruited n = 251 COPD-patients, n = 113 were clinically stable (no exacerbations for up to 24 years backdated from the day of interview), and - according to their history - n = 138 had more than one exacerbation during this time period. All COPD-patients were interviewed by a physician using a structured questionnaire on main health outcomes, social status, smoking history of their parents and themselves. Furthermore, pulmonary function was measured, and concomitant lung diseases were excluded. RESULTS: Both COPD groups were comparable in age, gender, smoking history at the beginning of the disease, and cigarette pack-years smoked. Patients whose mothers smoked during childhood had poorer lung function values: FEV (1) 45.2 % vs. 54 % (p = 0.037). Non-smoking patients with a history of maternal smoking had a 7-times higher exacerbation rate compared to patients without passive smoke exposure (p = 0.073). Paternal cigarette smoke exposure had no effect. CONCLUSION: Maternal cigarette smoke exposure in childhood aggravates the COPD disease and predisposes the patient for a higher disease severity.

Mandatory colposcopic findings of severe cervical dysplasia. Are there key-signs that need our special attention?

INTRODUCTION: To test for colposcopic differences between CIN2+ and non CIN2+ lesions of the "major changes" of the RIO 2011 nomenclature of the International Federation of Cervical Pathology (IFCPC). MATERIAL AND METHODS: Retrospective cohort analysis of colposcopic examinations of patients with histologically confirmed CIN2+ (n=99) and non CIN2+ (n=102) lesions during a four years period. MAIN OUTCOME MEASURES: leukoplakia, coarse mosaic and punctuation, dense acetowhitening, sharp boarders, ridge sign, atypical vessels. RESULTS: Only coarse punctuation (P≤0.001; OR 9.64; 95% CI 2.15-43.13), coarse mosaic (P≤0.001; OR 4.00; 95% CI 1.83-8.73) and dense acetowhitening (P≤0.05; OR 1.86; 95% CI 1.06-3.26) occurred more frequently in CIN2+ lesions which were confirmed as predictors by a regression analysis. CONCLUSIONS: Only coarse punctuation and coarse mosaic followed by dense acetowhitening as part of the "major changes" of the IFCPC Rio 2011 nomenclature achieve predictive values for CIN2+ lesions and should be therefore emphasized in colposcopy.

DAVID--a translucent multi-wire transmission ionization chamber for in vivo verification of IMRT and conformal irradiation techniques.

Permanent in vivo verification of IMRT photon beam profiles by a radiation detector with spatial resolution, positioned on the radiation entrance side of the patient, has not been clinically available so far. In this work we present the DAVID system, which is able to perform this quality assurance measurement while the patient is treated. The DAVID system is a flat, multi-wire transmission-type ionization chamber, placed in the accessory holder of the linear accelerator and constructed from translucent materials in order not to interfere with the light field. Each detection wire of the chamber is positioned exactly in the projection line of a MLC leaf pair, and the signal of each wire is proportional to the line integral of the ionization density along this wire. Thereby, each measurement channel essentially presents the line integral of the ionization density over the opening width of the associated leaf pair. The sum of all wire signals is a measure of the dose-area product of the transmitted photon beam and of the total radiant energy administered to the patient. After the dosimetric verification of an IMRT plan, the values measured by the DAVID system are stored as reference values. During daily treatment the signals are re-measured and compared to the reference values. A warning is output if there is a deviation beyond a threshold. The error detection capability is a leaf position error of less than 1 mm for an isocentric 1 cm x 1 cm field, and of 1 mm for an isocentric 20 cm x 20 cm field.

Blood concentrations of everolimus are markedly increased by ketoconazole.

The authors sought to quantify the influence of the CYP3A and P-glycoprotein inhibitor ketoconazole on the pharmacokinetics of everolimus in healthy subjects. This was a 2-period, single-sequence, crossover study in 12 healthy subjects. In period 1, subjects received the reference treatment of a single 2-mg dose of everolimus. In period 2, they received the test treatment of ketoconazole 200 mg twice daily for a total of 8 days and a single dose of everolimus coadministered on the fourth day of ketoconazole therapy. The test/reference ratio and 90% confidence interval were derived for everolimus maximum concentration and area under the curve. During ketoconazole coadministration, everolimus maximum concentration increased 3.9-fold (90% confidence interval, 3.4-4.6) from 15 +/- 4 ng/mL to 59 +/- 13 ng/mL. Everolimus area under the curve increased 15.0-fold (90% confidence interval, 13.6-16.6) from 90 +/- 23 ng*h/mL to 1324 +/- 232 ng*h/mL. Everolimus half-life was prolonged by 1.9-fold from 30 +/- 4 hours to 56 +/- 5 hours. Everolimus did not appear to alter ketoconazole predose concentrations. Given the magnitude of this drug interaction, use of ketoconazole should be avoided if possible in everolimus-treated patients.

Recent developments in streptogramin research.

The streptogramins are a class of antibiotics remarkable for their antibacterial activity and their unique mechanism of action. These antibiotics are produced naturally, but the therapeutic use of the natural compounds is limited because they do not dissolve in water. New semisynthetic derivatives, in particular the injectable streptogramin quinupristin/dalfopristin, offer promise for treating the rising number of infections that are caused by multiply resistant bacteria. The streptogramins consist of two structurally unrelated compounds, group A and group B. The group A compounds are polyunsaturated macrolactones: the group B compounds are cyclic hexadepsipeptides. Modifications of the group B components have been mainly performed on the 3-hydroxypicolinoyl, the 4-dimethylaminophenylalanine and the 4-oxo pipecolinic residues. Semi-synthesis on this third residue led to the water-soluble derivative quinupristin. Water-soluble group A derivatives were obtained by Michael addition of aminothiols to the dehydroproline ring of pristinamycin IIA. Followed by oxidation of the intermediate sulfide into the sulfone derivatives (i.e., dalfopristin). Water-soluble derivatives (both group A and group B) can now be obtained at the industrial scale. Modified group B compounds are now also being produced by mutasynthesis, via disruption of the papA gene. Mutasynthesis has proved particularly useful for producing PIB, the group B component of the oral streptogramin RPR 106972. The streptogramins inhibit bacterial growth by disrupting the translation of mRNA into protein. Both the group A and group B compounds bind to the peptidyltransferase domain of the bacterial ribosome. The group A compounds interfere with the elongation of the polypeptide chain by preventing the binding of aa-tRNA to the ribosome and the formation of peptide bonds, while the B compounds stimulate the dissociation of the peptidyl-tRNA and may also interfere with the release of the completed polypeptide by blocking its access to the channel through which it normally leaves the ribosome. The synergy between the group A and group B compounds appears to result from an enhanced affinity of the group B compounds for the ribosome. Apparently, the group A compound induces a conformational change such that B compound binds with greater affinity. The natural streptogramins are produced as mixtures of the group A and B compounds, the combination of which is a more potent antibacterial agent than either type of compound alone. Whereas the type A or type B compound alone has, in vitro and in animal models of infection, a moderate bacteriostatic activity, the combination of the two has strong bacteriostatic activity and often bactericidal activity. Minimal inhibitory concentrations of quinupristin/dalfopristin range from 0.20 to 1 mg/l for Streptococcus pneumonae, from 0.25 to 2 mg/l for Staphylococcus aureus and from 0.50 to 4 for Enterococcus faecium, the principal target organisms of this drug. Quinupristin/dalfopristin also has activity against mycoplasmas, Neisseria gonorrhoeae, Haemophilus influenz, Legionella spp. and Moraxella catarrhalis. Bacteria develop resistance to the streptogramms by ribosomal modification, by producing inactivating enzymes, or by causing an efflux of the antibiotic. Dimethylation of an adenine residue in rRNA, a reaction that is catalyzed by a methylase encoded by the erm gene class, affects the binding of group B compounds (as well as the macrolides and lincosamides; hence, MLSB resistance), but group A and B compounds usually maintain their synergy and their bactericidal effect against MLSB-resistant strains. erm genes are widespread both geographically and throughout numerous bacterial genera. Several types of enzymes (acetyltransferases, hydrolases) have been identified that inactivate the group A or the group B compounds. Genes involved in streptogramin efflux have so far been found only in staphylococci, particularly in coagulase-negative species

Biochemical disease-free survival following 125I prostate implantation.

PURPOSE: To assess the 5-year clinical and biochemical results of ultrasound-guided permanent 125I brachytherapy in early adenocarcinoma of the prostate. Biochemical disease-free survival (BDFS) is reported, using PSA follow-up and is compared to the surgical and radiation therapy literature. METHODS AND MATERIALS: From December 1988 through December 1993, ultrasound-guided brachytherapy was preplanned with 125I and delivered 160 Gy as the sole treatment in 499 patients. All were clinically staged as T1 or T2 node-negative adenocarcinoma of the prostate. Within the first year, 10 patients were lost to follow-up and have been excluded from further study. The remaining 489 patients form the basis of this report. Clinical status and prostate specific antigen (PSA) values were systematically recorded before and after treatment. RESULTS: With a median follow-up of 35 months (3-70), the actuarial clinical local control is 83%. Both stage and grade are shown to predict for this endpoint. Actuarial biochemical disease-free survival (BDFS) is also correlated with stage, grade, and PSA at presentation. Biochemical disease-free survival at 5 years is 94% for T1, 70% for unilateral T2, and 34% for T2c tumors. Grade is also predictive, ranging from 85% in low-grade tumors to 30% in high-grade tumors. In a multivariate analysis, the pretreatment PSA is most highly correlated (p < 0.0001) with BDFS, local control, and clinical disease-free survival. Patients with a normal pretreatment PSA enjoyed 93% BDFS, while those presenting with PSA > 10 had a BDFS of 40%. Complications have been few, with severe urinary urgency or dysuria in 4% and both incontinence and proctitis seen in 1%. CONCLUSIONS: While biochemical disease-free survival reports in the literature are immature and have short follow-up, our data compares favorably with studies following radical prostatectomy or radiation therapy. Further follow-up of this cohort is required. The complication rate is low and patient acceptance excellent. Permanent implantation of 125I as the sole treatment for early prostate adenocarcinoma is a viable alternative for patients with early-stage and low- to moderate-grade cancers. The PSA provides significant prognostic information and aids in case selection. Better management options are needed for high grade and bilateral tumors.