Developmental instability and phenotypic evolution in a small and isolated bear population.

We explored fluctuating asymmetry (FA) and morphological integration (MI) in the skull of the small, highly inbred and divergent Apennine bear (Ursus arctos marsicanus), to explore its uniqueness and investigate any potential effects of inbreeding depression. We used 3D geometric morphometrics contrasting Apennine bears with other two large outbred bear populations from Scandinavia and Kamchatka as controls. Shape divergence and variability were explored by a principal component analysis on aligned coordinates of 39 landmarks. Procrustes ANOVA, morphological disparity and the global integration index were used to explore FA, shape variance and MI. By remarking Apennine bears as a highly divergent phenotype, we recorded the highest FA and deviation from self-similarity compared with the other two control populations. We conclude that Apennine bears are likely facing developmental instability as a consequence of inbreeding depression, whereas the divergent trait covariance pattern may represent a potential source of evolutionary novelties. We discuss the implications for the conservation and management of this imperiled taxon.

Nuclear shadowing in the holographic framework.

The nucleon structure function F2(N) computed in a holographic framework can be used to describe nuclear deep inelastic scattering effects provided that a rescaling of the Q2 momentum and of the IR hard-wall parameter z0 is made. The ratios RA=F2(A)/F2(N) can be obtained in terms of a single rescaling parameter λA for each nucleus. The resulting ratios agree with the experiment in a wide range of the shadowing region.

Molecular systematics and evolutionary biogeography of the genus Talpa (Soricomorpha: Talpidae).

The range of the genus Talpa covers almost all Europe up to Western Asia. This genus has never been the object of comprehensive systematic studies using molecular and genetic techniques, such that the evolutionary relationships among species remain unclear. Talpa shows high levels of endemism, and the influence of past glaciation cycles on the distribution pattern of several species has been hypothesized. In this work, we assessed the molecular systematics of the genus using the mitochondrial gene cytochrome b from eight of the nine extant species of Talpa moles. Furthermore, molecular clock estimations were used to hypothesize a biogeographic scenario in concordance with fossil data. Results suggest a monophyletic origin of the genus and a common ancestor for the western European moles T. europaea, T. caeca, T. romana and T. occidentalis. The eastern species T. altaica and T. caucasica are basally divergent. The estimated ages of divergence among lineages are in accordance with a Miocene origin of the extant moles. The genus likely originated in Asia, spreading into Europe during the Pliocene. The evolution of moles appears to have been driven by changes in moisture levels that influenced extinction and speciation events during the Miocene and the Pliocene. Pleistocene climatic oscillations likely caused the range shrinkages and expansions that led to the current distribution pattern of most Talpa species.

The use of common bean (Phaseolus vulgaris) traditional varieties and their mixtures with commercial varieties to manage bean fly (Ophiomyia spp.) infestations in Uganda.

The bean fly (Ophiomyia spp.) is considered the most economically damaging field insect pest of common beans in Uganda. Despite the use of existing pest management approaches, reported damage has remained high. Forty-eight traditional and improved common bean varieties currently grown in farmers' fields were evaluated for resistance against bean fly. Data on bean fly incidence, severity and root damage from bean stem maggot were collected. Generalized linear mixed model (GLMM) revealed significant resistance to bean fly in the Ugandan traditional varieties. A popular resistant traditional variety and a popular susceptible commercial variety were selected from the 48 varieties and evaluated in pure and mixed stands. The incidence of bean fly infestation on both varieties in mixtures with different arrangements (systematic random versus rows), and different proportions within each of the two arrangements, was measured and analysed using GLMMs. The proportion of resistant varieties in a mixture and the arrangement type significantly decreased bean fly damage compared to pure stands, with the highest decrease in damage registered in the systematic random mixture with at least 50 % of resistant variety. The highest reduction in root damage, obvious 21 days after planting, was found in systematic random mixtures with at least 50 % of the resistant variety. Small holder farmers in East Africa and elsewhere in the world have local preferences for growing bean varieties in genetic mixtures. These mixtures can be enhanced by the use of resistant varieties in the mixtures to reduce bean fly damage on susceptible popular varieties.

Justification of noninferiority margin: methodology considerations in an exposure-response analysis.

The pivotal clinical trial to support the indication of liver transplantation for everolimus was based on a noninferiority trial design. The unique trial design made it impossible to estimate the noninferiority margin at the design stage. Even though the trial was conducted based on a noninferiority margin of 12% for the primary efficacy endpoint, the lack of consensus on this margin made the efficacy results difficult to interpret. A novel pharmacometric approach was applied to derive a new margin. Even though it was smaller than 12%, the new margin was large enough so that the observed efficacy results became interpretable. This novel analysis was an important contributor to the "totality of evidence" approach that led to the approval of everolimus for the new indication. This approval represents the approval of a new drug in more than 10 years for the indication of liver transplantation.

Azithromycin and terfenadine: lack of drug interaction.

A double-blind placebo-controlled study was conducted in healthy men to determine the effect of coadministration of azithromycin on the pharmacodynamics and pharmacokinetics of terfenadine. Administration of 500 mg azithromycin for 1 day and 250 mg on 4 subsequent days did not affect the pharmacokinetics of the pharmacologically active terfenadine carboxylate metabolite when 60 mg terfenadine was given twice daily for 12 days, starting 7 days before azithromycin administration. Terfenadine alone resulted in a 0.010 msec increase in the rate-corrected QT interval (QTc), but the incremental effects of azithromycin and placebo on QTc in volunteers receiving terfenadine were not statistically different. It is concluded that the potentially life-threatening disorders that have been attributed to a pharmacokinetic interaction between macrolide antibiotics and terfenadine are unlikely to take place in patients treated simultaneously with azithromycin and terfenadine.

Age and beta-adrenergic receptor sensitivity to S(-)- and R,S(+/-)-propranolol in humans.

The relationship between age and beta-adrenergic receptor sensitivity to the pharmacologically active S(-) enantiomer and the racemic mixture of propranolol was evaluated in 46 healthy male subjects (age range, 24 to 89 years). The in vivo apparent dissociation constants for S(-)- and R,S(+/-)-propranolol were determined on the basis of the unbound steady-state plasma concentration of each and the dose of isoproterenol needed to increase the heart rate of the subjects by 25 beats/min in the absence (I25) and then in the presence of a continuous propranolol infusion. The I25 was significantly correlated with age (r = 0.700, p less than 0.05). The apparent dissociation constant for S(-)- and R,S(+/-)-propranolol demonstrated a significant, although weak, increase with advancing age (r = 0.403 and r = 0.396, respectively; p less than 0.05). Although these findings confirm those of other studies, beta-receptor sensitivity to propranolol was only modestly decreased with age in this study.

Age and propranolol stereoselective disposition in humans.

The apparent oral clearance of S(-)- and R(+)-propranolol as a function of age was evaluated in 53 healthy male volunteers (age range, 21 to 84 years) after a single 40 mg oral dose of the racemic mixture. No significant age-associated change in the total (bound plus unbound) and unbound S(-) and R(+) apparent oral clearance was observed (p greater than 0.05). Stereoselectivity in apparent oral clearance (both total and unbound) remained unaffected by advancing age (p greater than 0.05). The relationship between age and propranolol enantiomer plasma protein binding was also evaluated in 70 subjects, 53 of whom were from this study (age range, 21 to 89 years). Plasma free fractions for S(-)- and R(+)-propranolol were unchanged with increasing age (p greater than 0.05), even though the binding was stereoselective (plasma free fractions for R(+) greater than plasma free fractions for S(-); p less than 0.05). The findings from this relatively large and extensive study indicate that age does not influence the stereoselective disposition of propranolol.

Evaluation of an experimental periodontal ligament for dental implants.

To improve the devices used in dental implantology, a new experimental supporting element has been developed. The device, made of titanium, poly(methylmethacrylate) and Dacron tissue, has been tested for the osteointegrability of its outer Dacron coat by implants in mandibular bone of rabbits. The Dacron filamentous tissue became incorporated by the bone at 3 month post-implantation. This might provide a reliable mechanical anchorage of the device and a barrier against epithelial proliferation and microbial contamination. Preliminary results relating to in vitro evaluation of the poly(methyl methacrylate)-Dacron fixation strength predict favourable mechanical behaviour at this interface and in the complete implanted device.

On the optimal energy of epithermal neutron beams for BNCT.

The optimal neutron energy for the treatment of deep-seated tumours using boron neutron capture therapy is studied by analysing various figures of merit. In particular, analysis of the therapeutic gain as a function of the neutron energy indicates that, with the currently available 10B carriers, the most useful neutrons for the treatment of deep-seated tumours, in particular glioblastoma multiforme, are those with an energy of a few keV. Based on the results of the simulations, a method is presented which allows us to evaluate the quality of epithermal neutron beams of known energy spectrum, thus allowing us to compare different neutron-producing reactions and beam-shaping assembly configurations used for accelerator-based neutron sources.

Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO syndrome).

Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy syndrome is a recently described rare disorder of infantile regression, intractable seizures, and cerebellar atrophy that occurs almost exclusively in the Finnish population. We report the first North American child with this condition.

Testing convergent and parallel adaptations in talpids humeral mechanical performance by means of geometric morphometrics and finite element analysis.

The shape and mechanical performance in Talpidae humeri were studied by means of Geometric Morphometrics and Finite Element Analysis, including both extinct and extant taxa. The aim of this study was to test whether the ability to dig, quantified by humerus mechanical performance, was characterized by convergent or parallel adaptations in different clades of complex tunnel digger within Talpidae, that is, Talpinae+Condylura (monophyletic) and some complex tunnel diggers not belonging to this clade. Our results suggest that the pattern underlying Talpidae humerus evolution is evolutionary parallelism. However, this insight changed to true convergence when we tested an alternative phylogeny based on molecular data, with Condylura moved to a more basal phylogenetic position. Shape and performance analyses, as well as specific comparative methods, provided strong evidence that the ability to dig complex tunnels reached a functional optimum in distantly related taxa. This was also confirmed by the lower phenotypic variance in complex tunnel digger taxa, compared to non-complex tunnel diggers. Evolutionary rates of phenotypic change showed a smooth deceleration in correspondence with the most recent common ancestor of the Talpinae+Condylura clade.

Biomarkers in solid organ transplantation.

This workshop was organized by the US Food and Drug Administration (FDA) Office of Clinical Pharmacology Review Team supporting the Division of Special Pathogen and Transplant Products in the Center for Drug Evaluation and Research. The main goal of the workshop was to enhance the knowledge base regarding biomarkers in solid-organ transplantation via presentation and discussion of scientific findings.

Exposure-response of posaconazole used for prophylaxis against invasive fungal infections: evaluating the need to adjust doses based on drug concentrations in plasma.

The purpose of this article is to report the exposure-response (E-R) relationship of posaconazole oral suspension (POS) for prophylaxis against invasive fungal infections (IFIs), on the basis of the US Food and Drug Administration (FDA) clinical pharmacology review of two randomized, active-controlled clinical studies. Posaconazole average steady state plasma concentrations (C(avg)) ranged from 22 to 3,650 ng/ml after administration of POS 200 mg three times daily (t.i.d.). In a double-blind, randomized clinical trial, the quartile ranges of C(avg) with midpoint values of 289, 736, 1,239, and 2,607 ng/ml had clinical failure rates of 44, 21, 18, and 18%, respectively, indicating an inverse association between C(avg) and clinical failure rate. There were no significant relationships between C(avg) and posaconazole-related major adverse events. Determining posaconazole concentrations in plasma will aid in assessing the need for either POS dose adjustment (e.g., increasing the POS dose) or switching to another systemic antifungal drug, thereby improving the effectiveness of prophylaxis against IFIs.

Design of an accelerator-based neutron source for neutron capture therapy.

The boron neutron capture therapy is mainly suited in the treatment of some tumor kinds which revealed ineffective to the traditional radiotherapy. In order to take advantage of such a therapeutic modality in hospital environments, neutron beams of suitable energy and flux levels provided by compact size facilities are needed. The advantages and drawbacks of several neutron beams are here analysed in terms of therapeutic gains. In detail the GEANT-3/MICAP simulations show that high tumor control probability, with sub-lethal dose at healthy tissues, can be achieved by using neutron beams of few keV energy having a flux of about 10(9) neutrons/(cm(2)s). To produce such a neutron beam, the feasibility of a proton accelerator is investigated. In particular an appropriate choice of the radiofrequency parameters (modulation, efficiency of acceleration, phase shift, etc.) allows the development of relatively compact accelerators, having a proton beam current of 30 mA and an energy of 2 MeV, which could eventually lead to setting up of hospital-based neutron facilities.

[Classification and etiopathogenesis of upper canine impaction]. / Classificazioni ed etiopatogenesis dell'inclusione del canino superior.

Classification and aetiopathogenesis of upper canine inclusion. The possible causes of upper canine inclusions are reviewed. After a detailed description of the factors that generally contribute to determining inclusions, it is stressed that correct aetiopathogenetic classification of this pathology can contribute to making the complex protocol for its treatment easier.

Stereoselective binding of propranolol in the elderly.

The influence of age on the stereoselective serum protein binding of propranolol was investigated. Serum was obtained from 10 young (mean age 23 +/- 2 years) and ten elderly (mean age 68 +/- 2 years) healthy male volunteers. The free fraction of propranolol (fu) was measured by equilibrium dialysis, using tritium labeled (+/-)- and (-)-propranolol. The fu values were 0.159 +/- 0.049 and 0.148 +/- 0.028 (+/-), 0.135 +/- 0.041 and 0.136 +/- 0.04 (-), 0.174 +/- 0.056 and 0.161 +/- 0.028 (+) in the young and elderly subjects, respectively. Serum alpha 1-acid glycoprotein (AAG) concentrations were 81.4 +/- 33.0 and 81.0 +/- 21.6 mg 100 ml-1 in young and elderly respectively (P greater than 0.05). Variability in AAG concentration accounted for most of the observed intersubject variability in the binding of both propranolol isomers. The stereoselective binding of propranolol does not appear to be affected by age.

Evaluation of guided bone regeneration in rabbit femur using collagen membranes.

The aim of the study was to evaluate the mechanical performance and the structure of neoformed bone around hydroxyapatite-coated titanium fixtures according to guided bone regeneration techniques. Ten hydroxyapatite-coated titanium fixtures were inserted in the femurs of five rabbits, in which a cortical defect was created and after the insertion of the fixture, covered with a resorbable membrane obtained from bovine Achilles tendon collagen Type I (A implant). In the same femur, a second fixture was inserted in similar cavities without application of the membrane (B implant). After 60 days, the animals were sacrificed, and block sections of the femoral bone containing the implants were embedded in polymethylmetacrylate and subjected to tensile shear-stress at break testing. After the detachment of the implants from the bone, their surfaces were examined with a scanning electron microscope. Tensile shear-stress values for A and B implant specimens were comparable to some extent, but the former had a lower performance. In this regard, scanning electron microscope observations showed that the neoformed cortical bone present cervically around implant A was much thicker than around implant B.

Bone regeneration guided by resorbable collagen membranes in rabbits: a pilot study.

Artificial cross-shaped intrabony defects were created in the mandibles of 12 rabbits and the cavities covered with Type I highly cross-linked resorbable collagen membranes for 30 days. Similar cavities were prepared in three control animals and left uncovered for the same time period. Morphological and analytical data were obtained by means of light microscopy, scanning electron microscopy, and x-ray energy-dispersive spectrometry. After the experimental period, the membrane covered cavities were completely filled with regenerated bone. In the control specimens, the artificial cavities were occupied by fibrous connective tissue.

Two methods for estimating body surface area in adult amputees.

Two methods for estimating body surface area (BSA) in adult amputees were developed. BSA in sq m was determined in 42 healthy, nonamputee men and women by summing the surface areas of individual body parts obtained using geometric measurements (BSAmeas) and by an equation using height and weight (BSAcalc). Linear regression analysis was used to determine correlations between BSAmeas and BSAcalc and between BSAmeas and surface-area measurements of individual body parts (SApart). The percentages of total BSA contributed by individual body parts in each subject were determined by the ratio of SApart to BSAmeas, and these percentages were compared with the corresponding percentages for body parts using the "Rule of Nines." BSAcalc and BSAmeas were significantly correlated, as were SApart and BSAmeas. Regression analysis of SApart versus BSAmeas yielded an equation for each measured body part that allowed calculation of SApart without direct measurement. SApart expressed as a percentage of total BSA differed from the percentage of BSA used in the "Rule of Nines" by a mean of 12.4-32% depending on the body part. Two methods of estimating BSA in amputees were proposed based on deduction of the surface area of the amputated part (calculated from the regression equation for SApart or as a percentage of total BSA) from total BSAcalc in adult amputees. The two methods developed in this study for estimating BSA may be useful in determining drug dosages in adult amputees and may provide more accurate information in burn therapy. Further studies are needed to validate the clinical application of these methods.