Transferring the entatic-state principle to copper photochemistry.

The entatic state denotes a distorted coordination geometry of a complex from its typical arrangement that generates an improvement to its function. The entatic-state principle has been observed to apply to copper electron-transfer proteins and it results in a lowering of the reorganization energy of the electron-transfer process. It is thus crucial for a multitude of biochemical processes, but its importance to photoactive complexes is unexplored. Here we study a copper complex-with a specifically designed constraining ligand geometry-that exhibits metal-to-ligand charge-transfer state lifetimes that are very short. The guanidine-quinoline ligand used here acts on the bis(chelated) copper(I) centre, allowing only small structural changes after photoexcitation that result in very fast structural dynamics. The data were collected using a multimethod approach that featured time-resolved ultraviolet-visible, infrared and X-ray absorption and optical emission spectroscopy. Through supporting density functional calculations, we deliver a detailed picture of the structural dynamics in the picosecond-to-nanosecond time range.

Defective iron-oxide nanoparticles synthesised by high temperature plasma processing: a magnetic characterisation versus temperature.

Magnetic properties and phase compositions of iron-oxide nanoparticles synthesised by a high temperature arc plasma route have been investigated by Mössbauer spectroscopy and high harmonic magnetic AC susceptibility measurements, and correlated with morphological and structural properties for different synthesis conditions. The Mössbauer spectra precisely determined the presence of different iron-oxide fractions in the investigated nanoparticles, while the high harmonic magnetic susceptibility measurements revealed the occurrence of metastable magnetic phases evolving in temperature and time. This study illustrates magnetic properties and dynamics of the magnetic configurations of iron-oxide nanoparticles grown by high temperature plasma, a process less explored so far but extremely useful for synthesising large numbers of nanoparticles for industrial applications.

A new approach to configurable primary data collection.

BACKGROUND AND OBJECTIVES: The formats, semantics and operational rules of data processing tasks in genomics (and health in general) are highly divergent and can rapidly change. In such an environment, the problem of consistent transformation and loading of heterogeneous input data to various target repositories becomes a critical success factor. The objective of the project was to design a new conceptual approach to configurable data transformation, de-identification, and submission of health and genomic data sets. Main motivation was to facilitate automated or human-driven data uploading, as well as consolidation of heterogeneous sources in large genomic or health projects. METHODS: Modern methods of on-demand specialization of generic software components were applied. For specification of input-output data and required data collection activities, we propose a simple data model of flat tables as well as a domain-oriented graphical interface and portable representation of transformations in XML. Using such methods, the prototype of the Configurable Data Collection System (CDCS) was implemented in Java programming language with Swing graphical interfaces. The core logic of transformations was implemented as a library of reusable plugins. RESULTS: The solution is implemented as a software prototype for a configurable service-oriented system for semi-automatic data collection, transformation, sanitization and safe uploading to heterogeneous data repositories-CDCS. To address the dynamic nature of data schemas and data collection processes, the CDCS prototype facilitates interactive, user-driven configuration of the data collection process and extends basic functionality with a wide range of third-party plugins. Notably, our solution also allows for the reduction of manual data entry for data originally missing in the output data sets. CONCLUSIONS: First experiments and feedback from domain experts confirm the prototype is flexible, configurable and extensible; runs well on data owner's systems; and is not dependent on vendor's standards.

Factors associated with thrombosis in pediatric patients with systemic lupus erythematosus.

OBJECTIVE: The risk of thrombosis is increased in patients with systemic lupus erythematosus (SLE). Few studies have assessed factors associated with thrombosis within the pediatric SLE (pSLE) population. We sought to better characterize these associated factors in pSLE patients using the Childhood Arthritis & Rheumatology Research Alliance (CARRA) registry. METHODS: Within the CARRA registry, patients with a history of thrombosis were compared to those without. Univariate logistic regression was used to calculate odds ratios. A multivariable logistic regression model was conducted that included variables from the univariate analysis that had a p value < 0.10 and other variables identified as clinically significant from published literature. RESULTS: Among the 979 pSLE patients in the CARRA registry, 24 (2.5%) patients had a history of arterial thrombosis and 35 (3.6%) of venous thrombosis. In the univariate analysis, the odds ratio of having a thrombotic event were found to be significantly higher in patients with a history of vasculitis, avascular necrosis (AVN), or antiphospholipid antibody (aPL). Similar results were found for vasculitis, AVN, and aPL in the multivariable analysis. CONCLUSION: Our study of pSLE patients suggests that vasculitis, positive APL, and AVN are associated with thrombotic events in this population.

Decreased morbidity and mortality of autologous hematopoietic transplants for children with malignant central nervous system tumors: the 'Head Start' trials, 1991-2009.

Since 1991, three sequential prospective clinical trials have been conducted by the 'Head Start' (HS) Consortium in which young children with newly-diagnosed malignant central nervous system (CNS) tumors were treated with induction chemotherapy followed by single-cycle marrow-ablative chemotherapy and autologous hematopoietic rescue as a means of improving disease cure rate and quality of survival through avoidance (<6 years old at diagnosis) or reduction (6-10 years old) of brain irradiation. Bone Marrow (HS I) or filgrastim-mobilized peripheral hematopoietic cells (HS II and III) were obtained following recovery from the first and/or second induction cycles. Radiotherapy was administered following all chemotherapy only for patients with residual tumor following completion of induction or with age greater than 6 years at diagnosis. Two hundred and twenty-six children were enrolled on three consecutive HS trials with primary malignant CNS tumors and underwent marrow-ablative chemotherapy. The 100-day treatment-related mortality (TRM) steadily declined as did grade IV transplant-related oropharyngeal mucositis. Factors most likely associated with the decrease in TRM and morbidity are increasing experience with the marrow-ablative chemotherapy regimen combined with improved leukapheresis and post-reinfusion supportive care techniques, contributing toward improved overall survival.

Pilot PET Study to Assess the Functional Interplay Between ABCB1 and ABCG2 at the Human Blood-Brain Barrier.

ABCB1 and ABCG2 work together at the blood-brain barrier (BBB) to limit brain distribution of dual ABCB1/ABCG2 substrates. In this pilot study we used positron emission tomography (PET) to assess brain distribution of two model ABCB1/ABCG2 substrates ([(11) C]elacridar and [(11) C]tariquidar) in healthy subjects without (c.421CC) or with (c.421CA) the ABCG2 single-nucleotide polymorphism (SNP) c.421C>A. Subjects underwent PET scans under conditions when ABCB1 and ABCG2 were functional and during ABCB1 inhibition with high-dose tariquidar. In contrast to the ABCB1-selective substrate (R)-[(11) C]verapamil, [(11) C]elacridar and [(11) C]tariquidar showed only moderate increases in brain distribution during ABCB1 inhibition. This provides evidence for a functional interplay between ABCB1 and ABCG2 at the human BBB and suggests that both ABCB1 and ABCG2 need to be inhibited to achieve substantial increases in brain distribution of dual ABCB1/ABCG2 substrates. During ABCB1 inhibition c.421CA subjects had significantly higher increases in [(11) C]tariquidar brain distribution than c.421CC subjects, pointing to impaired cerebral ABCG2 function.

Neuroblastomas vary widely in their sensitivities to herpes simplex virotherapy unrelated to virus receptors and susceptibility.

Although most high-risk neuroblastomas are responsive to chemotherapy, relapse is common and long-term survival is < 40%, underscoring the need for more effective treatments. We evaluated the responsiveness of 12 neuroblastoma cell lines to the Δγ134.5 attenuated oncolytic herpes simplex virus (oHSV), Seprehvir (HSV1716), which is currently used in pediatric phase I trials. We found that entry of Seprehvir in neuroblastoma cells is independent of the expression of nectin-1 and the sum of all four known major HSV entry receptors. We observed varying levels of sensitivity and permissivity to Seprehvir, suggesting that the cellular anti-viral response, not virus entry, is the key determinant of efficacy with this virus. In vivo, we found significant anti-tumor efficacy following Seprehvir treatment, which ranged from 6/10 complete responses in the CHP-134 model to a mild prolonged median survival in the SK-N-AS model. Taken together, these data suggest that anti-tumor efficacy cannot be solely predicted based on in vitro response. Whether or not this discordance holds true for other viruses or tumor types is unknown. Our results also suggest that profiling the expression of known viral entry receptors on neuroblastoma cells may not be entirely predictive of their susceptibility to Seprehvir therapy.

Incidence of cutaneous malignant melanoma in the Czech Republic: the risks of sun exposure for adolescents.

The Czech Republic reported one of the highest incidence rate in cutaneous melanoma (CM) in Europe and because this incidence has been increasing, mainly among young people, the main goal of our study was to establish sun exposure behavior risk factors for CM formation and to evaluate whether the young generation of Czechs is exposed to a higher risk of CM than the older generation. A questionnaire-based case-control study was conducted. We obtained 978 completed questionnaires: 216 from patients with CM and 762 from healthy respondents. The healthy individuals were further divided to adolescents (n = 460) and older respondents (n = 302). Three logistic regression models were developed: 1. patients with CM vs. healthy older respondents, 2. adolescents vs. healthy older respondents, and 3. patients with CM vs. adolescents. The main risk factors for all three models were the number of sunburn episodes and the use of the sunscreen in the childhood. The most alarming results for adolescents included: all day sun exposure, including times of maximum risk (11 AM to 3 PM), inadequate use of sunscreen in adulthood, and frequent mountain holidays. Our results show that sun-safety in the young generation is satisfactory, when the responsibility for sun exposure behavior is in the hands of their parents; however, when children become adolescents, they become immune to sun-safety and risk prevention campaigns and their behavior becomes much more risky. Our results further suggest the sun-safety campaigns need to be modified in such a way as to have greater impact and influence on adolescent sun-risk behaviors.

IFPA Meeting 2011 workshop report II: Angiogenic signaling and regulation of fetal endothelial function; placental and fetal circulation and growth; spiral artery remodeling.

Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At IFPA meeting 2011 there were twelve themed workshops, three of which are summarized in this report. These workshops related to vascular systems and circulation in the mother, placenta and fetus, and were divided in to 1) angiogenic signaling and regulation of fetal endothelial function; 2) placental and fetal circulation and growth; 3) spiral artery remodeling.

Diprosopus tetraophthalmus: CT as a complement to autopsy.

Diprosopus is the rarest form of conjoined twinning. This anomaly is characterised by craniofacial duplication to varying degrees and is associated with anomalies of the central nervous, cardiac, respiratory and musculoskeletal systems. We present an infant characterised as diprosopus tetraophthalmus who underwent post-mortem CT, which served as a highly useful complement to autopsy.

Pgp-mediated interaction between (R)-[11C]verapamil and tariquidar at the human blood-brain barrier: a comparison with rat data.

Using positron emission tomography (PET) imaging we assessed, in vivo, the interaction between a microdose of (R)-[(11)C]verapamil (a P-glycoprotein (Pgp) substrate) and escalating doses of the Pgp inhibitor tariquidar (3, 4, 6, and 8 mg/kg) at the blood-brain barrier (BBB) in healthy human subjects. We compared the dose-response relationship of tariquidar in humans with data obtained in rats using a similar methodology. Tariquidar was equipotent in humans and rats in its effect of increasing (R)-[(11)C]verapamil brain uptake (expressed as whole-brain volume of distribution (V(T))), with very similar half-maximum-effect concentrations. Both in humans and in rats, brain V(T) approached plateau levels at plasma tariquidar concentrations >1,000 ng/ml. However, Pgp inhibition in humans led to only a 2.7-fold increase in brain V(T) relative to baseline scans (before administration of tariquidar) as compared with 11.0-fold in rats. The results of this translational study add to the accumulating evidence that there are marked species-dependent differences in Pgp expression and functionality at the BBB.

Placental fetal thrombotic vasculopathy in severe congenital anomalies prompting EXIT procedure.

OBJECTIVE: The ex-utero intrapartum treatment (EXIT) procedure is used to secure fetal airway, cannulate for extracorporeal membrane oxygenation (ECMO), or resect a tumor during partial delivery in a modified cesarean section. This is a retrospective study of placental pathology from EXIT procedures. METHODS: Placental reports and glass slides from 36 placentas delivered by EXIT procedure (study group SG) and 36 placentas from pregnancies without perinatal mortality and delivered by cesarean sections and matched for gestational age were blindly reviewed. Indications for EXIT procedures were: 11 cervical teratomas, 9 diaphragmatic hernias, 4 pulmonary airway malformations, 4 micrognathias, 3 vascular malformations, 3 CHAOS, and 2 aortic stenoses. 22 clinical and 43 gross and histological placental features were compared using the analysis of variance or Yates χ(2) with Holm-Bonferroni correction, where appropriate. RESULTS: The average gestational age in the SG and the CG was 34.9 weeks. Histological features of fetal thrombotic vasculopathy were more frequently seen in the SG. Of the placental features, statistically significant differences were found in, partial fibrosis of chorionic villi (9.7 ± 7.9 vs. 6.1 ± 5.3 villi per placental section) [p = 0.035], clusters of at least 3 avascular chorionic villi (33 v. 6%) [p = 0.042], and abnormal umbilical cord insertion (8% vs. 0% (p = 0.045), in the SG and the CG respectively. CONCLUSION: To the best of our knowledge, this is the first study to describe the placentas from EXIT procedures. The presence of increased frequency of fetal thrombotic vasculopathy on histology indicates an underlying chronic and on-going stasis in fetal circulation due to the presence of conditions which were indications for the EXIT procedures. The possibility of coagulopathy should be considered in management of the fetuses and neonates undergoing EXIT procedure. Detailed examination of the placenta is of utmost importance in order to recognize and treat potentially life-threatening complications.

Plasma protein binding may reduce antimicrobial activity by preventing intra-bacterial uptake of antibiotics, for example clindamycin.

OBJECTIVES: although plasma protein binding (PPB) is accepted to be an essential factor in reducing antimicrobial activity, little is known about the underlying mechanisms. One possibility includes impaired penetration of an antimicrobial into bacterial cells in the presence of PPB. As a prerequisite for testing this hypothesis an optimized medium displaying high protein binding without impairing bacterial growth had to be identified for our model compound clindamycin. METHODS: determination of PPB, bacterial growth and antimicrobial killing was performed in Mueller-Hinton broth (MHB) containing various amounts of human albumin or serum. [(3)H]clindamycin was used to investigate clindamycin penetration into Staphylococcus aureus. RESULTS: of all investigated media only MHB(50%serum) and MHB(70%serum) achieved protein binding comparable to pure serum. In contrast, MHB(20%serum) and most media containing only albumin demonstrated considerably lower protein binding. Pure serum resulted in bacterial growth inhibition compared with MHB while MHB(16%albumin) and MHB(50%serum) did not result in significant differences in bacterial count after 24 h. However, in both MHB(16%albumin) and MHB(50%serum) the antimicrobial activity of clindamycin was reduced by >2 log(10) cfu/mL compared with pure MHB. The radioactive signal after administration of [(3)H]clindamycin to S. aureus was significantly decreased in pure serum as well as in MHB(16%albumin) and MHB(50%serum), while no significant difference was observed for MHB(4%albumin) and MHB(20%serum). CONCLUSIONS: reduction of the intracellular radioactive signal in the presence of serum proteins correlated both with the degree of protein binding and reduction of antimicrobial activity supporting the hypothesis of impairment of activity by PPB by reducing intra-bacterial antimicrobial concentrations.

A task failure has no effect on the electromechanical delay of the peroneus longus.

OBJECTIVE: Ankle inversion injuries represent the most common trauma sustained by athletes. Muscle fatigue from activity may contribute to a delay in the response of the ankle proprioceptors and dynamic restraints during unexpected inversion. The purpose of this investigation was to determine if the electromechanical delay (EMD) of the peroneus longus is influenced by a task failure exercise. SUBJECTS: Sixteen subjects (age 20 +/- 1.1 y; mass 71.6 +/- 12.5 kg; height 173.0 +/- 8.7 cm; 9 male, 1 female) with no lower extremity injuries reported for data collection. MEASUREMENTS: Data were collected from each subject's dominant leg using surface electromyography (EMG). Electrodes were applied over the peroneus longus (PL) using a standard protocol. A stimulating electrode was applied to the common peroneal nerve. Subjects were placed in a monopedal stance on a force platform. A low amplitude, short duration stimulus was applied to the common peroneal nerve. The EMG was used to determine timing of the M wave and the force platform was used to determine the onset of foot pronation. Once 6 trials were recorded, subjects completed 2 sets of an isotonic activity that isolated the peroneals. The task was completed to failure for each set. Immediately following the task failure exercise, subjects returned to the force platform for 6 additional trials recorded as before. Analysis of data was performed by determining the onset of the M wave as the beginning of positive EMG activity following the end of the imposed stimulus response. This point was superimposed on the force platform curve and the point at which a 10 N.m force change occurred was used to calculate the EMD (time difference between the force platform indicator and the M wave indicator). RESULTS: Average EMD prior to the task failure exercise was 13.35 +/- 3.47 ms. Following the task failure exercise, the average EMD was 12.67 +/- 3.86 ms. A paired samples t test revealed no significant differences with regard to EMD between pre- and post-task failure exercise for the PL (p = 0.448). CONCLUSION: We concluded that the task failure exercise did not affect the electromechanical delay of the PL.

Brachial plexus impingement: an unusual complication of bilateral breast augmentation.

Breast augmentation is one of the most commonly performed aesthetic procedures, with many studies documenting the early and long-term complications that might be expected. This report describes the case of an active young woman who experienced severe pain, particularly with movement. Surgical exploration showed the cause of this pain to be impingement of the patient's lower brachial plexus by the mammary prosthesis. Such a complication has not, to the authors' knowledge, been reported previously.

The effects of external support on electromechanical delay of the peroneus longus muscle.

Ankle taping and bracing is commonly used in athletics and both have been shown to be effective in reducing injury. Ankle proprioception has been shown to increase with external support due to the activation of cutaneous mechanoreceptors, however, the sensorimotor effect has not been studied Electromechanical delay (EMD) is defined as the time lag from the onset of electrical activity in the muscle to the subsequent mechanical response. The purpose of this investigation was to measure and compare the EMD of the peroneus longus muscle during ankle unsupported, braced, and taped conditions. Thirty-one (10 male, 21female) healthy, college-aged subjects participated in the study (age: 20.9 +/- 1.8 years, mass 70.3 +/- 15.8 kg, height 171.1 +/- 9.6 cm). Each subject was assigned a random order for the three external support conditions. The subject was positioned on a force platform and instructed to actively evert the ankle. We examined the time lag between the onset of electrical activity in the peroneus longus muscle and a change in force as detected by the force platform. Five trials were completed for each condition and a repeated measures ANOVA was used to determine statistical significance. The results showed no significant difference between the three external support conditions. We concluded that external support through taping and bracing does not affect the EMD of the peroneus longus muscle in healthy subjects.

The Novartis compound archive -- from concept to reality.

As HTS technologies come of age, pharmaceutical companies are focusing increasingly on the quality of their screening collections. Storage conditions and their influence on compound stability and solubility are debated intensely. At Novartis, a strategy was developed that is different to most other companies: (1) compounds unsuitable for storage in solution are excluded by computational methods; (2) compounds are stored at 4 degrees C/20% relative humidity in a DMSO/water mixture to avoid freeze-thaw cycles and water uptake and to allow rapid plate replication; (3) resolubilisation of compounds at regular intervals.

Laser techniques associated with facial aesthetic and reparative surgery.

Chronological aging is a natural biological event that is seen particularly in the face. Attempts to correct the results of this facial loss of structural form are sometimes successful. The skin itself is usually neglected, and surgery sometimes fails to achieve the goals expected by the patient. The surgical laser offers an extremely elegant and powerful solution to this problem to complement or enhance the results of selected surgical facial aesthetic procedures as follows: (1) ablative full-face CO2 laser resurfacing in combination with facelifting; (2) laser surgical technique for upper eyelid ptosis; (3) lower eyelid blepharoplasty with the aid of the CO2 laser; (4) full-face resurfacing following minilifting of the lower part of the face; (5) endoscopic eyebrow lifting combined with laser resurfacing; (6) perioral CO2 laser resurfacing in combination with facelifting; and (7) several miscellaneous procedures (e.g., treatment of upper and lower xanthelasma with laser upper blepharoplasty, laser resurfacing in combination with fillers, and laser resurfacing of periocular wrinkles after surgical blepharoplasty). In the hands of the authors, the combination of laser and standard surgical procedures presented herein has consistently produced good results and high patient satisfaction. The complication rate is low and the recovery rate is excellent. Laser treatment enhances the natural look obtained by conventional surgeries.