Tracing energy inputs into the seafloor using carbonate sediments.

Carbonate rocks provide unique and valuable sedimentary archives for secular changes in Earth's physical, chemical, and biological processes. However, reading the stratigraphic record produces overlapping, nonunique interpretations that stem from the difficulty in directly comparing competing biological, physical, or chemical mechanisms within a common quantitative framework. We built a mathematical model that decomposes these processes and casts the marine carbonate record in terms of energy fluxes across the sediment-water interface. Results showed that physical, chemical, and biological energy terms across the seafloor are subequal and that the energetic dominance of different processes varies both as a function of environment (e.g., onshore vs. offshore) as well as with time-varying changes in seawater chemistry and with evolutionary changes in animal abundance and behavior. We applied our model to observations from the end-Permian mass extinction-a massive upheaval in ocean chemistry and biology-revealing an energetic equivalence between two hypothesized drivers of changing carbonate environments: a reduction in physical bioturbation increased carbonate saturation states in the oceans. Early Triassic occurrences of 'anachronistic' carbonates-facies largely absent from marine environments after the Early Paleozoic-were likely driven more by reduction in animal biomass than by repeated perturbations to seawater chemistry. This analysis highlighted the importance of animals and their evolutionary history in physically shaping patterns in the sedimentary record via their impact on the energetics of marine environments.

Challenges and Opportunities in Rare Disease Drug Development.

Each month, Clinical Pharmacology & Therapeutics focuses on a particular theme. Twice a year, the associate editors, editors, and staff get together to discuss journal business and spend time setting up the calendar of themes. Often, there are no experts among us to take on a particular topic that we have chosen. The consequence is that one or two of us take on the theme and then have a crash course to learn as much as they can about it in order to solicit meaningful articles. This month's theme on rare diseases is such a case.

A systematic approach to predicting the risk of unicompartmental knee arthroplasty revision.

OBJECTIVE: Unicompartmental knee arthroplasty (UKA) revision is usually due to the degenerative degree of knee articular osteochondral tissue in the untreated compartment. However, it is difficult to simulate the biomechanical behavior on this tissue accurately. This study presents and validates a reliable system to predict which osteoarthritis (OA) patients may suffer revision as a result of biomechanical reasons after having UKA. DESIGN: We collected all revision cases available (n = 11) and randomly selected 67 UKA cases to keep the revision prevalence of almost 14%. All these 78 cases have been followed at least 2 years. An elastic model is designed to characterize the biomechanical behavior of the articular osteochondral tissue for each patient. After calculated the force on the tissue, finite element method (FEM) is applied to calculating the strain of each tissue node. Kernel Ridge Regression (KRR) method is used to model the relationship between the strain information and the risk of revision. Therefore, the risk of UKA revision can be predicted by this integrated model. RESULTS: Leave-one-out (LOO) cross-validation (CV) is implemented to assess the prediction accuracy. As a result, the mean prediction accuracy is 93.58% for all these cases, demonstrating the high value of this model as a decision-making assistant for surgical plaining of knee OA. CONCLUSIONS: The results of this study demonstrated that this integrated model can predict the risk of UKA revision with theoretically high accuracy. It combines bio-mechanical and statistical learning approach to create a surgical planning tool which may support clinical decision in the future.

Ignorance is not bliss: Statistical power is not probability of trial success.

The purpose of this commentary is to place probability of trial success, or assurance, in the context of decision making in drug development, and to illustrate its properties in an intuitive manner for the readers of Clinical Pharmacology and Therapeutics. The hope is that this will stimulate a dialog on how assurance should be incorporated into a quantitative decision approach for clinical development and trial design that uses all available information.

Whither pharmacometrics?: present state and future choices.

The theme of this month's issue of Clinical Pharmacology & Therapeutics is pharmacometrics. When looking back at the early days of pharmacometrics, current contributions to the drug development process look impressive. The questions are whether the original promise is being kept and how the impact can become even greater.

Geochemical modelling of the evolution and fate of metal pollutants arising from an abandoned gold mine tailings facility in Johannesburg.

Analytical techniques were combined with geochemical modelling to study the release mechanisms of pollutants from an abandoned gold mining tailings storage facility near Johannesburg. Inverse modelling of sampled tailings pond water and experimental single extractions using various solutions indicated which combination of naturally occurring leaching solutions were likely to give rise to the observed pond water quality. The potential fate of metals in the pond was predicted by modelling the formation of efflorescent crusts and adsorption onto hydrated iron oxide minerals.

Total artificial heart in the pediatric patient with biventricular heart failure.

Mechanical circulatory support emerged for the pediatric population in the late 1980s as a bridge to cardiac transplantation. The Total Artificial Heart (TAH-t) (SynCardia Systems Inc., Tuscon, AZ) has been approved for compassionate use by the Food and Drug Administration for patients with end-stage biventricular heart failure as a bridge to heart transplantation since 1985 and has had FDA approval since 2004. However, of the 1,061 patients placed on the TAH-t, only 21 (2%) were under the age 18. SynCardia Systems, Inc. recommends a minimum patient body surface area (BSA) of 1.7 m(2), thus, limiting pediatric application of this device. This unique case report shares this pediatric institution's first experience with the TAH-t. A 14-year-old male was admitted with dilated cardiomyopathy and severe biventricular heart failure. The patient rapidly decompensated, requiring extracorporeal life support. An echocardiogram revealed severe biventricular dysfunction and diffuse clot formation in the left ventricle and outflow tract. The decision was made to transition to biventricular assist device. The biventricular failure and clot formation helped guide the team to the TAH-t, in spite of a BSA (1.5 m(2)) below the recommendation of 1.7 m(2). A computed tomography (CT) scan of the thorax, in conjunction with a novel three-dimensional (3D) modeling system and team, assisted in determining appropriate fit. Chest CT and 3D modeling following implantation were utilized to determine all major vascular structures were unobstructed and the bronchi were open. The virtual 3D model confirmed appropriate device fit with no evidence of compression to the left pulmonary veins. The postoperative course was complicated by a left lung opacification. The left lung anomalies proved to be atelectasis and improved with aggressive recruitment maneuvers. The patient was supported for 11 days prior to transplantation. Chest CT and 3D modeling were crucial in assessing whether the device would fit, as well as postoperative complications in this smaller pediatric patient.

Sickle cell disease and complex congenital cardiac surgery: a case report and review of the pathophysiology and perioperative management.

Sickle cell anemia and thalassemia are hemoglobinopathies rarely encountered in the United States. Compounded with congenital heart disease, patients with sickle cell disease (SCD) requiring cardiopulmonary bypass and open-heart surgery represent the proverbial "needle in the haystack". As such, there is some trepidation on the part of clinicians when these patients present for complex cardiac surgery. SCD is an autosomal, recessive condition that results from a single nucleotide polymorphism in the ß-globin gene. Hemoglobin SS molecules (HgbSS) with this point mutation can polymerize under the right conditions, stiffening the erythrocyte membrane and distorting the cellular structure to the characteristic sickle shape. This shape change alters cellular transit through the microvasculature. As a result, circumstances such as hypoxia, hypothermia, acidosis or diminished blood flow can lead to aggregation, vascular occlusion and thrombosis. Chronically, SCD can give rise to multiorgan damage secondary to hemolysis and vascular obstruction. This review and case study details an 11-year-old African-American male with known SCD who presented to the cardiothoracic surgical service with congenital heart disease consisting of an anomalous, intramural right coronary artery arising from the left coronary sinus for surgical consultation and subsequent surgical correction. This case report will include a review of the pathophysiology and current literature regarding preoperative, intraoperative and postoperative management of SCD patients.

Network medicine: finding the links to personalized therapy.

Network medicine is a new approach that focuses on applying systems biology to pharmacology by "understanding the molecular system [and its perturbations] as a whole" so as to unravel the complex relationships among disease processes, genes, drugs, therapeutic indicators, and adverse effects.(1,2.)

Models of physiology and physiologically based models in clinical pharmacology.

As science matures, it becomes more mathematical, progressing from enumeration to the use of equations to the formulation of models. Clinical pharmacology has developed to the stage where models play an increasingly important role in predicting and analyzing drug pharmacokinetics and pharmacodynamics, and even in characterizing disease progression and therapeutic response. Useful models have two characteristics that are in ostensible conflict: (i) they must accurately represent the essential features of the underlying system and (ii) the representation must be sufficiently simplified to enable its salient features to be identified and investigated through further experimentation.

Pharmacokinetics, safety, and tolerability of atomoxetine and effect of CYP2D6*10/*10 genotype in healthy Japanese men.

Atomoxetine is a cytochrome P4502D6 (CYP2D6) substrate. The reduced-activity CYP2D6*10 allele is particularly prevalent in the Japanese population and may contribute to known ethnic differences in CYP2D6 metabolic capacity. The purpose of this study was to examine atomoxetine pharmacokinetics, safety, tolerability, and the effect of the CYP2D6*10/*10 genotype after single-stepped dosing (10, 40, 90, or 120 mg) and at steady state (40 or 60 mg twice a day for 7 days) in 49 healthy Japanese adult men. Dose proportionality was shown and tolerability confirmed at all doses studied. Comparison of pharmacokinetics, safety, and tolerability between Japanese and US subjects showed no clinically meaningful ethnic differences. The CYP2D6*10/*10 subjects had 2.1- to 2.2-fold and 1.8-fold higher area under the plasma concentration-time curve values relative to the CYP2D6*1/*1 and *1/*2 subjects and the CYP2D6*1/*10 and *2/*10 subjects, respectively. The adverse events reported by CYP2D6*10/*10 subjects were indistinguishable from those of other Japanese participants. The higher mean exposure in CYP2D6*10/*10 subjects is not expected to be clinically significant.

Motor cortical functional geometry in cerebral palsy and its relationship to disability.

OBJECTIVE: To investigate motor cortical map patterns in children with diplegic and hemiplegic cerebral palsy (CP), and the relationships between motor cortical geometry and motor function in CP. METHODS: Transcranial magnetic stimulation (TMS) was used to map motor cortical representations of the first dorsal interosseus (FDI) and tibialis anterior (TA) muscles in 13 children with CP (age 9-16 years, 6 males.) The Gross Motor Function Measure (GMFM) and Melbourne upper extremity function were used to quantify motor ability. RESULTS: In the hemiplegic participants (N = 7), the affected (right) FDI cortical representation was mapped on the ipsilateral (N = 4), contralateral (N = 2), or bilateral (N = 1) cortex. Participants with diplegia (N = 6) showed either bilateral (N = 2) or contralateral (N = 4) cortical hand maps. The FDI and TA motor map center-of-gravity mediolateral location ranged from 2-8 cm and 3-6 cm from the midline, respectively. Among diplegics, more lateral FDI representation locations were associated with lower Melbourne scores, i.e. worse hand motor function (Spearman's rho = -0.841, p = 0.036). CONCLUSIONS: Abnormalities in TMS-derived motor maps cut across the clinical classifications of hemiplegic and diplegic CP. The lateralization of the upper and lower extremity motor representation demonstrates reorganization after insults to the affected hemispheres of both diplegic and hemiplegic children. SIGNIFICANCE: The current study is a step towards defining the relationship between changes in motor maps and functional impairments in CP. These results suggest the need for further work to develop improved classification schemes that integrate clinical, radiologic, and neurophysiologic measures in CP.

Robotic systems in orthopaedic surgery.

Robots have been used in surgery since the late 1980s. Orthopaedic surgery began to incorporate robotic technology in 1992, with the introduction of ROBODOC, for the planning and performance of total hip replacement. The use of robotic systems has subsequently increased, with promising short-term radiological outcomes when compared with traditional orthopaedic procedures. Robotic systems can be classified into two categories: autonomous and haptic (or surgeon-guided). Passive surgery systems, which represent a third type of technology, have also been adopted recently by orthopaedic surgeons. While autonomous systems have fallen out of favour, tactile systems with technological improvements have become widely used. Specifically, the use of tactile and passive robotic systems in unicompartmental knee replacement (UKR) has addressed some of the historical mechanisms of failure of non-robotic UKR. These systems assist with increasing the accuracy of the alignment of the components and produce more consistent ligament balance. Short-term improvements in clinical and radiological outcomes have increased the popularity of robot-assisted UKR. Robot-assisted orthopaedic surgery has the potential for improving surgical outcomes. We discuss the different types of robotic systems available for use in orthopaedics and consider the indication, contraindications and limitations of these technologies.

Inbreeding depression in two seed-feeding beetles, Callosobruchus maculatus and Stator limbatus (Coleoptera: Chrysomelidae).

Inbreeding depression is well documented in insects but the degree to which inbreeding depression varies among populations within species, and among traits within populations, is poorly studied in insects other than Drosophila. Inbreeding depression was examined in two long-term laboratory colonies of the seed beetle, Callosobruchus maculatus (Fabricius), which are used frequently as models for experiments in ecology, evolution and behaviour. Inbreeding depression in these laboratory colonies are compared with one recently field-collected population of a different seed beetle, Stator limbatus Horn. Inbreeding reduced embryogenesis, egg hatch and larval survival in both species, such that eggs produced by sib matings were >17% less likely to produce an adult offspring. Inbred larvae also took 4-6% longer to develop to emergence in both species. Inbreeding depression varied among the measured traits but did not differ between the two populations of C. maculatus for any trait, despite the large geographic distance between source populations (western Africa vs. southern India). Inbreeding depression was similar in magnitude between C. maculatus and S. limbatus. This study demonstrates that these laboratory populations of C. maculatus harbour substantial genetic loads, similar to the genetic load of populations of S. limbatus recently collected from the field.

Mosquito repellents in frog skin.

The search for novel insect repellents has been driven by health concerns over established synthetic compounds such as diethyl-m-toluamide (DEET). Given the diversity of compounds known from frog skin and records of mosquito bite and ectoparasite infestation, the presence of mosquito repellents in frogs seemed plausible. We investigated frog skin secretions to confirm the existence of mosquito repellent properties. Litoria caerulea secretions were assessed for mosquito repellency by topical application on mice. The secretions provided protection against host-seeking Culex annulirostris mosquitoes. Olfactometer tests using aqueous washes of skin secretions from L. caerulea and four other frog species were conducted to determine whether volatile components were responsible for repellency. Volatiles from Litoria rubella and Uperoleia mjobergi secretions were repellent to C. annulirostris, albeit not as repellent as a DEET control. The demonstration of endogenous insect repellents in amphibians is novel, and demonstrates that many aspects of frog chemical ecology remain unexplored.

Complications associated with traction on the hip during arthroscopy.

We studied 16 hips (eight cadaver specimens) using arthrography, arthroscopy and anatomical dissection, under incremental traction of up to a maximum of 64 kg, to determine the relationship of the portals to nearby neurovascular structures. The distance of each arthroscopic portal (anterior, anterolateral, and posterolateral) to the associated neurovascular structures was measured after the application of 23 kg of traction. Traction of up to 64 kg on the lower limb failed to produce evidence of labral or capsular injury. Furthermore, traction of 23 kg resulted in little change in the position of adjacent neurovascular structures relative to the standard arthroscopic portals.

The influence of storm events on fine sediment transport, erosion and deposition within a reach of the River Swale, Yorkshire, UK.

The spatial and temporal dynamics of suspended sediment fluxes through a 55 km reach of the lowland River Swale, Yorkshire, UK are investigated for the period July 1994-June 1996. Seventeen storm events were monitored, each of which produced significant suspended sediment transport. Variations in sediment flux dynamics and reach sediment storage through events, representing a combination of channel bed erosion and/or deposition, bank erosion and floodplain deposition, were observed. Some, but not all, of this variation can be explained in terms of event size, precipitation distribution and intensity, and antecedent sediment storage conditions. In particular, marked variations in the size of the reach sediment store over the extremely wet 4-month winter period from December 1994 to April 1995 are demonstrated. Net sediment loss from the reach took place over during this winter period. These event-scale and seasonal patterns form a background to annual variations in the catchment sediment budget.