Search

Purpose Joint fractures must be accurately reduced minimising soft tissue damages to avoid negative surgical outcomes. To this regard, we have developed the RAFS surgical system, which allows the percutaneous reduction of intra-articular fractures and provides intra-operative real-time 3D image guidance to the surgeon. Earlier experiments showed the effectiveness of the RAFS system on phantoms, but also key issues which precluded its use in a clinical application. This work proposes a redesign of the RAFS’s navigation system overcoming the earlier version’s issues, aiming to move the RAFS system into a surgical environment. Methods The navigation system is improved through an image registration framework allowing the intra-operative registration between pre-operative CT images and intra-operative fluoroscopic images of a fractured bone using a custom-made fiducial marker. The objective of the registration is to estimate the relative pose between a bone fragment and an orthopaedic manipulation pin inserted into it intra-operatively. The actual pose of the bone fragment can be updated in real time using an optical tracker, enabling the image guidance. Results Experiments on phantom and cadavers demonstrated the accuracy and reliability of the registration framework, showing a reduction accuracy (sTRE) of about \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$0.88~\pm 0.2\,\hbox {mm}$$\end{document}0.88±0.2mm (phantom) and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$1.15\pm 0.8\,\hbox {mm}$$\end{document}1.15±0.8mm (cadavers). Four distal femur fractures were successfully reduced in cadaveric specimens using the improved navigation system and the RAFS system following the new clinical workflow (reduction error \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$1.2\pm 0.3\,\hbox {mm}$$\end{document}1.2±0.3mm, \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$2\pm 1{^{\circ }})$$\end{document}2±1∘). Conclusion Experiments showed the feasibility of the image registration framework. It was successfully integrated into the navigation system, allowing the use of the RAFS system in a realistic surgical application.

The treatment of joint-fractures is a common task in orthopaedic surgery causing considerable health costs and patient disabilities. Percutaneous techniques have been developed to mitigate the problems related to open surgery (e.g. soft tissue damage), although their application to joint-fractures is limited by the sub-optimal intra-operative imaging (2D-fluoroscopy) and by the high forces involved. Our earlier research toward improving percutaneous reduction of intra-articular fractures has resulted in the creation of a robotic system prototype, i.e. RAFS (Robot-Assisted Fracture Surgery) system.We propose a robot-bone attachment device for percutaneous bone manipulation, which can be anchored to the bone fragment through one small incision, ensuring the required stability and reducing the “biological cost” of the procedure. The device has been evaluated through the reduction of 9 distal femur fractures on human cadavers using the RAFS system.

A series of 2-pyridylquinolones has been prepared in 5–7 steps and through lead optimisation, antimalarial activity as low as 12 nM against Plasmodium falciparum (Pf) has been achieved. Compared with previous analogues in this series, selected molecules have improved solubility, a reduced potential for off-target toxicity and improved metabolic stability profiles. Docking studies performed with a homology model of the Pfbc1 complex target demonstrate a key role for the Tyr16 residues in the recognition of highly active quinolone based inhibitors.

Complex joint fractures often require an open surgical procedure, which is associated with extensive soft tissue damages and longer hospitalization and rehabilitation time. Percutaneous techniques can potentially mitigate these risks but their application to joint fractures is limited by the current sub-optimal 2D intra-operative imaging (fluoroscopy) and by the high forces involved in the fragment manipulation (due to the presence of soft tissue, e.g., muscles) which might result in fracture malreduction. Integration of robotic assistance and 3D image guidance can potentially overcome these issues. The authors propose an image-guided surgical robotic system for the percutaneous treatment of knee joint fractures, i.e., the robot-assisted fracture surgery (RAFS) system. It allows simultaneous manipulation of two bone fragments, safer robot-bone fixation system, and a traction performing robotic manipulator. This system has led to a novel clinical workflow and has been tested both in laboratory and in clinically relevant cadaveric trials. The RAFS system was tested on 9 cadaver specimens and was able to reduce 7 out of 9 distal femur fractures (T- and Y-shape 33-C1) with acceptable accuracy (≈1 mm, ≈5°), demonstrating its applicability to fix knee joint fractures. This study paved the way to develop novel technologies for percutaneous treatment of complex fractures including hip, ankle, and shoulder, thus representing a step toward minimally-invasive fracture surgeries. Electronic supplementary material The online version of this article (doi:10.1007/s10439-017-1901-x) contains supplementary material, which is available to authorized users.

A high-throughput screen (HTS) was undertaken against the respiratory chain dehydrogenase component, NADH:menaquinone oxidoreductase (Ndh) of Mycobacterium tuberculosis (Mtb). The 11000 compounds were selected for the HTS based on the known phenothiazine Ndh inhibitors, trifluoperazine and thioridazine. Combined HTS (11000 compounds) and in-house screening of a limited number of quinolones (50 compounds) identified similar to 100 hits and four distinct chemotypes, the most promising of which contained the quinolone core. Subsequent Mtb screening of the complete in-house quinolone library (350 compounds) identified a further similar to 90 hits across three quinolone subtemplates. Quinolones containing the amine-based side chain were selected as the pharmacophore for further modification, resulting in metabolically stable quinolones effective against multi drug resistant (MDR) Mtb. The lead compound, 42a (MTC420), displays acceptable antituberculosis activity (Mtb IC50 = 525 nM, Mtb Wayne IC50 = 76 nM, and MDR Mtb patient isolates IC50 = 140 nM) and favorable pharmacokinetic and toxicological profiles. National Institute of Health Research (NIHR, BRC Liverpool); Medical Research Council [MRC DPFS-G1002586]; Medical Research Council (MRC CiC) info:eu-repo/semantics/publishedVersion

There is an urgent need for new antimalarial drugs with novel mechanisms of action to deliver effective control and eradication programs. Parasite resistance to all existing antimalarial classes, including the artemisinins, has been reported during their clinical use. A failure to generate new antimalarials with novel mechanisms of action that circumvent the current resistance challenges will contribute to a resurgence in the disease which would represent a global health emergency. Here we present a unique generation of quinolone lead antimalarials with a dual mechanism of action against two respiratory enzymes, NADH:ubiquinone oxidoreductase ( Plasmodium falciparum NDH2) and cytochrome bc 1 . Inhibitor specificity for the two enzymes can be controlled subtly by manipulation of the privileged quinolone core at the 2 or 3 position. Inhibitors display potent (nanomolar) activity against both parasite enzymes and against multidrug-resistant P. falciparum parasites as evidenced by rapid and selective depolarization of the parasite mitochondrial membrane potential, leading to a disruption of pyrimidine metabolism and parasite death. Several analogs also display activity against liver-stage parasites ( Plasmodium cynomolgi ) as well as transmission-blocking properties. Lead optimized molecules also display potent oral antimalarial activity in the Plasmodium berghei mouse malaria model associated with favorable pharmacokinetic features that are aligned with a single-dose treatment. The ease and low cost of synthesis of these inhibitors fulfill the target product profile for the generation of a potent, safe, and inexpensive drug with the potential for eventual clinical deployment in the control and eradication of falciparum malaria.

Malaria is responsible for approximately 1 million deaths annually; thus, continued efforts to discover new antimalarials are required. A HTS screen was established to identify novel inhibitors of the parasite's mitochondrial enzyme NADH:quinone oxidoreductase (PfNDH2). On the basis of only one known inhibitor of this enzyme, the challenge was to discover novel inhibitors of PfNDH2 with diverse chemical scaffolds. To this end, using a range of ligand-based chemoinformatics methods, ~17000 compounds were selected from a commercial library of ~750000 compounds. Forty-eight compounds were identified with PfNDH2 enzyme inhibition IC(50) values ranging from 100 nM to 40 μM and also displayed exciting whole cell antimalarial activity. These novel inhibitors were identified through sampling 16% of the available chemical space, while only screening 2% of the library. This study confirms the added value of using multiple ligand-based chemoinformatic approaches and has successfully identified novel distinct chemotypes primed for development as new agents against malaria.

Following a program undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a novel enzyme target within the malaria parasite Plasmodium falciparum, hit to lead optimization led to identification of CK-2-68, a molecule suitable for further development. In order to reduce ClogP and improve solubility of CK-2-68 incorporation of a variety of heterocycles, within the side chain of the quinolone core, was carried out, and this approach led to a lead compound SL-2-25 (8b). 8b has IC(50)s in the nanomolar range versus both the enzyme and whole cell P. falciparum (IC(50) = 15 nM PfNDH2; IC(50) = 54 nM (3D7 strain of P. falciparum) with notable oral activity of ED(50)/ED(90) of 1.87/4.72 mg/kg versus Plasmodium berghei (NS Strain) in a murine model of malaria when formulated as a phosphate salt. Analogues in this series also demonstrate nanomolar activity against the bc(1) complex of P. falciparum providing the potential added benefit of a dual mechanism of action. The potent oral activity of 2-pyridyl quinolones underlines the potential of this template for further lead optimization studies.

A program was undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a dehydrogenase of the mitochondrial electron transport chain of the malaria parasite Plasmodium falciparum. PfNDH2 has only one known inhibitor, hydroxy-2-dodecyl-4-(1H)-quinolone (HDQ), and this was used along with a range of chemoinformatics methods in the rational selection of 17 000 compounds for high-throughput screening. Twelve distinct chemotypes were identified and briefly examined leading to the selection of the quinolone core as the key target for structure-activity relationship (SAR) development. Extensive structural exploration led to the selection of 2-bisaryl 3-methyl quinolones as a series for further biological evaluation. The lead compound within this series 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1H)-one (CK-2-68) has antimalarial activity against the 3D7 strain of P. falciparum of 36 nM, is selective for PfNDH2 over other respiratory enzymes (inhibitory IC(50) against PfNDH2 of 16 nM), and demonstrates low cytotoxicity and high metabolic stability in the presence of human liver microsomes. This lead compound and its phosphate pro-drug have potent in vivo antimalarial activity after oral administration, consistent with the target product profile of a drug for the treatment of uncomplicated malaria. Other quinolones presented (e.g., 6d, 6f, 14e) have the capacity to inhibit both PfNDH2 and P. falciparum cytochrome bc(1), and studies to determine the potential advantage of this dual-targeting effect are in progress.

Peter Gibbons is Executive Vice President of Global Supply Chain Operations at Starbucks. Gibbons, a native of Scotland, joined Starbucks in 2001, and he is responsible for all of the products that...

There has been considerable debate about profiling personality pathology when assessing and treating male perpetrators of domestic violence (DV). This study used the Millon Clinical Multiaxial Inventory (MCMI-III) to explore the severity and diversity of male perpetrator personality pathology and response bias in a group of DV perpetrators being assessed for a treatment program (N = 177). We analyzed the sample using the interpretive guidelines of White and Gondolf (2000); 54% of profiles in our sample fell into categories indicative of a personality disorder, and 37% of the total sample provided profiles indicative of severe personality pathology. These percentages were higher than White and Gondolf's findings but lower than some others. There was considerable diversity of personality pathology as well, supporting the contention that there is no one male DV perpetrator profile. Because of debate concerning the manner of responding on self-report instruments, we paid special attention to response biases in our sample. Twenty-six percent of our sample exaggerated (12%) or minimized (14%) their responses. We also found that response biases on the MCMI-III Modifying Indices were related to self-reported severity of psychopathology. This suggests that assessing severity of psychopathology is inadequate without reference to such biases.

N-tert-Butyl isoquine (4) (GSK369796) is a 4-aminoquinoline drug candidate selected and developed as part of a public-private partnership between academics at Liverpool, MMV, and GSK pharmaceuticals. This molecule was rationally designed based on chemical, toxicological, pharmacokinetic, and pharmacodynamic considerations and was selected based on excellent activity against Plasmodium falciparum in vitro and rodent malaria parasites in vivo. The optimized chemistry delivered this novel synthetic quinoline in a two-step procedure from cheap and readily available starting materials. The molecule has a full industry standard preclinical development program allowing first into humans to proceed. Employing chloroquine (1) and amodiaquine (2) as comparator molecules in the preclinical plan, the first preclinical dossier of pharmacokinetic, toxicity, and safety pharmacology has also been established for the 4-aminoquinoline antimalarial class. These studies have revealed preclinical liabilities that have never translated into the human experience. This has resulted in the availability of critical information to other drug development teams interested in developing antimalarials within this class.

A rapid, two-step synthesis of a range of dispiro-1,2,4,5-tetraoxanes with potent antimalarial activity both in vitro and in vivo has been achieved. These 1,2,4,5-tetraoxanes have been proven to be superior to 1,2,4-trioxolanes in terms of stability and to be superior to trioxane analogues in terms of both stability and activity. Selected analogues have in vitro nanomolar antimalarial activity and good oral activity and are nontoxic in screens for both cytotoxicity and genotoxicity. The synthesis of a fluorescent 7-nitrobenza-2-oxa-1,3-diazole (NBD) tagged tetraoxane probe and use of laser scanning confocal microscopy techniques have shown that tagged molecules accumulate selectively only in parasite infected erythrocytes and that intraparasitic formation of adducts could be inhibited by co-incubation with the iron chelator desferrioxamine (DFO).

High velocity low amplitude (HVLA) thrust techniques are amongst the most commonly used manipulative treatment techniques used by osteopaths. HVLA thrust techniques are considered potentially more dangerous when compared to non-impulse mobilisation type techniques because of the application of a rapid thrust or impulse. This has led to concerns as to the appropriateness of using HVLA thrust techniques in certain regions of the spine and in certain spinal pain presentations. Considerable research has been undertaken on both the effectiveness and potential adverse reactions arising from HVLA thrust techniques. This paper reviews the literature regarding the nature and incidence of transient and the more serious non-reversible impairments associated with the use of HVLA thrust techniques. Consideration is given to the efficacy and appropriateness of pre-manipulative vertebrobasilar artery screening protocols and suggestions are given as to ways in which practitioners may reduce perceived risk.

Background Edge Light Pupil Cycle Time (ELPCT) is a measure of the pupillary light reflex mediated via the autonomic nervous system (ANS). ELPCT is a measurable constant, unaffected by eye measured (i.e. left versus right eye), gender, visual acuity, refractive error, eye colour and pupil size. Previous research suggests that spinal manipulation techniques can produce distant effects mediated in part by the ANS. Objective To investigate the immediate effects of atlanto-axial high velocity low amplitude manipulation on ELPCT. Design A three group randomised controlled study. Methods Thirty participants (mean age=23.8) without eye, central or autonomic nervous system pathology had their ELPCT measured in both eyes pre- and post-manipulation. The manipulation technique used was a high velocity low amplitude (HVLA) rotatory thrust, with the applicator localised to the atlanto-axial joint on the left ( n =10) or right ( n =10) determined randomly. All HVLA manipulations were associated with audible cavitation. The control group ( n =10) underwent the same protocol, including pre-positioning for the manipulation, but without the thrust. Results ELPCT measures demonstrated a significant decrease between groups ( P =0.004) and between groups according to eye measured ( P =0.022). Significant decreases between pre- and post-manipulation measures of ELPCT indicated an association between side manipulated and eyes, with right-sided manipulation producing a decrease in ELPCT in the right eye ( P =0.001) and a left-sided manipulation producing a decrease in the left eye ( P =0.013). No other significant changes were observed. Conclusion ELPCT, mediated via the ANS, is directly influenced by HVLA manipulation with cavitation to the atlanto-axial joint. The ANS changes observed in this study demonstrated a unilateral response to HVLA manipulation.

Background Segmental paraspinal tissue texture irregularity and tenderness, particularly when detected in the paravertebral gutter (PVG), has been proposed to be an important diagnostic sign of intervertebral somatic dysfunction. The pathophysiology of tissues underlying sites that appear ‘abnormal to palpation and are reported tender' (AbPT) by the subject, is speculative, but it has been suggested that a difference in paraspinal muscle size in these regions could produce segmental tissue texture abnormalities. This study aimed to examine whether there was a difference in paraspinal muscle size between AbPT and ‘normal to palpation and non-tender' (NT) sites located in the PVG. Methods An experienced osteopath examined the thoracic PVG regions of 40 subjects (14 males, 26 females, age range 19–33 years, mean (SD)=22.3 (3.3); 33 asymptomatic, seven with mild thoracic symptoms) to detect an AbPT site in each individual. Three NT regions (immediately above, below and opposite the AbPT site) were also located, and the sites were marked with numbered stickers. An experienced ultrasonographer, who was blinded to the status of the marked regions, measured the anteroposterior cross-sectional dimension (thickness) of the paraspinal muscle bulk directly underlying each marked location, using diagnostic ultrasound. Results The AbPT and NT regions had similar mean anteroposterior dimensions (AbPT: 1.11cm±0.36, NT above: 1.12cm±0.34, NT below: 1.20cm±0.46, NT opposite: 1.10cm±0.36), and a one-way ANOVA determined that these means were not significantly different from each other ( F 3,156 =0.606, P =0.612). Conclusions The results of this study suggest that factors other than differences in paraspinal muscle thickness are likely to account for abnormal tissue texture detected with palpation in the thoracic PVG regions of young, largely asymptomatic adults.

Background: Segmental paraspinal tissue texture change has been proposed to be an important diagnostic sign of intervertebral somatic dysfunction. The nature and existence of these regions is speculative. Aims: The aim of this study was to examine whether deep, medial, paraspinal regions identified as having abnormal texture by palpation are confirmed as being more sensitive to pressure measured by a digital algometer. Methods: An osteopath examined the thoracic regions of 32 subjects (26 asymptomatic, six with mild thoracic symptoms) to detect an abnormal to palpation and tender (AbPT) site in each individual. Three non-tender and normal to palpation (NT) regions (immediately above, below and opposite the AbPT site) were also located. A digital pressure algometer, also known as a Palpometer, consisting of a 0.86cm force-sensing resistor (polymer film) attached to the palpating fingertip, recorded the pressure applied during palpation. Pressure pain threshold (PPT) measurements were recorded for all sites, with both researcher and subject blinded to the reading on the algometer. Results: The AbPT regions had a lower mean PPT than the three NT regions, and a one-way ANOVA determined these differences to be significant (P < 0.01). A Tukey post-hoc analysis revealed the significant differences to be between PPT scores for the AbPT location and all NT locations, but scores for the NT locations were not significantly different from each other. Conclusions: This study demonstrated that medial, paraspinal sites identified as having abnormal tissue texture and tenderness by palpation were significantly more tender than sites immediately above, below, and on the opposite side to the abnormal region. Further investigation of the nature of these AbPT sites is recommended.

Background: One of the diagnostic characteristics of the manipulable spinal lesion—a musculoskeletal disturbance that is claimed to be detected with manual palpation and corrected with manipulation—is said to be altered segmental tissue texture. Little evidence for the nature of abnormal paraspinal tissue texture exists, but indirect evidence from experimental studies supports the plausibility of the concept of protective muscle spasm, although investigations of increased paraspinal electromyography (EMG) associated with low back pain suggests complex changes in motor control rather than simple protective reflexes. Objectives: To review the literature for evidence that may support or refute proposed explanations for clinically observed altered paraspinal tissue texture associated with the manipulable spinal lesion. This review aims to highlight areas that require further research and make recommendations for future studies. Data Source: MEDLINE and CINAHL databases were searched using various combinations of the keywords paraspinal, muscle, palpation, EMG, spine, low back pain, pain, myofascial, hardness, manipulation, reliability, and somatic dysfunction, along with searching the bibliographies of selected articles and textbooks. Data Extraction: All relevant data were used. Results: Decreased paraspinal muscle activity and strength associated with low back pain is well established, and there is evidence of changes in muscle fiber composition and localized selective multifidus atrophy. Disturbances in microcirculation have been implicated in nonparaspinal muscle pain. The effect of spinal manipulation on paraspinal EMG activity is inconclusive but promising. Conclusion: Little direct evidence exists to support the existence or nature of paraspinal tissue texture change that is claimed to be detected with palpation. The proposal of segmental reflex paraspinal muscle contraction was not supported, at least in association with low back pain. There appears to be a complex relationship between deep paraspinal muscle inhibition during dynamic activity and nonvoluntary guarding behavior during static activity. The relationship between these findings and palpable tissue change is speculative, but increased activity, decreased activity, or both may be responsible for paraspinal tissues detected as abnormal with palpation. Recommendations are outlined for future research.

One of the diagnostic characteristics of the manipulable spinal lesion--a musculoskeletal disturbance detected by manual palpation and corrected with manipulation--is said to be altered segmental tissue texture. Various manual therapy authors have speculated on the possible nature of this tissue change, with some authors hypothesizing that it represents deep segmental muscle overactivity.To review the literature relating to the detection and nature of altered paraspinal tissue texture, proposed explanations for altered tissue texture, evidence for the plausibility of paraspinal muscle spasm, and evidence of muscle dysfunction associated with low back pain (LBP).MEDLINE and CINAHL databases were searched using various combinations of the keywords paraspinal, muscle, palpation, EMG, spine, low back pain, pain, myofascial, hardness, manipulation, reliability, and somatic dysfunction, along with searching the bibliographies of selected articles and textbooks.All relevant data were used.Little direct evidence exists for the nature of abnormal paraspinal tissue texture detected by palpation. Palpation for tenderness is more reliable than palpation for tissue texture change. Indirect evidence from animal studies and experimental muscle inflammation support the plausibility of protective paraspinal muscle contraction. Increased paraspinal electromyographic (EMG) activity observed in subjects with LBP appears to be a result of voluntary and nonvoluntary changes in motor control, modified by psychophysiological responses to perceived stress rather than a simple protective reflex.Although little direct evidence exists of the nature of clinically detected paraspinal tissue texture change, the concept of reactive muscle contraction appears plausible. Increased paraspinal EMG activity associated with LBP does not appear to be mediated by a simple protective reflex.

A recent review has concluded that: “Initial studies have found massage to be effective for persistent back pain. Spinal manipulation has small clinical benefits that are equivalent to those of other commonly used therapies. The effectiveness of acupuncture remains unclear. All of these treatments seem to be relatively safe. Preliminary evidence suggests that massage, but not acupuncture or spinal manipulation, may reduce the costs of care after an initial course of therapy” (Cherkin et al., Ann. Int. Med. 138(11) (2003) 898). This review was based on a meta-analysis comparing the value of manipulation with massage therapy and acupuncture that concluded that: “There is no evidence that spinal manipulative therapy is superior to other standard treatments for patients with acute or chronic low back pain” (Assendelft et al., Ann. Int. Med. 138(11) (2003) 871). A number of opinions were sought as to the validity of these conclusions, and a commentary was offered by Professor Edzard Ernst on these opinions.

Osteopaths commonly assess leg length. Inequalities in leg length are associated with an increased incidence of low back pain, adaptive muscle shortening, ligamentous and capsular hypomobility and degenerative joint disease. Accurate detection of leg length inequality could allow early preventative intervention. Several clinical methods of assessing leg length are documented, yet few show convincing reliability. The aim of this study was to determine the inter-examiner and intra-examiner reliability of the standing assessment of leg length inequality using heel inserts to simulate leg length discrepancy. Twenty-seven subjects (mean age=23) were examined by eight examiners. Assessment of leg length was performed by palpation of iliac crests, posterior superior iliac spines, greater trochanters and gluteal folds with the subjects standing. Examiners indicated whether leg length was equal or if there was a longer leg on the left or right. Subjects were assessed with no heel insert and heel inserts of 0.5cm and 1 cm in their shoes. Each insert intervention was examined twice on each subject by each examiner. Zero, 0.5cm and 1cm interventions demonstrated inter-examiner percentage agreement of 52.5% ( K =0.27), 53.9% ( K =0.28) and 63.4% ( K =0.19) respectively. Zero, 0.5cm and 1cm interventions demonstrated intra-examiner percentage agreement of 58.4% ( K =0.35), 60.7% ( K =0.34) and 63.5% ( K =0.14) respectively. The results of this study indicate that examiners are unable to reliably detect simulated leg length discrepancies of 1cm or less by standing assessment.

Study objective: To determine student and patient perspectives on clinical teaching in an out-patient setting. Design: Questionnaire using fixed-response, 5-point Likert scales, yes/no response and open comments. Setting: The Osteopathic Medicine Clinic, Victoria University, Australia. Participants: 100 patients and 152 senior clinical students and graduates. Measurements and main results: 96% of students found out-patient teaching to be a valuable way of gaining professional skills. 92% strongly agreed or agreed that out-patient teaching is an effective way to develop skills in history taking, conducting physical examinations (87%), enhancing communication skills (85%), and to develop record keeping (72%) and time-management skills (60%). The preferred location for the presentation of patient cases was in the tutorial room away from the patient. 100% of patients indicated that they were comfortable with the history taking in the out-patient setting with 84% of patients indicating that their experience of out-patient teaching would make them more likely to refer other patients. 96% of patients indicated that out-patient teaching did not make them anxious with 84% reporting that the clinical discussion of their case increased their knowledge of their clinical problem. 27% of patients suggested that there were some aspects of the clinical discussion that they didn't understand with 4% of patients finding that some discussion was inappropriate. Conclusions: Clinical teaching is a significant aspect of any medically focussed program of study. The clinical teaching environment should be a positive learning experience for the student while also providing for quality care of the patient. Reviews of student and patient perspectives regarding the out-patient teaching environment can be effective tools to inform curriculum development and clinic management.

Osteopaths, and other practitioners of manual medicine employ a variety of procedures in assessing a patient in order to determine a diagnosis and subsequent treatment plan. The physical assessment generally includes visual observation, static palpation and motion testing. Despite the reliance upon assessments of this type, many of the assessment procedures used remain questionable. The aim of this study was to determine the inter- and intra-examiner reliability of a commonly used three part positional diagnostic screen for the lumbar spine. Ten examiners performed the three part positional diagnostic screen on ten asymptomatic female subjects. Intraexaminer reliability ranged from less than chance to slight agreement ( K = −0.14 − 0.16) with a mean Kappa value of 0.04. Inter-examiner reliability showed slight agreement with a Kappa coefficient of 0.04. There was no real agreement either within or between examiners for the three-part static palpation diagnostic procedure for the lumbar spine. This might indicate that this particular procedure ought to be used with caution by new graduates, despite the fact that it would appear to be a well-known procedure, as documented in at least five widely utilised osteopathic texts. These results suggest that the reliability of the three part positional diagnostic screen for the lumbar spine remains questionable.

High velocity low amplitude (HVLA) thrust techniques are widely used by many manual therapists to treat low back pain. There is increasing evidence that spinal manipulation produces positive patient outcomes for acute low back pain. HVLA thrust techniques are associated with an audible release in the form of a pop or cracking sound that is widely accepted to represent cavitation of a spinal zygapophyseal joint. This audible release distinguishes these techniques from other manual therapy interventions. When using long lever HVLA thrust techniques spinal locking is necessary to localize forces and achieve cavitation at a specific vertebral segment. A critical factor in applying lumbar spine manipulation with minimal force is patient positioning and spinal locking. A knowledge of coupled movements of the lumbar spine aids an understanding of the patient positioning required to achieve spinal locking consistent with maximal patient comfort and cooperation. Excessive rotation can result in pain, patient resistance and failed technique. This masterclass presents a model of patient positioning for the lumbar spine that minimizes excessive use of rotation to achieve spinal locking prior to the application of the thrust.

Spinal manipulation is a commonly used modality for the treatment of low back pain with increasing evidence of positive outcomes. Adjunctive therapies such as hydrotherapy, flotation and exercise prescription are also used with effect for a range of clinical conditions including low back pain. This report introduces the potential role of combining spinal manipulation and adjunctive Flotation Restricted Environmental Stimulation Therapy (Flotation REST) in the treatment of acute non-specific low back pain. Outcome measures were used to assess the effectiveness of this combination of therapies and demonstrated both amelioration of pain and improvement in level of disability. The results support implementing a more detailed study with larger numbers of participants.

High velocity low amplitude (HVLA) thrust techniques are widely used by many manual medicine disciplines to treat spinal dysfunction. Techniques of this type are associated with an audible release in the form of a pop or cracking sound that is widely accepted to represent cavitation of a spinal zygapophyseal joint. This audible release distinguishes HVLA thrust techniques from other manual medicine interventions. Common indications for the use of HVLA thrust techniques are ‘joint fixation’, ‘joint locking’ and somatic dysfunction but various authors have also described other indications for the therapeutic use of these techniques. Despite a wide range of indications, there has been a decline in the use of HVLA thrust techniques. Concern regarding patient safety and the difficulty associated with gaining mastery of HVLA thrust techniques may be reasons for the decline in their use. While there are potential serious sequelae from the use of HVLA thrust techniques, the risks are low provided patients are thoroughly assessed and treated by appropriately trained practitioners. With increasing evidence that spinal manipulation produces positive patient outcomes for acute low back pain and some categories of neck pain and headache, there is a need to look critically at the indications for the use of HVLA thrust techniques as well as the actual risks and potential benefits of this therapeutic modality.

Background: The use of high velocity low amplitude (HVLA) manipulation has been advocated in the treatment of range of motion disorders. However, there remains speculation as to which direction of HVLA manipulative thrust is most effective in the amelioration of range of motion restriction. Objective: To investigate the effect of various directions of HVLA manipulation on the amelioration of goniometrically verified passive atlanto-axial (AA) rotation asymmetry. Methods: 40 asymptomatic subjects (mean age=28) who displayed a persistent unilateral passive atlanto-axial rotation asymmetry of 8° or more were randomly allocated to one of three treatment groups. The first group (n=14) received a single HVLA manipulation to the atlanto-axial joint with the thrust directed towards the most restricted range. The second group (n=14) received a single HVLA manipulation to the atlanto-axial joint with the thrust directed away from the most restricted range i.e. manipulated into the direction of greatest range. The third group (n=12) received bilateral manipulation to the atlanto-axial joint with the direction of initial thrust being determined randomly. For the purpose of this study a successful HVLA manipulation was defined as being accompanied by audible cavitation. HVLA manipulation was not accompanied by audible cavitation in 4 subjects. Measures of passive atlanto-axial end-range asymmetry were performed pre and post-manipulation. Results: HVLA manipulation of the atlanto-axial joint was found to produce a statistically significant immediate amelioration of atlanto-axial rotation asymmetry for all three-treatment groups. Conclusion: HVLA manipulation of the atlanto-axial articulation produces a significant immediate amelioration of passive atlanto-axial rotation asymmetry. The reduction in AA rotation asymmetry occurred regardless of whether the HVLA manipulation was applied unilaterally either towards or away from the restricted rotation ROM or bilaterally.

Background: A range of health care practitioners use cranial techniques. Palpation of a cranial rhythmic impulse (CRI) is a fundamental clinical skill used in diagnosis and treatment with these techniques. There has been little research establishing the reliability of CRI rate palpation. Objective: This study aimed to establish the intraexaminer and interexaminer reliability of CRI rate palpation and to investigate the "core-link" hypothesis of craniosacral interaction that is used to explain simultaneous motion at the cranium and sacrum. Design: Within-subjects, repeated-measures design. Subjects: Two registered osteopaths, both with postgraduate training in diagnosis and treatment, using cranial techniques, palpated 11 normal healthy subjects. Methods: Examiners simultaneously palpated for the CRI at the head and the sacrum of each subject. Examiners indicated the "full flexion" phase of the CRI by activating silent foot switches that were interfaced with a computer. Subject arousal was monitored using heart rate. Examiners were blind to each other's results and could not communicate during data collection. Results: Reliability was estimated from calculation of intraclass correlation coefficients (2,1). Intrarater reliability for examiners at either the head or the sacrum was fair to good, significant intraclass correlation coefficients ranging from +0.52 to +0.73. Interexaminer reliability for simultaneous palpation at the head and the sacrum was poor to nonexistent, ICCs ranging from −0.09 to +0.31. There were significant differences between rates of CRI palpated simultaneously at the head and the sacrum. Conclusions: The results fail to support the construct validity of the "core-link" hypothesis as it is traditionally held by proponents of craniosacral therapy and osteopathy in the cranial field.

SUMMARY. Despite the paucity of research into the reliability of static palpation, it is still employed extensively as a diagnostic tool by manual medicine practitioners. This study tested the inter- and intra-examiner agreement of ten senior osteopathic students using static palpation on ten asymptomatic subjects. Four assessments of the posterior superior iliac spine (PSIS), sacral sulcus (SS), and the sacral inferior lateral angle (SILA) on every subject by all examiners resulted in 1200 assessments in total. Kappa (Kg) yielded intra-examiner agreement that ranged between less-than-chance to substantial for the SILA (Kg 520.05 to 0.69; mean Kg 50.21), and slight to moderate for the PSIS (Kg 50.07 to 0.58; mean Kg 50.33) and the SS (Kg 50.02 to Kg 50.60; mean Kg 50.24), with 50% significant beyond the 0.05 level. Inter-examiner agreement was slight (PSIS Kg 50.04; SILA Kg 5 0.08; SS Kg 50.07) and significant at the 0.01 level. Intra-examiner agreement was greater than interexaminer agreement, which was consistent with existing palpation reliability studies. The poor reliability of clinical tests involving palpation may be partially explained by error in landmark location. # 2000 Harcourt Publishers Ltd

Summary In recent years muscle energy technique has been increasingly accepted into mainstream manual therapy worldwide. The muscle energy system of segmental spinal lesion diagnosis and treatment is predicated upon a model of spinal physiologic motion that was first outlined in the early 20th century. Current literature questions certain assumptions inherent within this model of spinal physiologic motion and, as a consequence, the system of segmental lesion diagnosis predicated upon it. The implications for assessment of spinal somatic dysfunction using this model are examined and an outline of what can reasonably be said about coupled spinal motion, in the light of current literature, is reviewed.

For many decades the osteopathic profession has embraced the model of physiologic motion of the spine as outlined by Harrison Fryette in 1918. Indeed his Laws of Physiologic Motion are often used as a predictive model for the assessment of spinal lesions and subsequent application of therapy. However, there is now increasing research that questions the validity and applicability of these Laws. This is a literature review of recent research into coupled motion of the spine.

Many design decisions for an autonomous crossing of the North Atlantic Ocean require an understanding of both the time that the vessel will need to be self-sufficient and the environmental conditions expected. Potential trans-Atlantic routes were evaluated to determine both the design conditions and selecting a route that has a relatively high probability of success. Factors included: prevailing winds, currents, ice, gales, calms, sea state, sunlight, starting date, boat characteristics and ship traffic. Two methods were used; an evaluation of numerous potential routes for initial planning to determine expected times and narrow the potential field of routes and an off-the-shelf sailing yacht route optimization program for routing immediately prior to or during the crossing. The long-term method used climatological data from Pilot Charts. A Velocity Prediction Program (VPP) was used to predict the boat’s performance. Calcualted passage times included the shortest, longest and most-likely. A northern and two southern routes with similar risk were identified.

NADH:quinone oxidoreductase (PfNDH2) represents a metabolic choke point in the respiratory chain of Plasmodium falciparum mitochondria and is the focus of a drug discovery programme. A miniaturised assay for recombinant PfNDH2 with robust assay performance measures was generated for the high throughput screening (HTS) of a focused library of 17,000 drug-like compounds. A quantitative structure-activity relationship has been developed around one of the chemical templates derived from the HTS hits. Lead molecules developed to date show selective inhibitory activity against PfNDH2 versus P. falciparum bc1 or dihydroorotate dehydrogenase (DHODH). Potent enzyme inhibition is accompanied by in vitro parasite kill of multidrug-resistant strains in the low nM range and clearance of parasites from in vivo P. berghei models. Lead molecules also display excellent in vitro therapeutic indices against human cell lines and bovine bc1. Initial metabolic studies in human liver microsomes and hepatocytes indicate favourable pharmacology. These data support the further development of this new candidate drug targeting a novel parasite component.

The mitochondrial respiratory chain of the malaria parasite Plasmodium falciparum differs from that of its human host in that it lacks a canonical protonmotive NADH:ubiquinone oxidoreductase (Complex I), containing instead a single sub-unit, non-protonmotive Ndh2, similar to that found in plant mitochondria, fungi and some bacteria [1,2]. As such, the P. falciparum Ndh 2 (PfNdh2) is a potentially attractive anti-malarial chemotherapeutic target. Using an E.coli NADH dehydrogenase knockout strain (ANN0222, ndh::tet nuoB::nptI-sacRB) we have developed a heterologous expression system for PfNdh2, facilitating its physicochemical and enzymological characterisation [2]. PfNdh2 represents a metabolic choke point in the respiratory chain of P. falciparum mitochondria and is the focus of a drug discovery programme towards the development of a novel therapy for uncomplicated malaria. Here we describe a miniaturised spectrophotometric assay for recombinant PfNdh2 (steady state NADH oxidation and ubiquinone reduction monitored at 340 nm and 283 nm respectively) with robust assay performance measures that has been utilised for the high throughput screening (HTS) of small molecule inhibitors. The objectives of the HTS were twofold: (i) Increase the number of selective PfNdh2 inhibitors and (ii) to expand the number of inhibitor chemotypes. At the time of screening, only one proof of concept molecule, 1-hydroxy-2-dodecyl-4-(1H)quinolone (HDQ), was known to have PfNdh2 inhibitory activity (IC50=70 nM) [3,4]. HDQ was used to initiate a primary similarity-based screen of 1000 compounds from a compound collection of 750,000 compounds (curated by Biofocus-DPI). Chemoinformatics methodology was applied to the hits from this initial phase in order to perform a hit expansion screen on a further ~16,000 compounds. Application of this chemoinformatic strategy allowed us to cover ~16% diversity whilst screening just ~2% of the compound collection. The HTS resulted in a hit rate of 0.29% and 1 50 compounds were progressed for potency against PfNdh2. Of these compounds, 50 were considered active with IC50s ranging from 100 nM to 40 μM. Currently seven distinct chemotypes are being progressed from hit to lead using traditional synthetic medicinal chemistry strategies.

Thiol-Olefin Co-Oxygenation (TOCO) methodology has been applied to the synthesis of a small library of weak base and polar 1,2,4-trioxanes. The 1,2,4-trioxane units synthesised exhibit remarkable stability as they survive base catalysed hydrolysis and mixed anhydride/amine coupling reactions. This unique stability feature has enabled a range of novel substitution patterns to be incorporated within the spiro 1,2,4-trioxane unit. Selected analogues express potent in vitro nM antimalarial activity, low cytotoxicity and oral activity in the Plasmodium berghei mouse model of malaria.

Submitted by Maria de Lurdes Cristiano (mcristi@ualg.pt) on 2014-06-05T11:25:48Z No. of bitstreams: 1 Endoperoxide Carbonyl Falcipain.pdf: 3053240 bytes, checksum: 93e4bc035883a70a584fe1ccff338ae7 (MD5) Approved for entry into archive by Merja Muzavor (mmuzavor@ualg.pt) on 2014-06-06T14:07:11Z (GMT) No. of bitstreams: 2 1312780297183882.zip: 3000583 bytes, checksum: 12698b38aab7e7f9531963cfcec74545 (MD5) Endoperoxide Carbonyl Falcipain.pdf: 3053240 bytes, checksum: 93e4bc035883a70a584fe1ccff338ae7 (MD5) Made available in DSpace on 2014-06-06T14:07:11Z (GMT). No. of bitstreams: 2 1312780297183882.zip: 3000583 bytes, checksum: 12698b38aab7e7f9531963cfcec74545 (MD5) Endoperoxide Carbonyl Falcipain.pdf: 3053240 bytes, checksum: 93e4bc035883a70a584fe1ccff338ae7 (MD5) Previous issue date: 2010