Clinical tests of musculoskeletal dysfunction in the diagnosis of cervicogenic headache

Persistent intermittent headache is a common disorder and is often accompanied by neck aching or stiffness, which could infer a cervical contribution to headache. However, the incidence of cervicogenic headache is estimated to be 14-18% of all chronic headaches, highlighting the need for clear criterion of cervical musculoskeletal impairment to identify cervicogenic headache sufferers who may benefit from treatments such as manual therapy. This study examined the presence of cervical musculoskeletal impairment in 77 subjects, 27 with cervicogenic headache, 25 with migraine with aura and 25 control subjects. Assessments included a photographic measure of posture, range of movement, cervical manual examination, pressure pain thresholds, muscle length, performance in the cranio-cervical flexion test and cervical kinaesthetic sense. The results indicated that when compared to the migraine with aura and control groups who scored similarly in the tests, the cervicogenic headache group had less range of cervical flexion/extension (P = 0.048) and significantly higher incidences of painful upper cervical joint dysfunction assessed by manual examination (all P < 0.05) and muscle tightness (P < 0.05). Sternocleidomastoid normalized EMG values were higher in the latter three stages of the cranio-cervical flexion test although they failed to reach significance. There were no between group differences for other measures. A discriminant analysis revealed that manual examination could discriminate the cervicogenic headache group from the other subjects (migraine with aura and control subjects combined) with an 80% sensitivity. (C) 2005 Elsevier Ltd. All rights reserved.

The predictive ability of clinical tests for contact lens induced dry eye

Approximately half of current contact lens wearers suffer from dryness and discomfort, particularly towards the end of the day. Contact lens practitioners have a number of dry eye tests available to help them to predict which of their patients may be at risk of contact lens drop out and advise them accordingly. This thesis set out to rationalize them to see if any are of more diagnostic significance than others. This doctorate has found: (1) The Keratograph, a device which permits an automated, examiner independent technique for measuring non invasive tear break up time (NITBUT) measured NITBUT consistently shorter than measurements recorded with the Tearscope. When measuring central corneal curvature the spherical equivalent power of the cornea was measured as being significantly flatter than with a validated automated keratometer. (2) Non-invasive and invasive tear break-up times significantly correlated to each other, but not the other tear metrics. Symptomology, assessed using the OSDI questionnaire, correlated more with those tests indicating possible damage to the ocular surface (including LWE, LIPCOF and conjunctival staining) than with tests of either tear volume or stability. Cluster analysis showed some statistically significant groups of patients with different sign and symptom profiles. The largest cluster demonstrated poor tear quality with both non-invasive and invasive tests, low tear volume and more symptoms. (3) Care should be taken in fitting patients new to contact lenses if they have a NITBUT less than 10s or an OSDI comfort rating greater than 4.2 as they are more likely to drop-out within the first 6 months. Cluster analysis was not found to be beneficial in predicting which patients will succeed with lenses and which will not. A combination of the OSDI questionnaire and a NITBUT measurement was most useful both in diagnosing dry eye and in predicting contact lens drop out.

Technological enhancements to optometric clinical tests

A sizeable amount of the testing in eye care, requires either the identification of targets such as letters to assess functional vision, or the subjective evaluation of imagery by an examiner. Computers can render a variety of different targets on their monitors and can be used to store and analyse ophthalmic images. However, existing computing hardware tends to be large, screen resolutions are often too low, and objective assessments of ophthalmic images unreliable. Recent advances in mobile computing hardware and computer-vision systems can be used to enhance clinical testing in optometry. High resolution touch screens embedded in mobile devices, can render targets at a wide variety of distances and can be used to record and respond to patient responses, automating testing methods. This has opened up new opportunities in computerised near vision testing. Equally, new image processing techniques can be used to increase the validity and reliability of objective computer vision systems. Three novel apps for assessing reading speed, contrast sensitivity and amplitude of accommodation were created by the author to demonstrate the potential of mobile computing to enhance clinical measurement. The reading speed app could present sentences effectively, control illumination and automate the testing procedure for reading speed assessment. Meanwhile the contrast sensitivity app made use of a bit stealing technique and swept frequency target, to rapidly assess a patient’s full contrast sensitivity function at both near and far distances. Finally, customised electronic hardware was created and interfaced to an app on a smartphone device to allow free space amplitude of accommodation measurement. A new geometrical model of the tear film and a ray tracing simulation of a Placido disc topographer were produced to provide insights on the effect of tear film breakdown on ophthalmic images. Furthermore, a new computer vision system, that used a novel eye-lash segmentation technique, was created to demonstrate the potential of computer vision systems for the clinical assessment of tear stability. Studies undertaken by the author to assess the validity and repeatability of the novel apps, found that their repeatability was comparable to, or better, than existing clinical methods for reading speed and contrast sensitivity assessment. Furthermore, the apps offered reduced examination times in comparison to their paper based equivalents. The reading speed and amplitude of accommodation apps correlated highly with existing methods of assessment supporting their validity. Their still remains questions over the validity of using a swept frequency sine-wave target to assess patient’s contrast sensitivity functions as no clinical test provides the range of spatial frequencies and contrasts, nor equivalent assessment at distance and near. A validation study of the new computer vision system found that the authors tear metric correlated better with existing subjective measures of tear film stability than those of a competing computer-vision system. However, repeatability was poor in comparison to the subjective measures due to eye lash interference. The new mobile apps, computer vision system, and studies outlined in this thesis provide further insight into the potential of applying mobile and image processing technology to enhance clinical testing by eye care professionals.

Influence of climate on clinical diagnostic dry eye tests: pilot study

Purpose. To analyze dry eye disease (DED) tests and their consistency in similar nonsymptomatic population samples living in two geographic locations with different climates (Continental vs. Atlantic). Methods. This is a pilot study including 14 nonsymptomatic residents from Valladolid (Continental climate, Spain) and 14 sex-matched and similarly aged residents from Braga (Atlantic climate, Portugal); they were assessed during the same season (spring) of two consecutive years. Phenol red thread test, conjunctival hyperemia, fluorescein tear breakup time, corneal and conjunctival staining, and Schirmer test were evaluated on three different consecutive visits. Reliability was assessed using the intraclass correlation coefficient and weighted kappa (J) coefficient for quantitative and ordinal variables, respectively. Results. Fourteen subjects were recruited in each city with a mean (TSD) age of 63.0 (T1.7) and 59.1 (T0.9) years (p = 0.08) in Valladolid and Braga, respectively. Intraclass correlation coefficient and J values of the tests performed were below 0.69 and 0.61, respectively, for both samples, thus showing moderate to poor reliability. Subsequently, comparisons were made between the results corresponding to the middle and higher outdoor relative humidity (RH) visit in each location as there were no differences in mean temperature (p Q 0.75) despite RH values significantly differing (p e 0.005). Significant (p e 0.05) differences were observed between Valladolid and Braga samples on tear breakup time (middle RH visit, 2.76 T 0.60 vs. 5.26 T 0.64 seconds; higher RH visit, 2.61 T 0.32 vs. 5.78 T 0.88 seconds) and corneal (middle RH, 0.64 T 0.17 vs. 0.14 T 0.10; higher RH, 0.60 T 0.22 vs. 0.0 T 0.0) and conjunctival staining (middle RH, 0.61 T 0.17 vs. 0.14 T 0.08; higher RH, 0.57 T 0.15 vs. 0.18 T 0.09). Conclusions. This pilot study provides initial evidence to support that DED test outcomes assessing the ocular surface integrity and tear stability are climate dependent. Future large-sample studies should support these outcomes also in DED patients. This knowledge is fundamental for multicenter clinical trials. Lack of consistency in diagnostic clinical tests for DED was also corroborated. (Optom Vis Sci 2015;92:e284Ye289)

A new clinical sign probably associated to left hemiplegia with left hemineglect syndrome: the crossed legs

Objetivo : Descrever um novo sinal clínico associado à síndrome de negligência unilateral (SNU) em pacientes com acidente vascular cerebral isquêmico (AVCi). Método : Em 150 pacientes com acidente vascular cerebral isquêmico, foram realizadas tomografias de crânio e aplicada a National Institute of Health Stroke Scale. Aqueles pacientes com lesões vasculares à direita, hemiplegia esquerda e perna direita persistentemente cruzada sobre a esquerda, foram submetidos a testes específicos para SNU. Trinta pacientes também com lesões vasculares à direita, hemiplegia esquerda, porém sem evidências de permanecerem com as pernas cruzadas, foram submetidos aos mesmos testes clínicos. Resultados : Entre 150 pacientes com AVCi, 9 apresentaram lesão vascular cerebral à direita, hemiplegia esquerda e tendência em permanecer com a perna direita cruzada sobre a esquerda. Em 8 deles, testes específicos realizados nos primeiros dias de internação, confirmaram SNU à esquerda. Um paciente morreu antes que os testes pudessem ser aplicados. Dos 30 pacientes que não cruzaram as pernas, os testes foram normais em 20. Dez pacientes apresentaram alterações mínimas, insuficientes para o diagnóstico de SNU. Conclusão : A perna direita cruzada sobre a esquerda pode representar um novo sinal semiológico associado à hemiplegia esquerda e SNU à esquerda.

Normal values of balance tests in women aged 20-80

OBJECTIVES: To determine normal values for four commonly used clinical functional balance tests from community-dwelling women aged 20 to 80 and to identify any significant decline due to aging. DESIGN: A cross-sectional study was undertaken to provide normative values for four clinical balance tests across 6 decade cohorts. SETTING: The Betty Byrne-Henderson Center for Women and Aging, Royal Womens' Hospital, Brisbane, Australia. PARTICIPANTS: Four hundred fifty-six community-dwelling, independently ambulant women with no obvious neurological or musculoskeletal-related disability, aged 20 to 80, were randomly recruited from a large metropolitan region. MEASUREMENTS: The clinical balance measures/tests were the Timed Up and Go test, step test, Functional Reach test, and lateral reach test. Multivariate analysis was used to test the effect for age, height, and activity level. RESULTS: Normal data were produced for each test across each decade cohort. Gradual decline in balance performance was confirmed, with significant effect for age demonstrated. CONCLUSION: New normative data across the adult age decades are available for these clinical tests. Use of clinical balance tests could complement other balance tests and be used to screen women aged 40 to 60 whose performance is outside the normal values for age and to decrease later falls risk.

Computer-aided drug design and ADMET predictions for identification and evaluation of novel potential farnesyltransferase inhibitors in cancer therapy

We have used various computational methodologies including molecular dynamics, density functional theory, virtual screening, ADMET predictions and molecular interaction field studies to design and analyze four novel potential inhibitors of farnesyltransferase (FTase). Evaluation of two proposals regarding their drug potential as well as lead compounds have indicated them as novel promising FTase inhibitors, with theoretically interesting pharmacotherapeutic profiles, when Compared to the very active and most cited FTase inhibitors that have activity data reported, which are launched drugs or compounds in clinical tests. One of our two proposals appears to be a more promising drug candidate and FTase inhibitor, but both derivative molecules indicate potentially very good pharmacotherapeutic profiles in comparison with Tipifarnib and Lonafarnib, two reference pharmaceuticals. Two other proposals have been selected with virtual screening approaches and investigated by LIS, which suggest novel and alternatives scaffolds to design future potential FTase inhibitors. Such compounds can be explored as promising molecules to initiate a research protocol in order to discover novel anticancer drug candidates targeting farnesyltransferase, in the fight against cancer. (C) 2009 Elsevier Inc. All rights reserved.

Immediate and lasting improvements in weight distribution seen in baropodometry following a high-velocity, low-amplitude thrust manipulation of the sacroiliac joint

The biomechanics of the sacroiliac joint makes the pelvic segment responsible for proper weight distribution between lower extremities; however, it is known to be susceptible to altered mobility. The objective of this study was to analyze baropodometric responses following thrust manipulation on subjects with sacroiliac joint restrictions. Twenty asymptomatic subjects were submitted to computerized baropodometric analysis before, after, and seven days following sacroiliac manipulation. The variables peak pressure and contact area were obtained at each of these periods as the average of absolute values of the difference between the right and left foot based on three trials. Data revealed significant reduction only in peak pressure immediately after manipulation and at follow-up when compared to pre-manipulative values (p < 0.05). Strong correlation was found between the dominant foot and the foot with greater contact area (r - 0.978), as well as between the side of joint restriction and the foot with greater contact area (r = 0.884). Weak correlation was observed between the dominant foot and the foot with greater peak pressure (r = 0.501), as well as between the side of joint restriction and the foot with greater peak pressure (r = 0.694). The results suggest that sacroiliac joint manipulation can influence peak pressure distribution between feet, but contact area does not seem to be related to the biomechanical aspects addressed in this study. (C) 2011 Elsevier Ltd. All rights reserved.

Testes de resistência, flexibilidade, e ativação/controlo muscular da região lombo pélvica em futebolistas amadores com e sem dor lombar

Introdução: A dor lombar é comum manifestar-se em atletas de futebol, pelo que se torna importante utilizar testes clínicos como forma de detetar alterações que estejam associadas à presença de dor lombar. Objetivo: Identificar a relação entre a presença de dor lombar e os testes de resistência, flexibilidade e ativação/controlo muscular da região lombo pélvica em futebolistas com e sem dor lombar. Métodos: Realizou-se o presente estudo transversal numa amostra de 25 futebolistas amadores, dos quais 8 apresentavam dor lombar. Foi avaliada a resistência e os rácios dos músculos globais do tronco, a flexibilidade dos flexores e extensores da anca bem como a ativação/controlo dos músculos transverso do abdómen e multífidos. Resultados: Os atletas com lombalgia apresentaram uma diminuição significativa do tempo de resistência muscular dos vários grupos musculares do tronco e da flexibilidade muscular comparativamente aos atletas sem lombalgia. Foi também identificado um aumento significativo no rácio flexores/extensores do tronco. Relativamente aos testes de ativação muscular, não foram encontradas associações com a presença de dor lombar. Conclusão: A aplicação de testes de resistência e flexibilidade parece diferenciar os indivíduos com e sem dor lombar, não se tendo verificado o mesmo quanto à ativação do transverso do abdómen e dos multífidos.

Novel approaches for culturing hepatocytes for drug testing applications

Dissertation presented to obtain the Ph.D degree in Biochemisry, Biotechnology

Activity of 9-acridanone-hydrazone drugs detected at the pre-postural phase, in the experimental schistosomiasis mansoni

The compound Ro-15.5458/000, derivative in the class of 9-acridanone-hydrazones, was found to be effective against Schistosoma mansoni in mice, killing almost all the skin schistosomules (24 hr after infection), when administered at the dose of 100 mg/kg. In experiments carried out with Cebus monkeys, the drug was shown to be fully effective at 25 mg/kg, 7 days after infection. These data, associated with the good results obtained earlier at the post-postural phase of schistosomiasis, allow the inference that this promising compound may be important in the set of antischistosomal drugs, depending on further toxicological and clinical tests.

In vitro inhibition of Plasmodium falciparum by substances isolated from Amazonian antimalarial plants

In the present study, a quassinoid, neosergeolide, isolated from the roots and stems of Picrolemma sprucei (Simaroubaceae), the indole alkaloids ellipticine and aspidocarpine, isolated from the bark of Aspidosperma vargasii and A. desmanthum (Apocynaceae), respectively, and 4-nerolidylcatechol, isolated from the roots of Pothomorphe peltata (Piperaceae), all presented significant in vitro inhibition (more active than quinine and chloroquine) of the multi-drug resistant K1 strain of Plasmodium falciparum. Neosergeolide presented activity in the nanomolar range. This is the first report on the antimalarial activity of these known, natural compounds. This is also the first report on the isolation of aspidocarpine from A. desmanthum. These compounds are good candidates for pre-clinical tests as novel lead structures with the aim of finding new antimalarial prototypes and lend support to the traditional use of the plants from which these compounds are derived.

Regional and hemispheric determinants of language laterality: Implications for preoperative fMRI.

Language is typically a function of the left hemisphere but the right hemisphere is also essential in some healthy individuals and patients. This inter-subject variability necessitates the localization of language function, at the individual level, prior to neurosurgical intervention. Such assessments are typically made by comparing left and right hemisphere language function to determine "language lateralization" using clinical tests or fMRI. Here, we show that language function needs to be assessed at the region and hemisphere specific level, because laterality measures can be misleading. Using fMRI data from 82 healthy participants, we investigated the degree to which activation for a semantic word matching task was lateralized in 50 different brain regions and across the entire cortex. This revealed two novel findings. First, the degree to which language is lateralized across brain regions and between subjects was primarily driven by differences in right hemisphere activation rather than differences in left hemisphere activation. Second, we found that healthy subjects who have relatively high left lateralization in the angular gyrus also have relatively low left lateralization in the ventral precentral gyrus. These findings illustrate spatial heterogeneity in language lateralization that is lost when global laterality measures are considered. It is likely that the complex spatial variability we observed in healthy controls is more exaggerated in patients with brain damage. We therefore highlight the importance of investigating within hemisphere regional variations in fMRI activation, prior to neuro-surgical intervention, to determine how each hemisphere and each region contributes to language processing. Hum Brain Mapp, 2010. © 2010 Wiley-Liss, Inc.

Effect of roscovitine on intracellular calcium dynamics: differential enantioselective responses.

Cyclin-dependent kinases (CDKs) inhibitors have emerged as interesting therapeutic candidates. Of these, (S)-roscovitine has been proposed as potential neuroprotective molecule for stroke while (R)-roscovitine is currently entering phase II clinical trials against cancers and phase I clinical tests against glomerulonephritis. In addition, (R)-roscovitine has been suggested as potential antihypertensive and anti-inflammatory drug. Dysfunction of intracellular calcium balance is a common denominator of these diseases, and the two roscovitine enantiomers (S and R) are known to modulate calcium voltage channel activity differentially. Here, we provide a detailed description of short- and long-term responses of roscovitine on intracellular calcium handling in renal epithelial cells. Short-term exposure to (S)-roscovitine induced a cytosolic calcium peak, which was abolished after stores depletion with cyclopiazonic acid (CPA). Instead, (R)-roscovitine caused a calcium peak followed by a small calcium plateau. Cytosolic calcium response was prevented after stores depletion. Bafilomycin, a selective vacuolar H(+)-ATPase inhibitor, abolished the small calcium plateau. Long-term exposure to (R)-roscovitine significantly reduced the basal calcium level compared to control and (S)-roscovitine treated cells. However, both enantiomers increased calcium accumulation in the endoplasmic reticulum (ER). Consistently, cells treated with (R)-roscovitine showed a significant increase in SERCA activity, whereas (S)-roscovitine incubation resulted in a reduced PMCA expression. We also found a tonic decreased ability to release calcium from the ER, likely via IP3 signaling, under treatment with (S)- or (R)-roscovitine. Together our data revealed that (S)-roscovitine and (R)-roscovitine exert distinct enantiospecific effects on intracellular calcium signaling in renal epithelial cells. This distinct pharmacological profile can be relevant for roscovitine clinical use.

Place de la clinique en médecine ambulatoire--les enseignements de l'etude TOPIC [The place of the clinic in primary case--the TOPIC study].

We know very little about the importance of history and physical examination compared to the importance of paraclinical tests in the diagnostic process in primary care. To answer this question, we examined prospectively 672 consecutive patients with chest pain in primary care. We recorded the timing and the clinical characteristics of the most frequent diagnosis. The resort to laboratory or other clinical tests and reference to specialist were influenced by: emergency consultation, potentially life-threatening aetiology, personal characteristics of the general practitioners' (GP) and patients' anxiety. GPs attributed the diagnosis to history and physical examination alone in 66% and to the association of history, physical examination and tests in 31% cases. This, clinical strategy remains the most important factor in the diagnostic process; even when they are insufficient, they allowed to generate hypotheses and guide investigations.