[(18)F]Fluoroethyltyrosine- positron emission tomography-guided radiotherapy for high-grade glioma.

BACKGROUND: To compare morphological gross tumor volumes (GTVs), defined as pre- and postoperative gadolinium enhancement on T1-weighted magnetic resonance imaging to biological tumor volumes (BTVs), defined by the uptake of (18)F fluoroethyltyrosine (FET) for the radiotherapy planning of high-grade glioma, using a dedicated positron emission tomography (PET)-CT scanner equipped with three triangulation lasers for patient positioning. METHODS: Nineteen patients with malignant glioma were included into a prospective protocol using FET PET-CT for radiotherapy planning. To be eligible, patients had to present with residual disease after surgery. Planning was performed using the clinical target volume (CTV = GTV union or logical sum BTV) and planning target volume (PTV = CTV + 20 mm). First, the interrater reliability for BTV delineation was assessed among three observers. Second, the BTV and GTV were quantified and compared. Finally, the geometrical relationships between GTV and BTV were assessed. RESULTS: Interrater agreement for BTV delineation was excellent (intraclass correlation coefficient 0.9). Although, BTVs and GTVs were not significantly different (p = 0.9), CTVs (mean 57.8 +/- 30.4 cm(3)) were significantly larger than BTVs (mean 42.1 +/- 24.4 cm(3); p < 0.01) or GTVs (mean 38.7 +/- 25.7 cm(3); p < 0.01). In 13 (68%) and 6 (32%) of 19 patients, FET uptake extended >or= 10 and 20 mm from the margin of the gadolinium enhancement. CONCLUSION: Using FET, the interrater reliability had excellent agreement for BTV delineation. With FET PET-CT planning, the size and geometrical location of GTVs and BTVs differed in a majority of patients.

Intravitreal ranibizumab for AMD : the individual rhythm of OCT guided retreatment intervals

Purpose: We intended to determine whether the need for retreatmentwith intravitreal ranibizumab follows an individual rhythm in patientswith exudative AMD. Setting: Prospective mono-centre cohort study.Methods: Prospective study. 48 patients with exudative AMD. 3 loadingdoses of ranibizumab, followed by a 12 months PRN regimen guided byearly exudative signs on SD-OCT. An intensified follow-up allowed todetect recurrences early.Results:Mean VA improved by 6.4 letters at month 3 and by 13.1 letters atmonth 12, with a mean of 8.0 injections (range 0-12) during the maintenancephase. The intra-individual variance of the intervals was relativelysmall and ranged within 20% of themean interval in 91% of patients.Thefirst interval was within 1 week of the mean interval in 84% of patients.The retreatment criteria were stable in 89% of patients.Conclusion: The relative stability of the intra-individual intervalsmay allowsimplifying the care for AMDpatients.Theremay be a predictive role for thefirst interval after the loading phase. The functional results of this PRNregimenwith early retreatmentwere excellent. Financial disclosure:None.

Ultrasound evaluation of synovitis in RA: Correlation with clinical disease activity and sensitivity to change in an observational cohort study.

OBJECTIVE: To evaluate the correlation between clinical measures of disease activity and a ultrasound (US) scoring system for synovitis applied by many different ultrasonographers in a daily routine care setting within the Swiss registry for RA (SCQM) and further to determine the sensitivity to change of this US Score. METHODS: One hundred and eight Swiss rheumatologists were trained in performing the Swiss Sonography in Arthritis and Rheumatism (SONAR) score. US B-mode and Power Doppler (PwD) scores were correlated with DAS28 and compared between the clinical categories in a cross-sectional cohort of patients. In patients with a second US (longitudinal cohort), we investigated if change in US score correlated with change in DAS and evaluated the responsiveness of both methods. RESULTS: In the cross-sectional cohort with 536 patients, correlation between the B-mode score and DAS28 was significant but modest (Pearson coefficient r=0.41, P<0.0001). The same was true for the PwD score (r=0.41, P<0.0001). In the longitudinal cohort with 183 patients we also found a significant correlation between change in B-mode and in PwD score with change in DAS28 (r=0.54, P<0.0001 and r=0.46, P<0.0001, respectively). Both methods of evaluation (DAS and US) showed similar responsiveness according to standardized response mean (SRM). CONCLUSIONS: The SONAR Score is practicable and was applied by many rheumatologists in daily routine care after initial training. It demonstrates significant correlations with the degree of as well as change in disease activity as measured by DAS. On the level of the individual, the US score shows many discrepancies and overlapping results exist.

Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers.

Methadone inhibits the cardiac potassium channel hERG and can cause a prolonged QT interval. Methadone is chiral but its therapeutic activity is mainly due to (R)-methadone. Whole-cell patch-clamp experiments using cells expressing hERG showed that (S)-methadone blocked the hERG current 3.5-fold more potently than (R)-methadone (IC50s (half-maximal inhibitory concentrations) at 37 degrees C: 2 and 7 microM). As CYP2B6 slow metabolizer (SM) status results in a reduced ability to metabolize (S)-methadone, electrocardiograms, CYP2B6 genotypes, and (R)- and (S)-methadone plasma concentrations were obtained for 179 patients receiving (R,S)-methadone. The mean heart-rate-corrected QT (QTc) was higher in CYP2B6 SMs (*6/*6 genotype; 439+/-25 ms; n=11) than in extensive metabolizers (non *6/*6; 421+/-25 ms; n=168; P=0.017). CYP2B6 SM status was associated with an increased risk of prolonged QTc (odds ratio=4.5, 95% confidence interval=1.2-17.7; P=0.03). This study reports the first genetic factor implicated in methadone metabolism that may increase the risk of cardiac arrhythmias and sudden death. This risk could be reduced by the administration of (R)-methadone.

Role of JNK isoforms in the development of neuropathic pain following sciatic nerve transection in the mouse.

ABSTRACT: BACKGROUND: Current tools for analgesia are often only partially successful, thus investigations of new targets for pain therapy stimulate great interest. Consequent to peripheral nerve injury, c-Jun N-terminal kinase (JNK) activity in cells of the dorsal root ganglia (DRGs) and spinal cord is involved in triggering neuropathic pain. However, the relative contribution of distinct JNK isoforms is unclear. Using knockout mice for single isoforms, and blockade of JNK activity by a peptide inhibitor, we have used behavioral tests to analyze the contribution of JNK in the development of neuropathic pain after unilateral sciatic nerve transection. In addition, immunohistochemical labelling for the growth associated protein (GAP)-43 and Calcitonin Gene Related Peptide (CGRP) in DRGs was used to relate injury related compensatory growth to altered sensory function. RESULTS: Peripheral nerve injury produced pain-related behavior on the ipsilateral hindpaw, accompanied by an increase in the percentage of GAP43-immunoreactive (IR) neurons and a decrease in the percentage of CGRP-IR neurons in the lumbar DRGs. The JNK inhibitor, D-JNKI-1, successfully modulated the effects of the sciatic nerve transection. The onset of neuropathic pain was not prevented by the deletion of a single JNK isoform, leading us to conclude that all JNK isoforms collectively contribute to maintain neuropathy. Autotomy behavior, typically induced by sciatic nerve axotomy, was absent in both the JNK1 and JNK3 knockout mice. CONCLUSIONS: JNK signaling plays an important role in regulating pain threshold: the inhibition of all of the JNK isoforms prevents the onset of neuropathic pain, while the deletion of a single splice JNK isoform mitigates established sensory abnormalities. JNK inactivation also has an effect on axonal sprouting following peripheral nerve injury.

The birth of the Rheic Ocean - Early Palaeozoic subsidence patterns and subsequent tectonic plate scenarios

New plate-tectonic reconstructions of the Gondwana margin suggest that the location of Gondwana-derived terranes should not only be guided by the models, but should also consider the possible detrital input from some Asian blocks (Hunia), supposed to have been located along the Cambrian Gondwana margin, and accreted in the Silurian to the North-Chinese block. Consequently, the Gondwana margin has to be subdivided into a more western domain, where the future Avalonian blocks will be separated from Gondwana by the opening Rheic Ocean, whereas in its eastern continuation, hosting the future basement areas of Central Europe, different periods of crustal extension should be distinguished. Instead of applying a rather cylindrical model, it is supposed that crustal extension follows a much more complex pattern, where local back-arcs or intra-continental rifts are involved. Guided by the age data of magmatic rocks and the pattern of subsidence curves, the following extensional events can be distinguished: During the early to middle Cambrian, a back-arc setting guided the evolution at the Gondwana margin. Contemporaneous intra-continental rift basins developed at other places related to a general post-PanAfrican extensional phase affecting Africa Upper Cambrian formation of oceanic crust is manifested in the Chamrousse area, and may have lateral cryptic relics preserved in other places. This is regarded as the oceanisation of some marginal basins in a context of back-arc rifting. These basins were closed in a mid-Ordovician tectonic phase, related to the subduction of buoyant material (mid-ocean ridge?) Since the Early Ordovician, a new phase of extension is observed, accompanied by a large-scale volcanic activity, erosion of the rift shoulders generated detritus (Armorican Quartzite) and the rift basins collected detrital zircons from a wide hinterland. This phase heralded the opening of Palaeotethys, but it failed due to the Silurian collision (Eo-Variscan phase) of an intra-oceanic arc with the Gondwana margin. During this time period, at the eastern wing of the Gondwana margin begins the drift of the future Hunia microcontinents, through the opening of an eastern prolongation of the already existing Rheic Ocean. The passive margin of the remaining Gondwana was composed of the Galatian superterranes, constituents of the future Variscan basement areas. Remaining under the influence of crustal extension, they will start their drift to Laurussia since the earliest Devonian during the opening of the Palaeotethys Ocean. (C) 2008 Elsevier B.V. All rights reserved.

Between manualized treatments and principle-guided psychotherapy: illustration in the case of Caroline

My case study of "Caroline"-a 26 year old presenting with depression, PTSD symptoms, and a history of sexual abuse as a teenager-represents a "third way" between (1) a strict adherence to a manualized treatment, and (2) a principle-guided therapy, in which the therapy follows particular theoretical concepts, but depends on the therapist's clinical judgement to flexibly apply them to the individual case. Specifically, in my therapy with Caroline (Kramer, 2009), I employed Foa and Rothbaum's (1998) cognitive-behavioral, "Prolonged Exposure" (PE) manual for PTSD, but deviated from it in certain ways based upon my evaluation of Caroline's individualized goals and reactions using Grawe and Caspar's "Plan Analysis," which is a cross-theoretical model for assessment and treatment planning. In their commentaries on my case study of Caroline, Caspar (2009) and Haldimann-Balli (see Appendix in Kramer, 2009) support my use of this third way. On the other hand, the other commentators-Muller (2009) and Hembree and Brinen (2009)-critique my handling of the case, arguing that strict adherence to the Foa and Rothbaum manual would have resulted in a more cost-effective therapy. In this article, I respond to the important issues raised by the four commentators.

Transcranial Doppler ultrasound in the acute phase of aneurysmal subarachnoid hemorrhage.

BACKGROUND: Angiographic studies suggest that acute vasospasm within 48 h of aneurysmal subarachnoid hemorrhage (SAH) predicts symptomatic vasospasm. However, the value of transcranial Doppler within 48 h of SAH is unknown. METHODS: We analyzed 199 patients who had at least 1 middle cerebral artery (MCA) transcranial Doppler examination within 48 h of SAH onset. Abnormal MCA mean blood flow velocity (mBFV) was defined as >90 cm/s. Delayed cerebral ischemia (DCI) was defined as clinical deterioration or radiological evidence of infarction due to vasospasm. RESULTS: Seventy-six patients (38%) had an elevation of MCA mBFV >90 cm/s within 48 h of SAH onset. The predictors of elevated mBFV included younger age (OR = 0.97 per year of age, p = 0.002), admission angiographic vasospasm (OR = 5.4, p = 0.009) and elevated white blood cell count (OR = 1.1 per 1,000 white blood cells, p = 0.003). Patients with elevated mBFV were more likely to experience a 10 cm/s fall in velocity at the first follow-up than those with normal baseline velocities (24 vs. 10%, p < 0.01), suggestive of resolving spasm. DCI developed in 19% of the patients. An elevated admission mBFV >90 cm/s during the first 48 h (adjusted OR = 2.7, p = 0.007) and a poor clinical grade (Hunt-Hess score 4 or 5, OR = 3.2, p = 0.002) were associated with a significant increase in the risk of DCI. CONCLUSION: Early elevations of mBFV correlate with acute angiographic vasospasm and are associated with a significantly increased risk of DCI. Transcranial Doppler ultrasound may be an early useful tool to identify patients at higher risk to develop DCI after SAH.

Bloc atrioventriculaire complet sur borréliose de Lyme: aspects etectrocardiographiques, diagnostiques et microbiologiques [Atrioventricular heart block in Lyme disease]

Lyme disease is the most common tick-borne disease in Europe and in the United States. In comparison to dermatological, neurological and rheumatological manifestations, heart disease is quite rare. Atrioventricular heart block is nevertheless the most frequent cardiological manifestation. We hereby report the case of a patient with high degree heart block due to Lyme disease. We focus on the electrocardiographical evolution during antibiotic therapy, as well as on microbiological and diagnostic aspects. Lyme disease is a rare cause of conduction disturbances but it is treatable and potentially reversible.

Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis.

BACKGROUND: For patients with acute iliofemoral deep vein thrombosis, it remains unclear whether the addition of intravascular high-frequency, low-power ultrasound energy facilitates the resolution of thrombosis during catheter-directed thrombolysis. METHODS AND RESULTS: In a controlled clinical trial, 48 patients (mean age 50 ± 21 years, 52% women) with acute iliofemoral deep vein thrombosis were randomized to receive ultrasound-assisted catheter-directed thrombolysis (N = 24) or conventional catheter-directed thrombolysis (N = 24). Thrombolysis regimen (20 mg r-tPA over 15 hours) was identical in all patients. The primary efficacy end point was the percentage of thrombus load reduction from baseline to 15 hours according to the length-adjusted thrombus score, obtained from standardized venograms and evaluated by a core laboratory blinded to group assignment. The percentage of thrombus load reduction was 55% ± 27% in the ultrasound-assisted catheter-directed thrombolysis group and 54% ± 27% in the conventional catheter-directed thrombolysis group (P = 0.91). Adjunctive angioplasty and stenting was performed in 19 (80%) patients and in 20 (83%) patients, respectively (P > 0.99). Treatment-related complications occurred in 3 (12%) and 2 (8%) patients, respectively (P > 0.99). At 3-month follow-up, primary venous patency was 100% in the ultrasound-assisted catheter-directed thrombolysis group and 96% in the conventional catheter-directed thrombolysis group (P = 0.33), and there was no difference in the severity of the post-thrombotic syndrome (mean Villalta score: 3.0 ± 3.9 [range 0-15] versus 1.9 ± 1.9 [range 0-7]; P=0.21), respectively. CONCLUSIONS: In this randomized controlled clinical trial of patients with acute iliofemoral deep vein thrombosis treated with a fixed-dose catheter thrombolysis regimen, the addition of intravascular ultrasound did not facilitate thrombus resolution. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01482273.

Changes in nuclear 3,5,3'-triiodothyronine receptor expression in rat dorsal root ganglia and sciatic nerve during development: comparison with regeneration.

The action of the thyroid hormones on responsive cells in the peripheral nervous system requires the presence of nuclear triiodothyronine receptors (NT3R). These nuclear receptors, including both the alpha and beta subtypes of NT3R, were visualized by immunocytochemistry with the specific 2B3 monoclonal antibody. In the dorsal root ganglia (DRG) of rat embryos, NT3R immunoreactivity was first discretely revealed in a few neurons at embryonic day 14 (E14), then strongly expressed by all neurons at E17 and during the first postnatal week; all DRG neurons continued to possess clear NT3R immunostaining, which faded slightly with age. The peripheral glial cells in the DRG displayed a short-lived NT3R immunoreaction, starting at E17 and disappearing from the satellite and Schwann cells by postnatal days 3 and 7 respectively. In the developing sciatic nerve, Schwann cells also exhibited transient NT3R immunoreactivity restricted to a short period ranging from E17 to postnatal day 10; the NT3R immunostaining of the Schwann cells vanished proximodistally along the sciatic nerve, so that the Schwann cells rapidly became free of detectable NT3R immunostaining. However, after the transection or crushing of an adult sciatic nerve, the NT3R immunoreactivity reappeared in the Schwann cells adjacent to the lesion by 2 days, then along the distal segment in which the axons were degenerating, and finally disappeared by 45 days, when the regenerating axons were allowed to re-occupy the distal segment.(ABSTRACT TRUNCATED AT 250 WORDS)

Outcomes of optic nerve sheath decompression for nonarteritic ischemic optic neuropathy.

Efficacy of optic nerve sheath decompression (ONSD) in treating non-arteritic ischemic optic neuropathy (NAION) is not clear. We retrospectively analyzed the records of 91 patients with NAION, who were examined during a two-year period, and compared the final Snellen visual acuities of eyes treated with ONSD with those of eyes that did not have surgery. Seven of 18 eyes with ONSD (39%) demonstrated increased visual acuity of two or more lines; whereas 23 of 71 eyes without surgery (32%) had increased acuity. The ONSD group and no surgery group were further subdivided into eyes with progressive visual loss and nonprogressive visual loss. No statistically significant differences in visual outcome between groups were found. We did not find the high frequency of visual improvement that has been reported in some studies of ONSD for NAION.

ACID-SENSING ION CHANNELS: functional and molecular characterization in putative nociceptors, and modulation by nerve injury and serine protease

Résumé Les canaux ioniques ASICs (acid-sensing ion channels) appartiennent à la famille des canaux ENaC/Degenerin. Pour l'instant, quatre gènes (1 à 4) ont été clonés dont certains présentent des variants d'épissage. Leur activation par une acidification rapide du milieu extracellulaire génère un courant entrant transitoire essentiellement sodique accompagné pour certains types d'ASICs d'une phase soutenue. Les ASICs sont exprimés dans le système nerveux, central (SNC) et périphérique (SNP). On leur attribue un rôle dans l'apprentissage, la mémoire et l'ischémie cérébrale au niveau central ainsi que dans la nociception (douleur aiguë et inflammatoire) et la méchanotransduction au niveau périphérique. Toutefois, les données sont parfois contradictoires. Certaines études suggèrent qu'ils sont des senseurs primordiaux impliqués dans la détection de l'acidification et la douleur. D'autres études suggèrent plutôt qu'ils ont un rôle modulateur inhibiteur dans la douleur. De plus, le fait que leur activation génère majoritairement un courant transitoire alors que les fibres nerveuses impliquées dans la douleur répondent à un stimulus nocif avec une adaptation lente suggère que leurs propriétés doivent être modulés par des molécules endogènes. Dans une première partie de ma thèse, nous avons abordé la question de l'expression fonctionnelle des ASICs dans les neurones sensoriels primaires afférents du rat adulte pour clarifier le rôle des ASICs dans les neurones sensoriels. Nous avons caractérisé leurs propriétés biophysiques et pharmacologiques par la technique du patch-clamp en configuration « whole-cell ». Nous avons pu démontrer que près de 60% des neurones sensoriels de petit diamètre expriment des courants ASICs. Nous avons mis en évidence trois types de courant ASIC dans ces neurones. Les types 1 et 3 ont des propriétés compatibles avec un rôle de senseur du pH alors que le type 2 est majoritairement activé par des pH inférieurs à pH6. Le type 1 est médié par des homomers de la sous-unité ASIC1 a qui sont perméables aux Ca2+. Nous avons étudié leur co-expression avec des marqueurs des nocicepteurs ainsi que la possibilité d'induire une activité neuronale suite à une acidification qui soit dépendante des ASICs. Le but était d'associer un type de courant ASIC avec une fonction potentielle dans les neurones sensoriels. Une majorité des neurones exprimant les courants ASIC co-expriment des marqueurs des nocicepteurs. Toutefois, une plus grande proportion des neurones exprimant le type 1 n'est pas associée à la nociception par rapport aux types 2 et 3. Nous avons montré qu'il est possible d'induire des potentiels d'actions suite à une acidification. La probabilité d'induction est proportionnelle à la densité des courants ASIC et à l'acidité de la stimulation. Puis, nous avons utilisé cette classification comme un outil pour appréhender les potentielles modulations fonctionnelles des ASICs dans un model de neuropathie (spared nerve injury). Cette approche fut complétée par des expériences de «quantitative RT-PCR ». En situation de neuropathie, les courants ASIC sont dramatiquement changés au niveau de leur expression fonctionnelle et transcriptionnelle dans les neurones lésés ainsi que non-lésés. Dans une deuxième partie de ma thèse, suite au test de différentes substances sécrétées lors de l'inflammation et l'ischémie sur les propriétés des ASICs, nous avons caractérisé en détail la modulation des propriétés des courants ASICs notamment ASIC1 par les sérines protéases dans des systèmes d'expression recombinants ainsi que dans des neurones d'hippocampe. Nous avons montré que l'exposition aux sérine-protéases décale la dépendance au pH de l'activation ainsi que la « steady-state inactivation »des ASICs -1a et -1b vers des valeurs plus acidiques. Ainsi, l'exposition aux serine protéases conduit à une diminution du courant quand l'acidification a lieu à partir d'un pH7.4 et conduit à une augmentation du courant quand l'acidification alleu à partir d'un pH7. Nous avons aussi montré que cette régulation a lieu des les neurones d'hippocampe. Nos résultats dans les neurones sensoriels suggèrent que certains courants ASICs sont impliqués dans la transduction de l'acidification et de la douleur ainsi que dans une des phases du processus conduisant à la neuropathie. Une partie des courants de type 1 perméables au Ca 2+ peuvent être impliqués dans la neurosécrétion. La modulation par les sérines protéases pourrait expliquer qu'en situation d'acidose les canaux ASICs soient toujours activables. Résumé grand publique Les neurones sont les principales cellules du système nerveux. Le système nerveux est formé par le système nerveux central - principalement le cerveau, le cervelet et la moelle épinière - et le système nerveux périphérique -principalement les nerfs et les neurones sensoriels. Grâce à leur nombreux "bras" (les neurites), les neurones sont connectés entre eux, formant un véritable réseau de communication qui s'étend dans tout le corps. L'information se propage sous forme d'un phénomène électrique, l'influx nerveux (ou potentiels d'actions). A la base des phénomènes électriques dans les neurones il y a ce que l'on appelle les canaux ioniques. Un canal ionique est une sorte de tunnel qui traverse l'enveloppe qui entoure les cellules (la membrane) et par lequel passent les ions. La plupart de ces canaux sont normalement fermés et nécessitent d'être activés pour s'ouvrire et générer un influx nerveux. Les canaux ASICs sont activés par l'acidification et sont exprimés dans tout le système nerveux. Cette acidification a lieu notamment lors d'une attaque cérébrale (ischémie cérébrale) ou lors de l'inflammation. Les expériences sur les animaux ont montré que les canaux ASICs avaient entre autre un rôle dans la mort des neurones lors d'une attaque cérébrale et dans la douleur inflammatoire. Lors de ma thèse je me suis intéressé au rôle des ASICs dans la douleur et à l'influence des substances produites pendant l'inflammation sur leur activation par l'acidification. J'ai ainsi pu montrer chez le rat que la majorité des neurones sensoriels impliqués dans la douleur ont des canaux ASICs et que l'activation de ces canaux induit des potentiels d'action. Nous avons opéré des rats pour qu'ils présentent les symptômes d'une maladie chronique appelée neuropathie. La neuropathie se caractérise par une plus grande sensibilité à la douleur. Les rats neuropathiques présentent des changements de leurs canaux ASICs suggérant que ces canaux ont une peut-être un rôle dans la genèse ou les symptômes de cette maladie. J'ai aussi montré in vitro qu'un type d'enryme produit lors de l'inflammation et l'ischémie change les propriétés des ASICs. Ces résultats confirment un rôle des ASICs dans la douleur suggérant notamment un rôle jusque là encore non étudié dans la douleur neuropathique. De plus, ces résultats mettent en évidence une régulation des ASICs qui pourrait être importante si elle se confirmait in vivo de part les différents rôles des ASICs. Abstract Acid-sensing ion channels (ASICs) are members of the ENaC/Degenerin superfamily of ion channels. Their activation by a rapid extracellular acidification generates a transient and for some ASIC types also a sustained current mainly mediated by Na+. ASICs are expressed in the central (CNS) and in the peripheral (PNS) nervous system. In the CNS, ASICs have a putative role in learning, memory and in neuronal death after cerebral ischemia. In the PNS, ASICs have a putative role in nociception (acute and inflammatory pain) and in mechanotransduction. However, studies on ASIC function are somewhat controversial. Some studies suggest a crucial role of ASICs in transduction of acidification and in pain whereas other studies suggest rather a modulatory inhibitory role of ASICs in pain. Moreover, the basic property of ASICs, that they are activated only transiently is irreconcilable with the well-known property of nociception that the firing of nociceptive fibers demonstrated very little adaptation. Endogenous molecules may exist that can modulate ASIC properties. In a first part of my thesis, we addressed the question of the functional expression of ASICs in adult rat dorsal root ganglion (DRG) neurons. Our goal was to elucidate ASIC roles in DRG neurons. We characterized biophysical and pharmacological properties of ASIC currents using the patch-clamp technique in the whole-cell configuration. We observed that around 60% of small-diameter sensory neurons express ASICs currents. We described in these neurons three ASIC current types. Types 1 and 3 have properties compatible with a role of pH-sensor whereas type 2 is mainly activated by pH lower than pH6. Type 1 is mediated by ASIC1a homomultimers which are permeable to Ca 2+. We studied ASIC co-expression with nociceptor markers. The goal was to associate an ASIC current type with a potential function in sensory neurons. Most neurons expressing ASIC currents co-expressed nociceptor markers. However, a higher proportion of the neurons expressing type 1 was not associated with nociception compared to type 2 and -3. We completed this approach with current-clamp measurements of acidification-induced action potentials (APs). We showed that activation of ASICs in small-diameter neurons can induce APs. The probability of AP induction is positively correlated with the ASIC current density and the acidity of stimulation. Then, we used this classification as a tool to characterize the potential functional modulation of ASICs in the spared nerve injury model of neuropathy. This approach was completed by quantitative RT-PCR experiments. ASICs current expression was dramatically changed at the functional and transcriptional level in injured and non-injured small-diameter DRG neurons. In a second part of my thesis, following an initial screening of the effect of various substances secreted during inflammation and ischemia on ASIC current properties, we characterized in detail the modulation of ASICs, in particular of ASIC1 by serine proteases in a recombinant expression system as well as in hippocampal neurons. We showed that protease exposure shifts the pH dependence of ASIC1 activation and steady-state inactivation to more acidic pH. As a consequence, protease exposure leads to a decrease in the current response if ASIC1 is activated by a pH drop from pH 7.4. If, however, acidification occurs from a basal pH of 7, protease-exposed ASIC1a shows higher activity than untreated ASIC1a. We provided evidence that this bi-directional regulation of ASIC1a function also occurs in hippocampal neurons. Our results in DRG neurons suggest that some ASIC currents are involved in the transduction of peripheral acidification and pain. Furthermore, ASICs may participate to the processes leading to neuropathy. Some Ca 2+-permeable type 1 currents may be involved in neurosecretion. ASIC modulation by serine proteases may be physiologically relevant, allowing ASIC activation under sustained slightly acidic conditions.

The clinical use of quantitative ultrasound (QUS) in the detection and management of osteoporosis

For the detection and management of osteoporosis and osteoporosis-related fractures, quantitative ultrasound (QUS) is emerging as a relatively low-cost and readily accessible alternative to dual-energy X-ray absorptiometry (DXA) measurement of bone mineral density (BMD) in certain circumstances. The following is a brief, but thorough review of the existing literature with respect to the use of QUS in 6 settings: 1) assessing fragility fracture risk; 2) diagnosing osteoporosis; 3) initiating osteoporosis treatment; 4) monitoring osteoporosis treatment; 5) osteoporosis case finding; and 6) quality assurance and control. Many QUS devices exist that are quite different with respect to the parameters they measure and the strength of empirical evidence supporting their use. In general, heel QUS appears to be most tested and most effective. Overall, some, but not all, heel QUS devices are effective assessing fracture risk in some, but not all, populations, the evidence being strongest for Caucasian females over 55 years old. Otherwise, the evidence is fair with respect to certain devices allowing for the accurate diagnosis of likelihood of osteoporosis, and generally fair to poor in terms of QUS use when initiating or monitoring osteoporosis treatment. A reasonable protocol is proposed herein for case-finding purposes, which relies on a combined assessment of clinical risk factors (CR.F) and heel QUS. Finally, several recommendations are made for quality assurance and control.