The Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD): The development and reliability testing of a novel clinical outcome measurement instrument for the severity of atopic dermatitis.

BACKGROUND: An Investigator Global Assessment (IGA) is recommended by health agencies for drug registration in atopic dermatitis (AD). Current IGA scales lack standardization. OBJECTIVES: To develop an IGA scale, training module, and clinical certification examination for use in AD trials; establish content validity; and assess reliability. METHODS: Expert dermatologists participated in the development of the validated IGA for AD (vIGA-ADTM). Reliability (interrater and intrarater) was assessed by 2 web-based surveys. Clinical certification for investigators consisted of a training module and examination. RESULTS: Expert consensus was achieved around a 5-point IGA scale including morphologic descriptions, and content validity was established. Survey 1 showed strong interrater reliability (Kendall's coefficient of concordance W [Kendall's W], 0.809; intraclass correlation [ICC], 0.817) and excellent agreement (weighted kappa, 0.857). Survey 2, completed 5 months after training of dermatologists, showed improvements in scale reliability (Kendall's W, 0.819; ICC, 0.852; weighted kappa, 0.889). In this study, 627 investigators completed vIGA-AD training and certification. LIMITATIONS: Ratings were assessed on photographs. CONCLUSION: A validated IGA scale and training module were developed with the intent of harmonizing assessment of disease severity in AD trials. Strong reliability and excellent agreement between assessments were observed.

Optimal Bone Flap Size for Decompressive Craniectomy for Refractory Increased Intracranial Pressure in Traumatic Brain Injury: Taking the Patient's Head Size into Account.

BACKGROUND: Decompressive craniectomy (DC) is a widely used treatment for refractory high intracranial pressure (ICP). While the Brain Trauma Foundation guidelines favor large DC, there remains a lack of consensus regarding the optimal size of DC in relationship to the patient's head size. The aim of this study is to determine the optimal size of DC to effectively control refractory ICP in traumatic brain injury and to measure that size with a method that takes into consideration the patient's head size. METHODS: All cases of unilateral DC performed to control refractory increased ICP due to cerebral edema during a 7½-year period were included. Demographic and injury-related data were collected by retrospective chart review. The patients were categorized in 2 groups: 21 patients with a "small flaps" and 9 patients with a "large flap." RESULTS: Two groups had similar preoperative characteristics. The amount of cerebrospinal fluid drained and the doses of hyperosmolar therapy given were not different between the 2 groups. The postoperative ICP was significantly lower for the large craniectomy flap group: 13.3 mm Hg confidence interval 99% [12.7, 13.8] versus 16.9 mm Hg confidence interval 99% [16.5, 17.2] (P = 0.01), and this difference was maintained for 96 hours postoperatively. CONCLUSIONS: Better ICP control was achieved in patients who underwent a large decompressive craniectomy (ratio >65%) when compared with smaller craniectomy sizes. The proposed method of measuring the craniectomy size, to our knowledge, is the first to take into account the patient's head size and can be easily measured intraoperatively.

Relationship between cervical muscle morphology evaluated by MRI, cervical muscle strength and functional outcomes in patients with degenerative cervical myelopathy.

BACKGROUND: Cervical muscle alterations have been reported in patients with chronic neck pain, but the assessment of muscle morphology and strength has been overlooked in patients with degenerative cervical myelopathy (DCM). OBJECTIVES: This study aimed to investigate the relationship between cervical muscle degenerative changes observed on MRI, muscle strength and symptoms severity in patients diagnosed with DCM. DESIGN: Observational study. METHODS: Cervical muscle measurements of total cross-sectional area (CSA), functional CSA (fat free area, FCSA) and ratio of FCSA/CSA (e.g. fatty infiltration) were obtained from T2-weighted axial MR images from C2-C3 to C6-C7 in 20 patients. Muscle strength was assessed manually using a microFET2 dynamometer. The association between cervical muscle morphology parameters, muscle strength, symptoms severity and functional status was investigated. RESULTS: Greater mean CSA and FCSA was associated with greater overall muscle strength. The mean FCSA explained 37%, 76%, 39%, 20% and 65% of the total variance in flexion, extension, right-side bending, left-side bending and overall muscle strength, respectively. The mean ratio of FCSA/CSA was not significantly associated with cervical muscle strength in any direction. However, greater FCSA/CSA ratio (e.g. less fatty infiltration) was associated with lower disability score (p = 0.02, R2 = 0.20). CONCLUSIONS: Cervical muscle lean muscle mass was positively associated with cervical muscle strength in patients with DCM. Moreover, greater fatty infiltration in the cervical extensor muscles was associated with lower functional score. Such findings suggest that clinicians should pay greater attention to cervical muscle morphology and function in patients with DCM.

Lack of significant anti-inflammatory activity with clindamycin in the treatment of rosacea: results of 2 randomized, vehicle-controlled trials.

Rosacea is a chronic inflammatory skin disease of the face. The objective of the studies described here was to evaluate the efficacy of clindamycin in the treatment of rosacea. Two multicenter, randomized, vehicle-controlled, phase 2 studies were conducted in participants with moderate to severe rosacea. Study A was a 12-week dose-comparison, 5-arm, parallel group comparison of clindamycin cream 1% or vehicle once or twice daily and clindamycin cream 0.3% once daily. Study B was a 2-arm comparison of twice daily clindamycin gel 1% versus vehicle gel. A total of 629 participants (study A, N=416; study B, N=213) were randomized. The results of these studies indicated that clindamycin cream 0.3% and 1% and clindamycin gel 1% were no more effective than the vehicle in the treatment of moderate to severe rosacea, suggesting clindamycin has no intrinsic anti-inflammatory activity in rosacea.

IL-17/Th17 pathway is activated in acne lesions.

The mechanisms of inflammation in acne are currently subject of intense investigation. This study focused on the activation of adaptive and innate immunity in clinically early visible inflamed acne lesions and was performed in two independent patient populations. Biopsies were collected from lesional and non-lesional skin of acne patients. Using Affymetrix Genechips, we observed significant elevation of the signature cytokines of the Th17 lineage in acne lesions compared to non-lesional skin. The increased expression of IL-17 was confirmed at the RNA and also protein level with real-time PCR (RT-PCR) and Luminex technology. Cytokines involved in Th17 lineage differentiation (IL-1ß, IL-6, TGF-ß, IL23p19) were remarkably induced at the RNA level. In addition, proinflammatory cytokines and chemokines (TNF-α, IL-8, CSF2 and CCL20), Th1 markers (IL12p40, CXCR3, T-bet, IFN-γ), T regulatory cell markers (Foxp3, IL-10, TGF-ß) and IL-17 related antimicrobial peptides (S100A7, S100A9, lipocalin, hBD2, hBD3, hCAP18) were induced. Importantly, immunohistochemistry revealed significantly increased numbers of IL-17A positive T cells and CD83 dendritic cells in the acne lesions. In summary our results demonstrate the presence of IL-17A positive T cells and the activation of Th17-related cytokines in acne lesions, indicating that the Th17 pathway is activated and may play a pivotal role in the disease process, possibly offering new targets of therapy.

Diagnosis and treatment monitoring of toenail onychomycosis by reflectance confocal microscopy: prospective cohort study in 58 patients.

BACKGROUND: The clinical presentation of onychomycosis is often nonspecific and can lead to inappropriate antifungal therapy. Available mycologic tests share many drawbacks. OBJECTIVE: We sought to evaluate the accuracy of reflectance confocal microscopy (RCM) for the diagnosis of onychomycosis compared with standard mycologic tests. METHODS: In all, 58 patients with suspected onychomycosis were enrolled prospectively. RCM, potassium hydroxide preparation, and fungal culture were performed at baseline and after treatment in patients with confirmed onychomycosis. RCM diagnosis of onychomycosis was based on the presence of filamentous and/or roundish structures in the nail plate, corresponding respectively to septate hyphae and/or arthroconidia. RESULTS: Of patients, 46 of 58 were correctly classified by RCM, with a diagnosis yield of 79.3%, sensitivity of 52.9%, specificity of 90.2%, positive predictive value of 69.2%, and negative predictive value of 82.2%. The use of a handheld RCM imager permitted a faster examination with the same accuracy. RCM performed after treatment in 9 patients showed a normal nail plate, and healing was confirmed by mycologic tests or by follow-up. LIMITATIONS: Existing RCM scanner heads are not intended for nail examination. CONCLUSION: RCM has excellent specificity and can be used as a rapid, office-based test to strengthen the prescription of antifungal therapy and for follow-up. Technical improvement could aid sensitivity.

Role of Kv1 potassium channels in regulating dopamine release and presynaptic D2 receptor function.

Dopamine (DA) release in the CNS is critical for motor control and motivated behaviors. Dysfunction of its regulation is thought to be implicated in drug abuse and in diseases such as schizophrenia and Parkinson's. Although various potassium channels located in the somatodendritic compartment of DA neurons such as G-protein-gated inward rectifying potassium channels (GIRK) have been shown to regulate cell firing and DA release, little is presently known about the role of potassium channels localized in the axon terminals of these neurons. Here we used fast-scan cyclic voltammetry to study electrically-evoked DA release in rat dorsal striatal brain slices. We find that although G-protein-gated inward rectifying (GIRK) and ATP-gated (K(ATP)) potassium channels play only a minor role, voltage-gated potassium channels of the Kv1 family play a major role in regulating DA release. The use of Kv subtype-selective blockers confirmed a role for Kv1.2, 1.3 and 1.6, but not Kv1.1, 3.1, 3.2, 3.4 and 4.2. Interestingly, Kv1 blockers also reduced the ability of quinpirole, a D2 receptor agonist, to inhibit evoked DA overflow, thus suggesting that Kv1 channels also regulate presynaptic D2 receptor function. Our work identifies Kv1 potassium channels as key regulators of DA release in the striatum.

Presynaptic action of neurotensin on dopamine release through inhibition of D(2) receptor function.

BACKGROUND: Neurotensin (NT) is known to act on dopamine (DA) neurons at the somatodendritic level to regulate cell firing and secondarily enhance DA release. In addition, anatomical and indirect physiological data suggest the presence of NT receptors at the terminal level. However, a clear demonstration of the mechanism of action of NT on dopaminergic axon terminals is lacking. We hypothesize that NT acts to increase DA release by inhibiting the function of terminal D2 autoreceptors. To test this hypothesis, we used fast-scan cyclic voltammetry (FCV) to monitor in real time the axonal release of DA in the nucleus accumbens (NAcc). RESULTS: DA release was evoked by single electrical pulses and pulse trains (10 Hz, 30 pulses). Under these two stimulation conditions, we evaluated the characteristics of DA D2 autoreceptors and the presynaptic action of NT in the NAcc shell and shell/core border region. The selective agonist of D2 autoreceptors, quinpirole (1 microM), inhibited DA overflow evoked by both single and train pulses. In sharp contrast, the selective D2 receptor antagonist, sulpiride (5 microM), strongly enhanced DA release triggered by pulse trains, without any effect on DA release elicited by single pulses, thus confirming previous observations. We then determined the effect of NT (8-13) (100 nM) and found that although it failed to increase DA release evoked by single pulses, it strongly enhanced DA release evoked by pulse trains that lead to prolonged DA release and engage D2 autoreceptors. In addition, initial blockade of D2 autoreceptors by sulpiride considerably inhibited further facilitation of DA release generated by NT (8-13). CONCLUSION: Taken together, these data suggest that NT enhances DA release principally by inhibiting the function of terminal D2 autoreceptors and not by more direct mechanisms such as facilitation of terminal calcium influx.

Guidelines for doctors attending detainees in police custody: a consensus conference in France.

Medical practice in police custody needs to be harmonized. A consensus conference was held on 2-3 December 2004 in Paris, France. The health, integrity, and dignity of detainees must be safeguarded. The examination should take place in the police station so that the doctor can assess the conditions in which the detainee is being held. If the minimum conditions needed for a medical examination are not available, the doctor may refuse to express an opinion as to whether the detainee is fit to be held in custody or may ask for the detainee to be examined in a hospital. Doctors are subject to a duty of care and prevention. They should prescribe any ongoing treatment that needs to be continued, as well as any emergency treatment required. Custody officers may monitor the detainee and administer medication. However, their role should not be expected to exceed that required of the detainee's family under normal circumstances and must be specified in writing on the medical certificate. Doctor's opinion should be given in a national standard document. If the doctors consider that the custody conditions are disgraceful, they may refuse to express an opinion as to whether the detainee is fit for custody.

Consensus panel recommendations for chronic and acute wound dressings.

OBJECTIVE: To seek a consensus on recommendations that would help health professionals choose appropriate wound dressings in daily practice, since a systematic review found only limited evidence to support reported indications for modern wound dressings. PARTICIPANTS: A steering committee selected a panel of 27 experts with no declared conflicts of interest from lists of nursing staff and physicians (specialists or general practitioners) with long-standing experience of wound care. The lists were put forward by 15 French learned societies. EVIDENCE: The panelists received a recent systematic review of the literature, a classification of indications established by a working group, and definitions for the dressings. CONSENSUS PROCESS: The steering committee designed questionnaires on chronic wounds and on acute wounds including burns for each of the 2 panels. The consensus method was derived from the nominal group technique adapted by RAND/UCLA. Panelists rated the relevance of each possible dressing-indication combination on the basis of the published evidence and their own experience. After the first round of rating, they met to discuss results and propose recommendations before taking part in a second round of rating. The working group peer reviewed the final recommendations. CONCLUSIONS: A strong consensus was reached for use of the following combinations: for chronic wounds, (1) debridement stage, hydrogels; (2) granulation stage, foam and low-adherence dressings; and (3) epithelialization stage, hydrocolloid and low-adherence dressings; and for the epithelialization stage of acute wounds, low-adherence dressings. For specific situations, the following dressings were favored: for fragile skin, low-adherence dressings; for hemorrhagic wounds, alginates; and for malodorous wounds, activated charcoal.

Dressings for acute and chronic wounds: a systematic review.

OBJECTIVE: To critically review the literature on the efficacy of modern dressings in healing chronic and acute wounds by secondary intention. DATA SOURCES: Search of 3 databases (MEDLINE, EMBASE, and the Cochrane Controlled Clinical Trials Register) from January 1990 to June 2006, completed by manual research, for articles in English and in French. STUDY SELECTION: The end points for selecting studies were the rate of complete healing, time to complete healing, rate of change in wound area, and general performance criteria (eg, pain, ease of use, avoidance of wound trauma on dressing removal, ability to absorb and contain exudates). Studies were selected by a single reviewer. Overall, 99 studies met the selection criteria (89 randomized controlled trials [RCTs], 3 meta-analyses [1 of which came from 1 of the selected systematic reviews], 7 systematic reviews, and 1 cost-effectiveness study). DATA EXTRACTION: The RCTs, meta-analyses, and cost-effectiveness studies were critically appraised by 2 reviewers to assess the clinical evidence level according to a modification of Sackett's 1989 criteria. Ninety-three articles were finally graded. DATA SYNTHESIS: We found no level A studies, 14 level B studies (11 RCTs and 3 meta-analyses), and 79 level C studies. Hydrocolloid dressings proved superior to saline gauze or paraffin gauze dressings for the complete healing of chronic wounds, and alginates were better than other modern dressings for debriding necrotic wounds. Hydrofiber and foam dressings, when compared with other traditional dressings or a silver-coated dressing, respectively, reduced time to healing of acute wounds. CONCLUSIONS: Our systematic review provided only weak levels of evidence on the clinical efficacy of modern dressings compared with saline or paraffin gauze in terms of healing, with the exception of hydrocolloids. There was no evidence that any of the modern dressings was better than another, or better than saline or paraffin gauze, in terms of general performance criteria. More wound care research providing level A evidence is needed.

[Transient ischemic stroke]. / Accident ischémique transitoire: une urgence médicale.

According to the new definition proposed by the TIA working group, transient ischemic stroke (TIA) is "a brief episode of neurologic dysfunction caused by focal brain or retinal ischemia, with clinical symptoms typically lasting less than one hour, and without evidence of acute infarction." Patient presenting with a TIA should be investigated and treated urgently because the risk of ischemic stroke is about 10% at one month with 50% of these events occurring during the first 48 hours. Atherosclerosis, cardioembolism and small vessel disease account for the majority of TA. Aspirin should be started as soon as possible after brain imaging has been performed. Other treatment such as oral anticoagulants or carotide surgery may be necessary, depending on the result of the electronical work up.

Clinical practice guidelines: medical follow-up of patients with asthma--adults and adolescents.

The follow-up of patients with asthma should focus on asthma control (disease course over a number of weeks).

M3-like muscarinic receptors mediate Ca2+ influx in rat mesencephalic GABAergic neurones through a protein kinase C-dependent mechanism.

GABAergic neurones in the mesencephalon are important regulators of dopamine neurones. Cholinergic projections from mesopontine nuclei preferentially synapse onto these GABAergic neurones, thus suggesting that ACh can regulate dopamine neurones indirectly by modulating GABAergic interneurones. Muscarinic receptors mediate excitation of these interneurones through a Ca(2+)-dependent mechanism. Using a mesencephalic primary culture model, we show here that muscarine (10 microM) increases intracellular Ca2+ concentrations ([Ca2+]i) in GABAergic interneurones. Compatible with previous anatomical data, our pharmacological studies further suggest that the M3 receptor is the primary mediator of this increase. The rise in [Ca2+]i induced by muscarine was not activity-dependent but required influx of Ca2+ from the extracellular medium. Consistent with the known coupling of the M3 receptor to PKC, the effect of muscarine was blocked by bisindolylmaleimide, a selective PKC antagonist. The effect of muscarine was inhibited by SKF 96365 and verapamil, drugs known to block non-selective cationic channels such as those formed by transient receptor potential (TRPC) proteins. Finally, GABAergic neurones were found to be immunopositive for TRPC1, 3, 5 and 6. Taken together, these results suggest that the Ca(2+)-dependent regulation of mesencephalic GABAergic neurones by muscarinic receptors requires activation of some receptor-operated Ca2+ channels through a PKC-dependent mechanism.

Long-term tolerability of benazepril in dogs with congestive heart failure.

OBJECTIVES: To test the tolerability of long-term administration of benazepril in dogs with congestive heart failure (CHF). METHODS: The study was a prospective, randomized, double-blinded, placebo-controlled clinical trial. A total of 162 dogs with New York Heart Association (NYHA) class II-IV heart failure caused by chronic valvular disease (CVD) or dilated cardiomyopathy (DCM) were enrolled. Benazepril (minimum dosage, 0.25 mg/kg) or placebo were administered orally once daily for up to 34 months. In this paper, we report results of plasma alanine aminotransferase (ALT), creatinine, potassium and urea. RESULTS: The two groups were matched at baseline (p>/=0.18). Plasma creatinine concentrations were lower during treatment with benazepril versus placebo for all dogs (p=0.14) and every sub-group tested (NYHA II, III or IV; CVD; DCM; initial creatinine >124 mumol/L), although statistical significance was not reached (p=0.14-0.6). However, significantly (p=0.035) more cases of creatinine >124 mumol/L during treatment occurred with placebo (47%) as compared to benazepril (30%). Plasma ALT and urea values did not differ between groups for all dogs (p>0.5) or any sub-group (p=0.23-1.0). Plasma potassium values did not differ between groups for all dogs (p>0.5). Although differences approached statistical significance for potassium in some sub-groups (p=0.07-0.1), there were no consistent differences between groups. CONCLUSIONS: Benazepril was well tolerated during long-term therapy in dogs with CHF and no specific precautions appear to be necessary regarding plasma ALT, creatinine, potassium or urea. The possible action of benazepril in improving renal function (evidenced via lower plasma creatinine) merits further investigation.

Paraneoplastic pemphigus is associated with the DRB1*03 allele.

Pemphigus is a group of autoimmune blistering diseases caused by autoantibodies directed against keratinocyte adhesion molecules. Pemphigus vulgaris (PV) and pemphigus foliaceus (PF), in which autoantibodies bind, respectively, to desmoglein 3 and desmoglein 1, are strongly associated with HLA-class II DR4 and DR14 alleles. In paraneoplastic pemphigus (PNP), a rare variant associated with neoplasia, autoantibodies target proteins of the plakin family in addition to desmogleins 1 and 3. The presence of anti-desmoglein antibodies in all types of pemphigus raises the question of common molecular mechanisms of susceptibility, particularly similar MHC-class II allele associations, in the different forms of the disease. HLA-DRB1 typing was performed in 13 PNP patients and results were compared to those obtained from 84 healthy controls, 37 PV and 31 PF patients. Our data demonstrate a significant association of PNP with HLA-DRB1*03 allele which was found in 61.5% of the patients, whereas DRB1*04 and DRB1*14 appear not to be involved in PNP susceptibility. Therefore, the HLA-genetic background of PNP differs from that of other types of pemphigus, which suggests that distinct mechanism(s) initiate(s) the immunological response in this form of pemphigus.