Secondary choriocapillaritis in infectious chorioretinitis.

PURPOSE: To analyse the indocyanine green angiography (ICGA) patterns of hypofluorescence that are compatible with choriocapillaritis that occur secondarily to toxoplasmic retinochoroiditis (ToRC), ocular tuberculosis (including tuberculous choroiditis, TuCR and multifocal serpiginoid choroiditis, TMSC) and syphilitic chorioretinitis (SyCR). METHODS: This was a single centre, retrospective case review study. Patients with a diagnosis of ToRC, TuCR, TMSC or SyCR were identified, their charts were reviewed and fundus photographs, fluorescein angiography (FA) and ICGA pictures were assessed. RESULTS: Indocyanine green angiography was performed at the initial presentation in 63 of the 105 patients with ToRC, in 37 of the 38 patients with TuCR, in six of six patients with TMSC and in two of four patients with SyCR. The following four ICGA patterns indicated choriocapillaritis: extension of hypofluorescence beyond the hypofluorescence of the actual infectious focus as seen on fundus photography or FA (seen only in ToRC and TuCR); small dark dots around the infectious focus (seen only in ToRC); multiple 'confetti-like' hypofluorescent areas or hypofluorescent geographical confluent areas (seen only in TMSC); and widespread areas of nonperfusion visible only in ICGA (seen only in SyCR). CONCLUSIONS: Patients with secondary choriocapillaritis have distinct typical ICGA findings. ICGA is thus an important diagnostic tool that can provide an explanation for otherwise obscure visual loss and that might have diagnostic value for specific conditions like ToRC and SyCR.

High-throughput hydrophilic interaction chromatography coupled to tandem mass spectrometry for the optimized quantification of the anti-Gram-negatives antibiotic colistin A/B and its pro-drug colistimethate.

Colistin is a last resort's antibacterial treatment in critically ill patients with multi-drug resistant Gram-negative infections. As appropriate colistin exposure is the key for maximizing efficacy while minimizing toxicity, individualized dosing optimization guided by therapeutic drug monitoring is a top clinical priority. Objective of the present work was to develop a rapid and robust HPLC-MS/MS assay for quantification of colistin plasma concentrations. This novel methodology validated according to international standards simultaneously quantifies the microbiologically active compounds colistin A and B, plus the pro-drug colistin methanesulfonate (colistimethate, CMS). 96-well micro-Elution SPE on Oasis Hydrophilic-Lipophilic-Balanced (HLB) followed by direct analysis by Hydrophilic Interaction Liquid Chromatography (HILIC) with Ethylene Bridged Hybrid - BEH - Amide phase column coupled to tandem mass spectrometry allows a high-throughput with no significant matrix effect. The technique is highly sensitive (limit of quantification 0.014 and 0.006μg/mL for colistin A and B), precise (intra-/inter-assay CV 0.6-8.4%) and accurate (intra-/inter-assay deviation from nominal concentrations -4.4 to +6.3%) over the clinically relevant analytical range 0.05-20μg/mL. Colistin A and B in plasma and whole blood samples are reliably quantified over 48h at room temperature and at +4°C (<6% deviation from nominal values) and after three freeze-thaw cycles. Colistimethate acidic hydrolysis (1M H2SO4) to colistin A and B in plasma was completed in vitro after 15min of sonication while the pro-drug hydrolyzed spontaneously in plasma ex vivo after 4h at room temperature: this information is of utmost importance for interpretation of analytical results. Quantification is precise and accurate when using serum, citrated or EDTA plasma as biological matrix, while use of heparin plasma is not appropriate. This new analytical technique providing optimized quantification in real-life conditions of the microbiologically active compounds colistin A and B offers a highly efficient tool for routine therapeutic drug monitoring aimed at individualizing drug dosing against life-threatening infections.

Testosterone Restoration by Enclomiphene Citrate in Men with Secondary Hypogonadism: a pharmacodynamic and Pharmacokinetic study.

OBJECTIVES: To determine the pharmacodynamic (PD) profile of serum total testosterone levels (TT) and luteinizing hormone (LH) in men with secondary hypogonadism following initial and chronic daily oral doses of enclomiphene citrate in comparison to transdermal testosterone. To determine the effects of daily oral doses of enclomiphene citrate (Androxal®) in comparison to transdermal testosterone on other hormones and markers in men with secondary hypogonadism. PATIENTS AND METHODS: This was a randomized, single blind, two-center phase II study to evaluate three different doses of enclomiphene citrate (6.25mg, 12.5mg and 25 mg Androxal®), versus AndroGel®, a transdermal testosterone, on 24-hour LH and TT in otherwise normal healthy men with secondary hypogonadism. Forty-eight men were enrolled in the trial (ITT Population), but 4 men had T levels >350 ng/dL at baseline. Forty-four men completed the study per protocol (PP population). All subjects enrolled in this trial had serum TT in the low range (<350 ng/dL) and had low to normal LH (<12 IU/L) on at least two occasions. TT and LH levels were assessed each hour for 24 hours to examine the effects at each of three treatment doses of enclomiphene versus a standard dose (5 grams) of transdermal testosterone (AndroGel). In the initial profile TT and LH were determined in a naïve population following a single initial oral or transdermal treatment (Day 1). This was contrasted to that seen after six weeks of continuous daily oral or transdermal treatment (Day 42). The pharmacokinetics of enclomiphene was performed in a select subpopulation. Serum samples were obtained over the course of the study to determine levels of various hormones and lipids. RESULTS: After six weeks of continuous use, the mean ± SD concentration of TT at Day 42 C0hrTT, was 604 ± 160 ng/dL for men taking the highest of dose of enclomiphene citrate (enclomiphene, 25 mg daily) and 500 ± 278 ng in those men treated with transdermal testosterone. These values were higher than Day 1 values but not different from each other (p = 0.23, T-test). All three doses of enclomiphene increased C0hrTT, CavgTT, CmaxTT, CminTT and CrangeTT. Transdermal testosterone also raised TT, albeit with more variability, and with suppressed LH levels. The patterns of TT over 24 hour period following six weeks of dosing could be fit to a non-linear function with morning elevations, mid-day troughs, and rising night-time levels. Enclomiphene and transdermal testosterone increased levels of TT within two weeks, but they had opposite effects on FSH and LH Treatment with enclomiphene did not significantly affect levels of TSH, ACTH, cortisol, lipids, or bone markers. Both transdermal testosterone and enclomiphene citrate decreased IGF-1 levels (p<0.05) but suppression was greater in the enclomiphene citrate groups. CONCLUSIONS: Enclomiphene citrate increased serum LH and TT; however, there was not a temporal association between the peak drug levels and the Cmax levels LH or TT. Enclomiphene citrate consistently increased serum TT into the normal range and increased LH and FSH above the normal range. The effects on LH and TT persisted for at least one week after stopping treatment.

Trypanosoma cruzi: effect of phenothiazines on the parasite and its interaction with host cells

Phenothiazines were observed to have a direct effect on Trypanosoma cruzi and on its in vitro interaction with host cells. They caused lysis of trypomastigotes (50 uM/24 h) and,to a lesser extent, epimastigote proliferation. Treatment of infected peritoneal macrophages with 12.5 uM chlorpromazine or triflupromazine inhibited the infection; this effect was found to be partially reversible if the drugs were removed after 24 h of treatment. At 60 uM, the drugs caused damage to amastigotes interiorized in heart muscle cells. However, the narrow margin of toxity between anti-trypanossomal activity and damage to host cells mitigates against in vivo investigation at the present time. Possible hypothesis for the mechanism of action of phenothiazines are discussed.

Protein interaction data curation: the International Molecular Exchange (IMEx) consortium.

The International Molecular Exchange (IMEx) consortium is an international collaboration between major public interaction data providers to share literature-curation efforts and make a nonredundant set of protein interactions available in a single search interface on a common website (http://www.imexconsortium.org/). Common curation rules have been developed, and a central registry is used to manage the selection of articles to enter into the dataset. We discuss the advantages of such a service to the user, our quality-control measures and our data-distribution practices.

Mutagenesis and modelling of the alpha(1b)-adrenergic receptor highlight the role of the helix 3/helix 6 interface in receptor activation.

Computer simulations on a new model of the alpha1b-adrenergic receptor based on the crystal structure of rhodopsin have been combined with experimental mutagenesis to investigate the role of residues in the cytosolic half of helix 6 in receptor activation. Our results support the hypothesis that a salt bridge between the highly conserved arginine (R143(3.50)) of the E/DRY motif of helix 3 and a conserved glutamate (E289(6.30)) on helix 6 constrains the alpha1b-AR in the inactive state. In fact, mutations of E289(6.30) that weakened the R143(3.50)-E289(6.30) interaction constitutively activated the receptor. The functional effect of mutating other amino acids on helix 6 (F286(6.27), A292(6.33), L296(6.37), V299(6.40,) V300(6.41), and F303(6.44)) correlates with the extent of their interaction with helix 3 and in particular with R143(3.50) of the E/DRY sequence.

Early mother-child interaction and later quality of attachment in infants with an orofacial cleft compared to infants without cleft.

Objective : The main objective of this study was to assess mother-child patterns of interaction in relation to later quality of attachment in a group of children with an orofacial cleft compared with children without cleft. Design : Families were contacted when the child was 2 months old for a direct assessment of mother-child interaction and then at 12 months for a direct assessment of the child's attachment. Data concerning socioeconomical information and posttraumatic stress symptoms in mothers were collected at the first appointment. Participants : Forty families of children with a cleft and 45 families of children without cleft were included in the study. Families were recruited at birth in the University Hospital of Lausanne. Results : Results showed that children with a cleft were more difficult and less cooperative during interaction at 2 months of age with their mother compared with children without a cleft. No significant differences were found in mothers or in dyadic interactive styles. Concerning the child's attachment at 12 months old, no differences were found in attachment security. However, secure children with a cleft were significantly more avoidant with their mother during the reunion episodes than secure children without cleft. Conclusion : Despite the facial disfigurement and the stress engendered by treatment during the first months of the infant's life, children with cleft and their mothers are doing as well as families without cleft with regard to the mothers' mental health, mother-child relationships, and later quality of attachment. A potential contribution for this absence of difference may be the pluridisciplinary support that families of children with cleft benefit from in Lausanne.

Approche des oedèmes du membre supérieur liés à une occlusion de la veine sous-clavière située en aval d'une fistule artério-veineuse [Approach to upper limb edema secondary to subclavian vein occlusion situated distal to an arteriovenous fistula]

AIM OF THE STUDY: To analyse the course of upper limb edema in patients with an arteriovenous fistula used for dialysis and to analyse the available therapeutic options. STUDY DESIGN: Retrospective study of patients with this type of edema, who were treated in our institution from 1992 to 1996. PATIENTS AND METHODS: Seven consecutive patients with an arterioveinous fistula treated for edema of the upper extremity, were reviewed. The fistula was created at the elbow in 6 patients and at the forearm in 1. The edema appeared immediately after operation in 4 patients and after a delay in 3 patients. Stenosis (3 patients) or occlusion (2 patients) of the subclavian vein was documented in 5 patients who were investigated by angiography. RESULTS: The edema regressed spontaneously in 4 patients because collaterals developed in 3 patients, and the fistula thrombosed in 1 patient. Surgical intervention allowed regression of the edema in the other 3 patients: excessive output of the fistula was reduced in 2 patients and an axillojugular bypass was performed in 1 patient. The fistula remained effective in 6 patients. Another fistula was performed on the contralateral arm in 1 patient. CONCLUSION: Non-operative management is recommended in patients who develop edema immediately after creation of the fistula, because spontaneous regression is likely. Measures aimed at reducing the output of the fistula or enhancing the venous capacities of the arm are required when edema appears at a later stage. The fistula can be saved in the majority of cases.

Stable stationary states of non-local interaction equations

"Vegeu el resum a l'inici del document del fitxer adjunt."

Interaction between calcium intake and menarcheal age on bone mass gain: an eight-year follow-up study from prepuberty to postmenarche.

Both late menarcheal age and low calcium intake (Ca intake) during growth are risk factors for osteoporosis, probably by impairing peak bone mass. We investigated whether lasting gain in areal bone mineral density (aBMD) in response to increased Ca intake varies according to menarcheal age and, conversely, whether Ca intake could influence menarcheal age. In an initial study, 144 prepubertal girls were randomized in a double-blind controlled trial to receive either a Ca supplement (Ca-suppl.) of 850 mg/d or placebo from age 7.9-8.9 yr. Mean aBMD gain determined by dual energy x-ray absorptiometry at six sites (radius metaphysis, radius diaphysis, femoral neck, trochanter, femoral diaphysis, and L2-L4) was significantly (P = 0.004) greater in the Ca-suppl. than in the placebo group (27 vs. 21 mg/cm(2)). In 122 girls followed up, menarcheal age was recorded, and aBMD was determined at 16.4 yr of age. Menarcheal age was lower in the Ca-suppl. than in the placebo group (P = 0.048). Menarcheal age and Ca intake were negatively correlated (r = -0.35; P < 0.001), as were aBMD gains from age 7.9-16.4 yr and menarcheal age at all skeletal sites (range: r = -0.41 to r = -0.22; P < 0.001 to P = 0.016). The positive effect of Ca-suppl. on the mean aBMD gain from baseline remained significantly greater in girls below, but not in those above, the median of menarcheal age (13.0 yr). Early menarcheal age (12.1 +/- 0.5 yr): placebo, 286 +/- 36 mg/cm(2); Ca-suppl., 317 +/- 46 (P = 0.009); late menarcheal age (13.9 +/- 0.5 yr): placebo, 284 +/- 58; Ca-suppl., 276 +/- 50 (P > 0.05). The level of Ca intake during prepuberty may influence the timing of menarche, which, in turn, could influence long-term bone mass gain in response to Ca supplementation. Thus, both determinants of early menarcheal age and high Ca intake may positively interact on bone mineral mass accrual.

Effects of azadirachtin on Rhodnius prolixus: immunity and trypanosoma interaction

The effects of azadirachtin, a tetranortriterpenoid from the neem tree Aradirachta indica J. on both immunity and Trypanosoma cruzi interaction within Rhodniusprolixus and other triatomines, were presented Given through a blood meal, azadirachtin affected the immune reactivity as shown by a significant reduction in numbers of hemocytes and consequently nodule formation follwing challenge with Enterobacter cloacae ß12, reduction in ability to produce antibacterial activities in the hemolymph when injected with bacteria, and decreased ability to destroy the infection caused by inoculation of E. cloacae cells. A single dose of azadirachtin was able to block the development of T. cruzi in R. prolixus if given through the meal at different intervals, together with, before or after parasite infection. Similary, these results were observed with different triatomine species and different strains of T. cruzi. Azadirachtin induced a permanent resistance of the vector against reinfection with T. cruzi. The significance of these data is discussed in relation to the general mode of azadirachtin action in insects.