Adolescent Nonsuicidal Self-Injury and Suicidality: A Latent Class Analysis and Associations with Clinical Characteristics in an At-Risk Cohort.

Nonsuicidal self-injury (NSSI) is frequently encountered in adolescents, but its predictive value for suicidality or other clinical characteristics is challenging due to its heterogeneous nature. This study used latent class analysis to identify subgroups of NSSI and compared these on sociodemographic characteristics, adverse outcomes and protective factors. The study included 966 high-risk adolescents, Mage 14.9 y, SD 0.9 y, 51.8% female. Four classes emerged: (1) "Low NSSI-Low suicidality", (2) "Moderate NSSI-Low suicidality", (3) "Moderate NSSI-High suicidality", and (4) "High NSSI-High suicidality". Girls predominated in the high suicidality classes. Generally, Class 4 had the poorest outcomes: more internalizing and externalizing problems, less social support from friends and families and worst self-esteem. These findings emphasize the need for interventions tailored to specific phenotypes of adolescents engaging in NSSI.

Measurement of the tilt of a moving domain wall shows precession-free dynamics in compensated ferrimagnets.

One fundamental obstacle to efficient ferromagnetic spintronics is magnetic precession, which intrinsically limits the dynamics of magnetic textures. We experimentally demonstrate that this precession vanishes when the net angular momentum is compensated in domain walls driven by spin-orbit torque in a ferrimagnetic GdFeCo/Pt track. We use transverse in-plane fields to provide a robust and parameter-free measurement of the domain wall internal magnetisation angle, demonstrating that, at the angular compensation, the DW tilt is zero, and thus the magnetic precession that caused it is suppressed. Our results highlight the mechanism of faster and more efficient dynamics in materials with multiple spin lattices and vanishing net angular momentum, promising for high-speed, low-power spintronic applications.

Novel Strongly Spin-Orbit Coupled Quantum Dimer Magnet: Yb_{2}Si_{2}O_{7}.

The quantum dimer magnet (QDM) is the canonical example of quantum magnetism. The QDM state consists of entangled nearest-neighbor spin dimers and often exhibits a field-induced triplon Bose-Einstein condensate (BEC) phase. We report on a new QDM in the strongly spin-orbit coupled, distorted honeycomb-lattice material Yb_{2}Si_{2}O_{7}. Our single crystal neutron scattering, specific heat, and ultrasound velocity measurements reveal a gapped singlet ground state at zero field with sharp, dispersive excitations. We find a field-induced magnetically ordered phase reminiscent of a BEC phase, with exceptionally low critical fields of H_{c1}∼0.4 and H_{c2}∼1.4 T. Using inelastic neutron scattering in an applied magnetic field we observe a Goldstone mode (gapless to within δE=0.037 meV) that persists throughout the entire field-induced magnetically ordered phase, suggestive of the spontaneous breaking of U(1) symmetry expected for a triplon BEC. However, in contrast to other well-known cases of this phase, the high-field (µ_{0}H≥1.2 T) part of the phase diagram in Yb_{2}Si_{2}O_{7} is interrupted by an unusual regime signaled by a change in the field dependence of the ultrasound velocity and magnetization, as well as the disappearance of a sharp anomaly in the specific heat. These measurements raise the question of how anisotropy in strongly spin-orbit coupled materials modifies the field induced phases of QDMs.

Sperm washing and virus nucleic acid detection to reduce HIV and hepatitis C virus transmission in serodiscordant couples wishing to have children.

BACKGROUND: Use of a motile spermatozoa isolation process was assessed for reducing the transmission of HIV and hepatitis C virus (HCV) during artificial insemination in HIV-serodiscordant couples in which the man is infected. PATIENTS: Thirty-two HIV-1-infected clinically asymptomatic men, having a median CD4 cell count of 396 x 10(6)/l and a median blood plasma HIV-1 RNA content of 414 copies/ml. Of these, 16 were infected with both HIV and HCV. METHODS: Motile spermatozoa were isolated from 51 semen samples by density gradient and 'swim-up'. HIV-1 and HCV genomes were detected and quantified in the blood plasma and seminal plasma, and detected in seminal cell fractions obtained during spermatozoa isolation. RESULTS: HIV-1 RNA was detected in 30% of seminal plasma samples. HIV-1 genomes were found in 18% of seminal cell samples, but in none of the motile spermatozoa fractions after 'swim-up'. There was no correlation between the HIV-1 RNA concentrations in the blood and seminal plasma. HIV-1 genome was detected intermittently in patients who gave more than one sample. HCV RNA was detected in 20% of seminal plasma samples from HCV viraemic patients, but in no seminal cells or motile spermatozoa fractions. CONCLUSIONS: Purification of motile spermatozoa by density gradient plus 'swim-up' reduced the HIV-1 and HCV genomes in the semen of infected individuals to undetectable levels. This method, associated with a standardized virus assay, could be useful for serodiscordant couples (males infected) who wish to have children.

Dependency of cyclosporine tissue distribution and metabolism on the age and gender of rats after a single intravenous dose.

In a previous study we demonstrated the dependency of cyclosporine (CyA) pharmacokinetics on the age and gender of Wistar rats given 10 mg/kg intravenously. The present study has been conducted under the same experimental conditions (10 mg/kg as a single intravenous dose) to identify the mechanisms behind such differences. On the one hand, drug distribution was studied by measuring the CyA levels in blood, liver, kidney, spleen, adipose tissue, skin and muscle at 48 h post-treatment by using a specific fluorescence polarization immunoassay (m-FPIA, Abbott Laboratories). Drug blood and tissue levels in male rats were significantly higher than the female counterparts except for adipose tissue where the concentrations were 2-fold higher in females. In males, the highest CyA concentrations were observed in the liver, followed in rank order by kidney and spleen, fat, skin, muscle, then blood. On the contrary, females showed the highest drug levels in fat, followed by liver, kidney, spleen, skin, muscle and blood. Age exerted a significant influence on CyA tissue levels in males but no effect was observed in females. The potential differences in drug metabolism were established by measuring (HPLC) the amounts of CyA and its metabolites accumulated in faeces after hepatic biotransformation and biliary excretion. The amounts of circulating metabolites in blood as well as those accumulated and excreted in the liver and urine were also estimated by using specific (m-FPIA) and non-specific fluorescence polarization immunoassay (p-FPIA, Abbott Laboratories), respectively. The analysis of faeces revealed that AM9 was the major identified metabolite with females excreting lower amounts of unchanged CyA than males. In addition, the comparison of the AUC values corresponding to parent CyA and total CyA derivatives suggested that blood concentrations of CyA metabolites were higher in females indicating higher biotransformation rates. Therefore, both CyA distribution and metabolism are responsible for the sex-associated differences in drug pharmacokinetics previously found in rats.

A polycaprolactone nanoparticle formulation of cyclosporin-A improves the prediction of area under the curve using a limited sampling strategy.

Therapeutic monitoring of Cyclosporine (CyA) by using area under the curve (AUC) from abbreviated kinetic profiles is of recent trend in clinical practice due to the potential improvement in transplant and clinical outcome with costs reduction in mind. Several papers describe successful use of the limited sampling strategy to predict AUCs in different transplant populations when treated with Sandimmun or Sandimmun Neoral. However, the same predictive potential is achieved for the latter formulation with lesser effort. The present paper describes the application of the limited sampling strategies to demonstrate the advantages of using CyA incorporated in polymeric nanoparticles (CyA-NP) as compared to two reference Sandimmun formulations which consisted of an emulsion of the oily solution in milk (SIM-EM) and a microemulsion (SIM-Neoral) formerly tried on rats. Two independent data batches were used: group 1 which included 36, 31 and 10 animals receiving SIM-EM, CyA-NP and SIM-Neoral, respectively, and group 2 made of nine and eight rats treated with SIM-EM and CyA-NP. Several limited sampling equations were derived for each formulation from group 1 by stepwise multiple linear regression. Statistical analysis disclosed that CyA concentrations 8 and 32 h after dose administration vouched for 88 and 69% variability in AUC (0-48 h) for CyA-NP and SIM-EM, respectively. When summed up, these two concentrations revealed nearly 97% of AUC (0-48 h) variability. CyA concentrations 8 h post-treatment with SIM-Neoral explained 89% variability in AUC (0-48 h). This value raised to 98% when a second CyA concentration (24 h) was introduced. The equations derived from group 1 were then employed to predict AUCs in group 2. CyA blood levels at 8 h post-treatment confirmed AUC for CyA-NP (r(2)=0.98) to be very precise and unbiased (error=1. 46%, interval -16.2 to 21.33%), while the results for SIM-EM obtained with the CyA concentration at 32 h were r(2)=0.93 plus error=5.71%, interval -44.33 to 105.94%. Similar results were obtained when the study period was reduced to 24 h. The use of these limited sampling models manifested the coincidence between CyA-NP and SIM-Neoral as well as the advantages of both formulations over SIM-EM when it comes to CyA monitoring.

Stability and freeze-drying of cyclosporine loaded poly(D,L lactide-glycolide) carriers.

The present paper describes the stability of poly (D, L-lactide-glycolide) nanoparticles (PLGA NP) and microspheres (MS), either alone or loaded with cyclosporine (CyA), stored at 8 degrees C and room temperature (RT). Freeze-drying of these formulations was evaluated as an alternative method to achieve long term stability. A significant polymer rupture was detected during PLGA MS preparation by solvent evaporation, which correlated with the stirring rates used for the formation of the primary emulsion. On the other hand, the polymer remained unchanged during NP formation. After 6 months of storage, PLGA NP of a size below 80 nm aggregated when stored at RT whereas no changes of particle size were observed for the remaining formulations and experimental conditions. Drug entrapment significantly increased by about 9.5% only during PLGA NP storage at RT. The PLGA molecular weight of NP dropped at RT being these changes related to the initial particle size and amount of CyA incorporated. The same effect was observed at 8 degrees C but only the particle size showed a significant influence. The drop of PLGA molecular weight observed during storage of MS was not dependent on the storage temperature but it was directly related to the molecular weights obtained after MS preparation. Freeze-drying studies revealed that it was not feasible to maintain the initial PLGA NP characteristics after reconstitution. On the other hand, MS lyophilized in the absence of cryoprotectants retained the drug initially entrapped; however, the presence of at least 5% cryoprotectant was essential to keep the initial particle size. Therefore, PLGA NP and MS show a significant instability when stored as suspensions. Freeze-drying offers a good alternative to stabilize polymeric MS but the preservation of the PLGA NP characteristics by freeze-drying needs for further investigations.

Stability of cyclosporine-loaded poly-sigma-caprolactone nanoparticles.

The aim was to evaluate the long-term stability of cyclosporin A-loaded nanoparticle suspensions, stored at 8 and 25 degrees C. The stability of freeze-dried samples was also investigated. Nanoparticles (NP) of poly-sigma-caprolactone (P sigma CL), a biodegradable polymer, were obtained by a modified nanoprecipitation method. A central composite experimental design was used to investigate the simultaneous effect of technological factors (temperature of the aqueous phase and needle gauge) and formulation variables (volume of acetone and the amount of polymer and surfactant). The effect of these variables on the stability of the 100-220 nm particles obtained was evaluated. The percentage of cyclosporin A (CyA) encapsulated in the NP suspensions stored at 8 and 25 degrees C for at least 3 months remained unaltered. Moreover, there was no change in the size of NP. After 4 months storage, the physical stability of the preparation was affected. NP aggregates could be observed by light microscopy. Reconstituted freeze-dried preparations showed a mean increase of 1% in the incorporated drug and also a considerable increase in mean size and size distribution. Additional experiments investigated the effect of freezing temperature (-70 and -196 degrees C) and of 5, 10 and 20% (w/v) cryoprotector (mannitol, sorbitol, glucose and threalose) on 100 nm particles. The addition of glucose and threalose at concentrations > 10% permitted adequate reconstitution of the freeze-dried product with conservation of the encapsulated CyA.

Application of central composite designs to the preparation of polycaprolactone nanoparticles by solvent displacement.

Cyclosporin A (CyA) is a good candidate for incorporation in colloidal carriers such as nanoparticles (NP) that would diminish the adverse effects associated with its use under conventional pharmaceutical dosage forms and improve bioavailability after oral administration. In this study a composite rotational experimental design was used to evaluate the joint influence of five formulation variables: temperature of the aqueous phase, needle gauge, volume of the organic phase, and the amounts of polymer and surfactant on the micromeritic characteristics of the CyA-loaded NP obtained by the method of Fessi et al. The percentage of drug encapsulated in the NP was also evaluated for each formulation, and the yield, which was expressed as the ratio between the experimentally measured quantity of drug in the formulation and the theoretical content, was determined because CyA undergoes surface absorption. Potential variables such as stirring speed (500 rpm), final drug concentration (100 micrograms/mL), or injection rates (GRi = 0.379 mL/s) were maintained constant. The ANOVA corresponding to the experimental design showed that the amounts of polymer and surfactant, and the diameter of the needle used in the preparation of NP, significantly affected the percentage of entrapped drug (I2 = 0.8916). The mean particle size was significantly affected by all the formulation variables tested except for the amount of surfactant dissolved in the external aqueous phase (r2 = 0.9518). Neither the yield (mean value of 99.61%) nor the size distribution parameters (polydispersity and coefficient of variation) presented good correlation coefficients for the equations obtained, although some variables showed statistical significance. A second study was carried out to investigate the effects on the drug-loaded NP characteristics of varying the global injection rates (GRi) for the organic phase into the aqueous medium. The results showed a dramatic decrease in both particle size and drug incorporation in the carrier as the rate of mixing increased. From the results of both the experimental design and the second study, a theoretical model for nanoparticle formation is proposed that considers the most significant variables, and an empirical relationship to predict mean particle size is presented. Thus, particle size can be controlled by the injection rates (GRi), the needle gauge, and the polymer concentration.

The genetic basis of porphyria cutanea tarda.

In order to confirm the genetic character of porphyria cutanea tarda (PCT), the quantitative and qualitative porphyrin excretion from 56 unrelated PCT patients and 259 relatives was analyzed by a sensitive fluorimetric thin-layer chromatographic technique. Porphyrin excretion abnormalities were observed in 111 (35.24%) of the 315 subjects studied. Of the 259 relatives, 55 (21.24%) suffered from manifest (24 cases) or subclinical (31 cases) PCT. The relatives from the older generation or a generation similar to the propositi were more frequently affected than those from a younger generation. A clear family incidence was observed in 32 families, while PCT was apparently limited to the propositi in the remaining 24. It is discussed whether these latter families correspond to the so-called "sporadic" type of PCT or include porphyric gene carriers lacking biochemical expression of the disease. While the measurements of the activity of the defective enzyme (uroporphyrinogen decarboxylase) for the genetic research of PCT turned out to be impracticable in hepatic tissue and contradictory in erythrocytes, our study confirms that the familial character of this disease may be revealed by the chromatographic analysis of the porphyrin excretion pattern.

[Idiopathic cyclic edema: disorders in water elimination accentuated by orthostasis]. / Oedème cyclique idiopathique: trouble de l'élimination hydrique à majoration orthostatique

Forty patients suffering from idiopathic oedema were studied. The disturbance in water excretion is characterised by a delay in excretion of a water load (20 ml/kg body weight), an inability to decrease urinary osmolarity below 137 mOsm/1 standing (normal: 60 mOsm +/- 25) and an inability to increase free water clearance: 2.36 +/- 2 ml/mn/1. 73 m2 (normal value: 6.8 ml/mn/1.73 m2) in the upright position. This problem of water excretion related to orthostasis defines and characterises the syndrome, the clinical picture of which is well known. The disturbance suggest a fault in the regulation of anti-diuretic hormone whilst the aldosteronism often described would seem to be inconstant and secondary to diuretic therapy too often prescribed without supervision.