Serum antimüllerian hormone levels remain stable through the menstrual cycle and after oral or vaginal administration of synthetic sex steroids

Rapport de synthèse : Objectif de l'étude : étudier si l'administration orale ou vaginale d'hormones contraceptives influence les concentrations sériques d'hormone antimüllérienne (AMH). Design : essai prospectif chez des femmes recrutées par annonce. Les femmes désireuses d'avoir une contraception ont été randomisées entre une contraception orale et une contraception vaginale. Celles qui ne souhaitaient pas de contraception ont été incluses dans le groupe témoin. Cadre de l'étude : unité de médecine de la reproduction d'un hôpital universitaire. Patientes : vingt-quatre jeunes femmes en bonne santé avec des cycles menstruels réguliers qui n'avaient pas utilisé de contraception hormonale pendant les trois mois précédant l'étude. Intervention : contraception orale ou vaginale du 5ème au 25ème jour du cycle menstruel dans les groupes contraception versus pas de contraception dans le groupe témoin. Mesure d'issue : variations inter et intra-cycle des concentrations sériques d'AMH dans les trois groupes: groupe témoin en cycle spontané et groupes sous contraception oestroprogestative orale ou vaginale. Résultats : les fluctuations d'AMH observées pendant le cycle menstruel (variations intra-cycle) restent dans les valeurs des variations entre deux cycles (variations inter-cycles) tant chez les femmes en cycle spontané que chez les femmes sous contraception orale ou vaginale. Conclusions : nos résultats confirment que les concentrations sériques d'AMH restent stables pendant le cycle menstruel et indiquent qu'elles ne sont pas influencées par l'administration exogène de stéroïdes sexuels contraceptifs, que ce soit par voie orale ou vaginale.

Topical and intravitreous administration of cationic nanoemulsions to deliver antisense oligonucleotides directed towards VEGF KDR receptors to the eye.

Antisense oligonucleotides (ODNs) specific for VEGFR-2-(17 MER) and inhibiting HUVEC proliferation in-vitro were screened. One efficient sequence was selected and incorporated in different types of nanoemulsions the potential toxicity of which was evaluated on HUVEC and ARPE19 cells. Our results showed that below 10 microl/ml, a 2.5% mid-chain triglycerides cationic DOTAP nanoemulsion was non-toxic on HUVEC and retinal cells. This formulation was therefore chosen for further experiments. In-vitro transfection of FITC ODNs in ARPE cells using DOTAP nanoemulsions showed that nanodroplets do penetrate into the cells. Furthermore, ODNs are released from the nanoemulsion after 48 h and accumulate into the cell nuclei. In both ex-vivo and in-vivo ODN stability experiments in rabbit vitreous, it was noted that the nanoemulsion protected at least partially the ODN from degradation over 72 h. The kinetic results of fluorescent ODN (Hex) distribution in DOTAP nanoemulsion following intravitreal injection in the rat showed that the nanoemulsion penetrates all retinal cells. Pharmacokinetic and ocular tissue distribution of radioactive ODN following intravitreal injection in rabbits showed that the DOTAP nanoemulsion apparently enhanced the intraretinal penetration of the ODNs up to the inner nuclear layer (INL) and might yield potential therapeutic levels of ODN in the retina over 72 h post injection.

Administration of IL-18BP by gene therapy reduces inflammation and prevents joint destruction by downregulation of MMP-9 in rat AIA Role of MMP-9 in bone and joint destruction in arthritis

Background and objectives: Interleukin-18 (IL-18) is a pleiotropic cytokine involved in rheumatoid arthritis (RA) pathogenesis. This studywas carried out to evaluate the efficicacy of interleukin-18 binding protein (IL-18BP) gene therapy in the rat adjuvant-induced arthritis (AIA) model and to decipher the mechanisms by which IL-18BP delivery lessens bone destruction. Materials and methods: Arthritis was induced in female Lewis rat by Mycobacterium butyricum and the mRNA expression of IL-18 and IL-18BP was determined in the joints. In a preventative study, rats were divided into an adenovirus producing IL-18BP-Fc (AdmIL-18BP-Fc) group (n=8) and an adenovirus producing green fluorescent protein (AdGFP) group (n=7). On day 8 after AIA induction, adenoviruses were injected. Clinical parameters were assessed. At day 18, during maximal arthritis, the rats were euthanized, ankles were collected, and X-rays were performed. mRNA and protein were extracted from joints for analyses by qRT-PCR, multiplex, Western blot, and zymography. Results: We observed a decrease in the [IL-18BP/IL-18] ratio from day 7 to day 45. Administration of AdmIL-18BPd-Fc decreased clinical parameters and prevented bone and joint destruction compared to AdGFP administration. IL-18BP delivery reduced the metalloproteinase 9 (MMP-9) levels by 33% (at protein level (Fig. 1B) and functional level (Fig. 1C) and the tartrate-resistant acid phosphatase (TRAP) level by 44% (Fig. 1D) in the joint homogenates from AdmIL-18BPd-Fc compared to AdGFP treated rats.However, no variationwas observed forMMP-2 at the protein level (Fig.1A) and functional level (Fig. 1C). Conclusions: In rat AIA, a decrease in the [IL-18BP/ IL-18] ratio was observed. IL-18BP delivery prevented joint and bone destruction by downregulating MMP-9 and TRAP, suggesting a potential benefit of a similar therapy in RA.

Audit report on the Iowa Department of Justice for the year ended June 30, 2013

Audit report on the Iowa Department of Justice for the year ended June 30, 2013

Effects of intranasal administration of synthetic (4-28)human atrial natriuretic peptide to normal volunteers.

The effects of intranasal administration of increasing doses of synthetic human natriuretic peptide (4-28 hANP) were studied in six healthy volunteers. The peptide was administered as a nasal spray at doses of 50, 100, 200, and 500 micrograms in ascending order at 48-h intervals. Vehicle was administered by the same route randomly between any two of the doses. Intranasal hANP administration had no effect on either blood pressure, heart rate (HR), or hematocrit. Diuresis did not change consistently, whereas natriuresis tended to rise with vehicle as well as with hANP administration. This was attributed to the infusion of isotonic saline during the experiment. There was no significant increase in plasma ANP levels after intranasal administration of any of the different doses. Thus, no evidence that the atrial natriuretic peptide tested (4-28 hANP) can cross the nasal mucosal barrier was found.

Viral suppression rates in salvage treatment with raltegravir improved with the administration of genotypic partially active or inactive nucleoside/tide reverse transcriptase inhibitors.

BACKGROUND: Nucleoside reverse transcriptase inhibitors (NRTIs) are often administered in salvage therapy even if genotypic resistance tests (GRTs) indicate high-level resistance, but little is known about the benefit of these additional NRTIs. METHODS: The effect of <2 compared with 2 NRTIs on viral suppression (HIV-1 RNA < 50 copies/mL) at week 24 was studied in salvage patients receiving raltegravir. Intent-to-treat and per-protocol analyses were performed; last observation carried forward imputation was used to deal with missing information. Logistic regressions were weighted to create a pseudopopulation in which the probability of receiving <2 and 2 NRTIs was unrelated to baseline factors predicting treatment response. RESULTS: One-hundred thirty patients were included, of whom 58.5% (n = 76) received <2 NRTIs. NRTIs were often replaced by other drug classes. Patients with 2 NRTIs received less additional drug classes compared with patients with <2 NRTIs [median (IQR): 1 (1-2) compared with 2 (1-2), P Wilcoxon < 0.001]. The activity of non-NRTI treatment components was lower in the 2 NRTIs group compared with the <2 NRTIs group [median (IQR) genotypic sensitivity score: 2 (1.5-2.5) compared with 2.5 (2-3), P Wilcoxon < 0.001]. The administration of <2 NRTIs was associated with a worse viral suppression rate at week 24. The odds ratios were 0.34 (95% confidence interval: 0.13 to 0.89, P = 0.027) and 0.19 (95% confidence interval: 0.05 to 0.79, P = 0.023) when performing the last observation carried forward and the per-protocol approach, respectively. CONCLUSIONS: Our findings showed that partially active or inactive NRTIs contribute to treatment response, and thus the use of 2 NRTIs in salvage regimens that include raltegravir seems warranted.

Iowa Department of Justice, Attorney General's Office Crime Victim Assistance Division, Three Year Program Reports, December 2014

Three year program reports

Report on the Iowa Department of Justice for the year ended June 30, 2014

Report on the Iowa Department of Justice for the year ended June 30, 2014

In vivo administration of a lentiviral vaccine targets DCs and induces efficient CD8(+) T cell responses.

The present study evaluates the potential of third-generation lentivirus vectors with respect to their use as in vivo-administered T cell vaccines. We demonstrate that lentivector injection into the footpad of mice transduces DCs that appear in the draining lymph node and in the spleen. In addition, a lentivector vaccine bearing a T cell antigen induced very strong systemic antigen-specific cytotoxic T lymphocyte (CTL) responses in mice. Comparative vaccination performed in two different antigen models demonstrated that in vivo administration of lentivector was superior to transfer of transduced DCs or peptide/adjuvant vaccination in terms of both amplitude and longevity of the CTL response. Our data suggest that a decisive factor for efficient T cell priming by lentivector might be the targeting of DCs in situ and their subsequent migration to secondary lymphoid organs. The combination of performance, ease of application, and absence of pre-existing immunity in humans make lentivector-based vaccines an attractive candidate for cancer immunotherapy.

Administration of growth hormone to underweight patients with chronic obstructive pulmonary disease. A prospective, randomized, controlled study.

Patients with chronic obstructive pulmonary disease (COPD) often develop weight loss, which is associated with increased mortality. Recombinant human growth hormone (rhGH) treatment has been proposed to improve nitrogen balance and to increase muscle strength in these patients. The aim of this study was to assess the effects of rhGH administration on the nutritional status, resting metabolism, muscle strength, exercise tolerance, dyspnea, and subjective well-being of underweight patients with stable COPD. Sixteen patients attending a pulmonary rehabilitation program (age: 66 +/- 9 yr; weight: 77 +/- 7% of ideal body weight; FEV1: 39 +/- 13% of predicted) were randomly treated daily with either 0.15 IU/kg rhGH or placebo during 3 wk in a double-blind fashion. Measurements were made at the beginning (DO) and at the end (D21) of treatment and 2 mo later (D81). Body weight was similar in the two groups during the study, but lean body mass was significantly higher in the rhGH group at D21 (p < 0.01) and D81 (p < 0.05). The increase in lean body mass was 2.3 +/- 1.6 kg in the rhGH group and 1.1 +/- 0.9 kg in the control group at D21 and 1.9 +/- 1.6 kg in the rhGH group and 0.7 +/- 2.1 kg in the control group at D81. At D21, the resting energy expenditure was increased in the rhGH group (107.8% of DO, p < 0.001 compared with the control group). At D21 and D81, the changes in maximal respiratory pressures, handgrip strength, maximal exercise capacity, and subjective well-being were similar in the two groups. At D21, the 6-min walking distance decreased in the rhGH group (-13 +/- 31%) and increased in the control group (+10 +/- 14%; p < 0.01). We conclude that the daily administration of 0.15 IU/kg rhGH during 3 wk increases lean body mass but does not improve muscle strength or exercise tolerance in underweight patients with COPD.

Drug concentration response relationships in normal volunteers after oral administration of losartan, an angiotensin II receptor antagonist.

The aim of this study was to investigate the relationships between plasma concentrations of losartan, an orally active angiotensin II inhibitor, its active metabolite EXP3174, and angiotensin II blockade. Six healthy subjects received single oral doses of 40, 80, or 120 mg losartan and placebo at 1-week intervals in a crossover study. Angiotensin II blockade was assessed by the blood pressure response to exogenous angiotensin II before and after losartan administration. EXP3174 reached higher plasma concentrations and was eliminated more slowly than its parent compound; its levels paralleled the profile of angiotensin II blockade closer than losartan. Inhibition of the pressure response was dose dependent. The Hill-shaped relationship between response and EXP3174 concentration (or time-integrated variables) approached a plateau with 80 mg. The dose-dependent increase in plasma renin and angiotensin II exhibited a considerable individual scatter. We conclude that losartan produces a dose-dependent, effective angiotensin II blockade that is largely determined by the active metabolite EXP3174.