Immunocontraception of male and female giraffes using the GnRH vaccine Improvac®.

The aim of this study was to develop protocols for contraception in both sexes of giraffes (Giraffa camelopardalis) by using the GnRH vaccine Improvac®. We evaluated the success of immunization by analyzing fecal reproductive hormone metabolites in female (n = 20) and male (n = 9) giraffes. Endocrine analysis provided the basis for the successful immunization protocol, as well as for assessing long-term effects. Reliable reduction of fecal steroid metabolites to baseline levels in female giraffes was achieved with three, and in males with four or five injections at 4-week intervals. Effective booster injections were administered at 2-month intervals in the first year of treatment and at three to 4-month intervals in the following years. In addition to endocrine analysis, we determined vaccination efficacy in bulls by assessing testicular atrophy. Long-term (>2 years) use in females was often accompanied by prolonged periods of persistent corpus luteum activity, although normal cycles were not observed. Problems might occur with reversibility, because in a few males and females, even after more than 2 years since treatment had been stopped, fecal hormone metabolites have not returned to pretreatment levels. The results are somewhat ambiguous, as reproduction can be suppressed by use of Improvac®, but the question of reversibility remains unsolved.

Bone mineral density and its determinants in men with opioid dependence.

Data on the influence of opioid substitution therapy (OST) on skeletal health in men is limited. This cross-sectional study aimed to determine the prevalence of low bone mass in male drug users and to evaluate the relationship between endogenous testosterone and bone mass. We recruited 144 men on long-term opioid maintenance therapy followed in the Center of Addiction Medicine in Basel, Switzerland. Data on medical and drug history, fracture risk and history of falls were collected. Bone mineral density (BMD) was evaluated by densitometry and serum was collected for measurements of gonadal hormones and bone markers. 35 healthy age- and BMI-matched men served as the control group. The study participants received OST with methadone (69 %), morphine (25 %) or buprenorphine (6 %). Overall, 74.3 % of men had low bone mass, with comparable bone mass irrespective of OST type. In older men (≥40 years, n = 106), 29.2 % of individuals were osteoporotic (mean T-score -3.0 ± 0.4 SD) and 48.1 % were diagnosed with osteopenia (mean T-score -1.7 ± 0.4 SD). In younger men (n = 38), 65.8 % of men had low bone mass. In all age groups, BMD was significantly lower than in age-and BMI-matched controls. In multivariate analyses, serum free testosterone (fT) was significantly associated with low BMD at the lumbar spine (p = 0.02), but not at the hip. When analysed by quartiles of fT, lumbar spine BMD decreased progressively with decreasing testosterone levels. We conclude that low bone mass is highly prevalent in middle-aged men on long-term opioid dependency, a finding which may partly be determined by partial androgen deficiency.

Influence of the force magnitude of fixed functional appliances for class II subdivision 1 treatment-a cephalometric study.

PURPOSE: To investigate the skeletal and dental effects of a hybrid fixed functional appliance (FFA) used with different force magnitudes for class II subdivision 1 treatment. METHODS: Treatment records from 70 patients were evaluated: 35 patients were treated with a FFA with standard activation (SUS group) and 35 with a FFA with an additional force-generating spring (TSUS group). Two control groups were matched from the American Association of Orthodontists Foundation (AAOF) Craniofacial Growth Legacy Collection for comparison with the two treatment groups to determine skeletal and dental treatment effects. The cephalometric parameters at T0 (before treatment) and T1 (before debonding) were assessed using the Munich standard cephalometric analysis and by the sagittal occlusal analysis (SO) according to Pancherz. Data were analyzed statistically using SPSS. RESULTS: No statistically significant difference for any cephalometric parameter was observed between the SUS and TSUS groups concerning the measurements at T0 and T1. Both treatment groups exhibited an effective class II therapy mainly due to a significant reduction in SNA, and ANB and an increase in SNB. In contrast to the control group, as the result of treatment a skeletal class I was achieved. CONCLUSION: No significant statistical differences were observed between the patient group treated with the FFA with standard activation (SUS) and those treated with an additional spring (TSUS) regarding the cephalometric parameters investigated. Both variants were equally effective in treating class II division 1 malocclusions.

Acupuncture in chemotherapy-induced dysgeusia (AcuDysg): study protocol of a randomised controlled trial.

INTRODUCTION: Dysgeusia is a common side effect of chemotherapy in patients with cancer, but to date, there is no effective treatment. Many patients with cancer request complementary medicine treatment in addition to their cancer treatments, and acupuncture is highly accepted for patients with cancer; however, evidence regarding the effectiveness of acupuncture for dysgeusia is scarce.The study investigates the effectiveness of an additional dysgeusia-specific acupuncture plus self-acupressure intervention compared with supportive acupuncture plus self-acupressure intervention alone for chemotherapy-induced dysgeusia in patients with cancer. METHODS AND ANALYSIS: This is a multicentre, randomised, controlled and two-armed parallel-group, single-blind trial involving 130 patients. Both groups will receive eight sessions of acupuncture treatment over a period of 8 weeks and will be trained to perform self-acupressure (eLearning combined with therapist instruction) at predefined acupressure points once a day during the whole treatment period. Patients in the control group will receive supportive routine care acupuncture and self-acupressure treatment only; in addition to this treatment, the intervention group will receive the dysgeusia-specific acupuncture and acupressure within the same treatment session. The primary outcome is the perceived dysgeusia over 8 weeks, measured weekly after the acupuncture treatment. Secondary outcomes include the indices from the objective taste and smell test, weight loss, perceived dysgeusia, fatigue, distress, nausea and vomiting, odynophagia, xerostomia and polyneuropathy, as well as quality of life at the different time points. ETHICS AND DISSEMINATION: The study has been approved by the Cantonal Ethics Committee (CEC) (Kanton Zürich Kantonale Ethikkommission) (approval no. KEK-ZH-Nr. 2020-01900). The results will be submitted to a peer-reviewed journal for publication. TRIAL REGISTRATION NUMBERS: DRKS00023348, SNCTP000004128.

Oxytocin receptor is a potential biomarker of the hyporesponsive HPA axis subtype of PTSD and might be modulated by HPA axis reactivity traits in humans and mice.

This study aimed to identify yet unavailable blood biomarkers for the responsive and the hyporesponsive hypothalamic-pituitary-adrenal (HPA) axis subtypes of posttraumatic stress disorder (PTSD). As, I, we recently discovered the intranasal neuropeptide oxytocin to reduce experimentally provoked PTSD symptoms, II, expression of its receptor (OXTR) has hitherto not been assessed in PTSD patients, and III, oxytocin and OXTR have previously been related to the HPA axis, we considered both as suitable candidates. During a Trier Social Stress Test (TSST), we compared serum oxytocin and blood OXTR mRNA concentrations between female PTSD patients, their HPA axis reactivity subtypes and sex and age-matched healthy controls (HC). At baseline, both candidates differentiated the hyporesponsive HPA axis subtype from HC, however, only baseline OXTR mRNA discriminated also between subtypes. Furthermore, in the hyporesponsive HPA axis subgroup, OXTR mRNA levels correlated with PTSD symptoms and changed markedly during the TSST. To assess the influence of (traumatic) stress on the cerebral expression of oxytocin and its receptor and to test their suitability as biomarkers for the mouse PTSD-like syndrome, we then analyzed oxytocin, its mRNA (Oxt) and Oxtr mRNA in three relevant brain regions and Oxt in blood of a PTSD mouse model. To further explore the HPA axis reactivity subtype dependency of OXTR, we compared cerebral OXTR protein expression between mice exhibiting two different HPA axis reactivity traits, i.e., FK506 binding protein 51 knockout vs. wildtype mice. In summary, blood OXTR mRNA emerged as a potential biomarker of the hyporesponsive HPA axis PTSD subtype and prefrontal cortical Oxtr and Oxt of the mouse PTSD-like syndrome. Moreover, we found first translational evidence for a HPA axis responsivity trait-dependent regulation of OXTR expression. The lack of a cohort of the (relatively rare) hyporesponsive HPA axis subtype of HC is a limitation of our study.

Impaired visual processing of letter and digit strings in adult dyslexic readers.

The slow word reading of developmental dyslexics may stem from a string processing impairment which in turn reflects visual attentional deficits. We indeed found substantially enhanced recognition time thresholds in the dyslexic adult readers. However, their position profiles were hard to reconcile with any of the discussed visual attentional deficit hypotheses and with the prediction that dyslexic readers suffer from an absent string processing system as they exhibited similar M-shaped position profiles for digit and letter strings as the normal reading controls.

A role for synapsin in FKBP51 modulation of stress responsiveness: Convergent evidence from animal and human studies.

Both the molecular co-chaperone FKBP51 and the presynaptic vesicle protein synapsin (alternatively spliced from SYN1-3) are intensively discussed players in the still insufficiently explored pathobiology of psychiatric disorders such as major depression, schizophrenia and posttraumatic stress disorder (PTSD). To address their still unknown interaction, we compared the expression levels of synapsin and five other neurostructural and HPA axis related marker proteins in the prefrontal cortex (PFC) and the hippocampus of restrained-stressed and unstressed Fkbp5 knockout mice and corresponding wild-type littermates. In addition, we compared and correlated the gene expression levels of SYN1, SYN2 and FKBP5 in three different online datasets comprising expression data of human healthy subjects as well as of predominantly medicated patients with different psychiatric disorders. In summary, we found that Fkbp5 deletion, which we previously demonstrated to improve stress-coping behavior in mice, prevents the stress-induced decline in prefrontal cortical (pc), but not in hippocampal synapsin expression. Accordingly, pc, but not hippocampal, synapsin protein levels correlated positively with a more active mouse stress coping behavior. Searching for an underlying mechanism, we found evidence that deletion of Fkbp5 might prevent stress-induced pc synapsin loss, at least in part, through improvement of pc Akt kinase activity. These results, together with our finding that FKBP5 and SYN1 mRNA levels were regulated in opposite directions in the PFC of schizophrenic patients, who are known for exhibiting an altered stress-coping behavior, provide the first evidence of a role for pc synapsin in FKBP51 modulation of stress responsiveness. This role might extend to other tissues, as we found FKBP5 and SYN1 levels to correlate inversely not only in human PFC samples but also in other expression sites. The main limitation of this study is the small number of individuals included in the correlation analyses. Future studies will have to verify the here-postulated role of the FKBP51-Akt kinase-synapsin pathway in stress responsiveness.

Identification and characterization of HPA-axis reactivity endophenotypes in a cohort of female PTSD patients.

Analysis of the function of the hypothalamic-pituitary-adrenal (HPA)-axis in patients suffering from posttraumatic stress disorder (PTSD) has hitherto produced inconsistent findings, inter alia in the Trier Social Stress Test (TSST). To address these inconsistencies, we compared a sample of 23 female PTSD patients with either early life trauma (ELT) or adult trauma (AT) or combined ELT and AT to 18 age-matched non-traumatized female healthy controls in the TSST which was preceded by intensive baseline assessments. During the TSST, we determined a variety of clinical, psychological, endocrine and cardiovascular parameters as well as expression levels of four HPA-axis related genes. Using a previously reported definition of HPA-axis responsive versus non-responsive phenotypes, we identified for the first time two clinically and biologically distinct HPA-axis reactivity subgroups of PTSD. One subgroup ("non-responders") showed a blunted HPA-axis response and distinct clinical and biological characteristics such as a higher prevalence of trauma-related dissociative symptoms and of combined AT and ELT as well as alterations in the expression kinetics of the genes encoding for the mineralocorticoid receptor (MR) and for FK506 binding protein 51 (FKBP51). Interestingly, this non-responder subgroup largely drove the relatively diminished HPA axis response of the total cohort of PTSD patients. These findings are limited by the facts that the majority of patients was medicated, by the lack of traumatized controls and by the relatively small sample size. The here for the first time identified and characterized HPA-axis reactivity endophenotypes offer an explanation for the inconsistent reports on HPA-axis function in PTSD and, moreover, suggest that most likely other factors than HPA-axis reactivity play a decisive role in determination of PTSD core symptom severity.

Therapeutic Action of Fluoxetine is Associated with a Reduction in Prefrontal Cortical miR-1971 Expression Levels in a Mouse Model of Posttraumatic Stress Disorder.

MicroRNAs (miRNA) are a class of small non-coding RNAs that have recently emerged as epigenetic modulators of gene expression in psychiatric diseases like schizophrenia and major depression. So far, miRNAs have neither been studied in patients suffering from posttraumatic stress disorder (PTSD) nor in PTSD animal models. Here, we present the first study exploring the connection between miRNAs and PTSD. Employing our previously established PTSD mouse model, we assessed miRNA profiles in prefrontal cortices (PFCs) dissected from either fluoxetine or control-treated wildtype C57BL/6N mice 74 days after their subjection to either a single traumatic electric footshock or mock-treatment. Fluoxetine is an antidepressant known to be effective both in PTSD patients and in mice suffering from a PTSD-like syndrome. Screening for differences in the relative expression levels of all potential miRNA target sequences of miRBase 18.0 by pairwise comparison of the PFC miRNA profiles of the four mouse groups mentioned resulted in identification of five miRNA candidate molecules. Validation of these miRNA candidates by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) revealed that the therapeutic action of fluoxetine in shocked mice is associated with a significant reduction in mmu-miR-1971 expression. Furthermore, our findings suggest that traumatic stress and fluoxetine interact to cause distinct alterations in the mouse PFC miRNA signature in the long-term.

Peroxiredoxin 6 is a potent cytoprotective enzyme in the epidermis.

Peroxiredoxin 6 is an enzyme that detoxifies hydrogen peroxide and various organic peroxides. In previous studies we found strongly increased expression of peroxiredoxin 6 in the hyperproliferative epidermis of wounded and psoriatic skin, suggesting a role of this enzyme in epidermal homeostasis. To address this question, we generated transgenic mice overexpressing peroxiredoxin 6 in the epidermis. Cultured keratinocytes from transgenic mice showed enhanced resistance to the toxicity of various agents that induce oxidative stress. However, overexpression of peroxiredoxin 6 did not affect skin morphogenesis or homeostasis. On skin injury, enhancement of wound closure was observed in aged animals. Most importantly, peroxiredoxin 6 overexpression strongly reduced the number of apoptotic cells after UVA or UVB irradiation. These findings demonstrate that peroxiredoxin 6 protects keratinocytes from cell death induced by reactive oxygen species in vitro and in vivo, suggesting that activation of this enzyme could be a novel strategy for skin protection under stress conditions.