Standardized Quantitative Evaluation of Clinical Effectiveness and Side Effect Profile of Subcutaneous and Sublingual Allergen-Specific Immunotherapy in Children: A 5-Year Single Center Experience

Objective: Allergen-specific immunotherapy (allergen-SIT) is a treatment method with variable efficacy in allergic diseases. This study aimed to investigate the effectiveness of allergen immunotherapy, frequency of LRs and SRs and variables affecting these parameters in patients who underwent allergen-SIT. Materials and Methods: In this study, the recorded data of 81 patients, who received subcutaneous (SCIT) or sublingual (SLIT) allergen immunotherapy for respiratory allergic diseases between 2014 and 2019, were analyzed. In asthma and/or allergic rhinoconjunctivitis (ARC) patients, the effectiveness of treatment was evaluated by analysing the change rates in disease symptom, medication and combined scores (symptom + medication) and visual analog score (VAS). Treatment success was defined by the degree of decrease in scores as; high response above 50%; low response between 20-50%; and failure <20%.Results: The mean age of allergen-SIT initiation was 11.4± 3.1 years. Diagnostic distributions of the patients were asthma (± ARC) in 64.2%, and ARC (without asthma) in 35.8%. The mode of allergen-SIT was SCIT in 77.8% (65% asthma and 35% ARC) and SLIT in 22.2% (61.1% asthma and 38.9% ARC). The main allergens used in allergen-SIT were mite (79%), grass-grain pollen (33.3%), alternaria (9.9%) and olea (8.6%). There was a significant decrease in symptoms, medication, combined and VAS scores in the asthma and ARC groups (p <0.0001), when end-SCIT values were compared to baseline. SLIT also resulted in significant decreases in these scores except asthma medication score. Among the asthma patients the rate of high-responders was 88.8% by SCIT and 50% by SLIT, according to combined asthma score. Among the ARC (without asthma) patients the rate of high-responders was 100% for both SCIT and SLIT. SCIT resulted in local (LR) and systemic side effects (SR) in 18% and 0.6% (all Grade I and Grade II) of the total injections performed. A high number of total injections was significantly associated with higher LR and SR rates. While LR was observed in 16.6% of the patients who underwent SLIT, no systemic reaction was found in any of the patients. Conclusion: SCIT was highly successful in the treatment of asthma and ARC in terms of the degree of therapeutic response. SLIT resulted in a high rate of good response in ARC patients, but a lower response degree in asthmatic patients. Systemic side effects were very low as a result of close risk monitoring and the dose adjustments performed. Keywords: Allergen-specific immunotherapy, SCIT, SLIT, efficacy, symptom score, medication score, visual analog score, side effects

Weight Loss Outcomes Among Early High Responders to Exenatide Treatment: A Randomized, Placebo Controlled Study in Overweight and Obese Women

ObjectiveAs there is significant heterogeneity in the weight loss response to pharmacotherapy, one of the most important clinical questions in obesity medicine is how to predict an individual’s response to pharmacotherapy. The present study examines patterns of weight loss among overweight and obese women who demonstrated early robust response to twice daily exenatide treatment compared to those treated with hypocaloric diet and matched placebo injections.MethodsWe randomized 182 women (BMI 25-48 kg/m2) to treatment with exenatide alone or matched placebo injections plus hypocaloric diet. In both treatment groups, women who demonstrated ≥ 5% weight loss at 12 weeks were characterized as high responders and those who lost ≥10% of body weight were classified as super responders. Our primary outcome was long-term change in body weight among early high responders to either treatment. An exploratory metabolomic analysis was also performed.ResultsWe observed individual variability in weight loss with both exenatide and hypocaloric diet plus placebo injections. There was a trend toward a higher percentage of subjects who achieved ≥ 5% weight loss with exenatide compared to diet (56% of those treated with exenatide, 76% of those treated with diet, p = 0.05) but no significant difference in those who achieved ≥ 10% weight loss (23% of individuals treated with exenatide and 36% of those treated with diet, p = 0.55). In both treatment groups, higher weight loss at 3 months of treatment predicted super responder status (diet p=0.0098, exenatide p=0.0080). Both treatment groups also demonstrated similar peak weight loss during the study period. We observed lower cysteine concentrations in the exenatide responder group (0.81 vs 0.48 p &lt; 0.0001) and a trend toward higher levels of serotonin, aminoisobutyric acid, anandamide, and sarcosine in the exenatide super responder group.ConclusionIn a population of early high responders, longer term weight loss with exenatide treatment is similar to that achieved with a hypocaloric diet.Clinical Trial Registrationwww.clinicaltrialsgov, identifier NCT01590433.

Preliminary Evidence of Endotoxin Tolerance in Dairy Cows during the Transition Period

The blastogenic response of bovine peripheral blood mononuclear cells (PBMCs) to lipopolysaccharides (LPS) has been investigated for a long time in our laboratories. In particular, a possible correlation between the blastogenic response to LPS and the disease resistance of dairy cows has been suggested in previous studies. Isolated PBMCs from eight cows at three different time points during the transition period (T0 = 15 days before calving; T1 = 7 days post-calving; T2 = 21 days post-calving) were cultured in the presence or absence of LPS, and the blastogenic response was assayed 72 h after in vitro stimulation. Moreover, the gene expression of proinflammatory cytokines and kynurenine pathway molecules was investigated by real-time RT-PCR on both unstimulated and stimulated PBMCs. The cows were retrospectively divided into healthy and diseased, based on the development of peripartum diseases (subclinical ketosis and placenta retention). The comparison between healthy and diseased cows suggested that healthy animals seemed to better control the response to LPS. On the contrary, diseased animals showed a much higher inflammatory response to LPS. Moreover, cows were retrospectively classified as high and low responders based on the in vitro proliferative response of PBMCs to LPS, using the median value as a threshold. Unstimulated PBMCs of low responders showed higher expression of the proinflammatory cytokines Interleukin 1-β (IL-1β), Interleukin 6 (IL-6) and Tumor Necrosis Factor-α (TNF-α), compared to high responders. Our preliminary data suggest that, during the peripartum period, high responders seem to be more tolerant to endotoxins and develop a lower inflammatory response to different stressors. Instead, low responders could be more prone to the development of unwanted inflammatory conditions in response to mild/moderate stressors.

Role of Letrozole in Management of Female Infertility; Review Article

Background: Letrozole is a highly steroidal and selective oral aromatase inhibitor (AI). Serval studies shows that Co-treatment with letrozole significantly reduced gonadotropin consumption and the incidence of Ovarian Hyperstimulation Syndrome in normal/high responders, with pregnancy outcomes comparable to or better than the other groups. In this article we will be looking at role of letrozole in treatment of infertility Methodology: A simple systematic review was carried out, searching databases PubMed, Google Scholar, and EBSCO. The authors extracted qualitative data, and then the author's names, year, study type, methodology, and the result were reported. Results and Conclusion: Letrozole has effectiveness which is near the usage of the Human Menopausal Gonadotrophin in the numbers of pregnancies per cycle but have much less cost which indicates cost effectiveness of the drug. Furthermore, studies show that administration of the drug is effective in inducing pregnancy, with higher dose more than 5mg and 7.5mg more effective.

Effect of GnRH Agonist Alone or Combined With Different Low-dose hCG on Cumulative Live Birth Rate for High Responders in GnRH Antagonist Cycles: a Retrospective Study

Background: There is insufficient evidence regarding the impact of dual trigger on oocyte maturity and reproductive outcomes in high responders. Thus, we aimed to explore the effect of gonadotropin-releasing hormone agonist (GnRHa) trigger alone or in combination with different low-dose human chorionic gonadotropin (hCG) regimens on rates of oocyte maturation and cumulative live birth in high responders who underwent a freeze-all strategy in GnRH antagonist cycles.Methods: A total of 1343 cycles were divided into three groups according to different trigger protocols: group A received GnRHa 0.2 mg (n=577), group B received GnRHa 0.2 mg and hCG 1000 IU (n=403), and group C received GnRHa 0.2 mg and hCG 2000 IU (n=363). Results: There were no significant differences in age, body mass index, and rates of oocyte maturation, fertilization, available embryo, and top-quality embryo between the groups. However, the incidence of moderate to severe ovarian hyperstimulation syndrome (OHSS) was significantly different between the three groups (0% in group A, 1.49% in group B, and 1.38% in group C). For the first frozen embryo transfer (FET) cycle, there were no significant differences in the number of transferred embryos and rates of implantation, clinical pregnancy, live birth, and early miscarriage between the three groups. Additionally, the cumulative ongoing pregnancy rate and cumulative live birth rate were not significantly different between the three groups. Similarly, there were no significant differences in gestational age, birth weight, birth height, and the proportion of low birth weight among subgroups stratified by singleton or twin.Conclusions: GnRHa trigger combined with low-dose hCG (1000 IU or 2000 IU) did not improve oocyte maturity and embryo quality and was still associated with an increased risk of moderate to severe OHSS. Therefore, for high responders treated with the freeze-all strategy, the GnRHa single trigger is recommended for final oocyte maturation, which can prevent the occurrence of moderate to severe OHSS and obtain satisfactory pregnancy and neonatal outcomes in subsequent FET cycles.

Interindividual Variability in Fat Mass Response to a 1-Year Randomized Controlled Trial With Different Exercise Intensities in Type 2 Diabetes: Implications on Glycemic Control and Vascular Function

Purpose: Little is known about the interindividual variability in fat mass (FM) loss in response to high-intensity interval training (HIIT) and moderate continuous training (MCT) in individuals with type 2 diabetes mellitus (T2DM). Moreover, the impact on health-related outcomes in those who fail to reduce FM is still unclear. The aims of this investigation were (1) to assess if the individuals with T2DM who FM differed across MCT, HIIT, and control groups over a 1-year intervention and (2) to assess the changes on glycemic control and vascular function in the exercising patients who failed to lose FM.Methods: Adults with T2DM were randomized into a 1-year intervention involving a control group (n=22), MCT with resistance training (RT; n=21), and HIIT with RT (n=19). FM was assessed using dual-energy X-ray absorptiometry and a change in total body FM above the typical error was used to categorize FM responders. Glycemic control and vascular stiffness and structure were assessed. A chi-square test and generalized estimating equations were used to model the outcomes.Results: Both MCT (n=10) and HIIT (n=10) had a similar proportion of individuals who were categorized as high responders for FM, with the percent change in FM on average −5.0±9.6% for the MCT and −6.0±12.1% for the HIIT, which differed from the control group (0.2±7.6%) after a 1-year intervention (p&lt;0.05). A time-by-group interaction for carotid artery intima-media thickness (cIMT) (p for interaction=0.042) and lower-limb pulse wave velocity (LL PWV; p for interaction=0.010) between those categorized as low FM responders and the control group. However, an interaction was observed between the high responders for FM loss and controls for both brachial and carotid hemodynamic indices, as well as in cIMT, carotid distensibility coefficient, carotid beta index, and LL PWV (p for interactions &lt;0.05). No interactions were found for glycaemic indices (p for interaction &gt;0.05).Conclusion: Our results suggest that the number of FM responders did not differ between the MCT or HIIT, compared to the control, following a 1-year exercise intervention in individuals with T2DM. However, low responders to FM may still derive reductions in arterial stiffness and structure.Clinical Trial Registration: Comparing Moderate and High-intensity Interval Training Protocols on Biomarkers in Type 2 Diabetes Patients (D2FIT study) – number: NCT03144505 (https://clinicaltrials.gov/ct2/show/NCT03144505).

Cannabidiol Modulates the Motivational and Anxiety-Like Effects of 3,4-Methylenedioxypyrovalerone (MDPV) in Mice

3,4-Methylenedioxypyrovalerone (MDPV) is a new psychoactive substance (NPS) and the most widespread and life-threatening synthetic cathinone of the “bath salts”. Preclinical research has proven the cocaine-like psychostimulant effects of MDPV and its potential for abuse. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid that has emerged as a new potential treatment for drug addiction. Here, we tested the effects of CBD (20 mg/kg) on MDPV (2 mg/kg)-induced conditioned place preference and MDPV (0.05 and 0.075 mg/kg/infusion) self-administration paradigms. In addition, we assessed the effects of the co-administration of CBD and MDPV (3 and 4 mg/kg) on anxiety-like behaviour using the elevated plus maze (EPM). CBD mitigated the MDPV-induced conditioned place preference. On the contrary, CBD administration throughout the MDPV (0.075 mg/kg/infusion) self-administration increased drug-seeking and taking behaviours, but only in the high-responders group of mice. Furthermore, CBD exerted anxiolytic-like effects, exclusively in MDPV-treated mice. Taken together, our results indicate that CBD modulation of MDPV-induced motivational responses in mice varies depending on the requirements of the learning task, resulting in a complex response. Therefore, further research attempting to decipher the behavioural and molecular interactions between CBD and MDPV is needed.