Delivery Characterization of SPL84 Inhaled Antisense Oligonucleotide Drug for 3849 + 10 kb C- > T Cystic Fibrosis Patients.

Recent advances in the therapeutic potential of RNA-related treatments, specifically for antisense oligonucleotide (ASO)-based drugs, have led to increased numbers of ASO regulatory approvals. In this study, we focus on SPL84, an inhaled ASO-based drug, developed for the treatment of the pulmonary disease cystic fibrosis (CF). Pulmonary drug delivery is challenging, due to a variety of biological, physical, chemical, and structural barriers, especially when targeting the cell nucleus. The distribution of SPL84 throughout the lungs, penetration into the epithelial cells and nucleus, and structural stability are critical parameters that will impact drug efficacy in a clinical setting. In this study, we demonstrate broad distribution, as well as cell and nucleus penetration of SPL84 in mouse and monkey lungs. In vivo and in vitro studies confirmed the stability of our inhaled drug in CF patient-derived mucus and in lung lysosomal extracts. The mobility of SPL84 through hyperconcentrated mucus was also demonstrated. Our results, supported by a promising preclinical pharmacological effect of full restoration of cystic fibrosis transmembrane conductance regulator channel activity, emphasize the high potential of SPL84 as an effective drug for the treatment of CF patients. In addition, successfully tackling the lung distribution of SPL84 offers immense opportunities for further development of SpliSense's inhaled ASO-based drugs for unmet needs in pulmonary diseases.

Validating the Persian Intuitive Eating Scale-2 Among Breast Cancer Survivors Who Are Overweight/Obese.

Women with breast cancer are at risk of being overweight/obese which may consequently increase mortality. Intuitive eating is an adaptive eating behavior which might be beneficial for weight outcomes. The present study validated the Persian Intuitive Eating Scale-2 (IES-2) among overweight/obese Iranian females with breast cancer. Women who were overweight/obese with breast cancer (n = 762; mean ± SD age = 55.1 ± 5.7 years) completed the following questionnaires: IES-2, General Self-Efficacy Scale (GSE-6), Hospital Anxiety and Depression Scale (HADS), Short Form-12 (SF-12), Weight Bias Internalization Scale (WBIS), Body Appreciation Scale-2 (BAS-2), and Eating Attitudes Test (EAT-26). Confirmatory factor analysis (CFA) and Rasch analysis were applied to examine the psychometric properties of the IES-2. Associations between IES-2 score and other scale scores were assessed. CFA and Rasch analysis suggested that the Persian IES-2 had robust psychometric properties and all IES-2 items were meaningful in their embedded domains. The four-factor structure of the Persian IES-2 was confirmed. Concurrent validity was supported by the positive correlations between the IES-2 score and scores on the GSE-6, SF-12 mental component, and BAS-2. Negative correlations were found between the IES-2 score and the HADS (anxiety and depression subscales), WBIS, and EAT-26. The present study demonstrated that the Persian IES-2 is a well-designed instrument and is applicable for women who are overweight/obese with breast cancer.

Effects of Panax ginseng, zearalenol, and estradiol on sperm function.

BACKGROUND: Estrogen signaling pathways are modulated by exogenous factors. Panax ginseng exerts multiple activities in biological systems and is classified as an adaptogen. Zearalenol is a potent mycoestrogen that may be present in herbs and crops arising from contamination or endophytic association. The goal of this study was to investigate the impact of P. ginseng, zearalenol and estradiol in tests on spermatozoal function. METHODS: The affinity of these compounds for estrogen receptor (ER)-alpha and beta (ERα and ERß)-was assessed in receptor binding assays. Functional tests on boar spermatozoa motility, movement and kinematic parameters were conducted using a computer-assisted sperm analyzer. Tests for capacitation, acrosome reaction (AR), and chromatin decondensation in spermatozoa were performed using microscopic analysis. RESULTS: Zearalenol-but not estradiol (E2)- or ginseng-treated spermatozoa-decreased the percentage of overall, progressive, and rapid motile cells. Zearalenol also decreased spontaneous AR and increased chromatin decondensation. Ginseng decreased chromatin decondensation in response to calcium ionophore and decreased AR in response to progesterone (P4) and ionophore. CONCLUSION: Zearalenol has adverse effects on sperm motility and function by targeting multiple signaling cascades, including P4, E2, and calcium pathways. Ginseng protects against chromatin damage and thus may be beneficial to reproductive fitness.

Impact of kudzu and puerarin on sperm function.

The goal of this study was to investigate the impact of kudzu (Pueraria mirifica) and the isoflavone puerarin in functional toxicological tests on spermatozoa and to assess the affinity of extracts and pure isoflavones for estrogen receptor (ER)-alpha and -beta (ERα, ERß) in receptor binding assays. Capacitation, acrosome reaction and chromatin decondensation in spermatozoa were analyzed using microscopic analysis. Kudzu, but not puerarin, reduced motility of sperm. Puerarin reduced the percent spontaneous acrosome reaction in spermatozoa. The pathways used by kudzu that affect sperm function are not fully mirrored by puerarin. Puerarin, kudzu and its other phytoestrogenic components displayed preferential affinity for ERß, however the diverse effects of kudzu and puerarin on sperm function implicate the involvement of multiple signaling systems.

Predictors of bariatric surgery among an interested population.

BACKGROUND: Severely obese patients considering bariatric surgery face a difficult decision given the tradeoff between the benefits and risks of surgery. The objectives of this study was to study the forces driving this decision and improve our understanding of the decision-making process. METHODS: A 64-item survey was developed to assess factors in the decision-making process for bariatric surgery. The survey included the decisional conflict scale, decision self-efficacy scale, EuroQol 5D, and the standard gamble. Patients were recruited from a regularly scheduled bariatric surgery interest group meeting associated with a large, university-based bariatric practice and administered a survey at the conclusion of the interest group. Logistic regression models were used to predict who pursued or still planned to pursue surgery at 12 months. RESULTS: 200 patients were recruited over an 8-month period. Mean age was 45 years; mean BMI was 48 kg/m(2), and 77% were female. The 12-month follow-up rate was 95%. At 12 months, 33 patients (17.6%) had surgery and 30 (16.0%) still planned to have surgery. There was no association between age, gender, or obesity-associated conditions and surgery or plan to have surgery. Patients having surgery or still planning to have surgery had significantly worse scores for quality of life and better scores for decisional conflict (indicating readiness to make a decision). CONCLUSION: The decision to have bariatric surgery is strongly associated with patients' perceptions of their current quality of life. In addition, lower decisional conflict and higher self-efficacy are predictive of surgery. Interestingly, factors that clinicians might consider important, such as gender, age, and the presence of obesity-associated co-morbidities did not influence patients' decisions.

Changes in long luteal protocol affects the number of days of stimulation: evolution of an assisted reproductive technology practice.

OBJECTIVE: To determine if the types of drugs used in controlled ovarian hyperstimulation influence the number of days of stimulation. STUDY DESIGN: This retrospective study of couples presenting at an assisted reproductive technology (ART) facility January 1997 through December 2007 included patients who were < 40 years of age, had a body mass index (BMI) of 20-35, used fresh sperm or oocytes, had > or = 3 embryos available on day 3, never had previous ART, and did not use a gestational carrier. Data analysis was limited to patients treated with long luteal stimulation. Data were separated into two groups: patients stimulated with urinary drugs and those stimulated with recombinant drugs. RESULTS: The groups were not different in age and day 3 follicle-stimulating hormone values, but were different in BMI, diagnoses, and fertilization methods. There were a significantly greater number of days of stimulation, total number of follicles produced, and peak estradiol level in the recombinant group. The recombinant group had less drug given per day, less endometrial thickness, and fewer embryos transferred. CONCLUSION: A change in our long luteal stimulation protocol appears to have lengthened the days of stimulation for our patients without altering pregnancy rate.

Evidence that bears are induced ovulators.

The objective of this study was to determine if black bears are induced ovulators. We conducted a single experiment with two replicates; each replicate was divided into two arms: females exposed to male bears and females without male exposure. We used laparoscopy to examine ovaries for corpora lutea and measured serum progesterone concentrations. Six of the seven isolated females failed to ovulate, while seven of the eight females exposed to males produced one to four corpora lutea. Furthermore, isolated females had significantly lower progesterone concentrations than females exposed to males. Thus, our data suggest that the American black bear is an induced ovulator. These results may aid biologists in their efforts to reproduce ursids in controlled environments.