Gene-Dose-Dependent Reduction Fshr Expression Improves Spatial Memory Deficits in Alzheimer's Mice.

Alzheimer's disease (AD) is a major progressive neurodegenerative disorder of the aging population. High post-menopausal levels of the pituitary gonadotropin follicle-stimulating hormone (FSH) are strongly associated with the onset of AD, and we have shown recently that FSH directly activates the hippocampal Fshr to drive AD-like pathology and memory loss in mice. To establish a role for FSH in memory loss, we used female 3xTg;Fshr+/+, 3xTg;Fshr+/- and 3xTg;Fshr-/- mice that were either left unoperated or underwent sham surgery or ovariectomy at 8 weeks of age. Unoperated and sham-operated 3xTg;Fshr-/- mice were implanted with 17ß-estradiol pellets to normalize estradiol levels. Morris Water Maze and Novel Object Recognition behavioral tests were performed to study deficits in spatial and recognition memory, respectively, and to examine the effects of Fshr depletion. 3xTg;Fshr+/+ mice displayed impaired spatial memory at 5 months of age; both the acquisition and retrieval of the memory were ameliorated in 3xTg;Fshr-/- mice and, to a lesser extent, in 3xTg;Fshr+/- mice- -thus documenting a clear gene-dose-dependent prevention of hippocampal-dependent spatial memory impairment. At 5 and 10 months, sham-operated 3xTg;Fshr-/- mice showed better memory performance during the acquasition and/or retrieval phases, suggesting that Fshr deletion prevented the progression of spatial memory deficits with age. However, this prevention was not seen when mice were ovariectomized, except in the 10-month-old 3xTg;Fshr-/- mice. In the Novel Object Recognition test performed at 10 months, all groups of mice, except ovariectomized 3xTg;Fshr-/- mice showed a loss of recognition memory. Consistent with the neurobehavioral data, there was a gene-dose-dependent reduction mainly in the amyloid ß40 isoform in whole brain extracts. Finally, serum FSH levels < 8 ng/mL in 16-month-old APP/PS1 mice were associated with better retrieval of spatial memory. Collectively, the data provide compelling genetic evidence for a protective effect of inhibiting FSH signaling on the progression of spatial and recognition memory deficits in mice, and lay a firm foundation for the use of an FSH-blocking agent for the early prevention of cognitive decline in postmenopausal women.

The impact of smoking and smoking cessation interventions on outcomes following single-level anterior cervical discectomy and fusion procedures.

BACKGROUND: While several studies explore the impact of smoking tobacco on spinal fusion outcomes, there is a paucity of literature on the influence of modern smoking cessation therapies on such outcomes in patients undergoing anterior cervical discectomy and fusion (ACDF). OBJECTIVE: Our study explores the outcomes of single-level ACDF surgery in nonsmokers, active smokers, and smokers undergoing cessation therapy. METHODS: MARINER30, an all-payer claims database, was utilized to identify patients undergoing single-level ACDF between 2010 and 2019. The primary outcomes were the rates of composite surgical complications, dysphagia, hematoma, symptomatic pseudarthrosis, instrumentation removal, need for revision surgery, and all-cause readmission rates within 30 and 90-days. RESULTS: The matched population consisted of 5769 patients undergoing single-level ACDF with 1923 (33.33%) in each of the following groups: (1) nonsmokers; (2) active smokers; and (3) patients undergoing smoking cessation therapy. Nonsmokers had significantly lower rates of composite surgical complications (3.74% vs 13.05% vs 15.08%), revision surgery (4.06% vs 20.07% vs 22.88%), instrumentation removal (0.83% vs. 2.08% vs. 2.76%), and dysphagia (0.36% vs 0.99% vs 0.62%) when compared to patients in the active smoking and smoking cessation groups, respectively. CONCLUSION: Patients using smoking cessation therapy were more likely to develop postoperative dysphagia and undergo revision surgery when compared to their actively smoking counterparts. While surgeons routinely recommend smoking cessation prior to surgery, the effects of smoking cessation therapies on surgical outcomes are not well characterized.

First-in-class humanized FSH blocking antibody targets bone and fat.

Blocking the action of FSH genetically or pharmacologically in mice reduces body fat, lowers serum cholesterol, and increases bone mass, making an anti-FSH agent a potential therapeutic for three global epidemics: obesity, osteoporosis, and hypercholesterolemia. Here, we report the generation, structure, and function of a first-in-class, fully humanized, epitope-specific FSH blocking antibody with a KD of 7 nM. Protein thermal shift, molecular dynamics, and fine mapping of the FSH-FSH receptor interface confirm stable binding of the Fab domain to two of five receptor-interacting residues of the FSHß subunit, which is sufficient to block its interaction with the FSH receptor. In doing so, the humanized antibody profoundly inhibited FSH action in cell-based assays, a prelude to further preclinical and clinical testing.

CaRE @ Home: Pilot Study of an Online Multidimensional Cancer Rehabilitation and Exercise Program for Cancer Survivors.

BACKGROUND: Although facility-based cancer rehabilitation and exercise programs exist, patients are often unable to attend due to distance, cost, and other competing obligations. There is a need for scalable remote interventions that can reach and serve a larger population. METHODS: We conducted a mixed methods pilot study to assess the feasibility, acceptability and impact of CaRE@Home: an 8-week online multidimensional cancer rehabilitation and exercise program. Feasibility and acceptability data were captured by attendance and adherence metrics and through qualitative interviews. Preliminary estimates of the effects of CaRE@Home on patient-reported and physically measured outcomes were calculated. RESULTS: A total of n = 35 participated in the study. Recruitment (64%), retention (83%), and adherence (80%) rates, along with qualitative findings, support the feasibility of the CaRE@Home intervention. Acceptability was also high, and participants provided useful feedback for program improvements. Disability (WHODAS 2.0) scores significantly decreased from baseline (T1) to immediately post-intervention (T2) and three months post-intervention (T3) (p = 0.03 and p = 0.008). Physical activity (GSLTPAQ) levels significantly increased for both Total LSI (p = 0.007 and p = 0.0002) and moderate to strenuous LSI (p = 0.003 and p = 0.002) from baseline to T2 and T3. Work productivity (iPCQ) increased from T1 to T3 (p = 0.026). There was a significant increase in six minute walk distance from baseline to T2 and T3 (p < 0.001 and p = 0.010) and in grip strength from baseline to T2 and T3 (p = 0.003 and p < 0.001). CONCLUSIONS: Results indicate that the CaRE@Home program is a feasible and acceptable cancer rehabilitation program that may help cancer survivors regain functional ability and decrease disability. In order to confirm these findings, a controlled trial is required.

A novel de novo frameshift mutation in NR0B1 and low prenatal estriol in adrenal hypoplasia congenita.

Mutations in the gene NR0B1 have been associated with several clinical phenotypes of X-linked adrenal hypoplasia congenita (AHC). The degree and onset of adrenal insufficiency and involvement of hypogonadotropic hypogonadism is variable and may not be concordant with the identified mutation. We review a patient with AHC in which prenatal estriol levels were low, presenting with early-onset mineralocorticoid deficiency in the newborn period followed by glucocorticoid deficiency 2 years later. The reported child is hemizygous for a novel mutation that is deemed de novo in the ligand-binding site of the protein (DAX1) expressed by NR0B1. The identified frameshift mutation results in a T407N/fs protein change. Low prenatal estriol levels may represent a sensitive marker of potentially fatal disorders associated with adrenal insufficiency and should be utilized more frequently. Additionally, accurate reporting of mutations in NR0B1 and the associated phenotype are important to eventually establish a genotype-phenotype correlation that may help anticipate guidance in AHC.

Validation of the APTIMA Combo 2 assay for the detection of Chlamydia trachomatis and Neisseria gonorrhoeae in SurePath liquid-based pap test samples taken with different collection devices.

Mocked samples of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) diluted in SurePath liquid-based Pap (L-Pap) fluid were detected by the APTIMA Combo 2 assay to end points 10-fold greater than dilutions in specimen transport media. Pooled L-Pap clinical specimens yielded CT-positive results after storage at room temperature for 10 days. Based on an infected patient standard for comparison, cervical swabs, urine, and SurePath L-Pap test samples collected with a SurePath cervical broom or ThinPrep cytobrush from 520 women then tested by APTIMA Combo 2 assay, detected 25 (4.8%) with CT, 5 (1.0%) with (GC), and 3 (0.6%) with both. Percent sensitivities (80-84), specificities (99.8-100), positive (99.5-100) and negative (99.2-99) predictive values of SurePath L-Pap for CT were validated as similar to those reported in a previously published multicenter trial. All values for GC were 100%. One collection device was not significantly better than the other.