Enlargement of the genital hiatus is associated with prolapse recurrence in patients undergoing sacrospinous ligament fixation.

OBJECTIVE: To correlate genital hiatus (GH) size with surgical failures in patients undergoing sacrospinous ligament fixation (SSLF) and compare anatomic outcomes after classification based on GH size. METHODS: A retrospective review of 81 patients who underwent SSLF for apical prolapse from 2010 to 2016 at a teaching hospital. Anatomical outcome is reported using the Pelvic Organ Prolapse Quantifications System. A comparison of parametric continuous variables was performed using unpaired Student t test. Categorical variables were evaluated using Pearson's χ2 test and Fisher's exact test. A P value <0.05 was considered significant. RESULTS: Among the 81 patients, no difference in age, parity, body mass index, preoperative prolapse stage or follow-up time was noted between those whose surgery succeeded and those with failed surgery. Postoperatively, a widened GH was significantly associated with recurrent prolapse (P < 0.001). When the preoperative size of the GH was dichotomized into widened (≥4 cm) or normal (<4 cm), there was a non-significant (P = 0.444) trend of more failures in the widened GH group. A posterior colporrhaphy did not improve success. CONCLUSION: Both preoperative and postoperative widened GH correlated with having more surgical failures following SSLF. Importantly, postoperatively a normal size GH was significantly associated with more surgical success.

Uterus-Sparing Surgery: Outcomes of Transvaginal Uterosacral Ligament Hysteropexy.

STUDY OBJECTIVE: Recently, there has been a paradigm shift toward uterine conservation during the surgical management of pelvic organ prolapse (POP), specifically uterine prolapse. There are few reports on transvaginal uterosacral ligament hysteropexy (TULH). This study aimed to describe our surgical technique and outcomes. DESIGN: Retrospective review and description of surgical technique. Anatomic outcome has been reported using the POP quantification system. Complications were segregated. A comparison of parametric continuous variables was performed using paired t test. Categoric variables were evaluated using the Pearson χ2 test and the Fisher exact test. A p-value <.05 was considered significant. SETTING: Teaching hospital. PATIENTS: Forty patients who underwent TULH from 2009 to 2017. INTERVENTIONS: TULH. MEASUREMENTS AND MAIN RESULTS: A total of 40 patients met the inclusion criteria. Of these, 56.1% had preoperative stage 3 prolapse. The median operative time was 116 minutes. The mean estimated blood loss was 158.5 mL. Transient ureteral obstruction occurred in 2 patients. The mean follow-up time was 17.2 months, and all patients had significant improvement of prolapse (p <.001). There was also an improvement in urinary incontinence and bladder storage symptoms (p <.001). None of the patients were reoperated on for recurrent POP. CONCLUSION: TULH is an effective uterus-preserving surgical alternative for the treatment of uterovaginal prolapse and provides good apical support. It is also associated with a low short-term recurrence and incidence of reoperation. TULH is a viable option for suitable patients with uterovaginal prolapse who desire uterine conservation.

Severe systemic delayed dermatitis in a patient with nickel-titanium sterilization microinserts perforating the uterus.

We report a case of severe systemic delayed dermatitis in a patient with nickel-titanium sterilization microinserts placement complicated by uterine perforation and polyethylene terephthalate (PET) exposure. We hypothesize that delayed dermatitis may be caused by the exposure of PET fibers in this patient with underlying autoimmune disorder. Further research on the use of PET and the potential of systemic dermatologic reactions when exposure occurs is needed, especially when considering the inclusion of PET in future implant device development.

Estradiol treatment improves biological rhythms in a preclinical rat model of menopause.

The perimenopausal transition at middle age is often associated with hot flashes and sleep disruptions, metabolic changes, and other symptoms. Whereas the mechanisms for these processes are incompletely understood, both aging (AG) and a loss of ovarian estrogens play contributing roles. Furthermore, the timing of when estradiol (E) treatment should commence and for how long are key clinical questions in the management of symptoms. Using a rat model of surgical menopause, we determined the effects of regimens of E treatment with differing time at onset and duration of treatment on diurnal rhythms of activity and core temperature and on food intake and body weight. Reproductively mature (MAT, ∼4 months) or AG (∼11 months) female rats were ovariectomized, implanted intraperitoneally with a telemetry device, and given either a vehicle (V) or E subcutaneous capsule implantation. Rats were remotely recorded for 10 days per month for 3 (MAT) or 6 (AG) months. To ascertain whether delayed onset of treatment affected rhythms, a subset of AG-V rats had their capsules switched to E at the end of 3 months. Another set of AG-E rats had their capsules removed at 3 months to determine whether beneficial effects of E would persist. Overall, activity and temperature mesor, robustness, and amplitude declined with AG. Compared to V treatment, E-treated rats showed (1) better maintenance of body weight and food intake; (2) higher, more consolidated activity and temperature rhythms; and (3) higher activity and temperature robustness and amplitude. In the AG arm of the study, switching treatment from V to E or E to V quickly reversed these patterns. Thus, the presence of E was the dominant factor in determining stability and amplitude of locomotor activity and temperature rhythms. As a whole, the results show benefits of E treatment, even with a delay, on biological rhythms and physiological functions.

The timing and duration of estradiol treatment in a rat model of the perimenopause: Influences on social behavior and the neuromolecular phenotype.

This study tested the effects of timing and duration of estradiol (E2) treatment, factors that are clinically relevant to hormone replacement in perimenopausal women, on social behavior and expression of genes in brain regions that regulate these behaviors. Female rats were ovariectomized (OVX) at 1year of age, roughly equivalent to middle-age in women, and given E2 or vehicle for different durations (3 or 6months) and timing (immediately or after a 3-month delay) relative to OVX. Social and ultrasonic vocalization (USV) behaviors were assessed at the 3 and 6month timepoints, and the rats' brains were then used for gene expression profiling in hypothalamus (supraoptic nucleus, paraventricular nucleus), bed nucleus of the stria terminalis, medial amygdala, and prefrontal cortex using a 48-gene qPCR platform. At the 3-month post-OVX testing period, E2 treatment significantly decreased the number of frequency-modulated USVs emitted. No effects of hormone were found at the 6-month testing period. There were few effects of timing and duration of E2 in a test of social preference of a rat given a choice between her same-sex cagemate and a novel conspecific. For gene expression, effects of timing and duration of E2 were region-specific, with the majority of changes found for genes involved in regulating social behavior such as neuropeptides (Oxt, Oxtr &Avp), neurotransmitters (Drd1, Drd2, Htr2a, Grin2d &Gabbr1), and steroid hormone receptors (Esr2, Ar, Pgr). These data suggest that the mode of E2 treatment has specific effects on social behavior and expression of target genes involved in the regulation of these behaviors.

Diet-Induced Obesity and Circadian Disruption of Feeding Behavior.

Feeding behavior shows a rhythmic daily pattern, which in nocturnal rodents is observed mainly during the dark period. This rhythmicity is under the influence of the hypothalamic suprachiasmatic nucleus (SCN), the main biological clock. Nevertheless, various studies have shown that in rodent models of obesity, using high-energy diets, the general locomotor activity and feeding rhythms can be disrupted. Here, we review the data on the effects of diet-induced obesity (DIO) on locomotor activity and feeding patterns, as well as the effect on the brain sites within the neural circuitry involved in metabolic and rewarding feeding behavior. In general, DIO may alter locomotor activity by decreasing total activity. On the other hand, DIO largely alters eating patterns, producing increased overall ingestion and number of eating bouts that can extend to the resting period. Furthermore, within the hypothalamic areas, little effect has been reported on the molecular circadian mechanism in DIO animals with ad libitum hypercaloric diets and little or no data exist so far on its effects on the reward system areas. We further discuss the possibility of an uncoupling of metabolic and reward systems in DIO and highlight a gap of circadian and metabolic research that may help to better understand the implications of obesity.

The effects of long-term estradiol treatment on social behavior and gene expression in adult female rats.

This study tested the effects of long-term estradiol (E2) replacement on social behavior and gene expression in brain nuclei involved in the regulation of these social behaviors in adult female rats. We developed an ultrasonic vocalization (USV) test and a sociability test to examine communications, social interactions, and social preference, using young adult female cagemates. All rats were ovariectomized (OVX) and implanted with a Silastic capsule containing E2 or vehicle, and housed in same-treatment pairs for a 3-month period. Then, rats were behaviorally tested, euthanized, and 5 nuclei in the brain's social decision-making circuit were selected for neuromolecular profiling by a multiplex qPCR method. Our novel USV test proved to be a robust tool to measure numbers and types of calls emitted by cagemates that had been reintroduced after a 1-week separation. Results also showed that E2-treated OVX rats had profoundly decreased numbers of USV calls compared to vehicle-treated OVX rats. In a test of sociability, in which a female was allowed to choose between her cagemate or a same-treatment novel rat, we found few effects of E2 compared to vehicle, although interestingly, rats chose the cagemate over an unfamiliar conspecific. Gene expression results revealed that the supraoptic nucleus had the greatest number of gene changes caused by E2: Oxt, Oxtr and Avp were increased, and Drd2, Htr1a, Grin2b, and Gabbr1 were decreased, by E2. No genes were affected in the prefrontal cortex, and 1-4 genes were changed in paraventricular nucleus (Pgr), bed nucleus of the stria terminalis (Oxtr, Esr2, Dnmt3a), and medial amygdala (Oxtr, Ar, Foxp1, Tac3). Thus, E2 changes communicative interactions between adult female rats, together with selected expression of genes in the brain, especially in the supraoptic nucleus.

Testing the critical window of estradiol replacement on gene expression of vasopressin, oxytocin, and their receptors, in the hypothalamus of aging female rats.

The current study tested the "critical window" hypothesis of menopause that postulates that the timing and duration of hormone treatment determine their potential outcomes. Our focus was genes in the rat hypothalamus involved in social and affiliative behaviors that change with aging and/or estradiol (E2): Avp, Avpr1a, Oxt, Oxtr, and Esr2 in the paraventricular nucleus (PVN) and supraoptic nucleus (SON). Rats were reproductively mature or aging adults, ovariectomized, given E2 or vehicle treatment of different durations, with or without a post-ovariectomy delay. Our hypothesis was that age-related changes in gene expression are mitigated by E2 treatments. Contrary to this, PVN Oxtr increased with E2, and Avpr1a increased with age. In the SON, Avpr1a increased with age, Oxtr with age and timing, and Avp was altered by duration. Thus, chronological age and E2 have independent actions on gene expression, with the "critical window" hypothesis supported by the observed timing and duration effects.

Polysomnographic sleep disturbances in nicotine, caffeine, alcohol, cocaine, opioid, and cannabis use: A focused review.

BACKGROUND AND OBJECTIVES: In the United States, approximately 60 million Americans suffer from sleep disorders and about 22 million Americans report substance dependence or use disorders annually. Sleep disturbances are common consequences of substance use disorders and are likely found in primary care as well as in specialty practices. The aim of this review was to evaluate the effects of the most frequently used substances-nicotine, alcohol, opioids, cocaine, caffeine, and cannabis-have on sleep parameters measured by polysomnography (PSG) and related clinical manifestations. METHODS: We used electronic databases such as PubMED and PsycINFO to search for relevant articles. We only included studies that assessed sleep disturbances using polysomnography and reviewed the effects of these substances on six clinically relevant sleep parameters: Total sleep time, sleep onset latency, rapid-eye movement, REM latency, wake after sleep onset, and slow wave sleep. RESULTS: Our review indicates that these substances have significant impact on sleep and that their effects differ during intoxication, withdrawal, and chronic use. Many of the substance-induced sleep disturbances overlap with those encountered in sleep disorders, medical, and psychiatric conditions. Sleep difficulties also increase the likelihood of substance use disorder relapse, further emphasizing the need for optimizing treatment interventions in these patients. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: Our review highlights the importance of systematically screening for substance use in patients with sleep disturbances and highlights the need for further research to understand mechanisms underlying substances-induced sleep disturbances and on effective interventions addressing these conditions.

Testing the Critical Window Hypothesis of Timing and Duration of Estradiol Treatment on Hypothalamic Gene Networks in Reproductively Mature and Aging Female Rats.

At menopause, the dramatic loss of ovarian estradiol (E2) necessitates the adaptation of estrogen-sensitive neurons in the hypothalamus to an estrogen-depleted environment. We developed a rat model to test the "critical window" hypothesis of the effects of timing and duration of E2 treatment after deprivation on the hypothalamic neuronal gene network in the arcuate nucleus and the medial preoptic area. Rats at 2 ages (reproductively mature or aging) were ovariectomized and given E2 or vehicle replacement regimes of differing timing and duration. Using a 48-gene quantitative low-density PCR array and weighted gene coexpression network analysis, we identified gene modules differentially regulated by age, timing, and duration of E2 treatment. Of particular interest, E2 status differentially affected suites of genes in the hypothalamus involved in energy balance, circadian rhythms, and reproduction. In fact, E2 status was the dominant factor in determining gene modules and hormone levels; age, timing, and duration had more subtle effects. Our results highlight the plasticity of hypothalamic neuroendocrine systems during reproductive aging and its surprising ability to adapt to diverse E2 replacement regimes.

Broad-based nutritional supplementation in 3xTg mice corrects mitochondrial function and indicates sex-specificity in response to Alzheimer's disease intervention.

Nutrition has been highlighted as a potential factor in Alzheimer's disease (AD) risk and decline and has been investigated as a therapeutic target. Broad-based combination diet therapies have the potential to simultaneously effect numerous protective and corrective processes, both directly (e.g., neuroprotection) and indirectly (e.g., improved vascular health). Here we administered either normal mouse chow with a broad-based nutritional supplement or mouse chow alone to aged male and female 3xTg mice and wildtype (WT) controls. After approximately 4 months of feeding, mice were given a battery of cognitive tasks and then injected with a radiolabeled glucose analog. Brains were assessed for differences in regional glucose uptake and mitochondrial cytochrome oxidase activity, AD pathology, and inflammatory markers. Supplementation induced behavioral changes in the 3xTg, but not WT, mice, and the mode of these changes was influenced by sex. Subsequent analyses indicated that differential response to supplementation by male and female 3xTg mice highlighted brain regional strategies for the preservation of function. Several regions involved have been shown to mediate responses to steroid hormones, indicating a mechanism for sex-based vulnerability. Thus, these findings may have broad implications for the human response to future therapeutics.

Elucidating the role of 5-HT(1A) and 5-HT(7) receptors on 8-OH-DPAT-induced behavioral recovery after experimental traumatic brain injury.

8-OH-DPAT is a 5-HT(1A/7) receptor agonist that enhances behavioral recovery after traumatic brain injury (TBI). This study is a first attempt to decipher whether the benefits induced by 8-OH-DPAT after TBI are mediated by 5-HT(1A) or 5-HT(7) receptors. A single i.p. injection of 8-OH-DPAT (0.5 mg/kg) alone or co-administered with either the 5-HT(1A) or 5-HT(7) receptor antagonists WAY 100635 (0.5 mg/kg) or SB 269970 HCl (2.0 mg/kg), respectively, or vehicle control (1.0 mL/kg) was given 15 min after cortical impact or sham injury. Function was assessed by established motor and cognitive tests. No difference in motor performance was observed among the TBI groups. Spatial acquisition was enhanced, relative to vehicle controls, by 8-OH-DPAT alone and when co-administered with WAY 100635, but not when combined with SB 269970 HCl. These data imply that 5-HT(1A) receptor antagonism does not abate the 8-OH-DPAT-induced cognitive benefits, but 5-HT(7) receptor antagonism does, which suggests that the 8-OH-DPAT-induced benefits in this single administration paradigm may be mediated more by 5-HT(7) versus 5-HT(1A) receptors. Evaluation of a specific 5-HT(7) receptor agonist will further elucidate the contribution of 5-HT(1A) and 5-HT(7) receptors on behavioral recovery conferred by acute 8-OH-DPAT treatment after TBI.

Biologic and plastic effects of experimental traumatic brain injury treatment paradigms and their relevance to clinical rehabilitation.

Neuroplastic changes, whether induced by traumatic brain injury (TBI) or therapeutic interventions, alter neurobehavioral outcome. Here we present several treatment strategies that have been evaluated by using experimental TBI models and discuss potential mechanisms of action (ie, plasticity) and how such changes affect function.

Cognitive-impairing effects of medroxyprogesterone acetate in the rat: independent and interactive effects across time.

RATIONALE: The synthetic progestin medroxyprogesterone acetate (MPA), widely used in hormone therapy (HT) and as the contraceptive Depo Provera, is implicated in detrimental cognitive effects in women. Recent evidence in aged ovariectomized (Ovx) rodents shows that short-term MPA treatment impairs cognition and alters the GABAergic system. OBJECTIVES: Using rats, we evaluated the long-lasting cognitive and GABAergic effects of MPA administered in young adulthood (Early-MPA), modeling contraception, and how this early exposure interacts with later MPA treatment (Late-MPA), modeling HT. METHODS: Early-MPA treatment involved weekly anti-ovulatory MPA injections (3.5 mg) from 4 to 8 months of age in ovary-intact rats. At 10 months old, rats were Ovx and weekly MPA injections were re-initiated and continued throughout testing for Late-MPA treatment. RESULTS: On the water radial-arm maze, all MPA-treated groups showed working memory impairment compared to Controls (p < 0.05); Early + Late-MPA rats were impaired on multiple dimensions of working memory (p < 0.05). On the Morris maze, Late-MPA rats showed greater overnight forgetting compared to Controls (p < 0.05). At study conclusion, MPA was detected in serum in all MPA-treated groups except Early-MPA, confirming treatment and clearance from serum in Early-MPA rats. In animals with detectable serum MPA, higher MPA levels were associated with less dorsal-hippocampal glutamic acid decarboxylase, the synthesizing enzyme for GABA (p = 0.0059). CONCLUSIONS: Findings suggest that MPA treatment leads to long-lasting cognitive impairments in the rodent, even in the absence of circulating MPA in animals given prior MPA treatment, which may relate to the GABAergic system. Further research defining the parameters of the negative impact of this widely used progestin on brain and cognition is warranted.