The ovarian follicle is the structural and functional unit of the ovary, composed of the female gamete (the oocyte) and supportive somatic cells. Follicles are not only the source of a female's germ ...cell supply, but also secrete important hormones necessary for proper endocrine function. Folliculogenesis, the growth and maturation of the follicular unit, is a complex process governed by both intrafollicular crosstalk and pituitary-secreted hormones. While the later stages of this process are gonadotropin-dependent, early folliculogenesis appears to be controlled by the ovarian microenvironment and intrafollicular paracrine and autocrine signaling. In vitro follicle culture remains challenging because of the limited knowledge of growth factors and other cytokines influencing early follicle growth. Here we discuss the current state of knowledge on paracrine and autocrine signaling influencing primary follicles as they develop into the antral stage. Given the importance of intrafollicular signaling and the ovarian microenvironment, we reviewed the current engineering approaches for in vitro follicle culture, including 3D systems using natural hydrogels such as alginate and synthetic hydrogels such as poly(ethylene glycol). Our discussion is focused on what drives the proliferation of granulosa cells, development of the thecal layer, and antrum formation-three processes integral to follicle growth up to the antral stage. Further research in this area may reveal the mechanisms behind these complex signaling relationships within the follicle, leading to more successful and physiologically-relevant in vitro culture methods that will translate well to clinical applications.
The 'Guidelines for Parenting Plan Evaluations in Family Law Cases (Guidelines)' are the product of the Association of Family and Conciliation Courts (AFCC) Task Force for the Revisions of the 'Model ...Standards of Practice for Child Custody Evaluation (Model Standards)'.
The medial prefrontal cortex (mPFC) modulates a range of behaviors, including responses to noxious stimuli. While various pain modalities alter mPFC function, our understanding of changes to specific ...cell types underlying pain-induced mPFC dysfunction remains incomplete. Proper activity of cortical GABAergic interneurons is essential for normal circuit function. We find that nerve injury increases excitability of layer 5 parvalbumin-expressing neurons in the prelimbic (PL) region of the mPFC from male, but not female, mice. Conversely, nerve injury dampens excitability in somatostatin-expressing neurons in layer 2/3 of the PL region; however, effects are differential between males and females. Nerve injury slightly increases the frequency of spontaneous excitatory post-synaptic currents (sEPSCs) in layer 5 parvalbumin-expressing neurons in males but reduces frequency of sEPSCs in layer 2/3 somatostatin-expressing neurons in females. Our findings provide key insight into how nerve injury drives maladaptive and sex-specific alterations to GABAergic circuits in cortical regions implicated in chronic pain.
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•Nerve injury enhances excitability of prelimbic PV+ neurons in male mice•Nerve injury reduces EPSC frequency in prelimbic SOM+ neurons in female mice•These changes to PV+ and SOM+ neurons are laminar specific•Nerve injury does not affect PV+ or SOM+ neurons in infralimbic cortex
Jones and Sheets show that a nerve injury model of chronic pain produces distinct changes to separate, but major, subclasses of GABAergic neurons in the prelimbic cortex. These changes are different between male and female mice and provide insight into how chronic pain alters brain circuits in a sex-specific manner.
The "trimorbidity" of substance use disorder and mental and physical illness is associated with living in precarious housing or homelessness. The extent to which substance use increases risk of ...psychosis and both contribute to mortality needs investigation in longitudinal studies. A community-based sample of 437 adults (330 men, mean SD age 40.6 11.2 years) living in Vancouver, Canada, completed baseline assessments between November 2008 and October 2015. Follow-up was monthly for a median 6.3 years (interquartile range 3.1-8.6). Use of tobacco, alcohol, cannabis, cocaine, methamphetamine, and opioids was assessed by interview and urine drug screen; severity of psychosis was also assessed. Mortality (up to November 15, 2018) was assessed from coroner's reports and hospital records. Using data from monthly visits (mean 9.8, SD 3.6) over the first year after study entry, mixed-effects logistic regression analysis examined relationships between risk factors and psychotic features. A past history of psychotic disorder was common (60.9%). Nonprescribed substance use included tobacco (89.0%), alcohol (77.5%), cocaine (73.2%), cannabis (72.8%), opioids (51.0%), and methamphetamine (46.5%). During the same year, 79.3% of participants reported psychotic features at least once. Greater risk was associated with number of days using methamphetamine (adjusted odds ratio aOR 1.14, 95% confidence interval CI 1.05-1.24, p = 0.001), alcohol (aOR 1.09, 95% CI 1.01-1.18, p = 0.04), and cannabis (aOR 1.08, 95% CI 1.02-1.14, p = 0.008), adjusted for demographic factors and history of past psychotic disorder. Greater exposure to concurrent month trauma was associated with increased odds of psychosis (adjusted model aOR 1.54, 95% CI 1.19-2.00, p = 0.001). There was no evidence for interactions or reverse associations between psychotic features and time-varying risk factors. During 2,481 total person years of observation, 79 participants died (18.1%). Causes of death were physical illness (40.5%), accidental overdose (35.4%), trauma (5.1%), suicide (1.3%), and unknown (17.7%). A multivariable Cox proportional hazard model indicated baseline alcohol dependence (adjusted hazard ratio aHR 1.83, 95% CI 1.09-3.07, p = 0.02), and evidence of hepatic fibrosis (aHR 1.81, 95% CI 1.08-3.03, p = 0.02) were risk factors for mortality. Among those under age 55 years, a history of a psychotic disorder was a risk factor for mortality (aHR 2.38, 95% CI 1.03-5.51, p = 0.04, adjusted for alcohol dependence at baseline, human immunodeficiency virus HIV, and hepatic fibrosis). The primary study limitation concerns generalizability: conclusions from a community-based, diagnostically heterogeneous sample may not apply to specific diagnostic groups in a clinical setting. Because one-third of participants grew up in foster care or were adopted, useful family history information was not obtainable. In this study, we found methamphetamine, alcohol, and cannabis use were associated with higher risk for psychotic features, as were a past history of psychotic disorder, and experiencing traumatic events. We found that alcohol dependence, hepatic fibrosis, and, only among participants <55 years of age, history of a psychotic disorder were associated with greater risk for mortality. Modifiable risk factors in people living in precarious housing or homelessness can be a focus for interventions.
Opsoclonus-myoclonus syndrome (OMS) is a rare syndrome characterized by opsoclonus, which is irregular, spontaneous, multivectorial saccadic eye movements, along with diffuse or focal myoclonus and ...sometimes ataxia. OMS is associated with paraneoplastic etiologies in 20%-40% of cases, with small-cell lung and breast cancers the most common associated primary neoplasms in adults, whereas neuroblastoma is more common in children and ovarian teratoma may occur in women younger than 30 years. Onconeural antibodies are often not identified. In existing literature, paraneoplastic OMS precedes identification of the neoplasm, and neurological recovery depends on treatment of the underlying cancer. We describe a 27-year-old woman with the delayed onset of OMS one month after resection of ovarian teratoma, likely due to immune trigger from antigen exposure at the time of resection. She was treated with intravenous methylprednisolone, immunoglobulins, and eventually rituximab with resolution of her symptoms. Identification of OMS after tumor resection and prompt immunotherapy are critical for neurologic recovery. At 30-month follow-up, this patient had not experienced recurrence of OMS.
The structure of a social network as well as peer behaviours are thought to affect personal substance use. Where substance use may create health risks, understanding the contribution of social ...networks to substance use may be valuable for the design and implementation of harm reduction or other interventions. We examined the social support network of people living in precarious housing in a socially marginalized neighborhood of Vancouver, and analysed associations between social network structure, personal substance use, and supporters' substance use.
An ongoing, longitudinal study recruited 246 participants from four single room occupancy hotels, with 201 providing social network information aligned with a 6-month observation period. Use of tobacco, alcohol, cannabis, cocaine (crack and powder), methamphetamine, and heroin was recorded at monthly visits. Ego- and graph-level measures were calculated; the dispersion and prevalence of substances in the network was described. Logistic mixed effects models were used to estimate the association between ego substance use and peer substance use. Permutation analysis was done to test for randomness of substance use dispersion on the social network.
The network topology corresponded to residence (Hotel) with two clusters differing in demographic characteristics (Cluster 1 -Hotel A: 94% of members, Cluster 2 -Hotel B: 95% of members). Dispersion of substance use across the network demonstrated differences according to network topology and specific substance. Methamphetamine use (overall 12%) was almost entirely limited to Cluster 1, and absent from Cluster 2. Different patterns were observed for other substances. Overall, ego substance use did not differ over the six-month period of observation. Ego heroin, cannabis, or crack cocaine use was associated with alter use of the same substances. Ego methamphetamine, powder cocaine, or alcohol use was not associated with alter use, with the exception for methamphetamine in a densely using part of the network. For alters using multiple substances, cannabis use was associated with lower ego heroin use, and lower ego crack cocaine use. Permutation analysis also provided evidence that dispersion of substance use, and the association between ego and alter use was not random for all substances.
In a socially marginalized neighborhood, social network topology was strongly influenced by residence, and in turn was associated with type(s) of substance use. Associations between personal use and supporter's use of a substance differed across substances. These complex associations may merit consideration in the design of interventions to reduce risk and harms associated with substance use in people living in precarious housing.
Right ventricular (RV) dysfunction early after tetralogy of Fallot (TOF) increases post-operative morbidity. We investigated associations of circulating biomarkers and socioeconomic factors with ...early post-operative RV systolic function. Single-center prospective cohort study of infants undergoing TOF repair. Six serologic biomarkers of myocardial fibrosis and wall stress collected at the time of surgery were measured with immunoassay. Geocoding was performed for socioeconomic factors. Multivariate adaptive regression splines (MARS) models identified factors associated with RV function parameters: fractional area change (FAC), global longitudinal strain and strain rate, and free wall strain and strain rate. Seventy-one patients aged 3.5 months (IQR 2.4, 5.2) were included. Galectin-3 was the highest ranked predictor for FAC, global longitudinal strain, and free wall strain, and procollagen type-I carboxy-terminal propeptide (PICP) was the highest ranked predictor for global longitudinal strain rate and free wall strain rate. Several neighborhood characteristics were also highly ranked. Models adjusted
R
2
ranged from 0.71 to 0.85 (FAC, global longitudinal strain/strain rate), and 0.55–0.57 (RV free wall strain/strain rate). A combination of serologic biomarkers, socioeconomic, and clinical variables explain a significant proportion of the variability in RV function after TOF repair. These factors may inform pre-operative risk-stratification for these patients.
Food allergy determined by means of ImmunoCAP was defined as food allergen-specific IgE (sIgE) levels that correlate to a greater than 95% positive predictive value of oral food challenge reaction in ...patients (peanut, 14 kilounits of allergen kUA/L; egg white, 7 kUA/L; and cow's milk, 15 kUA/L).6 sIgE values correlating to clinical food allergy for peanut, egg white, and cow's milk were associated with S aureus colonization (Fig 1). S aureus is a pathogenic microbe that produces multiple virulence factors (eg, superantigens, cytolysins, proteases, lipases, protein A, and microbial surface components recognizing adhesive matrix molecules) that can lead to break down of the epithelial barrier.9 Additionally, exposure of murine models to S aureus toxin leads to increased TH2-mediated responses4,5 and decreased regulatory T-cell function,4 both of which are described in patients with food allergy.10 We propose that the skin microbiome plays an important role in skin barrier function and directs immune responses.
Canada and the United States (U.S.) face an opioid use disorder (OUD) and opioid overdose epidemic. The most effective OUD treatment is opioid agonist therapy (OAT)—buprenorphine (with and without ...naloxone) and methadone. Although federal approval for OAT occurred decades ago, in both countries, access to and use of OAT is low. Restrictive policies and complex regulations contribute to limited OAT access. Through a non-systematic literature scan and a review of publicly available policy documents, we examined and compared OAT policies and practice at the federal (Canada vs. U.S.) and local levels (British Columbia B.C. vs. Oregon). Differences and similarities were noted between federal and local OAT policies, and subsequently OAT access. In Canada, OAT policy control has shifted from federal to provincial authorities. Conversely, in the U.S., federal authorities maintain primary control of OAT regulations. Local OAT health insurance coverage policies were substantively different between B.C. and Oregon. In B.C., five OAT options were available, while in Oregon, only two OAT options were available with administrative limitations. The differences in local OAT access and coverage policies between B.C. and Oregon, may be explained, in part, to the differences in Canadian and U.S. federal OAT policies, specifically, the relaxation of special federal OAT regulatory controls in Canada. The analysis also highlights the complicating contributions, and likely policy solutions, that exist within other drug policy sub-domains (e.g., the prescription regime, and drug control regime) and broader policy domains (e.g., constitutional rights). U.S. policymakers and health officials could consider adopting Canada’s regulatory policy approach to expand OAT access to mitigate the harms of the ongoing opioid overdose epidemic.
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