Correction: Neonatal Circumcision: What Are the Factors Affecting Parental Decision?

[This corrects the article DOI: 10.7759/cureus.19415.].

Strategies to Increase Testosterone in Men Seeking Fertility.

Prevalence of testosterone deficiency is increasing in the adolescent and young adult male population. As the average paternal age rises, there is a significant population of men with hypogonadism seeking testosterone therapy wishing to achieve or maintain fertility potential. Identification of potential lifestyle modifications that may improve the testosterone deficiency is one of the initial interventions of the holistic strategy in treatment. This is followed by drug therapy; however, traditional testosterone therapy acts as a contraceptive by suppressing the hypothalamus-pituitary-gonadal (HPG) axis and therefore cannot be used as a treatment strategy. A solution has been the off-label use of selective estrogen receptor modulators, human chorionic gonadotropin (hCG), and anastrozole inhibitors to treat hypogonadal symptoms while increasing intratesticular testosterone, a necessity for spermatogenesis. Recently, a novel therapy, Natesto intranasal testosterone gel, has been shown to increase serum testosterone levels while maintaining semen parameters. This is hypothesized to be because of its short-acting properties having lesser effect on the HPG axis, in contrast to the long-acting properties of traditional testosterone therapy. It is important to differentiate hypogonadal men between those seeking to achieve or maintain fertility status because the drug therapy of choice differs. This can be accomplished by determining the levels of 17-hydroxyprogesterone (17-OHP), because it is a biomarker for intratesticular testosterone. Those with low 17-OHP may wish to initiate treatment with alternative therapies, whereas those with high 17-OHP may trial short-acting testosterone therapies. As the urologist's armamentarium continues to increase, better strategies to increase testosterone levels in men seeking fertility can be achieved.

Neonatal Circumcision: What Are the Factors Affecting Parental Decision?

INTRODUCTION: The American Academy of Pediatrics (AAP) guidelines state that the health benefits of circumcision outweigh the risks, but these benefits are not enough to recommend universal newborn circumcision. Therefore, it is the guardians' decision to circumcise their son. In this study, we assess the factors that influence the decision-making process for newborn circumcision. METHODS: A prospective study was done from January to April 2020 for newborn circumcision. AAP guidelines were used as an educational tool and given to the parents on the day of patient circumcision assessment. On procedure day, a self-reported survey regarding the reasons for circumcision and the usefulness of the guideline as an educational resource was given to guardians. RESULTS:  A total of 265 parents completed the survey. Of the study variables, the future health of the child and the circumcision status of the father were considered extremely important factors influencing the decision-making process for 168 (63.4%) and 90 (34%) guardians, respectively. The study showed that 226 (85.3%) of the parents found the AAP guidelines helpful whereas 39 (14.7%) did not. CONCLUSION:  Overall results suggest that the health of the child and the father of the child being circumcised are the primary factors that influence the guardians' decision to circumcise their child. In addition, providing parents with an educational resource such as the AAP guidelines policy statement prior to circumcision may serve as a way to supplement the discussion between parents and providers.

Histopathology and Ultrastructural Findings of Fatal COVID-19 Infections on Testis.

PURPOSE: To evaluate the presence and analyze the pathological changes within the testes of patients who died or recovered from severe acute respiratory syndrome coronavirus 2 (COVID-19) complications. MATERIALS AND METHODS: Testis tissue was collected from autopsies of COVID-19 positive (n=6) and negative men (n=3). Formalin-fixed paraffin-embedded tissues were stained with hematoxylin and eosin (H&E) and subjected to immunofluorescence for angiotensin-converting enzyme 2 (ACE-2) expression. Fluorescent-labeled tissue slides were imaged on a quantitative pathology scope with various zoom levels allowing for qualitative and quantitative interpretation. Tissue from four COVID-19 positive autopsy cases and a live seroconverted patient was imaged with transmission electron microscopy (TEM). RESULTS: H&E histomorphology showed three of the six COVID-19 biopsies had normal spermatogenesis while the remaining three had impaired spermatogenesis. TEM showed the COVID-19 virus in testis tissue of one COVID-19 positive autopsy case and the live biopsy, H&E stain on the same autopsy case demonstrated interstitial macrophage and leukocyte infiltration. Immunofluorescent stained slides from six COVID-19 positive men demonstrated a direct association between increased quantitative ACE-2 levels and impairment of spermatogenesis. CONCLUSIONS: The novel COVID-19 has an affinity for ACE-2 receptors. Since ACE-2 receptor expression is high in the testes, we hypothesized that COVID-19 is prevalent in testes tissue of infected patients. This study suggests the male reproductive tract, specifically the testes, may be targets of COVID-19 infection. We found an inverse association between ACE-2 receptor levels and spermatogenesis, suggesting a possible mechanism of how COVID-19 can cause infertility.

Leydig stem cells and future therapies for hypogonadism.

PURPOSE OF REVIEW: In this review, we outline the most recent advances in the development of Leydig stem cells (LSCs) and summarize the current and upcoming treatments for hypogonadism. RECENT FINDINGS: In-vitro and in-vivo studies show that inducing stem cells to differentiate into testosterone-producing adult Leydig cells is possible. In addition, LSCs can be grafted with Sertoli cells to increase testosterone levels in vivo. This therapy causes minimal effects on luteinizing hormone and follicle stimulating hormone levels. Novel therapies for hypogonadism include varying methods of testosterone delivery such as intranasal and oral agents, as well as novel selective estrogen and androgen receptor modulators. SUMMARY: LSC therapies provide an effective way of increasing testosterone levels without detrimentally affecting gonadotropin levels. Next steps in developing viable Leydig cell grafting options for the treatment of hypogonadism should include the assessment of efficacy and potency of current animal models in human trials. Recently, both intranasal and oral testosterone have been made available and shown promising results in treating hypogonadism while maintaining fertility. Enclomiphene citrate and selective androgen receptor modulators have been suggested as future therapies for hypogonadism; however, further studies assessing efficacy and adverse effects are needed.

Long-term outcomes after surgery for catastrophic epilepsy in infants: institutional experience and review of the literature.

OBJECTIVE: Uncontrolled epilepsy is associated with serious deleterious effects on the neurological development of infants and has been described as "catastrophic epilepsy." Recently, there has been increased emphasis on early surgical interventions to preserve or rescue neurodevelopmental outcomes in infants with early intractable epilepsy. The enthusiasm for early treatments is often tempered by concerns regarding the morbidity of neurosurgical procedures in very young patients. Here, the authors report outcomes following the surgical management of infants (younger than 1 year). METHODS: The authors performed a retrospective review of patients younger than 1 year of age who underwent surgery for epilepsy at Miami (Nicklaus) Children's Hospital and Jackson Memorial Hospital between 1994 and 2018. Patient demographics, including the type of interventions, were recorded. Seizure outcomes (at last follow-up and at 1 year postoperatively) as well as complications are reported. RESULTS: Thirty-eight infants (median age 5.9 months) underwent a spectrum of surgical interventions, including hemispherectomy (n = 17), focal resection (n = 13), and multilobe resections (n = 8), with a mean follow-up duration of 9.1 years. Hemimegalencephaly and cortical dysplasia were the most commonly encountered pathologies. Surgery for catastrophic epilepsy resulted in complete resolution of seizures in 68% (n = 26) of patients, and 76% (n = 29) had a greater than 90% reduction in seizure frequency. Overall mortality and morbidity were 0% and 10%, respectively. The latter included infections (n = 2), infarct (n = 1), and immediate reoperation for seizures (n = 1). CONCLUSIONS: Surgical intervention for catastrophic epilepsy in infants remains safe, efficacious, and durable. The authors' work provides the longest follow-up of such a series on infants to date and compares favorably with previously published series.

Lesion Network Localization of Seizure Freedom following MR-guided Laser Interstitial Thermal Ablation.

Treatment-resistant epilepsy is a common and debilitating neurological condition, for which neurosurgical cure is possible. Despite undergoing nearly identical ablation procedures however, individuals with treatment-resistant epilepsy frequently exhibit heterogeneous outcomes. We hypothesized that treatment response may be related to the brain regions to which MR-guided laser ablation volumes are functionally connected. To test this, we mapped the resting-state functional connectivity of surgical ablations that either resulted in seizure freedom (N = 11) or did not result in seizure freedom (N = 16) in over 1,000 normative connectomes. There was no difference seizure outcome with respect to the anatomical location of the ablations, and very little overlap between ablation areas was identified using the Dice Index. Ablations that did not result in seizure-freedom were preferentially connected to a number of cortical and subcortical regions, as well as multiple canonical resting-state networks. In contrast, ablations that led to seizure-freedom were more functionally connected to prefrontal cortices. Here, we demonstrate that underlying normative neural circuitry may in part explain heterogenous outcomes following ablation procedures in different brain regions. These findings may ultimately inform target selection for ablative epilepsy surgery based on normative intrinsic connectivity of the targeted volume.

Primary Diffuse Leptomeningeal Melanomatosis: Case Report and Review of the Literature.

BACKGROUND: Primary diffuse leptomeningeal melanomatosis (PDLM) is an extremely rare pathologic condition that can mimic several other neurologic disease states. METHODS: We report a rare case of PDLM without evidence of a primary focus. In addition, we performed a comprehensive review of the literature to describe all previously reported cases of PDLM. RESULTS: In the reported case, making the diagnosis of PDLM was difficult. A brain and frontal dural biopsy was nondiagnostic. Computed tomography of the chest, abdomen, and pelvis did not show any distinct solitary mass. After a positron emission tomography scan was performed that showed lumbar sacral enhancement, lumbar dorsal rootlet biopsy was initiated, which was diagnostic of PDLM. Our literature review found 32 previously reported cases of PDLM. Sixteen cases (48.5%) had a distinct focus or mass discovered on imaging workup. The reported case was the seventeenth reported case of PDLM without a distinct focus or mass found on imaging workup. CONCLUSIONS: PDLM is an extremely rare disease, and diagnosis is difficult because of nonspecific clinical, radiographic, and laboratory findings. In approximately half of cases, no distinct mass is shown on imaging workup, which may further complicate diagnosis. PDLM should be on the differential diagnosis for cases of diffuse dural enhancement. Neurosurgical intervention is often limited to ventriculoperitoneal shunting for increased intracranial pressure and dural and cranial biopsy to obtain diagnosis. If the initial biopsy is nondiagnostic, hypermetabolic activity as seen on positron emission tomography may be helpful to find an alternative biopsy site.

Prospective Study of Nonbeneficial Care in Neurocritical Care Unit.

OBJECTIVE: We sought to determine whether a set of simple criteria can identify patients in the neuroscience intensive care unit (NICU) at high risk of poor outcome and delivery of nonbeneficial care early in the course of their illness. Secondarily, factors affecting limitation of care protocols were assessed. METHODS: We prospectively identified patients who were admitted to the NICU with partial loss of brainstem reflexes persisting for >24 hours due to an intrinsic lesion of the brain (trauma, stroke, hemorrhage, etc.). RESULTS: The study included 102 patients. Seventy-two of them died after a mean of 16 days (median: 8 days), and 23 remained comatose, locked-in, or in a vegetative state. Four were conscious and following commands, while 3 were minimally conscious, episodically obeying simple commands. Three out of 4 conscious patients were young males with traumatic brain injuries. Patients who remained full code spent a mean of 22.2 days in the NICU, compared with 10.4 for those who had withdrawal of care (P = 0.022) and 11.9 for patients who received a do-not-resuscitate order (P = 0.045). Time to death did not differ significantly between the groups. Overall, institution of various limitations of care protocols correlated positively with older age (odds ratio [OR] = 1.07, P = 0.0008), being treated on the neurology service (OR = 4.4, P = 0.043), and having health insurance (OR = 5.4, P = 0.03). CONCLUSIONS: We identified simple criteria that can be used to identify patients in the NICU setting for whom continued aggressive care is likely nonbeneficial. Our analysis revealed demographic, social, and economic factors correlating with proxies' willingness to consider limitation of care.

Anxious behavior induces elevated hippocampal Cb2 receptor gene expression.

Anxiety is differentially expressed across a continuum of stressful/fearful intensity, influenced by endocannabinoid systems and receptors. The hippocampus plays important roles in the regulation of affective behavior, emotion, and anxiety, as well as memory. Location of Cb1/Cb2 receptor action could be important in determining emotional valence, because while the dorsal hippocampus is involved in spatial memory and cognition, the ventral hippocampus has projections to the PFC, BNST, amygdala, and HPA axis, and is important for emotional responses to stress. During repeated social defeat in a Stress-Alternatives Model arena (SAM; an oval open field with escape portals only large enough for smaller mice), smaller C57BL6/N mice are subject to fear conditioning (tone=CS), and attacked by novel larger aggressive CD1 mice (US) over four daily (5min) trials. Each SAM trial presents an opportunity for escape or submission, with stable behavioral responses established by the second day of interaction. Additional groups had access to a running wheel. Social aggression plus fear conditioning stimulates enhanced Cb2 receptor gene expression in the dorsal CA1, dorsal and ventral dentate gyrus subregions in animals displaying a submissive behavioral phenotype. Escape behavior is associated with reduced Cb2 expression in the dorsal CA1 region, with freezing and escape latency correlated with mRNA levels. Escaping and submitting animals with access to running wheels had increased Cb2 mRNA in dorsal DG/CA1. These results suggest that the Cb2 receptor system is rapidly induced during anxiogenic social interactions plus fear conditioning or exercise; with responses potentially adaptive for coping mechanisms.

Intensity of anxiety is modified via complex integrative stress circuitries.

Escalation of anxious behavior while environmentally and socially relevant contextual events amplify the intensity of emotional response produces a testable gradient of anxiety shaped by integrative circuitries. Apprehension of the Stress-Alternatives Model apparatus (SAM) oval open field (OF) is measured by the active latency to escape, and is delayed by unfamiliarity with the passageway. Familiar OF escape is the least anxious behavior along the continuum, which can be reduced by anxiolytics such as icv neuropeptide S (NPS). Social aggression increases anxiousness in the SAM, reducing the number of mice willing to escape by 50%. The apprehension accompanying escape during social aggression is diminished by anxiolytics, such as exercise and corticotropin releasing-factor receptor 1 (CRF1) antagonism, but exacerbated by anxiogenic treatment, like antagonism of α2-adrenoreceptors. What is more, the anxiolytic CRF1 and anxiogenic α2-adrenoreceptor antagonists also modify behavioral phenotypes, with CRF1 antagonism allowing escape by previously submissive animals, and α2-adrenoreceptor antagonism hindering escape in mice that previously engaged in it. Gene expression of NPS and brain-derived neurotrophic factor (BDNF) in the central amygdala (CeA), as well as corticosterone secretion, increased concomitantly with the escalating anxious content of the mouse-specific anxiety continuum. The general trend of CeA NPS and BDNF expression suggested that NPS production was promoted by increasing anxiousness, and that BDNF synthesis was associated with learning about ever-more anxious conditions. The intensity gradient for anxious behavior resulting from varying contextual conditions may yield an improved conceptualization of the complexity of mechanisms producing the natural continuum of human anxious conditions, and potential therapies that arise therefrom.

Nuance and behavioral cogency: How the Visible Burrow System inspired the Stress-Alternatives Model and conceptualization of the continuum of anxiety.

By creating the Visible Burrow System (VBS) Bob Blanchard found a way to study the interaction of genetics, physiology, environment, and adaptive significance in a model with broad validity. The VBS changed the way we think about anxiety and affective disorders by allowing the mechanisms which control them to be observed in a dynamic setting. Critically, Blanchard used the VBS and other models to show how behavioral systems like defense are dependent upon context and behavioral elements unique to the individual. Inspired by the VBS, we developed a Stress Alternatives Model (SAM) to further explore the multifaceted dynamics of the stress response with a dichotomous choice condition. Like the VBS, the SAM is a naturalistic model built upon risk assessment and defensive behavior, but with a choice of response: escape or submission to a large conspecific aggressor. The anxiety of novelty during the first escape must be weighed against fear of the aggressor, and a decision must be made. Both outcomes are adaptively significant, evidenced by a 50/50 split in outcome across several study systems. By manipulating the variables of the SAM, we show that a gradient of anxiety exists that spans the contextual settings of escaping an open field, escaping from aggression, and submitting to aggression. These findings correspond with increasing levels of corticosterone and increasing levels of NPS and BDNF in the central amygdala as the context changes.Whereas some anxiolytics were able to reduce the latency to escape for some animals, only with the potent anxiolytic drug antalarmin (CRF1R-blocker) and the anxiogenic drug yohimbine (α2 antagonist) were we able to reverse the outcome for a substantial proportion of individuals. Our findings promote a novel method for modeling anxiety, offering a distinction between low-and-high levels, and accounting for individual variability. The translational value of the VBS is immeasurable, and it guided us and many other researchers to seek potential clinical solutions through a deeper understanding of regional neurochemistry and gene expression in concert with an ecological behavioral model.

Neuropeptide S and BDNF gene expression in the amygdala are influenced by social decision-making under stress.

In a newly developed conceptual model of stressful social decision-making, the Stress-Alternatives Model (SAM; used for the 1st time in mice) elicits two types of response: escape or remain submissively. Daily (4d) aggressive social interaction in a neutral arena between a C57BL6/N test mouse and a larger, novel aggressive CD1 mouse, begin after an audible tone (conditioned stimulus; CS). Although escape holes (only large enough for smaller test animals) are available, and the aggressor is unremittingly antagonistic, only half of the mice tested utilize the possibility of escape. During training, for mice that choose to leave the arena and social interaction, latency to escape dramatically decreases over time; this is also true for control C57BL6/N mice which experienced no aggression. Therefore, the open field of the SAM apparatus is intrinsically anxiogenic. It also means that submission to the aggressor is chosen despite this anxiety and the high intensity of the aggressive attacks and defeat. While both groups that received aggression displayed stress responsiveness, corticosterone levels were significantly higher in animals that chose submissive coexistence. Although both escaping and non-escaping groups of animals experienced aggression and defeat, submissive animals also exhibited classic fear conditioning, freezing in response to the CS alone, while escaping animals did not. In the basolateral amygdala (BLA), gene expression of brain-derived neurotrophic factor (BDNF) was diminished, at the same time neuropeptide S (NPS) expression was significantly elevated, but only in submissive animals. This increase in submission-evoked NPS mRNA expression was greatest in the central amygdala (CeA), which coincided with decreased BDNF expression. Reduced expression of BDNF was only found in submissive animals that also exhibit elevated NPS expression, despite elevated corticosterone in all socially interacting animals. The results suggest an interwoven relationship, linked by social context, between amygdalar BDNF, NPS and plasma corticosterone.

Anxiolytic function of the orexin 2/hypocretin A receptor in the basolateral amygdala.

The orexin/hypocretin system interacts with many of the same circuitries contributing to stress-associated disorders like depression and anxiety. These include potentially reciprocal connections with corticotropin releasing factor (CRF) neurons which drive the hypothalamic-pituitary-adrenal (HPA) endocrine response in addition to having an anxiogenic effect in the central amygdala (CeA). Antagonism of the orexin type 1 receptor (Orx1) in the hypothalamus has also been shown to block panic attacks. However, few studies have investigated the effect of orexinergic signaling in the basolateral amygdala (BLA) which is responsible for contextual fear, and modulates the activity of the CeA. To this end, we chronically stressed c57bl/6 mice with social defeat and examined the gene expression of the orexin receptors in the BLA. We found that the transcripts for the Orx1 and Orx2 receptors diverged in the BLA with Orx1 increasing and Orx2 decreasing in animals that were susceptible to the chronic defeat. These changes were not seen in the prelimbic cortex (PrL) which sends efferents to the BLA. We then tried to recapitulate these expression patterns in the BLA using short hairpin interfering sequences delivered by adeno-associated viruses to knock down the orexin receptors. While the Orx1 knockdown did reduce locomotor activity, it did not decrease depressive or anxious behaviors. Knocking down the Orx2 receptors in the BLA increased anxious behavior as measured by reduced social preference and reduced time spent in the center of an open field. Due to the divergent expression patterns of the two receptors in response to chronic stress, orexinergic activity in the BLA may be responsible for bidirectional modulation of anxious behavior. Furthermore, these data raise the possibility that an Orx2 agonist may serve as an effective means to treat anxiety disorders.