The homeostatic function of Regnase-2 restricts neuroinflammation.

The precise physiological functions and mechanisms regulating RNase Regnase-2 (Reg-2/ZC3H12B/MCPIP2) activity remain enigmatic. We found that Reg-2 actively modulates neuroinflammation in nontransformed cells, including primary astrocytes. Downregulation of Reg-2 in these cells results in increased mRNA levels of proinflammatory cytokines IL-1ß and IL-6. In primary astrocytes, Reg-2 also regulates the mRNA level of Regnase-1 (Reg-1/ZC3H12A/MCPIP1). Reg-2 is expressed at high levels in the healthy brain, but its expression is reduced during neuroinflammation as well as glioblastoma progression. This process is associated with the upregulation of Reg-1. Conversely, overexpression of Reg-2 is accompanied by the downregulation of Reg-1 in glioma cells in a nucleolytic NYN/PIN domain-dependent manner. Interestingly, low levels of Reg-2 and high levels of Reg-1 correlate with poor-glioblastoma patients' prognoses. While Reg-2 restricts the basal levels of proinflammatory cytokines in resting astrocytes, its expression is reduced in IL-1ß-activated astrocytes. Following IL-1ß exposure, Reg-2 is phosphorylated, ubiquitinated, and degraded by proteasomes. Simultaneously, the Reg-2 transcript is destabilized by tristetraprolin (TTP) and Reg-1 through the AREs elements and conservative stem-loop structure present in its 3'UTR. Thus, the peer-control loop, of Reg-1 and Reg-2 opposing each other, exists. The involvement of TTP in Reg-2 mRNA turnover is confirmed by the observation that high TTP levels correlate with the downregulation of the Reg-2 expression in high-grade human gliomas. Additionally, obtained results reveal the importance of Reg-2 in inhibiting human and mouse glioma cell proliferation. Our current studies identify Reg-2 as a critical regulator of homeostasis in the brain.

Intense pulsed light treatment for the management of meibomian gland dysfunction.

PURPOSE OF REVIEW: Meibomian gland dysfunction (MGD) is one of the most common disorders encountered by ophthalmologists, and its management can prove challenging for both clinicians and patients. Intense pulsed light (IPL), which has been historically used in the field of dermatology, has emerged as a tool to help improve meibomian gland function. The goal of this review is to assess the clinical efficacy, utility, and safety of IPL for the treatment of MGD. RECENT FINDINGS: In recent randomized controlled trials, IPL has been shown to improve meibomian gland function, and subsequently tear film quality and dry eye symptoms. The mechanism of action still remains unclear. Recent literature suggests that IPL may also be used in conjunction with other therapies, such as meibomian gland expression, low-level light therapy, and thermal pulsation. Careful attention should be placed on each patient's Fitzpatrick skin type, as well as protecting the ocular structures to reduce the risk of adverse effects. Cost, accessibility, as well as a limited duration of efficacy may be drawbacks. SUMMARY: There is significant evidence supporting that IPL may be used as a potential well tolerated and effective treatment for MGD, though there are certain caveats regarding its long-term efficacy, accessibility, and cost.

Yin Yang 1 controls cerebellar astrocyte maturation.

Diverse subpopulations of astrocytes tile different brain regions to accommodate local requirements of neurons and associated neuronal circuits. Nevertheless, molecular mechanisms governing astrocyte diversity remain mostly unknown. We explored the role of a zinc finger transcription factor Yin Yang 1 (YY1) that is expressed in astrocytes. We found that specific deletion of YY1 from astrocytes causes severe motor deficits in mice, induces Bergmann gliosis, and results in simultaneous loss of GFAP expression in velate and fibrous cerebellar astrocytes. Single cell RNA-seq analysis showed that YY1 exerts specific effects on gene expression in subpopulations of cerebellar astrocytes. We found that although YY1 is dispensable for the initial stages of astrocyte development, it regulates subtype-specific gene expression during astrocyte maturation. Moreover, YY1 is continuously needed to maintain mature astrocytes in the adult cerebellum. Our findings suggest that YY1 plays critical roles regulating cerebellar astrocyte maturation during development and maintaining a mature phenotype of astrocytes in the adult cerebellum.

What Really Works? Testing Augmented and Virtual Reality Messaging in Terrestrial Invasive Species Management Communications to Impact Visitor Preferences and Deter Visitor Displacement.

Natural resource management is rapidly shifting to incorporate a deeper understanding of ecological processes and functioning, including attention to invasive species. The shift to understand public perceptions of resource management and invasives is much slower. Information influences both landscape preference and behaviors. Theory suggests that increasingly engaging information should have concurrently greater impacts. This research tested the effect of increasingly engaging information on visitor preferences and intentions to return to landscapes treated in response to emerald ash borer (EAB; Agrilus planipennis). Park visitors in a midwestern-U.S. state randomly received one of four messages about forest management in response to EAB (control, photo, augmented reality (AR) and virtual reality (VR)). Messaging impacted preferences for three of the four management approaches, but significant changes in displacement intentions emerged in only one of the four. Specifically, VR and AR increased preferences for complete harvest compared to photos/text, but not differently from those who received no information. VR significantly lowered preferences for select harvest with natural regeneration. The photo/text treatment increased preference for select harvest with planted trees over no information. Any information reduced displacement in response to a photo depicting "select harvest, planted trees." Subsequently judicious use of advanced communications like VR can optimize increasing scarce resources and maintain or optimize ecological services. Future research directions across geographic and content areas are recommended.

Cellular inhibitor of apoptosis 2 (cIAP2) restricts neuroinflammation during experimental autoimmune encephalomyelitis.

BACKGROUND: Immune activation, neuroinflammation, and cell death are the hallmarks of multiple sclerosis (MS), which is an autoimmune demyelinating disease of the central nervous system (CNS). It is well-documented that the cellular inhibitor of apoptosis 2 (cIAP2) is induced by inflammatory stimuli and regulates adaptive and innate immune responses, cell death, and the production of inflammatory mediators. However, the impact of cIAP2 on neuroinflammation associated with MS and disease severity remains unknown. METHODS: We used experimental autoimmune encephalomyelitis (EAE), a widely used mouse model of MS, to assess the effect of cIAP2 deletion on disease outcomes. We performed a detailed analysis on the histological, cellular, and molecular levels. We generated and examined bone-marrow chimeras to identify the cIAP2-deficient cells that are critical to the disease outcomes. RESULTS: cIAP2-/- mice exhibited increased EAE severity, increased CD4+ T cell infiltration, enhanced proinflammatory cytokine/chemokine expression, and augmented demyelination. This phenotype was driven by cIAP2-deficient non-hematopoietic cells. cIAP2 protected oligodendrocytes from cell death during EAE by limiting proliferation and activation of brain microglia. This protective role was likely exerted by cIAP2-mediated inhibition of the non-canonical NLRP3/caspase-8-dependent myeloid cell activation during EAE. CONCLUSIONS: Our findings suggest that cIAP2 is needed to modulate neuroinflammation, cell death, and survival during EAE. Significantly, our data demonstrate the critical role of cIAP2 in limiting the activation of microglia during EAE, which could be explored for developing MS therapeutics in the future.

RelB controls adaptive responses of astrocytes during sterile inflammation.

In response to brain injury or infections, astrocytes become reactive, undergo striking morphological and functional changes, and secrete and respond to a spectrum of inflammatory mediators. We asked whether reactive astrocytes also display adaptive responses during sterile IL-1ß-induced neuroinflammation, which may limit tissue injury associated with many disorders of the central nervous system. We found that astrocytes display days-to-weeks long specific tolerance of cytokine genes, which is coordinated by NF-κB family member, RelB. However, in contrast to innate immune cells, astrocytic tolerance does not involve epigenetic silencing of the cytokine genes. Establishment of tolerance depends on persistent higher levels of RelB in tolerant astrocytes and its phosphorylation on serine 472. Mechanistically, this phosphorylation prevents efficient removal of RelB from cytokine promoters by IκBα and helps to establish tolerance. Importantly, ablation of RelB from astrocytes in mice abolishes tolerance during experimental neuroinflammation in vivo.

A detrimental role of RelB in mature oligodendrocytes during experimental acute encephalomyelitis.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS). It is firmly established that overactivation of the p65 (RelA) nuclear factor kappa B (NF-κB) transcription factor upregulates expression of inflammatory mediators in both immune and non-immune resident CNS cells and promotes inflammation during MS. In contrast to p65, NF-κB family member RelB regulates immune cell development and can limit inflammation. Although RelB expression is induced during inflammation in the CNS, its role in MS remains unknown. METHODS: To examine the role of RelB in non-immune CNS cells, we generated mice with RelB specifically deleted in astrocytes (RelBΔAST), oligodendrocytes (RelBΔOLIGO), or neural progenitor-derived cells (RelBΔNP). We used experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS, to assess the effect of RelB deletion on disease outcomes and performed analysis on the histological, cellular, and molecular level. RESULTS: Despite being a negative regulator of inflammation, conditional knockout of RelB in non-immune resident CNS cells surprisingly decreased the severity of EAE. This protective effect was recapitulated by conditional deletion of RelB in oligodendrocytes but not astrocytes. Deletion of RelB in oligodendrocytes reduced disease severity, promoted survival of mature oligodendrocytes, and correlated with increased activation of p65 NF-κB. CONCLUSIONS: These findings suggest that RelB fine tunes inflammation and cell death/survival during EAE. Importantly, our data points out the detrimental role RelB plays in controlling survival of mature oligodendrocytes, which could be explored as a viable option to treat MS in the future.

Ocular pyoderma gangrenosum: A systematic review.

BACKGROUND: Pyoderma gangrenosum (PG) is a rare, ulcerative cutaneous disorder. Ophthalmic involvement in PG is atypical, but can have devastating consequences. OBJECTIVE: We sought to characterize ocular PG to allow for earlier diagnosis and therapy. To our knowledge, this is the first systematic review summarizing this clinical variant. METHODS: A systematic review was conducted using PubMed and Web of Science. Data were extracted and studies were qualitatively assessed and analyzed. RESULTS: We identified all 34 cases of PG involving the eye and periorbital area, and categorized them into 4 different subtypes. Common presenting signs include ulceration, peripheral ulcerative keratitis, and decreased visual acuity. Although it is often difficult to biopsy ocular PG, histologic features are nonspecific. Combined therapy using corticosteroids and further surgical reconstruction as needed is the mainstay of treatment. Cases of the eye/orbit in particular should be treated aggressively, as these are more likely to relapse compared with cases of the periorbital area. LIMITATIONS: Use of case reports, paucity of ocular PG cases, and heterogeneity of studies are limitations. CONCLUSION: PG should be considered in the differential diagnosis of ulceration of ocular/periocular tissues. An aggressive, early, multimodal treatment strategy should be used to prevent relapse, especially in cases of the eye/orbit.

Sphingosine-1-phosphate inhibits IL-1-induced expression of C-C motif ligand 5 via c-Fos-dependent suppression of IFN-ß amplification loop.

The neuroinflammation associated with multiple sclerosis involves activation of astrocytes that secrete and respond to inflammatory mediators such as IL-1. IL-1 stimulates expression of many chemokines, including C-C motif ligand (CCL) 5, that recruit immune cells, but it also stimulates sphingosine kinase-1, an enzyme that generates sphingosine-1-phosphate (S1P), a bioactive lipid mediator essential for inflammation. We found that whereas S1P promotes IL-1-induced expression of IL-6, it inhibits IL-1-induced CCL5 expression in astrocytes. This inhibition is mediated by the S1P receptor (S1PR)-2 via an inhibitory G-dependent mechanism. Consistent with this surprising finding, infiltration of macrophages into sites of inflammation increased significantly in S1PR2(-/-) animals. However, activation of NF-κB, IFN regulatory factor-1, and MAPKs, all of which regulate CCL5 expression in response to IL-1, was not diminished by the S1P in astrocytes. Instead, S1PR2 stimulated inositol 1,4,5-trisphosphate-dependent Ca(++) release and Elk-1 phosphorylation and enhanced c-Fos expression. In our study, IL-1 induced the IFNß production that supports CCL5 expression. An intriguing finding was that S1P induced c-Fos-inhibited CCL5 directly and also indirectly through inhibition of the IFN-ß amplification loop. We propose that in addition to S1PR1, which promotes inflammation, S1PR2 mediates opposing inhibitory functions that limit CCL5 expression and diminish the recruitment of immune cells.

Wire in the hole: a case series of eroded intrapubic wire sutures causing genitourinary complications in the bladder exstrophy complex.

Bladder exstrophy and cloacal exstrophy are rare congenital defects of the genitourinary tract that require complex surgical reconstruction. Malrotation of the bony pelvis causes a characteristic diastasis of the pubic symphysis, which is surgically reduced at the time of initial bladder closure. For a successful primary closure without tension such that the bladder can be placed deep within the pelvis, pelvic osteotomy is often used. However, alternative techniques have been utilized to bring the pubic rami into apposition. The authors present four bladder/cloacal exstrophy patients in which an intrapubic wire was used for pubic apposition, resulting in significant genitourinary complications.

Laparoscopy and transseptal orchiopexy in the management of transverse testicular ectopia.

Transverse testicular ectopia (TTE) is a rare congenital anomaly in which both testes descend through the same inguinal canal. The most frequent clinical presentation is undescended testis (UDT) with ipsilateral inguinal hernia and contralateral non-palpable testis. This condition is often diagnosed during surgery and is frequently associated with other anomalies. There is controversy in the surgical management of TTE. Considerations for TTE repair include avoiding damage to the testes or vas deferens and detection of other congenital anomalies. Frequently, the vas deferens and testicular tissues are joined, and dissection of these structures can cause damage. In this article, we report four patients with TTE, describe the surgical approach made in each case, and provide a review of the literature.

Examining long-term outcomes of bladder exstrophy: a 20-year follow-up.

OBJECTIVE: To examine long-term quality-of-life, urinary continence and sexual function outcomes in patients diagnosed with bladder exstrophy (BE). PATIENTS AND METHODS: A total of 65 patients with BE and follow-up of at least 20 years were identified. After informed consent for inclusion in the study, the patients were asked to complete three validated questionnaires, the Short-Form 36 quality-of-life questionnaire (SF-36), the International Consultation on Incontinence Questionnaire (ICIQ) and the International Index of Erectile Function (IIEF), to assess quality of life, perceived urinary continence and sexual function. RESULTS: In all, 21 patients responded to the questionnaires, yielding a 32% response rate. High scores in each of the eight dimensions of the SF-36 reflected a positive perception of quality of life by respondents; calculated scores were compared with those of a normal control group. The only significant difference found between the groups was that the study population perceived their general health to be poorer than those in the control group. High scores on the ICIQ indicate high levels of subjective incontinence in patients, with scores ranging from 0 to 21. Reporting scores of 0 (continent), 12/21 patients perceived their continence to be normal, 9/21 patients had scores >2 (mild), with one patient scoring a 16, and 11 (severe incontinence), patients reported no identifiable leakage during normal activities. There was a 29% response rate for the IIEF (15 patients completed this). IIEF scores were broken down into five dimensions and mean scores were calculated. The mean scores showed mild to moderate dysfunction in each category, including overall satisfaction with sexual experience. CONCLUSIONS: The patient-reported quality of life in patients with BE was normal in all dimensions, with the exception of perception of general health. Half of the patients reported normal continence and had no complaints of urinary leakage. Sexual function in males was significantly affected across all dimensions, with mild to moderate dysfunction.

Real-world socioeconomic determinants of corneal crosslinking in a national cohort.

PURPOSE: To characterize recent socioeconomic trends in patients with keratoconus/corneal ectasias undergoing corneal crosslinking (CXL). SETTING: A deidentified administrative medical claims database comprised commercial and Medicare Advantage health claims from across the United States. DESIGN: Population-based retrospective cohort study. METHODS: This study identified 552 patients with keratoconus/corneal ectasia who underwent CXL and 2723 matched controls who did not undergo CXL based on Current Procedural Terminology coding from a U.S. national insurance claims database from 2016 to 2020. For each patient, characteristics, including sex, race, age, household net worth, education level, insurance plan type, and geographic region, were extracted. Multivariate logistic regression was conducted to determine the odds of undergoing crosslinking. RESULTS: Age 30 years or older (odds ratio [OR], 0.34, P < .001) was associated with decreased likelihood of undergoing CXL. Sex, race, education, and patient income were not associated with odds of undergoing CXL. Patients with health maintenance organization insurance had lower odds of undergoing CXL (OR, 0.64, P = .047). Geographically, patients on the east coast (OR, 0.37, P < .001) and Lower Midwest (OR, 0.31, P < .001) had statistically lower odds of undergoing crosslinking. CONCLUSIONS: This is the first study to identify socioeconomic determinants of CXL, and it highlights that geographic location and insurance type may limit accessibility to patients.

The association of stroke with herpes zoster ophthalmicus.

BACKGROUND/OBJECTIVES: Studies have reported an association between herpes zoster ophthalmicus (HZO) and stroke. We sought to validate this association with rigorous controls for both medical comorbidities and social factors using a nationwide U.S. administrative medical claims database. SUBJECTS/METHODS: A two-step approach was taken: first a retrospective case-control study was performed, followed by a self-controlled case series (SCCS). For the case control study, cox proportional hazard regression with inverse proportional treatment weighting assessed the hazard for stroke. In the SCCS, incidence of stroke was compared prior to and after the diagnosis of HZO. RESULTS: For the case-control study, 25,720 cases and 75,924 controls met our eligibility criteria. 1712 (6.7%) and 4544 (6.0%) strokes occurred in the case and control groups respectively, conferring an 18% increased risk of stroke in the observed 1-year post-HZO period (HR = 1.18, 95% CI: 1.12-1.25, p < 0.001). SCCS analysis showed the risk for stroke was highest in the month immediately after HZO episode compared to any other time range (1-30 days after, relative risk 1.58, p < 0.001) and even higher when assessing time more distal time points prior to the HZO diagnosis (days 1-30 after HZO diagnosis had RR = 1.69 (95% CI: 1.38-2.07) and RR = 1.93 (95% CI: 1.55-2.39) compared with days -120 to -91 and -150 to -121 prior to index, respectively (p < 0.001). CONCLUSIONS: After accounting for stroke risk factors, our analysis confirms the association between HZO and stroke, with highest risk in the immediate month after an episode.

Corneal Epithelial Thickness in Sjogren's Disease: A Pilot Study.

Purpose: This study was to assess corneal epithelial thickness (CET) in patients with Sjogren's disease (SjD). Methods: A retrospective chart review was conducted of SjD patients from September 2021 to January 2022. Patient demographics, unanesthetized Schirmer's test, serologic markers, and symptoms as measured by the Ocular Surface Disease Index (OSDI) were reviewed. Epithelial thickness from both eyes was measured using anterior segment OCT at the central 3mm and concentric 5mm, 7mm, and 9mm zones for the superior, temporal, inferior, and nasal corneal quadrants. Associations between corneal epithelial thickness with patient demographics, clinical characteristics, and symptoms were evaluated using regression models. Results: Fifteen SjD patients (100% female) were included with a mean age of 58.4 years. Patients with Sjogren's disease had a significantly thinner superior corneal epithelium compared to the inferior epithelium (mean 47.7mm vs 53.1mm, p = 0.001). The epithelial thickness mean standard deviation (MSD) was significantly inversely correlated with the unanesthetized Schirmer test (r=-0.39, p = 0.005), suggesting that an overall variability of CET correlates with decreased aqueous tear production. SS-A, SS-B, ANA, and RF positivity were not associated with any measures of CET. Conclusion: This pilot study suggests that there is significant superior versus inferior thinning of corneal epithelium in Sjogren's patients. There was a significant correlation between variability of corneal epithelial thickness and decreased tear production in Sjogren's patients. Further larger studies are needed to understand the relationship of CET with objective and subjective measurements of ocular surface disease.

Radial forearm free flap phalloplasty for penile inadequacy in patients with exstrophy.

PURPOSE: Male patients with bladder and cloacal exstrophy are born with demure genitalia and often desire phalloplasty during late adolescence or early adulthood. Radial forearm free flap phalloplasty was used successfully for congenital aphallia in a few small series. We present a series of patients treated with phalloplasty using a radial forearm free flap after the repair of bladder and cloacal exstrophy. MATERIALS AND METHODS: We reviewed the records of 10 patients who underwent radial forearm free flap phalloplasty between 2007 and 2012. Indications for phalloplasty were classic bladder exstrophy in 8 cases and cloacal exstrophy in 2. Nine patients underwent prior urinary diversion and 1 underwent urethroplasty at phalloplasty. In each case we reviewed the details of prior exstrophy repair, flap size, donor and recipient vessels, complications, need for subsequent surgeries and self-reported sensation. RESULTS: The graft survived in all 10 patients. Short-term complications requiring surgical intervention developed in 2 patients. Five patients subsequently underwent placement of a penile prosthesis and 2 devices were removed secondary to erosion. All 10 patients reported protective sensation and erogenous sensation with ability to achieve orgasm at last followup. CONCLUSIONS: Radial forearm free flap phalloplasty results in a sensate, cosmetic neophallus. No patient had long-term complications related to phalloplasty but complications related to penile prostheses continue to be a challenging aspect of phalloplasty. The long-term results of the forearm free flap are encouraging in this series of patients with bladder and cloacal exstrophy who desired phalloplasty.

Using a serosal trough for fashioning a continent catheterizable stoma: technique and outcomes.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Continent urinary diversion with bladder augmentation is an established method of providing urinary continence in children with bladder exstrophy, who are not suitable candidates or have a failed bladder neck reconstruction. Sub-mucosal implantation of the tubularized catheterizable stoma (usually the appendix) into the reservoir, with backing typically provided by either the bladder musculature or colonic taenia, is safe and highly effective in these children. In some cases of classic bladder exstrophy and in the majority of patients with cloacal exstrophy, the ileum is used for enterocystoplasty and therefore there is no taenia to back the implanted catheterizable channel. This study describes the steps for providing a reliable flap-valve mechanism for the continent catheterizable channel using the serosal trough technique. OBJECTIVES: To evaluate the efficacy and potential complications of the serosal-trough (ST) technique for the implantation of a continent catheterizable stoma (CCS) during enterocystoplasty. To describe the surgical technique and provide detailed illustrations. PATIENTS AND METHODS: Using an institutional review board-approved departmental database, children with bladder exstrophy, born after 1990, were selected, and patients who had undergone urinary diversion with a CCS created using the ST technique were identified. Demographic and technical characteristics, as well as the eventual clinical outcomes, were retrospectively reviewed. RESULTS: A total of 135 patients with urinary diversion were identified, of whom 26 (13 males) had undergone CCS implantation using the ST technique. Patients included 14 classic exstrophies, 10 cloacal exstrophies, and two epispadias. The appendix and tapered ileum were used for the creation of a CCS in 11 and 15 patients, respectively. The median (range) age at creation of a CCS was 10.7 (4.4-17.4) years. At the time of CCS creation, 21 patients underwent initial enterocystoplasty, four had repeat augmentations, and one had a CCS on a previously augmented bladder. Ileum (mean length 18 cm) was used in 24/25 augmentations and was selected owing to lack of redundant sigmoid in 52% of patients and intraoperative surgeon preference in the remaining cases. In one case of cloacal exstrophy, a hindgut remnant was used. In 24 (92%) cases, initial CCS resulted in complete continence of the catheterizable channel. After a median (range) of 2.5 (0.2-7.5) years' follow-up all patients were dry via intermittent catheterization. The CCS failed at postoperative months 6 and 21 and required complete revision in two cases. CONCLUSIONS: Using a ST to provide a strong backing for a catheterizable channel is an excellent option when a channel must be placed in the ileum, hindgut, or in an area of augmentation where muscular backing is not available. The ST technique provides a reliably catheterizable tunnel, durable continence mechanism and a good success rate when creating a CCS in combination with a urinary diversion.

Does benign prostatic hyperplasia treatment with alpha-blockers affect prostate cancer risk?

PURPOSE OF REVIEW: To determine whether alpha-blockers, commonly used for the treatment of benign prostatic hyperplasia, are associated with prostate cancer risk. RECENT FINDINGS: Alpha-blockers have been associated with a reduced risk of prostate cancer aggressiveness in some observational studies and an increased risk in other studies. However, this relationship is complex as different alpha-blockers have divergent effects in laboratory studies and there are many confounders in daily practice such as differential screening practices. SUMMARY: Both benign prostatic hyperplasia and prostate cancer are common conditions in the aging male population, such that an interaction between alpha-blockers and prostate cancer risk is clinically relevant. Prospective evidence is necessary to establish a definitive link.