Hyperbaric oxygen therapy as a treatment for erectile dysfunction: a meta-analysis.

INTRODUCTION: Hyperbaric oxygen therapy (HBOT) is a medical treatment in which the patient is exposed to 100% oxygen at a higher than atmospheric pressure. Over the past few decades, HBOT has been used to treat a variety of medical conditions. In recent times, there has been a rising curiosity regarding the potential therapeutic benefits of HBOT in the treatment of erectile dysfunction (ED). AIMS: The study sought to review and meta-analyze available data regarding the use of HBOT for ED, including its potential mechanisms of action and effectiveness. METHODS: We included only articles that evaluated the impact of HBOT on ED symptoms using the International Index of Erectile Function score. Prospective nonrandomized studies or randomized controlled clinical trials were included. Data extraction was performed in duplicate. Data analysis was conducted using Review Manager 5.41, and the presence of heterogeneity between studies was evaluated. The results were presented as the mean difference (MD) with 95% confidence interval (CI). RESULTS: A total of 5 studies that reported outcomes using the International Index of Erectile Function scores were included in this analysis. In patients with post-robotic-assisted laparoscopic prostatectomy-induced ED, the analysis showed a significant MD of -4.13 (95% CI, -6.08 to -2.18; P < .0001) in favor of the control group. Conversely, patients who received HBOT for reasons other than ED exhibited an MD of 4.58 (95% CI, 2.63 to 6.52; P < .00001). In the group that received HBOT for pure vasculogenic ED, the MD was 10.50 (95% CI, 9.92 to 11.08) in favor of HBOT. A meta-analysis of these data revealed a nonsignificant difference in erectile function scores, with an MD of 3.86 (95% CI, -2.13 to 9.86; P = .21). CONCLUSION: The use of HBOT in the treatment of ED appears to be a promising approach. While further research is needed to establish the efficacy and long-term effects of this treatment, preliminary studies have shown encouraging results in terms of improving erectile function in men with vasculogenic ED.

Metabolic preconditioning in CD4+ T cells restores inducible immune tolerance in lupus-prone mice.

Autoimmune disease has presented an insurmountable barrier to restoration of durable immune tolerance. Previous studies indicate that chronic therapy with metabolic inhibitors can reduce autoimmune inflammation, but it remains unknown whether acute metabolic modulation enables permanent immune tolerance to be established. In an animal model of lupus, we determined that targeting glucose metabolism with 2-deoxyglucose (2DG) and mitochondrial metabolism with metformin enables endogenous immune tolerance mechanisms to respond to tolerance induction. A 2-week course of 2DG and metformin, when combined with tolerance-inducing therapy anti-CD45RB, prevented renal deposition of autoantibodies for 6 months after initial treatment and restored tolerance induction to allografts in lupus-prone mice. The restoration of durable immune tolerance was linked to changes in T cell surface glycosylation patterns, illustrating a role for glycoregulation in immune tolerance. These findings indicate that metabolic therapy may be applied as a powerful preconditioning to reinvigorate tolerance mechanisms in autoimmune and transplant settings that resist current immune therapies.

Prevalence of high-risk bladder categorization with prenatal and postnatal myelomeningocele repair types.

INTRODUCTION: Urologic substudies of prenatal myelomeningocele (MMC) closure have focused primarily on continence without significant clinical benefit. Fetoscopic MMC repair (FMR) is a newer form of prenatal intervention and touts added benefits to the mother, but urological outcomes have yet to be analyzed. We set out to focus on bladder safety rather than continence and examined bladder outcomes with different prenatal MMC repairs (FMR and prenatal open [POMR]) and compared bladder-risk-categorization to traditional postnatal repair (PSTNR). METHODS: An IRB-approved retrospective analysis of all patients undergoing all forms of MMC repairs with inclusion and exclusion criteria based on the MOMS trial was performed. Bladder safety assessment required initial urodynamic studies (UDS), renal bladder ultrasound (RBUS), and/or voiding cystourethrogram (VCUG) within the 1st year of life. Follow-up analyses within the cohorts required follow-up studies within 18 months after initial evaluations. Outcomes assessed included bladder-risk-categorization based on the CDC UMPIRE study (high, intermediate, and safe), hydronephrosis (HN), and vesicoureteral reflux (VUR). A single reader evaluated each UDS. RESULTS: Initial UDS in 93 patients showed that the prevalence of high-risk bladders were 35% FMR versus 36% PSTNR and 60% POMR. Follow-up UDS showed only 8% of FMR were high-risk compared to 35% POMR and 36% PSTNR. Change from initial to follow-up bladder-risk-category did not reach significance (p = .0659); however, 10% PSTNR worsened to high-risk on follow-up, compared to none in either prenatal group. Subanalysis of follow-up UDS between the prenatal cohorts also was not significant (p = .055). Only 8% of FMR worsened or stayed high-risk compared to 35% with POMR (p = .1). HN was significantly different at initial and subsequent follow up between the groups with the least in the FMR group. CONCLUSIONS: Early outcome UDS analyses demonstrated lower incidence of high-risk bladders in FMR patients with a trend toward clinically significant improvement compared to POMR in regard to all evaluated metrics. Larger, prospective, confirmatory studies are needed to further evaluate the potential benefits on FMR on bladder safety and health.

Obesity is Associated with Longer Survival Independent of Sarcopenia and Myosteatosis in Metastatic and/or Castrate-Resistant Prostate Cancer.

PURPOSE: Obesity (body mass index 30 kg/m2 or greater) is associated with better overall survival in metastatic prostate cancer. Conversely, low muscle mass (sarcopenia) and low muscle radiodensity (myosteatosis) are associated with worse overall survival in many cancers. This study seeks to evaluate the relationship of sarcopenia, myosteatosis and obesity with overall survival in men with metastatic or castrate-resistant prostate cancer. MATERIALS AND METHODS: Retrospective analysis of men with metastatic or castrate-resistant prostate cancer and computerized tomography of abdomen/pelvis presenting to the Vanderbilt Comprehensive Prostate Cancer Clinic from 2012 to 2017 was performed. Demographic, pathological and survival data were described, with sarcopenia and myosteatosis determined from abdominal skeletal muscle area and skeletal muscle radiodensity, respectively. Kaplan-Meier curves and log-rank tests estimated the effect of body composition on survival. Multivariable Cox proportional hazard models were performed adjusting for age, Charlson comorbidity index, race and clinical stage. ANOVA was used to compare obese and nonobese men with and without sarcopenia or myosteatosis. RESULTS: Of 182 men accrued, 37.4% were obese, 53.3% sarcopenic and 59.3% myosteatotic. Over a median followup of 33.9 months, body mass index was associated with reduced mortality (HR 0.93, p=0.02), as was visceral adiposity (HR 0.99, p=0.003). Men with high body mass index without sarcopenia/myosteatosis lived significantly longer than men with high body mass index with sarcopenia/myosteatosis or normal body mass index men (F[3,91]=4.03, p=0.01). CONCLUSIONS: Both high body mass index and visceral adiposity in metastatic or castrate-resistant prostate cancer are associated with reduced mortality, independent of sarcopenia and myosteatosis. Therefore, routine clinical workup should include calculation of body mass index and measurement of waist circumference. Morphometric analysis of computerized tomography imaging can identify patients at risk for poor prognosis.

Regulation of Diabetogenic Immunity by IL-15-Activated Regulatory CD8 T Cells in Type 1 Diabetes.

Unchecked collaboration between islet-reactive T and B lymphocytes drives type 1 diabetes (T1D). In the healthy setting, CD8 T regulatory cells (Tregs) terminate ongoing T-B interactions. We determined that specific CD8 Tregs from NOD mice lack suppressive function, representing a previously unreported regulatory cell deficit in this T1D-prone strain. NOD mice possess 11-fold fewer Ly-49+ CD8 Tregs than nonautoimmune mice, a deficiency that worsens as NOD mice age toward diabetes and leaves them unable to regulate CD4 T follicular helper cells. As IL-15 is required for Ly-49+ CD8 Treg development, we determined that NOD macrophages inadequately trans-present IL-15. Despite reduced IL-15 trans-presentation, NOD Ly-49+ CD8 Tregs can effectively transduce IL-15-mediated survival signals when they are provided. Following stimulation with an IL-15/IL-15Ra superagonist complex, Ly-49+ CD8 Tregs expanded robustly and became activated to suppress the Ag-specific Ab response. IL-15/IL-15Ra superagonist complex-activated CD8+CD122+ T cells also delayed diabetes transfer, indicating the presence of an underactivated CD8 T cell subset with regulatory capacity against late stage T1D. We identify a new cellular contribution to anti-islet autoimmunity and demonstrate the correction of this regulatory cell deficit. Infusion of IL-15-activated CD8 Tregs may serve as an innovative cellular therapy for the treatment of T1D.

B lymphocytes protect islet ß cells in diabetes prone NOD mice treated with imatinib.

Imatinib (Gleevec) reverses type 1 diabetes (T1D) in NOD mice and is currently in clinical trials in individuals with recent-onset disease. While research has demonstrated that imatinib protects islet ß cells from the harmful effects of ER stress, the role the immune system plays in its reversal of T1D has been less well understood, and specific cellular immune targets have not been identified. In this study, we demonstrate that B lymphocytes, an immune subset that normally drives diabetes pathology, are unexpectedly required for reversal of hyperglycemia in NOD mice treated with imatinib. In the presence of B lymphocytes, reversal was linked to an increase in serum insulin concentration, but not an increase in islet ß cell mass or proliferation. However, improved ß cell function was reflected by a partial recovery of MafA transcription factor expression, a sensitive marker of islet ß cell stress that is important to adult ß cell function. Imatinib treatment was found to increase the antioxidant capacity of B lymphocytes, improving reactive oxygen species (ROS) handling in NOD islets. This study reveals a novel mechanism through which imatinib enables B lymphocytes to orchestrate functional recovery of T1D ß cells.

Healthy Donor Polyclonal IgMs Diminish B-Lymphocyte Autoreactivity, Enhance Regulatory T-Cell Generation, and Reverse Type 1 Diabetes in NOD Mice.

Autoimmune diseases such as type 1 diabetes (T1D) arise from unrestrained activation of effector lymphocytes that destroy target tissues. Many efforts have been made to eliminate these effector lymphocytes, but none has produced a long-term cure. An alternative to depletion therapy is to enhance endogenous immune regulation. Among these endogenous alternatives, naturally occurring Igs have been applied for inflammatory disorders but have lacked potency in antigen-specific autoimmunity. We hypothesized that naturally occurring polyclonal IgMs, which represent the majority of circulating, noninduced antibodies but are present only in low levels in therapeutic Ig preparations, possess the most potent capacity to restore immune homeostasis. Treatment of diabetes-prone NOD mice with purified IgM isolated from Swiss Webster (SW) mice (nIgMSW) reversed new-onset diabetes, eliminated autoreactive B lymphocytes, and enhanced regulatory T-cell (Treg) numbers both centrally and peripherally. Conversely, IgM from prediabetic NOD mice could not restore this endogenous regulation, which represents an unrecognized component of T1D pathogenesis. Of note, IgM derived from healthy human donors was similarly able to expand human CD4 Tregs in humanized mice and produced permanent diabetes protection in treated NOD mice. Overall, these studies demonstrate that a potent, endogenous regulatory mechanism, nIgM, is a promising option for reversing autoimmune T1D in humans.

Host Expression of the CD8 Treg/NK Cell Restriction Element Qa-1 is Dispensable for Transplant Tolerance.

Disruption of the non-classical Major Histocompatibility Complex (MHC) Ib molecule Qa-1 impairs CD8 Treg and natural killer (NK) cell function and promotes a lupus-like autoimmune disease. This immune perturbation would be expected to enhance anti-transplant responses and impair tolerance induction, but the effect of Qa-1 deficiency on the transplant response has not been previously reported. Qa-1 deficiency enhanced CD4 TFH and germinal center (GC) B cell numbers in naïve mice and hastened islet allograft rejection. Despite enhanced immunity in B6.Qa-1-/- mice, these mice did not generate an excessive primary CD4 TFH cell response nor an enhanced alloantibody reaction. Both CD8 Tregs and NK cells, which often regulate other cells through host Qa-1 expression, were targets of anti-CD45RB therapy that had not been previously recognized. However, B6.Qa-1-/- mice remained susceptible to anti-CD45RB mediated suppression of the alloantibody response and transplant tolerance induction to mismatched islet allografts. Overall, despite enhanced immunity as demonstrated by augmented CD4 TFH/GC B cell numbers and hastened islet allograft rejection in naïve 12-week old Qa-1 deficient mice, the CD8 Treg/NK cell restriction element Qa-1 does not regulate the primary cellular or humoral alloresponse and is not required for long-term transplant tolerance.

Hematopoietic Stem Cell Mobilization Is Necessary but Not Sufficient for Tolerance in Islet Transplantation.

Overcoming the immune response to establish durable immune tolerance in type 1 diabetes remains a substantial challenge. The ongoing effector immune response involves numerous immune cell types but is ultimately orchestrated and sustained by the hematopoietic stem cell (HSC) niche. We therefore hypothesized that tolerance induction also requires these pluripotent precursors. In this study, we determined that the tolerance-inducing agent anti-CD45RB induces HSC mobilization in nonautoimmune B6 mice but not in diabetes-prone NOD mice. Ablation of HSCs impaired tolerance to allogeneic islet transplants in B6 recipients. Mobilization of HSCs resulted in part from decreasing osteoblast expression of HSC retention factors. Furthermore, HSC mobilization required a functioning sympathetic nervous system; sympathectomy prevented HSC mobilization and completely abrogated tolerance induction. NOD HSCs were held in their niche by excess expression of CXCR4, which, when blocked, led to HSC mobilization and prolonged islet allograft survival. Overall, these findings indicate that the HSC compartment plays an underrecognized role in the establishment and maintenance of immune tolerance, and this role is disrupted in diabetes-prone NOD mice. Understanding the stem cell response to immune therapies in ongoing human clinical studies may help identify and maximize the effect of immune interventions for type 1 diabetes.

Regulation of B lymphocyte responses to Toll-like receptor ligand binding during diabetes prevention in non-obese diabetic (NOD) mice.

BACKGROUND: Interactions between genetic risk factors and the environment drive type 1 diabetes (T1D). The system of Toll-like receptors (TLR) detects these environmental triggers; however, the target cell that intermediates these interactions to drive T1D remains unknown. METHODS: We investigated the effect of TLR pathway activation (myeloid differentiation primary response 88 [MyD88] vs TIR-domain-containing adapter-inducing interferon-ß [TRIF]) on B cell subsets via flow cytometry, including their activation, survival, proliferation, and cytoskeletal mobilization. The effect of polyinosinic-polycytidylic acid (poly(I:C)) on diabetes development was addressed, including the B cell-dependent activation of diabetes-protective DX5+ cells, using genetic models and adoptive transfer. RESULTS: B lymphocytes from non-obese diabetic (NOD) mice expressed enhanced levels of TLR-responsive proteins. Ex vivo analysis of B lymphocyte subsets demonstrated that TLR3 stimulation via TRIF deletes cells exhibiting a marginal zone phenotype, whereas MyD88-dependent ligands enhance their survival. In vivo, marginal zone B cells were activated by poly(I:C) and were unexpectedly retained in the spleen of NOD mice, in contrast with the mobilization of these cells in non-autoimmune mice, a phenotype we traced to defective actin cytoskeletal dynamics. These activated B cells mediated TLR3-induced diabetes protection. CONCLUSIONS: Immunotherapies must account for both B cell location and activation, and these properties may differ in autoimmune and healthy settings.

Neonatal CD71+ Erythroid Cells Do Not Modify Murine Sepsis Mortality.

Sepsis is a major cause of neonatal mortality and morbidity worldwide. A recent report suggested that murine neonatal host defense against infection could be compromised by immunosuppressive CD71(+) erythroid splenocytes. We examined the impact of CD71(+) erythroid splenocytes on murine neonatal mortality to endotoxin challenge or polymicrobial sepsis and characterized circulating CD71(+) erythroid (CD235a(+)) cells in human neonates. Adoptive transfer or an Ab-mediated reduction in neonatal CD71(+) erythroid splenocytes did not alter murine neonatal survival to endotoxin challenge or polymicrobial sepsis challenge. Ex vivo immunosuppression of stimulated adult CD11b(+) cells was not limited to neonatal splenocytes; it also occurred with adult and neonatal bone marrow. Animals treated with anti-CD71 Ab showed reduced splenic bacterial load following bacterial challenge compared with isotype-treated mice. However, adoptive transfer of enriched CD71(+) erythroid splenocytes to CD71(+)-reduced animals did not reduce bacterial clearance. Human CD71(+)CD235a(+) cells were common among cord blood mononuclear cells and were shown to be reticulocytes. In summary, a lack of effect on murine survival to polymicrobial sepsis following adoptive transfer or diminution of CD71(+) erythroid splenocytes under these experimental conditions suggests that the impact of these cells on neonatal infection risk and progression may be limited. An unanticipated immune priming effect of anti-CD71 Ab treatment, rather than a reduction in immunosuppressive CD71(+) erythroid splenocytes, was likely responsible for the reported enhanced bacterial clearance. In humans, the well-described rapid decrease in circulating reticulocytes after birth suggests that they may have a limited role in reducing inflammation secondary to microbial colonization.