Two transcriptionally and functionally distinct waves of neutrophils during mouse acute liver injury.

BACKGROUND: Neutrophils are key mediators of inflammation during acute liver injury (ALI). Emerging evidence suggests that they also contribute to injury resolution and tissue repair. However, the different neutrophil subsets involved in these processes and their kinetics are undefined. Herein, we characterized neutrophil kinetics and heterogeneity during ALI. METHODS: We used the carbon tetrachloride model of ALI and employed flow cytometry, tissue imaging, and quantitative RT-PCR to characterize intrahepatic neutrophils during the necroinflammatory early and late repair phases of the wound healing response to ALI. We FACS sorted intrahepatic neutrophils at key time points and examined their transcriptional profiles using RNA-sequencing. Finally, we evaluated neutrophil protein translation, mitochondrial function and metabolism, reactive oxygen species content, and neutrophil extracellular traps generation. RESULTS: We detected 2 temporarily distinct waves of neutrophils during (1) necroinflammation (at 24 hours after injury) and (2) late repair (at 72 hours). Early neutrophils were proinflammatory, characterized by: (1) upregulation of inflammatory cytokines, (2) activation of the noncanonical NF-κB pathway, (3) reduction of protein translation, (4) decreased oxidative phosphorylation, and (5) higher propensity to generate reactive oxygen species and neutrophil extracellular traps. In contrast, late neutrophils were prorepair and enriched in genes and pathways associated with tissue repair and angiogenesis. Finally, early proinflammatory neutrophils were characterized by the expression of a short isoform of C-X-C chemokine receptor 5, while the late prorepair neutrophils were characterized by the expression of C-X-C chemokine receptor 4. CONCLUSIONS: This study underscores the phenotypic and functional heterogeneity of neutrophils and their dual role in inflammation and tissue repair during ALI.

Study Protocol for a Randomized Controlled Trial of Low Intensity Shockwave Therapy for the Treatment of Post-Radical Prostatectomy Erectile Dysfunction: "SHARP-ED TRIAL".

Introduction: Erectile Dysfunction (ED) is a common challenge post Radical Prostatectomy (RALP), affecting men's sexual health after undergoing definitive cancer therapy. Despite employing nerve-sparing techniques, ED remains a prevalent issue in this population. Studies indicate that approximately 70%-85% of men experience varying degrees of ED following RALP. The existing treatment landscape for post-RALP-ED presents limitations, and a discernible knowledge gap persists. To address this, our study aims to investigate the efficacy of Shockwave Therapy (SWT) as a potential intervention for managing ED after RALP. Methods: This prospective, randomized, sham-controlled clinical trial aims to recruit 189 eligible patients post-RP and assess the effects of SWT. Comprehensive screening, including medical history, physical examinations, and biochemical evaluations, will be conducted to confirm eligibility. The intervention involves utilizing a device to administer focal shockwaves targeted at cavernosal tissue. Safety measures include continuous monitoring for adverse events and rigorous reporting protocols. The primary endpoint assesses changes in participants' ability to engage in penetrative intercourse from baseline to study completion, while secondary endpoints encompass various measures of erectile function, including questionnaire-based assessments, ultrasound parameters, and clinical outcomes. Results: Statistical analysis, encompassing ANOVA for continuous variables and Fisher's exact test for categorical ones, will evaluate demographic characteristics, baseline data, and primary as well as secondary outcomes for statistical significance. Detailed analysis of trends, subgroup comparisons, and treatment effects will provide a comprehensive understanding of the impact of SWT on post-RP ED. Conclusion: This study protocol represents a rigorous investigation into the potential therapeutic role of SWT in managing post-RP ED. The outcomes from this study aim to contribute valuable insights into the efficacy, safety, and potential improvements in erectile function following SWT, providing significant guidance for future interventions aimed at addressing this challenging condition affecting men's health and quality of life.

A phase 2 randomized, placebo-controlled crossover trial to evaluate safety and efficacy of platelet-rich plasma injections for Peyronie's disease: clinical trial update.

Peyronie's Disease (PD) is characterized by fibrotic plaques in the penile tunica albuginea, causing curvature and painful erections. Current treatments have limited established efficacy. Platelet-Rich Plasma (PRP), known for modulating inflammation, offers a potential alternative. This randomized, placebo-controlled, crossover study at the University of Miami assesses PRP's safety and efficacy for PD. Forty-one PD patients were randomized into PRP-placebo (Group A) and placebo-PRP (Group B) sequences, receiving two injections of each treatment over three months, with a crossover to receive two injections of alternate treatment over the next three months. Assessments include pain scale, goniometry, questionnaires, and curvature evaluations. Preliminary analysis of 28 patients shows that PRP is safe. There were no adverse events, including penile complications, during follow-up. Pain scores during treatments showed no significant difference between PRP and placebo (p = 0.52). Over six months, the PRP-Placebo group's median PDQ score decreased from 1.9 (IQR: 1.7-2.9) to 1.4 (IQR: 0.7-2.1). This change was not statistically significant (p = 0.098). In contrast, the Placebo-PRP group showed a significant reduction from 1.8 (IQR: 1.4-2.6) to 1.2 (IQR: 1.0-2.0) (p = 0.020). No significant changes in IIEF scores were observed. Both groups initially had a median penile curvature of 40 degrees. At 3 months, the PRP-Placebo group's curvature decreased to 38 degrees (IQR: 35-47.5), while the Placebo-PRP group decreased to 35 degrees (IQR: 30-60). At 6 months, the PRP-Placebo group showed a significant reduction to 25 degrees (IQR: 20-40, p = 0.047), while the Placebo-PRP group's reduction to 32.5 degrees (IQR: 20-50) was not significant (p = 0.490). These early results indicate a delayed PRP effect, prompting further investigation into its long-term impacts. Although limited by sample size, this study suggests PRP injections as a safe treatment for PD, with ongoing research aiming to clarify its therapeutic value.

Assessing the energy trap of industrial agriculture in North America and Europe: 82 balances from 1830 to 2012.

Early energy analyses of agriculture revealed that behind higher labor and land productivity of industrial farming, there was a decrease in energy returns on energy (EROI) invested, in comparison to more traditional organic agricultural systems. Studies on recent trends show that efficiency gains in production and use of inputs have again somewhat improved energy returns. However, most of these agricultural energy studies have focused only on external inputs at the crop level, concealing the important role of internal biomass flows that livestock and forestry recirculate within agroecosystems. Here, we synthesize the results of 82 farm systems in North America and Europe from 1830 to 2012 that for the first time show the changing energy profiles of agroecosystems, including livestock and forestry, with a multi-EROI approach that accounts for the energy returns on external inputs, on internal biomass reuses, and on all inputs invested. With this historical circular bioeconomic approach, we found a general trend towards much lower external returns, little or no increases in internal returns, and almost no improvement in total returns. This "energy trap" was driven by shifts towards a growing dependence of crop production on fossil-fueled external inputs, much more intensive livestock production based on feed grains, less forestry, and a structural disintegration of agroecosystem components by increasingly linear industrial farm managements. We conclude that overcoming the energy trap requires nature-based solutions to reduce current dependence on fossil-fueled external industrial inputs and increase the circularity and complexity of agroecosystems to provide healthier diets with less animal products. Supplementary Information: The online version contains supplementary material available at 10.1007/s13593-023-00925-5.

Population Pharmacodynamic Modelling of the CD19+ Suppression Effects of Rituximab in Paediatric Patients with Neurological and Autoimmune Diseases.

BACKGROUND: Limited pharmacotherapy and the failure of conventional treatments in complex pathologies in children lead to increased off-label use of rituximab. We aimed to characterize the time course of CD19+ B lymphocytes (CD19+) under treatment with intravenous rituximab in children with neurologic and autoimmune diseases and to evaluate the impact of covariates (i.e., demographics, diagnosis and substitution between innovator and biosimilar product) on rituximab pharmacodynamics and disease activity. METHODS: Pre- and post-drug infusion CD19+ in peripheral blood were prospectively registered. A population pharmacodynamic model describing the time course of CD19+ was developed with NONMEM v7.4. Simulations of three different rituximab regimens were performed to assess the impact on CD19+. Logistic regression analysis was performed to identify predictors of clinical response recorded through disease activity scores. RESULTS: 281 measurements of CD19+ lymphocyte counts obtained from 63 children with neurologic (n = 36) and autoimmune (n = 27) diseases were available. The time course of CD19+ was described with a turn-over model in which the balance between synthesis and degradation rates is disrupted by rituximab, increasing the latter process. The model predicts half-lives (percent coefficient of variation, CV(%)) of rituximab and CD19+ of 11.6 days (17%) and 173.3 days (22%), respectively. No statistically significant effect was found between any of the studied covariates and model parameters (p > 0.05). Simulations of different regimens showed no clinically significant differences in terms of CD19+ repopulation times. A trend towards a lack of clinical response was observed in patients with lower CD19+ repopulation times and higher areas under the CD19+ versus time curve. CONCLUSIONS: Rituximab pharmacodynamics was described in a real-world setting in children suffering from autoimmune and neurologic diseases. Diagnosis, substitution between innovator rituximab and its biosimilars or type of regimen did not affect rituximab-induced depletion of CD19+ nor the clinical response in this cohort of patients. According to this study, rituximab frequency and dosage may be chosen based on clinical convenience or safety reasons without affecting CD19+ repopulation times. Further studies in larger populations are required to confirm these results.

The multifaceted role of macrophages during acute liver injury.

The liver is situated at the interface of the gut and circulation where it acts as a filter for blood-borne and gut-derived microbes and biological molecules, promoting tolerance of non-invasive antigens while driving immune responses against pathogenic ones. Liver resident immune cells such as Kupffer cells (KCs), a subset of macrophages, maintain homeostasis under physiological conditions. However, upon liver injury, these cells and others recruited from circulation participate in the response to injury and the repair of tissue damage. Such response is thus spatially and temporally regulated and implicates interconnected cells of immune and non-immune nature. This review will describe the hepatic immune environment during acute liver injury and the subsequent wound healing process. In its early stages, the wound healing immune response involves a necroinflammatory process characterized by partial depletion of resident KCs and lymphocytes and a significant infiltration of myeloid cells including monocyte-derived macrophages (MoMFs) complemented by a wave of pro-inflammatory mediators. The subsequent repair stage includes restoring KCs, initiating angiogenesis, renewing extracellular matrix and enhancing proliferation/activation of resident parenchymal and mesenchymal cells. This review will focus on the multifaceted role of hepatic macrophages, including KCs and MoMFs, and their spatial distribution and roles during acute liver injury.

Endometrioma Within the Anterior Abdominal Wall Causing Cyclic Abdominal Pain.

Lesions from endometriosis contain endometrial glands and stroma outside the uterine cavity. The lesions occur in the pelvis but are also found in the bowel, diaphragm, and pleural cavity. Endometriosis within the extraperitoneal abdominal wall is rare, though, and usually within c-section scars (incidence is .03%-.5%). The typical triad includes: mass in the abdominal wall, cyclical pain, and history of previous abdominal surgery. We present the case of a 28-year-old female with a past history of cesarean section and obesity (BMI = 31) who presented with approximately 3 years of abdominal pain which was "waxing and waning" in severity depending on her menstrual cycle. Multiple doctors and US imaging did not reveal a diagnosis. During consultation, she had a palpable 3 cm mass several centimeters above and right of her abdominal incision. She underwent a CT showing an inflamed subcutaneous mass abutting her anterior rectus sheath. She underwent wide excision which confirmed the diagnosis of endometrioma. This case demonstrates the need for good history and physical exam skills, as well as proficiency in reviewing radiographic imaging. Due to habitus and pain, the physical exam was difficult. However, there was a firm mass upon deep palpation. Her initial imaging was "negative," but review of the images revealed only intraperitoneal views and further imaging revealed the mass. There must be high clinical suspicion for this disease because failure to remove all tissue (including the surrounding fibrosis and desmoplastic tissue) or biopsy can lead to spread of residual endometrial cells and recurrence.

The use of amino acid formulas in pediatric patients with allergy to cow's milk proteins: Recommendations from a group of experts.

One of the most common food allergies in children is cow's milk allergy (CMA). In breast-fed infants with CMA, the mother is encouraged to avoid dairy products. If this is not possible, or in formula fed infants, use of hypoallergenic replacement formulas such as extensively hydrolyzed formulas (EHF) is recommended. However, in ∼5% of patients EHFs are not tolerated and/or allergy symptoms can persist. When EHFs are ineffective and in severe forms of CMA, amino acid-based formulas (AAF) should be considered. Six pediatric gastroenterologists with extensive experience in food allergy management reviewed scientific publications and international clinical practice guidelines to provide practical recommendations on AAF. The guidelines reviewed had discrepancies and ambiguities around the specific indications for using formulas as a milk substitute. The panel recommends AAFs as the first therapeutic option in anaphylaxis due to CMA, in acute and chronic severe food protein-induced enterocolitis syndrome, in CMA associated with multiple food allergy, and in cases of eosinophilic esophagitis not responding to an extended exclusion diet or not eating solids. The main benefit of AAF is its absence of residual allergenicity, making it a safe treatment option in severe CMA patients who do not tolerate or respond to an EHF.

Platelet-rich Plasma for the Treatment of Erectile Dysfunction: A Prospective, Randomized, Double-blind, Placebo-controlled Clinical Trial.

PURPOSE: We assessed the safety and efficacy of 2 injections of platelet-rich plasma for treating mild to moderate erectile dysfunction by conducting a prospective, randomized, double-blind, placebo-controlled clinical trial. MATERIALS AND METHODS: Men with mild to moderate erectile dysfunction (International Index of Erectile Function scores 11-25) were randomized to receive either 2 injections of platelet-rich plasma or placebo separated by 1 month. Primary outcome was percentage of men meeting minimum clinically important difference at 1 month after the second injection. Secondary outcomes were change in International Index of Erectile Function at 1, 3, and 6 months, and changes in penile vascular parameters and adverse events at 6 months. RESULTS: We randomized 61 men: 28 into platelet-rich plasma and 33 into placebo. There was no difference between groups in percentage of men meeting minimum clinically important difference at 1 month: 14 (58.3%) in platelet-rich plasma vs 15 (53.6%) in placebo (P = .730). Mean International Index of Erectile Function-Erectile Function domain changed from 17.4 (95% CI 15.8-19.0) to 21 (17.9-24.0) at 1 month in men receiving platelet-rich plasma, vs 18.6 (17.3-19.8) to 21.6 (19.1-24.1) in the placebo group; however, there was no significant difference between groups (P = .756). There were no major adverse events and only 1 minor adverse event in each group. There were no changes in penile Doppler parameters from baseline to 6 months. CONCLUSIONS: The results of our prospective, double-blind, randomized, placebo-controlled clinical trial suggest that 2 injections of intracavernosal platelet-rich plasma separated by 1 month in men with mild to moderate erectile dysfunction is safe, but we found no difference in efficacy between platelet-rich plasma and placebo.

Efficacy and safety outcomes of a compounded testosterone pellet versus a branded testosterone pellet in men with testosterone deficiency: a single-center, open-label, randomized trial.

Background: Testosterone deficiency (TD) is a prevalent condition, especially in men ≥45 years old, and testosterone therapy (TTh) can improve the quality of life in these patients. Aim: To evaluate the safety profile of compounded subcutaneous testosterone pellets and to compare the efficacy between compounded and market brand testosterone pellets for TTh: E100 (Empower Pharmacy) and Testopel (Food and Drug Administration approved), respectively. Methods: This was a prospective, phase 3, randomized, noninferiority clinical trial. We enrolled 75 men diagnosed with TD and randomized them 1:1 to a market brand group and a compounded pellet group. The patients were implanted with their respective testosterone pellets: Testopel (10 pellets of 75 mg) and E100 (8 pellets of 100 mg). Outcomes: We evaluated adverse events after implantation and followed men at 2, 4, and 6 months for morning laboratory levels (prior to 10 am): serum testosterone, estradiol, hematocrit, and prostate-specific antigen. Results: After randomization, 33 participants were enrolled in the Testopel arm and 42 in the E100 arm. Serum testosterone levels were similar between the groups at 2, 4, and 6 months, with most men (82%) dropping to <300 ng/dL by the end of the trial. Adverse events were also similar, such as elevations in prostate-specific antigen, estradiol, and hematocrit. Most dropouts were related to persistent TD symptoms and serum testosterone <300 ng/dL, with similar rates between the groups in the study. Clinical Implications: Men treated with Testopel and E100 pellets had comparable serum testosterone levels and similar adverse event rates, providing an effective choice of long-term TTh among men with TD. Strengths and Limitations: Strengths include the prospective, randomized, single-blinded study design and adequate follow-up. Limitations include the lack of external validity and the single-institution cohort. Conclusion: E100 compounded testosterone pellets are a noninferior option of TTh as compared with Testopel for men presenting with TD.

EvolClustDB: Exploring Eukaryotic Gene Clusters with Evolutionarily Conserved Genomic Neighbourhoods.

Conservation of gene neighbourhood over evolutionary distances is generally indicative of shared regulation or functional association among genes. This concept has been broadly exploited in prokaryotes but its use on eukaryotic genomes has been limited to specific functional classes, such as biosynthetic gene clusters. We here used an evolutionary-based gene cluster discovery algorithm (EvolClust) to pre-compute evolutionarily conserved gene neighbourhoods, which can be searched, browsed and downloaded in EvolClustDB. We inferred ∼35,000 cluster families in 882 different species in genome comparisons of five taxonomically broad clades: Fungi, Plants, Metazoans, Insects and Protists. EvolClustDB allows browsing through the cluster families, as well as searching by protein, species, identifier or sequence. Visualization allows inspecting gene order per species in a phylogenetic context, so that relevant evolutionary events such as gain, loss or transfer, can be inferred. EvolClustDB is freely available, without registration, at http://evolclustdb.org/.

Nutritional Analysis of the Spanish Population: A New Approach Using Public Data on Consumption.

Official population consumption data are frequently used to characterize the diet of countries; however, this information may not always be representative of reality. This study analyses the food consumption of the Spanish population by reconstructing the whole food chain. The results have been compared with the data provided by the National Consumption Panel to which the food losses/waste reported in the literature along the distribution chain have been added. The difference between them allowed a new calculation of the estimated food consumption that was subjected to a dietary-nutritional analysis. Most of the foods were consumed more than those officially reported (range of 5-50%). The unhealthy ratios of consumed foods and recommended servings were: meat products (Rcr = 3.6), fruits and legumes (Rcr = 0.5), and nuts (Rcr = 0.14). Caloric intake surpasses needs. The results were consistent with the data on the prevalence of overweight and obesity in Spain, as well as with the prevalence of associated diseases. To make a judgment about the quality of a country's diet, it is necessary to have reliable data on food consumption, as well as energy and nutrient intake. This study encourages other authors to implement this method to verify and quantify the possible difference between official and real consumption data.

Rationale and Design for the COCKTAIL Trial: A Single-center, Randomized, Double-blind, Sham-controlled Study Combining Shockwave Therapy and Platelet-rich Plasma for Erectile Dysfunction.

Restorative therapies are a promising option for the treatment of erectile dysfunction. Several studies have assessed platelet-rich plasma and shockwave therapy alone. However, COCKTAIL is the first study to evaluate the synergistic effects of these two therapies in combination.

Collagenase Clostridium histolyticum Treatment Improves Degree of Curvature in Peyronie's Disease with Calcified Plaques.

BACKGROUND: Peyronie's disease (PD) is a fibrotic condition of the penis characterized by abnormal plaque formation. Intralesional collagenase Clostridium histolyticum (CCh) is effective in noncalcified PD; however, its effectiveness in calcified PD is not well characterized. OBJECTIVE: To assess curvature improvement in calcified PD plaques treated with CCh. DESIGN, SETTING, AND PARTICIPANTS: We prospectively evaluated men with calcified PD electing CCh treatment at our institution from October 2018 to November 2020. We assessed curvature with artificial erection and goniometer before and at least 3 mo after treatment. We classified the type of plaque calcification based on ultrasound. INTERVENTION: Intralesional CCh. Each treatment cycle consisted of two CCh injections (0.58 mg) into the plaque at the point of maximal penile curvature. The second injection was performed 72 h to 1 wk later, after which participants began modeling. All men were intended to receive a total of eight injections in four cycles, each 6 wk apart. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Change in penile curvature after CCh was measured. We assessed for differences in outcomes based on the number of injections and type of calcification. Unless otherwise specified, data are presented as medians (interquartile range). RESULTS AND LIMITATIONS: Sixty men with calcified PD elected CCh; 47 had complete follow-up data. Thirty-nine men completed treatments with eight injections, while the remaining discontinued after a median of five (four to six) injections. There was no difference in response between type 2 and type 3 plaques. Curvature significantly improved by 17.5° (37.5-10.0°) in patients who completed treatment and by 15.0° (20.0-0.0°) in those who discontinued. Limitations include a small sample. CONCLUSIONS: Men with calcified PD plaques improve with CCh treatment and show similar improvements regardless of calcification type. PATIENT SUMMARY: In this study, we evaluated the efficacy of collagenase Clostridium histolyticum (CCh) treatment in calcified Peyronie's disease (PD) plaques. We found that treatment in calcified plaques demonstrated significant improvement in curvature and the grading of calcification did not impact the degree of curvature improvement. We conclude that participants with calcified PD plaques can benefit from nonsurgical CCh treatment.

A Phase 2 Randomized, Placebo-controlled Crossover Trial to Evaluate Safety and Efficacy of Platelet-rich Plasma Injections for Peyronie's Disease: Clinical Trial Update.

Intralesional injection of platelet-rich plasma for Peyronie's disease appears to be safe according to early observations from an ongoing clinical trial. Efficacy data remain elusive until completion of the trial.

Distinct spatial distribution and roles of Kupffer cells and monocyte-derived macrophages in mouse acute liver injury.

Macrophages are key regulators of inflammation and repair, but their heterogeneity and multiple roles in the liver are not fully understood. We aimed herein to map the intrahepatic macrophage populations and their function(s) during acute liver injury. We used flow cytometry, gene expression analysis, multiplex-immunofluorescence, 3D-reconstruction, and spatial image analysis to characterize the intrahepatic immune landscape in mice post-CCl4-induced acute liver injury during three distinct phases: necroinflammation, and early and late repair. We observed hepatocellular necrosis and a reduction in liver resident lymphocytes during necroinflammation accompanied by the infiltration of circulating myeloid cells and upregulation of inflammatory cytokines. These parameters returned to baseline levels during the repair phase while pro-repair chemokines were upregulated. We identified resident CLEC4F+ Kupffer cells (KCs) and infiltrating IBA1+CLEC4F- monocyte-derived macrophages (MoMFs) as the main hepatic macrophage populations during this response to injury. While occupying most of the necrotic area, KCs and MoMFs exhibited distinctive kinetics, distribution and morphology at the site of injury. The necroinflammation phase was characterized by low levels of KCs and a remarkable invasion of MoMFs suggesting their potential role in phagoctosing necrotic hepatocytes, while opposite kinetics/distribution were observed during repair. During the early repair phase, yolksac - derived KCs were restored, whereas MoMFs diminished gradually then dissipated during late repair. MoMFs interacted with hepatic stellate cells during the necroinflammatory and early repair phases, potentially modulating their activation state and influencing their fibrogenic and pro-repair functions that are critical for wound healing. Altogether, our study reveals novel and distinct spatial and temporal distribution of KCs and MoMFs and provides insights into their complementary roles during acute liver injury.

Advantages of the use of citrate over acetate as a stabilizer in hemodialysis fluid: A randomized ABC-treat study.

Hemodialysis (HD) with bicarbonate dialysis fluid (DF) requires the presence of an acid to prevent the precipitation of calcium and magnesium carbonate. The most used acid is acetic acid, with it several complications have been described. In a previous work we described the acute changes during an HD session with a DF with citrate instead of acetate. Now we report the results in the medium term, 16 weeks. It is a prospective, multicenter, crossover and randomized study, where 56 HD patients with bicarbonate three times a week were dialysed for 16 weeks with 3 mmol/L acetate and 16 weeks with 1 mmol/L citrate. Patients older than 18 years with a previous stay on HD of more than 3 months and with a normal functioning arteriovenous fistula were included. Epidemiological data, dialysis, bioimpedance, biochemistry before and after HD, as well as hypotensive episodes, were collected monthly. After 16 weeks of citrate treatment, preHD ionic calcium and magnesium were significantly lower and PTH higher than in the acetate period. No differences were observed in the effectiveness of dialysis. Hypotensive episodes were significantly more frequent with acetate than with citrate: 311 (14.1%) vs 238 (10.8%) sessions. The lean mass index increased by 0.96 ±â€¯2.33 kg/m2 when patients switched from LD with acetate to citrate. HD with citrate modifies several parameters of bone mineral metabolism, not only acutely as previously described, but also in the long term. The substitution of acetate for citrate improves hemodynamic stability, producing less hypotension and can improve nutritional status.

Sex-Dependent Hepatoprotective Role of IL-22 Receptor Signaling in Non-Alcoholic Fatty Liver Disease-Related Fibrosis.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is a major health problem with complex pathogenesis. Although sex differences in NAFLD pathogenesis have been reported, the mechanisms underlying such differences remain understudied. Interleukin (IL)22 is a pleiotropic cytokine with both protective and/or pathogenic effects during liver injury. IL22 was shown to be hepatoprotective in NAFLD-related liver injury. However, these studies relied primarily on exogenous administration of IL22 and did not examine the sex-dependent effect of IL22. Here, we sought to characterize the role of endogenous IL22-receptor signaling during NAFLD-induced liver injury in males and females. METHODS: We used immunofluorescence, flow cytometry, histopathologic assessment, and gene expression analysis to examine IL22 production and characterize the intrahepatic immune landscape in human subjects with NAFLD (n = 20; 11 men and 9 women) and in an in vivo Western high-fat diet-induced NAFLD model in IL22RA knock out mice and their wild-type littermates. RESULTS: Examination of publicly available data sets from 2 cohorts with NAFLD showed increased hepatic IL22 gene expression in females compared with males. Furthermore, our immunofluorescence analysis of liver sections from NAFLD subjects (n = 20) showed increased infiltration of IL22-producing cells in females. Similarly, IL22-producing cells were increased in wild-type female mice with NAFLD and the hepatic IL22/IL22 binding protein messenger RNA ratio correlated with expression of anti-apoptosis genes. The lack of endogenous IL22-receptor signaling (IL22RA knockout) led to exacerbated liver damage, inflammation, apoptosis, and liver fibrosis in female, but not male, mice with NAFLD. CONCLUSIONS: Our data suggest a sex-dependent hepatoprotective antiapoptotic effect of IL22-receptor signaling during NAFLD-related liver injury in females.

Platelet Rich Plasma (PRP) Growth Factor Concentration Varies in Men With Erectile Dysfunction.

BACKGROUND: Platelet Rich Plasma (PRP) is a novel therapy rich in growth factors and cytokines used to target the underlying causes of erectile dysfunction (ED). It is not known, however, if the composition of growth factors in PRP varies between men. AIM: To evaluate PRP growth factor variability among men with ED. METHODS: Whole blood was collected from 8 participants with at least a 6-month history of ED. Seven men with Peyronie's disease and 1 healthy male (without sexual dysfunction) were used as the control group. PRP was extracted from whole blood using the Arthrex Angel system. A Human Growth Factor Antibody Array for 41 proteins was performed using 3 participants and the healthy control. Using all 16 samples, quantitative detection of factors from the array that were decreased by 1.5-fold were validated with western blot. OUTCOMES: From the growth factor array, 2 growth factors-granulocyte-macrophage colony stimulating factor and transforming growth factor-ß were identified as having a 1.5-fold decrease between the participants and the control. Vascular endothelial growth factor (VEGF) was selected because androgens can upregulate VEGF production. Other than a weak negative correlation between VEGF expression and age, we found no correlation between growth factor expression for granulocyte-macrophage colony stimulating factor or transforming growth factor-ß and age, body mass index, or comorbidities. CLINICAL TRANSLATION: PRP growth factor concentration appears to vary among men with ED. PRP treatment for ED may need to be personalized for patients, depending on individual growth factor concentration. STRENGTHS AND LIMITATIONS: This study demonstrates the variability in PRP growth factors among men with ED. This is an important finding in the investigation of PRP as a restorative treatment option for men with ED. Our study, however, was limited by a small sample size. CONCLUSION: PRP growth factors vary among men with ED. Khodamoradi K, Dullea A, Golan R, et al. Platelet Rich Plasma (PRP) Growth Factor Concentration Varies in Men With Erectile Dysfunction. J Sex Med 2022;19:1488-1493.