IL-6 mediates the hepatic acute phase response after prerenal azotemia in a clinically defined murine model.

Prerenal azotemia (PRA) is a major cause of acute kidney injury and uncommonly studied in preclinical models. We sought to develop and characterize a novel model of PRA that meets the clinical definition: acute loss of glomerular filtration rate (GFR) that returns to baseline with resuscitation. Adult male C57BL/6J wild-type (WT) and IL-6-/- mice were studied. Intraperitoneal furosemide (4 mg) or vehicle was administered at time = 0 and 3 h to induce PRA from volume loss. Resuscitation began at 6 h with 1 mL intraperitoneal saline for four times for 36 h. Six hours after furosemide administration, measured glomerular filtration rate was 25% of baseline and returned to baseline after saline resuscitation at 48 h. After 6 h of PRA, plasma interleukin (IL)-6 was significantly increased, kidney and liver histology were normal, kidney and liver lactate were normal, and kidney injury molecule-1 immunofluorescence was negative. There were 327 differentially regulated genes upregulated in the liver, and the acute phase response was the most significantly upregulated pathway; 84 of the upregulated genes (25%) were suppressed in IL-6-/- mice, and the acute phase response was the most significantly suppressed pathway. Significantly upregulated genes and their proteins were also investigated and included serum amyloid A2, serum amyloid A1, lipocalin 2, chemokine (C-X-C motif) ligand 1, and haptoglobin; hepatic gene expression and plasma protein levels were all increased in wild-type PRA and were all reduced in IL-6-/- PRA. This work demonstrates previously unknown systemic effects of PRA that includes IL-6-mediated upregulation of the hepatic acute phase response.NEW & NOTEWORTHY Prerenal azotemia (PRA) accounts for a third of acute kidney injury (AKI) cases yet is rarely studied in preclinical models. We developed a clinically defined murine model of prerenal azotemia characterized by a 75% decrease in measured glomerular filtration rate (GFR), return of measured glomerular filtration rate to baseline with resuscitation, and absent tubular injury. Numerous systemic effects were observed, such as increased plasma interleukin-6 (IL-6) and upregulation of the hepatic acute phase response.

Association of Serum Carotenoids and Retinoids with Intraprostatic Inflammation in Men without Prostate Cancer or Clinical Indication for Biopsy in the Placebo Arm of the Prostate Cancer Prevention Trial.

Non-supplemental carotenoids and retinol may potentiate antioxidant and anti-inflammatory mechanisms. Chronic intraprostatic inflammation is linked to prostate carcinogenesis. We investigated the association of circulating carotenoids and retinol with intraprostatic inflammation in benign tissue. We included 235 men from the Prostate Cancer Prevention Trial placebo arm who had a negative end-of-study biopsy, most (92.8%) done without clinical indication. α-carotene, ß-carotene, ß-cryptoxanthin, lycopene, and retinol were assessed by high-performance liquid chromatography using pooled year 1 and 4 serum. Presence and extent of intraprostatic inflammation in benign tissue was assessed in 3 (of 6-10) biopsy cores. Logistic (any core with inflammation vs none) and polytomous logistic (some or all cores with inflammation vs none) regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of intraprostatic inflammation by concentration tertile adjusting for age, race, prostate cancer family history, and serum cholesterol. None of the carotenoids or retinol was associated with intraprostatic inflammation, except ß-cryptoxanthin, which appeared to be positively associated with any core with inflammation [vs none, T2: OR (95% CI) = 2.67 (1.19, 5.99); T3: 1.80 (0.84, 3.82), P-trend = 0.12]. These findings suggest that common circulating carotenoids and retinol are not useful dietary intervention targets for preventing prostate cancer via modulating intraprostatic inflammation.

The association between serum sex steroid hormone concentrations and intraprostatic inflammation in men without prostate cancer and irrespective of clinical indication for biopsy in the placebo arm of the Prostate Cancer Prevention Trial.

BACKGROUND: Intraprostatic inflammation is an emerging prostate cancer risk factor. Estrogens are pro-inflammatory while androgens are anti-inflammatory. Thus, we investigated whether serum sex steroid hormone concentrations are associated with intraprostatic inflammation to inform mechanistic links among hormones, inflammation, and prostate cancer. METHODS: We conducted a cross-sectional study among 247 men in the placebo arm of the Prostate Cancer Prevention Trial who had a negative end-of-study biopsy, most (92.7%) performed without clinical indication per trial protocol. Serum estradiol, estrone, and testosterone were previously measured by immunoassay in pooled baseline and Year 3 serum. Free estradiol and free testosterone were calculated. Inflammation was visually assessed (median of three prostate biopsy cores per man). Polytomous or logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) of some or all cores inflamed (both vs none) or any core inflamed (vs none) by hormone tertile, adjusting for age, race, and family history. We evaluated effect modification by waist circumference and body mass index (BMI). RESULTS: In all, 51.4% had some and 26.3% had all cores inflamed. Free (P-trend = .11) but not total estradiol was suggestively inversely associated with all cores inflamed. In men with waist circumference greater than or equal to 102 cm (P-trend = .021) and BMI ≥ 27.09 kg/m2 (P-trend = .0037) free estradiol was inversely associated with any core inflamed. Estrone was inversely associated with all cores inflamed (T3: OR = 0.36, 95% CI 0.14-0.95, P-trend = .036). Total (T3: OR = 1.91, 95% CI 0.91-4.02, P-trend = .11) and free (T3: OR = 2.19, 95% CI 1.01-4.74, P-trend = .05) testosterone were positively associated with any core inflamed, especially free testosterone in men with waist circumference less than 102 cm (T3: OR = 3.51, 95% CI 1.03-12.11, P-trend = .05). CONCLUSIONS: In this first study in men without prostate cancer and irrespective of clinical indication for biopsy, contrary to the hypothesis, circulating estrogens appeared to be inversely associated, especially in heavy men, whereas androgens appeared to be positively associated with intraprostatic inflammation.

The Multidisciplinary Approach to The Study of Chronic Pelvic Pain (MAPP) Research Network*: Design and implementation of the Symptom Patterns Study (SPS).

AIMS: The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network initiated a second observational cohort study-the Symptom Patterns Study (SPS)-to further investigate the underlying pathophysiology of Urologic Chronic Pelvic Pain Syndrome (UCPPS) and to discover factors associated with longitudinal symptom changes and responses to treatments. METHODS: This multisite cohort study of males and females with UCPPS features a run-in period of four weekly web-based symptom assessments before a baseline visit, followed by quarterly assessments up to 36 months. Controls were also recruited and assessed at baseline and 6 months. Extensive clinical data assessing urological symptoms, nonurological pain, chronic overlapping pain syndromes, and psychosocial factors were collected. Diverse biospecimens for biomarker and microbiome studies, quantitative sensory testing (QST) data under multiple stimuli, and structural and functional neuroimaging scans were obtained under a standardized protocol. RESULTS: Recruitment was initiated (July 2015) and completed (February 2019) at six discovery sites. A total of 620 males and females with UCPPS and 73 Controls were enrolled, including 83 UCPPS participants who re-enrolled from the first MAPP Network cohort study (2009-2012). Baseline neuroimaging scans, QST measures, and biospecimens were obtained on 578 UCPPS participants. The longitudinal follow-up of the cohort is ongoing. CONCLUSIONS: This comprehensive characterization of a large UCPPS cohort with extended follow-up greatly expands upon earlier MAPP Network studies and provides unprecedented opportunities to increase our understanding of UCPPS pathophysiology, factors associated with symptom change, clinically relevant patient phenotypes, and novel targets for future interventions.

Assessment of high-grade prostate cancer risk using prostate cancer biomarkers.

INTRODUCTION: To identify patients at risk of high-grade prostate cancer using prostate cancer biomarkers. MATERIALS AND METHODS: A total of 601 men were screened for prostate cancer in 2012, 2015, and 2016 using prostate cancer biomarkers: prostate health index (phi), 4KScore, and SelectMDx. The first two are blood tests that incorporate several PSA isoforms; SelectMDx measures mRNA levels of homeobox C6 and distal-less homeobox 1 in post-digital rectal examination urine samples. The performance of each biomarker was evaluated using cut off values based on published literature. Gleason Grade Group (GG) ≥ 2 is considered as high-grade prostate cancer. RESULTS: For patients with PSA < 1.5 ng/mL, none were at risk for GG ≥ 2 cancer based on SelectMDx > 0%, whereas 17.1% were at intermediate to high risk of finding GG ≥ 2 cancer with 4KScore ≥ 7.5%, and 3.5% were at risk of finding any prostate cancer with phi ≥ 36 at biopsy. For cut offs revised for finding men at high risk for GG ≥ 2 cancer at biopsy, only one patient with PSA < 1.5 ng/mL would be at risk with 4KScore ≥ 20% and none with phi ≥ 52.7. For patients with PSA 1.5 to 3.99 ng/mL, 2%, 8%, and 1% were at high risk for finding GG ≥ 2 cancer at biopsy based on phi, 4KScore, and SelectMDx, respectively. CONCLUSIONS: Men with PSA < 1.5 ng/mL are at very low risk of finding high-grade prostate cancer at biopsy. However, some men with PSA between 1.5 to 3.99 ng/mL may be at intermediate to high risk for high-grade prostate cancer. Thus, primary care physicians could run biomarkers test and refer those with positive biomarker results to a specialist for further evaluation.

The Ratio of the Number of Biopsy Specimens to Prostate Volume (Biopsy Density) Greater Than 1.5 Improves the Prostate Cancer Detection Rate in Men Undergoing Transperineal Biopsy of the Prostate.

PURPOSE: We sought to determine the minimum number of transperineal prostate mapping biopsies needed to optimize the prostate cancer detection rate. MATERIALS AND METHODS: A total of 436 men underwent transperineal prostate mapping biopsy at 2 institutions. Biopsy density was calculated as the ratio of the total number of specimens retrieved (mean 59.4) to prostate volume (mean 44.9 cc). Associations of biopsy density with prostate specific antigen, prostate specific antigen density, cancer diagnosis and the Gleason score were tested by ANOVA and the chi-square test. Regression analysis was done to determine factors associated with a positive transperineal prostate mapping biopsy and Gleason score 7 or higher cancer. RESULTS: Transperineal prostate mapping biopsy was positive in 299 of 436 men (68.6%). The mean number of positive cores was 7.1 (range 1 to 41) and mean biopsy density was 1.46 (range 0.39 to 3.67). The mean number of cores in positive vs negative transperineal prostate mapping biopsies was 1.61 vs 1.14 (p <0.001). Biopsy density cut points of 0.5 or less, greater than 0.5 to 1.0, greater than 1.0 to 1.5 and greater than 1.5 were associated with positive biopsy in 25%, 37.4%, 70.7% and 84.9% of patients (p <0.001). Dichotomizing biopsy density to 1.5 or less vs greater than 1.5 resulted in a positive biopsy rate of 56.4% vs 84.9% (OR 1.5, 95% CI 1.3-1.7, p <0.001). More Gleason score 6 cancers were diagnosed with higher biopsy density (94 of 158 or 59.5% vs 62 of 141 or 44.9%, p = 0.007). However, the number of positive cores with Gleason score 6 was greater in men with higher biopsy density at 4.9 vs 3.6 (p = 0.036). Prostate specific antigen (p = 0.053) and biopsy density (p = 0.012) were significant on regression analysis for positive transperineal prostate mapping biopsy and Gleason score 7+ disease. CONCLUSIONS: Biopsy density greater than 1.5 increases the diagnosis of prostate cancer by 1.5 times, detects higher volume Gleason score 6 disease and should be considered the optimal sampling approach when performing transperineal prostate mapping biopsy.

Prostatic adenocarcinoma CNS parenchymal and dural metastases: alterations in ERG, CHD1 and MAP3K7 expression.

BACKGROUND: Prostatic carcinoma metastatic to dura is commonly encountered at autopsy, but presenting as a dural or, especially parenchymal, brain metastasis during life is far less common. Our group has been interested in two immunohistochemical (IHC) markers previously shown to be downregulated in particularly aggressive primary prostatic carcinomas: CHD1 and MAP3K7. Here we assess protein expression in clinically-relevant CNS metastases. We also assessed how these two markers correlated with the most common genetic alteration in prostate cancer: TMPRSS2 fusion to ERG (40-60% of carcinomas at the primary site), which places ERG expression under the control of the androgen-regulated TMPRSS2 gene, increasing expression. DESIGN: Database query, 2000-2016, identified 16 metastases to dura, 5 to brain parenchyma. RESULTS: Four of five intraparenchymal metastases and 15/16 informative dural-based metastases were ERG-negative (90.5% overall). There was reduced expression of CHD1 in 8/21 and reduced MAP3K7 in 17/21 cases; 7/19 (37%) ERG-negative metastases had dual low expression of CHD1/MAP3K7. ERG-positive cases had high expression of one or both markers. CONCLUSION: Metastatic prostatic carcinoma to CNS demonstrates expression patterns consistent with particularly aggressive behavior. Lower ERG expression in dural and intraparenchymal metastases suggests a possibility that ERG-negative tumors with loss of MAP3K7 may become resistant to standard therapies and diffusely metastasize.

A Case-Crossover Study of Urological Chronic Pelvic Pain Syndrome Flare Triggers in the MAPP Research Network.

PURPOSE: Although many factors have been proposed to trigger symptom exacerbations (flares) in patients with interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome, few studies have investigated these factors empirically. Therefore, we embedded a case-crossover study in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain longitudinal study to evaluate a range of patient reported triggers. MATERIALS AND METHODS: We assessed exposure to proposed triggers, including diet, physical activities, sedentary behaviors, stress, sexual activities, infection-like symptoms and allergies, by questionnaire a maximum of 3 times when participants reported flares and at 3 randomly selected times. We compared participant preflare to nonflare exposures by conditional logistic regression. RESULTS: In our full analytical sample of 292 participants only 2 factors, including recent sexual activity (OR 1.44, 95% CI 1.06-1.96) and urinary tract infection symptoms (OR 3.39, 95% CI 2.02-5.68), which may overlap with those of flares, were associated with flare onset. On subanalyses restricted to flares with specific suspected triggers additional positive associations were observed for some factors such as certain dietary factors, abdominal muscle exercises, and vaginal infection-like symptoms and fever, but not for other factors (eg stress). CONCLUSIONS: Except for sexual activity our findings suggest that patient reported triggers may be individual or group specific, or they may not contribute to flares. These findings suggest caution in following rigid, global flare prevention strategies and support additional research to develop evidence-based strategies.

Fibrillary glomerulonephritis in an HIV patient without concurrent hepatitis C infection: Case report and review of the literature
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The most common renal disease associated with human immunodeficiency virus infection (HIV) is HIV-associated nephropathy (HIVAN), especially in the African American patient population. However, various patterns of glomerulonephritis (GN) are not uncommon, collectively accounting for nearly half of the renal biopsies performed in HIV patients. Most GNs that occur in HIV patients are immune complex mediated, often with concurrent infections such as hepatitis B or C. Fibrillary glomerulonephritis (FGN), a rare primary glomerular disease, has only been reported in 2 HIV patients, and both patients had concurrent hepatitis C (HCV) infection. Here we report a unique case of FGN with unusual ultrastructural morphology in an HIV-positive African American patient without concurrent HCV infection. The patient presented with nephrotic range proteinuria and renal insufficiency. A percutaneous kidney biopsy showed mesangial and segmental endocapillary proliferative GN with crescent formation. Immunofluorescence studies revealed IgG-, κ-, and C3-positive deposits in the mesangium and capillary loops. Electron microscopy demonstrated diagnostic features of FGN: randomly-arranged fibrillary deposits with a diameter of 15 - 30 nm. The deposits had an unusual distribution pattern of hump-like large deposits on the subepithelial aspect. Additionally, smaller deposits were also present in the mesangium. To our knowledge, this is the first reported case of FGN in an HIV patient without concurrent HCV infection.
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