Dicarbonyl Stress Mimics Diabetic Neurovascular Damage in the Retina.

The net effect of euglycemic treatment is grossly overestimated in diabetes mellitus and retinopathy, similar to what is observed in diabetic individuals, is found in the absence of chronic hyperglycemia. Explanations of this clinical paradox include the excess generation of reactive intermediates of metabolism. Excess formation or impaired detoxification of reactive intermediates can also result in multiple posttranslational modifications with a wide range of cellular dysfunctions. The multicellular neurovascular unit represents the response element of the retina which is crucial for the development of diabetic retinopathy. Current evidence suggests that increased reactive intermediates in the retina induce (micro-)glial activation, neurodegeneration and vasoregression similar to alterations found in the diabetic retina. Reactive metabolites can be lowered by metabolic signal blockade, by an activation of detoxification pathways and by quenching. The translation of these novel findings into treatment of patients with complications is important to reduce individual suffering and financial burden for societies.Quick Summary:Increased levels of reactive intermediates, independent of blood glucose levels, are linked to damage of the neurovascular unit of the diabetic retina.

Expression of metabolic sensing receptors in adipose tissues of periparturient dairy cows with differing extent of negative energy balance.

We recently showed that the mRNA expression of genes encoding for specific nutrient sensing receptors, namely the free fatty acid receptors (FFAR) 1, 2, 3, and the hydroxycarboxylic acid receptor (HCAR) 2, undergo characteristic changes during the transition from late pregnancy to lactation in certain adipose tissues (AT) of dairy cows. We hypothesised that divergent energy intake achieved by feeding diets with either high or low portions of concentrate (60% v. 30% concentrate on a dry matter basis) will alter the mRNA expression of FFAR 1, 2, 3, as well as HCAR2 in subcutaneous (SCAT) and retroperitoneal AT (RPAT) of dairy cows in the first 3 weeks postpartum (p.p.). For this purpose, 20 multiparous German Holstein cows were allocated to either the high concentrate ration (HC, n=10) or the low concentrate ration (LC, n=10) from day 1 to 21 p.p. Serum samples and biopsies of SCAT (tail head) and RPAT (above the peritoneum) were obtained at day -21, 1 and 21 relative to parturition. The mRNA abundances were measured by quantitative PCR. The concentrations of short-chain fatty acid (SCFA) in serum were measured by gas chromatography-flame ionisation detector. The FFAR1 and FFAR2 mRNA abundance in RPAT was higher at day -21 compared to day 1. At day 21 p.p. the FFAR2 mRNA abundance was 2.5-fold higher in RPAT of the LC animals compared to the HC cows. The FFAR3 mRNA abundance tended to lower values in SCAT of the LC group at day 21. The HCAR2 mRNA abundance was neither affected by time nor by feeding in both AT. On day 21 p.p. the HC group had 1.7-fold greater serum concentrations of propionic acid and lower concentrations of acetic acid (trend: 1.2-fold lower) compared with the LC group. Positive correlations between the mRNA abundance of HCAR2 and peroxisome proliferator-activated receptor γ-2 (PPARG2) indicate a link between HCAR2 and PPARG2 in both AT. We observed an inverse regulation of FFAR2 and FFAR3 expression over time and both receptors also showed an inverse mRNA abundance as induced by different portions of concentrate. Thus, indicating divergent nutrient sensing of both receptors in AT during the transition period. We propose that the different manifestation of negative EB in both groups at day 21 after parturition affect at least FFAR2 expression in RPAT.

Energy and metabolic sensing G protein-coupled receptors during lactation-induced changes in energy balance.

The free fatty acid receptor FFA1, FFA2, and FFA3 and hydroxy-carboxylic acid receptor (HCA2) are G protein-coupled receptors, acting as energy and metabolic sensors. Herein, we characterized the tissue-specific mRNA abundance of genes encoding for these receptors at different stages of lactation. In addition, potential effects of supplementation with or without conjugated linoleic acids (CLA) were tested. Tissues from pluriparous cows (subcutaneous adipose tissue [SAT] and liver) and from primiparous cows (3 SAT locations, 3 visceral adipose tissues, liver, mammary gland, and skeletal muscle) were used from 2 separate trials. In primiparous cows, the mRNA abundance of all receptors (FFA3 was not detectable by the applied protocol in muscle and udder) was lowest in muscle (P < 0.05). With the exception of FFA1, gene expression of the investigated receptors was higher in adipose tissue than in the non-adipose tissue. Expression of FFA1 in liver (P < 0.03), FFAR2 in SAT (P < 0.01), and HCA2 in SAT (P < 0.01) from pluriparous cows changed during the observation period (days 21 to 252 relative to parturition). The correlation between mRNA abundance of HCA2 and peroxisome proliferator-activated receptor gamma (PPARG) and likewise PPARG2 (P < 0.01) in SAT indicates a link between HCA2 and PPARG. Differences in receptor mRNA abundance between the CLA-fed and the control animals were scarce and limited to HCA2 and FFA1 in 1 and 2 time points, respectively (less hepatic HCA2mRNA in CLA-fed pluriparous cows and greater FFA1 mRNA abundance in 2 visceral adipose tissue depots in CLA-treated primiparous cows). In view of the metabolic changes occurring during the different phases of lactation, in particular, the altered concentrations of non-esterified fatty acids and ß-hydroxybutyrate acting as receptor ligands, the longitudinal tissue-specific characterization provided herein allows for a first insight into the regulation of these receptors at the gene expression level.

Relationship between obesity and race in predicting adverse pathologic variables in patients undergoing radical prostatectomy.

OBJECTIVES: To determine whether obesity is associated with more advanced prostate cancer (PCa) in radical prostatectomy patients and to explore the ethnic variability in body mass index (BMI) as a potential explanation for racial differences in PCa risk. METHODS: A multi-institutional retrospective analysis of the clinical and pathologic parameters was performed on data from 860 patients with PCa undergoing radical prostatectomy between 1992 and 1998. Patient height and weight was used to calculate the BMI, which categorized patients into obese (BMI 30 kg/m(2) or greater), overweight (BMI 25 to 30 kg/m(2)), and normal (BMI 25 kg/m(2) or less) groups. Age, serum prostate-specific antigen level, pathologic stage, and Gleason score for each group were compared. The distribution of the BMI in each of four ethnic groups was also determined. RESULTS: Of 860 patients, 171 (20%) were obese, 425 (49%) overweight, and 264 (31%) normal. The obese patients presented at a younger mean age (62 years, P = 0.001), had higher mean Gleason scores (6.7, P = 0.002), had a higher likelihood of Gleason score 7 or greater cancer (71%, P = 0.003), and had a lower chance of organ-confined cancer (46%, P = 0.050). The BMI was highest in blacks, followed by whites and Asians, and blacks had significantly higher grade cancers (P = 0.045). In multiple logistic regression analysis of the BMI and race, only BMI remained an independent predictor of Gleason grade. CONCLUSIONS: Obese patients with PCa present for radical prostatectomy at a younger age with higher grade and more pathologically advanced cancers. Blacks have higher grade cancers than other ethnic groups and, at the same time, have significantly higher BMIs. These findings suggest that obesity may in part account for the racial variability in PCa risk.

Multicenter patient self-reporting questionnaire on impotence, incontinence and stricture after radical prostatectomy.

PURPOSE: We determined the incidence of patient self-reported post-prostatectomy incontinence, impotence, bladder neck contracture and/or urethral stricture, sexual function satisfaction, quality of life and willingness to undergo treatment again in a large multicenter group of men who underwent radical prostatectomy. We also determined whether the morbidities of sexual function satisfaction, quality of life and bladder neck contracture and/or urethral stricture are predictable from demographic and postoperative prostate cancer factors. MATERIALS AND METHODS: A self-reporting questionnaire was completed and returned by 1,069 of 1,396 eligible patients (77%) who underwent radical prostatectomy between 1962 and 1997. Of the respondents 868 (85.7%) underwent surgery after 1990 and in all prostatectomy had been done a minimum of 6 months previously. Questionnaire results were independently analyzed by a third party for morbidity tabulation and the association of patient reported satisfaction. RESULTS: The patient self-reported incidence of any degree of post-prostatectomy incontinence, impotence and bladder neck contracture or urethral stricture was 65.6%, 88.4% and 20.5%, respectively. The incidence of incontinence requiring protection was 33% and only 2.8% of respondents had persistent bladder neck contracture or urethral stricture. Although incontinence and impotence significantly affected self-reported sexual function satisfaction, quality of life and willingness to undergo treatment again (p = 0.001), 77.5% of patients would elect surgery again. This finding remained true even after adjusting for demographic variables, and the time between surgery and the survey by multiple logistic regression. CONCLUSIONS: Although radical prostatectomy morbidity is common and affects self-reported overall quality of life, most patients would elect the same treatment again. Impotence and post-prostatectomy incontinence were significantly associated with sexual function satisfaction, quality of life and willingness to undergo treatment again. Bladder neck contracture and/or urethral stricture was associated with willingness to undergo treatment again after adjusting for demographic variables and time from surgery to the survey.

Development of a decision-making tool to predict risk of prostate cancer: the Cancer of the Prostate Risk Index (CAPRI) test.

OBJECTIVES: To provide a simple and reliable clinical prediction for an individual patient's overall risk of cancer at biopsy by deriving an easily implemented test based on a generalizable model. Four variables are analyzed for inclusion in the model: prostate-specific antigen (PSA) level, digital rectal examination (DRE) results, race, and age. METHODS: Two populations were used to develop and validate the test: a model (n = 633) and an independent, geographically separate, external population (n = 766). Pathology records for patients who underwent prostate biopsy between 1991 and 1995 were reviewed and screened for the presence of PSA and DRE results. Records where age and race could be determined were extracted. Multiple logistic regression was used with an iterative approach to optimize each test factor. The Wald chi-square test, receiver operating characteristic (ROC) curve, and Hosmer-Lemingshaw test were used to evaluate the model's predictive capability in the two populations. RESULTS: The model and external populations were significantly different for racial mix, PSA level, age, and biopsy detection rate, providing diverse populations to validate the test. Within a combined model, PSA, DRE, race, and age all demonstrated independent capability to predict cancer at biopsy. Predictive power of the overall test was high within the model population (ROC 80.8%), with minimal loss of power in the external population. The test demonstrated no significant lack of fit in either population. CONCLUSIONS: Within a combined test, PSA, DRE, race, and age all contribute significantly to prediction of prostate cancer at biopsy in an individual patient. The test depicts individual risk in an easily understood, visually provocative manner and should assist the clinician and patient in reaching a decision as to whether biopsy is appropriate.

Successful endoscopic removal of a severed, impacted Dormia basket.

We report the successful removal of a severed and impacted Dormia basket from an elderly patient with choledocholithiasis. One aspect of the case that increased its difficulty is that the basket had become trapped in the bile duct by attaching to an immobile stone that had formed on suture material from a prior biliary operation. Severed baskets that become entrapped in the bile duct are unusual complications of endoscopic bile duct stone removal which used to require surgical intervention. More recent reports suggest that retained baskets can be removed endoscopically in conjunction with some form of lithotripsy. The method used to remove the retained basket in our case involved advancing a Soehendra lithotripter over a looped guidewire after first shrinking the stone with extracorporeal shock wave and laser lithotripsy.

A long-term study of the efficacy of treatment of localized prostate cancer.

This paper presents a retrospective comparison of patients undergoing treatment for clinically localized prostate cancer. We reviewed the age, grade, and stage at diagnosis as well as the survival and recurrence rates of 222 patients treated for carcinoma of the prostate with either radical prostatectomy (RP) or radiotherapy (XRT) at four Army medical centers. Mean follow-up was 8.02 years (range 0.026-32.5 years). Stage and grade were similar in patients receiving either RP or XRT. Kaplan-Meier estimates showed that patients who underwent RP had a significantly greater disease-specific survival (p = 0.0001) and a significantly lower rate of distant metastases (p = 0.006) than did those who received XRT. There was no significant difference in the rate of local progression (p = 0.276) or in the mean time to local progression (XRT = 3.5, RP = 4.0 years) or to distant metastases (XRT = 3.79, RP = 4.52 years). Cox proportional hazards model incorporating age, stage, grade, and treatment type demonstrated that those patients who received XRT had more than two times the risk of dying of their disease than did those who underwent RP (risk ratio = 2.37; 95% confidence interval = 1.49-3.76). These data in similar groups of patients suggest that metastasis-free survival is improved in those who receive RP compared with XRT and that this translates into an enhanced survival advantage. Further study of larger groups of patients stratified by risk factors in randomized, prospective trials with longer follow-up will improve our ability to determine the best treatment for clinically localized prostate cancer.

Race, treatment, and long-term survival from prostate cancer in an equal-access medical care delivery system.

OBJECTIVE: To evaluate long-term survival of black and white prostate cancer patients in an equal-access medical care system to help distinguish biological from medical and social explanations of mortality differences. DESIGN AND SETTING: Retrospective study of US Department of Defense tumor registry patients with prostate cancer. Ethnicity, age, diagnosis, staging, risk factors, treatment, and survival end points were extracted. PATIENTS: Prostate cancer patients (N = 1606; 7.5% black, 92.5% white) who were active-duty personnel, dependents, or retirees eligible for care in the military medical system. MAIN OUTCOME MEASURES: Racial differences in tumor stage and grade, risk factors, recurrence, and treatment wait time (time between initial diagnosis and initial treatment); influence of stage, grade, treatment, wait time, age, and race on survival. RESULTS: No differences were found in behavioral risk factors or tumor grade or size, but blacks entered active treatment (P < .001) and exhibited a higher relative risk of cancer (P = .01) in younger age groups, presented with higher stage (P < .001), and demonstrated increased progression in distant metastatic disease (P = .01). No significant differences were detected in overall wait time. When adjusted for stage, no difference was found in type of treatment. Overall, stage, grade, and age were found to affect survival (P = .04 to P < .001), but race did not. When analyzed by stage, blacks demonstrated a clear trend of longer survival for distant metastatic disease (P = .04 to P = .06). This trend was confirmed using Kaplan-Meier estimates (P = .04, likelihood ratio). CONCLUSIONS: This analysis suggests that in an equal-access medical care system there are no stage-specific differences in treatment between black and white prostate cancer patients. Survival among blacks is similar to that among whites and may surpass it for high-stage disease.

Infrequent RAS oncogene mutations in human prostate cancer.

The RAS gene family includes three functional genes, H-RAS, K-RAS, and N-RAS, which have been most widely studied in human tumors. Point mutations most commonly occurring at codons 12, 13, or 61 of these genes allow the RAS protooncogene to be converted to a RAS oncogene. A variety of human tumors have been studied for RAS mutations to date, however, conflicting data has been reported regarding prostate cancer. Cell line studies and two American studies of clinical material have found a low incidence of RAS mutation in prostate cancer. The few mutations found were predominantly in the H-RAS gene. Conversely, a recent study of Japanese occult autopsy specimens found an approximate 25% incidence of K-RAS mutations. In this current study, DNA was extracted from 24 archival paraffin-embedded, formalin-fixed radical prostatectomy specimens. Twenty-one of the 24 cases had pathologic stage C disease, and paraffin blocks were selected having the most concentrated area of neoplasm. Twelve, seven, and five cases demonstrated moderate, well and poorly differentiated histologic grade respectively. Polymerase chain reaction (PCR) was used to amplify the K-RAS, N-RAS, and H-RAS 12, 13, 61 codons of these specimens and mutations were detected with mutation-specific oligonucleotide probe hybridization of southern and slot blots. No definite point mutations were detected. PCR's and hybridizations were performed three separate times by three investigators to confirm these results. PCR-generated mutation-specific positive controls and known negative controls were used and found to be important to interpret oligonucleotide hybridization assays. RAS gene mutations appear to be infrequent in clinical prostate carcinomas in American males.