Neuroprotective and anti-inflammatory properties of a novel non-thiazolidinedione PPARγ agonist in vitro and in MPTP-treated mice.

Peroxisome proliferator-activated receptor (PPAR)γ is a potential pharmacological target for disease-modification in Parkinson's disease (PD), mainly acting by modulating the neuroinflammatory response. However, currently available agonists thiazolidinediones (TZDs) present limitations due to safety concerns. We evaluated a novel thiobarbituric-like compound MDG548, which acts as a functional PPARγ agonist displaying higher and selective binding affinity as compared to TZDs. Neuroprotection by MDG548 was tested in vitro and in a mouse MPTP model of PD, and neuroinflammation was investigated as a putative underlying mechanism. Viability assay on rat cortical neurons showed lack of cytotoxic effect in the dose-range of 100 nM-10 µM, which was therefore used for testing in vitro protection against H2O2 and MPP+ neurotoxicity. MDG548 dose-dependently increased cell viability of rat cortical neurons co-treated with H2O2 or pre-exposed to MDG548 prior to H2O2. Moreover, MDG548 induced neuroprotection in MPP+-treated PC12 cells. NF-kB activation was investigated to assess anti-inflammatory activity. MDG548 dose-dependently decreased NF-kB activation induced by LPS (100 ng/100ml) in HEK-Blue-hTLR4 cells. Given the supposed cancer risk of other PPARγ agonists, Ames test for genotoxicity was performed in Salmonella typhimurium TA100 and TA98 strains, showing that MDG548 was not genotoxic. In vivo, BL/6J mice were treated with MPTP (20mg/kg i.p. once/day for 4 days) in association with saline or MDG548 (2, 5, 10 mg/kg i.p.). Stereological counting showed that MDG548 prevented the MPTP-induced reduction in TH-positive cells in the substantia nigra compacta (SNc) at all doses tested. Moreover, MDG548 reduced reactive microglia and iNOS induction in the SNc. MDG548, being a non-TZD compound with high PPARγ affinity, void of genotoxicity, and with in vitro as well as in vivo neuroprotective properties, provides a promising alternative in the search for safer PPARγ agonists to be tested as potential disease-modifying drugs in PD.

Effect of pioglitazone on cardiac sympathovagal modulation in patients with type 2 diabetes.

This study aims to examine the effect of pioglitazone on potential progression of autonomic damage in addition to changes in control of cardiovascular function in patients with type 2 diabetes (T2DM). Thirty patients with T2DM and 32 healthy subjects participated in the study. Sympathovagal activity, assessed by power spectral analysis (PSA) of R-R intervals variability, and blood pressure (BP) were studied during clinostatism and orthostatism in controls and patients. We have assessed blood pressure control by 24-hour monitoring of ambulatory blood pressure. Patients were treated with pioglitazone (30 mg/day) for 6 months, and then re-evaluated by PSA for heart rate variability (HRV). Reduced levels of HbA1c (P < 0.0001) and urinary albumin (P = 0.008) were observed in pioglitazone-treated patients compared to untreated baseline levels. Arterial BP remained unchanged following pioglitazone treatment. T2DM patients had reduced HRV (low-frequency power; LF; P < 0.0001 and LF/HF; LF/HF; P < 0.0001) at baseline (clinostatism) compared to controls. Baseline clinostatic differences between groups persisted after pioglitazone treatment and no effect of treatment on basal HRV variables was observed. In controls, HF decreased and LF and LF/HF ratio increased in the orthostatic position. A similar effect for HF was observed in patients, but LF and LF/HF did not increase. The normal difference between HF-power in clinostatism versus orthostatism observed for controls (P < 0.0001) was restored in patients following pioglitazone treatment (P = 0.028). A significant decrease from lying to standing position in orthostatic LF-power (P < 0.0001) and LF/HF (P < 0.0001) was also observed between patients and controls. Although no differences in autonomic control of HRV were observed between controls and patients with T2DM, significant differences were observed in sympathovagal balance following either clinostatic or orthostatic challenge. These findings provide initial evidence of a potential additional benefit afforded by pioglitazone for the improvement of cardiac sympathovagal balance in T2DM.

Sympathovagal imbalance in transsexual subjects.

CONTEXT: Autonomic nervous system imbalance is related to cardiovascular risk. Heart rate variability (HRV) indexes are associated with age, race, and sex, but the role of sex hormones is still unknown. OBJECTIVE: To evaluate sympathovagal balance (SB) in transsexuals. PATIENTS: Eighteen transsexual subjects, 12 male-to-female (group 1) and 6 female- to-male (group 2), compared with 34 age-matched controls: 17 males (group 3) and 17 females (group 4). Autonomic testing of SB was performed by Power Spectral Analysis (PSA) of HRV in clinostatism (c) and orthostatism (o). PSA identifies power peaks: high frequency (HF) expresses vagal activity, while low frequency (LF) expresses sympathetic activity. RESULTS: Group 1 showed lower LFc than groups 2, 3, and 4 (p<0.001, p=0.05, p<0.001, respectively), and lower LFo than groups 3 and 4 (p=0.01); HFc was lower than in groups 2, 3, and 4 (p=0.02, p=0.02, p<0.001, respectively), and HFo was lower than in groups 3 and 4 (p<0.001). LFo/HFo ratio was higher in group 1 than in group 4 (p<0.001). No differences emerged between groups 2 and 3. Group 2 showed lower HFo than group 4 (p=0.03), and a higher LFo/HFo ratio (p=0.01). Group 3 showed lower HFo and HFc than group 4 (p=0.02, p=0.05, respectively), and a higher LFo/HFo ratio (p=0.03). CONCLUSION: In this study we found a sympathovagal imbalance due to a reduced sympathetic and parasympathetic influence on heart rate. Sex hormone therapy per se may play a role in this imbalance, and HRV measurement could be useful in detecting cardiovascular risk in transsexuals.

Giant adrenal myelolipoma: report of a case and review of the literature.

Myelolipoma of the adrenal gland is a benign, endocrinologically inactive neoplasm composed of mature adipose tissue and a variable amount of hematopoietic elements. Rarely giant adrenal myelolipomas have been reported in literature and they are very unusual clinical entities. We describe a case in a 72 year-old woman observed at our Department of Urology for nausea, flank and abdominal pain. The surgical resected mass measured 16.5x11.5x10 cm and weighted 1 250 g. A survey of the literature on this topic is made.

Effects of recombinant human thyrotropin on heart rate variability and blood pressure in patients on l-thyroxine-suppressive therapy for differentiated thyroid carcinoma.

BACKGROUND: Recombinant human thyrotropin (rhTSH) is now currently used for the follow-up of patients with differentiated thyroid carcinoma (DTC) after total thyroid ablation. Side effects after rhTSH could involve the autonomic system and TSH receptors are possibly expressed in the heart and coronary arteries. METHODS: Heart rate variability (HRV), studied by power spectral analysis of low (LF) and high frequency (HF) powers, blood pressure (BP) and their responses to orthostatism were investigated before and 3, 6, 9 days after the first of two administrations of rhTSH on alternate days in 11 patients on chronic l-thyroxine (l-T4) suppressive therapy for DTC and in 31 healthy controls. RESULTS: A transient asymptomatic decrease in systolic and mean BP was observed during the rhTSH test, but rhTSH did not modify sympathovagal control of HRV and the lying to standing responses. Decreased LF power and LF/(LF + HF) and LF/HF ratios in DTC patients versus healthy controls indicated a sympathetic failure ascribed to the TSH-suppressive therapy with l-T4 rather than to direct effects of rhTSH. CONCLUSIONS: These findings allowed us to confirm the cardiovascular safety of rhTSH and the absence of its effects on sympathovagal control of HRV when used in the follow-up of patients with normal heart function after thyroid ablation for DTC.

A phase II study of tamoxifen in hormone-resistant metastatic prostate cancer: possible relation with prolactin secretion.

Recent experimental observations, showing the potential role of prolactin (PRL) as a tumor growth factor for prostate cancer and the unfavourable prognostic significance of enhanced chromogranin-A-secreting neuroendocrine cell proliferation, could contribute to a better understanding of the mechanisms responsible for the occurrence of hormone-resistance in the prostate cancer. Moreover, it has been shown that tamoxifen, which consistently exerts estrogenic activity in males, may inhibit prostate cancer cell proliferation in experimental studies. At present, there are no clinical data in humans. This preliminary phase II study was planned in an attempt to evaluate the therapeutic efficacy of tamoxifen in hormone-refractory metastatic prostate cancer. The study included 14 consecutive metastatic prostate cancer patients, who had progressed under the classical endocrine therapy with LHRH-analogs and/or anti-androgens. Patients received the same treatment plus tamoxifen at 20 mg/day orally. A decline greater than 50% in prostate-specific antigen (PSA) levels occurred in 4/14 (29%) patients within the first 2 months of therapy, with a median duration of 5 months. Mean pre-treatment levels of PRL were significantly higher in responder patients than in those who progressed. Moreover, abnormally high pre-treatment levels of PRL were found in 5/14 (36%) patients. The percent of clinical responses observed in patients with pre-treatment hyperprolactinemia was significantly higher than that found in patients with normal pre-treatment PRL concentrations. Finally, a significant decline in mean PRL levels upon tamoxifen therapy occurred only in the responder patients. This preliminary study seems to justify further clinical research to confirm the potential efficacy of tamoxifen in the treatment of hormone-refractory prostate cancer and to identify possible parameters, which may predict the response to treatment.

Paradoxical stimulation of prolactin secretion by L-dopa in metastatic prostate cancer and its possible role in prostate-cancer-related hyperprolactinemia.

OBJECTIVE: In addition to sex steroids, prolactin (PRL) may also stimulate prostate cancer growth. Abnormally high blood levels of PRL have been noted in metastatic prostate cancer patients. However, most studies have been limited to the evaluation of basal levels of PRL rather than to investigate its secretion in response to classical endocrine dynamic tests. This study was carried out to analyze PRL secretion in metastatic prostate cancer patients both at basal conditions and in response to L-Dopa and metoclopramide, which represents the most classical inhibitory and stimulatory tests for PRL secretion, respectively. METHODS: The study included 12 patients with metastatic prostate cancer. On separate occasions, PRL secretion was evaluated in response to L-Dopa (500 mg orally) and to metoclopramide (10 mg i.v. as a bolus). Serum levels of PRL were measured by RIA. RESULTS: Mean PRL concentrations significantly increased after metoclopramide administration, even though no PRL response occurred in 6 of 12 patients. L-Dopa was unable to reduce PRL levels, which, in contrast, paradoxically significantly increased in response to L-Dopa, with mean values comparable to those achieved after metoclopramide injection. CONCLUSION: By showing a paradoxical stimulatory effect of L-Dopa on PRL secretion and a lack of response to metoclopramide in some patients, this study would suggest the existence of evident alterations in the neuroendocrine regulation of PRL release in advanced prostate cancer.

Long-term results of intrarenal surgery for branched calculi: is such surgery still valid?

OBJECTIVE: To evaluate whether intrarenal surgery for branched calculi remains valid in the light of current new techniques, e.g. percutaneous nephrolithotomy and extracorporeal shockwave lithotripsy. PATIENTS AND METHODS: Between January 1978 and October 1984, 44 patients (24 male and 20 female, mean age 42.5 years, range 14-66) underwent complex surgery for large stones, requiring opening of the renal pelvis and a transparenchymal approach to the calices; 47 renal units were operated in 49 procedures. The evaluation before surgery included creatinine and blood nitrogen levels, blood pressure measurement, urine culture, abdominal plain X-ray (44 patients), intravenous urography (42) and isotopic renography with renal scintigraphy (five). Renal lithiasis was categorized and all patients underwent extended pyelolithotomy with a transparenchymal approach, achieved by partial nephrectomy (six patients), radial paravascular nephrotomy (10), posterior lower nephrolithotomy (29), resection of the posterior segment (two), and posterior segmentotomy and reconstruction (2); 16 operations were performed under ischaemia. In October 1996, the patients were clinically evaluated by serum creatinine levels (42), urine cultures (42), abdominal plain X-ray (42), IVU (34), isotopic renography (eight), renal ultrasonography (eight) and blood pressure measurement (44). The mean follow-up was 14.8 years. RESULTS: The major postoperative complications were; residual stones (six patients), fistula with ureteric stenosis (one, with a permanent nephrostomy), toxic temporary hepatic failure (one), femoral arterial embolism (one, resolved using a Fogarty catheter) and recurrent large stones (two, operated 1 and 5 years later). From 1984 to 1996, 19 patients had recurrent stones and two underwent dialysis. In October 1996, the renal function of 47 renal units was stable or normal in 36 (77%), reduced in seven (15%) and lost in four (8%); 24 patients were hypertensive (12 preoperatively), nine have urinary tract infection, three are positive for hepatitis B or C virus, and lithiasis has recurred in 15 renal units. CONCLUSIONS: Intrarenal surgery, conducted using modern anatomical guidelines, was an effective treatment for renal branched stones. The long-term results are satisfactory after appropriate correction of the urinary tract, with the consequent prevention of stasis and chronic infection. The definitive comparison between surgical and combined endoscopic/extracorporeal methods will only become clear when there is a comparable follow-up. Currently, surgery remains preferable in patients with giant calculi, a small pelvis and prevalent calyceal development.

[Radical prostatectomy: comparison of technics]. / Prostatectomia radicale: tecniche a confronto.

From 1989 until today 46 patients aged 44-75 years underwent a radical prostatectomy two of whom transperineal and another 44 patients underwent a retropubical prostatectomy (twenty of whom with the nerve sparing technique). Based on our experience, the clinical stages that benefit from a radical prostatectomy as are as followed: T1b, T1c, T2a, T2b; T2c, in patients who present a good A.S.A., a remaining life-span of ten years is expected. Our preference, regarding the best access was clearly the traditional retropubical which allowed us on a preliminary bases a bilateral iliaco-otturatorial lymphoadenectomy with extemporaneus histological exams. Based on our experience we do not see an indication for a radical surgical intervention in the following with: P.S.A. higher than 60 ng./ml in patients with a clinical stage C. Positive abdominal-pelvical computer tomography for macrometastical lymph nodes. Positive bone scintigraphy. Patients over the age of 75 years.