Role of AMP-activated protein kinase activators in antiproliferative multi-drug pituitary tumour therapies: effects of combined treatments with compounds affecting the mTOR-p70S6 kinase axis in cultured pituitary tumour cells.

AMP-activated protein kinase (AMPK) is activated under conditions that deplete cellular ATP levels and elevate AMP levels. We have recently shown that AMPK can represent a valid target for improving the medical treatment of growth hormone (GH)-secreting pituitary adenomas and the effects of its activation or inhibition in pituitary tumour cells are worthy of further characterisation. We aimed to determine whether AMPK may have a role in combined antiproliferative therapies based on multiple drugs targeting cell anabolic functions at different levels in pituitary tumour cells to overcome the risk of cell growth escape phenomena. Accordingly, we tried to determine whether a rationale exists in combining compounds activating AMPK with compounds targeting the phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR/p70S6K signalling pathway. AMPK down-regulation by specific small-interfering RNAs confirmed that activated AMPK had a role in restraining growth of GH3 cells. Hence, we compared the effects of compounds directly targeting the mTOR-p70S6K axis, namely the mTOR inhibitor rapamycin and the p70S6K inhibitor PF-4708671, with the effects of the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) on cell signalling and cell growth, in rat pituitary GH3 cells. AICAR was able to reduce growth factor-induced p70S6K activity, as shown by the decrease of phospho-p70S6K levels. However, it was far less effective than rapamycin and PF-4708671. We observed significant differences between the growth inhibitory effects of the three compounds in GH3 and GH1 cells. Interestingly, PF-4708671 was devoid of any effect. AICAR was at least as effective as rapamycin and the co-treatment was more effective than single treatments. AICAR induced apoptosis of GH3 cells, whereas rapamycin caused preferentially a decrease of cell proliferation. Finally, AICAR and rapamycin differed in their actions on growth factor-induced extracellular signal regulated kinase 1/2 phosphorylation. In conclusion, the results of the present study suggest the increased efficacy of combined antiproliferative therapies, including rapamycin analogues and AMPK activators in GH-secreting pituitary tumours, as a result of complementary and only partially overlapping mechanisms of action.

Chronic renal failure, end-stage renal disease, and peritoneal dialysis in Gitelman's syndrome.

The chronic state of hypovolemia, hypotension, and hypokalemia found in Bartter's syndrome has been shown to lead to a chronic nephropathy, which then can progress toward end-stage renal disease and dialysis. This progression, however, has never been reported for Gitelman's syndrome, a variant of Bartter's syndrome that shows a milder clinical picture. This report is the first to document this progression (ie, the development of end-stage renal disease in Gitelman's syndrome) as well as the first report of the use of peritoneal dialysis in either Bartter's syndrome or Gitelman's syndrome. The clinical course highlights the importance of and the need for careful control of hemodynamic status in these patients to slow the progression of renal injury. The hemodynamic alterations that characterize Bartter's syndrome and Gitelman's syndrome patients suggest that for patients requiring renal replacement therapy, peritoneal dialysis is a more appropriate treatment because of its less severe impact on these parameters.

Intravenous versus oral initial load of propafenone for conversion of recent-onset atrial fibrillation in the emergency room: a randomized trial.

BACKGROUND: Non-valvular paroxysmal atrial fibrillation is a common clinical condition associated with a high risk of thromboembolism and hemodynamic problems which increase with the duration of arrhythmia. Therefore, even if arrhythmia ceases spontaneously within 24 hours in about half of the patients, a higher early conversion rate is desirable. Propafenone either by intravenous or oral load has been shown effective in conversion to sinus rhythm. METHODS: We consecutively randomized all emergency patients with non-valvular atrial fibrillation lasting no more than 48 hours to either intravenous or oral initial load of propafenone. They all received further oral doses if still on atrial fibrillation after the initial load. Exclusion criteria were: mean ventricular rate < 65 b/min, age > 75 years, recent acute myocardial infarction, overt heart failure, conduction defects, ventricular preexcitation, thyroid dysfunction, renal or hepatic insufficiency, pregnancy, current treatment with propafenone or other antiarrhythmic drugs, and intolerance to propafenone. Primary and secondary end-points were the conversion to sinus rhythm within 12 and 48 hours of randomization respectively. RESULTS: Ninety-seven patients were randomized to intravenous (n = 49) or oral (n = 48) treatment. Overall, sinus rhythm restoration occurred in 83.3% of patients within 12 hours and in 98.9% at 24 hours. Recovery rate resulted significantly greater for intravenous treatment at 1 and 3 hours (p < 0.001 and p = 0.001, respectively). At 6, 12 and 24 hours no significant difference between the two groups was observed (p = 0.77, p = 0.81 and p = 0.99, respectively). No patient needed treatment suspension. CONCLUSIONS: In patients with recent-onset non-valvular atrial fibrillation treated with propafenone within 48 hours, conversion to sinus rhythm occurred in more than 80% within 12 hours. Even if intravenous initial load appears to be slightly more rapid, the oral way is easier to administer and cheaper. The choice may depend on the specific organization of the single emergency room.

Oxidative stress and nitric oxide system in post-transplant hypertension.

BACKGROUND: CsA-induced endothelial dysfunction and CsA-induced hypertension have been attributed to CsA effects on the endothelial-derived factors controlling vasomotor tone, but the mechanisms responsible are unclear. Endothelial nitric oxide (NO) is known to maintain a state of basal vasodilation and recently a NO mediated counterregulatory mechanism protective from CsA-induced vasoconstriction has been suggested. PATIENTS AND METHODS: Our study evaluates ecNOS gene status and NO metabolites in kidney transplanted patients under chronic CsA treatment with CsA-induced hypertension. Since CsA increases superoxide production, which metabolizes NO, plasma hydroperoxides and peroxynitrite were also evaluated as index of the presence of "oxidative stress". RESULTS: Quantification of monocyte ecNOS mRNA and NO metabolites plasma level from patients and control subjects (C) demonstrated NO system up regulation in patients notwithstanding hypertension. The mean ecNOS to beta-actin ratio was 2.00 +/- 0.87 vs 0.29 +/- 0.08 in C, p < 0.04. NO metabolite plasma level was 30.03 +/- 9.62 mM vs 9.37 +/- 3.86, p < 0.001. Hydroperoxides were also increased in patients: 3.6 +/- 1.6 i.a.u. vs 1.4 +/- 0.8, p < 0.007 (from cholesterol esters) and 10.8 +/- 6.6 vs 1.5 +/- 0.9, p < 0.008 (from triglycerides) as well as peroxynitrite plasma level: 0.36+/- 0.14 mM/L vs undetectable in C. CONCLUSIONS: This study confirms a NO system up-regulation in transplanted patients. However, the counterregolatory system to CsA-induced vasoconstriction, could be cancelled by CsA induced superoxide and free radicals production which, increasing NO metabolism could contribute to CsA induced vasoconstriction and hypertension.

Chronic delta-9-tetrahydrocannabinol treatment increases cAMP levels and cAMP-dependent protein kinase activity in some rat brain regions.

When Delta(9)-tetrahydrocannabinol (Delta(9)-THC,15 mg/kg) was injected intraperitoneally twice a day for 6 days, tolerance to its analgesic effect appeared to be complete. Chronic exposure to Delta(9)-THC caused a significant reduction in CB1 receptor binding in all brain areas that contain this receptor. Cannabinoid receptor density was markedly reduced in the cerebellum (52%), hippocampus (40%) and globus pallidum (47%) compared to 30% in the cortex and striatum. Chronic exposure enhanced the cAMP pathway, as shown by the significant increase of cAMP levels and PKA activity in the areas with receptor down-regulation (cerebellum, striatum and cortex). We propose that the increase in cAMP cascade is part of the biochemical basis of cannabinoid tolerance.

Water and its effects when drunk cold. The Physician's view (1576-1751).

Starting with Baldassare Pisanelli's book Trattato della natura de' cibi et del bere, published in Venice in 1586, the controversies that have kept physicians busy over the centuries regarding the relative importance of water in human health are traced. These controversies were of considerable importance as the Latin word for water 'aqua' is derived from the phrase 'a qua vinimus' (from whence we come). However, until the studies of Nicolas Lemery, one of the most important pharmacologists of the 18th century, the controversies were debated using more theoretical, philosophical arguments. Lemery's studies shifted the debates from those based on philosophical arguments to more physiologically and scientifically based arguments.

Giovan Battista Morgagni, a pioneer of clinical nephrology.

In the 18th century, Giovanni Battista Morgagni was the first to propose that specific signs and symptoms are linked to particular anatomical changes at autopsy and that these changes were the cause of the disease. This paper describes the report by Morgagni wherein he linked the anatomic findings at autopsy, specifically atrophied kidneys, with the signs and symptoms of a disease now known as uremia. From these findings, Morgagni felt that he had identified the factors responsible for the disease as well as its clinical course.

[Cholesterol screening in a pediatric population at atherosclerotic risk]. / Screening del colesterolo in una popolazione infantile a rischio aterosclerotico.

We studied 344 children (174 girls and 170 boys) between the ages of 6 and 15 years (average age 11 years 9 months) chosen on the basis of a positive family anamnesis for dismetabolic and/or precocious cardiovascular pathologies, and also on the basis of objective data obtained at medical examinations, such as obesity and hypertension. These subjects underwent blood tests for glycaemia, total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides. Children with total cholesterol levels above 170 mg/dl were considered to be hypercholesterolemic. 127 young people (65 girls and 62 boys) turned out to have excessively high cholesterol levels with an average level of 195.71 +/- 23.11 mg/dl and average LDL level of 127.05 +/- 25.08 mg/dl. 217 subjects (109 girls and 108 boys) turned out to be within the norm with total cholesterol level of 137.76 +/- 23.04 mg/dl and LDL cholesterol 75.59 +/- 22.89 mg/dl. We found a greater difference between the average values of LDL cholesterol and those of total cholesterol (40.5% compared to 29.61%), which shows that even at pediatric ages the LDL cholesterol concentration is the factor which best indicates the risk level for atherosclerotic development.

The release of thromboxane B2 and 6-keto-PGF1 alpha following pulmonary embolism.

It has been shown in animals that acute obstruction of pulmonary artery branches is followed by an early but shortly lived increase in blood levels of thromboxane B2 and a subsequent longer-lasting increase in blood levels of 6-keto-PGF1 alpha. Our study was conducted on twelve patients with acute pulmonary embolism. Nine were treated with urokinase; three could not be given thrombolytic or anticoagulant drugs due to bleeding peptic ulcer (2 cases) or recent cerebral hemorrhage (1 case). HPLC and RIA tests were performed on arterial blood samples at diagnosis and after 1, 6, 12 and 24 hours. Findings were compared with those in a control group of 6 healthy subjects. There was a difference in prostanoid behaviour between the untreated and urokinase treated patients. Among the former mean TxB2 was significantly raised at clinical onset and began to decline after 6-12 hours, approaching the mean level found among the controls after 24 hours. In contrast 6-keto-PGF1 alpha was raised after 1 hour and gradually declined thereafter. In the subjects treated with urokinase TxB2 was already close to the mean control level after 1 hour; 6-keto-PGF1 alpha had increased after 1 hour but had returned near the control level after 12. The behaviour of prostanoids appears to match the clinical course.

[Description of a case of tuberous sclerosis in a 2-month-old girl]. / Descrizione di un caso di sclerosi tuberosa in una bambina di 2 mesi.

Tuberous sclerosis was suspected in a 2 months old infant with hemilateral convulsions and typical skin lesions. C.A.T. and fundus exams confirmed the diagnosis. The case is interesting because of the very young age at which diagnosis was possible.

Transient hyperphosphatasemia of infancy. Fifteen new cases.

Alkaline phosphatase was assayed as part of the routine examinations performed in all children hospitalized for the first time in our ward. Fifteen children had transient hyperphosphatasemia of infancy (THI). Their clinical features suggested the presence of an infectious agent.

[Thymostimulin in the therapy of bronchiolitis: clinical evaluation in a controlled study]. / La timostimolina nella terapia della bronchiolite: valutazione clinica in uno studio controllato.

Twenty-eight infants with bronchiolitis were randomized divided into two groups. Clinical diagnosis was made by scores indicated by the Bronchopneumology Study Laziale. Group one received thymostimulin (TP-1 Serono: 1.5 mg/kg/die for five days), while in the second group it was not administered. Interferon concentration in frozen serum (-20 degrees C) was evaluated at entry and after 48 hours. Etiology, severity grade and clinical characteristic were similar in both groups; this has made reliable the present evaluation. Although, in the first four days clinical score was slightly lower in the first group than in the second, there were not observed differences with statistics significance and hospitalization was similar in both groups. Because there has been described in literature an increase in interferon's production after TP-1 administration we evaluated the influence of this hormone on interferon's production. There were no differences with statistics significance with or without treatment. This study has not showed an important TP-1's efficiency in the treatment of bronchiolitis.