Perugia urodynamic method of analysis (PUMA): a new advanced method of urodynamic analysis applied clinically and compared with other advanced methods.

AIMS: The aim of this study is to compare PUMA curves with different pathologic conditions causing bladder dysfunction in 158 men and 83 women. METHODS: PUMA results in terms of bladder outlet obstruction and detrusor contractility were compared in 92 men with benign prostatic hypertrophy (BPH) and p(ves) congruent with p(det) (i.e., p(abd) congruent with 0) with the results of the urodynamics operator's opinion, the provisional International Continence Society method, Abrams and Griffith's diagram, urethral resistence factor (URA), Sch?fer's diagram, and Watt factor. PUMA curves correlated reliably with different pathologic conditions such as obstructive BPH, orthotopic bladder, cystocele, the neurological bladder, and bladder diverticulum. Statistical analysis indicated excellent agreement between PUMA and URA; agreement with other methods was good in cases of obstruction and nonobstruction. In doubtful cases, as diagnosed by standard methods, PUMA agreed only with the Abrams and Griffith's diagram. PUMA and Wmax were in good agreement on detrusor con traction force. Agreement between PUMA and Sch?fer's diagram was excellent for patients with detrusor hypercontractility and good for patients with detrusor hypocontractility and normocontractility. PUMA is the only method applicable to women. It is easy to perform. When integrated with other diagnostic tests, it provides realistic data for diagnosis, medical or surgical therapy, and outcome.     

Prolactin and known modulators of rat splenocytes activate nuclear protein kinase C

Prolactin (PRL) and other trophic factors rapidly activate a nuclear pool(s) of protein kinase C (nPKC) in purified splenocyte nuclei. The PRL also enhanced [2-3H]glycerol incorporation into nuclear mono- and triacylglycerol. An assay was devised which not only probed the ability of the hormone to activate protein kinase C (PKC) but also demonstrated the presence of nuclear substrates. Using this methodology, a biphasic concentration-response curve to PRL was observed. Heterologous species of PRL and various growth factors also activated nPKC. The PRL-induced nPKC stimulation was antagonized by various immunomodulators, G protein-coupling inhibitors, PKC inhibitors, a calmodulin inhibitor, and a peripheral benzodiazepine agonist and antagonist. A monoclonal antibody to PKC, anti-rat PRL antiserum and a monoclonal anti-rat PRL receptor antibody antagonized PRL-induced PKC-dependent nuclear phosphorylation, further implicating nPKC and a PRL receptor-mediated activation process. Nuclear PKC may be a major target for trophic regulation in response to both positive and negative growth signals.     

Treatment of refractoriness to platelet transfusion by protein A column therapy

Ten thrombocytopenic patients (platelets < 10–24 × 10(9)/L) who were refractory to platelet transfusion were investigated for their responsiveness to staphylococcal protein A column therapy. Nine patients had previously been treated with steroids, intravenous immune globulin, and/or other forms of immunosuppressive therapy without improvement in their transfusion response. All patients were receiving multiple platelet transfusions without achieving 1-hour corrected count increments (CCIs) > or = 7500. Eight patients had antibodies that reacted with platelets and were directed against HLA class I antigens, ABO antigens, and/or platelet-specific alloantigens. Plasma (500-2000 mL) from each patient was passed over a protein A silica gel column and then returned to the patient. Patients received from 1 to 14 treatments. A positive response to protein A therapy was defined as at least a doubling of the pretreatment platelet count and/or two successive 10- to 120-minute posttransfusion CCIs > or = 7500. Following plasma treatments, 6 of 10 patients responded with daily platelet counts that averaged 48 +/− 11 × 10(9) per L as compared with counts of 16 +/− 7 × 10(9) per L (p < 0.0005) before treatment. Posttransfusion CCI values determined in four of these patients averaged 2480 +/− 810 and 10,010 +/− 3540 (p < 0.005) before and after treatment, respectively. In contrast, among the four unresponsive patients, platelet counts averaged 10 +/− 9 and 13 +/− 10 × 10(9) per L (p = NS), respectively, while posttransfusion CCIs were 700 +/− 1410 and 1520 +/− 2460 (p = NS), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Urinary Polyamines in Patients with Advanced Cervical Cancer or Pelvic Cancer Recurrence During and After Radiotherapy

The urinary excretion of polyamines was evaluated before, during and after radiotherapy in 16 patients with advanced squamous cell carcinoma of the uterine cervix (stage IIb or IIIb) and in 7 cases with pelvic recurrence after surgery for various types of carcinoma. The concentration of spermidine was significantly higher in the patients with primary tumors than in those with recurrent tumors. After the first radiation fractions putrescine increased in the patients with primary tumors whereas it decreased in patients with recurrent tumors. The values tended to return to baseline levels with time following treatment initiation. Polyamine increased markedly during treatment in patients who remained disease-free for at least 5 years but not in the patients with progressive disease or relapse. The results suggest a different polyamine metabolism and a different response to radiotherapy of recurrent tumors compared to primary tumors. The increase of urinary polyamines, but not the baseline values, seemed to be correlated to the response after radiotherapy.     

2-Alkynyl derivatives of adenosine and adenosine-5'-N-ethyluronamide as selective agonists at A2 adenosine receptors.

In the search for more selective A2-receptor agonists and on the basis that appropriate substitution at C2 is known to impart selectivity for A2 receptors, 2-alkynyladenosines 2a-d were resynthesized and evaluated in radioligand binding, adenylate cyclase, and platelet aggregation studies. Binding of [3H]NECA to A2 receptors of rat striatal membranes was inhibited by compounds 2a-d with Ki values ranging from 2.8 to 16.4 nM. 2-Alkynyladenosines also exhibited high-affinity binding at solubilized A2 receptors from human platelet membranes. Competition of 2-alkynyladenosines 2a-d for the antagonist radioligand [3H]DPCPX and for the agonist [3H]CCPA gave Ki values in the nanomolar range, and the compounds showed moderate A2 selectivity. In order to improve this selectivity, the corresponding 2-alkynyl derivatives of adenosine-5'-N-ethyluronamide 8a-d were synthesized and tested. As expected, the 5'-N-ethyluronamide derivatives retained the A2 affinity whereas the A1 affinity was attenuated, resulting in an up to 10-fold increase in A2 selectivity. A similar pattern was observed in adenylate cyclase assays and in platelet aggregation studies. A 30- to 45-fold selectivity for platelet A2 receptors compared to A1 receptors was found for compounds 8a-c in adenylate cyclase studies.     

2-Chloro-N6-[3H]cyclopentyladenosine ([3HCCPA) —a high affinity agonist radioligand for A1 adenosine receptors

Summary The tritiated analogue of 2-chloro-N⁶-cyclopentyladenosine (CCPA), an adenosine derivative with subnanomolar affinity and a 10000-fold selectivity for A₁ adenosine receptors, has been examined as a new agonist radioligand. [³H]CCPA was prepared with a specific radioactivity of 1.58 TBq/mmol (43 Ci/mmol) and bound in a reversible manner to A₁ receptors from rat brain membranes with a high affinityK _D-value of 0.2 nmol/l. In the presence of GTP aK _D-value of 13 nmol/l was determined for the low affinity state for agonist binding. Competition of several adenosine receptor agonists and antagonists for [³H]CCPA binding to rat brain membranes confirmed binding to an A₁ receptor. Solubilized A1 receptors bound [³H]CCPA with similar affinity for the high affinity state. At solubilized receptors a reduced association rate was observed in the presence of MgCl₂, as has been shown for the agonist [³H]N⁶-phenylisopropyladenosine ([³H]PIA). [³H]CCPA was also used for detection of A₁ receptors in rat cardio myocyte membranes, a tissue with a very low receptor density. A K_D-value of 0.4 nmol/l and aB _max-value of 16 fmol/ mg protein was determined in these membranes. In human platelet membranes no specific binding of [³H]CCPA was measured at concentrations up to 400 nmol/l, indicating that A2 receptors did not bind [³H]CCPA. Based on the subnanomolar affinity and the high selectivity for A₁ receptors [³H]CCPA proved to be a useful agonist radioligand for characterization of A₁ adenosine receptors also in tissues with very low receptor density.Abbreviations CHA N⁶-cyclopenyadenosine - CPA N⁶-cy-clopentyladen,osine - CCPA 2-chloro-N⁶-cyclopentyladenosine - CCCPA 2-chloro-5-chloro-5-deoxy-N⁶-cyclopentyladenosine; - CHAPS 3-[3-(cholamidopropyl)dimethylammonio]-1-propanesulfonate - DPCPX 8-cyclopentyl-1,3-dipropylxanthine - NECA N-ethylcarboxamidoadenosine - PEI polyethylenimine - PIA N⁶-phenylisopropyladenosine Send offprint requests to K.-N. Klotz at the above address     

Sociotropic cognition moderates stress-induced cardiovascular responsiveness in women through effects on total peripheral resistance, but not cardiac output.

Although cardiovascular disease (CVD) remains the leading cause of mortality in women, few studies have examined the role of psychosocial factors in its development. This study examined the moderating effects of sociotropic cognition (SC), a need for social acceptance and approval, on psychosocial stress-induced cardiovascular responsiveness (CVR) and affect reactivity in women. Sixty-eight normotensive, college-aged females were randomly assigned to a low or high social threat condition. Measures of systolic, diastolic and mean arterial blood pressures (SBP, DBP and MAP, respectively), heart rate (HR), cardiac output (CO), total peripheral resistance (TPR) and negative affect were collected during rest, and under conditions of high vs. low interpersonal threat. A two-step hierarchical regression analysis was performed to predict all response variables (BPs, HR, CO, TPR and affect). Increases in SBP, DBP, MAP, TPR and negative affect were greater in the high threat than low threat condition. Changes in SBP, MAP and TPR positively covaried with SC under conditions of high interpersonal threat, but showed no significant covariation in the low threat condition. The data suggest that an excessive need for social acceptance may contribute to rises in BP through an increase in TPR, but not CO under conditions of high social threat.     

Natural Convection Heat Transfer in a Porous Cavity with Sinusoidal Temperature Distribution Using Cu/Water Nanofluid: Double MRT Lattice Boltzmann Method

In this study, natural convection flow in a porous cavity with sinusoidal temperature distribution has been analyzed by a new double multi relaxation time (MRT) Lattice Boltzmann method (LBM). We consider a copper/water nanofluid filling a porous cavity. For simulating the temperature and flow fields, D2Q5 and D2Q9 lattices are utilized respectively, and the effects of different Darcy numbers (Da) (0.001-0.1) and various Rayleigh numbers (Ra) ($10^3$-$10^5$) for porosity ($ε$) between 0.4 and 0.9 have been considered. Phase deviation ($θ$) changed from 0 to $π$ and the volume fraction of nanoparticles (Ø) varied from 0 to 6%. The present results show a good agreement with the previous works, thus confirming the reliability the new numerical method proposed in this paper. It is indicated that the heat transfer rate increases at increasing Darcy number, porosity, Rayleigh number, the volume fraction of nanoparticles and phase deviation. However, the most sensitive parameter is the Rayleigh number. The maximum Nusselt deviation is 10%, 32% and 33% for Ra=$10^3$, $10^4$ and $10^5$, respectively, with $ε = 0.4$ to $ε = 0.9$. It can be concluded that the effect of Darcy number on the heat transfer rate increases at increasing Rayleigh number, yielding a maximum enhancement of the average Nusselt number around 12% and 61% for Ra=$10^3$ and Ra=$10^5$, respectively.     

2-Substituted N-ethylcarboxamidoadenosine derivatives as high-affinity agonists at human A3 adenosine receptors

A number of 2-substituted 5'-N-ethylcarboxamidoadenosine (NECA) derivatives was investigated for their affinity and selectivity at human A3 adenosine receptors. The compounds were tested in radioligand competition studies and modulation of adenylyl cyclase activity on membranes from CHO cell lines stably transfected with the four human adenosine receptor subtypes. In binding studies the most potent compound, 2-(3-hydroxy-3-phenyl)propyn-1-yl-NECA (PHPNECA), exhibited a subnanomolar affinity for A3 adenosine receptors with a Ki value of 0.4 nM. As opposed to the limited A3 selectivity of PHPNECA, a 100-fold selectivity compared to both A1 and A2A receptors was found for 2-(2-phenyl)ethynyl-NECA (PENECA; Ki 6 nM). The EC50 values for activation of adenylyl cyclase via A2A adenosine receptors were in good agreement with the respective Ki values from binding experiments. In contrast, IC50 values for A1 and A3 receptor-mediated inhibition of adenylyl cyclase were shifted to higher values compared to the respective affinities determined in radioligand competition studies. Similar discrepancies between binding and functional data have been observed for the inhibitory A1 adenosine receptor in previous studies. Therefore, the same A3 selectivity of PENECA compared to A1 receptors was found in binding and adenylyl cyclase inhibition whereas the selectivity compared to A2A receptors that was detected in ligand binding was obscured in the functional assay. The series of compounds presented in this study identifies 2-substitution of the purine system as a promising target for the development of A3-selective high-affinity ligands.     

The TETAMI Trial: The Safety and Efficacy of Subcutaneous Enoxaparin versus Intravenous Unfractionated Heparin and of Tirofiban versus Placebo in the Treatment of Acute Myocardial Infarction for Patients Not Thrombolyzed: Methods and Design

Patients with acute myocardial infarction (AMI) who do not receive early reperfusion therapy are at high risk of reinfarction or death, and the efficacy and safety of antithrombotic therapy in this group of patients has not been evaluated. Enoxaparin is a low-molecular-weight heparin (LMWH) that has previously been shown to reduce the incidence of ischemic events in patients with unstable angina or non–Q-wave MI. The principal aims of the TETAMI study are to investigate the efficacy and safety of treatment with enoxaparin or tirofiban (a glycoprotein IIb/IIIa receptor antagonist) alone or in combination for 2 to 8 days in patients with AMI who are not eligible for early reperfusion therapy. In this 2 by 2 factorial design study approximately 900 patients will be randomly assigned, in a blinded manner, to one of four treatments: enoxaparin alone, enoxaparin plus tirofiban, unfractionated heparin (UFH), or UFH plus tirofiban, with appropriate matched placebos. The primary end point is the composite of death, recurrent AMI, and recurrent angina, analyzed at 30 days after AMI. The design and methods of the TETAMI study are described in this article.