Late diagnosis of HIV infection at two academic medical centers: 1994-2004.

Over the last decade, there has been increased attention to the role of earlier HIV testing in the United States. Our objective was to determine if this has translated into changes in the proportion of inpatients with advanced disease at the time of initial HIV diagnosis. We identified inpatients discharged with a new diagnosis of HIV infection or AIDS between 1994 and 2004 at two academic medical centers. We examined trends in initial CD4 count at diagnosis over three time periods: 1994-1996, 1997-2000 and 2001-2004. Between 1994 and 2004, 235 inpatients were newly diagnosed with HIV infection or AIDS in the two centers. For the 217 patients with available CD4 count data, the median initial CD4 count was 41/microl (interquartile range 19-138/microl). Of the 217 patients, 184(85%) had CD4 < or =200/microl and 119/217 (55%) had CD4 < or =50/microl. There were no significant differences in median CD4 count by time period. A large majority of inpatients with newly diagnosed HIV infection at two academic medical centers between 1994 and 2004 had signs of advanced immunodeficiency. Over this recent 11-year period there was no evidence that inpatients with a new HIV diagnosis were identified at earlier stages of disease.

Discovery, synthesis, and in vivo activity of a new class of pyrazoloquinazolines as selective inhibitors of aurora B kinase.

The Aurora kinases have been the subject of considerable interest as targets for the development of new anticancer agents. While evidence suggests inhibition of Aurora B kinase gives rise to the more pronounced antiproliferative phenotype, the most clinically advanced agents reported to date typically inhibit both Aurora A and B. We have discovered a series of pyrazoloquinazolines, some of which show greater than 1000-fold selectivity for Aurora B over Aurora A kinase activity, in recombinant enzyme assays. These compounds have been designed for parenteral administration and achieve high levels of solubility by virtue of their ability to be delivered as readily activated phosphate derivatives. The prodrugs are comprehensively converted to the des-phosphate form in vivo, and the active species have advantageous pharmacokinetic properties and safety pharmacology profiles. The compounds display striking in vivo activity, and compound 5 (AZD1152) has been selected for clinical evaluation and is currently in phase 1 clinical trials.

Discovery of novel and potent thiazoloquinazolines as selective Aurora A and B kinase inhibitors.

The synthesis of a novel series of quinazolines substituted at C4 by five-membered ring aminoheterocycles is reported. Their in vitro structure-activity relationships versus Aurora A and B serine-threonine kinases is discussed. Our results demonstrate that quinazolines with a substituted aminothiazole at C4 possess potent Aurora A and B inhibitory activity and excellent selectivity against a panel of various serine-threonine and tyrosine kinases, as exemplified by compound 46. We found also that the position and nature of the substituent on the thiazole play key roles in cellular potency. Compounds with an acetanilide substituent at C5' have the greatest cellular activity. The importance of the C5' position for substitution has been rationalized by ab initio molecular orbital calculations. Results show that the planar conformation with the sulfur of the thiazole next to the quinazoline N-3 is strongly favored over the other possible planar conformation. Compound 46 is a potent suppressor of the expression of phospho-histone H3 in tumor cells in vitro as well as in vivo, where 46, administered as its phosphate prodrug 54, suppresses the expression of phospho-histone H3 in subcutaneously implanted tumors in nude mice.

International transoceanic kidney sharing.

The shortage of cadaver kidneys for transplantation persists in most regions of the United States. Because so many patients have preformed antibodies against prospective donors, identification of appropriate donor-recipient pairs is proving difficult in spite of computerized interregional sharing. To avoid wasting valuable human organs, we have shared 11 kidneys between Italy, the Soviet Union, West Germany and the USA, 10 of which resulted in successful transplants. Such sharing guarantees better utilization of kidneys bilaterally and aids in transplanting cytotoxic patients by increasing the total number of kidneys available.

The influence of pulsatile preservation on renal transplantation in the 1990s.

BACKGROUND: Unlike simple cold storage (CS), pulsatile machine preservation (MP) of kidneys for transplantation permits pharmacologic manipulation of the perfusate and aids in the pretransplant assessment of the kidney graft. These characteristics of MP may have importance in the era of increasing use of extended criteria donor kidneys. The overall aim of this article is to critically assess practices at our preservation unit with respect to graft function. Specific aims are to (1) compare the influence of MP versus CS on graft function, (2) determine which pretransplant variables have significance in pretransplant assessment, and (3) determine whether pharmacologic manipulation during MP is advantageous. METHODS: There were 650 consecutive kidneys preserved in our laboratory between January 1, 1993 and March 1, 999, by either MP or CS. All MP kidneys were preserved by continuous hypothermic pulsatile perfusion using Belzer-MPS or Belzer II solution. Perfusion parameters and electrolytes were measured serially during pulsatile perfusion. All CS kidneys were stored in University of Wisconsin solution. All kidneys obtained from donors exhibiting extended criteria features underwent pretransplant frozen section biopsies. Transmission electron microscopy (EM) was performed on a subset of kidneys undergoing pharmacologic manipulation. Four agents were assessed prospectively for their ability to influence MP characteristics when added to perfusate: PGE1, trifluoperazine, verapamil, and papaverine. RESULTS: MP was associated with improved immediate, 1-, and 2-year graft function and reduced length of initial hospital stay when compared with CS grafts. Changes in the machine perfusion variables flow and resistance, and the [Ca++] in perfusate, were significantly associated with delayed graft function (DGF) after the transplant. Biopsy information was not predictive of DGF. The addition of PGE1 to perfusate improved MP characteristics, reduced the release of [Ca++] into perfusate, and ameliorated mitochondrial ischemic injury in transmission EM images. Early graft function was improved in the presence of PGE1+MP, compared with function in the presence of other pharmacologic agents or CS alone. CONCLUSIONS: MP is associated with improved early and long term renal function. Moreover, PGE1 augments MP in improving graft function. The combination of MP+PGE1 may be important in optimizing the ability to use extended donor criteria kidneys and, thereby, improve the overall efficiency of cadaveric renal transplantation.

Effect of cold pressor test on the internal diameter of the radial artery.

The aim of this study was to investigate in normal subjects the effect of a cold pressor test on the caliber of the radial artery, a muscular artery of medium size. The internal diameter of this artery was measured continuously using a recently developed ultrasonic device. Immersion of one hand in ice water for two minutes increased blood pressure from 115/75 +/- 3/2 (Mean +/- SEM) to 136/90 +/- 6/2 mm Hg (P less than .001) and decreased the internal diameter of the radial artery from 2.82 +/- 0.12 to 2.60 +/- 0.09 mm (P less than .01). These data therefore indicate that the vasoconstriction induced by the cold pressor test involves not only arterioles, but also medium-size arteries.

Pushing the envelope in renal preservation; improved results with novel perfusate modifications for pulsatile machine perfusion of cadaver kidneys.

INTRODUCTION: Novel preservation techniques may diminish ischemia/reperfusion (I/R) injury. Our preservation laboratory has modified Belzer MPS for machine perfusion (MP) with prostaglandin E1 (PGE 1), nitroglycerin (NTG), and polyethylene glycol-superoxide dismutase (PEG-SOD) to attenuate I/R injury. We reviewed our recent experience using this novel formulation (NF) compared with standard perfusates. RESULTS: Between January 1998 and March 2000, 1060 consecutive kidneys were preserved in our laboratory. One hundred forty-eight kidneys (14%) were discarded. Fifty-eight percent of kidneys during this time period underwent MP (n = 532). En bloc kidney pairs were randomly assigned to pulsatile MP using Waters RM3 or MOX-100 perfusion systems using 1 of 3 perfusates; NF (NF; n = 119), Belzer MPS (MPS; n = 201), or Belzer II albumin gluconate (ALB; n = 212) Significant improvements in delayed graft function (DGF) rate were seen with NF versus other perfusates (8% vs 14% vs 19%, respectively; P =.03). At 6 months, graft survival was significantly improved with NF compared with MPS and ALB (96% vs 90% vs 87%, respectively; P =.03). NF also produced a significantly higher percentage of recipients with a serum creatinine level < or = 1.5 mg/dL. CONCLUSIONS: Novel modifications of standard MP perfusate improved outcomes after renal transplantation. Preservation-based interventions targeted to ameliorate I/R injury can improve outcomes and may allow expansion of the donor pool.

Evaluation of the biological activity of the molluscicidal fraction of Solanum sisymbriifolium against non target organisms.

The evaluation of the biocidal activity of the fruit of Solanum sisymbriifolium involving non target organisms such as aquatic insects, fish and snails lead to the isolation of the steroidal alkaloids, solamargine and ß-solamarine, from the active fractions. The fractions A3 and C, with biological activity against fish, snail and aquatic insect and larvae, are able to affect the good functioning of ecosystem found on alimentary chain. The fraction B seems to be less toxic to fish and aquatic insect and larvae. The fraction B could thus be used as molluscicide in the future.

Mutual-effect amplification of contractile responses elicited by simultaneous activation of alpha-1 adrenergic and 5-hydroxytryptamine2 receptors in isolated rat aorta.

5-Hydroxytryptamine (5-HT), and the selective alpha-1 agonists phenylephrine (PE) and oxymetazoline (OXY), were used to study the effects of simultaneous coactivation of the 5-HT2 and alpha-1 adrenergic receptors, respectively, on the contractile responses of isolated rat aortic rings. Dissociation constants (KA) were determined for each of the agonists at their respective receptor subtypes. The KA values for PE and OXY at the alpha-1 receptor were 316 nM and 1.82 microM, respectively, while the KA for 5-HT at the 5-HT2 receptor was 478 nM. Concentration-response curves for each agonist were analyzed by the Black and Leff operational model of pharmacological agonism to determine efficacy (tau) and slope factor values. The estimated tau for PE (16.02) was much greater than the tau for either OXY (4.15) or 5-HT (2.95), which had similar efficacies. Using a previously described drug concentration paradigm, a mutual-effect amplification of the 5-HT-induced contractile response was observed with mixtures of 5-HT and PE, whereas mixtures of OXY and 5-HT elicited a mutual-effect amplification of the observed response to OXY alone. In both cases, the theoretical concentration-response curve constructed using the Poch and Holzmann method of equiactive substitution demonstrated that mutual-effect amplification was largely the result of simple additivity of agonist effects. In addition, estimates of tau and slope factor determined from the Black and Leff equation were substituted into the Leff model of mutual-effect amplification and used to accurately predict the location of the concentration-response curves elicited by mixtures of 5-HT and PE, as well as mixtures of OXY and 5-HT. This represents the first time a mathematical model has been used to accurately predict the outcome of coactivation of the alpha-1 and 5-HT2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Short-term kidney preservation: to perfuse or not to perfuse with the new Belzer perfusate.

Delayed graft function is ischaemically induced and the consequence of high energy phosphate depletion. A new perfusate, described by Belzer, has been used in 43 kidney preservations, 16 of which had prolonged cold ischaemia. The overall immediate function rate was 37 of 43 kidneys or 86 per cent. Of 18 kidneys cold-stored during the same period, only nine functioned immediately. Twenty-six of these patients received cyclosporine for immunosuppression without an increase in delayed graft function or evidence of increased nephrotoxicity because of ischaemic injury or prolonged preservation.