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Erectile dysfunction (ED) affects millions of men worldwide with implications that go far beyond sexual activity. ED is now recognised as an early marker of cardiovascular disease, diabetes mellitus (DM) and depression. The risk factors that are associated with ED (sedentary lifestyle, obesity, smoking, hypercholesterolaemia and the metabolic syndrome) are very similar to those for cardiovascular disease (CVD). Arguably, the awareness of ED as a symptomatic entity in the post-Viagra™ age is on the rise. Nevertheless, ED is commonly missed when evaluating patients in the hospital setting, either because of lack of consideration or awareness, or through simple embarrassment (of both clinician and patient). This article provides an overview of the aetiology, assessment and importance of ED and hopes to promote its consideration in day-to-day clinical practice.

We report the SAR around a series of 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase. 2-Aminophenethyl analogs demonstrate excellent potency but moderate kinase selectivity, while 2-aminobenzyl analogs that fill the Ala571 subpocket exhibit good inhibition activity and excellent kinase selectivity., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Aims: Using psychological and quality of life assessment tools, we prospectively studied changes in health-related quality of life and emotional well-being in patients who had commenced GLP-1 analogue therapy (exenatide) and compared them with new insulin starters., Methods: Two matched groups of patients with type 2 diabetes who had suboptimal glycaemic control on oral medication were assessed using a battery of well-validated psychological and quality of life tests at baseline, prior to commencement of treatment and then again after 6 months of continuous therapy, along with body mass index (BMI) and hemoglobin A1c (HbA1c) measurements., Results: In the exenatide-treated patient group (n=71), treatment satisfaction was greater (P<.05), as was the well-being score, at 6 months (P<.05), and the Hospital Anxiety and Depression Scale scores were significantly reduced (P<.05) when compared with the insulin-treated group (n=67). This was also found to be independent of changes in BMI in an analysis of covariance calculation. The effect size (using Cohen's d) of these changes was however relatively small., Conclusions: Although exenatide and insulin appear to have similar efficacy for the treatment of type 2 diabetes mellitus, there are several differences between them that could influence outcomes from a patient's perspective. Exenatide affects both physiological and psychological parameters. 'Well-being' generally tends to improve in exenatide-treated patients and could be used as an adjunctive therapy for depression in the context of diabetes. A larger study is required to confirm these interesting findings., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: The Internet may provide an alternative option for rural lung cancer patients who lack access to on-site cancer support; however, Internet access and use among rural patients is unknown., Methods: An anonymous waiting-room survey was administered to all outpatient cardiothoracic surgery patients over 3 mo. Survey questions included age, gender, and diagnosis, possession of a home computer and Internet service, estimated Internet use, and use of the Internet for health information. Patients with known or suspected lung cancer were asked to indicate their interest in on-site and Internet cancer support., Results: There were 597 returned surveys (response rate 96%). The mean age was 64.6 y (SE 0.55), and 58% were men. Diagnoses included known or possible lung cancer (15.4%), lung disease (9.5%), heart disease (30.4%), other diagnoses (13.9%), and undetermined (30.6%). There were 343 patients (57.4%) with a home computer and 299 (50.1%) with home Internet service. Average Internet use was 8.5 h per wk (n = 298), and 225 patients used the Internet for health information. Of the 92 patients with lung cancer, 10 indicated interest in on-site support services while 37 expressed interest in Internet-based support., Conclusions: Based on survey results, a slight majority of rural patients have a home computer and Internet access. Internet use for health information appears relatively common. Overall interest for support services among lung cancer patients appears modest with a greater interest in Internet-based services compared with on-site support., (Copyright 2010 Elsevier Inc. All rights reserved.)

Introduction: Gender-related differences continue to challenge the management of lower extremity (LE) peripheral arterial disease (PAD) in women. We analyzed the time-trends in hospital care of such differences., Methods: Data for patients with PAD from New York, New Jersey, and Florida state hospital inpatient discharge databases (1998-2007) were analyzed using univariate and multivariate regression analyses., Results: The 2.4 million PAD-related inpatient discharge records analyzed showed a slight decrease of inpatient procedures for both genders. Compared with men, women had 18% to 27% fewer PAD and 33% to 49% fewer vascular procedural hospitalizations (P < .0001). They were persistently more likely than men to be admitted emergently (56% vs 51% in 1998 and 57% vs 53% in 2007) and discharged to a nursing home. During the study period, the amputation rate declined by 36% in women and 21% in men with PAD, and similarly, open procedures decreased by 36% and 30%. Endovascular procedures, however, increased by 150% in women and 144% in men. Procedural mortality was 4.95% vs 4.37% for men (P < .0001). Female mortality rates were persistently higher after amputations (9.89% vs 8.90%, P < .0001), open (5.49% vs 4.00%, P < .0001), and endovascular procedures (2.87% vs 2.10%, P < .0001). Time trends showed improved mortality for men and women, with a stable difference between the two., Conclusion: The analysis of representative state administrative databases of inpatient care records demonstrated improvements in mortality and amputation rates over time. However, a gender-related disparity in PAD outcomes remains that merits further investigation., (Copyright 2010 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: To report a case of metastatic thyroid cancer diagnosed on a technetium Tc 99m pertechnetate (TcO4-) thyroid scan., Methods: We present the clinical findings, laboratory results, imaging studies, and surgical pathology report in a man with thyrotoxicosis in whom metastatic well-differentiated thyroid cancer was diagnosed incidentally on a routine TcO4- thyroid scan in the setting of a presumed diagnosis of benign toxic thyroid disease. In addition, we review the literature regarding coexistence of metastatic thyroid cancer and thyrotoxicosis., Results: A 68-year-old man with thyrotoxicosis was referred for radioiodine therapy. A routine TcO4- thyroid scan revealed high-grade extrathyroidal uptake in the right upper hemithorax as well as in the left side of the thorax. In view of this finding, radioiodine treatment was deferred; further imaging with computed tomography revealed a 6.5-cm mass in a rib on the right side. A biopsy of the rib confirmed the presence of metastatic follicular carcinoma of the thyroid. Scintigraphy revealed sites of metastatic involvement predominantly in the bones along with a cold nodule in the left thyroid lobe, consistent with the primary tumor., Conclusion: This case emphasizes the impact of scintigraphic findings on determining the correct management of a patient who would have otherwise undergone inappropriate treatment. Through an extensive literature review, the incidence of malignant involvement in hyperfunctioning thyroid glands and the possible role of sodium iodide symporter expression by thyroid cancer metastatic lesions in preoperative detection of metastatic sites are addressed.

In mammals, the mechanisms regulating the number of active copies of the approximately 200 ribosomal RNA (rRNA) genes transcribed by RNA polymerase I are unclear. We demonstrate that depletion of the transcription factor upstream binding factor (UBF) leads to the stable and reversible methylation-independent silencing of rRNA genes by promoting histone H1-induced assembly of transcriptionally inactive chromatin. Chromatin remodeling is abrogated by the mutation of an extracellular signal-regulated kinase site within the high mobility group box 1 domain of UBF1, which is required for its ability to bend and loop DNA in vitro. Surprisingly, rRNA gene silencing does not reduce net rRNA synthesis as transcription from remaining active genes is increased. We also show that the active rRNA gene pool is not static but decreases during differentiation, correlating with diminished UBF expression. Thus, UBF1 levels regulate active rRNA gene chromatin during growth and differentiation.

A series of N-6 substituted 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones were prepared from N-substituted (5-methoxyphenyl)ethenylindoles. The target compounds were tested for their ability to inhibit the G2/M cell cycle checkpoint kinases, Wee1 and Chk1. Analogues with neutral or cationic N-6 side chains were potent dual inhibitors. Acidic side chains provided potent (average IC(50) 0.057 microM) and selective (average ratio 223-fold) Wee1 inhibition. Co-crystal structures of inhibitors bound to Wee1 show that the pyrrolo[3,4-c]carbazole scaffold binds in the ATP-binding site, with N-6 substituents involved in H-bonding to conserved water molecules. HT-29 cells treated with doxorubicin and then target compounds demonstrate an active Cdc2/cyclin B complex, inhibition of the doxorubicin-induced phosphorylation of tyrosine 15 of Cdc2 and abrogation of the G2 checkpoint.

A new series of MEK1 inhibitors, the 4-anilino-5-carboxamido-2-pyridones, were designed and synthesized using a combination of medicinal chemistry, computational chemistry, and structural elucidation. The effect of variation in the carboxamide side chain, substitution on the pyridone nitrogen, and replacement of the 4'-iodide were all investigated. This study afforded several compounds which were either equipotent or more potent than the clinical candidate CI-1040 (1) in an isolated enzyme assay, as well as murine colon carcinoma (C26) cells, as measured by suppression of phosphorylated ERK substrate. Most notably, pyridone 27 was found to be more potent than 1 in vitro and produced a 100% response rate at a lower dose than 1, when tested for in vivo efficacy in animals bearing C26 tumors.

Background: Curricula for surgical technical skills laboratories have traditionally been designed to accommodate the clinical activities of residents, so they typically consist of individual, episodic training sessions. We believe that the skills laboratory offers an opportunity to design a surgical skills curriculum based on the fundamental elements known to be important for motor skill instruction. We hypothesized that training novices with such a curriculum for a 1-month period would yield skills performance levels equivalent to those of second year surgery residents who had trained in a traditional program., Study Design: Fourth-year medical students served as study subjects (novice group) during a 4-week senior elective. They were taught each skill during a 1-week period. Subjects received instruction by a content expert followed by a 1-week period of deliberate practice with feedback. The novice performances were videotaped both before and after the intervention, and each videotape was evaluated in a blinded fashion by experts using a validated evaluation instrument. These results were compared with skill performance ratings of first- and second-year surgery residents that had been accumulated over the previous 3 years., Results: Average performance ratings for the novices substantially improved for all four skills after training. There was no marked difference between average performance ratings of postintervention novice scores when compared with the average scores in the resident group. Inter-rater agreement in scoring for the videotaped novice performances exceeded 0.87 (intraclass correlation) for all ratings of pre- and posttraining., Conclusions: These results demonstrate the effectiveness of a laboratory-based training program that includes fundamentals of motor skills acquisition.

Background: Few studies have examined the accuracy of patient-reported international normalized (INR) values for home anticoagulation testing (HAT). Our study objectives were to assess this accuracy and compare the percentage time within therapeutic range (PTWTR) based on HAT data to that obtained with testing through an anticoagulation clinic service (ACS)., Materials and Methods: Forty-nine anticoagulated patients were enrolled in a year-long, prospective, crossover study comparing HAT to ACS testing. Patients performed HAT for 6 months and telephoned their INR values. Thereafter, devices were interrogated for the 30 most recent INR readings. Data accuracy was calculated for each patient as the percentage of correctly telephoned INR values divided by the total number of INR values common to both the device and the telephone logs. The device-based PTWTR was compared to the PTWTR based on ACS data., Results: Of the 49 enrolled patients, 32 completed the study protocol. The mean accuracy of reporting was 94.0 +/- 13.0% (range, 48-100%); the median accuracy was 100%. Three patients had marked low accuracy (48, 60, 62%). No significant difference was seen between the PTWTR based on device data versus that obtained though the ACS (59.8 +/- 15.7% versus 59.5 +/- 19.4%, P=0.48)., Conclusions: The overall accuracy of patient-reported INR values is high and the PTWTR found with HAT is comparable to that obtained with clinic testing. However, the potential for noncompliance in a small number of patients raises the question of whether periodic confirmation of patient-reported INR values should be considered.

Many extrahepatic manifestations of hepatitis C have been described, including renal disease and vasculitis. We describe the novel finding of intimal hyperplasia associated with severe ischaemic events in two patients with hepatitis C. The combination of genotype 1a hepatitis C virus, rapidly progressive mesangiocapillary glomerulonephritis and intimal hyperplasia with ischaemic sequelae, may represent a new syndrome.

Renin is an aspartyl protease involved in the production of angiotensin II, a potent vasoconstrictor. Renin inhibitors can prevent blood vessel constriction and therefore could be useful for the treatment of hypertension. High-throughput screening efforts identified a small molecule renin inhibitor with a core substituted diaminopyrimidine ring. Parallel medicinal chemistry efforts based on this lead resulted in compound 1. A complex of 1 bound to renin was crystallized, and structural data were obtained by X-ray diffraction. The structure indicated that there were adjacent unoccupied binding pockets. Synthetic efforts were initiated to extend functionality into these pockets so as to improve affinity and adjust pharmacokinetic parameters. Thermodynamics data for inhibitor binding to renin were also collected using isothermal titration calorimetry. These data were used to help guide inhibitor optimization by suggesting molecular alterations to improve binding affinity from both thermodynamic and structural perspectives. The addition of a methoxypropyl group extending into the S3 subpocket improved inhibitor affinity and resulted in greater binding enthalpy. Initial additions to the pyrimidine ring template that extended into the large hydrophobic S2 pocket did not improve affinity and dramatically altered the thermodynamic driving force for the binding interaction. Binding of the core template was enthalpically driven, whereas binding of initial inhibitors with S2 extensions was both enthalpically and entropically driven but lost significant binding enthalpy. Additional electrostatic interactions were then incorporated into the S2 extension to improve binding enthalpy while taking advantage of the favorable entropy.

Background: Home anticoagulation testing (HAT) may be useful for rural patients who cannot attend an anticoagulation service clinic (ASC). Interest in HAT is unknown and was the focus of this study., Materials and Methods: Anticoagulated patients from two clinics, the ASC and vascular surgery clinic (VSC) were surveyed and compared for demographics, anticoagulation knowledge and opinions, and HAT interest. Logistic regression was performed, using the entire patient cohort, to identify factors associated with HAT interest., Results: There were 211 (141 ASC, 70 VSC) patients surveyed. Differences between the ASC and VSC patients included education level (13.2 versus 12.1 years; P = 0.02), time spent testing (60.5 +/- 33.5 versus 46.4 +/- 20.7 min; P = 0.001), use of fingerstick testing (90% versus 2.9%; P < 0.001), and knowledge of the potential interaction of warfarin with medications or diet (79% versus 59% P = 0.003). HAT interest was similar (62.1% ASC versus 50% VSC; P = 0.14). Factors associated with HAT interest included employment [odds ratio (OR) 2.9, 95% confidence interval (CI) 1.2-6.7], knowledge of potential interactions between medications and warfarin (OR 3.9, 95% CI 1.9-8.1), and a willingness to check international normalized ratio values more frequently if recommended (OR 2.4, 95% CI 1.2-4.6). Patients who received family help with medications appeared less interested in HAT (OR 0.29, 95% CI 0.12-0.68)., Conclusions: A slight majority of surveyed rural patients conveyed interest in HAT. Working patients and those assuming more responsibility for international normalized ratio control may be more interested in HAT. A possible association between anticoagulation knowledge and increased HAT interest was seen and should be further studied.

Background: Medical educators have indicated that feedback is one of the main catalysts required for performance improvement. However, medical students appear to be persistently dissatisfied with the feedback that they receive. The purpose of this study was to evaluate learning outcomes and perceptions in students who received feedback compared to those who received general compliments., Methods: All subjects received identical instruction on two-handed surgical knot-tying. Group 1 received specific, constructive feedback on how to improve their knot-tying skill. Group 2 received only general compliments. Performance was videotaped before and after instruction and after feedback. Subjects completed the study by indicating their global level of satisfaction. Three faculty evaluators observed and scored blinded videotapes of each performance. Intra-observer agreement among expert ratings of performance was calculated using 2-way random effects intraclass correlation (ICC) methods. Satisfaction scores and performance scores were compared using paired samples t-tests and independent samples t-tests., Results: Performance data from 33 subjects were analysed. Inter-rater reliability exceeded 0.8 for ratings of pre-test, pre-intervention and post-intervention performances. The average performance of students who received specific feedback improved (21.98 versus 15.87, P<0.001), whereas there was no significant change in the performance score in the group who received only compliments (17.00 versus 15.39, P=0.181) The average satisfaction rating in the group that received compliments was significantly higher than the group that received feedback (6.00 versus 5.00, P=0.005)., Discussion: Student satisfaction is not an accurate measure of the quality of feedback. It appears that satisfaction ratings respond to praise more than feedback, while learning is more a function of feedback.

Diabetes is an increasingly common condition and hence, managing dying patients with diabetes as a co-morbidity will become a frequent challenge. It is uncertain whether there is net beneficence in preventing hyperglycaemia in diabetic patients during the terminal phase or whether the distress involved in administering therapy and blood glucose monitoring may outweigh this ordeal. Since there is no available evidence upon which to base clinical decisions, a semi-structured questionnaire based around three clinical vignettes was sent to consultants in diabetes and palliative care in the UK. There was consensus of opinion from both groups of consultants that treatment and monitoring should be stopped in patients with type 2 diabetes, once in the terminal phase. There was less consensus regarding management of type 1 diabetes. Practical issues were raised by both groups of consultants and clinical guidelines are suggested.

Background: In vitro studies have shown that Vitamin E succinate (VES) arrests lung cancer proliferation; however, in vivo studies have not been performed. This study examined in vivo effects of VES on lung cancer., Methods: An in vitro dose-response curve of human A549 lung cancer tumors to VES was established. A549 tumors were established in the right submammary fat pads of athymic nude mice (C57/BL/6J-Hfh11nu). Seven days after injection, mice were separated into VES and control groups. VES mice (n = 12) underwent daily intraperitoneal (IP) injection of VES (150 mg/kg in 7% dimethyl sulfoxide, 93% polyethylene glycol); control mice (n = 11) were injected with vehicle only. At 27 days, harvested tumors were measured and weighed. Lungs were stained for metastases using hematoxylin-eosin. Tumor volume and weights were compared using a two-sample t test. Tumor growth curves were compared using a mixed model analysis of variance., Results: In vitro studies demonstrated dose-dependent manner inhibition of A549 cell proliferation by VES (IC(50) 18 mug/mL). Tumor volumes and weights differed significantly between VES and control mice with volumes of 192.6 +/- 20.4 mm(3)versus 292.9 +/- 31.4 mm(3) (P = 0.01) and weights of 168.6 +/- 20.0 mg versus 255.7 +/- 37.0 mg, respectively (P = 0.05). Tumor growth differed significantly (P < 0.001). Both groups of mice showed pulmonary metastases., Conclusions: Lung cancer cells appear to respond to VES, albeit incompletely. Because tumor cell response is seen, lung cancer patients may derive some benefit from VES and should be considered in eventual clinical studies using this vitamin E derivative.

Inhibition of the cell cycle kinase, cyclin-dependent kinase-4 (Cdk4), is expected to provide an effective method for the treatment of proliferative diseases such as cancer. The pyrido[2,3-d]pyrimidin-7-one template has been identified previously as a privileged structure for the inhibition of ATP-dependent kinases, and good potency against Cdks has been reported for representative examples. Obtaining selectivity for individual Cdk enzymes, particularly Cdk4, has been challenging. Here, we report that the introduction of a methyl substituent at the C-5 position of the pyrido[2,3-d]pyrimidin-7-one template is sufficient to confer excellent selectivity for Cdk4 vs other Cdks and representative tyrosine kinases. Further optimization led to the identification of highly potent and selective inhibitors of Cdk4 that exhibit potent antiproliferative activity against human tumor cells in vitro. The most selective Cdk4 inhibitors were evaluated for antitumor activity against MDA-MB-435 human breast carcinoma xenografts in mice.

A case series of six patients with HIV and Mycobacterium tuberculosis co-infection is presented. All patients were overseas-born and in all but one there was profound immunodeficiency. We recommend HIV screening of all cases of M. tuberculosis and a high degree of suspicion of tuberculosis in immigrants with HIV infection from endemic areas. Management problems included delayed diagnosis, rapid progression, paradoxical reactions and requirement for surgical intervention in three patients. Therapeutic complications included possible drug malabsorption, adverse events and drug interactions. M. tuberculosis was fully drug sensitive in all cases.

Objective: To evaluate a 2-week pilot ethnic media campaign that was implemented in 14 languages to promote awareness of HIV/AIDS and HIV testing among selected non-English speaking populations in Australia in November/December 2000., Methods: The main outcome measure was clinic attendances for the purpose of HIV testing by individuals from the target populations at one ofthree public sexual health clinics in Sydney and Melbourne prior to and immediately after the campaign., Results: The number of HIV tests on members of the 14 target language communities attending the clinics almost doubled from 66 to 122 tests. However, as a proportion of the total number of HIV tests performed at the three clinics this increase was not significant (16.3-18.8%; P = 0.31). For both periods in 2000 the proportion of HIV tests that were performed on members of the target language group were higher than during a 1999 comparison period (10.5%, both P < 0.01)., Conclusions and Implications: This study did not demonstrate a significant increase in testing attributable to the pilot intervention. A larger campaign, with a more extensive evaluation, would probably be needed to demonstrate a measurable effect.

To assess whether changes in mean cell volume (MCV) could be used as a surrogate marker of adherence, the percentage rise from the baseline MCV (%MCV rise) was compared to an independent marker of adherence, the number of days of medications dispensed in a 24-week period. Nucleoside analogues were found to differ in the extent to which they affect the MCV. The correlation between zidovudine (AZT) (30 subjects) and stavudine (D4T) (41 subjects) with adherence based on prescriptions was 0.82 (P<0.05) and 0.55 respectively (P<0.05). When adherence was categorized into 10% intervals, there was a progressive rise in the average MCV with increasing adherence that plateaus at 70% adherence. Plotting %MCV rise on time charts appears to detect those subjects with adherence of less than 70%. In conclusion, changes in MCV for HIV-positive patients taking either AZT or D4T may be a useful surrogate marker for adherence to anti-retroviral medications.

Background: Opinion differs as to whether anticoagulation is beneficial in preventing ischemic stroke in the early postoperative period after biological aortic valve replacement (AVR). The purpose of this study was to determine whether early anticoagulation with heparin and warfarin confers any significant advantage for patients undergoing such replacement., Methods and Results: Patients undergoing biological AVR between 1987 and 1996 were divided retrospectively into 2 groups based on their postoperative anticoagulation. Group A (109 patients) received heparin followed by warfarin for 3 months (prothrombin time, 20 to 25 seconds). Group B (76 patients) received no postoperative anticoagulation. Patients were followed for cerebral ischemic events, bleeding, repeat operation, hospital stay, and survival. There were 5 (4.6%), 3 (2.8%), and 12 (11%) postoperative cerebral ischemic events for group A at time points of < 24 hours, 24 hours to 3 months, and > 3 months, respectively; for group B patients, 3 (3.9%), 2 (2.6%), and 9 (11.8%) events were seen during the same respective time periods. There were no statistically significant differences for ischemic events during any of these time periods for the 2 groups. Bleeding complications occurred in 10 (9.2%) group A and 7 (9.2%) group B patients. Mean hospital stay was 12 days for both groups. Repeat operative AVR was required in 6 (5.5%) group A and 7 (9.2%) group B patients. A comparison of Kaplan-Meier survival rates between groups A and B (mean follow-up, 47 +/- 26 and 59 +/- 30 months, for groups A and B, respectively) was not statistically significant (P = 0.60). Survival rates were 93%, 84%, and 62% at 1, 5, and 7 years for group A and 87%, 74%, and 67% for group B, respectively., Conclusions: Early anticoagulation after AVR confers no advantage in the prevention of early cerebral ischemic events after biological AVR. No disadvantage in terms of bleeding or prolonged hospital stay was incurred by early anticoagulation. Long-term valve function and survival were not adversely affected by withholding early anticoagulation. We conclude that early anticoagulation after biological AVR is unnecessary.

Much of the improvement n quality and length of life achieved by HIV medical science is due to primary and secondary prophylaxis for opportunistic infection.

A series of 5-[[1-(4'-carboxybenzyl)imidazolyl]methylidene]hydantoins have been prepared and evaluated as in vitro and in vivo angiotensin II (Ang II) antagonists. Variation of substituents on the hydantoin ring leads to potent and selective Ang II antagonists with nanomolar IC50 values at the AT1 receptor and negligible affinity for the AT2 receptor. Preferred substituents include an n-butyl at R1 and an alkyl or heteroarylmethyl substituent at R2. The selection of the R2 substituent was guided in part by the calculation of its log P since a significant correlation was observed between CLOGP and AT1 binding affinity. The biphenyl tetrazole pharmacophore, common to a number of AT1 antagonists, could be replaced by, for example, a 4-carbomethoxyphenyl substituent resulting in potent Ang II antagonists both in vitro and in vivo. A representative compound of this series is 57, which reduced the mean arterial blood pressure of renal hypertensive rats by 40% at 30 mg/kg po and by 25% at 10 mg/kg po. In addition this compound was efficacious in the salt-deplete normotensive monkey model maximally decreasing blood pressure 27% at 10 mg/kg po. In summary, these compounds belong to a novel class of Ang II antagonists that lack the biphenyl tetrazole moiety yet display appreciable and long lasting oral activity.

It is often uncertain whether deaths that occur during active treatment for complications of AIDS result from diagnostic or therapeutic failure. Accurate diagnosis of infections is particularly important, and has relevance not only for the patient but also to partners, relatives, hospital staff and other patients. In the absence of adequate physical facilities and in view of the lack of success in obtaining formal autopsies in patients dying with AIDS, a limited autopsy protocol was devised for routine application at our hospital, beginning in 1989. The major aim of this protocol was to enable the safe collection of diagnostic material from patients who died despite active therapy, to ascertain unrecognized conditions and confirm existing diagnoses. We present findings from the first 16 limited autopsies which resulted in 12 additional diagnoses and a revision of the principal cause of death in 7 cases.

A novel series of nonpeptide angiotensin II (AII) receptor antagonists containing a 1H-pyrrol-1-yl moiety at the 4-position of the imidazole have been developed. The pyrrole group occupies the same lipophilic pocket at the receptor as the chloro group in DuP 753 (68) and EXP 3174 (69) and the pentafluoro group in DuP 532 (70), respectively. The impetus for its selection came from bioisosteric considerations based on hydrophobic and electronic substituent constants. An extensive study of the structure-activity relationships revealed several highly potent AII receptor antagonists. An acyl substitution at the 2-position of the pyrrole ring improved activity, most notably in the in vivo rat model. In addition, the 2-substituted pyrrole compounds improved chemical stability toward extremely facile decarboxylation reaction associated with unsubstituted pyrrole analogues, thus facilitating development of these agents. The IC50's of 18, 20, and 42 (< 1 nM) were better than the reference compounds 69 and 70, respectively. These compounds were selective AII antagonists that compete at the AT1 receptor and showed no affinity at the AT2 receptor at concentrations up to 10 microM. Upon intravenous administration in a normotensive rat model, compound 18 inhibited the AII-induced responses with ED50 of 6 micrograms/kg per min. In a renal hypertensive rat model, the antihypertensive potency of compound 18, at a dose of 10 mg/kg, was very similar to those 68 and 69, respectively. Compound 18 demonstrated a dose-related (3-30 mg/kg) decrease in blood pressure that was sustained for greater than 24 h. On the basis of its profile, compound 18, designated as CI-996, has been selected for in-depth studies. The design, synthesis, in vitro, and in vivo structure-activity relationships are described.

The incidence of colorectal cancer in the United States is increasing. Because more than half of patients with colorectal cancer have liver metastases develop, the number of patients with hepatic metastases also is increasing. Unfortunately, metastatic disease will be limited to the liver in perhaps 25% of these patients and confined to only one lobe of the liver 25% of this subgroup. Consequently, solitary or unilobar colorectal metastases are found in as few as 5% of patients with colorectal cancer. The median survival of patients with unresected hepatic metastases is approximately 10.6 months. Patients with solitary lesions or small tumor burdens may attain a median survival of 16-20 months, but 5-year survivors are extremely rare. In contrast, rates of 5-year survival average approximately 36% after resections of solitary hepatic lesions and may approach the same level in selected patients with multiple lesions. Factors that appear to adversely effect survival include detection of metastatic disease because of signs or symptoms of disease, an elevated carcinoembryonic antigen (CEA) level, elevated liver function tests, poorly differentiated primary lesions, lymph node-positive primary lesions, extrahepatic sites of metastases, more than four hepatic lesions, bilobar disease, a satellite pattern of metastases in the liver, positive margins of the liver resection, positive extrahepatic lymph nodes, and more than 10 units of blood transfusion during the perioperative period. Operative mortality for liver resections should remain approximately 4%, and major morbidity should be in the range of 20-30%. Modalities other than surgical resection have not improved survival in patients with colorectal hepatic metastases. Thus, when feasible, patients with metastatic colorectal cancer limited to one lobe of the liver should undergo hepatic resection. Unfortunately, only approximately 5% of patients with colorectal cancer fall into this category, so resection of hepatic metastases can improve overall survival of patients with colorectal cancer by only 1-2%.

A novel series of non-biphenylyltetrazole angiotensin II receptor antagonists which contain a 1H-pyrrol-1-ylacetyl residue in place of the benzoyl residue in EXP 6803 have been developed. The receptor binding activity of several members of this new series was in the 10(-8) M range, which was better than that of EXP 6803. Introduction of a carboxylic acid moiety at the 2-position of the pyrrole ring enhanced the in vitro binding affinity at the receptor by 10-fold. Compounds containing an acetic acid (18) or a propionic acid residue (20) at the 5-position of the imidazole were more potent than the carboxylic acid analogue (24). The binding IC50 of the most potent compound 20 was 22 nM. Compounds 18, 20, and 24 in their best fit conformations were manually overlayed on that of the template conformation of EXP 6803 and EXP 8623, respectively. The synthesis and structure-activity relationship data are described.

A series of primate renin inhibitors containing difluorocarbinol and difluoroketone groups at the P1-P1' position have been synthesized and studied both in vitro and in vivo. In vitro, the compounds were evaluated as inhibitors of monkey renin and the closely related aspartic proteinase, cathepsin D (bovine), as a measure of enzyme selectivity. Interestingly, the difluoroketone derivatives showed greatly reduced selectivity compared with the corresponding alcohols. However, selectivity could be enhanced by judicious choice of other substituents. Sites influencing selectivity, included not only P2, which is well-known to strongly affect selectivity, but also the P4, P1-P1', and P2' sites. These results make possible the design of inhibitors with a greater selectivity for either renin versus cathepsin D. In vivo several of the compounds in the difluoroketone series have shown good oral activity in the salt depleted normotensive cynomolgus monkey model.

Structure-activity relationships are reported for a novel class of 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid derivatives that displace 125I-labeled angiotensin II from a specific subset of angiotensin II (Ang II) binding sites in rat adrenal preparations. This binding site is not the Ang II receptor mediating vascular contraction or aldosterone release, but, rather, is one whose function has not yet been fully elucidated. It has been identified in a number of tissues and has a similar affinity for Ang II and its peptide analogues as does the vascular receptor. The non-peptide compounds reported here are uniquely specific in displacing Ang II at this binding site and are inactive in antagonizing Ang II at the vascular receptor or in pharmacological assays measuring vascular effects. PD 123,319 (79), one of the most potent compounds, has an IC50 of 34 nM. Certain of these compounds may have utility in the definition and study of Ang II receptor subtypes.

A case of systemic allergic-type vasculitis after the administration of quinidine and digoxin is described. The renal biopsy findings are unique in that they describe an arteritis with eosinophilic infiltration and non-caseating granulomata. We believe quinidine is the antigen that was responsible for the reported findings.

Sera from 86 well controlled diabetics were examined for the presence of immune complexes. Thirty-six patients were receiving standard insulins, 19 monocomponent preparations, 24 oral hypoglycaemic agents and seven dietary restriction alone. Three methods were used to detect complexes: measurement of complement components, a Clq binding assay (BA) and the Raji cell radioimmunoassay (RIA). Complement components were normal in all patients. Eleven (31%) of the group on standard insulins had a positive Raji cell RIA; none had an abnormal Clq-BA. One patient on monocomponent therapy had a mildly positive Raji cell RIA; Clq-BA was negative in each patient of this group. Thirteen (54%) of the patients on oral hypoglycaemic agents were positive on one or both assays while one patient on diet alone was abnormal on both assays. These data show that immune complex production is common in both insulin-requiring and non-insulin-requiring diabetics and that this phenomenon is strikingly less frequent in patients on monocomponent insulins. Such observations could bear relevance to the pathogenesis of microvascular complications in diabetes.

Circulating immune complexes were measured by the Clq binding assay in 49 cases of rheumatoid disease. Raised levels showed a positive correlation with activity of the arthritis, the number of involved joints and the erythrocyte sedimentation rate. No correlation was found with age, sex, duration of disease, rheumatoid nodules, presented of radiographic joint erosions or other haematological and serological parameters. In 12 patients the arthritis subsequently remitted and this remission in disease activity correlated with reduced levels of immune complexes.