Combined (99m)Tc-methoxyisobutylisonitrile scintigraphy and fine-needle aspiration cytology offers an accurate and potentially cost-effective investigative strategy for the assessment of solitary or dominant thyroid nodules.

PURPOSE: Fine-needle aspiration (FNA) has revolutionised the care of patients with thyroid nodules and is the initial investigation of choice. However, as a result of nondiagnostic (Thy1) and nonneoplastic (Thy2) specimens, it remains an imperfect sole solution with a range of sensitivities and a high inadequate ratio. Therefore the British Thyroid Association (BTA) guidelines recommend a second FNA immediately for Thy1 specimens and 3-6 months later for Thy2 specimens. Patients must be followed up to exclude malignancy. In this study we assessed the performance of MIBI scintigraphy for diagnosing thyroid malignancy and the cost-effectiveness of a combined FNA/MIBI investigative strategy for the management of thyroid nodules. METHODS: The diagnostic performance of MIBI scintigraphy was calculated from a retrospective review of local data combined with a meta-analysis of the published literature. Decision tree analysis was used to calculate the cost-effectiveness of a combined FNA/MIBI investigative strategy compared to the BTA guidelines. RESULTS: From 712 patients, the sensitivity, specificity, PPV and NPV of MIBI scintigraphy for the diagnosis of malignancy were 96 %, 46 %, 34 % and 97 %, respectively. MIBI-based strategies were more accurate and associated with lower cost per patient (£1,855/2,125 vs. £2,445/2,801) and lower cost per cancer diagnosed (£1,902/2,179 vs. £2,469/2,828) with negligible change in life expectancy. CONCLUSION: Due to its high NPV, MIBI scintigraphy can usefully exclude malignancy for Thy1 and Thy2 lesions. Its low specificity means MIBI scintigraphy cannot be recommended as a first-line investigation, but as a second-line investigation MIBI scintigraphy may lead to a lower rate of unnecessary thyroidectomies. Combined FNA/MIBI strategies are potentially cost-effective in the management of solitary or dominant thyroid nodules.

Highly selective 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase.

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.

Erectile dysfunction in general medicine.

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.

Synthesis and structure-activity relationships of N-6 substituted analogues of 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as inhibitors of Wee1 and Chk1 checkpoint kinases.

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.

4-anilino-5-carboxamido-2-pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein kinase kinase.

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.

Pyrido[2,3-d]pyrimidin-7-ones as specific inhibitors of cyclin-dependent kinase 4.

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.

Mean cell volume (MCV) changes in HIV-positive patients taking nucleoside reverse transcriptase inhibitors (NRTIs): a surrogate marker for adherence.

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.

Diabetes and HIV.

The co-existence of diabetes mellitus and HIV infection poses significant challenges for both patient and physician. This article reviews the clinical problems, the implications for treatment plans and potential confusions that can arise when managing patients who have both conditions.

Psychological and quality of life changes in patients using GLP-1 analogues.

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.

Unusual initial manifestation of metastatic follicular carcinoma of the thyroid with thyrotoxicosis diagnosed by technetium Tc 99m pertechnetate scan: case report and review of literature.

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.

Binding thermodynamics of substituted diaminopyrimidine renin inhibitors.

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.

Evaluation of an ethnic media campaign on patterns of HIV testing among people from culturally and linguistically diverse backgrounds in Australia.

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.