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Abstract Background In the presence of both HIV infection and cervical intraepithelial neoplasia (CIN), the risk of cancer development despite treatment may be greater. We investigated clinical predictors of persistent cytological abnormalities in women who had had a large loop excision of the transformation zone (LLETZ). Methods Women with high grade squamous intraepithelial lesions or worse (HSIL), less severe abnormalities which persisted and any abnormality in women who are HIV-infected, were referred to the colposcopy clinic. HIV infection was ascertained by self-report. A LLETZ was performed on all patients with HSIL or higher on Papanicolaou (Pap) smear or colposcopy, LSIL or higher in patients who are HIV-infected, where the colposcopy is inadequate, and when there was a discrepancy between colposcopy and cytology by one or more grades. Women with abnormal follow-up smears were compared to those with normal smears. We examined the association between abnormal follow-up smears and demographic and clinical predictors using logistic regression Results The median time between LLETZ and first follow-up Pap smear was rather short at 122 days. Persistent cytological abnormalities occurred in 49% of our patients after LLETZ. Predictors of persistence included the presence of disease at both margins and HIV infection. Among the latter, disease at the excision margins and CD4+ cell count were important predictors. In these women, disease at the endocervical margin, both margins, and disease only at the ectocervical margin were associated with increased odds of persistent abnormalities on follow-up cervical smear. Conclusion We showed extremely high risk of cytological abnormality at follow-up after treatment more so in patients with incomplete excision and in the presence of immunocompromise. It remains uncertain whether recurrent CIN is a surrogate marker for invasive cervical cancer.

Background: Correctly eliciting and interpreting physical examination (PEx) signs contributes to successful diagnosis and is fundamental to patient care. A significant decline in the time spent acquiring these skills by medical students, and the decreased ability to elicit and recognise signs is widely acknowledged. However, organising teaching to counteract this in the busy clinical environment is challenging. We evaluated the prior exposure to clinical signs, and experience of examination teaching among a cohort of final-year medical students. Following this, we assessed the utility of a structured circuit-based approach (Signs Circuits) using hospital inpatients and junior doctors to provide high-yield PEx teaching and overcome these limitations., Materials and Methods: Qualitative and quantitative survey feedback, including a standardised list of 62 clinical signs, was sought from final-year medical students during their rotations at a teaching hospital in London, UK, before and after the provision of Signs Circuits., Results: Prior to the course the 63 students reported limited exposure to even the most common clinical signs. For example, the murmurs of mitral and tricuspid regurgitation and the sound of lung crackles eluded 43%, 87%, and 32%, respectively. From qualitative feedback, the reasons for this included that much of their prior PEx experience had focused on the performance of appropriate examination steps and techniques in patients without pathology. During the course, students were exposed to an average of 4.4 new signs, and left with increased confidence examining and eliciting signs, and a firmer belief in their importance to diagnosis., Conclusion: Medical students continue to have limited exposure to clinical signs in medical school. This signs-focused approach to PEx teaching is an effective and reproducible way to counter the deficiencies identified in signsexposure.

Light probes interacting with heavy bound states such as black holes give rise to observables containing valuable dynamical information. Recently, a family of black hole microstates was shown to admit an exact string worldsheet description. We construct the physical vertex operators of these models, and compute an extensive set of novel heavy-light correlators. We then obtain the first match between worldsheet correlators in black hole microstates and the holographically dual conformal field theory. We conjecture a closed formula for correlators with an arbitrary number of light insertions. As an application, we compute the analogue of the Hawking radiation rate for these microstates.

Allophonic patterns of variation in English laterals have been well studied in phonetics and phonology for decades, but establishing broad generalizations across varieties has proven challenging. In this study, a typology of onset/coda lateral distinctions in English is advanced using crowdsourced recordings from 95 speakers across twelve dialects of Anglo (UK) English. Results confirm the existence of dialects with and without onset/coda distinctions, and conditional inference trees are used to identify three main patterns in the data: (1) clear onsets and dark codas; (2) intermediate/dark onsets and dark codas, but with a positional distinction intact; and (3) dark onsets and dark codas, with minimal or no distinctions between positions.

Trifluoromethyl groups are widespread in medicinal chemistry, yet there are limited 18F-radiochemistry techniques available for the production of the complementary PET agents. Herein, we report the first radiosynthesis of the anticancer nucleoside analogue trifluridine, using a fully automated, clinically-applicable 18F-trifluoromethylation procedure. [18F]Trifluridine was obtained after two synthetic steps in <2 hours. The isolated radiochemical yield was 3% ± 0.44 (n = 5), with a radiochemical purity >99%, and a molar activity of 0.4 GBq μmol-1 ± 0.05. Biodistribution and PET-imaging data using HCT116 tumour-bearing mice showed a 2.5 %ID g-1 tumour uptake of [18F]trifluridine at 60 minutes post-injection, with bone uptake becoming a prominent feature thereafter. In vivo metabolite analysis of selected tissues revealed the presence of the original radiolabelled nucleoside analogue, together with deglycosylated and phosphorylated [18F]trifluridine as the main metabolites. Our findings suggest a potential role for [18F]trifluridine as a PET radiotracer for elucidation of drug mechanism of action.

Dielectric relaxation of the ionic liquid, 1-ethyl-3-methylimidazolium ethyl sulfate (EMI + ETS - ), is studied using molecular dynamics (MD) simulations. The collective dynamics of polarization arising from cations and anions are examined. Characteristics of the rovibrational and translational components of polarization dynamics are analyzed to understand their respective roles in the microwave and terahertz regions of dielectric relaxation. The MD results are compared with the experimental low-frequency spectrum of EMI + ETS - , obtained via ultrafast optical Kerr effect (OKE) measurements.

We construct the first family of horizonless supergravity solutions that have the same mass, charges, and angular momenta as general supersymmetric rotating D1-D5-P black holes in five dimensions. This family includes solutions with arbitrarily small angular momenta, deep within the regime of quantum numbers and couplings for which a large classical black hole exists. These geometries are well approximated by the black-hole solution, and in particular exhibit the same near-horizon throat. Deep in this throat, the black-hole singularity is resolved into a smooth cap. We also identify the holographically dual states in the N=(4,4) D1-D5 orbifold conformal field theory (CFT). Our solutions are among the states counted by the CFT elliptic genus, and provide examples of smooth microstate geometries within the ensemble of supersymmetric black-hole microstates.

During efforts to prepare the known compound , a new tetracyclic compound, called VG1, was prepared in six steps. This compound was found to have good activity as an inhibitor of nonsense-mediated mRNA decay.

Rainfall partitioning and redistribution by canopies are important ecohydrological processes underlying ecosystem dynamics. We quantified and contrasted spatial and temporal variations of rainfall redistribution for a juniper (Juniperus virginiana, redcedar) woodland and a tallgrass prairie in the south-central Great Plains, USA. Our results showed that redcedar trees had high canopy storage capacity (S) ranging from 2.14 mm for open stands to 3.44 mm for closed stands. The canopy funneling ratios (F) of redcedar trees varied substantially among stand type and tree size. The open stands and smaller trees usually had higher F values and were more efficient in partitioning rainfall into stemflow. Larger trees were more effective in partitioning rainfall into throughfall and no significant changes in the total interception ratios among canopy types and tree size were found. The S values were highly variable for tallgrass prairie, ranging from 0.27 mm at early growing season to 3.86 mm at senescence. As a result, the rainfall interception by tallgrass prairie was characterized by high temporal instability. On an annual basis, our results showed no significant difference in total rainfall loss to canopy interception between redcedar trees and tallgrass prairie. Increasing structural complexity associated with redcedar encroachment into tallgrass prairie changes the rainfall redistribution and partitioning pattern at both the temporal and spatial scales, but does not change the overall canopy interception ratios compared with unburned and ungrazed tallgrass prairie. Our findings support the idea of convergence in interception ratio for different canopy structures under the same precipitation regime. The temporal change in rainfall interception loss from redcedar encroachment is important to understand how juniper encroachment will interact with changing rainfall regime and potentially alter regional streamflow under climate change.

Cytostatic agents that interfere with specific cellular components to prevent cancer cell growth offer an attractive alternative, or complement, to traditional cytotoxic chemotherapy. Here, we describe the synthesis and characterization of a new binuclear Ru(II) -Pt(II) complex [Ru(tpy)(tpypma)Pt(Cl)(DMSO)](3+) (tpy=2,2':6',2''-terpyridine and tpypma=4-([2,2':6',2''-terpyridine]-4'-yl)-N-(pyridin-2-ylmethyl)aniline), VR54, which employs the extended terpyridine tpypma ligand to link the two metal centres. In cell-free conditions, VR54 binds DNA by non-intercalative reversible mechanisms (Kb =1.3×10(5)  M(-1) ) and does not irreversibly bind guanosine. Cellular studies reveal that VR54 suppresses proliferation of A2780 ovarian cancer cells with no cross-resistance in the A2780CIS cisplatin-resistant cell line. Through the preparation of mononuclear Ru(II) and Pt(II) structural derivatives it was determined that both metal centres are required for this anti-proliferative activity. In stark contrast to cisplatin, VR54 neither activates the DNA-damage response network nor induces significant levels of cell death. Instead, VR54 is cytostatic and inhibits cell proliferation by up-regulating the cyclin-dependent kinase inhibitor p27(KIP1) and inhibiting retinoblastoma protein phosphorylation, which blocks entry into S phase and results in G1 cell cycle arrest. Thus, VR54 inhibits cancer cell growth by a gain of function at the G1 restriction point. This is the first metal-coordination compound to demonstrate such activity., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Sun exposure is associated with several ophthalmic diseases, including pterygium which may develop in adolescence. This study reports the prevalence of pterygium and its associations in a large cohort of young Australian adults. Conjunctival ultraviolet autofluorescence, a biomarker of ocular sun exposure, has recently been characterized in some Australian populations., Design: Cross-sectional population-based study., Participants: One thousand three hundred forty-four subjects aged 18-22 years in the Western Australian Pregnancy Cohort (Raine) Study., Methods: Standardized colour and ultraviolet autofluorescence photographs of the nasal and temporal conjunctiva were taken, and assessed for presence of pterygium and area of autofluorescence. Sun exposure and protective factors were assessed by structured questionnaire., Main Outcome Measures: Area of conjunctival ultraviolet autofluorescence in square millimetre (mm(2)) and presence of pterygium., Results: Median total conjunctival autofluorescence was 44.2 mm(2) (interquartile range 20.2-69.8 mm(2)). Median conjunctival autofluorescence was higher in nasal than in temporal quadrants (23.8 mm(2) vs. 18.9 mm(2), P < 0.001), but did not differ according to age or gender. Higher body mass index was associated with lower levels of autofluorescence. Total autofluorescence increased with increasing time spent outdoors. Prevalence of pterygium was 1.2% (95% confidence interval 0.6-1.8%), and was associated with male gender (odds ratio 6.71, P = 0.012). Participants with pterygium had significantly more conjunctival autofluorescence than those without (median 73.4 mm(2) vs. 44.0 mm(2), P = 0.001)., Conclusions: Conjunctival ultraviolet autofluorescence is associated with increased time spent outdoors, and increased prevalence of pterygium. The association of this biomarker with other ophthalmohelioses, including cataract, ocular surface squamous neoplasia and eyelid malignancy, has yet to be determined., (© 2014 Royal Australian and New Zealand College of Ophthalmologists.)

Background: Management of infection is a major clinical problem. Staphylococcus aureus is a Gram-positive bacterium which colonises approximately one third of the adult human population. Staphylococcal infections can be life-threatening and are frequently complicated by multi-antibiotic resistant strains including methicillin-resistant S. aureus (MRSA). Fluorodeoxyglucose ([(18)F]FDG) imaging has been used to identify infection sites; however, it is unable to distinguish between sterile inflammation and bacterial load. We have modified [(18)F]FDG by phosphorylation, producing [(18)F]FDG-6-P to facilitate specific uptake and accumulation by S. aureus through hexose phosphate transporters, which are not present in mammalian cell membranes. This approach leads to the specific uptake of the radiopharmaceutical into the bacteria and not the sites of sterile inflammation., Methods: [(18)F]FDG-6-P was synthesised from [(18)F]FDG. Yield, purity and stability were confirmed by RP-HPLC and iTLC. The specificity of [(18)F]FDG-6-P for the bacterial universal hexose phosphate transporter (UHPT) was confirmed with S. aureus and mammalian cell assays in vitro. Whole body biodistribution and accumulation of [(18)F]FDG-6-P at the sites of bioluminescent staphylococcal infection were established in a murine foreign body infection model., Results: In vitro validation assays demonstrated that [(18)F]FDG-6-P was stable and specifically transported into S. aureus but not mammalian cells. [(18)F]FDG-6-P was elevated at the sites of S. aureus infection in vivo compared to uninfected controls; however, the increase in signal was not significant and unexpectedly, the whole-body biodistribution of [(18)F]FDG-6-P was similar to that of [(18)F]FDG., Conclusions: Despite conclusive in vitro validation, [(18)F]FDG-6-P did not behave as predicted in vivo. However at the site of known infection, [(18)F]FDG-6-P levels were elevated compared with uninfected controls, providing a higher signal-to-noise ratio. The bacterial UHPT can transport hexose phosphates other than glucose, and therefore alternative sugars may show differential biodistribution and provide a means for specific bacterial detection.

The synthesis of two new luminescent dinuclear Ir(III)-Ru(II) complexes containing tetrapyrido[3,2-a:2',3'-c:3'',2''-h:2''',3'''-j]phenazine (tpphz) as the bridging ligand is reported. Unlike many other complexes incorporating cyclometalated Ir(III) moieties, these complexes display good water solubility, allowing the first cell-based study on Ir(III)-Ru(II) bioprobes to be carried out. Photophysical studies indicate that emission from each complex is from a Ru(II) excited state and both complexes display significant in vitro DNA-binding affinities. Cellular studies show that each complex is rapidly internalised by HeLa cells, in which they function as luminescent nuclear DNA-imaging agents for confocal microscopy. Furthermore, the uptake and nuclear targeting properties of the complex incorporating cyclometalating 2-(4-fluorophenyl)pyridine ligands around its Ir(III) centre is enhanced in comparison to the non-fluorinated analogue, indicating that fluorination may provide a route to promote cell uptake of transition-metal bioprobes., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The first transition-metal complex-based two-photon absorbing luminescence lifetime probes for cellular DNA are presented. This allows cell imaging of DNA free from endogenous fluorophores and potentially facilitates deep tissue imaging. In this initial study, ruthenium(II) luminophores are used as phosphorescent lifetime imaging microscopy (PLIM) probes for nuclear DNA in both live and fixed cells. The DNA-bound probes display characteristic emission lifetimes of more than 160 ns, while shorter-lived cytoplasmic emission is also observed. These timescales are orders of magnitude longer than conventional FLIM, leading to previously unattainable levels of sensitivity, and autofluorescence-free imaging., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: After previously reporting the presence of disease by cytology findings after treatment for cervical intra-epithelial neoplasia (CIN) in 64.6% of HIV-infected women and in 13.0% of HIV-negative women, we aimed to determine the severity of cytological disease after treatment in HIV-infected women., Methods: We studied HIV-infected (N=571) women treated at the Colposcopy Clinic at Chris Hani Baragwanath Hospital, Gauteng, between April 2003 and December 2006. We compared the initial histology results with Pap smears ≥6 months later, and evaluated factors associated with reduction in the grade of disease., Results: Mean age was 36.68 (SD+7.33) years; mean parity was 2 (SD+1.46); mean CD4+ count was 242.70 cells/mm3 (SD+187.56); 262 (45.80%) were receiving antiretroviral treatment. Persistent disease was detected on the repeat Pap smear in 199 (65.03%); of these, 223 (72.88%) were of a lesser grade than in the original histology results. Of the 152 with histologically confirmed CIN3, 67 (44.08%) had improved to a lesser grade, and 54 (44.63%) had normal cytology results. Among the latter two subject groups (n=141) who had CIN2 histologically, 91 (64.53%) had improved, 29 (20.57%) remained unchanged, and 20 (14.88%) had CIN3; 13 (4.25%) patients with CIN1 returned for follow-up; 11 (84.62%) of these had normal Pap smears and 2 (15.38%) had CIN3., Conclusion: Recurrences were of a lesser degree than initial histology results. This reduction in the grade of disease was related to CD4+ count, complete excision and parity. Antiretroviral therapy use did not improve outcome, perhaps owing to low initial CD4 counts.

Introduction: Choline radiotracers are widely used for clinical PET diagnosis in oncology. [(11)C]Choline finds particular utility in the imaging of brain and prostate tumor metabolic status, where 2-[(18)F]fluoro-2-deoxy-D-glucose ('FDG') shows high background uptake. More recently we have extended the clinical utility of [(11)C]choline to breast cancer where radiotracer uptake correlates with tumor aggressiveness (grade). In the present study, a new choline analog, [(18)F]fluoro-[1,2-(2)H(4)]choline, was synthesized and evaluated as a potential PET imaging probe., Methods: [(18)F]Fluorocholine, [(18)F]fluoro-[1-(2)H(2)]choline and [(18)F]fluoro-[1,2-(2)H(4)]choline were synthesized by alkylation of the relevant precursor with [(18)F]fluorobromomethane or [(18)F]fluoromethyl tosylate. Radiosynthesis of [(18)F]fluoromethyl tosylate required extensive modification of the existing method. [(18)F]Fluorocholine and [(18)F]fluoro-[1,2-(2)H(4)]choline were then subjected to in vitro oxidative stability analysis in a chemical oxidation model using potassium permanganate and an enzymatic model using choline oxidase. The two radiotracers, together with the corresponding di-deuterated compound, [(18)F]fluoro-[1-(2)H(2)]choline, were then evaluated in vivo in a time-course biodistribution study in HCT-116 tumor-bearing mice., Results: Alkylation with [(18)F]fluoromethyl tosylate proved to be the most reliable radiosynthetic route. Stability models indicate that [(18)F]fluoro-[1,2-(2)H(4)]choline possesses increased chemical and enzymatic (choline oxidase) oxidative stability relative to [(18)F]fluorocholine. The distribution of the three radiotracers, [(18)F]fluorocholine, [(18)F]fluoro-[1-(2)H(2)]choline and [(18)F]fluoro-[1,2-(2)H(4)]choline, showed a similar uptake profile in most organs. Crucially, tumor uptake of [(18)F]fluoro-[1,2-(2)H(4)]choline was significantly increased at late time points compared to [(18)F]fluorocholine and [(18)F]fluoro-[1-(2)H(2)]choline., Conclusions: Stability analysis and biodistribution suggest that [(18)F]fluoro-[1,2-(2)H(4)]choline warrants further in vivo investigation as a PET probe of choline metabolism., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Unlabelled: The integrin alpha v beta3 receptor is upregulated on tumor cells and endothelium and plays important roles in angiogenesis and metastasis. Arg-Gly-Asp (RGD) peptide ligands have high affinity for these integrins and can be radiolabeled for PET imaging of angiogenesis or tumor development. We have assessed the safety, stability, and tumor distribution kinetics of a novel radiolabeled RGD-based integrin peptide-polymer conjugate, 18F-AH111585, and its feasibility to detect tumors in metastatic breast cancer patients using PET., Methods: The biodistribution of 18F-AH111585 was assessed in 18 tumor lesions from 7 patients with metastatic breast cancer by PET, and the PET data were compared with CT results. The metabolic stability of 18F-AH111585 was assessed by chromatography of plasma samples. Regions of interest (ROIs) defined over tumor and normal tissues of the PET images were used to determine the kinetics of radioligand binding in tissues., Results: The radiopharmaceutical and PET procedures were well tolerated in all patients. All 18 tumors detected by CT were visible on the 18F-AH111585 PET images, either as distinct increases in uptake compared with the surrounding normal tissue or, in the case of liver metastases, as regions of deficit uptake because of the high background activity in normal liver tissue. 18F-AH111585 was either homogeneously distributed in the tumors or appeared within the tumor rim, consistent with the pattern of viable peripheral tumor and central necrosis often seen in association with angiogenesis. Increased uptake compared with background (P = 0.002) was demonstrated in metastases in lung, pleura, bone, lymph node, and primary tumor., Conclusion: 18F-AH111585 designed to bind the alpha v beta3 integrin is safe, metabolically stable, and retained in tumor tissues and detects breast cancer lesions by PET in most anatomic sites.

2-Acetyl-1-(4'-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, one of the most potent non-competitive AMPA antagonists described to date, has been labelled with carbon-11 and tritium and evaluated as a potential ligand for in vivo imaging of AMPA receptors using PET. The carbon-11 labelled compound showed good initial brain uptake in rats, but with rapid clearance and relatively homogenous distribution. In saturation binding studies, the tritiated racemic ligand was found to be highly potent with a Kd of 14.8+/-1.8 nM. We conclude that the low receptor density labelled with this compound, its rapid clearance from the CNS and low specific binding makes it unsuitable as an in vivo PET imaging agent for AMPA receptors.

Usual causes of intolerance to thyroxine sodium include coronary artery disease, advanced age, untreated adrenal insufficiency, and severe hypothyroidism. We describe 4 patients with iron deficiency anemia and primary hypothyroidism. After treatment with thyroxine sodium, these patients developed palpitations and feelings of restlessness, which necessitated discontinuation of the thyroid hormone. After the anemia was treated with ferrous sulfate for 4 to 7 weeks, they were able to tolerate thyroxine sodium therapy. Iron deficiency anemia coexisting with primary hypothyroidism results in a hyperadrenergic state. In such patients, we postulate that thyroid hormone administration causes palpitations, nervousness, and feelings of restlessness. Correction of any existing pronounced anemia in hypothyroid patients who are intolerant to thyroxine sodium therapy may result in tolerance to this agent.

Purpose: To examine the effects of propylthiouracil (PTU) pretreatment on the outcome of initial I-131 therapy for Graves' disease., Design: A retrospective chart review was done., Patients and Methods: The authors studied 106 patients in an outpatient nuclear medicine setting who were given initial I-131 therapy for Graves' disease from September 1989 to March 1993 and followed for at least 6 months after therapy. These patients were divided into groups based on whether they had ever received PTU or, if they had received PTU, the length of time between the last dose of PTU and the I-131 therapy dose. Measured failure rates of initial I-131 therapy were based on recurrent or continued hyperthyroidism., Results: Treatment failure rates increased markedly from 2.5% in non-PTU-treated patients (n = 80) to 23.1% (n = 26) in patients pretreated with PTU (P = 0.003). Although not significant, two PTU-pretreated subgroups showed a trend toward increased failure rates. The failure rate was 15.4% (n = 13) in patients whose last dose of PTU was 7-14 days before I-131 therapy, and it increased further to 30.8% (n = 13) in patients whose last dose of PTU was within 1 week of I-131 therapy., Conclusions: PTU pretreatment within 2 weeks of I-131 treatment is a strong independent risk factor in failure rates after initial I-131 therapy in patients with Graves' disease. Patients should be free of PTU for 2 weeks before I-131 therapy if they are able to tolerate it, otherwise the dose of I-131 may need to be adjusted upward to diminish the risk that the initial I-131 therapy will fail.

Propionyl-L-carnitine (PLC) is under development as a therapeutic for the treatment of peripheral artery disease, coronary heart disease and chronic heart failure. Three methods were examined for labelling PLC in its propionyl group with positron-emitting carbon-11 (t12 = 20.3 min), one chemical and two chemoenzymatic. The former was based on the preparation of [11C]propionyl chloride as labelling agent via 11C-carboxylation of ethylmagnesium bromide with cyclotron-produced [11C]carbon dioxide and subsequent chlorination. Reaction of carrier-added [11C]propionyl chloride with L-carnitine in trifluoroacetic acid gave [11C]PLC in 12% radiochemical yield (decay-corrected) from cyclotron-produced [11C]carbon dioxide. However, the radiosynthesis was unsuccessful at the no-carrier-added (NCA) level of specific radioactivity. [11C]Propionate, as a radioactive precursor for chemoenzymatic routes, was prepared via carboxylation of ethylmagnesium bromide with [11C]carbon dioxide and hydrolysis. NCA [11C]PLC was prepared in 68 min in 14% radiochemical yield (decay-corrected) from [11C]propionate via sequential conversions catalysed by acetate kinase, phosphotransacetylase and carnitine acetyltransferase. A superior chemoenzymatic synthesis of NCA [11C]PLC was developed, based on the use of a novel supported Grignard reagent for the synthesis of [11C]propionate and conversions by S-acetyl-CoA synthetase and carnitine acetyltransferase. This gave an overall radiochemical yield of 30-48% (decay-corrected). This synthesis was automated for radiation safety and provides pure NCA [11C]PLC in high radioactivities ready for intravenous administration within 25 min from radionuclide production. The [11C]PLC is suitable for pharmacokinetic studies in human subjects with PET and the elucidation of the fate of the propionyl group of PLC in vivo.

Although no existing imaging procedure is as effective as an experienced surgeon for locating abnormal parathyroid glands in patients without previous neck surgery, preoperative parathyroid localization is considered essential for patients undergoing reoperations. The need for parathyroid imaging in patients undergoing an initial exploration remains controversial. Scintigraphy with (99m)Tc-sestamibi has largely replaced (99m)Tc-pertechnetate/(201)Tl chloride subtraction scintigraphy for parathyroid imaging because of its superior sensitivity and false-positive rate. Positron emission tomography, another technique recently applied to parathyroid imaging, is of uncertain value at present.

A case of galactorrhea caused by painful esophagitis, a previously unreported etiology, is presented. The galactorrhea promptly resolved with appropriate treatment of the esophagitis. It is proposed that the mechanism of production of galactorrhea is similar to that seen with chest wall lesions. This cause should be kept in mind when evaluating unusual causes of galactorrhea.

The status of the radiochemical development and biological evaluation of radioligands for PET studies of central benzodiazepine (BZ) receptors and the so-called peripheral benzodiazepine binding sites, here discriminated and referred to as PK binding sites, is reviewed against current pharmacological knowledge, indicating those agents with present value and those with future potential. Practical recommendations are given for the preparation of two useful radioligands for PET studies, [N-methyl-11C]flumazenil for central BZ receptors, and [N-methyl-11C]PK 11195 for PK binding sites. Quality assurance and plasma metabolite analysis are also reviewed for these radioligands and practical recommendations are given on methodology for their performance.

The etiology of incidentally discovered, nonfunctional adrenal nodules was evaluated by using the 17-hydroxyprogesterone (17-OHP) response to synthetic adrenocorticotrophin (cosyntropin) (ACTH) administration. Patients who were discovered to have adrenal nodules and age-matched volunteers were studied. A total of 12 patients with adrenal nodules and 10 control subjects were studied. None of the patients with adrenal nodules had any evidence of hormonal hypersecretion consistent with pheochromocytoma, Cushing's syndrome or hyperaldosteronism. All subjects had serum 17-OHP and cortisol responses measured at baseline and at 30 and 60 min following the intravenous administration of 250 micrograms of ACTH. Baseline 17-OHP levels in patients with adrenal nodules were not significantly different from those of the normal controls (adrenal nodules 17-OHP: 75 +/- 13 vs control 68 +/- 11 ng/dl). After stimulation with ACTH, both 30 min and 60 min 17-OHP levels in patients with adrenal nodules (322 +/- 47 and 361 +/- 54 ng/dl, respectively) were significantly elevated over the responses seen with the controls (169 +/- 29 ng/dl at 30 min, p < 0.015, and 158 +/- 20 ng/dl at 60 min, p < 0.004). Baseline and post-ACTH serum cortisol levels were similar in both groups. Out of these twelve patients with adrenal nodules, nine were reevaluated twelve months later. In this group the basal 17-OHP remained comparable to normal levels (72 +/- 8.4 ng/dl) whereas the post-ACTH levels still remained exaggerated (30 and 60 min values 327 +/- 37 and 373 +/- 39 ng/dl).(ABSTRACT TRUNCATED AT 250 WORDS)

PK 11195 is a selective ligand for the peripheral-type benzodiazepine binding site (PTBBS). There are few such sites in normal brain but their number increases in association with tissue necrosis. The time-course of appearance of PTBBS around a focally induced ischaemic lesion in frontal cortex of rat brain was established by autoradiography using [N-methyl-3H]PK 11195. Using this information and the same experimental model of ischaemia, the distribution of radioactivity after injection of carbon-11 (t1/2 = 20.3 min, beta+ = 99.8%) labelled PK 11195 was studied. The purpose was to synthesize [N-methyl-11C]PK 11195 and to test its suitability as a tracer for depicting the presence of PTBBS in ischaemic lesions. The time-profiles of distribution of radioactivity in brain regions after intravenous injection of tracer and the ratio of radioactivity in lesioned compared with unlesioned cortex were determined. Data for the temporal (days after lesion induction) and for the regional retention of radioactivity were consistent with independent evidence (autoradiographic and immunohistochemical) for the occurrence of increased numbers of PTBBS, predominantly in association with macrophages, in areas undergoing necrosis.

The Mursi are a small group of herders and cultivators living in the Lower Omo Valley of southwestern Ethiopia. Over the past 20 years they have suffered a disaster of classic proportions, involving drought, famine, migration and war. Measures taken to ensure the physical survival of people, and especially cattle, in the face of regular and expected attacks by their neighbours have made the economy of the Mursi more vulnerable to climatic uncertainty. A crude materialist explanation of warfare is not, therefore, supported by this case but it is clear also that warfare has played a key part in Mursi expansion northwards, over the past century, into the territory of the Bodi. Warfare, in this context, is a means of establishing and maintaining the separate political identities of neighbouring groups. The problem of survival does not present itself to the Mursi and their neighbours as a choice between political and physical survival: the only way they know of saving lives is to save their way of life.

In vivo autoradiography of [N-methyl-3H]citalopram in rat brain shows a differential regional localization which correlates with the localization of 5-HT re-uptake binding sites defined in vitro. A comparison of the biodistribution of [N-methyl-3H]citalopram over 2 h after i.v. injection in (1) control rats (2) rats pre-dosed with either citalopram or paroxetine and (3) rats chemically-lesioned with p-chloroamphetamine provides an estimate of specific binding relative to total binding in vivo. The ratio of binding in certain regions (e.g. cingulate) to binding in a reference tissue (e.g. cerebellum) at 30-120 min post injection is c. 1.4. In view of these results a method was developed for labelling citalopram with carbon-11 (t1/2 = 20.3 min, beta + = 99.8%) to provide a potential radioligand for studies using positron emission tomography. Thus, reaction of nca [11C]iodomethane, prepared from cyclotron-produced [11C]carbon dioxide, with norcitalopram in ethanol containing 2,2,6,6-tetramethyl-piperidine for 5 min at 95 degrees C gives crude [N-methyl-11C]citalopram in 60% radiochemical yield, decay-corrected. HPLC on silica gel provides radiochemically and chemically pure [N-methyl-11C]citalopram, as assessed by TLC, HPLC and MS. This product (isolated radiochemical yield, 49%) is easily formulated for i.v. injection. Up to 2 GBq of formulated product with a specific activity of c. 15 GBq/mumol have been prepared within 40 min from the end of radionuclide production. The described radiosynthesis has also been applied to give the single biologically active (+)-enantiomer of [N-methyl-11C]citalopram rather than the racemate. This product gives enhanced specific signal in the rat following i.v. injection, the ratio of uptake in regions of interest relative to cerebellum approaching 2 at 90 min.

S-[11C]Nomifensine (S-[11C]NMF) is a positron-emitting tracer suitable for positron emission tomography, which binds to both dopaminergic and noradrenergic reuptake sites in the striatum and the thalamus. Modelling of the cerebral distribution of this drug has been hampered by the rapid appearance of glucuronide metabolites in the plasma, which do not cross the blood--brain barrier. To date, [11C]NMF uptake has simply been expressed as regional versus nonspecific cerebellar activity ratios. We have calculated a "free" NMF input curve from red cell activity curves, using the fact that the free drug rapidly equilibrates between red cells and plasma, while glucuronides do not enter red cells. With this free [11C]NMF input function, all regional cerebral uptake curves could be fitted to a conventional two-compartment model, defining tracer distribution in terms of [11C]NMF regional volume of distribution. Assuming that the cerebellar volume of distribution of [11C]NMF represents the nonspecific volume of distribution of the tracer in striatum and thalamus, we have calculated an equilibrium partition coefficient for [11C]NMF between freely exchanging specific and nonspecific compartments in these regions, representing its "binding potential" to dopaminergic or noradrenergic uptake sites (or complexes). This partition coefficient was lower in the striatum when the racemate rather than the active S-enantiomer of [11C]NMF was administered. In the striatum of patients suffering from Parkinson's disease and multiple-system atrophy, the specific compartmentation of S-[11C]NMF was significantly decreased compared with that of age-matched volunteers.

Practical methods are described for the quality assurance of three labelled agents (L-6-[18F]fluoro-DOPA, S-[N-methyl-11C]nomifensine and [O-methyl-11C]raclopride) now produced regularly for PET studies of the dopaminergic system in man. These include indirect methods for the initial determination of label position (e.g. 13C-NMR spectroscopy) and also direct methods for the assessment of chiral purity (TLC and HPLC) and the routine determination of radiochemical purity, chemical purity and specific activity (HPLC). Mass spectrometry has been used to identify some impurities. L-6-hydroxy-DOPA (a precursor in vivo of the neurotoxin, L-6-hydroxydopamine) has been detected by HPLC in some preparations of L-6-[18F]fluoro-DOPA. Formulated S-[N-methyl-11C]nomifensine has been found to decrease in radiochemical purity with storage, whereas formulated [O-methyl-11C]raclopride has been found to be stable. Some quality assurance issues are discussed in relation to experience in the application of the described methods and the obtained results.