A series of five glucosamine-conjugated organometallic complexes of the tricarbonyl cores of technetium-99m and rhenium were made. Glucosamine was derivatized at the C-2 nitrogen with long chain alkyl spacers linked to either pyridyl-tert-nitrogen-phenol tridentate chelates or cyclopentadienyl ligating groups. The metal complexes of the tridentate ligands were formed by refluxing with [Re(CO)(3)(H(2)O)(3)]Br, or with a base and [(99m)Tc(CO)(3)(H(2)O)(3)](+). These ligands were found to be competent chelates in binding the [(99m)Tc(CO)(3)](+) core as radiolabeling yields ranged from 87 to 93% and the resulting complexes are stable to cysteine and histidine challenges for 24 h. The cyclopentadienyl analogues were formed using a double ligand transfer reaction for the rhenium complexes and a single ligand transfer for the technetium-99m complexes. All five rhenium complexes were tested as substrates of hexokinase; two of these complexes were tested as hexokinase inhibitors and they were found to be competent inhibitors, suggesting that they may be able to interact with hexokinase. MTT cytotoxicity studies were performed and the complexes tested were found to be non-toxic to the concentrations tested (100 microM or 1 mM). GLUT-1 mediated cell uptake studies were performed on all five technetium-99m complexes, and their cell entry was found to parallel their lipophilicities, suggesting that cellular uptake is by passive diffusion and is not mediated by GLUT-1.

BackgroundThe impact of male sex as a determinant of health outcomes in systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) is controversial. The primary objective of this study was to evaluate the effect of sex on survival in patients with SSc-PAH. The secondary objectives were to evaluate the effect of sex on age of PAH diagnosis, time from SSc diagnosis to PAH diagnosis, and SSc disease manifestations.MethodsSex-based disparities were evaluated in a cohort of SSc-PAH patients with a primary outcome of time from PAH diagnosis to all-cause mortality. Secondary outcomes were differences in age of diagnosis, disease duration, and SSc manifestations. Survival differences were evaluated using Kaplan-Meier and Cox proportional hazard models.ResultsWe identified 378 SSc-PAH (58 males, 320 females) patients, with a female:male ratio of 5.5:1. Males had a shorter mean ± standard deviation time from SSc diagnosis to PAH diagnosis (1.7 ± 14 versus 5.5 ± 14.2 years); shorter PAH duration (3.5 ± 3.1 versus 4.7 ± 4.2 years), increased frequency of renal crisis (19 % versus 8 %, relative risk (RR) 2.33, 95 %CI 1.22, 4.46), interstitial lung disease (67 % versus 48 %, RR 1.41, 95 %CI 1.14, 1.74), and diffuse subtype (40 % versus 22 %, RR 1.84, 95 %CI 1.26, 2.69). Males appeared to have decreased 1-, 2-, 3-, and 5-year survival (83.2 %, 68.7 %, 53.2 %, 45.6 %) compared to females (85.7 %, 75.7 %, 66.4 %, 57.4 %). However, there was no difference in mortality between sexes (HR 1.43 (95 %CI 0.97, 2.13).ConclusionsSex disparities appear to exist in the frequency of PAH, time to PAH diagnosis, PAH disease duration and SSc disease burden. However, male sex does not independently impact SSc-PAH survival.

Compared with IPAH patients, RA-PAH patients have an older age of onset and lower baseline mPAP. RA-PAH patients have comparable survival to IPAH patients.

Objectives: The study was conducted to improve our understanding of the epidemiology of cancer in systemic sclerosis (SSc) by evaluating the incidence, prevalence, relative risk of overall and site-specific malignancies, predictors and cancer-attributable mortality. Methods: MEDLINE, CINAHL, EMBASE and Cochrane Library (inception-May 2012) were searched. Estimates were combined using a random effects model. Consistency was evaluated using the I 2 statistic. Results: 4876 citations were searched to identify 60 articles. The average incidence of malignancy in SSc was 14 cases/1000 person-years; the prevalence ranged between 4%-22%. Cancer was the leading cause of non-SSc related deaths with a mean of 38%. Overall SIR for all-site malignancy risk was 1.85 (95%CI 1.52, 2.25; I 2 76%). There was a greater risk of lung (SIR 4.69, 95%CI 2.84, 7.75; I 2 93%) and haematological (SIR 2.58, CI 95% 1.75, 3.81; I 2 0%) malignancies, including non-Hodgkin's lymphoma (SIR 2.55, 95%CI 1.40, 4.67; I 2 0%). SSc patients were at a higher risk of leukemia (SIR 2.79, 95%CI 1.22, 6.37; I 2 0%), malignant melanoma (SIR 2.92, 95%CI 1.76, 4.83; I 2 35%), liver (SIR 4.75, 95%CI 3.09, 7.31; I 2 0%), cervical (SIR 2.28, 95%CI 1.26, 4.09; I 2 54%) and oropharyngeal (SIR 5.0, 95%CI 2.18, 11.47; I 2 58%) cancers. Risk factors include a-RNAP I/III seropositivity, male sex, and late onset SSc. Smoking and longstanding interstitial lung disease increase the risk of lung cancer; Barrett's esophagus and a positive family history of breast cancer, respectively, increase the risk of esophageal adenocarcinoma and breast cancer. Conclusions: SSc patients have a twofold increase in all-site malignancy, and greater risk of lung and haematological malignancies that contribute significantly to mortality. Vigilance should be considered in SSc patients with risk factors for cancer.