Biochemistry and biology of 2'-Fluoro-2'-deoxythymidine (FT), a putative highly selective substrate for thymidine kinase type 2 (TK2)

2'-Deoxy-2'-fluorothymidine (FT) is a bioisostere of both thymidine (TdR), in which F replaces H at C-2' in the ribosyl configuration, and methyluridine, in which F replaces OH at C-2' in the ribosyl configuration. Fluorine is bioisosteric with H with respect to atomic radius and is bioisosteric with OH with respect to polarity and H-bonding as an H acceptor. The consequences of this C-2' F for H substitution on cytotoxicity, nucleoside transporter affinity, phosphorylation by thymidine kinases (TK1, TK2), cell uptake and biodistribution of FT in a murine tumor model are now reported. FT toxicity against a bank of murine and human cells was seen only at very high (?1 mM) concentrations, although the cellular uptake of [3H]FT in these cells was comparable to that of [3H]TdR over a 24 h period. Human equilibrative nucleoside transporters (hENT1, hENT2) displayed weaker affinity for FT than for TdR, but the concentrative transporters (hCNT1, hCNT2, hCNT3) had much higher affinities for FT. FT was phosphorylated by both mitochondrial thymidine kinase (TK2) (58 % of TdR) and cytosolic thymidine kinase (TK1) (39 % of TdR). Preliminary in vivo imaging with [18F]FT in mice bearing implanted KBALB and contralateral KBALB-STK tumors showed highly selective uptake, with a tumor:blood ratio of 33 in a small herpes simplex type 1 (HSV-1 TK) expressing tumor. In conclusion, [18F]FT appears to be a strong candidate for PET imaging of viral TK transgene imaging, based on its TK1:TK2 phosphorylation differential, its selective uptake by an HSV-TK expressing murine tumor model, its interaction with nucleoside transporters and its low toxicity.     

Short-term outcome of patients with ST-segment elevation myocardial infarction (STEMI) treated with an everolimus-eluting bioresorbable vascular scaffold

Objectives

To evaluate safety and efficacy of the everolimus-eluting bioresorbable scaffold (BVS) in patients with ST-segment elevation myocardial infarction (STEMI).

Background

According to the current guidelines, drug-eluting stents are the treatment of choice in patients with STEMI. BVS represents a new technology capable to restore the native vessel vasomotion and potentially avoiding long-term limitations such as stent thrombosis.

Methods

From October 2012 to May 2013, patients with evidence of STEMI eligible for BVS implantation were included in this study. Exclusion criteria were not defined.

Results

A total of 25 patients, respectively 31 lesions, were treated. Procedural success was achieved in 97 %. Two major adverse cardiac events occurred during hospitalization and follow-up: one patient with cardiogenic shock at the index procedure subsequently died. One patient suffered from instable angina with need for interventional revascularization of a previously untreated vessel. One target vessel failure as a consequence of an intra-procedural dissection was seen. However, no target lesion failure was noted. During 132.7 ± 68.7 days of follow-up none of the patients died.

Conclusion

Our findings suggest that implantation of BVS in STEMI patients is feasible in this small cohort of highly selected patients. Further evaluation in randomized-controlled trials is needed.     

Does using tampons or menstrual cups increase early IUD expulsion rates?

BackgroundMany intrauterine device (IUD) users utilize intravaginal menstrual cups or tampons during menses, but no studies have investigated the impact this practice may have on IUD expulsions.Study DesignRetrospective chart survey.ResultsOf the 930 women having IUDs placed and reporting menstrual protection, 10.3% (96) used menstrual cups, 74.2% (690) used tampons, and 43.2% (402) used pads (many women reported using more than one method). In the 743 women with adequate follow-up information, there was a full or partial expulsion (i.e., part of the IUD in the cervical canal) rate of 2.5% (27) during the first 6 weeks after insertion. There was no difference in the women using cups, tampons or pads (confidence intervals overlap).ConclusionsFrom this study, there is no evidence that women who report using menstrual cups or tampons for menstrual protection had higher rates of early IUD expulsion.     

Reversible pulmonary arterial hypertension associated with interferon-beta treatment for multiple sclerosis

Interferon (IFN) therapy has an important role in the treatment of multiple sclerosis and chronic hepatitis C infection. A few case reports have described an association between IFN therapy and the development of irreversible pulmonary arterial hypertension (PAH), and it is currently listed as a possible drug-induced cause of PAH in the most recent classification of pulmonary hypertension. A causal link between IFN use and PAH remains to be elucidated; many reports of PAH resulting from IFN occur in individuals with some other risk factor for PAH. The authors present a case involving a patient with multiple sclerosis with no known risk factors for PAH, who developed severe PAH after exposure to IFN therapy. The patient experienced significant clinical and hemodynamic improvement, with normalization of her pulmonary pressures after the initiation of combination therapy for PAH. At 28 months after diagnosis, she remains asymptomatic with no hemodynamic evidence of PAH and has been off all PAH therapy for 10 months.