Regioisomeric Preference in Ring-Opening Polymerization of 3',5'-Cyclic Phosphoesters of Functional Thymidine DNA Analogues.

Regioregularity is a crucial property in the synthesis of DNA analogues, as natural DNA is synthesized exclusively in the 5' to 3' direction. We have focused our attention on the determination of the regioisomeric distribution of poly(3',5'-cyclic 3-(3-butenyl) thymidine ethylphosphate)s obtained from the ring-opening polymerization of (R)-3',5'-cyclic 3-(3-butenyl) thymidine ethylphosphate. The regioisomeric preference was investigated by comparison to synthesized model compounds of 3',3'-, 3',5'-, and 5',5'-linkages, where the model 3'-phosphoester linkages were to the secondary alcohol of 3-hydroxytetrahydrofuran and the model 5'-linkages derived from coupling to the primary alcohol of tetrahydrofurfuryl alcohol. From the 31P resonance frequency assignments of those small molecule model compounds, 31P NMR spectra revealed the major connectivity in the polymer backbone to be 3',5'-linkages, with ≤30% of other isomeric forms. Model reactions employing a series of alcohol initiators imparting various degrees of steric hindrance, to mimic the increased steric hindrance of the propagating alcohol relative to the initiator, were then conducted to afford the corresponding ring-opened unimer adducts and to gain understanding of the regioselectivity during the ring-opening polymerization. 1H-31P heteronuclear multiple-bond correlation spectroscopy showed ethanol and 4-methoxybenzyl alcohol initiation to yield only the P-O5' bond cleavage product, whereas attack by isopropyl alcohol upon (R)-3',5'-cyclic 3-(3-butenyl) thymidine ethylphosphate afforded both P-O3' and P-O5' bond cleavage products, supporting our hypothesis that the increased steric hindrance of the propagating species dictates the regioselectivity of the P-O bond cleavage. Further model reactions suggested that the P-O5' bond cleavage products can be detected upon the formation of dimers during the ring-opening polymerization. Overall, this work provides a fundamental understanding of the polymerization behavior of six-membered cyclic phosphoesters and broadens the scope of DNA analogues from the ring-opening polymerization of 3',5'-cyclic phosphoesters.

Intermittent Hypoxia and Hypercapnia Accelerate Atherosclerosis, Partially via Trimethylamine-Oxide.

Obstructive sleep apnea (OSA) is a common disorder characterized by intermittent hypoxia and hypercapnia (IHC) during sleep. OSA has been shown to be a risk factor for atherosclerosis, but the relation of IHC to the induction or progression of atherosclerosis is not well understood. To dissect the mechanisms involved, we compared atherosclerotic lesion formation in two mouse models, i.e., apolipoprotein E (ApoE) and low density lipoprotein receptor (Ldlr)-deficient mice, with or without IHC exposure. Ten-week-old ApoE-/- or Ldlr-/- mice were fed a high-fat diet for 4 or 8 weeks while being exposed to IHC for 10 hours/day or room air (RA) for 24 hours/day. En face lesions of the aorta, aortic arch, and pulmonary artery (PA) were examined. Moreover, 3,3-dimethyl-1-butanol (DMB), an inhibitor of microbial trimethylamine (TMA) production, was used to determine the contribution of TMA-oxide (TMAO) to IHC-induced atherosclerosis. Eight weeks of IHC exposure expedited the formation of atherosclerosis in both the PA and aortic arch of ApoE-/- mice, but only in the PA of Ldlr-/- mice (ApoE-/- PA 8 wk, IHC 35.4 ± 1.9% versus RA 8.0 ± 2.8%, P < 0.01). The atherosclerotic lesions evolved faster and to a more severe extent in ApoE-/- mice as compared with Ldlr-/- mice (PA IHC 8 wk, ApoE-/- 35.4 ± 1.9% versus Ldlr-/- 8.2 ± 1.5%, P < 0.01). DMB significantly attenuated but did not totally eliminate IHC-induced PA atherosclerosis. Our findings suggest that IHC, a hallmark of OSA, accelerates the progression of atherosclerosis in the aorta and especially in the PA. This process is partly inhibited by DMB, demonstrating that microbial metabolites may serve as therapeutic targets for OSA-induced atherosclerosis.

Comparison of mechanical and nonmechanical failure rates associated with rotating hinged total knee arthroplasty in nontumor patients.

Rotating hinge total knee arthroplasty (TKA) has had acceptable to poor results in terms of clinical outcomes and survivorship, leading to skepticism with regard to its use. A total of 271 hinged TKAs performed between 1998 and 2008 were studied to determine survivorship and factors affecting survivorship. A median survivorship of 6.9 years was found for the best-case cohort (n = 111), and 4.1 years, for the worst-case group (n = 174). Of the 111 patients, 51 (45.9%) experienced a failure that required reoperation, with more than half of these (29/51, or 56.9%) due to nonmechanical modes of failure. Comparison of the kinematic hinge implants with the distal femoral replacements showed that the Kaplan-Meier survivorship was slightly higher for the patients with distal femoral replacements, although this was not significant (P = .962). Our study suggests that the hinge TKA is well designed and provides acceptable survivorship in healthy patients who do not have nonmechanical complications.