On the characterization of pH-sensitive liposome/polymer complexes

A randomly alkylated copolymer of N-isopropylacrylamide, methacrylic acid and N-vinyl-2-pyrrolidone was characterized with regard to its pH- and temperature-triggered conformational change. It was then complexed to liposomes to produce pH-responsive vesicles. Light scattering and differential scanning calorimetry experiments performed at neutral pH revealed that the polymer underwent coil-to-globule phase transition over a wide range of temperatures. At 37 degrees C and pH 7.4, although the polymer was water-soluble, Fourier transform infrared spectroscopy analysis showed that it was partly dehydrated. At acidic pH, the decrease in the lower critical solution temperature was accompanied by an increase in cooperativity degree of the phase transition. Complexation of copolymer to liposomes did not substantially influence its phase transition. The liposome/copolymer complexes were stable at neutral pH but rapidly released their contents under acidic conditions. The copolymer slightly increased liposome circulation time following intravenous administration to rats. The addition of poly(ethylene glycol) to the formulation had a detrimental effect on pH-sensitivity but enhanced substantially the circulation time.     

The importance of using absolute mutant frequencies to compare mutation spectra

Because damage to the cellular DNA is very hazardous for a cell, it is important to identify compounds, which can cause DNA damage. To investigate the mutagenic effect of a particular agent of interest, usually mutation spectra are determined in a selected target gene. The most commonly used method to compare different mutation spectra with each other, is the comparison of the percentages of each type of mutation. In this paper, it is emphasized that comparison of percentages can lead to incorrect conclusions and therefore another determinant, the absolute mutant frequency, should be used.     

Repeated post-exercise administration with a mixture of leucine and glucose alters the plasma amino acid profile in Standardbred trotters

Background  

The branched chain amino acid leucine is a potent stimulator of insulin secretion. Used in combination with glucose it can increase the insulin response and the post exercise re-synthesis of glycogen in man. Decreased plasma amino acid concentrations have been reported after intravenous or per oral administration of leucine in man as well as after a single per oral dose in horses. In man, a negative correlation between the insulin response and the concentrations of isoleucine, valine and methionine have been shown but results from horses are lacking. This study aims to determine the effect of repeated per oral administration with a mixture of glucose and leucine on the free amino acid profile and the insulin response in horses after glycogen-depleting exercise.     

Left sided ablation for Atrioventricular Nodal Re-entrant Tachycardia: Frequency,Characteristics and Outcomes

BackgroundLeft-sided ablation, targeting left inferior AV nodal extensions, is thought to be necessary for success in a small proportion of atrioventricular nodal re-entrant tachycardia (AVNRT) ablations; however Indian data are scarce in this regard.MethodsConsecutive cases of AVNRT undergoing slow pathway ablation in a single centre over an 18-month period were retrospectively analyzed. Left-sided ablation at the posteroseptal mitral annulus was performed if right-sided ablation failed to abolish AVNRT.ResultsFrom January 2017 to June 2018, out of 215 consecutive supraventricular tachycardia (SVT) cases, 154 (71.6%) were AVNRT (47.1 ± 13.1 years, 46.1% male). Trans-septal ablation was required in 5 (3.2%) cases (mean age 48.8 ± 9.4 years; 4 female, 1 male); all with typical (slow-fast) form of AVNRT. Compared with cases needing only right-sided ablation, radiofrequency time (50.8 ± 16.9 vs. 9.9 ± 8.5 min; p = 0.005) and procedure time (166.0 ± 35.0 vs 79.6 ± 35.9 min; p = 0.004) were significantly longer for trans-septal cases, while baseline intervals and tachycardia cycle length were not significantly different. Junctional ectopy was seen in only 2 of the 5 cases during left-sided ablation, but acute success (non-inducibility) was obtained in 3 cases. There were no instances of AV block. Over mean follow-up of 12.2 ± 4.0 months, clinical recurrence of AVNRT occurred in one case, while others remained arrhythmia-free without medication.ConclusionLeft-sided ablation was required in a small proportion of AVNRT ablations. Trans-septal approach targeting the posteroseptal mitral annulus was safe and yielded good mid-term clinical success.     

Dyssynchronous Ventricular Activation in Asymptomatic Wolff-Parkinson-White Syndrome: A Risk Factor for Development of Dilated Cardiomyopathy

A subset of children and adults with Wolff-Parkinson-White (WPW) syndrome develop dilated cardiomyopathy (DCM). Although DCM may occur in symptomatic WPW patients with sustained tachyarrhythmias, emerging evidence suggests that significant left ventricular dysfunction may arise in WPW in the absence of incessant tachyarrhythmias. An invariable electrophysiological feature in this non-tachyarrhythmia type of DCM is the presence of a right-sided septal or paraseptal accessory pathway. It is thought that premature ventricular activation over these accessory pathways induces septal wall motion abnormalities and ventricular dyssynchrony. LV dyssynchrony induces cellular and structural ventricular remodelling, which may have detrimental effects on cardiac performance. This review summarizes recent evidence for development of DCM in asymptomatic patients with WPW, discusses its pathogenesis, clinical presentation, management and treatment. The prognosis of accessory pathway-induced DCM is excellent. LV dysfunction reverses following catheter ablation of the accessory pathway, suggesting an association between DCM and ventricular preexcitation. Accessory pathway-induced DCM should be suspected in all patients presenting with heart failure and overt ventricular preexcitation, in whom no cause for their DCM can be found.     

The role of nucleotide excision repair of Escherichia coli in repair of spontaneous and gamma-radiation-induced DNA damage in the lacZalpha gene

Base excision repair (BER) is a very important repair mechanism to remove oxidative DNA damage. A major oxidative DNA damage after exposure to ionizing radiation is 7,8-dihydro-8-oxoguanine (8oxoG). 8oxoG is a strong mutagenic lesion, which may cause G:C to T:A transversions if not repaired correctly. Formamidopyrimidine-DNA glycosylase (Fpg), a repair enzyme which is part of BER, is the most important enzyme to repair 8oxoG. In the past years, evidence evolved that nucleotide excision repair (NER), a repair system originally thought to repair only bulky DNA lesions, can also repair some oxidative DNA damages. Examples of DNA damages which are recognized by NER are thymine glycol and abasic sites (AP sites). The main objective of this study is to determine if NER can act as a backup system for the repair of spontaneous and gamma-radiation-induced damages when Fpg is deficient. For that purpose, the effect of a NER-deficiency on the spontaneous and gamma-radiation-induced mutation spectrum in the lacZ gene was determined, using double-stranded (ds) M13 DNA, with the lacZalpha gene inserted as mutational target sequence. Subsequently the DNA was transfected into a fpg(-)uvrA(-) Escherichia coli strain (BH420) and the mutational spectra were compared with the spectra of a fpg(-) E. coli strain (BH410) and a wild type E. coli strain (JM105), which were determined in an earlier study. Furthermore, to examine effects which are caused by UvrA-deficiency, and not by Fpg-deficiency, the spontaneous and gamma-radiation-induced mutation spectra of an E. coli strain in which only UvrA is deficient (BH430) were also determined and compared with a wild type E. coli strain (JM105). The results of this study indicate that if only UvrA is deficient, there is an increase in spontaneous G:C to T:A transversions as compared to JM105 and a decrease in A:T to G:C transitions. The gamma-radiation-induced mutation spectrum of BH420 (fpg(-)uvrA(-)) shows a significant decrease in G:C to A:T and G:C to T:A mutations, as compared to BH410 where only Fpg is deficient. Based on these results, we conclude that in our experiments NER is not acting as a backup system if Fpg is deficient. Instead, NER seems to make mistakes, leading to the formation of mutations.     

Histone H3 lysine 4 trimethylation in sperm is transmitted to the embryo and associated with diet-induced phenotypes in the offspring

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