孤立性肺结节的高分辨CT

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Preclinical PK and PD Studies on 2��-O-Methyl-phosphorothioate RNA Antisense Oligonucleotides in the mdx Mouse Model

Antisense oligonucleotides (AONs) are being developed as RNA therapeutic molecules for Duchenne muscular dystrophy. For oligonucleotides with the 2′-O-methyl-phosphorothioate (2OMePS) RNA chemistry, proof of concept has been obtained in patient-specific muscle cell cultures, the mouse and dog disease models, and recently by local administration in Duchenne patients. To further explore the pharmacokinetic (PK)/pharmacodynamic (PD) properties of this chemical class of oligonucleotides, we performed a series of preclinical studies in mice. The results demonstrate that the levels of oligonucleotides in dystrophin-deficient muscle fibers are much higher than in healthy fibers, leading to higher exon-skipping levels. Oligonucleotide levels and half-life differed for specific muscle groups, with heart muscle showing the lowest levels but longest half-life (~46 days). Intravenous (i.v.), subcutaneous (s.c.), and intraperitoneal (i.p.) delivery methods were directly compared. For each method, exon-skipping and novel dystrophin expression were observed in all muscles, including arrector pili smooth muscle in skin biopsies. After i.v. administration, the oligonucleotide peak levels in plasma, liver, and kidney were higher than after s.c. or i.p. injections. However, as the bioavailability was similar, and the levels of oligonucleotide, exon-skipping, and dystrophin steadily accumulated overtime after s.c. administration, we selected this patient-convenient delivery method for future clinical study protocols.     

Psychosocial outcomes of group prenatal care

Journal of Public Health - Group prenatal care provides an alternative model of prenatal care that allows for collaboration with peers, education, discussion, and self-management training in...     

Social–emotional delays at 2 years in extremely low gestational age survivors: Correlates of impaired orientation/engagement and emotional regulation

Background

Premature infants are less socially and emotionally competent at school age than infants born at term.

Aims

To evaluate the correlates of social and emotional delays at 2 years of age among prematurely born children.

Study design

This is a prospective cohort study.

Subjects

904 children born at < 28 weeks gestation during 2002–2004 and enrolled in the ELGAN study who survived until age 2 years and returned for a developmental assessment.

Outcome measures

The Bayley Behavior Rating Scale (BRS), a neurological examination, and the Bayley Scales of Infant Development II (BSID-II).

Results

Fully 31% of children had a non-optimal (14%) or questionable (17%) (NO/Q) BRS score for Emotional Regulation (ER), and 27% had a non-optimal (13%) or questionable (14%) score for Orientation/Engagement (O/E). Children with NO/Q scores on ER and O/E were more likely than others to have MDI and PDI scores < 70 and be unable to walk. Antecedents of NO/Q OE scores included multi-fetal pregnancy, while antecedents of NO/Q scores for both ER and O/E included indicators of socioeconomic disadvantage, and male sex.

Conclusions

Over 25% of children born extremely premature exhibit socio-emotional delays during developmental assessment at age 2 years. Antecedents of these delays include sociodemographic characteristics, as well as those common antecedents of other impairments commonly observed among extremely preterm infants.     

Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice

The carboxypeptidase ACE2 is a homologue of angiotensin-converting enzyme (ACE). To clarify the physiological roles of ACE2, we generated mice with targeted disruption of the Ace2 gene. ACE2-deficient mice were viable, fertile, and lacked any gross structural abnormalities. We found normal cardiac dimensions and function in ACE2-deficient animals with mixed or inbred genetic backgrounds. On the C57BL/6 background, ACE2 deficiency was associated with a modest increase in blood pressure, whereas the absence of ACE2 had no effect on baseline blood pressures in 129/SvEv mice. After acute Ang II infusion, plasma concentrations of Ang II increased almost 3-fold higher in ACE2-deficient mice than in controls. In a model of Ang II-dependent hypertension, blood pressures were substantially higher in the ACE2-deficient mice than in WT. Severe hypertension in ACE2-deficient mice was associated with exaggerated accumulation of Ang II in the kidney, as determined by MALDI-TOF mass spectrometry. Although the absence of functional ACE2 causes enhanced susceptibility to Ang II-induced hypertension, we found no evidence for a role of ACE2 in the regulation of cardiac structure or function. Our data suggest that ACE2 is a functional component of the renin-angiotensin system, metabolizing Ang II and thereby contributing to regulation of blood pressure.     

Transmural and endocardial Purkinje activation in pigs before local myocardial activation after defibrillation shocks.

BACKGROUND: Earliest recorded postshock myocardial activations in pigs originate in the subepicardium of the apex and lateral free wall of the left ventricle (LV) 30-90 ms after the shock. OBJECTIVE: The purpose of this study was to determine whether the Purkinje system is a candidate for the source of postshock activations by performing endocardial and transmural postshock activation mapping. METHODS: In five pigs, 32 plunge needles with 12 electrodes (1-mm spacing) were inserted into the LV apex and lateral free wall. Up to 70 plunge needles with six electrodes (2-mm spacing) were spread throughout the remainder of the LV, while 9-12 plunge needles with four electrodes (2-mm spacing) were inserted into the right ventricle. A basket catheter with 32 bipolar recording sites was inserted into the LV. Defibrillation-threshold (DFT)-level shocks were delivered during 10 episodes of electrically induced ventricular fibrillation. Electrograms of postshock activation cycles were analyzed for Purkinje and myocardial activations. RESULTS: Purkinje activations were recorded before local myocardial activation in 9% of basket electrograms and in 15% of plunge needles during the first postshock activation cycle. Purkinje activations were identified during the first and subsequent several postshock activation cycles in at least one basket and one needle electrogram in 96% and 98% of defibrillation episodes, respectively. CONCLUSIONS: The Purkinje system is active during the early postshock activation cycles after DFT-level shocks. Further studies are required to determine whether activation initiates in the Purkinje system or whether it is activated by the myocardium or by Purkinje-myocardial junctional cells.