Paracrine action of FGF4 during periimplantation development maintains trophectoderm and primitive endoderm

FGF4, a member of the fibroblast growth factor (FGF) family, is absolutely required for periimplantation mouse development, although its precise role at this stage remains unknown. The nature of the defect leading to postimplantation lethality of embryos lacking zygotic FGF4 is unclear and little is known about downstream targets of FGF4-initiated signaling within the various cellular compartments of the blastocyst. Here we report that postimplantation lethality of Fgf4(-/-) embryos is unlikely to reflect strictly mitogenic requirements for FGF4. Rather, our results suggest that FGF4 is required to maintain trophectoderm and primitive endoderm identity at embryonic day 4.5. This result is consistent with the reported in vitro activity of FGF4 in maintaining trophoblast stem cells and with the requirement for receptor tyrosine kinase signaling in primitive endoderm formation. Thus, postimplantation lethality of Fgf4(-/-) embryos likely results from the failure of proper differentiation and function of extraembryonic cell types.     

Alien inhibits E2F1 gene expression and cell proliferation

Recently, using a proteomic approach we have identified the corepressor Alien as a novel interacting factor of the cell cycle regulator E2F1. Unclear was whether this interaction influences cell proliferation and endogenous E2F1 target gene expression. Here, we show by chromatin immunoprecipitation (ChIP) that Alien is recruited in vivo to the E2F binding sites present in the E2F1 gene promoter, inhibits the transactivation of E2F1 and represses endogenous E2F1 gene expression. Interestingly, using synchronized cells to assess the expression of Alien profile during cell cycle the levels of endogenous Alien are increased during G1, G1/S and G2 phase. Furthermore, stable transfection of Alien leads to reduction of cell proliferation. Thus, the data suggest that Alien acts as a corepressor for E2F1 and is involved in cell cycle regulation.     

Lower-extremity muscle atrophy and fat infiltration after chronic spinal cord injury

Background:

Atrophy and fatty-infiltration of lower-extremity muscle after spinal cord injury (SCI) predisposes individuals to metabolic disease and related mortality.

Objectives:

To determine the magnitude of atrophy and fatty-infiltration of lower-extremity muscles and related factors in a group of individuals with chronic SCI and diverse impairment.

Methods:

Muscle cross-sectional area and density were calculated from peripheral quantitative computed tomography scans of the 66% site of the calf of 70 participants with chronic SCI [50 male, mean age 49 (standard deviation 12) years, C2-T12, AIS A-D] and matched controls. Regression models for muscle area and density were formed using 16 potential correlates selected a priori.

Results:

Participants with motor-complete SCI had ≈32% lower muscle area, and ≈43% lower muscle density values relative to controls. Participants with motor-incomplete SCI had muscle area and density values that were both ≈14% lower than controls. Body mass (+), tetraplegia (+), motor function (+), spasticity (+), vigorous physical activity (+), wheelchair use (-), age (-), and waist circumference (-) were associated with muscle size and/or density in best-fit regression models.

Conclusions:

There are modifiable factors related to muscle size, body composition, and activity level that may offer therapeutic targets for preserving metabolic health after chronic SCI.     

A new class of orally active glycol renin inhibitors containing phenyllactic acid at P3

We prepared a new series of renin inhibitors based on dipeptide glycols, replacing the P4-P3 subsites with an O-(N-morpholinocarbonyl)-3-L-phenyllactic acid residue. This modification proved bioisosteric with Boc-L-phenylalanine, giving rise to highly potent human renin inhibitors (1-5 nM), e.g., SC-46944 (IC50 = 5 nM). Moreover, this change produced compounds that are orally efficacious in reducing plasma renin activity in salt-depleted marmosets.     

Differential Item Functioning in the SF-36 Physical Functioning and Mental Health Sub-Scales: A Population-Based Investigation in the Canadian Multicentre Osteoporosis Study

Background

Self-reported health status measures, like the Short Form 36-item Health Survey (SF-36), can provide rich information about the overall health of a population and its components, such as physical, mental, and social health. However, differential item functioning (DIF), which arises when population sub-groups with the same underlying (i.e., latent) level of health have different measured item response probabilities, may compromise the comparability of these measures. The purpose of this study was to test for DIF on the SF-36 physical functioning (PF) and mental health (MH) sub-scale items in a Canadian population-based sample.

Methods

Study data were from the prospective Canadian Multicentre Osteoporosis Study (CaMos), which collected baseline data in 1996–1997. DIF was tested using a multiple indicators multiple causes (MIMIC) method. Confirmatory factor analysis defined the latent variable measurement model for the item responses and latent variable regression with demographic and health status covariates (i.e., sex, age group, body weight, self-perceived general health) produced estimates of the magnitude of DIF effects.

Results

The CaMos cohort consisted of 9423 respondents; 69.4% were female and 51.7% were less than 65 years. Eight of 10 items on the PF sub-scale and four of five items on the MH sub-scale exhibited DIF. Large DIF effects were observed on PF sub-scale items about vigorous and moderate activities, lifting and carrying groceries, walking one block, and bathing or dressing. On the MH sub-scale items, all DIF effects were small or moderate in size.

Conclusions

SF-36 PF and MH sub-scale scores were not comparable across population sub-groups defined by demographic and health status variables due to the effects of DIF, although the magnitude of this bias was not large for most items. We recommend testing and adjusting for DIF to ensure comparability of the SF-36 in population-based investigations.     

Brain type carnosinase in dementia: a pilot study

Background  

The pathological processes underlying dementia are poorly understood and so are the markers which identify them. Carnosinase is a dipeptidase found almost exclusively in brain and serum. Carnosinase and its substrate carnosine have been linked to neuropathophysiological processes.     

The "systolic volume balance" method for the noninvasive estimation of cardiac output based on pressure wave analysis

Cardiac output (CO) monitoring is essential for the optimal management of critically ill patients. Several mathematical methods have been proposed for CO estimation based on pressure waveform analysis. Most of them depend on invasive recording of blood pressure and require repeated calibrations, and they suffer from decreased accuracy under specific conditions. A new systolic volume balance (SVB) method, including a simpler empirical form (eSVB), was derived from basic physical principles that govern blood flow and, in particular, a volume balance approach for the conservation of mass ejected into and flowed out of the arterial system during systole. The formulas were validated by a one-dimensional model of the systemic arterial tree. Comparisons of CO estimates between the proposed and previous methods were performed in terms of agreement and accuracy using "real" CO values of the model as a reference. Five hundred and seven different hemodynamic cases were simulated by altering cardiac period, arterial compliance, and resistance. CO could be accurately estimated by the SVB method as follows: CO = C × PP(ao)/(T - P(sm) × T(s)/P(m)) and by the eSVB method as follows: CO = k × C × PP(ao)/T, where C is arterial compliance, PP(ao) is aortic pulse pressure, T is cardiac period, P(sm) is mean systolic pressure, T(s) is systolic duration, P(m) is mean pressure, and k is an empirical coefficient. SVB applied on aortic pressure waves did not require calibration or empirical correction for CO estimation. An empirical coefficient was necessary for brachial pressure wave analysis. The difference of SVB-derived CO from model CO (for brachial waves) was 0.042 ± 0.341 l/min, and the limits of agreement were -0.7 to 0.6 l/min, indicating high accuracy. The intraclass correlation coefficient and root mean square error between estimated and "real" CO were 0.861 and 0.041 l/min, respectively, indicating very good accuracy. eSVB also provided accurate estimation of CO. An in vivo validation study of the proposed methods remains to be conducted.