Distinct thyroid hormone‐dependent expression of trkB and p75NGFR in nonneuronal cells during the critical TH‐dependent period of the cochlea

Analyzing the thyroid hromone (TH)‐dependent period of the inner ear, we observed that the presence of triiodothyronine (T3) between postnatal day 3 (P3) and P12 is sufficient for functional maturation of the auditory system. Within this short time period, an unusual transient TH‐dependent expression of nonneuronal neurotrophin receptors (NT‐R) trkB and p75^NGFR was observed in correlation with neuronal and morphogenetic processes. The availability of thyroid hormone was revealed to be invariably correlated with (a) a transient expression of full‐length trkB in TRα1‐, TRα2‐ and TRβ1‐expressing hair cells concomitant to the segregation of afferent fibers and the synaptogenesis of efferent fibers; and (b) a transient expression of p75^NGFR in TRα1‐ and TRβ1‐expressing great epithelia ridge cells in direct spatiotemporal correlation with the appearance of apoptotic cells and morphogenetic maturation of the organ. For the first time, these data suggest a TH dependency of the expression of neurotrophin receptors in nonneuronal cells. A potential role of these peculiar neurotrophin receptor expression for the conversion of the biological function of TH on innervation patterning and morphogenesis during the critical TH‐dependent period of the inner ear may be considered. © 1999 John Wiley & Sons, Inc. J Neurobiol 38: 338–356, 1999     

Empirical Bayes estimation of random effects parameters in mixed effects logistic regression models

We extend an approach for estimating random effects parameters under a random intercept and slope logistic regression model to include standard errors, thereby including confidence intervals. The procedure entails numerical integration to yield posterior empirical Bayes (EB) estimates of random effects parameters and their corresponding posterior standard errors. We incorporate an adjustment of the standard error due to Kass and Steffey (KS; 1989, Journal of the American Statistical Association 84, 717-726) to account for the variability in estimating the variance component of the random effects distribution. In assessing health care providers with respect to adult pneumonia mortality, comparisons are made with the penalized quasi-likelihood (PQL) approximation approach of Breslow and Clayton (1993, Journal of the American Statistical Association 88, 9-25) and a Bayesian approach. To make comparisons with an EB method previously reported in the literature, we apply these approaches to crossover trials data previously analyzed with the estimating equations EB approach of Waclawiw and Liang (1994, Statistics in Medicine 13, 541-551). We also perform simulations to compare the proposed KS and PQL approaches. These two approaches lead to EB estimates of random effects parameters with similar asymptotic bias. However, for many clusters with small cluster size, the proposed KS approach does better than the PQL procedures in terms of coverage of nominal 95% confidence intervals for random effects estimates. For large cluster sizes and a few clusters, the PQL approach performs better than the KS adjustment. These simulation results agree somewhat with those of the data analyses.     

Histochemical characterization of an antigen specific for the great alveolar cell in the mouse lung

Summary Previous papers reported on a specific antigenic marker for the great alveolar (type-II) cell of the mouse lung and described its recognition by a specific rabbit antiadult mouse lung serum. In the present study light- and electron-microscopical immunohistochemistry on fixed mouse lung sections showed the presence of the marker on the alveolar surface. The antigenic determinants recognized by the antibody were further characterized by immunoblotting and immunoprecipitation studies after in vitro translation of mouse lung messenger RNA.Immunoblots of a surfactant-enriched pellet of a bronchoalveolar lavage fraction of mouse lung showed that the antibody reacted with surfactant-associated proteins having apparent molecular weights of about 27,000, 32,000, and 38,000 daltons in SDS gels. Immunoblots of mouse-lung homogenate revealed the presence of 27,000, 30,000, 39,000, and 41,000 dalton proteins, presumably also surfactant-associated proteins. Immunoprecipitation after in vitro translation of mouse-lung mRNA showed specific reactivity only with a 12,000 dalton polypeptide, a component of the cell marker we were unable to relate to surfactant. Our findings indicate that the 12,000 dalton component of the antigenic marker for the great alveolar cell is a polypeptide whose synthesis is a lung-specific process and that the immunoreaction of the larger and surfactant-associated components is due to post-translational modifications.     

Probabilistic Firing of Neurons Considered as a First Passage Problem

A formalized neuron receiving unitary excitatory impulses at random is considered. Each impulse provokes an effect of equal magnitude and of a duration not constant for each impulse, but which varies according to an exponential distribution. The effects sum until a threshold is reached when a response occurs. The distribution of intervals between successive responses is computed and compared with those obtained from a model in which the effects decay exponentially with time. Upon introducing inhibitory impulses also, the theory is applied to data on discharge characteristics of driven and spontaneously active thalamic neurons reported in the literature.     

TNFR1 and the TNFα axis as a targetable mediator of liver injury from stereotactic body radiation therapy

IntroductionRadiation therapy for the management of intrahepatic malignancies can adversely affect liver function. Liver damage has been associated with increased levels of inflammatory cytokines, including tumor necrosis factor alpha (TNFα). We hypothesized that an inflammatory state, characterized by increased soluble TNFα receptor (sTNFR1), mediates sensitivity of the liver to radiation.Materials/MethodsPlasma samples collected during 3 trials of liver radiation for liver malignancies were assayed for sTNFR1 level via enzyme-linked immunosorbent assay (ELISA). Univariate and multivariate logistic regression and longitudinal models were used to characterize associations between liver toxicity (defined as a ≥2-point increase in Child-Pugh [CP] score within 6 months of radiation treatment) and sTNFR1 levels, ALBI score, biocorrected mean liver dose (MLD), age, and baseline laboratory values.ResultsSamples from 78 patients given liver stereotactic body radiation therapy [SBRT] (92%) or hypofractionated radiation were examined. There was a significant association between liver toxicity and sTNFR1 levels, and higher values were associated with increased toxicity over a range of mean liver doses. When ALBI score and biocorrected dose were included in the model with sTNFR1, baseline ALBI score and change in ALBI (ΔALBI) were significantly associated with toxicity, but sTNFR1 was not. Baseline aminotransferase levels also predicted toxicity but not independently of ALBI score.ConclusionsElevated plasma sTNFR1 levels are associated with liver injury after liver radiation, suggesting that elevated inflammatory cytokine activity is a predictor of radiation-induced liver dysfunction. Future studies should determine whether administration of agents that decrease inflammation prior to treatment is warranted.     

Job strain, job insecurity, and incident cardiovascular disease in the Women's Health Study: results from a 10-year prospective study

Objectives

Research about work-related stressors and cardiovascular disease (CVD) has produced mixed findings. Moreover, a paucity of data exists regarding the long-term associations between job strain and job insecurity and CVD among women.

Methods

We used Cox proportional hazard models to examine the relationship between job strain, job insecurity, and incident CVD over 10 years of follow-up among 22,086 participants in the Women’s Health Study (mean age 57±5 years).

Results

During 10 years of follow-up there were 170 myocardial infarctions (MI), 163 ischemic strokes, 440 coronary revascularizations, and 52 CVD deaths. In models adjusted for age, race, education, and income, women with high job strain (high demand, low control) were 38% more likely to experience a CVD event than their counterparts who reported low job strain (low demand, high control; Rate Ratio (RR) = 1.38, 95% Confidence Interval (CI) = 1.08–1.77), and women with active jobs (high demand, high control) were 38% more likely to experience a CVD event relative to women who reported low job strain (95% CI = 1.07–1.77). Outcome-specific analyses revealed that high job strain predicted non-fatal myocardial infarction (RR = 1.67, CI = 1.04–2.70), and coronary revascularization (RR = 1.41, CI = 1.05–1.90). No evidence of an association between job insecurity and long-term CVD risk was observed.

Conclusion

High strain and active jobs, but not job insecurity, were related to increased CVD risk among women. Both job strain and job insecurity were significantly related to CVD risk factors. With the increase of women in the workforce, these data emphasize the importance of addressing job strain in CVD prevention efforts among working women.     

Role of ultrasonography in diagnosing early rheumatoid arthritis and remission of rheumatoid arthritis - a systematic review of the literature

Introduction

Ultrasonography (US) might have an added value to clinical examination in diagnosing early rheumatoid arthritis (RA) and assessing remission of RA. We aimed to clarify the added value of US in RA in these situations performing a systematic review.

Methods

A systematic literature search was performed for RA, US, diagnosis and remission. Methodological quality was assessed; the wide variability in the design of studies prohibited pooling of results.

Results

Six papers on the added value of US diagnosing early RA were found, in which at least bilateral metacarpophalangeal (MCP), wrists and metatarsophalangeal (MTP) joints were scanned. Compared to clinical examination, US was superior with regard to detecting synovitis and predicting progression to persistent arthritis or RA. Eleven papers on assessing remission were identified, in which at least the wrist and the MCP joints of the dominant hand were scanned. Often US detected inflammation in patients clinically in remission, irrespective of the remission criteria used. Power Doppler signs of synovitis predicted X-ray progression and future flare in patients clinically in remission.

Conclusions

US appears to have added value to clinical examination for diagnosing of RA when scanning at least MCP, wrist and MTP joints, and, when evaluating remission of RA, scanning at least wrist and MCP joints of the dominant hand. For both purposes primarily power Doppler US might be used since its results are less equivocal than those of greyscale US.     

Evolution of networks for body plan patterning; interplay of modularity, robustness and evolvability

A major goal of evolutionary developmental biology (evo-devo) is to understand how multicellular body plans of increasing complexity have evolved, and how the corresponding developmental programs are genetically encoded. It has been repeatedly argued that key to the evolution of increased body plan complexity is the modularity of the underlying developmental gene regulatory networks (GRNs). This modularity is considered essential for network robustness and evolvability. In our opinion, these ideas, appealing as they may sound, have not been sufficiently tested. Here we use computer simulations to study the evolution of GRNs' underlying body plan patterning. We select for body plan segmentation and differentiation, as these are considered to be major innovations in metazoan evolution. To allow modular networks to evolve, we independently select for segmentation and differentiation. We study both the occurrence and relation of robustness, evolvability and modularity of evolved networks. Interestingly, we observed two distinct evolutionary strategies to evolve a segmented, differentiated body plan. In the first strategy, first segments and then differentiation domains evolve (SF strategy). In the second scenario segments and domains evolve simultaneously (SS strategy). We demonstrate that under indirect selection for robustness the SF strategy becomes dominant. In addition, as a byproduct of this larger robustness, the SF strategy is also more evolvable. Finally, using a combined functional and architectural approach, we determine network modularity. We find that while SS networks generate segments and domains in an integrated manner, SF networks use largely independent modules to produce segments and domains. Surprisingly, we find that widely used, purely architectural methods for determining network modularity completely fail to establish this higher modularity of SF networks. Finally, we observe that, as a free side effect of evolving segmentation and differentiation in combination, we obtained in-silico developmental mechanisms resembling mechanisms used in vertebrate development.