The developing shoulder has a limited capacity to recover after a short duration of neonatal paralysis

Mechanical stimuli are required for the proper development of the musculoskeletal system. Removal of muscle forces during fetal or early post-natal timepoints impairs the formation of bone, tendon, and their attachment (the enthesis). The goal of the current study was to examine the capacity of the shoulder to recover after a short duration of neonatal rotator cuff paralysis, a condition mimicking the clinical condition neonatal brachial plexus palsy. We asked if reapplication of muscle load to a transiently paralyzed muscle would allow for full recovery of tissue properties. CD-1 mice were injected with botulinum toxin A to paralyze the supraspinatus muscle from birth through 2 weeks and subsequently allowed to recover. The biomechanics of the enthesis was determined using tensile testing and the morphology of the shoulder joint was determined using microcomputed tomography and histology. A recovery period of at least 10 weeks was required to achieve control properties, demonstrating a limited capacity of the shoulder to recover after only two weeks of muscle paralysis. Although care must be taken when extrapolating results from an animal model to the human condition, the results of the current study imply that treatment of neonatal brachial plexus palsy should be aggressive, as even short periods of paralysis could lead to long-term deficiencies in enthesis biomechanics and shoulder morphology.     

Functional Grading of Mineral and Collagen in the Attachment of Tendon to Bone

Attachment of dissimilar materials is a major challenge because high levels of localized stress may develop at their interfaces. An effective biologic solution to this problem exists at one of nature's most extreme interfaces: the attachment of tendon (a compliant, structural “soft tissue”) to bone (a stiff, structural “hard tissue”). The goal of our study was to develop biomechanical models to describe how the tendon-to-bone insertion derives its mechanical properties. We examined the tendon-to-bone insertion and found two factors that give the tendon-to-bone transition a unique grading in mechanical properties: 1), a gradation in mineral concentration, measured by Raman spectroscopy; and 2), a gradation in collagen fiber orientation, measured by polarized light microscopy. Our measurements motivate a new physiological picture of the tissue that achieves this transition, the tendon-to-bone insertion, as a continuous, functionally graded material. Our biomechanical model suggests that the experimentally observed increase in mineral accumulation within collagen fibers can provide significant stiffening of the partially mineralized fibers, but only for concentrations of mineral above a “percolation threshold” corresponding to formation of a mechanically continuous mineral network within each collagen fiber (e.g., the case of mineral connectivity extending from one end of the fiber to the other). Increasing dispersion in the orientation distribution of collagen fibers from tendon to bone is a second major determinant of tissue stiffness. The combination of these two factors may explain the nonmonotonic variation of stiffness over the length of the tendon-to-bone insertion reported previously. Our models explain how tendon-to-bone attachment is achieved through a functionally graded material composition, and provide targets for tissue engineered surgical interventions and biomimetic material interfaces.     

Algorithms for incorporating prior topological information in HMMs: application to transmembrane proteins

Background  

Hidden Markov Models (HMMs) have been extensively used in computational molecular biology, for modelling protein and nucleic acid sequences. In many applications, such as transmembrane protein topology prediction, the incorporation of limited amount of information regarding the topology, arising from biochemical experiments, has been proved a very useful strategy that increased remarkably the performance of even the top-scoring methods. However, no clear and formal explanation of the algorithms that retains the probabilistic interpretation of the models has been presented so far in the literature.     

Does conjugation of antioxidants improve their antioxidative/anti-inflammatory potential?

A series of symmetric and asymmetric spermine (SPM) conjugates with all-trans-retinoic acid (ATRA), acitretin (ACI), (E)-3-(trioxsalen-4′-yl)acrylic acid (TRAA) and l-DOPA, amides of ACI, l-DOPA and TRAA with 1-aminobutane, benzylamine, dopamine and 1,12-diaminobutane as well as hybrid conjugates of O,O′-dimethylcaffeic acid (DMCA) with TRAA or N-fumaroyl-indole-3-carboxanilide (FICA) and 2-(2-aminoethoxy)ethanol were synthesized and their antioxidant properties were studied. The reducing activity (RA)% of the compounds were evaluated using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical-scavenging assay and found to be in the range 0–92(20 min)%/96(60 min)% at 100 μM, the most powerful being the conjugates l-DOPA-SPM-l-DOPA (8, RA = 89%/96%) and l-DOPA-dopamine (13, RA = 92%/92%). Conjugate DMCA-NH(CH₂CH₂O)₂-FICA (14) was the most powerful LOX inhibitor with IC₅₀ 33.5 μM, followed by the conjugates ACI-NHCH₂Ph (10, IC₅₀ 40.5 μM), ACI-SPM-TRAA (7, IC₅₀ 41.5 μM), DMCA-NH(CH₂CH₂O)₂-TRAA (15, IC₅₀ 65 μM), 13 (IC₅₀ 81.5 μM) and ACI-dopamine (11, IC₅₀ 87 μM). The most potent inhibitors of lipid peroxidation at 100 μM were the conjugates 15 (98%) and ACI-SPM-ACI (4, 97%) whereas all other compounds showed activities comparable or lower than trolox. The most interesting compounds, namely ATRA-SPM-ATRA (3), 4, 10, 11 and 15, as well as unconjugated compounds such as ATRA and dopamine, were studied for their anti-inflammatory activity in vivo on rat paw oedema induced by Carrageenan and found to exhibit, for doses of 0.01 mmol/mL of conjugates per Kg of rat body weight, weaker anti-inflammatory activities (3.6–40%) than indomethacin (47%) with conjugate 3 being the most potent (40%) in this series of compounds. The cytocompatibility of selected compounds was evaluated by the viability of RAMEC cells in the presence of different concentrations (0.5–50 μM) of the compounds. Conjugates 3 (IC₅₀ 2.6 μM) and 4 (IC₅₀ 4.7 μM) were more cytotoxic than the corresponding unconjugated retinoids ATRA (IC₅₀ 18.3 μM) and ACI (IC₅₀ 14.6 μM), whereas conjugate 15 (IC₅₀ 12.9 μM) was less cytotoxic than either DCSP (IC₅₀ 11.3 μM) or the tert-butyl ester of TRAA (IC₅₀ 2.9 μM).     

Prenatal and Postpartum Evening Salivary Cortisol Levels in Association with Peripartum Depressive Symptoms

Background

The biology of peripartum depression remains unclear, with altered stress and the Hypothalamus-Pituitary-Adrenal axis response having been implicated in its pathophysiology.

Methods

The current study was undertaken as a part of the BASIC project (Biology, Affect, Stress, Imaging, Cognition), a population-based longitudinal study of psychological wellbeing during pregnancy and the postpartum period in Uppsala County, Sweden, in order to assess the association between evening salivary cortisol levels and depressive symptoms in the peripartum period. Three hundred and sixty-five pregnant women from the BASIC cohort were recruited at pregnancy week 18 and instructed to complete a Swedish validated version of the Edinburgh Postnatal Depression Scale at the 36th week of pregnancy as well as the sixth week after delivery. At both times, they were also asked to provide evening salivary samples for cortisol analysis. A comprehensive review of the relevant literature is also provided.

Results

Women with postpartum EPDS score ≥ 10 had higher salivary evening cortisol at six weeks postpartum compared to healthy controls (median cortisol 1.19 vs 0.89 nmol/L). A logistic regression model showed a positive association between cortisol levels and depressive symptoms postpartum (OR = 4.1; 95% CI 1.7–9.7). This association remained significant even after controlling for history of depression, use of tobacco, partner support, breastfeeding, stressful life events, and sleep problems, as possible confounders (aOR = 4.5; 95% CI 1.5–14.1). Additionally, women with postpartum depressive symptoms had higher postpartum cortisol levels compared to both women with depressive symptoms antenatally and controls (p = 0.019 and p = 0.004, respectively).

Conclusions

Women with depressive symptoms postpartum had higher postpartum cortisol levels, indicating an altered response of the HPA-axis in postpartum depression.     

Effect of zooming on texture features of ultrasonic images

Background

The effect of age on common carotid artery diameter is unclear for varying atherosclerosis risk levels.

Methods

Cross-sectional data from the Atherosclerosis Risk in Communities Limited Access Data set were used to estimate the association of age with B-mode ultrasound common carotid artery diameter for three atherosclerosis risk levels. Based on information from clinical examinations, B-mode ultrasounds, questionnaires, blood and other tests, participants were categorized into three groups: pre-existing disease (prevalent stroke and/or coronary heart disease), high risk group (no pre-existing disease, but prevalent diabetes, hypertension, plaques/shadowing, body mass index >= 30, current smoking, or hyperlipidemia), and a low risk group (no pre-existing disease, no plaques/shadowing, and no major elevated risk factors). Multivariable linear regression analyses modeled the common carotid artery diameter relationship with age.

Results

Age was positively and significantly associated with common carotid artery diameter after risk factor adjustment in the overall sample, but age had a larger effect among persons with evidence of atherosclerosis (interaction p < 0.05). Each year of older age was associated with 0.03 mm larger diameter/year among persons with pre-existing disease, with 0.027 mm larger diameter/year in the high risk group, but only 0.017 mm/year among the low risk group. Results were qualitatively similar using plaques/shadowing status to indicate atherosclerosis severity.

Conclusion

The significant impact of age on common carotid artery diameter among low risk, middle-aged, black and white men and women suggests arterial remodelling may occur in the absence of identified risk factors. The significantly larger impact of age among persons with, compared to persons without identified atherosclerosis or its risk factors, suggests that arterial remodelling may be an indicator of exposure duration.     

Power of the Wilcoxon–Mann–Whitney test for non‐inferiority in the presence of death‐censored observations

In clinical trials with patients in a critical state, death may preclude measurement of a quantitative endpoint of interest, and even early measurements, for example for intention‐to‐treat analysis, may not be available. For example, a non‐negligible proportion of patients with acute pulmonary embolism will die before 30 day measurements on the efficacy of thrombolysis can be obtained. As excluding such patients may introduce bias, alternative analyses, and corresponding means for sample size calculation are needed. We specifically consider power analysis in a randomized clinical trial setting in which the goal is to demonstrate noninferiority of a new treatment as compared to a reference treatment. Also, a nonparametric approach may be needed due to the distribution of the quantitative endpoint of interest. While some approaches have been developed in a composite endpoint setting, our focus is on the continuous endpoint affected by death‐related censoring, for which no approach for noninferiority is available. We propose a solution based on ranking the quantitative outcome and assigning worst rank scores to the patients without quantitative outcome because of death. Based on this, we derive power formulae for a noninferiority test in the presence of death‐censored observations, considering settings with and without ties. The approach is illustrated for an exemplary clinical trial in pulmonary embolism. The results there show a substantial effect of death on power, also depending on differential effects in the two trial arms. Therefore, use of the proposed formulae is advisable whenever there is death to be expected before measurement of a quantitative primary outcome of interest.     

Interaction of spatial diffusion and delays in models of genetic control by repression

A class of models based on the Jacob and Monod theory of genetic repression for control of biosynthetic pathways in cells is considered. Both spatial diffusion and time delays are taken into account. A method is developed for representing the effects of spatial diffusion as distributed delay terms. This method is applied to two specific models and the interaction between the diffusion and the delays is treated in detail. The destabilization of the steadystate and the bifurcation of oscillatory solutions are studied as functions of the diffusivities and the delays. The limits of very small and very large diffusivities are analyzed and comparisons with well-mixed compartment models are made.On leave from North Carolina State University     

Variation in breeding parameters of Eleonora’s falcon (Falco eleonorae) and factors affecting its reproductive performance

We gathered data for a four-year period (2004?C2007) on the nesting ecology and reproductive performance of Eleonora??s falcon in the Aegean Sea. We investigated in an indirect way the relation between clutch size and pre-laying food availability, the significance of site and pair quality on productivity, and the effects of habitat and intraspecific competition on breeding success. Overall, the species selected nest sites sheltered from sun exposure but not from the prevailing wind. Hatching, fledging, and breeding success rates were estimated at 64, 72%, and 60%, respectively. Fledglings per breeding pair ranged from 1.19 to 1.75, and fledglings per successful pair from 1.84 to 2.0, between the years. Productivity depended on parental care rather than nest-site quality. Breeding parameters varied significantly between the years, exhibiting a strong spatial yet local effect. Low success rates were recorded in specific colonies, which were attributed to adverse weather conditions and habitat degradation. Insect food availability prior to egg-laying, estimated via plant biomass, was positively correlated to clutch size. Meanwhile, low wind strengths in August, large distances from the mainland, and population size in the vicinity of the colonies had negative effects on breeding success. Considering data at the Mediterranean scale, a longitudinal trend is observed across the breeding range of this species, with breeding parameters slightly decreasing from west to east.