AIM： To investigate the clinical presentations associated with bile acid synthesis defects and to describe identification of individual disorders and diagnostic pitfalls. METHODS： We describe ...semiquantitative determination of 16 urinary bile acid metabolites by electrospray ionization-tandem mass spectrometry. Sample preparation was performed by solid-phase extraction. The total analysis time was 2 min per sample. We determined bile acid metabolites in 363 patients with suspected defects in bile acid metabolism. RESULTS： Abnormal bile acid metabolites were found in 36 patients. Two patients had bile acid synthesis defects but presented with atypical presentations. In 2 other patients who were later shown to be affected by biliary atresia and cystic fibrosis the profile of bile acid metabolites was initially suggestive of a bile acid synthesis defect. Three adult patients suffered from cerebrotendinous xanthomatosis. Nineteen patients had peroxisomal disorders, and 10 patients had cholestatic hepatopathy of other cause. CONCLUSION： Screening for urinary cholanoids should be done in every infant with cholestatic hepatopathy as well as in children with progressive neurological disease to provide specific therapy.
Compared with Caucasian Americans (CAs), African Americans (AAs) with colorectal cancer have poorer survival, especially younger-age patients. A robust lymphocytic reaction within colorectal cancers ...is strongly associated with better survival, but whether immune response impacts the disparity in colorectal cancer survival is unknown.
The study population was comprised of 211 histologically confirmed colorectal cancers at the Medical University of South Carolina (Charleston, SC; 159 CAs and 52 AAs) diagnosed between Jan 01, 2000, and June 30, 2013. We constructed a lymphocyte score based on blinded pathologic assessment of the four different types of lymphocytic reactions. Cox proportional hazards regression was used to evaluate the association between the lymphocyte score and risk of death by race.
Colorectal cancers in AAs (vs. CAs) had a stronger lymphocytic reaction at diagnosis. A high lymphocyte score (vs. the lowest) was associated with better survival in AAs HR 0.19; 95% confidence interval (CI), 0.04-0.99 and CAs (HR 0.47; 95% CI, 0.15-1.45). AAs with no lymphocytic reaction (vs. other categories) had poor survival HR 4.48 (1.58-12.7) whereas no difference was observed in CAs. The risk of death in AAs (vs. CA) was more pronounced in younger patients (HR 2.92; 95% CI, 1.18-7.22) compared with older (HR 1.20; 95% CI, 0.54-2.67), especially those with lymphocytic poor colorectal cancers.
The lymphocytic reaction in tumor impacted the racial disparity in survival.
Our results confirm the importance of the lymphocytic score on survival and highlight the need to fully characterize the immune environment of colorectal cancers by race.
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Influenza is an important cause of morbidity and mortality for frail older people. Whilst the antiviral drug oseltamivir (a neuraminidase inhibitor) is approved for treatment and prophylaxis of ...influenza during outbreaks, there have been no trials comparing treatment only (T) versus treatment and prophylaxis (T&P) in Aged Care Facilities (ACFs). Our objective was to compare a policy of T versus T&P for influenza outbreaks in ACFs.
We performed a cluster randomised controlled trial in 16 ACFs, that followed a policy of either "T"-oseltamivir treatment (75 mg twice a day for 5 days)-or "T&P"-treatment and prophylaxis (75 mg once a day for 10 days) for influenza outbreaks over three years, in addition to enhanced surveillance. The primary outcome measure was the attack rate of influenza. Secondary outcomes measures were deaths, hospitalisation, pneumonia and adverse events. Laboratory testing was performed to identify the viral cause of influenza-like illness (ILI) outbreaks. The study period 30 June 2006 to 23 December 2008 included three southern hemisphere winters. During that time, influenza was confirmed as the cause of nine of the 23 ILI outbreaks that occurred amongst the 16 ACFs. The policy of T&P resulted in a significant reduction in the influenza attack rate amongst residents: 93/255 (36%) in residents in T facilities versus 91/397 (23%) in T&P facilities (p=0.002). We observed a non-significant reduction in staff: 46/216 (21%) in T facilities versus 47/350 (13%) in T&P facilities (p=0.5). There was a significant reduction in mean duration of outbreaks (T=24 days, T&P=11 days, p=0.04). Deaths, hospitalisations and pneumonia were non-significantly reduced in the T&P allocated facilities. Drug adverse events were common but tolerated.
Our trial lacked power but these results provide some support for a policy of "treatment and prophylaxis" with oseltamivir in controlling influenza outbreaks in ACFs.
corrected Australian Clinical Trials Registry ACTRN12606000278538.
Proteins adsorbed at fluid/fluid interfaces influence many phenomena: food emulsion and foam stability (Murray et al. Langmuir 2002, 18, 9476 and Borbas et al. Colloids Surf., A 2003, 213, 93), ...two-phase enzyme catalysis (Cascao-Pereira et al. Biotechnol. Bioeng. 2003, 83, 498; 2002, 78, 595), human lung function (Lunkenheimer et al. Colloids Surf., A 1996, 114, 199; Wustneck et al.; and Banerjee et al. 2000, 15, 14), and cell membrane mechanical properties (Mohandas et al. 1994, 23, 787). Time scales important to these phenomena are broad, necessitating an understanding of the dynamics of biological macromolecules at interfaces. We utilize interfacial shear and dilatational deformations to study the rheology of a globular protein, lysozyme, and a disordered protein, beta-casein, at the hexadecane/water interface. Linear viscoelastic properties are measured using small amplitude oscillatory flow, stress relaxation after a sudden dilatational displacement, and shear creep response to probe the rheological response over broad experimental time scales. Our studies of lysozyme and beta-casein reveal that the interfacial dissipation mechanisms are strongly coupled to changes in the protein structure upon and after adsorption. For beta-casein, the interfacial response is fluidlike in shear deformation and is dominated by interfacial viscous dissipation, particularly at low frequencies. Conversely, the dilatational response of beta-casein is dominated by diffusion dissipation at low frequencies and viscous dissipation at higher frequencies (i.e., when the experimental time scale is faster than the characteristic time for diffusion). For lysozyme in shear deformation, the adsorbed protein layer is primarily elastic with only a weak frequency dependence. Similarly, the interfacial dilatational moduli change very little with frequency. In comparison to beta-casein, the frequency response of lysozyme does not change substantially after washing the protein from the bulk solution. Apparently, it is the irreversibly adsorbed fraction that dominates the dynamic rheological response for lysozyme. Using stress relaxation after a sudden dilatational displacement and shear creep response, the characteristic time of relaxation was found to be 1000 s in both modes of deformation. The very long relaxation time for lysozyme likely results from the formation of a glassy interfacial network. This network develops at high interfacial concentrations where the molecules are highly constrained because of conformation changes that prevent desorption.
Immobilization of proteins and enzymes on solid supports has been utilized in a variety of applications, from improved protein stability on supported catalysts in industrial processes to fabrication ...of biosensors, biochips, and microdevices. A critical requirement for these applications is facile yet stable covalent conjugation between the immobilized and fully active protein and the solid support to produce stable, highly bio-active conjugates. Here, we report functionalization of solid surfaces (gold nanoparticles and magnetic beads) with bio-active proteins using site-specific and biorthogonal labeling and azide-alkyne cycloaddition, a click chemistry. Specifically, we recombinantly express and selectively label calcium-dependent proteins, calmodulin and calcineurin, and cAMP-dependent protein kinase A (PKA) with N-terminal azide-tags for efficient conjugation to nanoparticles and magnetic beads. We successfully immobilized the proteins on to the solid supports directly from the cell lysate with click chemistry, forgoing the step of purification. This approach is optimized to yield low particle aggregation and high levels of protein activity post-conjugation. The entire process enables streamlined workflows for bioconjugation and highly active conjugated proteins.
Graphical Abstract
This work analyzes the overall computational complexity of the stochastic Galerkin finite element method (SGFEM) for approximating the solution of parameterized elliptic partial differential ...equations with both affine and non-affine random coefficients. To compute the fully discrete solution, such approaches employ a Galerkin projection in both the deterministic and stochastic domains, produced here by a combination of finite elements and a global orthogonal basis, defined on an isotopic total degree index set, respectively. To account for the sparsity of the resulting system, we present a rigorous cost analysis that considers the total number of coupled finite element systems that must be simultaneously solved in the SGFEM. However, to maintain sparsity as the coefficient becomes increasingly nonlinear in the parameterization, it is necessary to also approximate the coefficient by an additional orthogonal expansion. In this case we prove a rigorous complexity estimate for the number of floating point operations (FLOPs) required per matrix–vector multiplication of the coupled system. Based on such complexity estimates we also develop explicit cost bounds in terms of FLOPs to solve the stochastic Galerkin (SG) systems to a prescribed tolerance, which are used to compare with the minimal complexity estimates of a stochastic collocation finite element method (SCFEM), shown in our previous work (Galindo et al., 2015). Finally, computational evidence complements the theoretical estimates and supports our conclusion that, in the case that the coefficient is affine, the coupled SG system can be solved more efficiently than the decoupled SC systems. However, as the coefficient becomes more nonlinear, it becomes prohibitively expensive to obtain an approximation with the SGFEM.
Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe ...clinically diagnosed Coffin-Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting.
Clinicians entered clinical data in an extensive web-based survey.
79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified.
There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.
Background/aim: It has been suggested that sun exposure may be a risk factor for age related macular degeneration (AMD) and that skin sensitivity to sunlight and iris colour could be confounding ...factors. The aim was to investigate this further in the white population. Methods: 446 cases with end stage AMD were compared with 283 spouse controls. Data on sun exposure, places of residence, iris colour, subjective assessment of change in iris colour, hair colour at age 20, and skin sensitivity were obtained using a questionnaire. Iris colour was graded clinically by comparison with standard photographs. AMD was graded using stereoscopic colour fundus photographs as well as clinical examination and was defined as the presence of geographic atrophy or choroidal neovascularisation. All variables were included in a multiple logistic regression model including age, sex, and smoking. Results: There was no association between AMD and sun exposure or related factors except for the suggestion of an association between sunburn prone skin type and geographic atrophy which reached borderline significance. Conclusions: No significant association between AMD and sun exposure, iris colour, change in iris colour, or hair colour was demonstrated.
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