Miracle-dz/UniFAR-FTUs huggingface dataset:
An Evidence-Based Model Comparing the Cost-effectiveness of Platelet-Rich Plasma Gel to Alternative Therapies for Patients with Nonhealing Diabetic Foot Ulcers

OBJECTIVE: A cost-effectiveness analysis compared the potential economic benefit of an autologous, platelet-rich plasma (PRP) gel to alternative therapies in treating nonhealing diabetic foot ulcers. DESIGN: An economic model used peer-reviewed data to simulate clinical and cost outcomes and quality-adjusted life-years (QALYs) associated with PRP gel and other treatment modalities. PATIENTS: The model varies rates of healing, recurrence, infection, amputation, death, and associated costs for a hypothetical group of 200,000 patients with full-thickness, nonhealing diabetic foot ulcers for 5 years or until death. MAIN OUTCOME MEASURES: The model simulates the clinical, cost, and QALY outcomes associated with PRP gel versus other modalities in treating nonhealing diabetic foot ulcers over a 5-year period. MAIN RESULTS: The average 5-year direct wound care cost per modality and QALYs were PRP gel, $15,159 (2.87); saline gel, $33,214 (2.70); standard of care, $40,073 (2.65); noncontact kilohertz ultrasound therapy, $32,659 (2.73); human fibroblast-derived dermal substitute, $40,569 (2.65); allogenic bilayered culture skin substitute, $24,374 (2.79); bilayered cellular matrix, $37,340 (2.71); negative pressure wound therapy, $20,964 (2.81); and recombinant human platelet-derived growth factor BB, $47,252 (2.69). CONCLUSION: Use of PRP gel resulted in improved quality of life and lower cost of care over a 5-year period than other treatment modalities for nonhealing diabetic foot ulcers. Although actual treatment outcomes may differ from those modeled, PRP gel represents a potentially attractive treatment alternative for insurers and health care providers to address the cost burden and health effects of nonhealing diabetic foot ulcers.
Identification of Disease Specific Pathways Using in Vivo SILAC Proteomics in Dystrophin Deficient mdx Mouse*

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder caused by a mutation in the dystrophin gene. DMD is characterized by progressive weakness of skeletal, cardiac, and respiratory muscles. The molecular mechanisms underlying dystrophy-associated muscle weakness and damage are not well understood. Quantitative proteomics techniques could help to identify disease-specific pathways. Recent advances in the in vivo labeling strategies such as stable isotope labeling in mouse (SILAC mouse) with 13C6-lysine or stable isotope labeling in mammals (SILAM) with 15N have enabled accurate quantitative analysis of the proteomes of whole organs and tissues as a function of disease. Here we describe the use of the SILAC mouse strategy to define the underlying pathological mechanisms in dystrophin-deficient skeletal muscle. Differential SILAC proteome profiling was performed on the gastrocnemius muscles of 3-week-old (early stage) dystrophin-deficient mdx mice and wild-type (normal) mice. The generated data were further confirmed in an independent set of mdx and normal mice using a SILAC spike-in strategy. A total of 789 proteins were quantified; of these, 73 were found to be significantly altered between mdx and normal mice (p < 0.05). Bioinformatics analyses using Ingenuity Pathway software established that the integrin-linked kinase pathway, actin cytoskeleton signaling, mitochondrial energy metabolism, and calcium homeostasis are the pathways initially affected in dystrophin-deficient muscle at early stages of pathogenesis. The key proteins involved in these pathways were validated by means of immunoblotting and immunohistochemistry in independent sets of mdx mice and in human DMD muscle biopsies. The specific involvement of these molecular networks early in dystrophic pathology makes them potential therapeutic targets. In sum, our findings indicate that SILAC mouse strategy has uncovered previously unidentified pathological pathways in mouse models of human skeletal muscle disease.
Multimolecular Analysis of Stable Immunological Synapses Reveals Sustained Recruitment and Sequential Assembly of Signaling Clusters*

The formation of the immunological synapse between T cells and antigen-presenting cells (APC) begins within minutes of contact and can take hours for full T-cell activation. Although early phases of the synapse have been extensively studied for a select number of proteins, later phases have not yet been examined in detail. We studied the signaling network in stable synapses by measuring the simultaneous localization of 25 signaling and structural molecules over 2 h at the level of individual synapses using multi-epitope ligand cartography (MELC). Signaling proteins including phospho(p)ZAP70, pSLP76, pCD3ζ, and pLAT, along with proteins that influence synapse structure such as F-actin, tubulin, CD45, and ICAM-1, were localized in images of synapses and revealed the multidimensional construction of a mature synapse. The construction of the stable synapse included intense early TCR signaling, a phase of recruitment of structural proteins, and a sustained increase in signaling molecules and colocalization of TCR and pLAT signaling clusters in the center of the synapse. Consolidation of TCR and associated proteins resulted in formation of a small number of discrete synaptic microclusters. Development of synapses and cSMAC composition was greatly affected by the absence of Vav1, with an associated loss in PLCγ1 recruitment, pSLP76, and increased CXCR4. Together, these data demonstrate the use of multi-epitope ligand cartography to quantitatively analyze synapse formation and reveal successive recruitment of structural and signaling proteins and sustained phosphorylation at the mature synapse.
Nepenthesin from Monkey Cups for Hydrogen/Deuterium Exchange Mass Spectrometry*

Studies of protein dynamics, structure and interactions using hydrogen/deuterium exchange mass spectrometry (HDX-MS) have sharply increased over the past 5–10 years. The predominant technology requires fast digestion at pH 2–3 to retain deuterium label. Pepsin is used almost exclusively, but it provides relatively low efficiency under the constraints of the experiment, and a selectivity profile that renders poor coverage of intrinsically disordered regions. In this study we present nepenthesin-containing secretions of the pitcher plant Nepenthes, commonly called monkey cups, for use in HDX-MS. We show that nepenthesin is at least 1400-fold more efficient than pepsin under HDX-competent conditions, with a selectivity profile that mimics pepsin in part, but also includes efficient cleavage C-terminal to “forbidden” residues K, R, H, and P. High efficiency permits a solution-based analysis with no detectable autolysis, avoiding the complication of immobilized enzyme reactors. Relaxed selectivity promotes high coverage of disordered regions and the ability to “tune” the mass map for regions of interest. Nepenthesin-enriched secretions were applied to an analysis of protein complexes in the nonhomologous end-joining DNA repair pathway. The analysis of XRCC4 binding to the BRCT domains of Ligase IV points to secondary interactions between the disordered C-terminal tail of XRCC4 and remote regions of the BRCT domains, which could only be identified with a nepenthesin-based workflow. HDX data suggest that stalk-binding to XRCC4 primes a BRCT conformation in these remote regions to support tail interaction, an event which may be phosphoregulated. We conclude that nepenthesin is an effective alternative to pepsin for all HDX-MS applications, and especially for the analysis of structural transitions among intrinsically disordered proteins and their binding partners.
Plasma Membrane Proteomics of Tumor Spheres Identify CD166 as a Novel Marker for Cancer Stem-like Cells in Head and Neck Squamous Cell Carcinoma*

Patients with advanced head and neck squamous cell carcinoma (HNSCC) have a poor prognosis with the currently available therapy, and tumor recurrence is frequently observed. The discovery of specific membrane-associated cancer stem cell (CSC) markers is crucial for the development of novel therapeutic strategies to target these CSCs. To address this issue, we established sphere cultures to enrich CSCs and used them for plasma membrane proteomics to identify specific membrane signatures of the HNSCC spheres. Of a dataset that included a total of 376 identified proteins, 200 were bona fide membrane proteins. Among them, 123 proteins were at least 1.5-fold up- or down-regulated in the spheres relative to the adherent cultures. These proteins included cell adhesion molecules, receptors, and transporter proteins. Some of them play key roles in wnt, integrin, and TGFβ signaling pathways. When we compared our dataset with two published hESC membrane protein signatures, we found 18 proteins common to all three of the databases. CD166 and CD44 were two such proteins. Interestingly, the expression of CD166, rather than that of the well-established HNSCC CSC marker CD44, was significantly related to the malignant behavior of HNSCC. Relative to CD166low HNSCC cells, CD166high HNSCC cells had a greater sphere-formation ability in vitro and tumor formation ability in vivo. Patients whose tumors expressed high levels of CD166 had a significantly poorer clinical outcome than those whose tumors expressed low levels of CD166 (cohort 1: 96 cases, p = 0.040), whereas the level of CD44 expression had only a marginal influence on the clinical outcome of patients with HNSCC (p = 0.078). The level of CD166 expression in HNSCC tumors was also associated with the tumor recurrence rate (cohort 2: 104 cases, p = 0.016). This study demonstrates that CD166 is a valuable cell surface marker for the enrichment of HNSCC stem cells and that plasma membrane proteomics is a promising biological tool for investigating the membrane proteins of CSCs.
Hidroxiuréia em pacientes com síndromes falciformes acompanhados no Hospital Hemope, Recife, Brasil

O uso de hidroxiureia promove a elevacao dos niveis de hemoglobina fetal (Hb F) em pacientes portadores de sindromes falciformes (SF) e o medicamento vem sendo estudado em varios grupos de pacientes, incluindo adultos e criancas. O presente trabalho analisou a eficacia e tolerabilidade do uso de hidroxiureia em criancas na faixa etaria entre 5 e 17 anos de idade e em adultos jovens acima de 18 anos, portadores de hemoglobinopatia SS ou Sb0 que foram acompanhados regularmente no ambulatorio do Hospital Hemope. Os pacientes pediatricos foram tratados com dose inicial de hidroxiureia de 10 mg/kg/dia, a qual era aumentada em 5 mg/kg por dia em intervalos de oito semanas, ate a dose maxima de 25 mg/kg/dia. Para os adultos, o tratamento foi iniciado com 500 mg/dia de hidroxiureia ate a dose maxima de 1g/dia. Foi observada reducao do numero de crises algicas assim como do numero de internacoes hospitalares, elevacao do nivel de Hb F e do Volume Corpuscular Medio, no grupo pediatrico. Entre os pacientes maiores de 18 anos, tambem se observou melhora clinica e significância estatistica com aumento dos valores da hemoglobina e reducao dos valores de reticulocitos, leucocitos e plaquetas. Nao foram observados sinais ou sintomas sugestivos de toxicidade medicamentosa em ambos os grupos. O uso de hidroxiureia em todos os pacientes parece ser seguro e eficaz e assegura melhora da qualidade de vida e beneficios a seus familiares. Ademais, as doses preconizadas de hidroxiureia aparentemente nao foram mielotoxicas, nao tendo sido necessaria a suspensao do tratamento em nenhum dos pacientes.
Maximizing Peptide Identification Events in Proteomic Workflows Using Data-Dependent Acquisition (DDA)*

Current analytical strategies for collecting proteomic data using data-dependent acquisition (DDA) are limited by the low analytical reproducibility of the method. Proteomic discovery efforts that exploit the benefits of DDA, such as providing peptide sequence information, but that enable improved analytical reproducibility, represent an ideal scenario for maximizing measureable peptide identifications in “shotgun”-type proteomic studies. Therefore, we propose an analytical workflow combining DDA with retention time aligned extracted ion chromatogram (XIC) areas obtained from high mass accuracy MS1 data acquired in parallel. We applied this workflow to the analyses of sample matrixes prepared from mouse blood plasma and brain tissues and observed increases in peptide detection of up to 30.5% due to the comparison of peptide MS1 XIC areas following retention time alignment of co-identified peptides. Furthermore, we show that the approach is quantitative using peptide standards diluted into a complex matrix. These data revealed that peptide MS1 XIC areas provide linear response of over three orders of magnitude down to low femtomole (fmol) levels. These findings argue that augmenting “shotgun” proteomic workflows with retention time alignment of peptide identifications and comparative analyses of corresponding peptide MS1 XIC areas improve the analytical performance of global proteomic discovery methods using DDA.
Profile of inmates of a special school for the mentally ill and disabled in Kancheepuram district, Tamil Nadu: An institution based cross-sectional study

Context : The health care and social welfare needs of persons with mental illness and differently abled persons should not be ignored. Aim: The aim of the study is to assess the socio-demographic and morbidity profiles of the inmates in the special school and to explore the reasons that have contributed to their admission in the school. Materials and Methods: A cross-sectional descriptive study of six months duration (September 2013 to February 2014) was conducted in a special school for mentally ill and differently abled people of Kanchipuram district in Tamilnadu. All the inmates staying in the school during the study period were included as study participants. The socio-demographic profile of the inmates was obtained with the help of caretaker/family members/records maintained by the center while their morbidity profile was explored with the help of specialists from different departments. Statistical analysis was done using SPSS version 18 and the frequency distributions and percentages were calculated for all the variables. Results: Most of the study participants, 31 (56.4%) were from the 40-60 years age group. Overall, 51 (92.7%) inmates were suffering from some type of mental disorders with/without multiple disabilities while 4 (7.2%) inmates were enrolled in the special school because of their old age. The unwillingness of the family members to take care of the affected person was cited as the most common cause in 32 (58.1%) of the inmates for enrolling in the special school. Conclusion: Most of the inmates of the special school were suffering from mental illnesses with/without multiple disabilities. A definite improvement in the quality of life of inmates has been observed after the extension of healthcare services by the medical college.
Profiling of the Chromatin-associated Proteome Identifies HP1BP3 as a Novel Regulator of Cell Cycle Progression *

The chromatin-associated proteome (chromatome) regulates cellular gene expression by restricting access of transcriptional machinery to template DNA, and dynamic re-modeling of chromatin structure is required to regulate critical cell functions including growth and replication, DNA repair and recombination, and oncogenic transformation in progression to cancer. Central to the control of these processes is efficient regulation of the host cell cycle, which is maintained by rapid changes in chromatin conformation during normal cycle progression. A global overview of chromatin protein organization is therefore essential to fully understand cell cycle regulation, but the influence of the chromatome and chromatin binding topology on host cell cycle progression remains poorly defined. Here we used partial MNase digestion together with iTRAQ-based high-throughput quantitative proteomics to quantify chromatin-associated proteins during interphase progression. We identified a total of 481 proteins with high confidence that were involved in chromatin-dependent events including transcriptional regulation, chromatin re-organization, and DNA replication and repair, whereas the quantitative data revealed the temporal interactions of these proteins with chromatin during interphase progression. When combined with biochemical and functional assays, these data revealed a strikingly dynamic association of protein HP1BP3 with the chromatin complex during different stages of interphase, and uncovered a novel regulatory role for this molecule in transcriptional regulation. We report that HP1BP3 protein maintains heterochromatin integrity during G1–S progression and regulates the duration of G1 phase to critically influence cell proliferative capacity.
A Protein Profile of Visceral Adipose Tissues Linked to Early Pathogenesis of Type 2 Diabetes Mellitus*

Adipose tissue is increasingly recognized as an endocrine organ playing important pathophysiological roles in metabolic abnormalities, such as obesity, cardiovascular disease, and type 2 diabetes mellitus (T2DM). In particular, visceral adipose tissue (VAT), as opposed to subcutaneous adipose tissue, is closely linked to the pathogenesis of insulin resistance and T2DM. Despite the importance of VAT, its molecular signatures related to the pathogenesis of T2DM have not been systematically explored. Here, we present comprehensive proteomic analysis of VATs in drug-naïve early T2DM patients and subjects with normal glucose tolerance. A total of 4,707 proteins were identified in LC-MS/MS experiments. Among them, 444 increased in abundance in T2DM and 328 decreased. They are involved in T2DM-related processes including inflammatory responses, peroxisome proliferator-activated receptor signaling, oxidative phosphorylation, fatty acid oxidation, and glucose metabolism. Of these proteins, we selected 11 VAT proteins that can represent alteration in early T2DM patients. Among them, up-regulation of FABP4, C1QA, S100A8, and SORBS1 and down-regulation of ACADL and PLIN4 were confirmed in VAT samples of independent early T2DM patients using Western blot. In summary, our profiling provided a comprehensive basis for understanding the link of a protein profile of VAT to early pathogenesis of T2DM.
Eating behaviors and nutritional status according to the purpose of exercise

The aim of this study was to investigate the eating behavior and nutritional status of subjects according to their purpose of exercise. A total of 214 subjects, 20 to 30 years of age, who visited fitness centers in Seoul were enrolled. Anthropometrics, exercise habits, nutritional knowledge, and eating behaviors were analyzed using a questionnaire. Nutritional status was assessed by serial 24 h recalls. The subjects were divided into two groups based on their purpose of exercise: increasing muscle (Muscle growth, n
The Market For Infectious Diseases Specialists

The emergence of managed care and health care reform has raised questions as to the need for infectious diseases specialists. To ascertain the need for infectious diseases specialists, regular advertisements for subspecialty physicians in the New England Journal of Medicine were counted for the last 22 years and the Annuals of Internal Medicine for the last 10 years. For infectious diseases specialists, there are now over 150 advertisements per year. Approximately 15% of those are for academic or research positions. The relative market value index for infectious diseases specialists (ratio of advertisements per year per graduating fellows) is lower than for hematology/oncologists but comparable with or greater than for rheumatologists and endocrinologists. Judging from the market place of medical journal job advertisements, there are a growing number of jobs available for physicians with training in infectious diseases with the apparent opportunities in private practice more than in academic medicine or research.
Therapeutic Residential Care for Children and Youth: Developing Evidence-Based International Practice

The authors of this edited book ‘believe that properly designed and monitored Therapeutic Residential Care represents one critical form of specialized mental health treatment’ to be located in a broader array of child and family services’ (p.25). To make this a reality, this book shows the need for providers/ practitioners to deploy multiple evidence-based interventions; whether for a specific or milieu setting, there needs to be diagnostic-specific, efficacious interventions enabling the right placement for the right child the first time he or she requires substitute care.
Generating and trapping metalla-N-heterocyclic carbenes.

By means of a combined experimental and theoretical approach, the electronic features and chemical behavior of metalla-N-heterocyclic carbenes (MNHCs, N-heterocyclic carbenes containing a metal atom within the heterocyclic skeleton) have been established and compared with those of classical NHCs. MNHCs are strongly basic (proton affinity and pK(a) values around 290 kcal mol(-1) and 36, respectively) with a narrow singlet-triplet gap (around 23 kcal mol(-1)). MNHCs can be generated from the corresponding metalla-imidazolium salts and trapped by addition of transition-metal complexes affording the corresponding heterodimetallic dicarbene derivatives, which can serve as carbene transfer agents.
Sagittal Alignment of the Spine and Pelvis in the Presence of L5–S1 Isthmic Lysis and Low-Grade Spondylolisthesis

Study Design. A radiographic study of 82 patients with L5–S1 spondylolysis or spondylolisthesis of less than 50% displacement of L5 on S1. Objective. To measure and describe the sagittal alignment of the spine and pelvis in patients with spondylolysis before the development of a large secondary deformity associated with progression of the spondylolisthesis. Summary of Background Data. Several publications have addressed the alignment of the spine and pelvis as an important factor in the occurrence, symptomatology, progression, and treatment of spondylolysis and spondylolisthesis. To our knowledge, this is the first report to systematically document the native sagittal alignment of affected patients and compare them to a large control population. Materials and Methods. The sagittal alignment in this cohort of 82 patients was compared with a control population of 160 patients without symptoms of back pain or radiographic abnormalities of the spine and pelvis that was the subject of a previous study. Results. Patients with spondylolysis and low-grade spondylolisthesis demonstrate increased pelvic incidence, increased lumbar lordosis, but less segmental extension between L5 and S1 than in a normal population. Conclusions. These data suggest that differences in the sagittal alignment of the spine and pelvis may influence the biomechanical environment that results in the development of spondylolysis and progressive spondylolisthesis.