Physical Therapy Intervention for Individuals with Rett Syndrome

Individuals with Rett syndrome (RS) present a vast array of orthopedic and neurological difficulties. Typical problems, which may need to be addressed, when treating this population are functional limitations, low cardiovascular capacity, hypotonia, ataxia, apraxia, loss of transitional movements, spasticity, scoliosis and/or kyphosis, loss of ambulation, loss of hand function, foot deformities, and spatial disorientation. Coping with such difficulties and overcoming the associated limitations carry a wearisome task for the individual with Rett as well as for her family. An informed and intensely applied physical therapy regime can help the child and the family cope and even overcome the above-mentioned limitations. The present article presents some insights regarding the intervention with individuals with RS, an overview of typical neuromuscular problems associated with RS, and appropriate suggestions pertaining to clinical intervention that have been found to contribute to this populations well-being. The information presented is mainly based on the clinical knowledge of the authors

Matched-pair analysis of hematopoietic progenitor cell mobilization using G-CSF vs. cyclophosphamide, etoposide, and G-CSF: Enhanced CD34+ cell collections are not necessarily cost-effective

AbstractUsing matched-pair analysis, we compared two popular methods of stem cell mobilization in 24 advanced-stage breast cancer patients who underwent two consecutive mobilizing procedures as part of a tandem transplant protocol. For the first cycle, 10 microg/kg/day granulocyte colony-stimulating factor (G-CSF) was given and apheresis commenced on day 4 and continued for < or =5 days (median 3 days). One week after the first cycle of apheresis, 4000 mg/m2 cyclophosphamide, 400 mg/m2 etoposide, and 10 microg/kg G-CSF were administered for < or =16 days (cycle 2). Apheresis was initiated when the white blood cell (WBC) count exceeded 5000 cells/microL and continued for < or =5 days (median 3 days). Mean values of peripheral blood WBC (31,700+/-3200 vs. 30,700+/-3300/microL) were not significantly different between cycles 1 and 2. Mean number of mononuclear cells (MNC) collected per day was slightly greater with G-CSF mobilization than with the combination of chemotherapy and G-CSF (2.5+/-0.21x10(8) vs. 1.8+/-0.19x10(8) cells/kg). Mean daily CD34+ cell yield, however, was nearly six times higher (12.9+/-4.4 vs. 2.2+/-0.5x10(6)/kg; p = 0.01) with chemotherapy plus G-CSF. With G-CSF alone, 13% of aphereses reached the target dose of 5x10(6) CD34+ cells/kg in one collection vs. 57% with chemotherapy plus G-CSF. Transfusions of red blood cells or platelets were necessary in 18 of 24 patients in cycle 2. Three patients were hospitalized with fever for a median of 3 days after cycle 2. No patients received transfusions or required hospitalization during mobilization with G-CSF alone. Resource utilization (cost of drugs, aphereses, cryopreservation, transfusions, hospitalization) was calculated comparing the median number of collections to obtain a target CD34+ cell dose of 5x10(6) cells/kg: four using G-CSF vs. one using the combination in this data set. Resources for G-CSF mobilization cost $7326 vs.$8693 for the combination, even though more apheresis procedures were performed using G-CSF mobilization. The cost of chemotherapy administration, more doses of G-CSF, transfusions, and hospitalizations caused cyclophosphamide, etoposide, and G-CSF to be more expensive than G-CSF alone. A less toxic and less expensive treatment than cyclophosphamide, etoposide, and G-CSF is needed to be more cost-effective than G-CSF alone for peripheral blood progenitor cell mobilization.Biol Blood Marrow Transplant 1999;5(6):379-85

On-road emissions of ammonia: An underappreciated source of atmospheric nitrogen deposition

We provide updated spatial distribution and inventory data for on-road NH3 emissions for the continental United States (U.S.) On-road NH3 emissions were determined from on-road CO2 emissions data and empirical NH3:CO2 vehicle emissions ratios. Emissions of NH3 from on-road sources in urbanized regions are typically 0.1– 1.3 t km−2 yr−1 while NH3 emissions in agricultural regions generally range from 0.4–5.5 t km−2 yr−1, with a few hot spots as high as 5.5–11.2 t km−2 yr−1. Counties with higher vehicle NH3 emissions than from agriculture include 40% of the U.S. population. The amount of wet inorganic N deposition as NH4+ from the National Atmospheric Deposition Program (NADP) network ranged from 37 to 83% with a mean of 58.7%. Only 4% of the NADP sites across the U.S. had \u3c45% of the N deposition as NH4+ based on data from 2014 to 2016, illustrating the near-universal elevated proportions of NH4+ in deposition across the U.S. Case studies of on-road NH3 emissions in relation to N deposition include four urban sites in Oregon and Washington where the average NH4- N:NO3-N ratio in bulk deposition was 2.3. At urban sites in the greater Los Angeles Basin, bulk deposition of NH4-N and NO3-N were equivalent, while NH4-N:NO3-N in throughfall under shrubs ranged from 0.6 to 1.7. The NH4-N:NO3-N ratio at 7–10 sites in the Lake Tahoe Basin averaged 1.4 and 1.6 in bulk deposition and throughfall, and deposition of NH4-N was strongly correlated with summertime NH3 concentrations. On-road emissions of NH3 should not be ignored as an important source of atmospheric NH3, as a major contributor to particulate air pollution, and as a driver of N deposition in urban and urban-affected regions

Identifying Critical Non-Catalytic Residues that Modulate Protein Kinase A Activity

Distal interactions between discrete elements of an enzyme are critical for communication and ultimately for regulation. However, identifying the components of such interactions has remained elusive due to the delicate nature of these contacts. Protein kinases are a prime example of an enzyme with multiple regulatory sites that are spatially separate, yet communicate extensively for tight regulation of activity. Kinase misregulation has been directly linked to a variety of cancers, underscoring the necessity for understanding intramolecular kinase regulation.A genetic screen was developed to identify suppressor mutations that restored catalytic activity in vivo from two kinase-dead Protein Kinase A mutants in S. cerevisiae. The residues defined by the suppressors provide new insights into kinase regulation. Many of the acquired mutations were distal to the nucleotide binding pocket, highlighting the relationship of spatially dispersed residues in regulation.The suppressor residues provide new insights into kinase regulation, including allosteric effects on catalytic elements and altered protein-protein interactions. The suppressor mutations identified in this study also share overlap with mutations identified from an identical screen in the yeast PKA homolog Tpk2, demonstrating functional conservation for some residues. Some mutations were independently isolated several times at the same sites. These sites are in agreement with sites previously identified from multiple cancer data sets as areas where acquired somatic mutations led to cancer progression and drug resistance. This method provides a valuable tool for identifying residues involved in kinase activity and for studying kinase misregulation in disease states

Structural and Functional Diversity of the Microbial Kinome

The eukaryotic protein kinase (ePK) domain mediates the majority of signaling and coordination of complex events in eukaryotes. By contrast, most bacterial signaling is thought to occur through structurally unrelated histidine kinases, though some ePK-like kinases (ELKs) and small molecule kinases are known in bacteria. Our analysis of the Global Ocean Sampling (GOS) dataset reveals that ELKs are as prevalent as histidine kinases and may play an equally important role in prokaryotic behavior. By combining GOS and public databases, we show that the ePK is just one subset of a diverse superfamily of enzymes built on a common protein kinase–like (PKL) fold. We explored this huge phylogenetic and functional space to cast light on the ancient evolution of this superfamily, its mechanistic core, and the structural basis for its observed diversity. We cataloged 27,677 ePKs and 18,699 ELKs, and classified them into 20 highly distinct families whose known members suggest regulatory functions. GOS data more than tripled the count of ELK sequences and enabled the discovery of novel families and classification and analysis of all ELKs. Comparison between and within families revealed ten key residues that are highly conserved across families. However, all but one of the ten residues has been eliminated in one family or another, indicating great functional plasticity. We show that loss of a catalytic lysine in two families is compensated by distinct mechanisms both involving other key motifs. This diverse superfamily serves as a model for further structural and functional analysis of enzyme evolution

Integrating transcriptomics, metabolomics, and GWAS helps reveal molecular mechanisms for metabolite levels and disease risk

Transcriptomics data have been integrated with genome-wide association studies (GWASs) to help understand disease/trait molecular mechanisms. The utility of metabolomics, integrated with transcriptomics and disease GWASs, to understand molecular mechanisms for metabolite levels or diseases has not been thoroughly evaluated. We performed probabilistic transcriptome-wide association and locus-level colocalization analyses to integrate transcriptomics results for 49 tissues in 706 individuals from the GTEx project, metabolomics results for 1,391 plasma metabolites in 6,136 Finnish men from the METSIM study, and GWAS results for 2,861 disease traits in 260,405 Finnish individuals from the FinnGen study. We found that genetic variants that regulate metabolite levels were more likely to influence gene expression and disease risk compared to the ones that do not. Integrating transcriptomics with metabolomics results prioritized 397 genes for 521 metabolites, including 496 previously identified gene-metabolite pairs with strong functional connections and suggested 33.3% of such gene-metabolite pairs shared the same causal variants with genetic associations of gene expression. Integrating transcriptomics and metabolomics individually with FinnGen GWAS results identified 1,597 genes for 790 disease traits. Integrating transcriptomics and metabolomics jointly with FinnGen GWAS results helped pinpoint metabolic pathways from genes to diseases. We identified putative causal effects of UGT1A1/UGT1A4 expression on gallbladder disorders through regulating plasma (E,E)-bilirubin levels, of SLC22A5 expression on nasal polyps and plasma carnitine levels through distinct pathways, and of LIPC expression on age-related macular degeneration through glycerophospholipid metabolic pathways. Our study highlights the power of integrating multiple sets of molecular traits and GWAS results to deepen understanding of disease pathophysiology.Peer reviewe

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects