Degree of improving TMS focality through a geometrically stable solution of an inverse TMS problem.

The Transcranial Magnetic Stimulation (TMS) inverse problem (TMS-IP) investigated in this study aims to focus the TMS induced electric field close to a specified target point defined on the gray matter interface in the M1HAND area while otherwise minimizing it. The goal of the study is to numerically evaluate the degree of improvement of the TMS-IP solutions relative to the well-known sulcus-aligned mapping (a projection approach with the 90∘ local sulcal angle). In total, 1536 individual TMS-IP solutions have been analyzed for multiple target points and multiple subjects using the boundary element fast multipole method (BEM-FMM) as the forward solver. Our results show that the optimal TMS inverse-problem solutions improve the focality - reduce the size of the field "hot spot" and its deviation from the target - by approximately 21-33% on average for all considered subjects, all observation points, two distinct coil types, two segmentation types, two intracortical observation surfaces under study, and three tested values of the field threshold. The inverse-problem solutions with the maximized focality simultaneously improve the TMS mapping resolution (differentiation between neighbor targets separated by approximately 10 mm) although this improvement is quite modest. Coil position/orientation and conductivity uncertainties have been included into consideration as the corresponding de-focalization factors. The present results will change when the levels of uncertainties change. Our results also indicate that the accuracy of the head segmentation critically influences the expected TMS-IP performance.

Evaluation of unfractionated heparin versus low-molecular-weight heparin and fondaparinux for pharmacologic venous thromboembolic prophylaxis in critically ill patients with cancer.

Essentials Critically ill cancer patients require pharmacologic prophylaxis for venous thromboembolism (VTE). Patients from 566 hospitals in the United States between 2010 and 2014 were included. Low-molecular-weight heparin (LMWH) prophylaxis was not associated in a reduction of VTE rates. LMWH prophylaxis was associated with a reduction in bleeding and heparin induced thrombocytopenia. SUMMARY: Background Critically ill patients with cancer are at increased risk of venous thromboembolism (VTE) from physical and cellular factors, requiring pharmacologic prophylaxis to reduce the risk of VTE. Objectives To assess whether low-molecular-weight heparin (LMWH) prophylaxis reduces in-hospital rates of VTE or improves clinical outcomes compared with unfractionated heparin (UFH) prophylaxis in critically ill patients with cancer. Methods We used a propensity-matched comparative-effectiveness cohort from the Premier Database. Patients aged 18 years or older with a primary diagnosis of cancer, intensive care unit admission and VTE prophylaxis within 2 days of admission between 1 January 2010 and 31 December 2014 were included. Patients were divided into LMWH or UFH prophylaxis groups. Results A total of 103 798 patients were included; 75 321 (72.6%) patients received LMWH and 28 477 (27.4%) patients received UFH. Propensity analysis matched (2 : 1) 42 343 LMWH patients and 21 218 UFH patients. Overall, LMWH was not associated with a decreased incidence of VTE (5.32% vs. 5.50%). LMWH prophylaxis was associated with a reduction in pulmonary embolism (0.70% vs. 0.99%), significant bleeding (13.3% vs. 14.8%) and heparin-induced thrombocytopenia (HIT) (0.06% vs. 0.19%). In non-metastatic solid disease, LMWH was associated with decreased VTE (4.27% vs. 4.84%) and PE (0.47% vs. 0.95%). Conclusions The use of an LMWH for VTE prophylaxis was not associated with a reduction in the incidence of in-hospital VTE as compared with UFH, but was associated with significant reductions in PE, clinically important bleeding events, and incidence of HIT in critically ill patients with cancer.

Evidence for cell fusion is absent in vascular lesions associated with pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a fatal disease associated with severe remodeling of the large and small pulmonary arteries. Increased accumulation of inflammatory cells and apoptosis-resistant cells are contributing factors. Proliferative apoptosis-resistant cells expressing CD133 are increased in the circulation of PAH patients. Circulating cells can contribute to tissue repair via cell fusion and heterokaryon formation. We therefore hypothesized that in the presence of increased leukocytes and CD133-positive (CD133(pos)) cells in PAH lung tissue, cell fusion and resulting genomic instability could account for abnormal cell proliferation and the genesis of vascular lesions. We performed analyses of CD45/CD133 localization, cell fusion, and proliferation during late-stage PAH in human lung tissue from control subjects and subjects with idiopathic (IPAH) and familial (FPAH) PAH. Localization, proliferation, and quantitation of cell populations in individual patients were performed by immunolocalization. The occurrence of cellular fusion in vascular lesions was analyzed in lung tissue by fluorescence in situ hybridization. We found the accumulation of CD45(pos) leukocytic cells in the tissue parenchyma and perivascular regions in PAH patients and less frequently observed myeloid cells (CD45/CD11b). CD133(pos) cells were detected in occlusive lesions and perivascular areas in those with PAH and were more numerous in those with IPAH lesions than in FPAH lesions. Cells coexpressing CD133 and smooth muscle alpha-actin were occasionally observed in occlusive lesions and perivascular areas. Proliferating cells were more prominent in IPAH lesions and colocalized with CD45 or CD133. We found no evidence of increased ploidy to suggest cell fusion. Taken together, these data suggest that abnormal lesion formation in PAH occurs in the absence of cell fusion.

Adult lung side population cells have mesenchymal stem cell potential.

BACKGROUND: The development of stem cell therapy for pulmonary diseases remains a challenge. Many diverse cell types reside within the lung and a common stem cell has not yet been identified. A basic understanding of lung stem cell fate during disease may prove important for drug intervention as well as autologous therapies. Niches for resident mesenchymal stem cells (MSC) have been identified in many adult tissues and more recently in the lung. We present data to confirm the observation that non-hematopoietic CD45(neg) lung side population (SP) cells contain MSC, single cells capable of multilineage differentiation. METHODS We carried these observations forward by analyzing the MSC potential of single-cell clones, as well as their chromosomal stability and telomerase activity. RESULTS: The expression of MSC markers was characterized in mouse CD45(neg) lung SP by flow cytometry on freshly isolated or cultured clonal populations. The karyotype of these cells was subsequently assayed by banding analysis, and telomerase activity was assessed using quantitative polymerase chain reaction. MSC differentiation potential was confirmed by the characteristic ability of single-cell clones to differentiate into cells of three mesenchymal lineages, chondrocytes, adipocytes and osteocytes. Differentiation was confirmed by histochemical analysis. All analyzed populations of CD45(neg) lung SP expressed mesenchymal markers (CD44, CD90, CD105, CD106, CD73 and Sca-I) and lacked hematopoietic markers (CD45, c-kit, CD11b, CD34 and CD14). The cultured and clonal CD45(neg) lung SP had normal chromosomal structures and expressed high levels of telomerase. After being expanded and cultured in differentiation medium, all populations of CD45(neg) lung SP demonstrated adipogenic, osteogenic and chrondrogenic potential. Adult CD45(neg) lung SP cells are a source of MSC. DISCUSSION: In defining this tissue-specific stem cell population in the lung, we are now better able to clarify a potential role for them in lung diseases.

Progenitor cells in acute lung injury.

AIM: Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are common and serious pulmonary illnesses associated with a high morbidity and mortality. A specific therapy that improves outcomes in these disorders has not been forthcoming. There is growing interest to explore novel therapies, namely stem cells, to repair damage to the lung that is observed in these disorders. In this manuscript, stem cell investigations in the field of pulmonary medicine are delineated, with a focus on endothelial progenitor cells (EPCs) in the setting of ALI. METHODS: A review of the pertinent literature in this field is presented, including recent investigations in animal models. Work related to the assessment of EPCs in human subjects after transplantation and in patients with pneumonia is described. The measurement of circulating EPCs in those with ALI is presented in detail. RESULTS: Patients with ALI have an increased number of circulating EPCs than do healthy controls. Further, a greater number of circulating EPCs is associated with improved outcomes in a multivariable analysis correcting for the effects of age, gender, and severity of illness scores. CONCLUSIONS: EPCs represent a rapidly expanding interest in critical care medicine. However, their specific properties and utilities with regards to lung injury need to be further delineated prior to their use in the therapy of ALI.

The effect of alcohol abuse on ARDS and multiple organ dysfunction.

A history of alcohol abuse is very common and many times unrecognized in critically ill patients. The consequences of alcohol abuse are multifactorial, and it is associated with excessive morbidity and increased mortality. Alcohol causes acute and chronic dysfunction in multiple organ systems, and the underlying mechanisms responsible for organ injury are complex. In adults with septic shock, a history of alcohol abuse is associated with an increased incidence of Acute Respiratory Distress Syndrome (ARDS) and the development of more severe organ dysfunction. This increased susceptibility to developing acute lung injury has been evaluated by many investigators, and the common variable appears to be oxidative stress. In this article, we review the epidemiology of alcohol abuse and its association with ARDS. In addition, we provide an overview of the mechanisms thought to contribute to ARDS and multiple organ dysfunction.

Acquired weakness in the ICU: critical illness myopathy and polyneuropathy.

Illnesses commonly encountered in the ICU, such as sepsis, have frequently been associated with neuromuscular weakness and may play a role in the development of CIM and CIP, whose incidence in the critically ill is greater than initially reported. Although difficult to diagnose from history and clinical/laboratory findings alone, the use of electromyographic and nerve conduction testing is helpful in establishing these diagnoses. Information regarding prognosis of these disorders is limited, and there are no specific therapies that improve outcome. Acquired neuromuscular weakness in the ICU affects a significant number of patients and may continue to affect their quality of life long after discharge. Although diagnostic techniques are readily available, additional research is necessary to obtain adequate prognostic information and therapeutic options for these patients.

Influence of growth oxygen level on eicosanoid release from lung endothelial cells during hypoxia.

Eicosanoid products of arachidonic acid are suspected modulators of hypoxic vasoconstriction in the pulmonary vasculature. Vascular endothelial cells (EC) release several eicosanoids, but there is disagreement regarding the effect of hypoxia on EC eicosanoid release. We postulated that the oxygen level of growth in culture might influence the release of eicosanoids during acute hypoxia. We studied EC cultured from the main pulmonary arteries of pigs and grown at either 5% or near 20% oxygen, representing the normal limits of oxygen exposure to endothelium in normal lungs. Although cultures grown in 5% oxygen grew slightly faster by 4 days, the confluent cell number, protein content, and baseline eicosanoid release were no different compared with paired cultures grown in 20% oxygen. However, with an acute decrease in oxygen level, cultures grown in 5% oxygen released less prostaglandin E2, F2 alpha, and 6-ketoprostaglandin F1 alpha compared with amounts released at the growth oxygen level. In contrast, cultures grown in 20% oxygen released increased amounts of these eicosanoids compared with release at the growth oxygen level. Release of thromboxane B2 was not significantly different during hypoxia between cultures grown at 5% vs. 20% oxygen. In other experiments, cyclooxygenase activity, stimulated arachidonic acid release by calcium ionophore A23187, and uptake of arachidonic acid were no different in cultures grown at 5% vs. 20% oxygen. However, arachidonic acid release during hypoxia was reduced in 5% cultures and increased in 20% cultures.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of hypoxia on muscle capillarity in rats.

Capillary density, fiber cross-sectional area, capillary/fiber ratio and fiber composition were determined in gastrocnemius and diaphragm muscles of laboratory rats following five weeks at 350 Torr ambient pressure. Growth rates of hypoxic rats were lower than normoxic controls, but the periods of sacrifice were adjusted to achieve similar body masses for the two groups. Hypoxic rats had significantly higher hematocrits and heart masses, characteristic of acclimation to hypoxia. However, capillary/fiber ratios in gastrocnemius and diaphragm were similar for hypoxic and normoxic rats suggesting that hypoxia did not stimulate capillarity in either muscle. In diaphragm, but not gastrocnemius, diffusion distances were significantly shorter in hypoxic rats than in controls. We conclude that the differences in diffusion distances represent an important secondary effect of hypoxia on the diaphragm associated with changes in demands on ventilation in response to low oxygen pressures.