Study of serum 3,5,3'-triiodothyronine sulfate concentration in patients with systemic non-thyroidal illness.
Sulfation is an important pathway of triiodothyronine (T3) metabolism. Increased serum T3 sulfate (T3S) values have been observed during fetal life and in pathological conditions such as hyperthyroidism and selenium deficiency. Similar variations have also been reported in a small number of patients with systemic non-thyroidal illness, but the underlying mechanisms have not been elucidated. In this study, serum T3S concentrations have been measured by a specific radioimmunoassay in 28 patients with end-stage neoplastic disease (ESND) and in 44 patients with chronic renal failure (CRF); 41 normal subjects served as controls. Both ESND and CRF patients had lower serum total T4 (TT4) and total T3 (TT3) than normal controls, while serum reverse T3 (rT3) was increased significantly in ESND (0.7 +/- 0.5 nmol/l; p < 0.001 vs. controls) but not in CRF (0.3 +/- 0.1 nmol/l). The TT3/rT3 ratio, an index of type I iodothyronine monodeiodinase (type I MD) activity, was reduced significantly in both groups of patients. Serum T4-binding globulin (TBG) was decreased in CRF but not in ESND patients. Serum T3S was significantly higher both in ESND (71 +/- 32 pmol/l) and CRF (100 +/- 24 pmol/l) than in controls (50 +/- 16 pmol/l, p < 0.001). Serum T3S values showed a positive correlation with rT3 values and a negative correlation with both TT3 and FT3 values in ESND, but not in CRF. In the latter group a positive correlation was observed between T3S and TBG values. The T3S/FT3 ratio was higher both in CRF (18 +/- 5) and in ESND (23 +/- 18) as compared to controls (10 +/- 4). Serum inorganic sulfate was increased and correlated positively with T3S values in CRF patients. In conclusion, the results of this study in a large series of patients confirm that patients with systemic non-thyroidal illness have increased serum T3S levels. The mechanisms responsible for these changes appear to be different in ESND and CRF patients. In ESND the increase in serum T3S levels is mainly related to reduced degradation of the hormone by type I MD, whereas in CRF it might be driven by the enhanced sulfate ion concentration, and could be partially dependent on the impaired renal excretion of T3S. Because T3S can be reconverted to T3, it is possible that increased T3S concentrations contribute to maintenance of the euthyroid state in systemic non-thyroidal disease.


Maternal transmission of a ring chromosome 15.
A 5-year-old boy with Silver-Russell-like phenotype and developmental delay was found to have a ring chromosome 15. The same r(15) was found in his slightly mentally retarded mother with mild dysmorphism. Analysis of the literature showed 34 families with direct vertical transmission of a ring autosome. In 30 of these families abnormal chromosomes were inherited from the mothers; both maternal and paternal transmission was shown in different generations of one family; and only in 3 families ring chromosomes were inherited from the fathers. The possible explanations of preponderance of maternal transmission are briefly discussed.


A DFT-based mechanistic proposal for the light-driven insertion of dioxygen into Pt(ii)-C bonds.
The photocatalyzed insertion of dioxygen into the Pt(ii)-methyl bond in terpyridine platinum complexes has been shown to proceed efficiently, but its mechanism remains a challenge. In particular, there are serious counter-intuitive differences in the reactivity of structurally similar complexes. M06 calculations in solvent with a valence double-ζ basis set supplemented by polarization and diffusion shells (benchmarked against ωB97x-D calculations with a larger basis set) are able to provide a satisfactory mechanistic answer. The proposed mechanism starts with the absorption of a photon by the metal complex, which then evolves into a triplet state that reacts with the triplet dioxygen fragment. A variety of possible reaction paths have been identified, some leading to the methylperoxo product and others reverting to the reactants, and the validity of some of these paths has been confirmed by additional experiments. The balance between the barriers towards productive and unproductive paths reproduces the diverging experimental behavior of similar complexes and provides a general mechanistic picture for these processes.


Identification and characterization of a new surface membrane antigen found predominantly on malignant B lymphocytes.
A monoclonal antibody, 1D10, was derived that identifies a new antigenic epitope on the surface of malignant B lymphocytes. Normal resting and stimulated lymphocytes do not express the antigen. The majority of individuals with acute Epstein-Barr virus infection express the antigen on their lymphocytes, and in these patients, the T lymphocyte may also be antigen positive. The antigen was found on B-lymphoid neoplasia from the early pre-B cell stage through terminally differentiated plasma cells, a characteristic not reported for other B cell-associated antigens. Studies on homozygous typing cells and cells from individuals with known HLA phenotypes indicate that the antigen does not segregate in a pattern characteristic for major histocompatibility antigens. The molecule is a heterodimeric polypeptide with the molecular weight and isoelectric points of the alpha and beta chains being 32,000 d/4 and 28,000 d/6, respectively. Evidence is presented that the 1D10 molecule is not HLA-DR, -DP, or -DQ. By extrapolation, we suggest that this novel molecule may represent HLA D-region gene expression of a gene(s) not normally expressed. Potential candidates are D-region pseudogenes. We conclude that the antigenic epitope identified by the 1D10 monoclonal antibody is unique among previously described B-lymphocyte antigens. Further studies of the factors controlling the expression of this molecule, as well as studies designed to look at the possible cellular function, may provide insights for understanding crucial events in the malignant transformation of lymphocytes.


Social-information-processing factors in reactive and proactive aggression in children's peer groups.
We examined social-information-processing mechanisms (e.g., hostile attributional biases and intention-cue detection deficits) in chronic reactive and proactive aggressive behavior in children's peer groups. In Study 1, a teacher-rating instrument was developed to assess these behaviors in elementary school children (N = 259). Reactive and proactive scales were found to be internally consistent, and factor analyses partially supported convergent and discriminant validities. In Study 2, behavioral correlates of these forms of aggression were examined through assessments by peers (N = 339). Both types of aggression related to social rejection, but only proactively aggressive boys were also viewed as leaders and as having a sense of humor. In Study 3, we hypothesized that reactive aggression (but not proactive aggression) would occur as a function of hostile attributional biases and intention-cue detection deficits. Four groups of socially rejected boys (reactive aggressive, proactive aggressive, reactive-proactive aggressive, and nonaggressive) and a group of average boys were presented with a series of hypothetical videorecorded vignettes depicting provocations by peers and were asked to interpret the intentions of the provocateur (N = 117). Only the two reactive-aggressive groups displayed biases and deficits in interpretations. In Study 4, attributional biases and deficits were found to be positively correlated with the rate of reactive aggression (but not proactive aggression) displayed in free play with peers (N = 127). These studies supported the hypothesis that attributional biases and deficits are related to reactive aggression but not to proactive aggression.


Integrated multimodal cell atlas of Alzheimer's disease.
Alzheimer's disease (AD) is the most common cause of dementia in older adults. Neuropathological and imaging studies have demonstrated a progressive and stereotyped accumulation of protein aggregates, but the underlying molecular and cellular mechanisms driving AD progression and vulnerable cell populations affected by disease remain coarsely understood. The current study harnesses single cell and spatial genomics tools and knowledge from the BRAIN Initiative Cell Census Network to understand the impact of disease progression on middle temporal gyrus cell types. We used image-based quantitative neuropathology to place 84 donors spanning the spectrum of AD pathology along a continuous disease pseudoprogression score and multiomic technologies to profile single nuclei from each donor, mapping their transcriptomes, epigenomes, and spatial coordinates to a common cell type reference with unprecedented resolution. Temporal analysis of cell-type proportions indicated an early reduction of Somatostatin-expressing neuronal subtypes and a late decrease of supragranular intratelencephalic-projecting excitatory and Parvalbumin-expressing neurons, with increases in disease-associated microglial and astrocytic states. We found complex gene expression differences, ranging from global to cell type-specific effects. These effects showed different temporal patterns indicating diverse cellular perturbations as a function of disease progression. A subset of donors showed a particularly severe cellular and molecular phenotype, which correlated with steeper cognitive decline. We have created a freely available public resource to explore these data and to accelerate progress in AD research at SEA-AD.org.


Automated detection of breast cancer in resected specimens with fluorescence lifetime imaging.
Re-excision rates for breast cancer lumpectomy procedures are currently nearly 25% due to surgeons relying on inaccurate or incomplete methods of evaluating specimen margins. The objective of this study was to determine if cancer could be automatically detected in breast specimens from mastectomy and lumpectomy procedures by a classification algorithm that incorporated parameters derived from fluorescence lifetime imaging (FLIm). This study generated a database of co-registered histologic sections and FLIm data from breast cancer specimens (N = 20) and a support vector machine (SVM) classification algorithm able to automatically detect cancerous, fibrous, and adipose breast tissue. Classification accuracies were greater than 97% for automated detection of cancerous, fibrous, and adipose tissue from breast cancer specimens. The classification worked equally well for specimens scanned by hand or with a mechanical stage, demonstrating that the system could be used during surgery or on excised specimens. The ability of this technique to simply discriminate between cancerous and normal breast tissue, in particular to distinguish fibrous breast tissue from tumor, which is notoriously challenging for optical techniques, leads to the conclusion that FLIm has great potential to assess breast cancer margins. Identification of positive margins before waiting for complete histologic analysis could significantly reduce breast cancer re-excision rates.


Health-Related Quality of Life and Cognitive Functioning in Pediatric Liver Transplant Recipients.
The goal of this work was to examine the change in health-related quality of life (HRQOL) and cognitive functioning from early childhood to adolescence in pediatric liver transplantation (LT) recipients. Patients were recruited from 8 North American centers through the Studies of Pediatric Liver Transplantation consortium. A total of 79 participants, ages 11-18 years, previously tested at age 5-6 years in the Functional Outcomes Group study were identified as surviving most recent LT by 2 years and in stable medical follow-up. The Pediatric Quality of Life 4.0 Generic Core Scale, Pediatric Quality of Life Cognitive Function Scale, and PROMIS Pediatric Cognitive Function tool were distributed to families electronically. Data were analyzed using repeated measures and paired t tests. Predictive variables were analyzed using univariate regression analysis. Of the 69 families contacted, 65 (94.2%) parents and 61 (88.4%) children completed surveys. Median age of participants was 16.1 years (range, 12.9-18.0 years), 55.4% were female, 33.8% were nonwhite, and 84.0% of primary caregivers had received at least some college education. Median age at LT was 1.1 years (range, 0.1-4.8 years). The majority of participants (86.2%) were not hospitalized in the last year. According to parents, adolescents had worse HRQOL and cognitive functioning compared with healthy children in all domains. Adolescents reported HRQOL similar to healthy children in all domains except psychosocial, school, and cognitive functioning (P = 0.02; P < 0.001; P = 0.04). Participants showed no improvement in HRQOL or cognitive functioning over time. For cognitive and school functioning, 60.0% and 50.8% of parents reported "poor" functioning, respectively (>1 standard deviation below the healthy mean). Deficits in HRQOL seem to persist in adolescence. Over half of adolescent LT recipients appear to be at risk for poor school and cognitive functioning, likely reflecting attention and executive function deficits.


Palmitic acid and DGAT1 deficiency enhance osteoclastogenesis, while oleic acid-induced triglyceride formation prevents it.
Both obesity and diabetes mellitus are associated with alterations in lipid metabolism as well as a change in bone homeostasis and osteoclastogenesis. We hypothesized that increased fatty acid levels affect bone health by altering precursor cell differentiation and osteoclast activation. Here we show that palmitic acid (PA, 16:0) enhances receptor activator of NF-κB ligand (RANKL)-stimulated osteoclastogenesis and is sufficient to induce osteoclast differentiation even in the absence of RANKL. TNFα expression is crucial for PA-induced osteoclastogenesis, as shown by increased TNFα mRNA levels in PA-treated cells and abrogation of PA-stimulated osteoclastogenesis by TNFα neutralizing antibodies. In contrast, oleic acid (OA, 18:1) does not enhance osteoclast differentiation, leads to increased intracellular triglyceride accumulation, and inhibits PA-induced osteoclastogenesis. Adenovirus-mediated expression of diacylglycerol acyl transferase 1 (DGAT1), a gene involved in triglyceride synthesis, also inhibits PA-induced osteoclastogenesis, suggesting a protective role of DGAT1 for bone health. Accordingly, Dgat1 knockout mice have larger bone marrow-derived osteoclasts and decreased bone mass indices. In line with these findings, mice on a high-fat PA-enriched diet have a greater reduction in bone mass and structure than mice on a high-fat OA-enriched diet. Thus, we propose that TNFα mediates saturated fatty acid-induced osteoclastogenesis that can be prevented by DGAT activation or supplementation with OA.


Microbial metabolism of pyridinium compounds. Radioisotope studies of the metabolic fat of 4-carboxy-1-methylpyridinium chloride.
Extracts of Achromobacter D formed CO(2), methylamine, succinate and formate as metabolic end-products from N-methylisonicotinic acid (4-carboxy-1-methylpyridinium chloride). The origin of the CO(2) in the 4-carboxyl group and of the methylamine in the N-methyl group of N-methylisonicotinate was demonstrated with carboxyl-(14)C- and N-Me-(14)C-labelled substrates respectively. The carbon skeletons of formate and succinate were shown to arise from the C-2 and the C-3-C-6 atoms of the heterocyclic ring respectively by using N-methyl[2,3-(14)C(2)]isonicotinate. This result is consistent with ring cleavage by the organism between C-2 and C-3.


Unique spatial heterogeneity in ionic liquids.
A multiscale coarse-graining model for ionic liquids has been extended to investigate the unique aggregation of cations in ionic liquids through computer simulation. It has been found that, with sufficiently long side chains, the tail groups of cations aggregate to form spatially heterogeneous domains, while headgroups of the cations and the anions distribute as uniformly as possible. This is understood as the result of competition between the charged electrostatic interactions between headgroups and anions and the collective short-range interactions between the neutral tail groups. This aggregation can help to explain a number of experimentally observed physical phenomena in ionic liquids.


Acute Pain in the African Prehospital Setting: A Scoping Review.
Acute pain is a common reason for seeking prehospital emergency care. Regrettably, acute pain is often underestimated and poorly managed in this setting. The scoping review was conducted to gain insight into existing research on the topic and to make recommendations for future work. To identify all available evidence related to acute pain assessment and management in the African prehospital setting, describe the extent of the evidence, encapsulate findings, and identify research gaps. The scoping review considered primary and secondary research related to acute pain assessment and management of both medical and traumatic origins in all age groups in the African prehospital setting. The search strategy aimed to identify published, unpublished, and ongoing research which met the inclusion criteria. Potentially eligible studies were identified by a comprehensive search of electronic databases, trial registers, dissertation/thesis databases, grey literature databases, and conference proceedings. Screening and data extraction were conducted independently and in duplicate. The comprehensive search identified 3823 potential studies, duplicate titles were removed, and 3358 titles/abstracts were screened. Full text of 66 potentially eligible titles was screened, 60 were excluded, and six publications met the inclusion criteria. Despite recommendations for pain assessment during general patient care, most studies reported no/limited pain assessment. In general, pain management was concluded to be insufficient and not conforming to best practice. Only six publications addressing prehospital acute pain care in Africa could be identified, possibly indicative of a knowledge gap. Future research is indicated to enable a better understanding of the epidemiology of acute pain and barriers and enablers of acute pain care and to develop evidence-based clinical practice guidelines (CPGs) catering for all EMS systems in Africa. Additionally, educational initiatives should be implemented to improve the quality of acute pain care and to monitor quality through continuous quality improvement (CQI) programs.


The injured spinal cord. Evaluation with magnetic resonance and intraoperative sonography.
MR is now the study of choice in evaluating both the acutely and previously injured spinal cord. A number of crucial diagnoses can be made with MR that are difficult to obtain otherwise. The discovery of acute disk herniation in association with a fracture/dislocation may indicate the need to remove the disk and stabilize the patient on a relatively urgent basis, and the approach to the stabilization procedure (either anterior or posterior) can be determined by the MR findings. Hemorrhage outside the cord may require immediate surgical attention, and identification of abnormal signals from the cord itself consistent with hemorrhage or edema may help to explain the patient's clinical status. Our experience indicates that obtaining an MR in acutely injured patients who have incomplete injuries is particularly helpful in their surgical management. The presence of intramedullary or extramedullary cysts in the previously injured spine can explain a worsening clinical picture and direct the surgeon to the proper area (or areas) for decompression. Flow-sensitive studies currently under evaluation are giving a greater insight into the dynamics of these cysts. Late decompression of cord tissue and roots requires accurate preoperative MR evaluation of possible bone or disk impingement on neural tissue. In surgery of both the acute and chronically injured spine, intraoperative sonography plays a crucial role. The adequate shunting of intramedullary and subarachnoid cysts, the confirmation of the efficaciously placed Harrington rods, the demonstration of removal of compressive bone or disk fragments, and the uncovering of important but unanticipated abnormalities such as subligamentous hematoma or an incidentally herniated disk all attest to sonography's value in the operating room. MR preoperatively and sonography intraoperatively are important tools utilized in the care of spine-injured patients.


Nevi, Ambient Ultraviolet Radiation, and Thyroid Cancer Risk: A French Prospective Study.
Incidence rates have increased considerably worldwide for both differentiated thyroid cancer and cutaneous melanoma, and two-way associations between these neoplasms have been described. Whether melanoma risk factors are associated with thyroid cancer risk remains unknown. Using Cox regression modeling, we prospectively analyzed the relationship between self-reported pigmentary traits, baseline residential ultraviolet (UV) exposure, and thyroid cancer risk in 86,960 women from the E3N cohort, followed-up over 1990-2008 through biennial questionnaires. We assessed associations of pigmentary traits and UV exposure with personal history of benign thyroid diseases using logistic regression modeling. All statistical tests were two sided. In models adjusted for age and thyroid cancer risk factors, number of nevi was positively associated with thyroid cancer risk ("very many" vs. "none": hazards ratio [HR] = 1.7, 95% confidence interval [CI] = 1.0, 2.8; Ptrend = 0.01), independently of residential UV exposure or iodine intake. Risk was inversely associated with latitude and positively associated with mean daily UV level at baseline (HRs for the fourth vs. first quartile of latitude and spring/summer UVB level = 0.7, 95% CI = 0.5, 0.9; Ptrend = 0.03, and HR = 1.9, 95% CI = 1.4, 2.7; Ptrend = 0.02, respectively); associations were restricted to women with dietary iodine below the median intake. Number of nevi and UV level were also associated with personal histories of dysthyroidism and of goiter/nodules, although more weakly so. Our results suggest that number of nevi and residential UV exposure are associated with the risks of thyroid cancer and benign conditions. They point to novel pathways in thyroid cancer or melanoma etiologies and warrant replication.


Physicians' Perspectives on Inpatient Portals: Systematic Review.
Inpatient portals are online platforms that allow patients to access their personal health information and monitor their health while in the acute care setting. Despite their potential to improve quality of care and empower patients and families to participate in their treatment, adoption remains low. Outpatient portal studies have shown that physician endorsement can drive patients' adoption of these systems. Insights on physicians' perspectives on use of these platforms can help improve patient and physician satisfaction and inpatient portal uptake. The purpose of this systematic review is to better understand physicians' perspectives toward inpatient portals. A systematic literature review was conducted for studies published between 1994 and November 2021 using keywords for physicians' perspectives toward patient portals and personal health records. Databases included PubMed, MEDLINE, Web of Science, and Scopus. Articles solely focused on nonphysician clinicians or addressing only outpatient settings or shared notes were excluded from this review. Two reviewers performed title, abstract, and full-text screening independently. Bias assessment was performed using the JBI SUMARI Critical Appraisal Tool (Joanna Briggs Institute). Inductive thematic analysis was done based on themes reported by original authors. Data were synthesized using narrative synthesis and reported according to overarching themes. In all, 4199 articles were collected and 9 included. All but 2 of the studies were conducted in the United States. Common themes identified were communication and privacy, portal functionality and patient use, and workflow. In studies where physicians had no prior patient portal experience, concerns were expressed about communication issues created by patients' access to laboratory results and potential impact on existing workflow. Concerns about negative communication impacts were not borne out in postimplementation studies. Physicians perceived inpatient portals to be beneficial to patients and saw improvement in communication as a result. This is consistent with outpatient studies and highlights the need to improve training on portal use and include physicians during the design process. Health care organizations and information technology entities can take steps to increasing clinician comfort. Physician concerns involving patient portal usage and managing patient expectations also need to be addressed. With improved clinician support, initial pessimism about communication and workload issues can be overcome. Limitations of this review include the small number of pre- and postimplementation studies found. This is also not a review of perspectives on open notes, which merits separate discussion.


Food imprinting in the snapping turtle, Chelydra serpentina.
Three groups of hatchling snapping turtles, totaling 20, were fed either meat, fish, or worms. When they were tested for preference after 12 daily feedings, each preferred the diet to which it was accustomed. After 12 more days of eating a different food, each still preferred its original diet. A form of imprinting may be operative in the feeding behavior of this species.


Hydra: A mixture modeling framework for subtyping pediatric cancer cohorts using multimodal gene expression signatures.
Precision oncology has primarily relied on coding mutations as biomarkers of response to therapies. While transcriptome analysis can provide valuable information, incorporation into workflows has been difficult. For example, the relative rather than absolute gene expression level needs to be considered, requiring differential expression analysis across samples. However, expression programs related to the cell-of-origin and tumor microenvironment effects confound the search for cancer-specific expression changes. To address these challenges, we developed an unsupervised clustering approach for discovering differential pathway expression within cancer cohorts using gene expression measurements. The hydra approach uses a Dirichlet process mixture model to automatically detect multimodally distributed genes and expression signatures without the need for matched normal tissue. We demonstrate that the hydra approach is more sensitive than widely-used gene set enrichment approaches for detecting multimodal expression signatures. Application of the hydra analysis framework to small blue round cell tumors (including rhabdomyosarcoma, synovial sarcoma, neuroblastoma, Ewing sarcoma, and osteosarcoma) identified expression signatures associated with changes in the tumor microenvironment. The hydra approach also identified an association between ATRX deletions and elevated immune marker expression in high-risk neuroblastoma. Notably, hydra analysis of all small blue round cell tumors revealed similar subtypes, characterized by changes to infiltrating immune and stromal expression signatures.


Parasites of wombats (family Vombatidae), with a focus on ticks and tick-borne pathogens.
Ticks (Arachnida: Acari) are vectors for pathogens and the biggest threat to animal health. Many Australian ticks are associated with pathogens that impact humans, domestic animals and livestock. However, little is known about the presence or impact of tick-borne pathogens in native Australian wildlife. Wombats are particularly susceptible to the effects of the ectoparasite Sarcoptes scabiei which causes sarcoptic mange, the reason for which is unknown. Factors such as other ectoparasites and their associated pathogens may play a role. A critical understanding of the species of ectoparasites that parasitise wombats and their pathogens, and particularly ticks, is therefore warranted. This review describes the ectoparasites of wombats, pathogens known to be associated with those ectoparasites, and related literature gaps. Pathogens have been isolated in most tick species that typically feed on wombats; however, there are minimal molecular studies to determine the presence of pathogens in any other wombat ectoparasites. The development of next-generation sequencing (NGS) technologies allows us to explore entire microbial communities in ectoparasite samples, allowing fast and accurate identification of potential pathogens in many samples at once. These new techniques have highlighted the diversity and uniqueness of native ticks and their microbiomes, including pathogens of potential medical and veterinary importance. An increased understanding of all ectoparasites that parasitise wombats, and their associated pathogens, requires further investigation.


The ABC7 regimen: a new approach to metastatic breast cancer using seven common drugs to inhibit epithelial-to-mesenchymal transition and augment capecitabine efficacy.
Breast cancer metastatic to bone has a poor prognosis despite recent advances in our understanding of the biology of both bone and breast cancer. This article presents a new approach, the ABC7 regimen (Adjuvant for Breast Cancer treatment using seven repurposed drugs), to metastatic breast cancer. ABC7 aims to defeat aspects of epithelial-to-mesenchymal transition (EMT) that lead to dissemination of breast cancer to bone. As add-on to current standard treatment with capecitabine, ABC7 uses ancillary attributes of seven already-marketed noncancer treatment drugs to stop both the natural EMT process inherent to breast cancer and the added EMT occurring as a response to current treatment modalities. Chemotherapy, radiation, and surgery provoke EMT in cancer generally and in breast cancer specifically. ABC7 uses standard doses of capecitabine as used in treating breast cancer today. In addition, ABC7 uses 1) an older psychiatric drug, quetiapine, to block RANK signaling; 2) pirfenidone, an anti-fibrosis drug to block TGF-beta signaling; 3) rifabutin, an antibiotic to block beta-catenin signaling; 4) metformin, a first-line antidiabetic drug to stimulate AMPK and inhibit mammalian target of rapamycin, (mTOR); 5) propranolol, a beta-blocker to block beta-adrenergic signaling; 6) agomelatine, a melatonergic antidepressant to stimulate M1 and M2 melatonergic receptors; and 7) ribavirin, an antiviral drug to prevent eIF4E phosphorylation. All these block the signaling pathways - RANK, TGF-beta, mTOR, beta-adrenergic receptors, and phosphorylated eIF4E - that have been shown to trigger EMT and enhance breast cancer growth and so are worthwhile targets to inhibit. Agonism at MT1 and MT2 melatonergic receptors has been shown to inhibit both breast cancer EMT and growth. This ensemble was designed to be safe and augment capecitabine efficacy. Given the expected outcome of metastatic breast cancer as it stands today, ABC7 warrants a cautious trial.


The Dramatic Role of IFN Family in Aberrant Inflammatory Osteolysis.
Skeletal system has been considered a highly dynamic system, in which bone-forming osteoblasts and bone-resorbing osteoclasts go through a continuous remodeling cycle to maintain homeostasis of bone matrix. It has been well acknowledged that interferons (IFNs), acting as a subgroup of cytokines, not only have crucial effects on regulating immunology but also could modulate the dynamic balance of bone matrix. In the light of different isoforms, IFNs have been divided into three major categories in terms of amino acid sequences, recognition of specific receptors and biological activities. Currently, type I IFNs consist of a multi-gene family with several subtypes, of which IFN-α exerts pro-osteoblastogenic effects to activate osteoblast differentiation and inhibits osteoclast fusion to maintain bone matrix integrity. Meanwhile, IFN-β suppresses osteoblast-mediated bone remodeling as well as exhibits inhibitory effects on osteoclast differentiation to attenuate bone resorption. Type II IFN constitutes the only type, IFN-γ, which exerts regulatory effects on osteoclastic bone resorption and osteoblastic bone formation by biphasic ways. Interestingly, type III IFNs are regarded as new members of IFN family composed of four members, including IFN-λ1 (IL-29), IFN-λ2 (IL-28A), IFN-λ3 (IL-28B) and IFN-λ4, which have been certified to participate in bone destruction. However, the direct regulatory mechanisms underlying how type III IFNs modulate the metabolic balance of bone matrix, remains poorly elucidated. In this review, we have summarized functions of IFN family during physiological and pathological conditions and described the mechanisms by which IFNs maintain bone matrix homeostasis via affecting the osteoclast-osteoblast crosstalk. In addition, the potential therapeutic effects of IFNs on inflammatory bone destruction diseases such as rheumatoid arthritis (RA), osteoarthritis (OA) and infectious bone diseases are also well displayed, which are based on the predominant role of IFNs in modulating the dynamic equilibrium of bone matrix.


Identification of specific calcium-binding noncollagenous proteins associated with glutaraldehyde-preserved bovine pericardium in the rat subdermal model.
Calcification of glutaraldehyde-preserved bioprosthetic heart valves (BHVs) results in their clinical failure. The mechanism of this pathologic calcification is not well defined. Since serum proteins are known to be taken up in mineralized tissue, we hypothesized that serum proteins derived from several calcium-binding noncollagenous proteins (NCPs) of bone and teeth also may be associated with pathologically mineralized BHVs. Using a rat subdermal model of BHV calcification, glutaraldehyde-preserved bovine pericardium (GPBP) was implanted for 1, 3, 14, and 60 days, and then subjected to an extraction procedure designed to isolate only NCPs tightly bound to the mineral phase. Gel electrophoresis and Coomassie Brilliant Blue staining demonstrated that these proteins became associated with GPBP over time, paralleling reported calcium uptake by the tissue. Stains-All staining demonstrated a marked accumulation of highly acidic, phosphorylated NCPs associated with 60-day GPBP extracts. Some of these proteins were detected in rat serum but were absent from extracts of GPBP incubated in rat serum in vitro. Western blotting with antibodies to three NCPs found in bone and teeth-bone acidic glycoprotein 75 (BAG 75), osteopontin, and SPARC-demonstrated that these NCPs were tightly bound to the mineral phase of calcified GPBP. A fourth NCP, bone sialoprotein II (BSP II) was barely detectable. Thus each identified NCP showed a different pattern of GPBP association relative to mineral deposition, suggesting unique roles for each in pathologic calcification. SPARC increased within 3 days of GPBP implantation but decreased by 2 weeks. BAG 75 and osteopontin uptake was detected in the initial mineral deposits and increased mineralization proceeded. BSP II never increased significantly over the entire-period. Further studies, which should include immunohistochemistry, will be important for delineating the source, location, and function of these three NCPs and for identifying others that also may be involved in this pathological process. Most important, the new insights into the mechanism of pathologic calcification described here present exciting opportunities for novel approaches to BHV calcification prevention.


Clinically-relevant anticancer-antidepressant drug interactions.
Depression is a condition that often arises in patients with cancer. As in many cases, the simultaneous use of anticancer drugs (ACD) and antidepressants (AD) may result in potential drug interactions that can lead to worsened medical outcomes and poorer quality of life in these patients. It is therefore essential that such interactions are carefully considered when treating patients for depression who already have cancer. The objective of this article is to discuss the potential anticancer-antidepressant drug (ACD-AD) interactions that may be clinically important in cancer patients. This systematic review describes the drug-drug interactions (DDIs) encountered for each tumour type so that oncology practitioners can target specific sections of the paper based on their specific clinical interests and specialties. From our knowledge, there is currently no oncology-specific database that allows for DDI searches by both individual ACDs and multiple-agent chemotherapy regimens. Therefore, one-stop consolidated databases like OncoRx have been developed to reduce the time and effort for conducting DDI searches. The authors believe that epigenetic therapy combined with the rapid development of the semantic web can improve the scientific knowledge and lead to the development of new databases in the near future with novel strategies of detecting DDIs, so that the pharmaceutical care of cancer patients will ultimately be improved.


The importance of local mucosal HIV-specific CD8(+) cytotoxic T lymphocytes for resistance to mucosal viral transmission in mice and enhancement of resistance by local administration of IL-12.
Although crucial to mucosal vaccine development, the mechanisms of defense against mucosal viral infection are still poorly understood. Protection, cytotoxic T lymphocytes (CTL), and neutralizing antibodies have all been observed, but cause and effect have been difficult to determine. The ability of CTL in the mucosa to mediate protection against mucosal viral transmission has never been proven. Here, we use an HIV peptide immunogen and an HIV-1 gp160-expressing recombinant vaccinia viral intrarectal murine challenge system, in which neutralizing antibodies do not play a role, to demonstrate for the first time that long-lasting immune resistance to mucosal viral transmission can be accomplished by CD8(+) CTL that must be present in the mucosal site of exposure. The resistance is ablated by depleting CD8(+) cells in vivo and requires CTL in the mucosa, whereas systemic (splenic) CTL are shown to be unable to protect against mucosal challenge. Furthermore, the resistance as well as the CTL response can be increased by local mucosal delivery of IL-12 with the vaccine. These results imply that induction of local mucosal CTL may be critical for success of a vaccine against viruses transmitted through a mucosal route, such as HIV.


Facial reactions in response to dynamic emotional stimuli in different modalities in patients suffering from schizophrenia: a behavioral and EMG study.
Emotional facial expression is an important low-level mechanism contributing to the experience of empathy, thereby lying at the core of social interaction. Schizophrenia is associated with pervasive social cognitive impairments, including emotional processing of facial expressions. In this study we test a novel paradigm in order to investigate the evaluation of the emotional content of perceived emotions presented through dynamic expressive stimuli, facial mimicry evoked by the same stimuli, and their functional relation. Fifteen healthy controls and 15 patients diagnosed with schizophrenia were presented with stimuli portraying positive (laugh), negative (cry) and neutral (control) emotional stimuli in visual, auditory modalities in isolation, and congruently or incongruently associated. Participants where requested to recognize and quantitatively rate the emotional value of the perceived stimuli, while electromyographic activity of Corrugator and Zygomaticus muscles was recorded. All participants correctly judged the perceived emotional stimuli and prioritized the visual over the auditory modality in identifying the emotion when they were incongruently associated (Audio-Visual Incongruent condition). The neutral emotional stimuli did not evoke any muscle responses and were judged by all participants as emotionally neutral. Control group responded with rapid and congruent mimicry to emotional stimuli, and in Incongruent condition muscle responses were driven by what participants saw rather than by what they heard. Patient group showed a similar pattern only with respect to negative stimuli, whereas showed a lack of or a non-specific Zygomaticus response when positive stimuli were presented. Finally, we found that only patients with reduced facial mimicry (Internalizers) judged both positive and negative emotions as significantly more neutral than controls. The relevance of these findings for studying emotional deficits in schizophrenia is discussed.


Material degradation in implant-retained cobalt-chrome and titanium frameworks.
The purpose of the study was to estimate in vitro material degradation in implants and cobalt-chrome or titanium frameworks, before and after exposure to artificial saliva. Four full-arch implant frameworks were fabricated according to the Cresco™ method (Astra Tech AB, Mölndal, Sweden), two in a cobalt-chrome alloy and two in commercially pure (CP) titanium. They were cut vertically, and the three central sections of each framework were used. Element leakage into an artificial saliva solution was observed with mass spectrometry. Before artificial saliva exposure, three Brånemark System(®) implants (Nobel Biocare AB, Gothenburg, Sweden) were screw-retained to cobalt-chrome sections, and three to titanium sections. The contact surfaces with the implants of the framework sections and the corresponding surfaces of six implants were examined with optical interferometry before and after exposure to artificial saliva to evaluate material degradation. Conventional descriptive statistics were used to present the mass spectrometry and interferometry data. One-way anova and Dunnett's T3 post hoc test were used to identify and study differences between the groups. To highlight changes within the groups, the Student's t-test was used. The significance level was set at 5%. There was significantly more leakage of cobalt elements than of titanium and chrome (P < 0·05). After saliva exposure and framework connection, the implants roughened (P < 0·05). The titanium frameworks were generally rougher than the cobalt-chrome frameworks, both before and after saliva exposure (P < 0·05). The findings in this study suggest active material degradation processes for both implants and framework materials.


Effect of the type of acidic monomer on the bond durability of two-bottle type ceramic primer.
Ceramic primers consisting of γ-methacryloxypropyl trimethoxysilane (γ-MPS) and either 4-methacryloyloxyethyl trimellitate (4-MET) or 10-methacryloyloxydecyl dihydrogen phosphate (MDP) are useful for facilitating bonding of resin cement to silica-based ceramic surfaces. However, bond stability at the resin-ceramic interface differs among commercial ceramic primers. To determine the ability of 4-MET or MDP to hydrolyze the methoxy group in γ-MPS, the author designed two-bottle experimental ceramic primers comprising γ-MPS solution and an activator solution of 4-MET or MDP. The effects of the type of acidic monomer on contact angle and ceramic bond durability of resin were investigated. MDP and 4-MET promoted chemisorption of γ-MPS on the ceramic surface and enhanced the ceramic bond strength of the resin. However, thermocycling decreased ceramic bond strengths, as reflected by the increased number of bonded specimens that exhibited interfacial resin failure. Bond strength was greater for 4-MET-activated ceramic primer than for the MDP-activated ceramic primer, although most bonded specimens exhibited interfacial resin failure. Degradation behavior differed between the 4-MET-activated and MDP-activated ceramic primers.


Pulmonary artery catheterization via the external jugular vein.
The use of pulmonary artery catheters in assessing and managing critically ill patients has become a common practice. The risks associated with insertion of the Swan-Ganz catheter via the internal jugular or subclavian vein include pneumothorax, puncture of the carotid or subclavian artery, mediastinal infiltration, and neurologic damage. I evaluated the success and complication rates associated with placement of a pulmonary artery catheter via the external jugular vein in 25 unselected consecutive patients. Catheterization was successful in 23 of 25 patients on the first attempt. In one patient there was no visible external jugular vein, and in the other the J-wire could not be passed centrally. No complications resulted. It is concluded that pulmonary artery catheterization via the external jugular vein is safe and reliable.


Partial neuromuscular blockade in humans enhances muscle blood flow during exercise independently of muscle oxygen uptake and acetylcholine receptor blockade.
This study examined the role of acetylcholine for skeletal muscle blood flow during exercise by use of the competitive neuromuscular blocking agent cisatracurium in combination with the acetylcholine receptor blocker glycopyrrone. Nine healthy male subjects performed a 10-min bout of one-legged knee-extensor exercise (18 W) during control conditions and with cisatracurium blockade, as well as with cisatracurium blockade with prior glycopyrrone infusion. Thigh blood flow and vascular conductance in control and with cisatracurium infusion were similar at rest and during passive movement of the leg, but higher (P < 0.05) during exercise with cisatracurium than in control (3.83 +/- 0.42 vs. 2.78 +/- 0.21 l/min and 26.9 +/- 3.4 vs. 21.8 +/- 2.0 ml.min(-1).mmHg(-1) at the end of exercise). Thigh oxygen uptake was similar in control and with cisatracurium infusion both at rest and during exercise, being 354 +/- 33 and 406 +/- 34 ml/min, at the end of exercise. Combined infusion of cisatracurium and glycopyrrone caused a similar increase in blood flow as cisatracurium infusion alone. The current results demonstrate that neuromuscular blockade leads to enhanced thigh blood flow and vascular conductance during exercise, events that are not associated with either acetylcholine or an increased oxygen demand. The results do not support an essential role for acetylcholine, released form the neuromuscular junction, in exercise hyperemia or for the enhanced blood flow during neuromuscular blockade. The enhanced exercise hyperemia during partial neuromuscular blockade may be related to a greater recruitment of fast-twitch muscle fibers.


[Obesity, diabetes, cancer and cardiovascular risk: a trans-generational network].
The prevalence of obesity has reached epidemic proportions, predisposing to the development of type 2 diabetes, cardiovascular disease and cancer. Lifestyle and genetic heritability are causes of this phenomenon, together with the nutritional environment during intra-uterine life and birth weight. We examine the above mentioned relationships in the family tree of a patient with diabetes, central obesity and cardiovascular disease.


Requirement for Jak3 in mature T cells: its role in regulation of T cell homeostasis.
The tyrosine kinase Jak3 plays a key role in transducing signals from the IL-2, -4, -7, -9, and -15 receptors. Mice lacking Jak3 exhibit a profound, early block in both B and T cell development. To examine the mechanisms whereby Jak3 influences T cell function, we have reconstituted thymic development in Jak3-/- animals by introducing a Jak3 transgene in which expression was driven by the lck proximal promoter. Thymic reconstitution required Jak3 kinase activity, as catalytically inactive Jak3 did not restore early thymic development. Furthermore, the thymus-restricted expression pattern of the transgene allowed us to assess the requirement for Jak3 in peripheral T cells. In these mice, loss of Jak3 expression was associated with a failure to proliferate in response to antigen receptor crosslinking, the accumulation of T cells manifesting an activated cell surface phenotype, and an increased CD4/CD8 ratio among peripheral T cells, all of which are characteristics that were observed in Jak3-/- animals. Finally, we present data which suggest that peripheral T cells proliferate more rapidly in vivo and also undergo apoptosis more rapidly, upon loss of Jak3. Hence Jak3 exerts effects on mature peripheral T lymphocytes, as well as on thymocytes, resulting in the proper maintenance of circulating, quiescent cells.


The Language of First-Trimester Nonviable Pregnancy: Patient-Reported Preferences and Clarity.
To document the terminology patients hear during the treatment course for a nonviable pregnancy and to ask patients their perceived clarity and preference of terminology to identify a patient-centered lexicon. We performed a preplanned substudy survey of English-speaking participants in New York, Pennsylvania, and California at the time of enrollment in a randomized multisite trial of medical management of first-trimester early pregnancy loss. The six-item survey, administered on paper or an electronic tablet, was developed and piloted for internal and external validity. We used a visual analog scale and quantified tests of associations between participant characteristics and survey responses using risk ratios. We approached 155 English-speaking participants in the parent study, of whom 145 (93.5%) participated. In the process of receiving their diagnosis from a clinician, participants reported hearing the terms "miscarriage" (n=109 [75.2%]) and "early pregnancy loss" (n=73 [50.3%]) more than "early pregnancy failure" (n=31 [21.3%]) and "spontaneous abortion" (n=21 [14.4%]). The majority selected "miscarriage" (n=79 [54.5%]) followed by "early pregnancy loss" (n=49 [33.8%]) as their preferred term. In multivariable models controlling for study site, ethnicity, race, history of induced abortion, and whether the current pregnancy was planned, women indicated that "spontaneous abortion" and "early pregnancy failure" were significantly less clear than "early pregnancy loss" (53/145, adjusted risk ratio 0.12, 95% CI 0.07-0.19 and 92/145, adjusted risk ratio 0.38, 95% CI 0.24-0.61, respectively, as compared with 118/145 for "early pregnancy loss"). "Miscarriage" scored similarly to "early pregnancy loss" in clarity (119/145, adjusted risk ratio 1.05, 95% CI 0.62-1.77). The terminology used to communicate "nonviable pregnancy in the first trimester" is highly variable. In this cohort of women, most preferred the term "miscarriage" and classified both "miscarriage" and "early pregnancy loss" as clear labels for a nonviable pregnancy. Health care providers can use these terms to enhance patient-clinician communication. ClinicalTrials.gov, NCT02012491.


Population patterns of Anopheles albimanus and their significance to malaria abatement.
Data obtained between 1967 and 1972 on naturally occurring populations of A. albimanus in El Salvador were used to construct 24-hour and seasonal patterns of activity for the species. The resulting patterns are discussed in terms of control implications, and specific examples are given to relate the importance of a knowledge of population dynamics to the success of conventional and alternative methods of anopheline control in malaria abatement programmes. A retrospective view of a successful feasibility study of the sterile-male release technique illustrates the importance of population studies in the selection of release sites, the formulation of release schedules, and the selection of survey methodology for the evaluation of results.


The effect of seating force and die spacing on pulpward cementation pressure transmission: a laboratory study.
Pulpward pressure transmission during crown cementation occurs via the dentinal tubules. The present study investigated the effect of crown seating forces and the effect of increasing the die spacing on pulpward pressure transmission. Twenty upper premolars were prepared with 1 mm shoulder margins for non-precious metal full crowns. A 0-104 kPa pressure transducer (Mediamate EA, Data Instruments, Baltimore, MD, USA) was connected, via the sectioned root of the premolar, to the pulp chamber which was perfused with saline at 83 kPa driven by nitrogen gas, for two hours prior to cementation. Crowns with 2 or 6 layers of die-spacing were seated with 25 N or 100 N force using zinc-phosphate cement. The pressure transducer was connected to a Wheatstone bridge (Measurements Group, Instruments Division) and the extent of crown seating and output from the pressure transducer was recorded. Results indicate that 25 N seating force produced a lower mean pulpward pressure (41 +/- 54 Pa) compared to the 100 N seating force (251 +/- 276 Pa). Seating was significantly improved with 6 layers of die-spacing (seating discrepancy 18 +/- 12 mm) compared with 2 layers (139 +/- 111 mm). It is concluded that a higher seating force increases pulpward pressure transmission. Increasing die spacing improved crown seating but did not affect the amount of pressure transmitted.


[The Gulf War Syndrome twenty years on].
After Operation Desert Storm which took place in Iraq from August 1990 to July 1991 involving a coalition of 35 countries and a 700,000 strong contingent of mainly American men, some associations of war veterans, the media and researchers described a new diagnostic entity: the Gulf War Syndrome (GWS). GWS seems to be a new disorder which associates a litany of functional symptoms integrating the musculoskeletal, digestive, tegumentary and neurosensory systems. The symptoms presented do not allow a syndrome already known to be considered and the aetiology of the clinical picture remains unexplained, an increasing cause for concern resulting from the extent of the phenomenon and its media coverage. It quickly appears that there is no consensus amongst the scientific community concerning a nosographic description of GWS: where can all these functional complaints arise from? Different aetiopathogenic hypotheses have been studied by the American administration who is attempting to incriminate exposure to multiple risks such as vaccines and their adjuvants, organophosphorous compounds, pyridostigmine (given to the troops for the preventive treatment of the former), impoverished uranium, and the toxic emanations from oil well fires. But despite extremely in-depth scientific investigations, 10 years after the end of the war, no objective marker of physical suffering has been retained to account for the disorders presented. It would appear that the former soldiers are in even better objective health than the civil population whereas their subjective level of health remains low. Within this symptomatic population, some authors have begun to notice that the psychological disorders appear and persist associating: asthenia, fatigability, mood decline, sleep disorders, cognitive disorders and post-traumatic stress disorder (PTSD). Within the nosological framework, does GWS cause functional disorders or somatisation? Finally, 20 years after the end of the fighting, only PTSD has been causally attributed to military deployment. Certain functional symptoms of GWS occur during the latent phase of a future reexperiencing syndrome, latent phase which is the locus of nonspecific symptoms. The psychotraumatised subject does not express himself spontaneously and waits to be invited to do so: if the social context does not allow this expression, the suffering can remain lodged in a few parts of the body. How can the inexpressible part of the trauma be recounted, particularly if the social context does not allow it? For civil society, calling into question "the somatic word" of veterans is difficult: why were they sent to face these hardships? What could we learn from these soldiers we do not wish to listen to: the horror of the war, the aggressive impulse of men, and the confrontation with death? Another obstacle to this reflection is the reference to stress as a prevalent aetiopathogenic model of the psychological trauma. A model like this, considering that PTSD is a normal reaction to an abnormal situation, finally discredits the subject and society and disempowers them by freezing them in a passive status of victim. However, as GWS affects approximately a quarter of subjects deployed, it is not very likely that all these symptoms are caused by a psychotraumatic reaction. Many veterans suffering from GWS have themselves rejected the diagnosis of PTSD, arguing that they do not suffer repetition nightmares. What the veterans rightly tell us here is that the notions of stress and trauma cannot strictly be superimposed. A subject may have been intensely stressed without ever establishing traumatic flashbacks and likewise; a psychological trauma can be experienced without stress and without fear but in a moment of terror. This clarification is in line with the first criterion of the DSM-IV-TR which necessarily integrates the objective and subjective dimensions as determinants of PTSD. Yet, scientific studies relating to GWS are struggling to establish opposition or continuity links between the objective external exposure (smoke from petrol wells, impoverished uranium, biological agents, chemicals) and the share of inner emotion albeit reactive and characterised by a subjective stress. There were no lack of stress factors for the troops deployed: repeated alerts of chemical attacks, hostility of the environment with its sandstorms and venomous animals, climatic conditions making long hours of backup and static observation difficult, collecting bodies, lack of knowledge of the precise geography of their movements and uncertainty of the duration of the conflict. The military anti-nuclear-bacteriological-chemical uniform admittedly provided protective confinement, shutting out the hostile world from which the threat would come but, at the same time, this isolation increases the fear of a hypothetical risk whilst the internal perceptions are increased and can open the way to future somatisations. In a context like this, the somatic manifestations of anxiety (palpitations, sweating, paresthesia…) are willingly associated with somatised functional disorders to which can also be assigned over-interpretations of bodily feelings according to a hypochondriacal mechanism. The selective attention to somatic perceptions in the absence of mentalisations, the request for reassurance reiterated and the excessive use of the treatment system will be diagnostic indices of these symptoms caused by the stress. Rather than toxic exposure to such and such a substance, the non-specific syndrome called "Gulf War Syndrome" is the result of exposure to the eponymous operational theatre. But if the psychological and psychosomatic suffering occurring in veterans is immutable throughout history, the expression of these difficulties has specificities according to the past cultural, political and scientific context. In the example of GWS, the diffusion of the fear of a pathology resulting from chemical weapons has promoted this phenomenon. In the end, biochemical and biological weapons have not been used on a large scale but the mediatisation of this possibility has led to a deleterious… To spare the bother of a group psychological reflection, the scientific and political authorities chose to investigate the implication of environmental factors in the genesis of the disorder. At individual as well as social level, rather than accept a psychogenic origin, a common defence mechanism is to assign the suffering to an external cause. With the perspective of preventing the risk of diffusion of other unexplained syndromes, which could occur following future armed conflicts, new epidemiological diagnostic models must be defined. The media also has considerable responsibility for the diffusion of epidemic psychological reactions but at the same time, they can inform the population about certain individual or group psychopathological mechanisms. The GWS exists: it is not an "imaginary illness" but a serious public health issue which has led to tens of thousands of complaints and swallowed up millions of dollars. To reply to human suffering, a new nosographic entity can spread through society taking the epidemic expression of a somatised disorder via identification, imitation and suggestion mechanisms. This possibility questions not only mental health but also the sociology and politics. It is necessary to inform the leaders and the general population of the possibility of this type of mass reaction, which can take the shape of a highly contagious complex functional syndrome.


Affective iconic words benefit from additional sound-meaning integration in the left amygdala.
Recent studies have shown that a similarity between sound and meaning of a word (i.e., iconicity) can help more readily access the meaning of that word, but the neural mechanisms underlying this beneficial role of iconicity in semantic processing remain largely unknown. In an fMRI study, we focused on the affective domain and examined whether affective iconic words (e.g., high arousal in both sound and meaning) activate additional brain regions that integrate emotional information from different domains (i.e., sound and meaning). In line with our hypothesis, affective iconic words, compared to their non-iconic counterparts, elicited additional BOLD responses in the left amygdala known for its role in multimodal representation of emotions. Functional connectivity analyses revealed that the observed amygdalar activity was modulated by an interaction of iconic condition and activations in two hubs representative for processing sound (left superior temporal gyrus) and meaning (left inferior frontal gyrus) of words. These results provide a neural explanation for the facilitative role of iconicity in language processing and indicate that language users are sensitive to the interaction between sound and meaning aspect of words, suggesting the existence of iconicity as a general property of human language.


Propagation of senescent mice using nuclear transfer embryonic stem cell lines.
Senescent mice are often infertile, and the cloning success rate decreases with age, making it almost impossible to produce cloned progeny directly from such animals. In this study, we tried to produce offspring from such "unclonable" senescent mice using nuclear transfer techniques. Donor fibroblasts were obtained from the tail tips of mice aged up to 2 years and 9 months. Although most attempts failed to produce cloned mice by direct somatic cell nuclear transfer, we managed to establish nuclear transfer embryonic stem (ntES) cell lines from all aged mice with an establishment rate of 10-25%, irrespective of sex or strain. Finally, cloned mice were obtained from these ntES cells by a second round of nuclear transfer. In addition, healthy offspring was obtained from all aged donors via germline transmission of ntES cells in chimeric mice. This technique is thus applicable to the propagation of a variety of animals, irrespective of age or fertile potential.


Bread making technology influences postprandial glucose response: a review of the clinical evidence.
Lowering postprandial glucose and insulin responses may have significant beneficial implications for prevention and treatment of metabolic disorders. Bread is a staple food consumed worldwide in a daily basis, and the use of different baking technologies may modify the glucose and insulin response. The aim of this review was to critically record the human studies examining the application of different bread making processes on postprandial glucose and insulin response to bread. Literature is rich of results which show that the use of sourdough fermentation instead of leavening with Saccharomyces cerevisiae is able to modulate glucose response to bread, whereas evidence regarding its efficacy on lowering postprandial insulin response is less clear. The presence of organic acids is possibly involved, but the exact mechanism of action is still to be confirmed. The reviewed data also revealed that the alteration of other processing conditions (method of cooking, proofing period, partial baking freezing technology) can effectively decrease postprandial glucose response to bread, by influencing physical structure and retrogradation of starch. The development of healthier bread products that benefit postprandial metabolic responses is crucial and suggested baking conditions can be used by the bread industry for the promotion of public health.


Multilinear Compressive Learning.
Compressive learning (CL) is an emerging topic that combines signal acquisition via compressive sensing (CS) and machine learning to perform inference tasks directly on a small number of measurements. Many data modalities naturally have a multidimensional or tensorial format, with each dimension or tensor mode representing different features such as the spatial and temporal information in video sequences or the spatial and spectral information in hyperspectral images. However, in existing CL frameworks, the CS component utilizes either random or learned linear projection on the vectorized signal to perform signal acquisition, thus discarding the multidimensional structure of the signals. In this article, we propose multilinear CL (MCL), a framework that takes into account the tensorial nature of multidimensional signals in the acquisition step and builds the subsequent inference model on the structurally sensed measurements. Our theoretical complexity analysis shows that the proposed framework is more efficient compared to its vector-based counterpart in both memory and computation requirement. With extensive experiments, we also empirically show that our MCL framework outperforms the vector-based framework in object classification and face recognition tasks, and scales favorably when the dimensionalities of the original signals increase, making it highly efficient for high-dimensional multidimensional signals.


Oligonol a low molecular weight polyphenol of lychee fruit extract inhibits proliferation of influenza virus by blocking reactive oxygen species-dependent ERK phosphorylation.
The emergence of resistance to anti-influenza drugs calls for the search for new antiviral molecules with different resistance profiles. Polyphenolic compounds are found in various plants and have antiviral and antioxidative properties. We tested the hypothesis that oligonol, a lychee fruit-derived low molecular weight polyphenol, possesses anti-influenza effects by inhibiting phosphorylation of extracellular-signal-regulated kinases (ERK). Real time PCR, plaque assay, and immunofluorescence techniques were used to study the effects of oligonol on proliferation of influenza virus. Oligonol inhibits influenza virus proliferation by blocking attachment of the virus to MDCK cells and by suppression of nuclear export of influenza virus ribonucleoprotein (RNP). Infection of MDCK cells with influenza virus leads to an increase in production of reactive oxygen species (ROS) and induction of a ROS-dependent ERK phosphorylation. Inhibition of ERK activation by a dominant negative mutant of ERK or N-acetyl-cysteine (NAC) leads to inhibition of influenza RNP nuclear export. Phorbol 12-myristate 13-acetate (PMA) induces ROS production, ERK phosphorylation and enhances influenza proliferation in MDCK cells. Oligonol and NAC inhibit PMA-induced ERK phosphorylation and ROS production. Our studies suggest that the underlying mechanism for the inhibitory effect of oligonol on influenza virus RNP nuclear export is blocking of ROS-dependent induction of ERK phosphorylation.


Methotrexate resistance conferred by transplantation of drug-resistant transgenic marrow cells fractionated bycounterflow elutriation.
Introduction of genes conferring drug resistance into hematopoietic cells may allow for improved chemotherapy by protection of normally drug-sensitive cells from the toxic side-effects of antitumor agents. We recently reported that transplantation of murine marrow transgenic for drug-resistant dihydrofolate reductase (DHFR) protected mice from lethal doses of methotrexate (MTX), demonstrating the feasibility of imparting drug resistance to recipients of marrow expressing drug-resistant DHFR activity. In order to optimize this strategy it is necessary to identify the hematopoietic cell populations which mediate drug resistance. For this purpose, we separated committed progenitor populations from primitive hematopoietic cells in DHFR transgenic marrow by counterflow elutriation (CE). As expected, supplementation with a fraction containing committed progenitors afforded protection from MTX-induced aplasia observed early after transplantion in animals administered MTX. In contrast, supplementation with a fraction containing primitive hematopoietic cells depleted of committed progenitors failed to provide immediate protection from early aplasia, but instead contributed to drug resistance 4 to 5 weeks after transplantation. The presence of primitive hematopoietic progenitors in both fractions was evident from Southern hybridization analysis for donor transgenic cells 2 months post-transplant. We conclude that protection from aplasia associated with MTX administration immediately after transplantation requires expression of drug-resistant DHFR activity in more differentiated, committed hematopoietic cells, while primitive DHFR transgenic progenitors contribute to long-term drug resistance. These results help to define the appropriate target cells for improved chemotherapy by protection of hematopoietic cells through the introduction of new genes conferring drug resistance.


Comparison between the Effects of Oral and Intramuscular Administration of Shin'iseihaito (Xinyiqingfeitang) in a Streptococcus pyogenes-Induced Murine Sinusitis Model.
Streptococcus pyogenes (S. pyogenes) is a species of Gram-positive coccoid bacteria having many virulence factors. Its capsule and exotoxins can cause upper respiratory tract infections such as sinusitis. The general treatment for S. pyogenes-induced sinusitis is administration of antibiotics such as penicillin and macrolides; however, a serious problem associated with these antibiotics is their attenuated effect. Shin'iseihaito (Xinyiqingfeitang), a formula of Japanese traditional Kampo medicine and traditional Chinese medicine, has been used for the treatment of sinusitis. In general, formulas of Japanese traditional Kampo medicine are orally administered. This is in contrast to certain formulas of traditional Chinese medicine, which are being recently administered intramuscularly or intravenously. Regarding these traditional Chinese medicine formulas, the injection methodology is reported to be more effective than oral intake. In this study, we compared the efficacy between orally and intramuscularly administered Shin'iseihaito against S. pyogenes-induced sinusitis. We evaluated the antibacterial effect of Shin'iseihaito extract (SSHT) against S. pyogenes by K-B disk diffusion assay. Furthermore, we investigated the nasal colonization of S. pyogenes, determined cytokine (TNF-α, IL-1β, and IL-6) levels, and conducted a splenocyte proliferative assay in a murine sinusitis model. SSHT displayed direct anti-S. pyogenes activity. Intramuscular administration of SSHT decreased the nasal colonization of S. pyogenes compared with oral administration. Thymidine uptake analysis revealed that the proliferation of splenocytes from S. pyogenes-infected mice under intramuscular SSHT treatment was upregulated compared to that of splenocytes from S. pyogenes-infected mice under oral SSHT treatment. We also found that TNF-α, IL-1β, and IL-6 levels in the nasal discharge from intramuscularly treated S. pyogenes-infected mice were lower than those from orally treated mice. Our findings suggest that intramuscular administration of Shin'iseihaito may be useful for the treatment of murine S. pyogenes-induced sinusitis.


Switching from transdermal drugs: an observational "N of 1" study of fentanyl and buprenorphine.
The aim of this study was to confirm that the concomitant presence of transdermal fentanyl (TTS FE) and buprenorphine (TTS BU) may be feasible without important consequences, using doses presumed to be equianalgesic. A prospective "N of 1" study was carried out in a sample of volunteers with cancer pain receiving stable doses of TTS FE or TTS BU, with adequate pain and symptom control. In the study design, each patient provided data before and after a switch from one opioid to the other and then back to the previous one. Sixteen patients receiving daily stable doses of 0.6 or 1.2mg of TTS FE were switched to TTS BU using an FE-BU ratio of 0.6-0.8. After three days, the TTS BU patch was removed and TTS FE patch was placed for another three days. Six patients receiving TTS BU were switched to TTS FE and then rotated back to TTS BU with the same dosing considerations. No statistical differences in changes in pain and symptom intensity during switching and between the two different sequences were observed. No significant changes in rescue doses of oral morphine were reported at the same intervals. Cancer patients receiving stable doses of TTS FE or TTS BU can be safely switched to the alternative transdermal opioid. Further studies should be performed to gather data about the use of TTS BU with other opioids, at different doses, and in different clinical conditions.


Tailored host-guest lipidic cubic phases: a protocell model exhibiting nucleic acid recognition.
A classical conundrum in origin-of-life studies relates to the nature of the first chemical system: was it a carrier of genetic information or a facilitator of cellular compartmentalization? Here we present a system composed of tailor-made nucleolipids and hydrated monoolein, which assemble at ambient temperatures to form host-guest lipidic cubic phase (LCP) materials that are stable in bulk water and can perform both functions. As such, they may represent a molecular model for a protocell in origin-of-life studies. Nucleolipids within the lipidic material sequester and bind selectively complementary oligonucleotide sequences from solution by virtue of base-pairing; noncomplementary sequences diffuse freely between the LCP material and the bulk aqueous environment. Sequence specific enrichment of nucleic acids within the LCP material demonstrates an effective mechanism for selection of genetic material in these cell-mimetic systems.


Effects of resistance, endurance, and concurrent exercise on training outcomes in men.
The specificity of training principle predicts that combining resistance and endurance training (concurrent training) could interfere with the maximum development of strength and endurance capacity that results from either type of training alone. To determine whether endurance and resistance training performed concurrently produces different performance and physiologic responses compared with each type of training alone. Untrained male volunteers were randomly assigned to one of three groups: endurance training (ET, N = 12); resistance training (RT, N = 13); and concurrent training (CT, N = 16). The following measurements were made on all subjects before and after 12 wk of training: weight, percent body fat, peak oxygen consumption (VO(2peak)), isokinetic peak torque and average power produced during single-leg flexion and extension at 60 and 180 degrees.s, one-repetition maximum (1RM) leg press, 1RM bench press, vertical jump height, and calculated jump power. Weight and lean body mass (LBM) increased significantly in the RT and CT groups (P < 0.05). Percent body fat was significantly decreased in the ET and CT groups. VO(2peak) was significantly improved only in the ET group. Peak torque during flexion and extension at 180 degrees.s(-1) increased in the RT group. Improvements in 1RM leg press and bench press were significant in all groups, but were significantly greater in the RT and CT compared to the ET group. Jump power improved significantly only in the RT group, and no group showed a significant change in vertical jump height. Concurrent training performed by young, healthy men does not interfere with strength development, but may hinder development of maximal aerobic capacity.


Tailored Biologics Selection in Severe Asthma.
The management of severe asthma presents a significant challenge in asthma treatment. Over the past few decades, remarkable progress has been made in developing new treatments for asthma, primarily in the form of biological agents. These advances have been made possible through a deeper understanding of the underlying pathogenesis of asthma. Most biological agents focus on targeting specific inflammatory pathways known as type 2 inflammation. However, recent developments have introduced a new agent targeting upstream alarmin signaling pathways. This opens up new possibilities, and it is anticipated that additional therapeutic agents targeting various pathways will be developed in the future. Despite this recent progress, the mainstay of asthma treatment has long been inhalers. As a result, the guidelines for the appropriate use of biological agents are not yet firmly established. In this review, we aim to emphasize the current state of biological therapy for severe asthma and provide insights into its future prospects.


[Adjustment of several spirometric reference equations to a population-based sample in Mexico].
To compare several forced spirometry reference equations used in Mexico in order to know which of them have a better fit to a population-based sample. Spirometric values of 225 healthy subjects 40 years of age or older from Metropolitan area of Mexico City, were compared to several reference equations. The sample is population-based and it was done from June to December 2003. The difference between observed and expected values was calculated. A concordance analysis between both observed and expected values was done and the percentage of subjects under normality lower limit was obtained. The equations with better fit for FEV1 and FVC were: NHANES III for Mexican-Americans and Euro-Americans; and from PLATINO. Predicted values according to Knudson were lower, and those from Cruz-Mérida, larger than observed values. Percentage of subjects below lower limit of normal was closest to 5% in the reference values from PLATINO. We recommend the use of reference values from the study NHANES III (for Mexican-Americans or European-Americans) and PLATINO.


[Paragangliomas and paraganglioma syndromes].
Paragangliomas are rare tumors of neural crest origin. They are benign in the majority of cases and are characterized by a strong vascularisation. In the head and neck region they most commonly occur as carotid body tumors. Jugulotympanic and especially vagal paragangliomas are seen less frequently. Complete surgical resection represents the only curative treatment option even though resection of locally advanced tumors regularly results in lesions of the lower cranial nerves and major vessels. Approximately 30% of all head and neck paragangliomas (HNPs) are hereditary and associated with different tumor syndromes. The paraganglioma syndromes 1, 3 and 4 (PGL 1, 3 and 4) make up the majority of those familial cases. PGL 1 is associated with mutations of the succinate dehydrogenase subunit D (SDHD) gene, PGL 3 is caused by SDHC and PGL 4 by SDHB gene mutations. Multiple HNPs and the occurrence of HNPs together with pheochromocytomas are seen in SDHD as well as SDHB mutation carriers. In patients with SDHB mutations the risk for the development of malignant paraganglial tumors is significantly higher compared to SDHC and SDHD patients as well as patients with sporadic tumors. SDHC mutation carriers almost exclusively present with benign HNPs that are unifocal in the majority of cases. The role of transmission is autosomal dominant for all 3 symptoms. Interestingly, there is a "parent-of-origin-dependent-inheritance" in subjects with SDHD gene mutations. This means that the disease phenotype may only become present if the mutation is inherited through the paternal line. We recommend screening for mutations of the genes SDHB, SDHC and SDHD in all patients with HNPs. Certain clinical parameters can help to set up the order in which the 3 genes should be tested.


Contributing factors of teenage pregnancy among African-American females living in economically disadvantaged communities.
To identify contributing factors that increased the risk of pregnancy among African-American adolescent females living in economically disadvantaged communities and to evaluate the current pregnancy prevention programs addressing these factors in order to provide suggestions for the development of tailored pregnancy prevention programs for this target population. Pregnancy rates among adolescents in the United States have declined over the past several years. Despite this trend, the pregnancy rate for African-American adolescent females is disproportionately higher than the adolescent pregnancy rates for other ethnicities. Limited attempts have been made to compile and synthesize the factors that increase risk of pregnancy in this population or to evaluate the effectiveness of intervention programs for African-American females that incorporate these risk factors. An integrative literature review was conducted to identify the major contributing factors of pregnancy among African American adolescents living in economically disadvantaged areas. Of the identified contributing risk factors for early pregnancy among African-American adolescent females, the five most supported risk factors were: parental influence, peer influence, social messages, substance use including alcohol, and pregnancy desire. Twelve pregnancy prevention programs were identified that addressed one or more of the five contributing factors to pregnancy. Parental influence and social messages were the most addressed factors among these programs. This review found five contributing factors related to teenage pregnancy; however, current intervention programs are not well addressed substance use as a component of alcohol use. Thus, development of a tailored pregnancy prevention program incorporating those factors will help decrease the high pregnancy rate among this target population.


Murine FSH Production Depends on the Activin Type II Receptors ACVR2A and ACVR2B.
Activins are selective regulators of FSH production by pituitary gonadotrope cells. In a gonadotrope-like cell line, LβT2, activins stimulate FSH via the activin type IIA receptor (ACVR2A) and/or bone morphogenetic protein type II receptor (BMPR2). Consistent with these observations, FSH is greatly reduced, though still present, in global Acvr2a knockout mice. In contrast, FSH production is unaltered in gonadotrope-specific Bmpr2 knockout mice. In light of these results, we questioned whether an additional type II receptor might mediate the actions of activins or related TGF-β ligands in gonadotropes. We focused on the activin type IIB receptor (ACVR2B), even though it does not mediate activin actions in LβT2 cells. Using a Cre-lox strategy, we ablated Acvr2a and/or Acvr2b in murine gonadotropes. The resulting conditional knockout (cKO) animals were compared with littermate controls. Acvr2a cKO (cKO-A) females were subfertile (~70% reduced litter size), cKO-A males were hypogonadal, and both sexes showed marked decreases in serum FSH levels compared with controls. Acvr2b cKO (cKO-B) females were subfertile (~20% reduced litter size), cKO-B males had a moderate decrease in testicular weight, but only males showed a significant decrease in serum FSH levels relative to controls. Simultaneous deletion of both Acvr2a and Acvr2b in gonadotropes led to profound hypogonadism and FSH deficiency in both sexes; females were acyclic and sterile. Collectively, these data demonstrate that ACVR2A and ACVR2B are the critical type II receptors through which activins or related TGF-β ligands induce FSH production in mice in vivo.


How should an incident case of atopic dermatitis be defined? A systematic review of primary prevention studies.
Eczema prevention is now an active area of dermatologic and allergy research. Defining an incident case is therefore a prerequisite for such a study. We sought to examine how an incident case of atopic dermatitis was defined in previous atopic dermatitis prevention studies in order to make recommendations on a standard definition of new atopic dermatitis cases for use in future prevention trials. We conducted a systematic review of controlled interventional atopic dermatitis prevention studies by using searches of MEDLINE and Cochrane databases for studies published from 1980 to the end of January 2011. Studies that included atopic dermatitis as a secondary outcome, such as asthma prevention trials, were included. One hundred two studies were included in the final analysis, of which 27 (26.5%) did not describe any criteria for defining an incident case of atopic dermatitis. Of the remaining 75 studies with reported disease criteria, the Hanifin-Rajka criteria were the most commonly used (28 studies). A disease definition unique to that particular study (21 studies) was the second most commonly used disease definition, although the sources for such novel definitions were not cited. The results from this systematic review highlight the need for improved reporting and standardization of the definition used for an incident case in atopic dermatitis prevention studies. Most prevention studies have used disease definitions such as the Hanifin-Rajka criteria that include disease chronicity. While acceptable for cumulative incidence outcomes, inclusion of disease chronicity precludes the precise measurement of disease onset. We propose a definition based on existing scientific studies that could be used in future prospective studies.


Digital motion analysis as a tool for analysing the shape and performance of the circulatory system in transparent animals.
The analysis of perfusion parameters using the frame-to-frame technique and the observation of small blood vessels in transparent animals using video microscopy can be tedious and very difficult because of the poor contrast of the images. Injection of a fluorescent probe (fluorescein isothiocynate, FITC) bound to a high-molecular-mass dextran improved the visibility of blood vessels, but the gray-scale histogram showed blurring at the edges of the vessels. Furthermore, injection of the fluorescent probe into the ventricle of small zebrafish (Danio rerio) embryos (body mass approximately 1 mg) often resulted in reduced cardiac activity. Digital motion analysis, however, proved to be a very effective tool for analysing the shape and performance of the circulatory system in transparent animals and tissues. By subtracting the two fields of a video frame (the odd and the even frame), any movement that occurred within the 20 ms necessary for the acquisition of one field could be visualised. The length of the shifting vector generated by this subtraction, represented a direct measure of the velocity of a moving particle, i.e. an erythrocyte in the vascular system. By accumulating shifting vectors generated from several consecutive video frames, a complete trace of the routes over which erythrocytes moved could be obtained. Thus, a cast of the vascular system, except for those tiny vessels that are not entered by erythrocytes, could be obtained. Because the gray-scale value of any given pixel or any given group of pixels increased with the number of erythrocytes passing it, digital motion analysis could also be used to visualise the distribution of blood cells in transparent tissues. This method was used to describe the development of the peripheral vascular system in zebrafish larvae up to 8 days post-fertilisation. At this stage, food intake resulted in a clear redistribution of blood between muscle tissue and the gut, and alpha-adrenergic control of peripheral blood flow was established.


Enhancing the efficacy of delivering reperfusion therapy: a European and North American experience with ST-segment elevation myocardial infarction networks.
Advances in technique and adjunctive medication have improved outcome of ST-segment elevation myocardial infarction (STEMI) patients. However, the timely delivery and administration of reperfusion strategies to all eligible patients remain challenging. Currently, up to one-third of eligible STEMI patients in industrialized countries worldwide receive no specific reperfusion treatment, a problem that is rectified by the development and implementation of STEMI networks, as also recommended by the latest European Society of Cardiology and American College of Cardiology/American Heart Association guidelines. Indeed, over the last 5 years, published figures demonstrate that STEMI networks increase the percentage of patients treated by any reperfusion strategy, and the percentage of patients receiving treatment within the recommended time frames has also improved, thereby reducing in-hospital and long-term mortality to very low levels. This manuscript demonstrates how STEMI networks can be adapted to local needs and circumstances against pre-existing barriers and despite the heterogeneity in local situations, patient's characteristics, treatment delays, and distances for transfer. Modern and efficacious networks must be prepared to offer both primary percutaneous coronary intervention and thrombolytic therapy, preferably prehospital, as long as primary percutaneous coronary intervention cannot be guaranteed to all individuals within the recommended timeline.


Design of High-Performance Organic Nonlinear Optical and Terahertz Crystals by Controlling the van der Waals Volume.
In the development of new organic crystals for nonlinear optical and terahertz (THz) applications, it is very challenging to achieve the essentially required non-centrosymmetric molecular arrangement. Moreover, the resulting crystal structure is mostly unpredictable due to highly dipolar molecular components with complex functional substituents. In this work, new organic salt crystals with top-level macroscopic optical nonlinearity by controlling the van der Waals volume (VvdW ), rather than by trial and error, are logically designed. When the VvdW of molecular ionic components varies, the corresponding crystal symmetry shows an observable trend: change from centrosymmetric to non-centrosymmetric and back to centrosymmetric. All non-centrosymmetric crystals exhibit an isomorphic P1 crystal structure with an excellent macroscopic second-order nonlinear optical response. Apart from the top-level macroscopic optical nonlinearity, new organic crystals introducing highly electronegative fluorinated substituents with strong secondary bonding ability show excellent performance in efficient and broadband THz wave generation, high crystal density, high thermal stability, and good bulk crystal growth ability.


Pharmacokinetics of itraconazole (oral solution) in two groups of human immunodeficiency virus-infected adults with oral candidiasis.
The pharmacokinetics of itraconazole formulated in a hydroxypropyl-beta-cyclodextrin oral solution was determined for two groups of human immunodeficiency virus (HIV)-infected adults with oral candidiasis (group A, 12 patients with CD4+ T-cell count of >200/mm3 and no AIDS, and group B, 11 patients with CD4+ T-cell count of <100/mm3 and AIDS). Patients received 100 mg of itraconazole every 12 h for 14 days. Concentrations of itraconazole and hydroxyitraconazole, the main active metabolite, were measured in plasma and saliva by high-performance liquid chromatography. Pharmacokinetic parameters determined at days 1 and 14 (the area under the concentration-time curve from 0 to 10 h, the maximum concentration of drug in plasma [Cmax], and the time to Cmax) were comparable in both groups. Trough levels in plasma (Cmin) were similar in both groups for the complete duration of the study. An effective concentration of itraconazole in plasma (>250 ng/ml) was reached at day 4. At day 14, Cmin values of itraconazole were 643 +/- 304 and 592 +/- 401 ng/ml for groups A and B, respectively, and Cmin values of hydroxyitraconazole were 1,411 +/- 594 and 1,389 +/- 804 ng/ml for groups A and B, respectively. In saliva, only unchanged itraconazole was detected, and mean concentrations were still high (>250 ng/ml) 4 h after the intake, which may contribute to the fast clinical response. In conclusion, the oral solution of itraconazole generates effective levels in plasma and saliva in HIV-infected patients; its relative bioavailability is not modified by the stage of HIV infection.


Neuromuscular blocking agents in acute respiratory distress syndrome: a systematic review and meta-analysis of randomized controlled trials.
Randomized trials investigating neuromuscular blocking agents in adult acute respiratory distress syndrome (ARDS) have been inconclusive about effects on mortality, which is very high in this population. Uncertainty also exists about the associated risk of ICU-acquired weakness. We conducted a systematic review and meta-analysis. We searched the Cochrane (Central) database, MEDLINE, EMBASE, ACP Journal Club, and clinical trial registries for randomized trials investigating survival effects of neuromuscular blocking agents in adults with ARDS. Two independent reviewers abstracted data and assessed methodologic quality. Primary study investigators provided additional unpublished data. Three trials (431 patients; 20 centers; all from the same research group in France) met inclusion criteria for this review. All trials assessed 48-hour infusions of cisatracurium besylate. Short-term infusion of cisatracurium besylate was associated with lower hospital mortality (RR, 0.72; 95% CI, 0.58 to 0.91; P=0.005; I2=0). This finding was robust on sensitivity analyses. Neuromuscular blockade was also associated with lower risk of barotrauma (RR, 0.43; 95% CI, 0.20 to 0.90; P=0.02; I2=0), but had no effect on the duration of mechanical ventilation among survivors (MD, 0.25 days; 95% CI, 5.48 to 5.99; P=0.93; I2=49%), or the risk of ICU-acquired weakness (RR, 1.08; 95% CI, 0.83 to 1.41; P=0.57; I2=0). Primary studies lacked protracted measurements of weakness. Short-term infusion of cisatracurium besylate reduces hospital mortality and barotrauma and does not appear to increase ICU-acquired weakness for critically ill adults with ARDS.


Trophic effects of mesenchymal stem cells in chondrocyte co-cultures are independent of culture conditions and cell sources.
Earlier, we have shown that the increased cartilage production in pellet co-cultures of chondrocytes and bone marrow-derived mesenchymal stem cells (BM-MSCs) is due to a trophic role of the MSC in stimulating chondrocyte proliferation and matrix production rather than MSCs actively undergoing chondrogenic differentiation. These studies were performed in a culture medium that was not compatible with the chondrogenic differentiation of MSCs. In this study, we tested whether the trophic role of the MSCs is dependent on culturing co-culture pellets in a medium that is compatible with the chondrogenic differentiation of MSCs. In addition, we investigated whether the trophic role of the MSCs is dependent on their origins or is a more general characteristic of MSCs. Human BM-MSCs and bovine primary chondrocytes were co-cultured in a medium that was compatible with the chondrogenic differentiation of MSCs. Enhanced matrix production was confirmed by glycosaminoglycans (GAG) quantification. A species-specific quantitative polymerase chain reaction demonstrated that the cartilage matrix was mainly of bovine origin, indicative of a lack of the chondrogenic differentiation of MSCs. In addition, pellet co-cultures were overgrown by bovine cells over time. To test the influence of origin on MSCs' trophic effects, the MSCs isolated from adipose tissue and the synovial membrane were co-cultured with human primary chondrocytes, and their activity was compared with BM-MSCs, which served as control. GAG quantification again confirmed increased cartilage matrix production, irrespective of the source of the MSCs. EdU staining combined with cell tracking revealed an increased proliferation of chondrocytes in each condition. Irrespective of the MSC source, a short tandem repeat analysis of genomic DNA showed a decrease in MSCs in the co-culture over time. Our results clearly demonstrate that in co-culture pellets, the MSCs stimulate cartilage formation due to a trophic effect on the chondrocytes rather than differentiating into chondrocytes, irrespective of culture condition or origin. This implies that the trophic effect of MSCs in co-cultures is a general phenomenon with potential implications for use in cartilage repair strategies.


Genetic diversity of Toxoplasma gondii isolates in Egyptian feral cats reveals new genotypes.
Cats are important in the epidemiology of Toxoplasma gondii because they are the only hosts that excrete environmentally resistant oocysts in feces. In the present study, 115 viable T. gondii isolates from tissues of cats from Egypt were genotyped using 10 PCR-restriction fragment length polymorphism markers (SAG1, SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, and Apico) and DNA from tachyzoites. Seven genotypes were recognized including the clonal Type II, Type III (2 genotypes), and 4 atypical genotypes. Ninety percent (103 of 115) of isolates were clonal, i.e., Type II (n = 61) and Type III (n = 42) strains. Of the 61 Type II strains, all had the Type II alleles at all loci, except for 2 strains that had allele I at Apico. Eight isolates were divided into 4 atypical genotypes. One of these genotypes (with 4 isolates) was previously reported in dogs from Sri Lanka and in sand cats from the United Arab Emirates. Four isolates had mixed infections. These results revealed a strong clonal population structure with the dominance of clonal Type II and III lineages of T. gondii in feral cats from Egypt.


[Characteristics of rickettsial morphology during intracellular development].
The normal anatomy of rickettsiae has been characterized with the use of R. prowazekii, R. conorii and R. akari in continuous cell cultures L-929, Al, FL and in primary chick embryo fibroblast culture. Rickettsiae are short rod-shaped cells with the dense cytoplasm and the regular structure of the cell wall--cytoplasmic membrane complex. The study has shown the absence of polymorphism in rickettsiae growing under permissive conditions, but at the same time these organisms easily develop into pathological forms. Pathological forms can be detected alongside normal rickettsiae in the same cells. The classification of the pathological forms of rickettsiae is presented. In this classification the compensating (reversible) and destructive (irreversible) forms of alterations, as well as hypertrophic and dystrophic processes on the level of the whole rickettsial cell or its organelles, are pointed out.